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Pancreatic ductal adenocarcinoma (PDAC) poses a significant threat due to its tendency to evade early detection, frequent metastasis, and the subsequent challenges in devising effective treatments. Processes that govern epithelial-mesenchymal transition (EMT) in PDAC hold promise for advancing novel therapeutic strategies. SAMD1 (SAM domain-containing protein 1) is a CpG island-binding protein that plays a pivotal role in the repression of its target genes. Here, we revealed that SAMD1 acts as a repressor of genes associated with EMT. Upon deletion of SAMD1 in PDAC cells, we observed significantly increased migration rates. SAMD1 exerts its effects by binding to specific genomic targets, including CDH2, encoding N-cadherin, which emerged as a driver of enhanced migration upon SAMD1 knockout. Furthermore, we discovered the FBXO11-containing E3 ubiquitin ligase complex as an interactor and negative regulator of SAMD1, which inhibits SAMD1 chromatin-binding genome-wide. High FBXO11 expression in PDAC is associated with poor prognosis and increased expression of EMT-related genes, underlining an antagonistic relationship between SAMD1 and FBXO11. In summary, our findings provide insights into the regulation of EMT-related genes in PDAC, shedding light on the intricate role of SAMD1 and its interplay with FBXO11 in this cancer type.

Methods sections are often missing essential details. Methodological shortcut citations, in which authors cite previous papers instead of describing the method in detail, may contribute to this problem. This meta-research study used 3 approaches to examine shortcut citation use in neuroscience, biology, and psychiatry. First, we assessed current practices in more than 750 papers. More than 90% of papers used shortcut citations. Other common reasons for using citations in the methods included giving credit or specifying what was used (who or what citation) and providing context or a justification (why citation). Next, we reviewed 15 papers to determine what can happen when readers follow shortcut citations to find methodological details. While shortcut citations can be used effectively, they can also deprive readers of essential methodological details. Problems encountered included difficulty identifying or accessing the cited materials, missing or insufficient descriptions of the cited method, and shortcut citation chains. Third, we examined journal policies. Fewer than one quarter of journals had policies describing how authors should report previously described methods. We propose that methodological shortcut citations should meet 3 criteria; cited resources should provide (1) a detailed description of (2) the method used by the citing authors', and (3) be open access. Resources that do not meet these criteria should be cited to give credit, but not as shortcut citations. We outline actions that authors and journals can take to use shortcut citations responsibly, while fostering a culture of open and reproducible methods reporting.

Gaseous and semi-volatile organic compounds emitted by the transport sector contribute to air pollution and have adverse effects on human health. To reduce harmful effects to the environment as well as to humans, renewable and sustainable bio-hybrid fuels are explored and investigated in the cluster of excellence "The Fuel Science Center" at RWTH Aachen University. However, data on the effects of bio-hybrid fuels on human health is scarce, leaving a data gap regarding their hazard potential. To help close this data gap, this study investigates potential toxic effects of a Ketone-Ester-Alcohol-Alkane (KEAA) fuel blend on A549 human lung cells. Experiments were performed using a commercially available air-liquid interface exposure system which was optimized beforehand. Then, cells were exposed at the air-liquid interface to 50-2000 ppm C3.7 of gaseous KEAA for 1 h. After a 24 h recovery period in the incubator, cells treated with 500 ppm C3.7 KEAA showed significant lower metabolic activity and cells treated with 50, 250, 500 and 1000 ppm C3.7 KEAA showed significant higher cytotoxicity compared to controls. Our data support the international occupational exposure limits of the single KEAA constituents. This finding applies only to the exposure scenario tested in this study and is difficult to extrapolate to the complex in vivo situation.

The deluge of genomic data raises various challenges for computational protein annotation. The definition of superfamilies, based on conserved folds, or of families, showing more recent homology signatures, allow a first categorization of the sequence space. However, for precise functional annotation or the identification of the unexplored parts within a family, a division into subfamilies is essential. As curators of an expert database, the Carbohydrate Active Enzymes database (CAZy), we began, more than 15 years ago, to manually define subfamilies based on phylogeny reconstruction. However, facing the increasing amount of sequence and functional data, we required more scalable and reproducible methods. The recently popularized sequence similarity networks (SSNs), allows to cope with very large families and computation of many subfamily schemes. Still, the choice of the optimal SSN subfamily scheme only relies on expert knowledge so far, without any data-driven guidance from within the network. In this study, we therefore decided to investigate several network properties to determine a criterion which can be used by curators to evaluate the quality of subfamily assignments. The performance of the closeness centrality criterion, a network property to indicate the connectedness within the network, shows high similarity to the decisions of expert curators from eight distinct protein families. Closeness centrality also suggests that in some cases multiple levels of subfamilies could be possible, depending on the granularity of the research question, while it indicates when no subfamily emerged in some family evolution. We finally used closeness centrality to create subfamilies in four families of the CAZy database, providing a finer functional annotation and highlighting subfamilies without biochemically characterized members for potential future discoveries.

Endosymbiotic dinoflagellates (Family Symbiodiniaceae) are the primary producer of energy for many cnidarians, including corals. The intricate coral-dinoflagellate symbiotic relationship is becoming increasingly important under climate change, as its breakdown leads to mass coral bleaching and often mortality. Despite methodological progress, assessing the phenotypic traits of Symbiodiniaceae in-hospite remains a complex task. Bio-optics, biochemistry, or "-omics" techniques are expensive, often inaccessible to investigators, or lack the resolution required to understand single-cell phenotypic states within endosymbiotic dinoflagellate assemblages. To help address this issue, we developed a protocol that collects information on cell autofluorescence, shape, and size to simultaneously generate phenotypic profiles for thousands of Symbiodiniaceae cells, thus revealing phenotypic variance of the Symbiodiniaceae assemblage to the resolution of single cells. As flow cytometry is adopted as a robust and efficient method for cell counting, integration of our protocol into existing workflows allows researchers to acquire a new level of resolution for studies examining the acclimation and adaptation strategies of Symbiodiniaceae assemblages.

Arthrofibrosis following total knee arthroplasty is a fibroproliferative joint disorder marked by dysregulated biosynthesis of extracellular matrix proteins, such as collagens and proteoglycans. The underlying cellular events remain incompletely understood. Myofibroblasts are highly contractile matrix-producing cells characterized by increased alpha-smooth muscle actin expression and xylosyltransferase-I (XT-I) secretion. Human XT-I has been identified as a key mediator of arthrofibrotic remodeling. Primary fibroblasts from patients with arthrofibrosis provide a useful in vitro model to identify and characterize disease regulators and potential therapeutic targets. This study aims at characterizing primary synovial fibroblasts from arthrofibrotic tissues (AFib) regarding their molecular and cellular phenotype by utilizing myofibroblast cell culture models. Compared to synovial control fibroblasts (CF), AFib are marked by enhanced cell contractility and a higher XT secretion rate, demonstrating an increased fibroblast-to-myofibroblast transition rate during arthrofibrosis. Histochemical assays and quantitative gene expression analysis confirmed higher collagen and proteoglycan expression and accumulation in AFib compared to CF. Furthermore, fibrosis-based gene expression profiling identified novel modifier genes in the context of arthrofibrosis remodeling. In summary, this study revealed a unique profibrotic phenotype in AFib that resembles some traits of other fibroproliferative diseases and can be used for the future development of therapeutic interventions.

