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Meteorological fronts are important due to their associated surface impacts, including extreme precipitation and extreme winds. Objective identification of fronts is therefore of interest in both operational weather prediction and research settings. The aim of this study is to produce a front identification algorithm based on earlier studies that is portable and scalable to different resolution datasets. We have made a number of changes to an earlier objective front identification algorithm, applied these to reanalysis datasets, and present the improvements associated with these changes. First, we show that a change in the order of operations yields smoother fronts with fewer breaks. Next, we propose the selection of the front identification thresholds in terms of climatological quantiles of the threshold fields. This allows for comparison between datasets of differing resolutions. Finally, we include a number of numerical improvements in the implementation of the algorithm and better handling of short fronts, which yield further benefits in the smoothness and number of breaks. This updated version of the algorithm has been made fully portable and scalable to different datasets in order to enable future climatological studies of fronts and their impacts. [ABSTRACT FROM AUTHOR]

Inhibitors of monoamine oxidases (MAOs) are of interest for the treatment of neurodegenerative disorders and other human pathologies. In this frame, the present work describes different synthetic strategies to obtain MAO inhibitors via the coupling of the aminocoumarin core with arylsulfonyl chlorides followed by copper azide-alkyne cycloaddition, leading to coumarin–sulfonamide–nitroindazolyl–triazole hybrids. The nitration position on the coumarin moiety was confirmed through nuclear magnetic resonance spectroscopy and molecular electron density theory in order to elucidate the molecular mechanism and selectivity of the electrophilic aromatic substitution reaction. The coumarin derivatives were evaluated for their inhibitory potency against monoamine oxidases and cholinesterases. Molecular docking calculations provided a rational binding mode of the best compounds in the series with MAO A and B. The work identified hybrids 14a–c as novel MAO inhibitors, with a selective action against isoform B, of potential interest to combat neurological diseases. [ABSTRACT FROM AUTHOR]

Background and Aim: People with inflammatory bowel disease (IBD) have an increased risk of cardiovascular disease, including in younger adulthood. This may arise in part from chronic, systemic low‐grade inflammation. The process of atherosclerosis may begin in childhood. We sought to determine whether pediatric IBD is associated with adverse changes in arterial structure and function as a marker of early increased cardiovascular risk. Methods: We performed a case–control study comparing children with IBD for a median disease duration of 2.49 (interquartile range 1.23, 4.38) years with healthy children. In a single visit, we collected baseline clinical and anthropometric data, and measured blood pressure, pulse wave velocity, carotid artery distensibility, and aortic and carotid intima‐media thickness. High‐sensitivity C‐reactive protein and fasting lipids were measured. Results: We enrolled 81 children with IBD (40 with Crohn's disease, 40 with ulcerative colitis, and 1 with unspecified IBD) and 82 control participants. After adjusting for age, sex, body mass index z‐score, blood pressure, and low‐density lipoprotein cholesterol, there was no difference in measures of arterial structure and function in children with IBD compared with controls, nor between those with Crohn's disease or ulcerative colitis. Conclusion: We did not show any differences in arterial structure and function in children with a history of IBD for less than 5 years compared with healthy controls. IBD diagnosed in childhood may provide a window of opportunity to actively reduce standard cardiovascular risk factors and improve future cardiovascular outcomes. [ABSTRACT FROM AUTHOR]

Biodegradable starch-based films are an environmentally friendly solution to reduce the use of petroleum-derived polymers. Thus, this work aims to obtain corn starch films by incorporating 5% w/w of cellulose nanocrystals (CNC), different concentrations of titanium dioxide nanoparticles (TiO2) (0, 0.25, 0.5, 1, and 2% w/w), and 40% w/w of glycerol and sorbitol (plasticizers), in a 1:1 ratio. The films showed a high potential for UV-light barrier, with an increase of 307% incorporating only 2 wt% of TiO2 in relation to the film without incorporation of TiO2. The use of TiO2 increased the white pigmentation capacity of the samples and decreased the lower water solubility – a reduction of approximately 28% using 0.5 wt% TiO2 compared to the CNC control sample was observed. The incorporation of TiO2 nanoparticles increased the tensile strength by adding 1 wt% of TiO2 nanoparticles with 34% increase in the tensile strength of the film without incorporation of TiO2. The thermal stability of the films with 1 wt% TiO2 and 5 wt% CNC increased by 85°C. Thus, the addition of CNC and TiO2 enabled an improvement in the physical/thermal/chemical properties of the films, making them possible alternatives for use in food packaging. [ABSTRACT FROM AUTHOR]

