Handgrip and finger flexion strength in children: A cross-sectional assessment of age-related normative data and application as a clinical functional marker in paediatric neuromuscular disorders.

BACKGROUND: The aim of this study was to evaluate handgrip and finger flexion strength (HGFS) as functional marker for disease progression in children with neuromuscular disorders (NMD) and present normative data in a paediatric healthy cohort. METHODS: We applied the fixed hand and finger dynamometer HFD 200 to assess HGFS under standardised, isometric and biomechanical conditions. In our cross-sectional study HGFS was analysed in n = 233 paediatric healthy controls (HC) and a cohort of n = 33 children with NMD between five and 18 years. In seven children with spinal muscular atrophy (SMA), HGFS were assessed prior to and under treatment with nusinersen over a two months period. HGFS of children with NMD was correlated with respiratory parameters, anthropometric data, hand function and motor scores. RESULTS: Patients with NMD exhibited a heterogenous HGFS pattern. HGFS was lower than in HC (p < 0.001). Children with SMA gained a significant increase in strength after two months of treatment (p < 0.05, r = 0.75-0.9). CONCLUSION: HGFS is a sensitive functional marker in paediatric NMD to identify minimal changes in distal muscle strength. HGFS may evolve as a sensitive outcome measure to monitor upcoming therapeutic interventions in particular for non-ambulant patients with NMD.

Comparison of extraction methods for intracellular metabolomics of human tissues.

Analyses of metabolic compounds inside cells or tissues provide high information content since they represent the endpoint of biological information flow and are a snapshot of the integration of many regulatory processes. However, quantification of the abundance of metabolites requires their careful extraction. We present a comprehensive study comparing ten extraction protocols in four human sample types (liver tissue, bone marrow, HL60, and HEK cells) aiming to detect and quantify up to 630 metabolites of different chemical classes. We show that the extraction efficiency and repeatability are highly variable across protocols, tissues, and chemical classes of metabolites. We used different quality metrics including the limit of detection and variability between replicates as well as the sum of concentrations as a global estimate of analytical repeatability of the extraction. The coverage of extracted metabolites depends on the used solvents, which has implications for the design of measurements of different sample types and metabolic compounds of interest. The benchmark dataset can be explored in an easy-to-use, interactive, and flexible online resource (R/shiny app MetaboExtract: http://www.metaboextract.shiny.dkfz.de) for context-specific selection of the optimal extraction method. Furthermore, data processing and conversion functionality underlying the shiny app are accessible as an R package: https://cran.r-project.org/package=MetAlyzer.

Deep Metabolic Profiling Assessment of Tissue Extraction Protocols for Three Model Organisms.

Metabolic profiling harbors the potential to better understand various disease entities such as cancer, diabetes, Alzheimer's, Parkinson's disease or COVID-19. To better understand such diseases and their intricate metabolic pathways in human studies, model animals are regularly used. There, standardized rearing conditions and uniform sampling strategies are prerequisites towards a successful metabolomic study that can be achieved through model organisms. Although metabolomic approaches have been employed on model organisms before, no systematic assessment of different conditions to optimize metabolite extraction across several organisms and sample types has been conducted. We address this issue using a highly standardized metabolic profiling assay analyzing 630 metabolites across three commonly used model organisms (Drosophila, mouse, and zebrafish) to find an optimal extraction protocol for various matrices. Focusing on parameters such as metabolite coverage, concentration and variance between replicates we compared seven extraction protocols. We found that the application of a combination of 75% ethanol and methyl tertiary-butyl ether (MTBE), while not producing the broadest coverage and highest concentrations, was the most reproducible extraction protocol. We were able to determine up to 530 metabolites in mouse kidney samples, 509 in mouse liver, 422 in zebrafish and 388 in Drosophila and discovered a core overlap of 261 metabolites in these four matrices. To enable other scientists to search for the most suitable extraction protocol in their experimental context and interact with this comprehensive data, we have integrated our data set in the open-source shiny app "MetaboExtract". Hereby, scientists can search for metabolites or compound classes of interest, compare them across the different tested extraction protocols and sample types as well as find reference concentration values.

The importance of direct and indirect trophic interactions in determining the presence of a locally rare day-flying moth.