A powerful avenue through which to promote the preservation of the natural and cultural environment is to afford cultural and environmental objects moral significance. In this research, we examine a range of factors that may give rise to moral concern regarding the protection of culturel and environmental objects as ends in themselves. In this way, we also extend theorizing and evidence beyond a focus on sentience as a focal determinant of moral significance Across five studies we show that non-sentient objects can sometimes be viewed as possessing intrinsically valuable properties that afford them moral standing (independent of their extrinsic/means-end value or any perception of their capacity to think and feel). People judge it morally wrong to harm things that are beautiful, sacred, rare, or old, and this cannot be explained merely by their usefulness or economic value. Our findings provide new insight into ways to elevate the protection of natural and cultural objects to an issue of moral significance, and suggest avenues through which to motivate the preservation of a natural and cultural environments.

Bottom-up models of functionally relevant patterns of neural activity provide an explicit link between neuronal dynamics and computation. A prime example of functional activity patterns are propagating bursts of place-cell activities called hippocampal replay, which is critical for memory consolidation. The sudden and repeated occurrences of these burst states during ongoing neural activity suggest metastable neural circuit dynamics. As metastability has been attributed to noise and/or slow fatigue mechanisms, we propose a concise mesoscopic model which accounts for both. Crucially, our model is bottom-up: it is analytically derived from the dynamics of finite-size networks of Linear-Nonlinear Poisson neurons with short-term synaptic depression. As such, noise is explicitly linked to stochastic spiking and network size, and fatigue is explicitly linked to synaptic dynamics. To derive the mesoscopic model, we first consider a homogeneous spiking neural network and follow the temporal coarse-graining approach of Gillespie to obtain a "chemical Langevin equation", which can be naturally interpreted as a stochastic neural mass model. The Langevin equation is computationally inexpensive to simulate and enables a thorough study of metastable dynamics in classical setups (population spikes and Up-Down-states dynamics) by means of phase-plane analysis. An extension of the Langevin equation for small network sizes is also presented. The stochastic neural mass model constitutes the basic component of our mesoscopic model for replay. We show that the mesoscopic model faithfully captures the statistical structure of individual replayed trajectories in microscopic simulations and in previously reported experimental data. Moreover, compared to the deterministic Romani-Tsodyks model of place-cell dynamics, it exhibits a higher level of variability regarding order, direction and timing of replayed trajectories, which seems biologically more plausible and could be functionally desirable. This variability is the product of a new dynamical regime where metastability emerges from a complex interplay between finite-size fluctuations and local fatigue.

Tinnitus is a complex and not yet fully understood phenomenon. Often the treatments provided are effective only for subgroups of sufferers. We are presently not able to predict benefit with the currently available diagnostic tools and analysis methods. Being able to identify and specifically treat sub-categories of tinnitus would help develop and implement more targeted treatments with higher success rate. In this study we use a clustering analysis based on 17 predictors to cluster an audiologically homogeneous group of normal hearing participants, both with and without tinnitus. The predictors have been chosen to be either tinnitus-specific measures or measures that are thought to be connected to cochlear synaptopathy. Our aim was to identify a subgroup of participants with characteristics consistent with the current hypothesized impact of cochlear synaptopathy. Our results show that this approach can separate the listeners into different clusters. But not in all cases could the tinnitus sufferers be separated from the control group. Another challenge is the use of categorical measures which seem to dominate the importance analysis of the factors. The study showed that data-driven clustering of a homogeneous listener group based on a mixed set of experimental outcome measures is a promising tool for tinnitus sub-typing, with the caveat that sample sizes might need to be sufficiently high, and higher than in the present study, to keep a meaningful sample size after clustering.

In biotechnology, cell growth is one of the most important properties for the characterization and optimization of microbial cultures. Novel live-cell imaging methods are leading to an ever better understanding of cell cultures and their development. The key to analyzing acquired data is accurate and automated cell segmentation at the single-cell level. Therefore, we present microbeSEG, a user-friendly Python-based cell segmentation tool with a graphical user interface and OMERO data management. microbeSEG utilizes a state-of-the-art deep learning-based segmentation method and can be used for instance segmentation of a wide range of cell morphologies and imaging techniques, e.g., phase contrast or fluorescence microscopy. The main focus of microbeSEG is a comprehensible, easy, efficient, and complete workflow from the creation of training data to the final application of the trained segmentation model. We demonstrate that accurate cell segmentation results can be obtained within 45 minutes of user time. Utilizing public segmentation datasets or pre-labeling further accelerates the microbeSEG workflow. This opens the door for accurate and efficient data analysis of microbial cultures.

Seroprevalence studies can contribute to a better assessment of the actual incidence of infection. Since long-term data for Germany are lacking, we determined the seroprevalence of immunoglobulin G (IgG) antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in residual plasma samples of 3,759 German regular blood donors between July 2020 and June 2021. Over almost the entire study period, the incidences determined based on our data were higher than those officially reported by the Robert Koch Institute, the public health institute in Germany. Using our serological testing strategy, we retrospectively detected natural infection in 206/3,759 (5.48%; 95% confidence interval (CI): 4.77-6.25) individuals. The IgG seroprevalence ranked from 5.15% (95% CI: 3.73-6.89) in Lower Saxony to 5.62% (95% CI: 4.57-6.84) in North Rhine Westphalia. The analyses of follow-up samples of 88 seropositive blood donors revealed a comparable fast decay of binding and neutralizing anti-SARS-CoV-2 IgG antibodies. The antibody avidity remained at a low level throughout the whole follow-up period of up to 181 days. Interestingly, female donors seem to express a stronger and longer lasting humoral immunity against the new coronavirus when compared to males. Conclusion: Overall, our data emphasizes that seroprevalence measurements can and should be used to understand the true incidence of infection better. Further characterization of follow-up samples from seropositive donors indicated rapid antibody waning with sex-specific differences concerning the strength and persistence of humoral immune response.

Mortality due to COVID-19 is not increased in immunosuppressed individuals after liver transplantation (OLT) compared to individuals without immunosuppression. Data on long-term protective immunity against SARS-CoV-2 in immunosuppressed convalescents, is limited. We prospectively measured immune responses against SARS-CoV-2 by quantifying antibodies against 4 different antigens (spike protein 1 and 2, receptor binding domain, nucleocapsid) and T cell responses by IFN-γ ELISPOT against 4 antigens (membrane, nucleocapsid, spike protein 1 and 2) in 24 OLT convalescents with immunosuppressive therapy longitudinally in the first year after COVID-19 including a booster vaccination in comparison to a matched cohort of non-immunosuppressed convalescents (non-IS-Con). Pre-pandemic OLT samples were retrieved from our prospective OLT biorepository (n = 16). No relevant T cell reactivity or immunoglobulin G (IgG) against SARS-CoV-2 were detectable in pre-pandemic samples of OLT recipients despite reactivity against endemic corona-viruses. OLT convalescents had a lower prevalence of IgG against nucleocapsid (54% vs. 90%) but not against spike protein domains (98-100% vs. 100%) after vaccination in the second half-year after COVID-19 compared to non-IS-Con. Also, concentrations of anti-nucleocapsid IgG were lower in OLT convalescents than in non-IS-Con. Concentration of IgG against spike protein domains was significantly increased by a booster vaccination in OLT convalescents. But concentration of IgG against two of three spike protein domains remains slightly lower compared to non-IS-Con finally. However, none of these differences was mirrored by the cellular immunity against SARS-CoV-2 that remained stable during the first year after COVID-19 and was not further stimulated by a corona vaccination in OLT convalescents. In conclusion, despite lower concentrations of anti-SARS-CoV-2 IgG in OLT convalescents anti-SARS-CoV-2 cellular immunity was as robust as in non-IS-Con.