AimThe purpose of this study is to collect available evidence on the feasibility and efficacy of stereotactic arrhythmia radio ablation (STAR), including both photon radiotherapy (XRT) and particle beam therapy (PBT), in the treatment of atrial fibrillation (AF), and to provide cardiologists and radiation oncologists with a practical overview on this topic.MethodsThree hundred and thirty-five articles were identified up to November 2021 according to preferred reporting items for systematic reviews and meta-analyses criteria; preclinical and clinical studies were included without data restrictions or language limitations. Selected works were analyzed for comparing target selection, treatment plan details, and the accelerator employed, addressing workup modalities, acute and long-term side-effects, and efficacy, defined either by the presence of scar or by the absence of AF recurrence.ResultsTwenty-one works published between 2010 and 2021 were included. Seventeen studies concerned XRT, three PBT, and one involved both. Nine studies (1 in silico and 8 in vivo; doses ranging from 15 to 40 Gy) comprised a total of 59 animals, 12 (8 in silico, 4 in vivo; doses ranging from 16 to 50 Gy) focused on humans, with 9 patients undergoing STAR: average follow-up duration was 5 and 6 months, respectively. Data analysis supported efficacy of the treatment in the preclinical setting, whereas in the context of clinical studies the main favorable finding consisted in the detection of electrical scar in 4/4 patients undergoing specific evaluation; the minimum dose for efficacy was 25 Gy in both humans and animals. No acute complication was recorded; severe side-effects related to the long-term were observed only for very high STAR doses in 2 animals. Significant variability was evidenced among studies in the definition of target volume and doses, and in the management of respiratory and cardiac target motion.ConclusionSTAR is an innovative non-invasive procedure already applied for experimental treatment of ventricular arrhythmias. Particular attention must be paid to safety, rather than efficacy of STAR, given the benign nature of AF. Uncertainties persist, mainly regarding the definition of the treatment plan and the role of the target motion. In this setting, more information about the toxicity profile of this new approach is compulsory before applying STAR to AF in clinical practice.

BackgroundThe incidence of major surgery is on the rise globally, and more than 20% of patients are readmitted to hospital following discharge from hospital. During their hospital stay, patients are monitored for early detection of clinical deterioration, which includes regularly measuring physiological parameters such as blood pressure, heart rate, respiratory rate, temperature, and pulse oximetry. This monitoring ceases upon hospital discharge, as patients are deemed clinically stable. Monitoring after discharge is relevant to detect adverse events occurring in the home setting and can be made possible through the development of digital technologies and mobile networks. Smartwatches and other technological devices allow patients to self-measure physiological parameters in the home setting, and Bluetooth connectivity can facilitate the automatic collection and transfer of this data to a secure server with minimal input from the patient. ObjectiveThis paper presents the protocol for the DREAMPath (Domiciliary Recovery After Medicalization Pathway) study, which aims to measure compliance with a multidevice remote monitoring kit after discharge from hospital following major surgery. MethodsDREAMPath is a single-center, prospective, observational, cohort study, comprising 30 patients undergoing major intracavity surgery. The primary outcome is to assess patient compliance with wearable and interactive smart technology in the first 30 days following discharge from hospital after major surgery. Secondary outcomes will explore the relation between unplanned health care events and physiological data collected in the study, as well as to explore a similar relationship with daily patient-reported outcome measures (Quality of Recovery–15 score). Secondary outcomes will be analyzed using appropriate regression methods. Cardiopulmonary exercise testing data will also be collected to assess correlations with wearable device data. ResultsRecruitment was halted due to COVID-19 restrictions and will progress once research staff are back from redeployment. We expect that the study will be completed in the first quarter of 2022. ConclusionsDigital health solutions have been recently made possible due to technological advances, but urgency in rollout has been expedited due to COVID-19. The DREAMPath study will inform readers about the feasibility of remote monitoring for a patient group that is at an increased risk of acute deterioration. Trial RegistrationISRCTN Registry ISRCTN62293620; https://www.isrctn.com/ISRCTN62293620 International Registered Report Identifier (IRRID)DERR1-10.2196/30638