Ecosystem engineers affect other organisms by creating, maintaining or modifying habitats, potentially supporting species of conservation concern. However, it is important to consider these interactions alongside non-engineering trophic pathways. We investigated the relative importance of trophic and non-trophic effects of an ecosystem engineer, red deer, on a locally rare moth, the transparent burnet (Zygaena purpuralis). This species requires specific microhabitat conditions, including the foodplant, thyme, and bare soil for egg-laying. The relative importance of grazing (i.e., trophic effect of modifying microhabitat) and trampling (i.e., non-trophic effect of exposing bare soil) by red deer on transparent burnet abundance is unknown. We tested for these effects using a novel method of placing pheromone-baited funnel traps in the field. Imago abundance throughout the flight season was related to plant composition, diversity and structure at various scales around each trap. Indirect effects of red deer activity were accounted for by testing red deer pellet and trail presence against imago abundance. Imago abundance was positively associated with thyme and plant diversity, whilst negatively associated with velvet grass and heather species cover. The presence of red deer pellets and trails were positively associated with imago abundance. The use of these sites by red deer aids the transparent burnet population via appropriate levels of grazing and the provision of a key habitat condition, bare soil, in the form of deer trails. This study shows that understanding how both trophic and non-trophic interactions affect the abundance of a species provides valuable insights regarding conservation objectives.

Pre-analytical processing of plasma and serum samples for combined proteome and metabolome analysis.

Metabolomic and proteomic analyses of human plasma and serum samples harbor the power to advance our understanding of disease biology. Pre-analytical factors may contribute to variability and bias in the detection of analytes, especially when multiple labs are involved, caused by sample handling, processing time, and differing operating procedures. To better understand the impact of pre-analytical factors that are relevant to implementing a unified proteomic and metabolomic approach in a clinical setting, we assessed the influence of temperature, sitting times, and centrifugation speed on the plasma and serum metabolomes and proteomes from six healthy volunteers. We used targeted metabolic profiling (497 metabolites) and data-independent acquisition (DIA) proteomics (572 proteins) on the same samples generated with well-defined pre-analytical conditions to evaluate criteria for pre-analytical SOPs for plasma and serum samples. Time and temperature showed the strongest influence on the integrity of plasma and serum proteome and metabolome. While rapid handling and low temperatures (4°C) are imperative for metabolic profiling, the analyzed proteomics data set showed variability when exposed to temperatures of 4°C for more than 2 h, highlighting the need for compromises in a combined analysis. We formalized a quality control scoring system to objectively rate sample stability and tested this score using external data sets from other pre-analytical studies. Stringent and harmonized standard operating procedures (SOPs) are required for pre-analytical sample handling when combining proteomics and metabolomics of clinical samples to yield robust and interpretable data on a longitudinal scale and across different clinics. To ensure an adequate level of practicability in a clinical routine for metabolomics and proteomics studies, we suggest keeping blood samples up to 2 h on ice (4°C) prior to snap-freezing as a compromise between stability and operability. Finally, we provide the methodology as an open-source R package allowing the systematic scoring of proteomics and metabolomics data sets to assess the stability of plasma and serum samples.

Neuronal response to high negative affective stimuli in major depressive disorder: An fMRI study.

BACKGROUND: Disturbed emotion processing underlies depression. We examined the neuronal underpinnings of emotional processing in patients (PAT) with major depressive disorder (MDD) compared to healthy volunteers (HV) using functional magnetic resonance (fMRI) scan. METHODS: Thirty-six MDD patients and 30 HV underwent T2-weighted fMRI assessments during the presentation of an implicit affective processing task in three conditions. They differed regarding their affective quality (=valence, high negative, low negative and neutral stimuli) and regarding the arousal based on stimuli from the International Affective Picture System. RESULTS: Group contrasts showed lower left-sided activation in dorsolateral prefrontal cortex (DLPFC), anterior PFC, precentral and premotor cortex in PAT compared with HV (Cluster-level threshold, 5000 iterations, p<0.01). We found a significant interaction effect of valence and group, a significant effect of emotional valence and a significant effect of group. All effects were shown in brain regions within the emotional network (Cluster-level threshold, 5000 iterations, p<0.01). Higher arousal (rho=-0.33, p<0.01) and higher valence (rho=-0.33, p<0.01) during high negative stimuli presentation as well as more severe depression (Beck Depression Inventory II [BDI II]; r = 0.39, p = 0.01) were significantly negatively associated with left DLFPC activity in patients. LIMITATIONS: Potential influence of psychopharmacological drugs on functional activation is one of the most discussed source of bias in studies with medicated psychiatric patients. CONCLUSIONS: The results highlight the importance of left DLPFC during the processing of negative emotional stimuli in MDD. The integration of a neurophysiological model of emotional processing in MDD may help to clarify and improve therapeutic options.