IntroductionMultiple camera systems are widely used for 3D-motion analysis. Due to increasing accuracies these camera systems gained interest in biomechanical research areas, where high precision measurements are desirable. In the current study different measurement systems were compared regarding their measurement accuracy.Materials and methodsTranslational and rotational accuracy measurements as well as the zero offset measurements of seven different measurement systems were performed using two reference devices and two different evaluation algorithms. All measurements were performed in the same room with constant temperature at the same laboratory. Equal positions were measured with the systems according to a standardized protocol. Measurement errors were determined and compared.ResultsThe highest measurement errors were seen for a measurement system using active ultrasonic markers, followed by another active marker measurement system (infrared) having measurement errors up to several hundred micrometers. The highest accuracies were achieved by three stereo camera systems, using passive 2D marker points having errors typically below 20 μm.ConclusionsThis study can help to better assess the results obtained with different measurement systems. With the focus on the measurement accuracy, only one aspect in the selection of a system was considered. Depending on the requirements of the user, other factors like measurement frequency, the maximum analyzable volume, the marker type or the costs are important factors as well.

Defendants can deny they have agency, and thus responsibility, for a crime by using a defense of mental impairment. We argue that although this strategy may help defendants evade blame, it may carry longer-term social costs, as lay people's perceptions of a person's agency might determine some of the moral rights they grant them. Three randomized between-group experiments (N = 1601) used online vignettes to examine lay perceptions of a hypothetical defendant using a defense of mental impairment (versus a guilty plea). We find that using a defense of mental impairment significantly reduces responsibility, blame, and punitiveness relative to a guilty plea, and these judgments are mediated by perceptions of reduced moral agency. However, after serving their respective sentences, those using the defense are sometimes conferred fewer rights, as reduced agency corresponds to an increase in perceived dangerousness. Our findings were found to be robust across different types of mental impairment, offences/sentences, and using both manipulated and measured agency. The findings have implications for defendants claiming reduced agency through legal defenses, as well as for the broader study of moral rights and mind perception.

BackgroundPostoperative sepsis is an important cause of morbidity and mortality in patients with infective endocarditis undergoing surgical therapy. Blood purification using hemoadsorption therapy shows promising results in the treatment of sepsis. In this study, the clinical effects of intraoperative hemoadsorption in high-risk patients with infective endocarditis were evaluated.MethodsEligible candidates were high-risk patients with infective endocarditis undergoing cardiac surgery between January 2014 and December 2019. Patients with intraoperative hemoadsorption (hemoadsorption) were compared to patients without hemoadsorption (control). The endpoints were the incidence of postoperative sepsis, sepsis-associated death and in-hospital mortality. Additionally, postoperative vasopressor need, systemic vascular resistance indices and Sequential Organ Failure Assessment (SOFA) scores were compared.ResultsAfter propensity score matching, 70 high-risk patients were included. Postoperative sepsis occurred in 14 patients in the hemoadsorption group and in 16 patients in the control group, p = 0.629. Four patients died due to postoperative sepsis in the hemoadsorption group, while 11 postoperative septic patients died in the control group, p = 0.041. In-hospital mortality was 34% in the hemoadsorption group versus 43% in the control group, p = 0.461. On ICU-admission and the first postoperative day, the cumulative vasopressor need was 0.17 versus 0.25 μg/kgBW/min, p = 0.123 and 0.06 versus 0.11 μg/kgBW/min, p = 0.037, and the systemic vascular resistance index was 1448 versus 941 dyn·s·cm-5, p = 0.013 and 1156 versus 858 dyn·s·cm-5, p = 0.110 in the hemoadsorption versus control group, respectively. Postoperative course of SOFA score normalized significantly (p = 0.01) faster in the hemoadsorption group.ConclusionsIn high-risk cardiac surgical patients with infective endocarditis, intraoperative hemoadsorption significantly reduced sepsis-associated mortality. Furthermore, intraoperative hemoadsorption resulted in significant faster recovery of hemodynamics and organ function. Intraoperative hemoadsorption seems to attenuate the severity of postoperative sepsis.

Researchers, policy makers and science communicators have become increasingly been interested in factors that affect public’s trust in science. Recently, one such potentially important driving factor has emerged, the COVID-19 pandemic. Have trust in science and other science-related beliefs changed in Germany from before to during the pandemic? To investigate this, we re-analyzed data from a set of representative surveys conducted in April, May, and November 2020, which were obtained as part of the German survey Science Barometer, and compared it to data from the last annual Science Barometer survey that took place before the pandemic, (in September 2019). Results indicate that German’s trust in science increased substantially after the pandemic began and slightly declined in the months thereafter, still being higher in November 2020 than in September 2019. Moreover, trust was closely related to expectations about how politics should handle the pandemic. We also find that increases of trust were most pronounced among the higher-educated. But as the pandemic unfolded, decreases of trust were more likely among supporters of the populist right-wing party AfD. We discuss the sustainability of these dynamics as well as implications for science communication.

Targeting the tumor-associated carbonic anhydrase XII (CA XII) is considered a promising strategy to improve cancer treatment. As such progress is highly demanded for ovarian carcinomas, the present study aimed to provide deeper information about their CA XII expression profile. A large collection of tissue specimens was stained immunohistochemically with a specific anti-CA XII antibody to evaluate the expression in neoplastic and non-neoplastic epithelial ovarian cells. In addition, flow cytometry was used to measure CA XII expression on tumor cells from malignant ascites fluid. Binding of the antibody revealed a significant CA XII expression in most ovarian carcinoma tissue samples and ascites-derived ovarian carcinoma cells. Moreover, CA XII was expressed at higher levels in ovarian carcinomas as compared to borderline ovarian tumors and non-neoplastic ovarian epithelia. Within the carcinoma tissues, high expression of CA XII was associated with higher tumor grading and a trend towards shorter overall survival. Our results indicate that CA XII plays a crucial role for the malignancy of ovarian carcinoma cells and emphasize the potential of CA XII as a diagnostic marker and therapeutic target in the management of ovarian carcinomas.

PurposeThe COVID-19 pandemic has imposed severe challenges on medical education at German university hospitals. In this first German nationwide expert survey, we addressed the responsible university teaching coordinators in obstetrics and gynecology departments and investigated their experiences during the pandemic as well as their opinions on future developments, especially with regard to the broader implementation of e-learning in the standard curriculum.MethodsThe questionnaire included 42 items and was disseminated among teaching coordinators at all 41 departments of obstetrics and gynecology at German university hospitals via an email that included a weblink to the online survey provider. Responses were collected between 19 April and 7 June 2021.ResultsIn total, 30 responses were collected from 41 departments across Germany and their respective teaching coordinators in obstetrics and gynecology. The general opinion of the medical teaching provided during the pandemic was positive, whereas the teaching quality in practical skills was considered inferior and not equivalent to the standard face-to-face curriculum. Lectures and seminars had to be substituted by remote-learning alternatives, while clinical clerkships were reduced in length and provided less patient contact. Students in their final year experienced only a few differences in the clinical and teaching routine. Teaching coordinators in obstetrics and gynecology stated that they intend to incorporate more e-learning into the curriculum in the future.ConclusionThe medical educators' views presented here may help to complement the already-thoroughly investigated experiences of students under the restrictions of the COVID-19 pandemic. Medical educators in obstetrics and gynecology at German university hospitals have successfully established online and hybrid teaching alternatives to their standard face-to-face courses. Building on recent experiences, digitalization could help to improve future medical education.

