Somatic mutational profiling and clinical impact of driver genes in Latin-Iberian medulloblastomas: Towards precision medicine.

Medulloblastoma (MB) is the most prevalent malignant brain tumor in children, known for its heterogeneity and treatment-associated toxicity, and there is a critical need for new therapeutic targets. We analyzed the somatic mutation profile of 15 driver genes in 69 Latin-Iberian molecularly characterized medulloblastomas using the Illumina TruSight Tumor 15 panel. We classified the variants based on their clinical impact and oncogenicity. Among the patients, 66.7% were MBSHH, 13.0% MBWNT, 7.3% MBGrp3, and 13.0% MBGrp4. Among the 63 variants found, 54% were classified as Tier I/II and 31.7% as oncogenic/likely oncogenic. We observed 33.3% of cases harboring at least one mutation. TP53 (23.2%, 16/69) was the most mutated gene, followed by PIK3CA (5.8%, 4/69), KIT (4.3%, 3/69), PDGFRA (2.9%, 2/69), EGFR (1.4%, 1/69), ERBB2 (1.4%, 1/69), and NRAS (1.4%, 1/69). Approximately 41% of MBSHH tumors exhibited mutations, TP53 (32.6%) being the most frequently mutated gene. Tier I/II and oncogenic/likely oncogenic TP53 variants were associated with relapse, progression, and lower survival rates. Potentially actionable variants in the PIK3CA and KIT genes were identified. Latin-Iberian medulloblastomas, particularly the MBSHH, exhibit higher mutation frequencies than other populations. We corroborate the TP53 mutation status as an important prognostic factor, while PIK3CA and KIT are potential therapeutic targets.

Integrative toolbox to assess the quality of freshwater sediments contaminated with potentially toxic metals.

The Guadiana Basin is a transnational basin, presenting historical contamination with potentially toxic metals (PTM), which origin can be both natural and anthropogenic. This study explores the use of a set of observational, chemical and ecotoxicological assays with Heterocypris incongruens, Vibrio fischeri, Pseudokirchneriella subcapitata, Thamnocephalus platyurus, identifying the most sensitive to be included in a toolbox to analyze the quality of freshwater sediments related to this type of contamination. The study included the analysis of a reservoir and streams sediments of Guadiana basin, in two consecutive years with different climate conditions 2017 (dry year) and 2018 (normal year). The results showed high chemical variability along the basin, with greater contamination with PTM in the reservoir sediments. The calculated Enrichment Factors (EF) indicated high anthropogenic contamination by Cd, followed by Pb (EF > 1.5). The geoaccumulation index (Igeo) revealed that the sediments were severely polluted with Cd, and slightly polluted with Pb and Cu, inducing a higher sublethal toxicity to Heterocypris incongruens. Among the parameters evaluated, and after the use of multivariate statistical techniques, the toolbox for assessing sediments quality, in similar climate and geological conditions, should include the analysis of: meteorology, land use/cover in the area, granulometry, organic matter content, PTM concentrations, contamination indices (e.g., Igeo and EF), and sublethal bioassays with H. incongruens (total sediment analysis) and Vibrio fisheri luminescence inhibition (pore water analysis).

Single nCounter assay for prediction of MYCN amplification and molecular classification of medulloblastomas: a multicentric study.

PURPOSE: Medulloblastoma is the most frequent pediatric malignant brain tumor, and is divided into four main subgroups: WNT, SHH, group 3, and group 4. MYCN amplification is an important medulloblastoma prognostic biomarker. We aimed to molecular classify and predict MYCN amplification in a single assay. METHODS: It was included 209 medulloblastomas from 205 patients (Brazil, Argentina, and Portugal), divided into training (n = 50) and validation (n = 159) sets. A nCounter assay was carried out using a custom panel for molecular classification, with additional genes, including MYCN. nSolver 4.0 software and the R environment were used for profiling and MYCN mRNA analysis. MYCN amplification by FISH was performed in 64 cases. RESULTS: The 205 medulloblastomas were classified in SHH (44.9%), WNT (15.6%), group 3 (18.1%) and group 4 (21.4%). In the training set, MYCN amplification was detected in three SHH medulloblastomas by FISH, which showed significantly higher MYCN mRNA counts than non-FISH amplified cases, and a cutoff for MYCN amplification was established ([Formula: see text] + 4σ = 11,124.3). Applying this threshold value in the validation set, we identified MYCN mRNA counts above the cutoff in three cases, which were FISH validated. CONCLUSION: We successfully stratified medulloblastoma molecular subgroups and predicted MYCN amplification using a single nCounter assay without the requirement of additional biological tissue, costs, or bench time.