Stent Graft Placement by Pseudoaneurysm of the Hepatic Arteries: Efficacy and Patency Rate in Follow-up.

PURPOSE: To investigate efficacy and patency status of stent graft implantation in the treatment of hepatic artery pseudoaneurysm. MATERIALS AND METHODS: A retrospective analysis of patients who had undergone endovascular treatment of hepatic artery pseudoaneurysms between 2011 and 2020 was performed. Medical records were examined to obtain patients' surgical histories and to screen for active bleeding. Angiographic data on vascular access, target vessel, material used and technical success, defined as the exclusion of the pseudoaneurysm by means of a stent graft with sufficient control of bleeding, were collected. Vessel patency at follow-up CT was analyzed and classified as short-term (< 6 weeks), mid-term (between 6 weeks and 1 year), and long-term patency (> 1 year). In case of stent occlusion, collateralization and signs of hepatic hypoperfusion were examined. RESULTS: In total, 30 patients were included and of these, 25 and 5 had undergone stent graft implantation and coiling, respectively. In patients with implanted stent grafts, technical success was achieved in 23/25 patients (92%). Follow-up CT scans were available in 16 patients, showing stent graft patency in 9/16 patients (56%). Short-term, mid-term, and long-term short-term stent patency was found in 81% (13/16), 40% (4/10), and 50% (2/4). In patients with stent graft occlusion, 86% (6/7) exhibited maintenance of arterial liver perfusion via collaterals and 14% (1/7) exhibited liver abscess during follow-up. CONCLUSION: Stent graft provides an effective treatment for hepatic artery pseudoaneurysms. Even though patency rates decreased as a function of time, stent occlusion was mainly asymptomatic due to sufficient collateralization.

Heat stress reduces the contribution of diazotrophs to coral holobiont nitrogen cycling.

Efficient nutrient cycling in the coral-algal symbiosis requires constant but limited nitrogen availability. Coral-associated diazotrophs, i.e., prokaryotes capable of fixing dinitrogen, may thus support productivity in a stable coral-algal symbiosis but could contribute to its breakdown when overstimulated. However, the effects of environmental conditions on diazotroph communities and their interaction with other members of the coral holobiont remain poorly understood. Here we assessed the effects of heat stress on diazotroph diversity and their contribution to holobiont nutrient cycling in the reef-building coral Stylophora pistillata from the central Red Sea. In a stable symbiotic state, we found that nitrogen fixation by coral-associated diazotrophs constitutes a source of nitrogen to the algal symbionts. Heat stress caused an increase in nitrogen fixation concomitant with a change in diazotroph communities. Yet, this additional fixed nitrogen was not assimilated by the coral tissue or the algal symbionts. We conclude that although diazotrophs may support coral holobiont functioning under low nitrogen availability, altered nutrient cycling during heat stress abates the dependence of the coral host and its algal symbionts on diazotroph-derived nitrogen. Consequently, the role of nitrogen fixation in the coral holobiont is strongly dependent on its nutritional status and varies dynamically with environmental conditions.

Prediction of response to Certolizumab-Pegol in rheumatoid arthritis (PreCePRA) by functional MRI of the brain - Study protocol for a randomized double-blind controlled study.