During ovarian development, gonadal ridge epithelial-like (GREL) cells arise from the epithelial cells of the ventral surface of the mesonephros. They ultimately develop into follicular granulosa cells or into ovarian surface epithelial cells. Stromal fibroblasts arise from the mesonephros and penetrate the ovary. We developed methods for isolating and culturing fetal ovarian GREL cells and ovarian fibroblasts by expansion of colonies without passage. In culture, these two cell types were morphologically different. We examined the expression profile of 34 genes by qRT-PCR, of which 24 genes had previously been studied in whole fetal ovaries. Expression of nine of the 10 newly-examined genes in fetal ovaries correlated with gestational age (MUC1, PKP2, CCNE1 and CCNE2 negatively; STAR, COL4A1, GJA1, LAMB2 and HSD17B1 positively). Comparison between GREL cells and fetal fibroblasts revealed higher expression of KRT19, PKP2, OCLN, MUC1, ESR1 and LGR5 and lower expression of GJA1, FOXL2, NR2F2, FBN1, COL1A1, NR5A1, CCND2, CCNE1 and ALDH1A1. Expression of CCND2, CCNE1, CCNE2, ESR2 and TGFBR1 was higher in the fetal fibroblasts than in adult fibroblasts; FBN1 was lower. Expression of OCLN, MUC1, LAMB2, NR5A1, ESR1, ESR2, and TGFBR3 was lower in GREL cells than ovarian surface epithelial cells. Expression of KRT19, DSG2, PKP2, OCLN, MUC1, FBN1, COL1A1, COL3A1, STAR and TGFBR2 was higher and GJA1, CTNNB1, LAMB2, NR5A1, CYP11A1, HSD3B1, CYP19A1, HSD17B1, FOXL2, ESR1, ESR2, TGFBR3 and CCND2 was lower in GREL cells compared to granulosa cells. TGFβ1 altered the expression of COL1A1, COL3A1 and FBN1 in fetal fibroblasts and epidermal growth factor altered the expression of FBN1 and COL1A1. In summary, the two major somatic cell types of the developing ovary have distinct gene expression profiles. They, especially GREL cells, also differ from the cells they ultimately differentiate in to. The regulation of cell fate determination, particularly of the bi-potential GREL cells, remains to be elucidated.

The purpose of biomedicine is to serve society, yet its hierarchical and closed structure excludes many citizens from the process of innovation. We propose a collection of reforms to better integrate citizens within the research community, reimagining biomedicine as more participatory, inclusive, and responsive to societal needs.

Mycobacterium tuberculosis (Mtb) genetic micro-diversity in clinical isolates may underline mycobacterial adaptation to tuberculosis (TB) infection and provide insights to anti-TB treatment response and emergence of resistance. Herein we followed within-host evolution of Mtb clinical isolates in two cohorts of TB patients, either with delayed Mtb culture conversion (> 2 months), or with fast culture conversion (< 2 months). We captured the genetic diversity of Mtb isolates obtained in each patient, by focusing on minor variants detected as unfixed single nucleotide polymorphisms (SNPs). To unmask antibiotic tolerant sub-populations, we exposed these isolates to rifampicin (RIF) prior to whole genome sequencing (WGS) analysis. Thanks to WGS, we detected at least 1 unfixed SNP within the Mtb isolates for 9/15 patients with delayed culture conversion, and non-synonymous (ns) SNPs for 8/15 patients. Furthermore, RIF exposure revealed 9 additional unfixed nsSNP from 6/15 isolates unlinked to drug resistance. By contrast, in the fast culture conversion cohort, RIF exposure only revealed 2 unfixed nsSNP from 2/20 patients. To better understand the dynamics of Mtb micro-diversity, we investigated the variant composition of a persistent Mtb clinical isolate before and after controlled stress experiments mimicking the course of TB disease. A minor variant, featuring a particular mycocerosates profile, became enriched during both RIF exposure and macrophage infection. The variant was associated with drug tolerance and intracellular persistence, consistent with the pharmacological modeling predicting increased risk of treatment failure. A thorough study of such variants not necessarily linked to canonical drug-resistance, but which are prone to promote anti-TB drug tolerance, may be crucial to prevent the subsequent emergence of resistance. Taken together, the present findings support the further exploration of Mtb micro-diversity as a promising tool to detect patients at risk of poorly responding to anti-TB treatment, ultimately allowing improved and personalized TB management.

BackgroundThe novel coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread across the world. The aim of our study was to characterize mild courses and to determine the antibody status for these patients.MethodsWe initiated an appeal for convalescent plasma donations. 615 people contacted us, and we ultimately included 426 in our analyses, in whom it was possible to assume COVID-19 based on detection of specific SARS-CoV-2 antibodies or virus detection during the disease using RT-PCR.ResultsThe median duration of the disease was 12 days and the most common symptoms were fatigue, cough and olfactory and gustatory dysfunction. Anti-SARS-CoV-2 IgG was detected in 82.4% of the persons and IgA antibodies were found in 73.9%. In 10.8%, no antibodies were detectable despite a positive RT-PCR result during the disease. Nevertheless, of 24 persons with asymptomatic courses of COVID-19, antibodies against SARS-CoV-2 could be detected in 23 (96%). Furthermore, there was a correlation between the duration of the disease and the detection of IgG antibodies. In addition, a correlation between the determined IgG antibodies and neutralizing antibodies was shown.ConclusionIn this study, we were able to describe mild COVID-19 courses and determine antibody statuses for them. It could be shown that, despite SARS-CoV-2 detection during the disease, not all individuals developed antibodies or their level of antibodies had dropped below the detection limit shortly after the end of the disease. The extent to which immunity to re-infection is given in persons with undetectable antibodies (IgG, IgA) needs to be investigated in future studies.

Aiming at streamlining GPCR production from E. coli inclusion bodies for structural analysis, we present a generic approach to assess and optimize refolding yield through thermostability analysis. Since commonly used hydrophobic dyes cannot be applied as probes for membrane protein unfolding, we adapted a technique based on reacting cysteins exposed upon thermal denaturation with fluorescent 7-Diethylamino-3-(4-maleimidophenyl)-4-methylcoumarin (CPM). Successful expression, purification and refolding is shown for two G protein-coupled receptors (GPCR), the sphingosine-1-phosphate receptor S1P1, and the orphan receptor GPR3. Refolded receptors were subjected to lipidic cubic phase crystallization screening.

The study of meaning in life has largely centered on its relationship with personal well-being, while a focus on how meaning is related to enhancing the well-being of others has received less research attention. Although searching for meaning may imply lower personal well-being, we find that meaning-seekers are more motivated to perform costly prosocial actions for the sake of others’ well-being, given the perceived meaningfulness of these behaviors. Studies 1–4 (N = 780) show that meaning-seeking correlates with the motivation to engage in a range of costly prosocial behaviors. Meaning-seeking is further shown to be distinct from pursuing happiness in its relationship with costly prosociality (Study 2 & 3) and to share a stronger association with high-cost than low-cost prosociality (Study 3 & 4). Study 5 (N = 370; pre-registered) further shows that the search for meaning is related to costly prosocial behavior in the recent past. While our studies are cross-sectional, the pattern of findings suggests that seeking meaning (rather than happiness) may play an important role in motivating altruistic tendencies.

Despite recent emphasis and implementation of national and international anti-money laundering policies, illegal product markets, and their associated illicit profit remain a global problem. In addition to law enforcement aimed at reducing money-laundering, enforcement also takes place during (1) the production (e.g. crop eradication) and (2) sale (e.g. seizure of products during transportation that interrupts buyer and seller transactions) of the illegal product. Since funds for enforcement come from limited budgets, understanding where in this production-trade-laundering cycle law enforcement is most impactful becomes a global question. Using laboratory experimental markets and a seizure rate of 20%, we find that law enforcement focused on seizing laundered profits does little to reduce illegal market activity when compared to no law enforcement, suggesting that focusing law enforcement on money laundering will likely be ineffective at reducing crime. Results further show the amount of illicit trade is nearly 32% lower when law enforcement is focused at the point of sale, and there may be additional economic incentives that reduce illicit trade in the long run when compared to no law enforcement. Enforcement at the point of production also reduces market activity, but not as effectively as enforcement at the point of sale. Lastly, the empirical findings deviate from equilibrium predictions, suggesting law enforcement policy based on theory alone may lead to inefficient allocation of limited law enforcement resources.