Clinical evidence for a biological effect of epigenetically active decitabine in relapsed or progressive rhabdoid tumors.

BACKGROUND: Refined therapy has helped to improve survival rates in rhabdoid tumors (RT). Prognosis for patients with chemoresistant, recurrent, or progressive RT remains dismal. Although decitabine, an epigenetically active agent, has mainly been evaluated in the management of hematologic malignancies in adults, safety in children has also been demonstrated repeatedly. MATERIALS AND METHODS: A retrospective series of patients who received decitabine upon relapse or progression following therapy according to the EU-RHAB regimen is presented. Due to the retrospective nature of analyses, response was defined as measurable regression of at least one lesion on imaging. 850k methylation profiling was done whenever tumor tissue was available. RESULTS: A total of 22 patients with RT of any anatomical localization were included. Most patients (19/22) presented with metastases. All received low-dose decitabine with or preceding conventional chemotherapy. Patients received a median of two (1-6) courses of decitabine; 27.3% (6/22) demonstrated a radiological response. Molecular analyses revealed increased methylation levels in tumors from responders. No excessive toxicity was observed. Clinical benefits for responders included eligibility for early phase trials or local therapy. Responders showed prolonged time to progression and overall survival. Due to small sample size, statistical correction for survivorship bias demonstrated no significant effect on survival for responders. CONCLUSIONS: Patients with RT demonstrate promising signs of antitumor activity after multiagent relapse therapy including decitabine. Analyses of methylation data suggest a specific effect on an epigenetic level. We propose to consider decitabine and other epigenetic drugs as candidates for further clinical investigations in RT.

Clinical Outcomes of 217 Patients with Acute Erythroleukemia According to Treatment Type and Line: A Retrospective Multinational Study.

Acute erythroleukemia (AEL) is a rare disease typically associated with a poor prognosis. The median survival ranges between 3-9 months from initial diagnosis. Hypomethylating agents (HMAs) have been shown to prolong survival in patients with myelodysplastic syndromes (MDS) and AML, but there is limited data of their efficacy in AEL. We collected data from 210 AEL patients treated at 28 international sites. Overall survival (OS) and PFS were estimated using the Kaplan-Meier method and the log-rank test was used for subgroup comparisons. Survival between treatment groups was compared using the Cox proportional hazards regression model. Eighty-eight patients were treated with HMAs, 44 front line, and 122 with intensive chemotherapy (ICT). ICT led to a higher overall response rate (complete or partial) compared to first-line HMA (72% vs. 46.2%, respectively; p ≤ 0.001), but similar progression-free survival (8.0 vs. 9.4 months; p = 0.342). Overall survival was similar for ICT vs. HMAs (10.5 vs. 13.7 months; p = 0.564), but patients with high-risk cytogenetics treated with HMA first-line lived longer (7.5 for ICT vs. 13.3 months; p = 0.039). Our results support the therapeutic value of HMA in AEL.

Food Fraud Conceptualization: An Exploratory Study with Portuguese Consumers.

