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SummaryAt the turn of the past century, unresectable metastatic melanoma was primarily treated with different chemotherapeutic agents, such as dacarbazine, with only poor efficacy. Immunotherapeutic agents, such as interleukin‑2 or adjuvant interferon alpha, were used with modest results but frequent side effects. In the last 10 years, modern immunotherapy using checkpoint inhibition has dramatically changed the treatment landscape of metastatic melanoma and is now considered the first-line treatment for stage IV melanoma. Consequently, median overall survival has increased from 9.1 months with dacarbazine to up to 72.1 months using the current gold standard ipilimumab + nivolumab first-line. In 2023, in Europe, the anti-PD1 antibodies nivolumab and pembrolizumab are licensed in the adjuvant and metastatic setting and the combination therapies ipilimumab + nivolumab and relatlimab + nivolumab are approved in the metastatic setting. Nevertheless, despite tremendous progress in the last two decades, at least 50% of our patients with stage IV melanoma still die. Currently, research focuses on combining checkpoint inhibition with other drugs such as cancer vaccines, BRAF/MEK inhibition, other tyrosine kinase inhibitors or histone deacetylase inhibitors.

The coronavirus disease 2019 (COVID-19) pandemic has led to an increase of digitally supported home-based sport and exercise activities. This paper asks how these digital sport and exercise (DSE) offers are experienced by consumers and compares the experiential value of DSE activities with similar on-site, offline sport and exercise (OSE) activities. The paper is based on cross-sectional online survey data from active members of two university sports centers in Germany. Findings reveal that a relative strength of DSE compared to similar OSE offers is the higher degree of autonomy experienced by users. However, this comes at the expense of the social, physical, affective, competence, and motivational experience. DSE courses are somewhat better rated by self-disciplined and healthy individuals, but lower rated by participants with a high motor competence. Overall, data lend support to the notion that DSE was just a stopgap for many during the lockdowns. For becoming a real alternative to on-site sports, DSE offers should be developed further in such a way that emotional and social experiences are enhanced.

Stream sediments move at low flow forming migrating ripples. These ripples can cover substantial areas where benthic communities experience erosion-resting cycles of sand grains. Sediment surface and interstitial space is colonized by meiobenthos, an assemblage of microscopic invertebrates. Here we describe how sediment migration influences the structure of the meiobenthic community. We sampled migrating and stationary sediment patches in five streams. Sediments in migrating ripple patches were characterized by coarser grain size and higher oxygen concentration, but less organic matter and chlorophyll than stationary patches. Meiobenthos was more abundant in the superficial layer of stationary sediment compared to the underlying layer, whereas comparable abundances were observed in both layers of migrating patches. This suggests that ripple migration enhances the vertical mixing of interstitial communities. Among the environmental drivers measured, meiobenthos community structure was most related to sediment transport regime: Rotatoria were more abundant in migrating patches, whereas Chironomidae, Ceratopogonidae, Copepoda and Hydrachnidia were more abundant in stationary patches. Body-size structure was affected by sediment migration, with fewer larger organisms in migrating ripples. By modifying the distribution of benthic resources and of meiobenthic consumers, ripple migration likely affects energy flow paths through benthic food webs.

Seasonal life history events are often interdependent, but we know relatively little about how the relationship between different events is influenced by the abiotic and biotic environment. Such knowledge is important for predicting the immediate and evolutionary phenological response of populations to changing conditions. We manipulated germination timing and shade in a multi-factorial experiment to investigate the relationship between spring and autumn phenology in seedlings of the pedunculate oak, Quercus robur, and whether this relationship was mediated by natural colonization of leaves by specialist fungal pathogens (i.e., the oak powdery mildew complex). Each week delay in germination corresponded to about 2 days delay in autumn leaf senescence, and heavily shaded seedlings senesced 5-8 days later than seedlings in light shade or full sun. Within seedlings, leaves on primary-growth shoots senesced later than those on secondary-growth shoots in some treatments. Path analyses demonstrated that germination timing and shade affected autumn phenology both directly and indirectly via pathogen load, though the specific pattern differed among and within seedlings. Pathogen load increased with later germination and greater shade. Greater pathogen load was in turn associated with later senescence for seedlings, but with earlier senescence for individual leaves. Our findings show that relationships between seasonal events can be partly mediated by the biotic environment and suggest that these relationships may differ between the plant and leaf level. The influence of biotic interactions on phenological correlations across scales has implications for understanding phenotypic variation in phenology and for predicting how populations will respond to climatic perturbation.