Impaired exercise tolerance and lung function is a marker for increased mortality in lung cancer patients undergoing lung resection surgery. Recent data suggest that the gut-lung axis regulates systemic metabolic and immune functions, and microbiota might alter exercise tolerance. Here, we aimed to evaluate the associations between gut microbiota and outcomes in lung cancer patients who underwent lung resection surgery. We analysed stool samples, from 15 early-stage lung cancer patients, collected before and after surgical resection using shotgun metagenomic and Internal Transcribed Spacer (ITS) sequencing. We analysed microbiome and mycobiome associations with post-surgery lung function and cardiopulmonary exercise testing (CPET) to assess the maximum level of work achieved. There was a significant difference, between pre- and post-surgical resection samples, in microbial community functional profiles and several species from Alistipes and Bacteroides genus, associated with the production of SCFAs, increased significantly in abundance. Interestingly, an increase in VO2 coincides with an increase in certain species and the "GABA shunt" pathway, suggesting that treatment outcome might improve by enriching butyrate-producing species. Here, we revealed associations between specific gut bacteria, fungi, and their metabolic pathways with the recovery of lung function and exercise capacity.

Defendants can deny they have agency, and thus responsibility, for a crime by using a defense of mental impairment. We argue that although this strategy may help defendants evade blame, it may carry longer-term social costs, as lay people's perceptions of a person's agency might determine some of the moral rights they grant them. In this registered report protocol, we seek to expand upon preliminary findings from two pilot studies to examine how and why those using the defense of mental impairment are seen as less deserving of certain rights. The proposed study uses a hypothetical vignette design, varying the type of mental impairment, type of crime, and type of sentence. Our design for the registered study improves on various aspects of our pilot studies and aims to rigorously test the reliability and credibility of our model. The findings have implications for defendants claiming reduced agency through legal defenses, as well as for the broader study of moral rights and mind perception.

Human-controlled regimes can entrain behavioural responses and may impact animal welfare. Therefore, understanding the influence of schedules on animal behaviour can be a valuable tool to improve welfare, however information on behaviour overnight and in the absence of husbandry staff remains rare. Bottlenose dolphins (Tursiops spp.) are highly social marine mammals and the most common cetacean found in captivity. They communicate using frequency modulated signature whistles, a whistle type that is individually distinctive and used as a contact call. We investigated the vocalisations of ten dolphins housed in three social groups at uShaka Sea World dolphinarium to determine how patterns in acoustic behaviour link to dolphinarium routines. Investigation focused on overnight behaviour, housing decisions, weekly patterns, and transitional periods between the presence and absence of husbandry staff. Recordings were made from 17h00 - 07h00 over 24 nights, spanning May to August 2018. Whistle (including signature whistle) presence and production rate decreased soon after husbandry staff left the facility, was low over night, and increased upon staff arrival. Results indicated elevated arousal states particularly associated with the morning feeding regime. Housing in the pool configuration that allowed observation of staff activities from all social groups was characterised by an increase in whistle presence and rates. Heightened arousal associated with staff presence was reflected in the structural characteristics of signature whistles, particularly maximum frequency, frequency range and number of whistle loops. We identified individual differences in both production rate and the structural modification of signature whistles under different contexts. Overall, these results revealed a link between scheduled activity and associated behavioural responses, which can be used as a baseline for future welfare monitoring where changes from normal behaviour may reflect shifts in welfare state.

In this study, topology optimized, patient specific osteosynthesis plates (TOPOS-implants) are evaluated for the mandibular reconstruction using fibula segments. These shape optimized implants are compared to a standard treatment with miniplates (thickness: 1.0 mm, titanium grade 4) in biomechanical testing using human cadaveric specimen. Mandible and fibula of 21 body donors were used. Geometrical models were created based on automated segmentation of CT-scans of all specimens. All reconstructions, including cutting guides for osteotomy as well as TOPOS-implants, were planned using a custom-made software tool. The TOPOS-implants were produced by electron beam melting (thickness: 1.0 mm, titanium grade 5). The fibula-reconstructed mandibles were tested in static and dynamic testing in a multi-axial test system, which can adapt to the donor anatomy and apply side-specific loads. Static testing was used to confirm mechanical similarity between the reconstruction groups. Force-controlled dynamic testing was performed with a sinusoidal loading between 60 and 240 N (reconstructed side: 30% reduction to consider resected muscles) at 5 Hz for up to 5 · 105 cycles. There was a significant difference between the groups for dynamic testing: All TOPOS-implants stayed intact during all cycles, while miniplate failure occurred after 26.4% of the planned loading (1.32 · 105 ± 1.46 · 105 cycles). Bone fracture occurred in both groups (miniplates: n = 3, TOPOS-implants: n = 2). A correlation between bone failure and cortical bone thickness in mandible angle as well as the number of bicortical screws used was demonstrated. For both groups no screw failure was detected. In conclusion, the topology optimized, patient specific implants showed superior fatigue properties compared to miniplates in mandibular reconstruction. Additionally, the patient specific shape comes with intrinsic guiding properties to support the reconstruction process during surgery. This demonstrates that the combination of additive manufacturing and topology optimization can be beneficial for future maxillofacial surgery.

BackgroundTranscatheter methods have been rapidly evolving to provide an alternative less invasive therapeutic option, mainly because redo patients often present with multiple comorbidities and high operative risk. We sought to evaluate and compare our experience with transapical transcatheter mitral valve replacement (TA-TMVR) to conventional redo mitral valve replacement in patients presenting with degenerated biological mitral valve prostheses or failed valve annuloplasty.Methods and materialBetween March 2012 and November 2020, 74 consecutive high-risk patients underwent surgical redo mitral valve replacement (n = 33) or TA-TMVR (n = 41) at our institution. All patients presented with a history of a surgical mitral valve procedure. All transcatheter procedures were performed using the SAPIEN XT/3™ prostheses. Data collection was prospectively according to MVARC criteria.ResultsThe mean logistic EuroSCORE-II of the whole cohort was 19.9±16.7%, and the median STS-score was 11.1±12.5%. The mean age in the SMVR group was 63.7±12.8 years and in the TMVR group 73.6±9.7 years. Patients undergoing TA-TMVR presented with significantly higher risk scores. Echocardiography at follow up showed no obstruction of the left ventricular outflow tract, no paravalvular leakage and excellent transvalvular gradients in both groups (3.9±1.2 mmHg and 4.2±0.8 mmHg in the surgical and transcatheter arm respectively). There was no difference in postoperative major adverse events between the groups with no strokes in the whole cohort. Both methods showed similar survival rates at one year and a 30-day mortality of 15.2% and 9.8% in SAVR and TMVR group, respectively. Despite using contrast dye in the transcatheter group, the rate of postoperative acute kidney failure was similar between the groups.ConclusionDespite several contraindications for surgery, we showed the non-inferiority of TA-TMVR compared to conventional surgical redo procedures in high-risk patients. With its excellent hemodynamic and similar survival rate, TA-TMVR offers a feasible alternative to the conventional surgical redo procedure in selected patients.

Coordination of fate transition and cell division is crucial to maintain the plant architecture and to achieve efficient production of plant organs. In this paper, we analysed the stem cell dynamics at the shoot apical meristem (SAM) that is one of the plant stem cells locations. We designed a mathematical model to elucidate the impact of hormonal signaling on the fate transition rates between different zones corresponding to slowly dividing stem cells and fast dividing transit amplifying cells. The model is based on a simplified two-dimensional disc geometry of the SAM and accounts for a continuous displacement towards the periphery of cells produced in the central zone. Coupling growth and hormonal signaling results in a nonlinear system of reaction-diffusion equations on a growing domain with the growth rate depending on the model components. The model is tested by simulating perturbations in the level of key transcription factors that maintain SAM homeostasis. The model provides new insights on how the transcription factor HECATE is integrated in the regulatory network that governs stem cell differentiation.