BACKGROUND: Tumor necrosis factor inhibitors (TNFi) signify a major advance in the treatment of rheumatoid arthritis (RA). However, treatment success initially remains uncertain as approximately half of the patients do not respond adequately to TNFi. Thus, an unmet need exists to better predict therapeutic outcome of biologicals. OBJECTIVES: We investigated whether brain activity associated with arthritis measured by functional magnetic resonance imaging (fMRI) of the brain can serve as a predictor of response to TNFi in RA patients. METHODS: PreCePRA is a multi-center, randomized, double-blind, placebo-controlled fMRI trial on patients with RA [1] [2]. Active RA patients failing csDMARDs therapy with a DAS28 > 3.2 and at least three tender and/or swollen joints underwent a brain BOLD (blood-oxygen-level dependent) fMRI scan upon joint compression at screening. Patients were then randomized into a 12-week double-blinded treatment phase with 200 mg Certolizumab Pegol (CZP) every two weeks (arm 1: fMRI BOLD signal activated volume > 2000 voxel, i.e. 2 cm3; arm 2: fMRI BOLD signal activated volume <2000 voxel) or placebo (arm 3). DAS28 low disease activity at 12 weeks was assigned as primary endpoint. A 12-week follow-up phase in which patients were switched from the placebo to the treatment arm followed the blinded phase. fMRI was carried out at screening as well as after 12 and 24 weeks of receiving CZP or placebo. CONCLUSION: We hypothesize that high-level central nervous representation of pain in patients with rheumatoid arthritis predicts response to the TNFi CZP which we further investigate in the PreCePRA trial.

Hypoxia Routes Tryptophan Homeostasis Towards Increased Tryptamine Production.

The liver is the central hub for processing and maintaining homeostatic levels of dietary nutrients especially essential amino acids such as tryptophan (Trp). Trp is required not only to sustain protein synthesis but also as a precursor for the production of NAD, neurotransmitters and immunosuppressive metabolites. In light of these roles of Trp and its metabolic products, maintaining homeostatic levels of Trp is essential for health and well-being. The liver regulates global Trp supply by the immunosuppressive enzyme tryptophan-2,3-dioxygenase (TDO2), which degrades Trp down the kynurenine pathway (KP). In the current study, we show that isolated primary hepatocytes when exposed to hypoxic environments, extensively rewire their Trp metabolism by reducing constitutive Tdo2 expression and differentially regulating other Trp pathway enzymes and transporters. Mathematical modelling of Trp metabolism in liver cells under hypoxia predicted decreased flux through the KP while metabolic flux through the tryptamine branch significantly increased. In line, the model also revealed an increased accumulation of tryptamines under hypoxia, at the expense of kynurenines. Metabolic measurements in hypoxic hepatocytes confirmed the predicted reduction in KP metabolites as well as accumulation of tryptamine. Tdo2 expression in cultured primary hepatocytes was reduced upon hypoxia inducible factor (HIF) stabilisation by dimethyloxalylglycine (DMOG), demonstrating that HIFs are involved in the hypoxic downregulation of hepatic Tdo2. DMOG abrogated hepatic luciferase signals in Tdo2 reporter mice, indicating that HIF stability also recapitulates hypoxic rewiring of Trp metabolism in vivo. Also in WT mice HIF stabilization drove homeostatic Trp metabolism away from the KP towards enhanced tryptamine production, leading to enhanced levels of tryptamine in liver, serum and brain. As tryptamines are the most potent hallucinogens known, the observed upregulation of tryptamine in response to hypoxic exposure of hepatocytes may be involved in the generation of hallucinations occurring at high altitude. KP metabolites are known to activate the aryl hydrocarbon receptor (AHR). The AHR-activating properties of tryptamines may explain why immunosuppressive AHR activity is maintained under hypoxia despite downregulation of the KP. In summary our results identify hypoxia as an important factor controlling Trp metabolism in the liver with possible implications for immunosuppressive AHR activation and mental disturbances.

Heat stress destabilizes symbiotic nutrient cycling in corals.