© 2015 European Association of Urology. Context Given the highly variable behavior and clinical course of prostate cancer (PCA) and the multiple available treatment options, a personalized approach to oncologic risk stratification is important. Novel genetic approaches offer additional information to improve clinical decision making. Objective To review the use of genomic biomarkers in the prognostication of PCA outcome and prediction of therapeutic response. Evidence acquisition Systematic literature review focused on human clinical studies reporting outcome measures with external validation. The literature search included all Medline, Embase, and Scopus articles from inception through July 2014. Evidence synthesis An improved understanding of the genetic basis of prostate carcinogenesis has produced an increasing number of potential prognostic and predictive tools, such as transmembrane protease, serine2:v-ets avian erythroblastosis virus E26 oncogene homolog (TMPRSS2:ERG) gene fusion status, loss of the phosphatase and tensin homolog (PTEN) gene, and gene expression signatures utilizing messenger RNA from tumor tissue. Several commercially available gene panels with external validation are now available, although most have yet to be widely used. The most studied commercially available gene panels, Prolaris, Oncotype DX Genomic Prostate Score, and Decipher, may be used to estimate disease outcome in addition to clinical parameters or clinical nomograms. ConfirmMDx is an epigenetic test used to predict the results of repeat prostate biopsy after an initial negative biopsy. Additional future strategies include using genetic information from circulating tumor cells in the peripheral blood to guide treatment decisions at the initial diagnosis and at subsequent decision points. Conclusions Major advances have been made in our understanding of PCA biology in recent years. Our field is currently exploring the early stages of a personalized approach to augment traditional clinical decision making using commercially available genomic tools. A more comprehensive appreciation of value, limitations, and cost is important. Patient summary We summarized current advances in genomic testing in prostate cancer with a special focus on the estimation of disease outcome. Several commercial tests are currently available, but further understanding is needed to appreciate the potential benefits and limitations of these novel tests.

ContextGiven the highly variable behavior and clinical course of prostate cancer (PCa) and the multiple available treatment options, a personalized approach to oncologic risk stratification is important. Novel genetic approaches offer additional information to improve clinical decision making.ObjectiveTo review the use of genomic biomarkers in the prognostication of PCa outcome and prediction of therapeutic response.Evidence acquisitionSystematic literature review focused on human clinical studies reporting outcome measures with external validation. The literature search included all Medline, Embase, and Scopus articles from inception through July 2014.Evidence synthesisAn improved understanding of the genetic basis of prostate carcinogenesis has produced an increasing number of potential prognostic and predictive tools, such as transmembrane protease, serine2:v-ets avian erythroblastosis virus E26 oncogene homolog (TMPRSS2:ERG) gene fusion status, loss of the phosphatase and tensin homolog (PTEN) gene, and gene expression signatures utilizing messenger RNA from tumor tissue. Several commercially available gene panels with external validation are now available, although most have yet to be widely used. The most studied commercially available gene panels, Prolaris, Oncotype DX Genomic Prostate Score, and Decipher, may be used to estimate disease outcome in addition to clinical parameters or clinical nomograms. ConfirmMDx is an epigenetic test used to predict the results of repeat prostate biopsy after an initial negative biopsy. Additional future strategies include using genetic information from circulating tumor cells in the peripheral blood to guide treatment decisions at the initial diagnosis and at subsequent decision points.ConclusionsMajor advances have been made in our understanding of PCa biology in recent years. Our field is currently exploring the early stages of a personalized approach to augment traditional clinical decision making using commercially available genomic tools. A more comprehensive appreciation of value, limitations, and cost is important.Patient summaryWe summarized current advances in genomic testing in prostate cancer with a special focus on the estimation of disease outcome. Several commercial tests are currently available, but further understanding is needed to appreciate the potential benefits and limitations of these novel tests.

In this work, 2-alkyl-10-chloro-1,2,3,4-tetrahydrobenzo[b][1,6]naphthyridines were obtained and their reactivity was studied. Novel derivatives of the tricyclic scaffold, including 1-phenylethynyl (5), 1-indol-3-yl (8), and azocino[4,5-b]quinoline (10) derivatives, were synthesized and characterized herein for the first time. Among the newly synthesized derivatives, 5c–h proved to be MAO B inhibitors with potency in the low micromolar range. In particular, the 1-(2-(4-fluorophenyl)ethynyl) analog 5g achieved an IC50 of 1.35 μM, a value close to that of the well-known MAO B inhibitor pargyline.