Local scale estimates of temperature change in the twenty-first century are necessary for informed decision making in both the public and private sector. In order to generate such estimates for Chile, weather station data of the Dirección Meteorológica de Chile are used to identify large-scale predictors for local-scale temperature changes and construct individual empirical-statistical models for each station. The geographical coverage of weather stations ranges from Arica in the North to Punta Arenas in the South. Each model is trained in a cross-validated stepwise linear multiple regression procedure based on (24) weather station records and predictor time series derived from ERA-Interim reanalysis data. The time period 1979–2000 is used for training, while independent data from 2001 to 2015 serves as a basis for assessing model performance. The resulting transfer functions for each station are then directly coupled to MPI-ESM simulations for future climate change under emission scenarios RCP2.6, RCP4.5 and RCP 8.5 to estimate the local temperature response until 2100 A.D. Our investigation into predictors for local scale temperature changes support established knowledge of the main drivers of Chilean climate, i.e. a strong influence of the El Niño Southern Oscillation in northern Chile and frontal system-governed climate in central and southern Chile. Temperature downscaling yields high prediction skill scores (ca. 0.8), with highest scores for the mid-latitudes. When forced with MPI-ESM simulations, the statistical models predict local temperature deviations from the 1979–2015 mean that range between − 0.5–2 K, 0.5–3 K and 2–7 K for RCP2.6, RCP4.5 and RCP8.5 respectively.

What effect does seeing a member of a historically marginalized group in high-level office have on attitudes toward government among those who identify with that group? We hypothesize that, when salient, increased descriptive representation will increase feelings of government responsiveness among members of historically marginalized groups. Moreover, we hypothesize that this effect will persist even when substantive representation is not expected, that is, when the official is viewed as unlikely to represent the individual's own political interests. We explore this theory by taking advantage of two exogenous changes in descriptive representation: the election of the first African–American president, Barack Obama, and the confirmation of the first Latino on the Supreme Court, Sonia Sotomayor. Using panel data and a difference-in-differences design, we analyze within-person changes in attitudes toward government among African–Americans and Latinos, from before to after these events. In doing so, we attempt to separate descriptive from anticipated substantive representation.

In the present study a single screen-printed carbon electrode (SPCE) and chemometric techniques were utilized for forensic differentiation of Brazilian American lager beers. To differentiate Brazilian beers at the manufacturer and brand level, the classification techniques: soft independent modeling of class analogy (SIMCA), partial least squares regression discriminant analysis (PLS-DA), and support vector machines discriminant analysis (SVM-DA) were tested. PLS-DA model presented an inconclusive assignment ratio of 20%. On the other hand, SIMCA models had a 0 inconclusive rate but an sensitivity close to 85%. While the non-linear technique (SVM-DA) showed an accuracy of 98%, with 95% sensitivity and 98% specificity. The SPCE-SVM-DA technique was then used to distinguish at brand level two highly frauded beers. The SPCE coupled with SVM-DA performed with an accuracy of 97% for the classification of both brands. Therefore, the proposed electrochemicalsensor configuration has been deemed an appropriate tool for discrimination of American lager beers according to their producer and brands.

It is widely believed that civic associations are capable to produce social capital, here understood as an individual asset resulting from relations of mutual support and assistance. Although hardly anybody denies that socializing is widespread in many civic associations, it still remains to be shown that this socializing provides a genuine commitment to support. This paper explores the relationship between involvement in civic organizations and social support. The data analysed come from a nation-wide survey “Organized Sport and Social Capital—Revisited” (OSSCAR) representing the adult population in Germany. Findings show that participation in civic associations is associated with higher levels of social support. This effect is stronger for active participants and weaker for passive members. Path analyses further indicate that this effect is mediated by a person’s sociability orientations as well as her commitment to prosocial values. These findings help providing a more nuanced understanding of mechanisms of social capital formation in civic associations. Justus-Liebig-Universität Gießen (3114)