BACKGROUND:Recurrent respiratory papillomatosis (RRP) is characterized by repeated formation of papillomas in the respiratory tract and is caused by human papillomavirus (HPV) types 6 and 11. Women with genital HPV infection are slow to develop weak humoral immunity, but respond robustly to the HPV vaccine. We wondered if people with RRP had a similar immune response. METHODS:A convenience cross-sectional sample of patients with RRP were recruited into one of four groups: 1) adults and adolescents with active RRP, 2) children with active RRP, 3) RRP patients who had undergone HPV vaccination prior to enrollment and, 4) people with RRP who were in remission. Anti-HPV6 and HPV11 serology was determined by cLIA on a single blood draw. RESULTS:Of the 70 subjects enrolled, 36, 16, 8, and 10, were in groups 1, 2, 3, and 4, respectively. 47% of participants aged >11 years and 81% aged ≤11 years possessed no antibodies against HPV6 or HPV11 (ie. double seronegative). 61% of patients in remission were double seronegative. All participants who had received HPV vaccine previously were seropositive to at least one of these low risk HPV types (ie none of them were double seronegative). Among patients who had active RRP and never had HPV vaccination (n = 52) there was an association between duration of symptoms and seropositivity. Of those who were seropositive, the geometric mean duration of symptoms was 11 years compared to 4.7 years for those who were seronegative (p = 0.001). CONCLUSION:People with RRP are capable of developing a humoral response to HPV6 and HPV11. That response appears to be robust when initiated by the HPV vaccine, but either nonexistent or slow to develop in response to infection. Most in remission do not have demonstrable antibody levels against HPV6 or HPV11.

Trust between couples is a prerequisite for stable and satisfactory romantic relationships. However, there has been no valid research tool to assess partner-specific trust behavior including costly investments in the trustworthiness of the romantic partner. We here present a comprehensive validation of the newly developed Trust Game for Couples (TGC) by means of various self-report and implicit relationship-related measures. The TGC operationalizes trust by measuring an individual's willingness to invest his or her own financial resources in pro-relationship attitudes of their romantic partner (collected by dichotomous responses to relationship-relevant items, e.g., answering yes to "I am absolutely sure that I love my partner"). Thirty-five healthy couples between 20 and 34 years completed the TGC in an interactive (both partners present), but anonymous setting (no information on the partner's responses revealed). Trust, as measured by the TGC, correlates positively with self-reported trust, satisfaction, and felt closeness in the relationship, but not with general interpersonal trust, confirming both its convergent and discriminant validity. In addition to explicit criteria for construct validity, implicit measures of partner valence and confidence explained variance in the TGC, demonstrating that it constitutes an economical measure of implicit and explicit ingredients of trust between couples. In sum, the TGC provides a novel, specific behavioral tool for a sensitive assessment of trust in dyadic relationships with potential for numerous research fields.

Moral vitalism refers to a tendency to view good and evil as actual forces that can influence people and events. The Moral Vitalism Scale had been designed to assess moral vitalism in a brief survey form. Previous studies established the reliability and validity of the scale in US-American and Australian samples. In this study, the cross-cultural comparability of the scale was tested across 28 different cultural groups worldwide through measurement invariance tests. A series of exact invariance tests marginally supported partial metric invariance, however, an approximate invariance approach provided evidence of partial scalar invariance for a 5-item measure. The established level of measurement invariance allows for comparisons of latent means across cultures. We conclude that the brief measure of moral vitalism is invariant across 28 cultures and can be used to estimate levels of moral vitalism with the same precision across very different cultural settings.

With digitalization and virtual entertainment being the megatrends of the 21st century, there is reasonable concern about the role of physical activity (PA) in the daily life of children and adolescents. To identify risk-groups with insufficient PA and to guide interventions, continuous and representative tracking of PA is crucial. In this paper, representative PA data of children and adolescents from the Motorik-Modul (MoMo) baseline study (2003-2006, N = 4,528) is compared to those of Wave 2 (2014-2017, N = 3,708). Participants aged 4-17 were drawn out of 167 sample points in Germany and the data was weighted to ensure representativeness for Germany. Organized (sports clubs and schools) and unorganized (unorganized sports and playing outside) PA was measured by questionnaire and stratified by sex, age, and socioeconomic status. Contrary to common expectation, overall PA remained stable among youths in the past ten years, however, there is an ongoing trend towards organized forms of PA at the expense of unorganized sports and playing outside. Besides different trends in settings, there is inequality in PA distribution among socioeconomic status and gender, unequally pronounced in different settings.

Tracking changes in total biomass production or land productivity is an essential part of monitoring land transformations and long-term alterations of the health and productive capacity of land that are typically associated with land degradation. Persistent declines in land productivity impact many terrestrial ecosystem services that form the basis for sustainable livelihoods of human communities. Protected areas (PAs) are key to globally conserve biodiversity and ecosystem services that are critical for human well-being, and cover about 15% of the land worldwide. Here we globally assess the trends in land productivity in PAs of at least 10 km2 and in their unprotected surroundings (10 km buffers) from 1999 to 2013. We quantify the percentage of the protected and unprotected land that shows stable, increasing or decreasing trends in land productivity, quantified as long-term (15 year) changes in above-ground biomass derived from satellite-based observations with a spatial resolution of 1 km. We find that 44% of the land in PAs globally has retained the productivity at stable levels from 1999 to 2013, compared to 42% of stable productivity in the unprotected land around PAs. Persistent increases in productivity are more common in the unprotected lands around PAs (32%) than within PAs (18%) globally, while about 14% of the protected land and 12% of the unprotected land around PAs has experienced declines in land productivity. Oceania has the highest percentage of land with stable productivity in PAs (57%), whereas Europe has the lowest percentage (38%) and also the largest share of protected land with increasing land productivity (32%). We discuss the observed differences between PAs and unprotected lands, and between different parts of the world, in relation to different types and levels of human activities and their impact on land productivity. Our assessment of land productivity dynamics helps to characterise the state, pressures and changes in and around protected areas globally. Further research may focus on more detailed analyses to disentangle the relative contribution of specific drivers (from climate change to land use change) and their interaction with land productivity dynamics and potential land degradation in different regions of the world.

Ecosystems provide multiple services that are necessary to maintain human life. Agroecosystems are very productive suppliers of biomass-related provisioning ecosystem services, e.g. food, fibre, and energy. At the same time, they are highly dependent on good ecosystem condition and regulating ecosystem services such as soil fertility, water supply or soil erosion regulation. Assessments of this interplay of ecosystem condition and services are needed to understand the relationships in highly managed systems. Therefore, the aim of this study is twofold: First, to test the concept and indicators proposed by the European Union Working Group on Mapping and Assessment of Ecosystems and their Services (MAES) for assessing agroecosystem condition at a regional level. Second, to identify the relationships between ecosystem condition and the delivery of ecosystem services. For this purpose, we applied an operational framework for integrated mapping and assessment of ecosystems and their services. We used the proposed indicators to assess the condition of agroecosystems in Northern Germany and regulating ecosystem service control of erosion rates. We used existing data from official databases to calculate the different indicators and created maps of environmental pressures, ecosystem condition and ecosystem service indicators for the Federal State of Lower Saxony. Furthermore, we identified areas within the state where pressures are high, conditions are unfavourable, and more sustainable management practices are needed. Despite the limitations of the indicators and data availability, our results show positive, negative, and no significant correlations between the different pressures and condition indicators, and the control of erosion rates. The idea behind the MAES framework is to indicate the general condition of an ecosystem. However, we observed that not all proposed indicators can explain to what extent ecosystems can provide specific ecosystem services. Further research on other ecosystem services provided by agroecosystems would help to identify synergies and trade-offs. Moreover, the definition of a reference condition, although complicated for anthropogenically highly modified agroecosystems, would provide a benchmark to compare information on the condition of the ecosystems, leading to better land use policy and management decisions.