Fire in the tropical peatland forests of Borneo is an environmental issue interactioning with climate change and deforestation, and the consequences have local and global implications. While research has shown that fire severity and frequency are expected to increase with climate change, there is conflicting model and observational data as to the effect of deforestation on precipitation, which is a key metric for fire risk. To better understand the changes in fire risk from deforestation and climate change we ran simulations of the climate scenario RCP8.5 with and without total deforestation using regional climate model RegCM4. The output was then used for calculations of the fire weather index. We find that annual temperature change from deforestation at elevations above 500 m is 53% of the change over the 21st century in RCP8.5. Fire risk is significantly affected by both climate change and deforestation, despite some increases in precipitation from deforestation. While the multi model dry season (June–August) mean increases in fire risk are larger from elevated atmospheric carbon dioxide, the increases in maximum fire risk are larger from deforestation. The altitude is a good predictor of fire risk change, with larger increases at more densely populated lower elevations where the peatlands are concentrated and smaller increases at higher elevations. Therefore, while deforestation generally causes a smaller increase in climate-related fire risk than climate change, its local control and heterogeneous effects compared to global carbon emissions makes it critical for climate mitigation policy. These high-resolution simulations provide a guide to the most vulnerable areas of Borneo from climatic increases in fire risk.

Background Endomyocardial biopsy (EMB) is part of 2010 Task Force Criteria (TFC) for arrhythmogenic right ventricular cardiomyopathy (ARVC). However, its usage has been curtailed because of its low presumed diagnostic yield, and it is now a poorly used tool. This study aims to analyze the contribution of EMB to the final diagnosis of ARVC. Methods and Results We included 104 consecutive patients evaluated for a suspicion of ARVC, who were referred for EMB. Patients with suspected left dominant pattern were excluded from the primary analysis. Subjects were initially stratified according to TFC without considering EMB. After EMB, patients were reclassified accordingly, and the reclassification rate was calculated. EMB yielded a diagnostic finding in 92 patients (85.5%). After including EMB evaluation, 20 (43%) more patients “at risk” received a definite diagnosis of ARVC. Overall, 59 patients received a definite diagnosis of ARVC, 34% only after EMB. EMB appeared to be the better‐performing exam with respect to the final diagnosis (β, 2.2; area uder the curve, 0.73; P

Introdução: A Leucemia Aguda Indiferenciada não possui a expressão de nenhum marcador definidor de linhagem. Para categoriza-lá, é necessário realizar imunofenotipagem com um painel de anticorpos monoclonais abrangente para excluir leucemias de linhagens incomuns, como as derivadas de precursores de células dendríticas, de células NK, basófilos e tumores não hematopoiéticos. Essa entidade é rara, com incidência desconhecida. Os blastos não apresentam características de diferenciação mielóide, são negativos para as colorações mieloperoxidade e esterase. Geralmente expressam HLA-DR, CD34 e/ou CD38 e podem ser positivos para TdT. O CD7, embora frequentemente considerado um antígeno de células T, é expresso fracamente em alguns progenitores hematopoiéticos CD34+ e pode ser expresso de forma semelhante nessas leucemias. Relato de caso: Mulher, 25 anos, previamente hígida, encaminhada para Hematologia em julho de 2021 devido a anemia, plaquetopenia e leucocitose. Na admissão, apresentava abscesso amigdaliano, além de petéquias em membros e na região do tronco. A análise de sangue periférico e de medula óssea evidenciou presença de 97% de blastos de tamanho grande, com relação núcleo-citoplasmática intermediária, citoplasma basofílico e agranular, alguns apresentando vacúolos, núcleo com cromatina frouxa, contorno irregular, apresentando 1 a 3 nucléolos evidentes. Imunofenotipagem mostrou os seguintes marcadores: CD45dim, CD34-, CD117+, CD33-, HLA-DR+, CD38+, CD123+(fraco), CD14-, CD7+, CD11b-, CD56-, CD13-, CD19-, CD11c-, CD64-, CD15-, CD133-, CD41a-, CD61-, TdT+, cCD79a-, CD3-, cCD3-, MPO-. A citogenética convencional apresentou deleção do 13q. Realizado também RT-PCR para BCR-ABL1 qualitativo que resultou negativo. Solicitado também Biologia Molecular com pesquisa dos rearranjos RUNX1-RUX1T1, CBFBetaMYH11 e das mutações FLT3 e NPM1, ainda com resultados pendentes. O tratamento proposto foi esquema de indução de remissão com daunorrubicina 60 mg/m2/dia nos dias 1-3, e citarabina, 100 mg/m2 infusão intravenosa contínua de 24 horas nos dias 1-7. Programado reavaliação da medula óssea após recuperação hematológica da primeira indução de remissão. Discussão: Nos últimos anos ocorreram avanços no diagnóstico e estratificação de risco das Leucemias Agudas, o que nos permite reconhecer a situação descrita neste relato de caso. A paciente do caso apresenta um fenótipo indiferenciado associado a uma alteração citogenética que, no contexto de uma LMA, classificaria como relacionada a alterações mielodisplásicas. Porém, pacientes com fenótipo indiferenciado também podem apresentar alterações citogenéticas. O tratamento indicado é semelhante ao da LMA de alto risco, sendo indicado Transplante de Medula Óssea Alogênico. Conclusão: Os dados para avaliação de estratificação de risco e prognóstico nessa situação são limitados, sendo necessário mais estudos científicos.