Food fraud refers to deceptive practices conducted for economic gain, and incidents of such fraud are often reported in the media and scientific literature. However, little is known about how European consumers perceive food fraud. To address this gap, a study explored Portuguese consumers' knowledge and perceptions of food fraud using qualitative methods such as free word association and semi-structured interviews. For this research, 340 participants were recruited, providing 911 valid words, classified into categories, major categories, and dimensions. Differences between consumers' previous exposure to food fraud and sociodemographic characteristics were explored. Additionally, other thirty-six participants were selected and interviewed, following a semi-structured guide. Interviews were transcribed, coded, and analyzed using a thematic analysis procedure. The results suggest that Portuguese consumers view food fraud as a morally reprehensible deception and are aware of its causes and impacts. However, not all consumers know the different forms of food fraud or the types of products vulnerable to fraud. Among the most repeated words were "deception", "expiration date", and "falsification". Despite this food fraud awareness, most consumers believed they were not exposed to food fraud and stated that they do not conduct daily practices to reduce exposure to it. Following the chi-square and Mann-Whitney tests, significant differences (p ≤ 0.05) were identified between participants exposed and not exposed to food fraud. The study also found that consumers with higher education and self-reported exposure to food fraud had a better understanding of the issue. This study provides insights for quantitative research on consumer perceptions and beliefs about food fraud to explore further vulnerable food categories and types of food fraud in real-world scenarios.

Pesticide water variability and prioritization: The first steps towards improving water management strategies in irrigation hydro-agriculture areas.

The presence of pesticides in aquatic ecosystems poses significant risks to non-target organisms, necessitating monitoring and environmental risk assessment. This study aimed to evaluate the dynamics and environmental risk of pesticides in a hydro-agricultural area with intensive agricultural practices, in the Mediterranean region (South of Portugal). Seasonality and location influenced pesticide numbers and concentrations, with the highest levels observed during the dry season. Triazines, phenylureas, and organophosphates were the predominant pesticide classes, with terbuthylazine, bentazone, terbutryn, diazinon, and metolachlor exhibiting the highest detection frequencies (68 % to 72 %). Notably, 44 % of the quantified pesticides are no longer authorized in Portugal, with 33 % posing a high environmental risk. Some insecticides, including imidacloprid, methiocarb, and malathion, were occasionally detected at concentrations that posed high risks to the aquatic ecosystem (RQ ≥ 1). Irgarol, an algicide used in irrigation canals, presented a high risk in 91 % of the analysed samples. The study's distribution profile of pesticides revealed a significant transportation of these compounds from reservoirs to irrigation hydrants, establishing them as a secondary source of crop and environmental contamination. Additionally, the assessment of spatial distribution and environmental risk allowed for the identification of specific pollutants in different locations, prioritizing them based on their ecotoxicological risk to aquatic ecosystems. These findings reinforce the importance of implementing management measures at the level of hydro-agricultural areas, helping to stop the cycle of pesticide contamination. Only this type of strategy will make it possible to protect water quality, biodiversity and the health of citizens, contributing to the European Union's objectives of improving the condition of freshwater bodies and promoting the sustainable use of pesticides.

Quality of Life and Hormonal Impairment in Pediatric Patients With Craniopharyngiomas.

INTRODUCTION: Craniopharyngiomas (CP) are tumors in the sellar region that, despite a high survival rate, are associated with significant morbidity, including hypothalamic, hormonal, and visual dysfunction. This study aimed to assess the quality of life (QoL) in pediatric patients with CP and to evaluate its relationship with various factors, with a focus on the impact of endocrine dysfunction. METHODS: In this observational cross-sectional study, patients with CP aged between 0 and 18 years, currently followed up in a tertiary hospital by a multidisciplinary team, were included. QoL was assessed using the validated PEDS-QL4.0 questionnaire, which was administered to parents. This tool estimates Global QoL (QoL-G), further divided into Physical (QoL-P) and Psychosocial (QoL-PS) dimensions, including Emotional (QoL-Em), Social (QoL-S), and School (QoL-Sc) aspects. In Portugal, the estimated average QoL-G is 79.8, QoL-P is 83.5, and QoL-PS is 78.2. Variables studied included gender, current and diagnostic age, follow-up time, presence of hydrocephalus, hypothalamic involvement, type of resection (total or subtotal), radiotherapy, visual impairment, hormonal deficits, and therapy. RESULTS: The study included 11 patients with a median age of 15.2 years (interquartile ratio (IQR), 9.7-17.9 years) and a mean age at diagnosis of 9.3±4.1 years. Of these patients, 54.5% were male, and 36.4% were obese. Subtotal resection was performed in 72.7% of cases. Hydrocephalus was present in 54.5% of the patients, hypothalamic involvement in 63.7%, radiotherapy was received by 81.8%, and visual impairment was noted in 54.5%. All patients presented with at least one hormonal deficit. The average QoL-G was 69.9±22.5, with QoL-P at 66.9±30.0 and QoL-PS at 70.9±21.4. A worse QoL-S was associated with female gender (p=0.030) and subtotal resection (p=0.048). Worse QoL-G, QoL-P, QoL-Em, and QoL-PS were linked to hypothalamic involvement (p values 0.008, 0.025, 0.015, and 0.009, respectively). Irradiated patients had worse QoL-G (p=0.006). Treatment with sexual hormones enhanced QoL-Global (p=0.035) and QoL-Emotional (p=0.020), while treatment for adrenal insufficiency and diabetes insipidus improved QoL-Emotional (p=0.021 and p=0.013). No significant associations with visual deficit or obesity were found. CONCLUSIONS: Pediatric patients with CP appear to have poorer QoL-G, QoL-P, and QoL-PS compared to the healthy Portuguese population. However, the small sample size limits statistically significant associations with many of these variables. Predictors of worse QoL include female gender, hypothalamic involvement, subtotal resection, and radiotherapy. The results may be biased due to the small sample size, questionnaire administration to parents, and possible inadequacy of the questionnaire for the studied population. There is a need for a more suitable tool to enable a more precise assessment of QoL in these patients.