ZusammenfassungDie Forschung über abenteuer- und erlebnispädagogische Programme hat vielfach auf positive Effekte z. B. für Selbstwirksamkeit, Kompetenzerwerb oder psychosoziale Gesundheit hingewiesen. Weniger gut erforscht ist hingegen die Frage, unter welchen Bedingungen diese Effekte zu Stande kommen bzw. welche Erfahrungen mit welchen Veränderungen assoziiert sind. Anknüpfend an erlebnispädagogische Theorien gehen wir davon aus, dass a) die Neuartigkeit der Erfahrungen, b) die erfolgreiche Selbstüberwindung, c) das Kompetenzerleben und d) die Qualität der Einbindung in die Gruppe zentrale Erfolgsbedingungen darstellen. Empirisch prüfen wir die Bedeutung dieser Bedingungen in einem Prätest-Posttest-Design bei Jugendlichen (N = 76; 63 % männlich, 37 % weiblich) im Alter von 13 bis 20 Jahren, die an einer 10-tägigen erlebnispädagogischen Ferienfreizeit teilnahmen. Die Ergebnisse zeigen zunächst, dass sich im Durchschnitt positive Veränderungen in der Selbstwirksamkeitserwartung, im Selbstwertgefühl und im emotionalen Wohlbefinden im Verlauf des Programms ergeben haben. Diese Effekte sind besonders bei den Jugendlichen zu beobachten, die sich bei den Programmaktivitäten als sehr kompetent erlebten. Punktuell hängen positive Veränderungen auch mit der Neuartigkeit der Aktivität und der Qualität des Gemeinschaftserlebens zusammen. Der oft in der Theoriedebatte fokussierte Aspekt der Selbstüberwindung scheint weniger relevant zu sein.

BackgroundRisk stratification is an important public health priority that is central to clinical decision making and resource allocation. The aim of the present study was to examine how different combinations of self-rated and objective health status predict (i) all-cause mortality and (ii) cause-specific mortality from leading causes of death in the UK.MethodsThe UK Biobank study recruited >500,000 participants, aged 37-73, between 2006–2010. The health cross-classification examined incorporated self-rated health (poor, fair, good or excellent) and health status derived from medical history and current disease status, including 81 cancer and 443 non-cancer illnesses. We examined all-cause mortality and six specific causes of death: ischaemic heart disease, cerebrovascular disease, influenza and pneumonia, dementia and Alzheimer’s disease, chronic lower respiratory disease and malignant neoplasm.ResultsAnalyses included >370,000 middle-aged and older adults with a median follow-up of 11.75 (IQR = 1.4) years, yielding 4,320,270 person years of follow-up. Compared to excellent self-rated health and favourable health status, all other levels of the health cross-classification were associated with a greater risk of mortality, with hazard ratios ranging from 1.22 (95% CI 1.15-1.29, pBonf. < 0.001) for good self-rated health and favourable health status to 7.14 (95% CI 6.70-7.60, pBonf. < 0.001) for poor self-rated health and unfavourable health status.ConclusionsOur findings highlight that self-rated health captures additional health-related information and should be more widely assessed across settings. The cross-classification between health status and self-rated health represents a straightforward metric for risk stratification, with applications to population health, clinical decision making and resource allocation.

Based on a theoretical framework informed by Self-Determination Theory, this paper argues that sports activities’ impact on subjective well-being is moderated by the goals and motivations associated with the sport. Precisely, we hypothesize that intrinsic sport motivations like enjoyment, sociality, and relaxation, may enhance subjective well-being, whereas the well-being effect of sport is less pronounced or even negative when sport is functionalized for extrinsic goals, e.g. to control weight or to compete for medals. These hypotheses are tested with a large-scale sample of university students in Germany. The results indicate that students who practice sport regularly and habitually have a higher satisfaction with life compared to non-athletes. Moreover, the type of motivation matters: Sport motivations that refer to intrinsic goals and states (enjoyment, relaxation, sociality, fitness) come along with a surplus of satisfaction with life, whereas motivations aiming at extrinsic goals (competition, weight control, distraction) contribute to a lesser degree to satisfaction with life. Hence, playful forms of exercise and sport, conceived as an end in itself, have more potential to enhance well-being compared to competitive and weight-related sports.