ObjectivesTo compare virologic and immunologic outcomes of integrase inhibitor (INSTI)-containing, contemporary boosted protease inhibitor (PI/b)-containing and non-nucleotide reverse transcriptase inhibitor (NNRTI)-containing regimens in a real-life setting.MethodsUsing logistic regression, virologic and immunologic outcomes of INSTI use were compared to outcomes of PI/b or NNRTI treatment 12 months after treatment start or switch, for participants in the RESPOND cohort consortium. A composite treatment outcome (cTO) was used, defining success as viral load (VL) ResultsBetween January 2012 and January 2019, 13,703 (33.0% ART-naïve) individuals were included, of whom 7,147 started/switched to a regimen with an INSTI, 3,102 to a PI/b and 3,454 to an NNRTI-containing regimen. The main reason for cTO failure in all treatment groups were changes in ART regimen. Compared to INSTIs, the adjusted odds ratio (aOR) of cTO success was significantly lower for PI/b (0.74 [95% confidence interval, CI 0.67-0.82], p ConclusionIn this large analysis of a real-world population, cTO and on-treatment success were similar between INSTIs and NNRTIs, but lower for PI/b, though residual confounding cannot be fully excluded. Obtaining favorable immunologic outcomes were more likely for INSTIs than the other drug classes.

Polycystic ovary syndrome (PCOS) affects around 10% of young women, with adverse consequences on fertility and cardiometabolic outcomes. PCOS appears to result from a genetic predisposition interacting with developmental events during fetal or perinatal life. We hypothesised that PCOS candidate genes might be expressed in the fetal ovary when the stroma develops; mechanistically linking the genetics, fetal origins and adult ovarian phenotype of PCOS. In bovine fetal ovaries (n = 37) of 18 PCOS candidate genes only SUMO1P1 was not expressed. Three patterns of expression were observed: early gestation (FBN3, GATA4, HMGA2, TOX3, DENND1A, LHCGR and FSHB), late gestation (INSR, FSHR, and LHCGR) and throughout gestation (THADA, ERBB4, RAD50, C8H9orf3, YAP1, RAB5B, SUOX and KRR1). A splice variant of FSHB exon 3 was also detected early in the bovine ovaries, but exon 2 was not detected. Three other genes, likely to be related to the PCOS aetiology (AMH, AR and TGFB1I1), were also expressed late in gestation. Significantly within each of the three gene groups, the mRNA levels of many genes were highly correlated with each other, despite, in some instances, being expressed in different cell types. TGFβ is a well-known stimulator of stromal cell replication and collagen synthesis and TGFβ treatment of cultured fetal ovarian stromal cells inhibited the expression of INSR, AR, C8H9orf3 and RAD50 and stimulated the expression of TGFB1I1. In human ovaries (n = 15, < 150 days gestation) many of the same genes as in bovine (FBN3, GATA4, HMGA2, FSHR, DENND1A and LHCGR but not TOX3 or FSHB) were expressed and correlated with each other. With so many relationships between PCOS candidate genes during development of the fetal ovary, including TGFβ and androgen signalling, we suggest that future studies should determine if perturbations of these genes in the fetal ovary can lead to PCOS in later life.

[This corrects the article DOI: 10.1371/journal.pcbi.1002586.].

[This corrects the article DOI: 10.1371/journal.pone.0197610.].

The epidemiology of human Salmonella enterica infections in Guadeloupe (French West Indies) appears to be specific, with a higher prevalence of the subspecies enterica serovars Panama and Arechavaleta (Panama and Arechavaleta) than in other regions. A study was performed in Guadeloupe to identify the reservoir of Salmonella serovars by comparing their distribution in warm- and cold-blooded animals and in humans living in Guadeloupe and mainland France. Furthermore, a case-control study was conducted in 2012-2013 to identify the main epidemiologic risk factors for S. enterica infection among children under 15 years of age. Between June 2011 and December 2014, feces from 426 reptiles (322 anoles, 69 iguanas and 35 geckos) and 50 frogs distributed throughout Guadeloupe and nearby islands were investigated. The frequency of S. enterica carriage was 15.0% (n = 64) in reptiles but varied by species. The only significant risk factor for S. enterica infection was a more frequent presence of frogs in the houses of cases than in those of controls (P = 0.042); however, isolates were not collected. Panama and Arechavaleta were the two serovars most often recovered between 2005 and 2014 from humans living in Guadeloupe (24.5% (n = 174) and 11.5% (n = 82), respectively), which is in contrast to the low prevalence in mainland France (0.4%). Their presence at low frequencies in wild reptiles (4.6% (n = 3) and 3.1% (n = 2), respectively) and pigs (7.5% (n = 5) and 1.5% (n = 1), respectively) suggests a broad host range, and humans may be infected by indirect or direct contact with animals. These serovars are probably poorly adapted to humans and therefore cause more severe infections. The unusual subspecies houtenae serovar 43:z4,z32:- was a major subspecies in wild reptiles (24.6%, n = 16) and humans (9.4%, n = 67) but was not recovered from warm-blooded animals, suggesting that reptiles plays a key role in human infection.

Cervids are known to be reservoirs of zoonotic bacteria transmitted by ticks. This study aimed to identify the Anaplasma species carried by captive red deer and swamp deer in a wild fauna reserve in France. Blood from 59 red deer and 7 swamp deer was collected and analyzed over a period of two years. A semi-nested PCR targeting the 23S rRNA was performed to detect and characterize Anaplasma spp. and determine the presence of zoonotic species. Anaplasma phagocytophilum was identified in 14/59 red deer (23.7%) but it was not identified in any of the swamp deer (7 animals). Three sequences could not be assigned to any particular species based on the 23S rRNA sequences. Complementary nested PCR targeting 16S rRNA, gltA and groEL genes and sequencing analysis then identified these sequences as a recently reported zoonotic species, Anaplasma capra; this species was found in 2 red deer (Cervus elaphus) and 1 swamp deer (Rucervus duvaucelii). This is the first report of the tick-borne zoonotic bacterium A. capra in France, a species otherwise described only in China, Japan, Malaysia and South Korea in goats, sheep, deer, cattle and Japanese serows (Capricornis crispus). While this bacterium may have been introduced into the reserve by infected imported animals, its local epidemiological cycle via tick transmission seems possible as locally born deer were found infected. Diagnostic methods, especially molecular ones, should take into account the potential infection of animals and humans with this species.