Community Empowerment Assessment and Community Nursing Diagnosis for Climate Change Mitigation and Adaptation in the Northern Region of the Portuguese Atlantic Coast: A Mixed-Methods Study Using MAIEC Framework.

The Community Intervention and Empowerment Assessment Model (MAIEC) offers a framework for community empowerment in several fields such as Climate Change (CC), the largest health emergency crisis globally, through diagnosis and interventions in Community Health Nursing. This study aims to assess the level of community empowerment in climate change mitigation and adaptation, and to identify nursing diagnosis through the MAIEC clinical decision matrix, within a local intermunicipal association in the northern region of the Portuguese Atlantic Coast. A convergent mixed-methods design was used, applying a focus group technique to a purposive sampling of ten key stakeholders of this community. A Portuguese version of the Empowerment Assessment Rating Scale and a questionnaire were both applied to the same participants, and qualitative and quantitative data generated were analysed using a content analysis technique and an Excel database sheet created using Microsoft Office 365. The analysis of the Portuguese northern community exposed: a low level of community empowerment for mitigation and adaptation to climate change; a nursing diagnosis of community management impairments in several dimensions, such as community process, community participation and community leadership. However, the study confirmed that MAIEC contributed to future community-based solutions, responding to the challenges of climate change, and enabling the planning of interventions to address MAIEC diagnoses in the form of CC-specific training and recommendations for new cooperation approaches from all stakeholders. This study was not registered.

Nursing Interventions to Reduce Health Risks from Climate Change Impact in Urban Areas: A Scoping Review Protocol.

Considering that the public health sector has been considered as a key stakeholder in climate action, it seems important to understand what interventions are carried out globally by trusted professionals such as nurses engaged in health promotion and environmental health in optimizing the health of individuals, families, and communities toward the dissemination of lifestyle decarbonization and guidance on healthier climate-related choices. The objective of this review was to understand the extent and type of evidence related to the community-based interventions of nurses that are being led or have been implemented thus far with the aim of reducing the health risks from climate change impact in urban areas. The present protocol follows the JBI methodological framework. Databases to be searched include PubMed, MEDLINE complete, CINAHL, Scopus, Embase, Web of Science, SciELO (Scientific Electronic Library Online), and BASE (Bielefeld Academic Search Engine). Hand searched references were also considered for inclusion. This review will include quantitative, qualitative, and mixed methods studies from 2008 onwards. Systematic reviews, text, opinion papers, and the gray literature in English and Portuguese were also considered. Mapping the nurse led interventions or those that have been implemented thus far in urban areas may lead to further reviews that may help identify the best practices and gaps within the field. The results are presented in tabular format alongside a narrative summary.

Callous and Unemotional Traits as Precursors to the Development of Female Psychopathy.