Purpose Human papillomavirus (HPV) can cause condylomata acuminata, also known as genital warts. Our aim was to evaluate the long-term recurrence of genital warts after primary carbon dioxide laser treatment before the introduction of the vaccination against HPV. Methods Recurrence rate and localization of genital warts were analysed in a retrospective study in 1798 women presenting with a new diagnosis of genital warts from 1992 to 2009 at a University hospital and had received laser treatment. Additionally, data on topography, pregnancy status, and cervical smear were available for women treated from 2003 to 2009 (n = 825, data subset 1) and systematic follow-up data for women treated in 2006 and 2007 (n = 242, data subset 2). Results Median time from laser treatment to first recurrence was 14.6 weeks (data subset 2). The site most affected was the vulva (90.7%) followed by the perineum/perianal region (59.3%) and the vagina (47.3%). Abnormal Pap smear was observed in 22.6%. Systematic follow-up with a median follow-up time of 3.1 years revealed at least one recurrence in 68 (28.1%) of 242 women. Women with multifocal genital warts had a 2.9 times increased risk for recurrence compared to women with unifocal lesions (p = 0.01). Conclusions Nearly 30% of women presenting with genital warts experienced at least one recurrence after treatment with carbon dioxide laser. Multifocal lesions are the strongest indicator of recurrence. These data provide an important insight to recurrence rates of genital warts before HPV vaccination and underline the significance of a long-term follow-up and HPV vaccination.

Opinions toward gay marriage, also known as same-sex marriage, have become dramatically more favorable in the last 20 years. Given the more accepting attitudes of younger Americans, generational replacement is one widely noted engine of change. However, the pace of shifts in public attitudes has been too rapid for this to be the sole explanation. Identifying other causes of increasing support has been difficult due to reliance on cross-sectional associations. Using nationally representative panel data from 2008 to 2016, we test three potential explanations for changes in public attitudes toward gay marriage. Our findings suggest that increased interpersonal contact with gays and lesbians, declining religiosity, and increasing levels of education in the U.S. all contributed to the rise in public support for same-sex marriage.

This article focuses on feminist analyses and concepts of care, highlighting their potential for the development of a radical reconceptualization of “the economy” as opposed to traditional economic thought. It illustrates how feminist economic concepts of care correspond to feminist sociological and philosophical concepts. We begin by identifying some feminist economic perspectives and their contribution to the assessment, conceptualization and measurement of care as a form of reproductive labor and their critique of neoclassical economics. We then examine some feminist (economic) analyses of capitalist regimes of accumulation and the commodification of care that go beyond traditional economic thought. We conclude by showing how feminist economic conceptualizations of the kind suggested by Ina Praetorius (2015) could be a starting point for rethinking the economy and policy by putting care at their center.

Research on sport events and well-being yield inconclusive results with some studies suggesting that well-being is increasing during major sport events while other studies fail to establish such a relationship. The present study aims at investigating the relationship between sport events and life satisfaction more closely, while at the same time avoiding some methodical pitfalls of prior research. The study uses a representative sample from Germany and had a longitudinal design, covering the time before, during and after the UEFA EURO 2016. Findings demonstrate a significant increase in life satisfaction in Germany during the football competition (d = .17). Further analyses reveal that satisfaction with life is elevated particularly among subjects with a genuine interest in football in general and in the EURO in particular, whereas for those respondents uninterested in football, changes in life satisfaction were mostly insignificant and marginal in size. However, two months after the EURO life satisfaction was already on the decline and drifted towards the baseline level. Hence, the EURO did not produce a persistent change, but rather a short peak in life satisfaction among football affine groups.

Salmonella outbreaks related to fruits and vegetables have been reported being lettuce one of the most contaminated. Peracetic acid (PA) at 50 mg/L, sodium dichloroisocyanurate (SD) at 100 mg/L, and the combination of SD at 100 mg/L and babacu coconut (Attalea speciosa) oil detergent at 100 mg/L were applied to fresh lettuce. Natural contaminant microbiota, physicochemical characteristics, and sensory attributes were evaluated. PA and SD reduced mesophilic aerobic counts by 2.1 and 1.5 log cfu/g, respectively. The most efficient treatment in reducing natural microbiota (i.e., PA) was applied alone and in combination with ultrasound (US). It reduced Salmonella enterica Typhimurium counts to undetectable levels (