Recurrent mass bleaching events are pushing coral reefs worldwide to the brink of ecological collapse. While the symptoms and consequences of this breakdown of the coral-algal symbiosis have been extensively characterized, our understanding of the underlying causes remains incomplete. Here, we investigated the nutrient fluxes and the physiological as well as molecular responses of the widespread coral Stylophora pistillata to heat stress prior to the onset of bleaching to identify processes involved in the breakdown of the coral-algal symbiosis. We show that altered nutrient cycling during heat stress is a primary driver of the functional breakdown of the symbiosis. Heat stress increased the metabolic energy demand of the coral host, which was compensated by the catabolic degradation of amino acids. The resulting shift from net uptake to release of ammonium by the coral holobiont subsequently promoted the growth of algal symbionts and retention of photosynthates. Together, these processes form a feedback loop that will gradually lead to the decoupling of carbon translocation from the symbiont to the host. Energy limitation and altered symbiotic nutrient cycling are thus key factors in the early heat stress response, directly contributing to the breakdown of the coral-algal symbiosis. Interpreting the stability of the coral holobiont in light of its metabolic interactions provides a missing link in our understanding of the environmental drivers of bleaching and may ultimately help uncover fundamental processes underpinning the functioning of endosymbioses in general.

Tryptophan metabolism drives dynamic immunosuppressive myeloid states in IDH-mutant gliomas.

The dynamics and phenotypes of intratumoral myeloid cells during tumor progression are poorly understood. Here we define myeloid cellular states in gliomas by longitudinal single-cell profiling and demonstrate their strict control by the tumor genotype: in isocitrate dehydrogenase (IDH)-mutant tumors, differentiation of infiltrating myeloid cells is blocked, resulting in an immature phenotype. In late-stage gliomas, monocyte-derived macrophages drive tolerogenic alignment of the microenvironment, thus preventing T cell response. We define the IDH-dependent tumor education of infiltrating macrophages to be causally related to a complex re-orchestration of tryptophan metabolism, resulting in activation of the aryl hydrocarbon receptor. We further show that the altered metabolism of IDH-mutant gliomas maintains this axis in bystander cells and that pharmacological inhibition of tryptophan metabolism can reverse immunosuppression. In conclusion, we provide evidence of a glioma genotype-dependent intratumoral network of resident and recruited myeloid cells and identify tryptophan metabolism as a target for immunotherapy of IDH-mutant tumors.

[Rheumatology in German MD curricula]. / Rheumatologie im Medizinstudium.

Transmitting a substantial amount of basic knowledge in Rheumatology to all medical students is essential for the future medical care of patients with rheumatic diseases for two reasons: on the one hand, future general practitioners will need to master the patterns of rheumatic diseases to recognize them fast enough in new-onset patients and to refer them in time and directly to rheumatologists. On the other hand, the shortage of rheumatologists can only then be relieved in the future when we are able to inspire enthusiasm for our specialty. Adequate rheumatological structures are established only in some of the German faculties of medicine. Structural improvements happen in small steps only but were achieved at several sites. The better the local structures, the higher the chances of committed university teachers in rheumatology to reach all medical students. Probably from 2026 onwards, the learning objectives relevant for examinations will be defined by the national competence-based catalogue of learning objectives in medicine (NKLM), which is currently in the final stages of completion together with the German Federal Institute for Medical and Pharmaceutical Examinations (IMPP). It now appears that systemic autoimmune diseases and inflammatory rheumatic diseases are adequately depicted in this catalogue. If this is achieved, students will know more about these diseases in the future and will diagnose them faster in patients. Work on the NKLM is therefore of highest importance. In addition to the work on the learning objectives, up to date learning materials are required, which have to be available throughout Germany. A Rheumatology script just finished by the committee for medical student education of the German Society of Rheumatology (DGRh) and now available on the DGRh homepage should close this gap.

The Genome of the Cauliflower Coral Pocillopora verrucosa.

Climate change and ocean warming threaten the persistence of corals worldwide. Genomic resources are critical to study the evolutionary trajectory, adaptive potential, and genetic distinctiveness of coral species. Here, we provide a reference genome of the cauliflower coral Pocillopora verrucosa, a broadly prevalent reef-building coral with important ecological roles in the maintenance of reefs across the Red Sea, the Indian Ocean, and the Pacific Ocean. The genome has an assembly size of 380,505,698 bp with a scaffold N50 of 333,696 bp and a contig N50 of 75,704 bp. The annotation of the assembled genome returned 27,439 gene models of which 89.88% have evidence of transcription from RNA-Seq data and 97.87% show homology to known genes. A high proportion of the genome (41.22%) comprised repetitive elements in comparison to other cnidarian genomes, in particular in relation to the small genome size of P. verrucosa.