OBJECTIVE: Conduct a systematic review concerning the literature that reflects whether the callous and unemotional traits present in childhood and/or adolescence are precursors in the development of female psychopathy in adulthood. MATERIALS AND METHODS: A systematic review involved consulting three databases-EBSCO, the Web of Science, and PubMed-for peer-reviewed and quantitative studies within the period 2000-2023. Nine articles with quality of three and above were included. RESULTS: The presence of callous and unemotional traits designates a group of youth that show characteristics associated with psychopathy, specifically when predicting a more severe and chronic pattern of antisocial behaviour. Children with high rates of callous and unemotional traits, who show symptoms of attention deficit hyperactivity disorder in combination with severe conduct problems, are most likely to show features associated with psychopathy. The multidimensional psychopathy construct is considered a better predictor of future and stable antisocial behaviour than the callous and unemotional traits alone model. CONCLUSIONS: According to the studies selected, the callous and unemotional traits in childhood seem to be precursors of female psychopathy in adulthood, but only because of the way they seem to enhance conduct problems, disruptive behaviour disorders, and, as a possible outcome, delinquency and antisocial traits, which may be precursors of future psychopathy.

Fire-Pollutant-Atmosphere Components and Its Impact on Mortality in Portugal During Wildfire Seasons.

This study analyzed fire-pollutant-meteorological variables and their impact on cardio-respiratory mortality in Portugal during wildfire season. Data of burned area, particulate matter with a diameter of 10 or 2.5 µm (µm) or less (PM10, PM2.5), carbon monoxide (CO), nitrogen dioxide (NO2), ozone (O3), temperature, relative humidity, wind speed, aerosol optical depth and mortality rates of Circulatory System Disease (CSD), Respiratory System Disease (RSD), Pneumonia (PNEU), Chronic Obstructive Pulmonary Disease, and Asthma (ASMA), were used. Only the months of 2011-2020 wildfire season (June-July-August-September-October) with a burned area greater than 1,000 ha were considered. Principal component analysis was used on fire-pollutant-meteorological variables to create two indices called Pollutant-Burning Interaction (PBI) and Atmospheric-Pollutant Interaction (API). PBI was strongly correlated with the air pollutants and burned area while API was strongly correlated with temperature and relative humidity, and O3. Cluster analysis applied to PBI-API divided the data into two Clusters. Cluster 1 included colder and wetter months and higher NO2 concentration. Cluster 2 included warmer and dried months, and higher PM10, PM2.5, CO, and O3 concentrations. The clusters were subjected to Principal Component Linear Regression to better understand the relationship between mortality and PBI-API indices. Cluster 1 showed statistically significant (p-value < 0.05) correlation (r) between RSDxPBI (r RSD = 0.58) and PNEUxPBI (r PNEU = 0.67). Cluster 2 showed statistically significant correlations between RSDxPBI (r RSD = 0.48), PNEUxPBI (r PNEU = 0.47), COPDxPBI (r COPD = 0.45), CSDxAPI (r CSD = 0.70), RSDxAPI (r CSD = 0.71), PNEUxAPI (r PNEU = 0.49), and COPDxAPI (r PNEU = 0.62). Cluster 2 analysis indicates that the warmest, driest, and most polluted months of the wildfire season were associated with cardio-respiratory mortality.

High frequency of WNT-activated medulloblastomas with CTNNB1 wild type suggests a higher proportion of hereditary cases in a Latin-Iberian population.