Inland waters are unique ecosystems offering services and habitat resources upon which many species depend. Despite the importance of, and threats to, inland water, global assessments of protected area (PA) coverage and trends have focused on land habitats or have assessed land and inland waters together. We here provide the first assessment of the level of protection of inland open surface waters and their trends (1984-2015) within PAs for all countries, using a globally consistent, high-resolution (30 m) and validated dataset on permanent and seasonal surface waters based on Landsat images. Globally, 15% of inland surface waters are covered by PAs with mapped boundaries. Estimated inland water protection increases to 16.4% if PAs with reported area but delineated only as points are included as circular buffers. These coverage estimates slightly exceed the comparable figure for land but fall below the 17% goal of the Convention on Biological Diversity's Aichi Target 11 for 2020. Protection levels are very uneven across countries, half of which do not yet meet the 17% target. The lowest coverage of surface water by PAs (

The increasing amount of clinical research conducted outside the "traditional" countries raises questions about the benefits of hosting offshored clinical research. The extent to which trials contribute to the scientific knowledge base and, in particular, whether there are differences between different types of trials remain open questions. By examining a change in clinical trial regulations in India, a country often viewed as a first-choice offshoring location, we study how the relaxation of clinical trial regulations affects the number and the type of clinical trials as well as the domestic scientific knowledge base. Based on trial data from ClinicalTrials.gov and data on associated publication activities, our empirical analysis suggests that, despite an initial increase in the number of clinical trials, relaxing clinical trial regulations has a limited impact on the domestic scientific knowledge base. More specifically, the number of Indian researchers involved in the production of trial-related scientific knowledge remains modest. Furthermore, the potential to learn from the additional trials appears to be limited: the influx of phase 3 trials-mainly sponsored by Western-pharmaceutical firms-is accompanied by a lower likelihood that the trial results will be used in Indian researchers' subsequent research activities when compared to phase 3 trials with preceding phase 2 trials, as was required before the regulatory change. Overall, our results contradict expectations that relaxing the regulatory requirements for conducting late-stage clinical trials is an appropriate means of supporting the development of the domestic scientific knowledge base.

Investigating approach-avoidance behavior regarding affective stimuli is important in broadening the understanding of one of the most common psychiatric disorders, social anxiety disorder. Many studies in this field rely on approach-avoidance tasks, which mainly assess hand movements, or interpersonal distance measures, which return inconsistent results and lack ecological validity. Therefore, the present study introduces a virtual reality task, looking at avoidance parameters (movement time and speed, distance to social stimulus, gaze behavior) during whole-body movements. These complex movements represent the most ecologically valid form of approach and avoidance behavior. These are at the core of complex and natural social behavior. With this newly developed task, the present study examined whether high socially anxious individuals differ in avoidance behavior when bypassing another person, here virtual humans with neutral and angry facial expressions. Results showed that virtual bystanders displaying angry facial expressions were generally avoided by all participants. In addition, high socially anxious participants generally displayed enhanced avoidance behavior towards virtual people, but no specifically exaggerated avoidance behavior towards virtual people with a negative facial expression. The newly developed virtual reality task proved to be an ecological valid tool for research on complex approach-avoidance behavior in social situations. The first results revealed that whole body approach-avoidance behavior relative to passive bystanders is modulated by their emotional facial expressions and that social anxiety generally amplifies such avoidance.

IntroductionOpioids are one of the most important and effective drug classes in pain medicine with a key role in most medical fields. The increase of opioid prescription over time has led to higher numbers of prescription opioid misuse, abuse and opioid-related deaths in most developed OECD (Organisation for Economic Co-operation and Development) countries around the world. Whilst reliable data on the prevalence of opioid treatment is accessible for many countries, data on Germany specifically is still scarce. Considering Germany being the largest country in the European Union, the lack of evidence-based strategies from long-term studies is crucial. The aim of this work is to review and summarise relevant published literature on the prevalence of opioid prescription in Germany to adequately inform health policy strategies.MethodsA systematic review of the epidemiology of opioid prescription in Germany was conducted, searching PubMed and Web of Science. Eligibility criteria were defined prior to conducting the search. Literature concerning Germany, published in English and German was included and the search was replicated by three independent researchers. Two levels of screening were employed. Disagreement was resolved by face-to-face discussion, leading to a consensus judgement.ResultsOur electronic search yielded 735 articles. Reviewing titles and abstracts yielded 19 relevant articles. Three authors examined each article's full text more closely and determined that twelve papers should be included. Of the twelve identified studies-with publication dates ranging from 1985 to 2016-six were retrospective cross-sectional studies and six were retrospective repeated-measures cross-sectional studies. Sample sizes ranged from 92,842 to ≈ 11,000,000 participants. Data sources of included studies showed vast heterogeneity. The reviewed literature suggested an increase in the number of patients with opioid prescriptions and defined daily doses of opioids per recipient in Germany over time. The majority of opioid prescriptions was used for patients with non-cancer pain. Opioid use was more common in older people, women and in the north of Germany. Fentanyl was shown to be the most prescribed strong opioid in outpatient settings in Germany, despite not being the first-line choice for chronic pain conditions. All data published before 2000-but none of the more recent studies-suggested an insufficient treatment of pain using opioids. There were no signs for a current opioid epidemic in Germany.ConclusionsDespite some limitations of the review and the heterogeneity of studies, it can be stated that the number of opioid prescriptions overall as well as the number of people receiving opioid treatment have increased over time. Most prescriptions were found to be for strong opioids and patients with non-cancer pain. Even though patterns of opioid prescription follow trends observed in other developed countries, there are no signs of an opioid epidemic in Germany. Therefore, this review could currently not find a need for urgent health policy interventions regarding opioid prescription practices. However, critical gaps in the literature remain and more research is needed to make more reliable judgements.

BackgroundIn 2017, more than 1.1 million children were living with type 1 diabetes mellitus (T1DM) globally. The goal in paediatric diabetes therapy is reaching optimal glycaemic control as early as possible in order to avoid complications and early mortality without compromising the quality of life (QoL) of children. Several different insulin regimens are available for T1DM patients to reach this goal.AimsThis review set out to analyse whether continuous subcutaneous insulin infusion (CSII) regimens are superior to multiple daily injection (MDI) therapy in T1DM youth regarding QoL. Additionally, it assessed glycaemic control and adverse events as secondary outcomes and discussed potential future public health implications and justifications for using CSII as a first-line therapy in diabetic youth.MethodsA systematic review and random effects meta-analysis was performed on studies investigating the association between QoL and diabetes treatment regimen. Differences in adverse event rates between groups were analysed using a Mann-Whitney U test. Lastly, differences in glycaemic control were assessed using a random effects meta-analysis.ResultsQoL and glycaemic control was significantly better in CSII subjects at baseline and follow-up. No significant differences in adverse events were found between study groups. No significant changes over time could be shown for either QoL or glycaemic control.ConclusionCSII proved to provide similar or slightly better outcomes in all analysed fields. This is consistent with previous research. However, to make credible recommendations, better-designed studies are needed to investigate the impact of CSII in children.

BackgroundRecurrent Respiratory Papillomatosis (RRP) is a rare disease characterized by the growth of papillomas in the airway and especially the larynx. The clinical course is highly variable among individuals and there is poor understanding of the factors that drive an aggressive vs an indolent course.MethodsA convenience cohort of 339 affected subjects with papillomas positive for only HPV6 or HPV11 and clinical course data available for 1 year or more, from a large multicenter international study were included. Exploratory data analysis was conducted followed by inferential analyses with frequentist and Bayesian statistics.ResultsWe examined 339 subjects: 82% were diagnosed prior to the age of 18 years, 65% were infected with HPV6, and 69% had an aggressive clinical course. When comparing age at diagnosis with clinical course, the probability of aggressiveness is high for children under five years of age then drops rapidly. For patients diagnosed after the age of 10 years, an indolent course is more common. After accounting for confounding between HPV11 and young age, HPV type was minimally associated with aggressiveness. Fast and Frugal Trees (FFTs) were utilized to determine which algorithms yield the highest accuracy to classify patients as having an indolent or aggressive clinical course and consistently created a branch for diagnostic age at ~5 years old. There was no reliable strong association between clinical course and socioeconomic or parental factors.ConclusionIn the largest cohort of its type, we have identified a critical age at diagnosis which demarcates a more aggressive from less aggressive clinical course.