The Impact of Pregnancy on Outcomes After Bariatric Surgery.

BACKGROUND: Bariatric surgery is performed mostly on obese women of reproductive age. Many studies have analyzed pregnancy outcomes after bariatric surgery, but only a small number have studied the impact of pregnancy on the postoperative outcomes. PURPOSE: To study the effect of pregnancy on outcomes after bariatric surgery in women of childbearing age. METHODS: From January 2010 to October 2017, a retrospective study of a prospectively maintained database was conducted at the University Hospital of Geneva (HUG), where 287 women between the ages of 18 and 45 years had undergone Roux-en-Y gastric bypass (RYGB). A comparison of the results during a 5-year follow-up was performed between women who became pregnant after their bariatric surgery (pregnancy group, n = 40) and postoperative non-pregnant women (non-pregnancy group, n = 247). The two groups were compared for weight loss, complications, and nutritional deficiencies. RESULTS: The pregnancy group was significantly younger (29.2 ± 5.5 vs. 36.4± 6.3 years, p < 0.001) and heavier (124.0 ± 18.0 kg vs. 114.7 ± 17.1, p < 0.001) compared with the non-pregnancy group at the time of surgery. The percentage of excess BMI loss (%EBMI loss) was similar in both groups during the 5-year follow-up. Complications after RYGB and nutritional deficiencies were nearly identical in the two groups. The interval of time between bariatric surgery and first pregnancy was a median of 20.8 months. Out of 40 first pregnancies, 28 women completed pregnancy successfully with live birth. CONCLUSION: Pregnancy after bariatric surgery is safe and does not adversely affect outcomes after RYGB.

Correlation Between Sarcopenia and Growth Rate of the Future Liver Remnant After Portal Vein Embolization in Patients with Colorectal Liver Metastases.

PURPOSE: To investigate whether sarcopenia and myosteatosis correlate with the degree of hypertrophy (DH) and kinetic growth rate (KiGR) of the future liver remnant (FLR) in patients with colorectal liver metastases undergoing portal vein embolization (PVE) in preparation for right hepatectomy. MATERIALS AND METHODS: Forty-two patients were included. Total liver volume and FLR volume were measured before and 2-4 weeks after PVE. KiGR of the FLR was calculated. Sarcopenia was assessed using the total psoas muscle volume (PMV), the psoas muscle cross-sectional area (PMCS) and the total skeletal muscle index (L3SMI) at the level of 3rd lumbar vertebra. Degree of myosteatosis was assessed by mean muscle attenuation at L3 (L3MA). Correlations between muscle indices and DH and KiGR were assessed using simple linear regression analyses. RESULTS: Mean DH was 8.9 ± 5.7%, and mean KiGR was 3.6 ± 2.3. Mean PMV was 55.56 ± 14.19 cm3/m3, mean PMCS was 8.76 ± 2.3 cm2/m2, mean L3SMI was 45.6 ± 9.89 cm2/m2, and mean L3MA was 27.9 ± 18.6 HU. There was a strong positive correlation between PMV and DH (R = 0.503, p = 0.001) and PMV and KiGR (R = 0.545, p < 0.001). Furthermore, there was a moderate correlation between PMCS and KiGR (R = 0.389, p = 0.014). L3SMI and L3MA were neither associated with DH (p = 0.390 and p = 0.768, respectively) nor with KiGR (p = 0.188 and p = 0.929, respectively). CONCLUSION: We identified a positive correlation between PMV and PMCS, as markers for sarcopenia, and the KiGR of the FLR after PVE. PMV and PMCS might therefore aid to identify patients who are poor candidates for FLR augmentation using PVE alone.

Forensic age assessment of living adolescents and young adults at the Institute of Legal Medicine, Münster, from 2009 to 2018.