Purpose: Medulloblastomas are the most common primary malignant brain tumors in children. They are divided into molecular subgroups: WNT-activated, SHH-Activated, TP53 mutant or wild type, and non-WNT/non-SHH (Groups 3 and 4). WNT-activated medulloblastomas are usually caused by mutations in the CTNNB1 gene (85%-90%), and most remaining cases of CTNNB1 wild type are thought to be caused by germline mutations in APC. So far, the frequencies of CTNNB1 have been reported mainly in North American and European populations. The aim of this study was to report the frequency of CTNNB1 mutations in WNT-activated medulloblastomas in a Latin-Iberian population and correlate with their clinicopathological characteristics. Methods: A total of 266 medulloblastomas from seven different institutions from Brazil (n=211), Portugal (n=38), and Argentina (n=17) were evaluated. Following RNA and DNA isolation from formalin-fixed, paraffin-embedded (FFPE) tumor tissues, the molecular classification and CTNNB1 mutation analysis were performed by nCounter and Sanger sequencing, respectively. Results: WNT-activated medulloblastomas accounted for 15% (40/266) of the series. We observed that 73% of WNT-activated medulloblastomas harbored CTNNB1 mutations. CTNNB1 wild-type cases (27%) were more prevalent in female individuals and suggested to be associated with a worse outcome. Among the CTNNB1 wild-type cases, the available analysis of family history revealed two cases with familiar adenomatous polyposis, harboring APC germline variants. Conclusion: We observed a lower incidence of CTNNB1 mutations in WNT-activated medulloblastomas in our Latin-Iberian cohort compared to frequencies previously described in other populations. Considering that CTNNB1 wild-type cases may exhibit APC germline mutations, our study suggests a higher incidence (~30%) of hereditary WNT-activated medulloblastomas in the Latin-Iberian population.

A Rare Case of Pleural Empyema Caused by Campylobacter rectus.

Campylobacter rectus is considered to be a primary periodontal pathogen that is rarely identified in extraoral specimens. We report a case of pleural empyema caused by Campylobacter rectus: the pathogen was isolated in the drained pleural fluid sample. Since the patient had previously undergone multiple antibiotic treatments, oral cultures were highly unlikely to be positive, although poor dental hygiene appears to be the leading risk factor for C. rectus systemic infections. The present case illustrates that C. rectus can be a cause of not only periodontal disease but also pulmonary infection.

Climate Change Prevention through Community Actions and Empowerment: A Scoping Review.

As society tries to tackle climate change around the globe, communities need to reduce its impact on human health. The purpose of this review is to identify key stakeholders involved in mitigating and adapting to climate change, as well as the type and characteristics of community empowerment actions implemented so far to address the problem. Published and unpublished studies from January 2005 to March 2022 in English and Portuguese were included in this review. The search, conducted on PubMed, CINAHL, Scopus, MEDLINE, Scopus, Web of Science, SciELO, and RCAAP (Repositório Científico de Acesso Aberto de Portugal), followed a three-step search strategy. Data extraction was performed by two independent reviewers, using an extraction tool specifically designed for the review questions. Twenty-seven studies were eligible for inclusion: six used interviews as a qualitative method, three were systematic reviews, three were case study analyses, three used surveys and questionnaires as quantitative methods, two used integrative baseline reviews, and three utilized a process model design. Six studies targeted local, public and private stakeholders. Community settings were the context target of fifteen studies, whereas twelve specifically referred to urban settings. Seven types of community actions were acknowledged across the globe, characterised as hybrid interventions and referring to the leading stakeholders: local governments, non-governmental organizations, civil society, universities, public health, and private sectors.

Differential Quercus spp. pollen-particulate matter interaction is dependent on geographical areas.

Particulate matter (PM) and pollen interaction, either airborne or at the respiratory mucosa needs further clarification, as allergic reaction intensification can be related to the PM physical characteristics and toxicity. This study aimed to investigate the physical-chemical properties of PM that can adhere to the pollen wall during its transport or inhalation, using Quercus spp. as a model, in three Portuguese cities with different geographical locations, meteorological influence and urbanization levels. Possible sources were evaluated through air masses trajectory analysis using the HYSPLIT model and correlation with meteorological factors. The sampling was performed using a 7-days Hirst-type volumetric sampler, and the pollen grains were observed using a Field Emission Electron Probe Microanalyser for PM analysis. A secondary electron image of each pollen grain was taken, to determine the adhered particles characteristics and energy dispersive x-ray spectroscopy (EDS) spectra were obtained for individual particles. A total of 484 pollen grains was observed, with 7683 particles counted and 1914 EDS spectra analyzed. The particle's equivalent diameter ranged from 0.3-16 µm, with most having a diameter < 3 µm. For the three cities, there were significant differences in the number of particles per pollen and the % area occupied by the particles. Particles adhered were mainly Si-rich, but variations in other dominant groups were observed. For Évora and Guarda, Ca-rich, SO-rich were second and third more representative, while Porto were Organic and Cl-rich. Metals&Oxides were found in all cities with the highest number in Porto. P-rich particles were only found in Évora. Sea salt particles were observed in Évora, coincide with air mass trajectories possible carrying them from the Mediterranean Sea. In conclusion, the PM physical characteristics are similar between the studied cities, however, the dominant chemical composition is different, certainly impacting the exposome influence and pollen-allergy intensification towards the same pollen type and concentration.