This paper coins the term ‘football patriotism’ to describe the open, expressive handling of national symbols (e. g. flags, anthems, national colors) in the context of international football events. Based on a representative online survey of the adult German population (N = 1092), which was carried out in the course of the 2016 UEFA EURO, this paper presents, for the first time, empirical findings on three essential questions: (1) Which proportion of the German population was involved in which forms of football-related patriotic behavior? (2) To what extent does this proportion vary between different social demographic groups? (3) Which political and ideological attitudes are associated with football patriotism? The results illustrate that roughly 15% of German adults were involved in three or more different patriotic actions during the EURO. This proportion was lower among older, East German and immigrant respondents and higher in families with children. Football patriots positioned themselves less often as politically ‘left’ and endorsed patriotic and nationalistic statements more strongly.

Als Reiseimpfungen fur Kinder sind Cholera, Gelbfieber, japanische Enzephalitis, Tollwut, Tuberkulose und Typhus hinsichtlich der Zulassung fur das entsprechende Alter des Kindes und des Reiseziels zu berucksichtigen. Die epidemiologische Situation am Reiseziel kann aus Internetquellen zeitnah ermittelt werden.

Observational and experimental studies show that leisure time sporting activity (LTSA) is associated with higher well-being. However, scholars often seem to assume that 1) LTSA fosters “general” life satisfaction, thereby ignoring effects on domain satisfaction; 2) the effect of LTSA on well-being is linear and independent of a person’s general activity level; 3) the amount of LTSA is more important than the repertoire of LTSA, i.e. the number of different activities; 4) all kinds of LTSA are equal in their effects, irrespective of spatial and organisational context conditions. Using data from the German SALLSA-Study (“Sport, Active Lifestyle and Life Satisfaction”), a large-scale CAWI-Survey (N = 1008) representing the population ≥ 14 years, the paper takes a closer look on these assumptions. Findings demonstrate that LTSA is associated with general life satisfaction and domain-specific satisfaction (concerning relationships, appearance, leisure, work and health), but that the relationship is most pronounced for leisure satisfaction. Associations of sport with life satisfaction, leisure satisfaction and subjective health are non-linear, approaching an injection point from which on additional LTSA is no longer beneficial. Moreover, findings lend support to the notion that diversity in LTSA matters, as individuals with higher variation in sports activities are more satisfied. Finally, results with regard to spatial and organizational context suggest that outdoor sports and club-organized sports have additional benefits.

Calcineurin is important for fungal virulence and a potential antifungal target, but compounds targeting calcineurin, such as FK506, are immunosuppressive. Here we report the crystal structures of calcineurin catalytic (CnA) and regulatory (CnB) subunits complexed with FK506 and the FK506-binding protein (FKBP12) from human fungal pathogens (Aspergillus fumigatus, Candida albicans, Cryptococcus neoformans and Coccidioides immitis). Fungal calcineurin complexes are similar to the mammalian complex, but comparison of fungal and human FKBP12 (hFKBP12) reveals conformational differences in the 40s and 80s loops. NMR analysis, molecular dynamic simulations, and mutations of the A. fumigatus CnA/CnB-FK506-FKBP12-complex identify a Phe88 residue, not conserved in hFKBP12, as critical for binding and inhibition of fungal calcineurin. These differences enable us to develop a less immunosuppressive FK506 analog, APX879, with an acetohydrazine substitution of the C22-carbonyl of FK506. APX879 exhibits reduced immunosuppressive activity and retains broad-spectrum antifungal activity and efficacy in a murine model of invasive fungal infection., FK506 is a potential antifungal compound that inhibits calcineurin, but it also has immunosuppressive activity. Here, Juvvadi et al. report the structure of FK506 in complex with the FK506-binding protein FKPB12 and calcineurin, and design a less immunosuppresive FK506 analog with antifungal activity in mice.

Immunsuppression unterschiedlicher Genese ist mit einem erhohten Infektionsrisiko verbunden; daher ist die Pravention von impfpraventablen Erkrankungen bei den betroffenen Personengruppen besonders wichtig. Allerdings ist das Angehen von Impfungen oftmals reduziert bzw. die Applikation von Lebendimpfungen wahrend Immunsuppression kontraindiziert.