Due to high migration inflows to Europe, forensic age assessment of living persons has clearly gained importance. If there is a legal justification for X-ray examinations without a medical indication, the Study Group on Forensic Age Diagnostics (AGFAD) recommends the combination of a physical examination with anamnesis, an X-ray examination of the hand and a dental examination with evaluation of an orthopantomogram for age assessments of adolescents and young adults. If the development of the hand skeleton has been completed, an additional CT examination of the clavicles is to be performed. To demonstrate the outcome of forensic age assessments according to AGFAD recommendations with regard to migrants of doubtful minority declaration, this study analyzes the expert reports carried out at the Institute of Legal Medicine, Münster, from 2009 to 2018. A total of 597 age assessments were performed during the study period. A total of 227 age assessments were issued on behalf of youth welfare offices in the legal area of social law, 282 in family law proceedings, 76 in criminal proceedings, and 12 age assessments in immigration law proceedings. In 211 out of 597 cases, the stated age was compatible with the findings of the age assessment. In the remaining 386 cases, the average difference between the stated age and the minimum age was 1.9 years. The average difference between stated age and most probable age was 5.1 years. Of the 521 age assessments carried out outside criminal proceedings, 197 unaccompanied minors with questionable age minority (37.8%) have reached the age of majority beyond doubt. A total of 388 unaccompanied minors (74.5%) have most probably reached the age of majority. Forensic age assessments with the AGFAD methodology make an important contribution to legal certainty, the welfare of the child, and the fair distribution of resources.

High levels of floridoside at high salinity link osmoadaptation with bleaching susceptibility in the cnidarian-algal endosymbiosis.

Coral reefs are in global decline mainly due to increasing sea surface temperatures triggering coral bleaching. Recently, high salinity has been linked to increased thermotolerance and decreased bleaching in the sea anemone coral model Aiptasia. However, the underlying processes remain elusive. Using two Aiptasia host--endosymbiont pairings, we induced bleaching at different salinities and show reduced reactive oxygen species (ROS) release at high salinities, suggesting a role of osmoadaptation in increased thermotolerance. A subsequent screening of osmolytes revealed that this effect was only observed in algal endosymbionts that produce 2-O-glycerol-α-D-galactopyranoside (floridoside), an osmolyte capable of scavenging ROS. This result argues for a mechanistic link between osmoadaptation and thermotolerance, mediated by ROS-scavenging osmolytes (e.g., floridoside). This sheds new light on the putative mechanisms underlying the remarkable thermotolerance of corals from water bodies with high salinity such as the Red Sea or Persian/Arabian Gulf and holds implications for coral thermotolerance under climate change.This article has an associated First Person interview with the first author of the paper.

Short-Term Oral Sorafenib for Therapy of Intratumoral Shunts of Hepatocellular Carcinoma to Enable Intraarterial Treatment.

INTRODUCTION: Significant intratumoral shunts between tumor-supplying arteries and portal or liver veins are a contraindication for transarterial therapy of HCC because interventional treatment of these shunts is frequently insufficient. Sorafenib has anti-angiogenic effects and is indicated for palliative treatment of patients with HCC. Here, we report our experience with the use of sorafenib for the closure of intratumoral shunts in patients scheduled for transarterial therapy of HCC. MATERIALS AND METHODS: Three patients with HCC, aged 65, 82 and 79 years, exhibited a significant intratumoral shunting from tumor artery to portal (n = 1) or liver veins (n = 2). In all cases, intratumoral shunting had already been suspected based on pre-interventional CT angiography, and DSA confirmed the shunt. Oral sorafenib (800 mg/day) was administered for at least four weeks, only and specifically to occlude the shunt. Hereafter, patients were re-evaluated by CT and DSA. RESULTS: All patients tolerated the full prescribed dose for at least 4 weeks. In one case, therapy was prolonged with an adapted dose (400 mg/day) due to sorafenib-related hand-foot syndrome. After sorafenib treatment, CT and DSA confirmed a complete closure of intratumoral shunts for all patients. No tumor progression was observed. All three patients hereafter underwent successful transarterial treatment by TACE (n = 2) or TARE (n = 1) without complications. Progression-free survival according to mRECIST was 501, 397 and 599 days, respectively. CONCLUSION: Even short-term oral sorafenib seems to effectively close intratumoral shunts in patients with HCC and thus might enable transarterial treatment of these patients.