Adrenal carcinoma as the first manifestation of a Li­Fraumeni syndrome in three paediatric patients.

Not required for clinical vignette.

Infants and Newborns with Atypical Teratoid Rhabdoid Tumors (ATRT) and Extracranial Malignant Rhabdoid Tumors (eMRT) in the EU-RHAB Registry: A Unique and Challenging Population.

Introduction: Malignant rhabdoid tumors (MRT) predominantly affect infants and young children. Patients below six months of age represent a particularly therapeutically challenging group. Toxicity to developing organ sites limits intensity of treatment. Information on prognostic factors, genetics, toxicity of treatment and long-term outcomes is sparse. Methods: Clinical, genetic, and treatment data of 100 patients (aged below 6 months at diagnosis) from 13 European countries were analyzed (2005-2020). Tumors and matching blood samples were examined for SMARCB1 mutations using FISH, MLPA and Sanger sequencing. DNA methylation subgroups (ATRT-TYR, ATRT-SHH, and ATRT-MYC) were determined using 450 k / 850 k-profiling. Results: A total of 45 patients presented with ATRT, 29 with extracranial, extrarenal (eMRT) and 9 with renal rhabdoid tumors (RTK). Seventeen patients demonstrated synchronous tumors (SYN). Metastases (M+) were present in 27% (26/97) at diagnosis. A germline mutation (GLM) was detected in 55% (47/86). DNA methylation subgrouping was available in 50% (31 / 62) with ATRT or SYN; for eMRT, methylation-based subgrouping was not performed. The 5-year overall (OS) and event free survival (EFS) rates were 23.5 ± 4.6% and 19 ± 4.1%, respectively. Male sex (11 ± 5% vs. 35.8 ± 7.4%), M+ stage (6.1 ± 5.4% vs. 36.2 ± 7.4%), presence of SYN (7.1 ± 6.9% vs. 26.6 ± 5.3%) and GLM (7.7 ± 4.2% vs. 45.7 ± 8.6%) were significant prognostic factors for 5-year OS. Molecular subgrouping and survival analyses confirm a previously described survival advantage for ATRT-TYR. In an adjusted multivariate model, clinical factors that favorably influence the prognosis were female sex, localized stage, absence of a GLM and maintenance therapy. Conclusions: In this cohort of homogenously treated infants with MRT, significant predictors of outcome were sex, M-stage, GLM and maintenance therapy. We confirm the need to stratify which patient groups benefit from multimodal treatment, and which need novel therapeutic strategies. Biomarker-driven tailored trials may be a key option.

Major threats to European freshwater fish species.

In Europe, freshwater fish are the richest group amongst European vertebrates and the second most threatened animal group, surpassed only by freshwater molluscs. The identification of threats is a major benefit for conservation efforts, as it allows actions to be bespoke to specific threats imperilling fish communities in sensitive areas. In this work, we analyse all threats identified under the International Union for Conservation of Nature (IUCN) Red List of Threatened Species for all European native freshwater dependent fish and lamprey species and relate them with the species distribution, conservation status and migratory phenology. Results show that the current level of imperilment of European freshwater fish fauna is high, especially in the Iberian Peninsula fish communities where low richness is combined with a proportion of threatened species surpassing 50% in several catchments The most relevant threats affecting European freshwater fish are: "Dams & Water Management/Use", "Droughts", "Invasive Non-Native/Alien Species/Diseases", "Agricultural & Forestry Effluents" and "Fishing & Harvesting Aquatic Resources". The present work contributes to the ultimate goal of species conservation by highlighting the main threats affecting freshwater fish species in Europe and by demonstrating how specific regions need particular attention. Increasing longitudinal connectivity stands out as a measure with the potential to increase species' resilience to the several threats affecting them, and it should be coupled with additional efforts to reduce water pollution, control alien species and effectively manage fishing.