TERRA (do inglês telomeric repeat-containing RNA) é um RNA longo não-codificante transcrito a partir das regiões subteloméricas e teloméricas. Os transcritos de TERRA possuem sequências repetidas em tandem ricas em Guanina oriundas das sequências teloméricas TTAGGG e formam híbridos de DNA:RNA nas regiões teloméricas denominados R-loops. A alta expressão de TERRA e a formação de R-loops promove dano ao DNA telomérico e, consequente, encurtamento telomérico. TERRA participa de um mecanismo de feedback que depende do ciclo celular e do comprimento telomérico. Em telômeros longos, os R-loops são degradados pelas enzimas RNaseH1 e RNaseH2 antes da replicação telomérica, o que permite o alongamento telomérico a partir da telomerase. Em tolemeros criticamente curtos, essas enzimas não são recrutadas, ocorre acúmulo de R-loops, estresse replicativo e ativação de vias de reparo dirigido por homologia. Essas vias promovem alongamento telomérico por via alternativas a telomerase. As leucemias mielóides agudas (LMAs) são caracterizadas pela expansão de células mielóides imaturas e insuficiência da medula óssea. Atualmente, as LMAs são classificadas em 6 grandes grupos: 1) LMAs com alterações citogenéticas recorrentes; 2) LMAs relacionadas a terapia; 3) LMAs relacionadas a alterações Mielodisplásicas; 4) LMAs sem outra especificação; 5) Sarcoma mielóide e 6) proliferação mielóide relacionada a Síndrome de Down. Como exposto anteriormente, o acúmulo de TERRA em telômeros curtos desencadeia, indiretamente, vias de reparo homólogo que podem promover alongamento telomérico independente de telomerase. Comprimento telomérico curto é uma característica de blastos na LMA. O objetivo do presente estudo foi determinar a contribuição de TERRA para a leucemogênese na LMA. Para isso, a dinâmica telomérica e a expressão de TERRA foram investigadas em células leucêmicas de medula óssea de pacientes ao diagnóstico e em linhagens de LMA. A RNaseH1 foi superexpressa em linhagens com alta expressão de TERRA e telômero curto para verificar se há aumento da taxa de apoptose. Oitenta e oito pacientes foram utilizados na análise final. A média de idade foi de 43 anos, sendo a relação M:F de 1:1. O diagnóstico de LMA foi categorizado conforme a atualização da OMS de 2016, sendo: Leucemia promielocítica aguda, 23/88 pacientes; LMA com t(8;21)(q22;q22.1), RUNX1-RUNX1T1, 9/88 pacientes; LMA com t(16;16)(p13.1;q22), CBFB-MYH11, 3/88 pacientes; LMA com NPM1 mutado, 11/98 pacientes, LMA com mutação bialélica do CEBPA, 2/88 pacientes; LMA sem outra especificações, 40/88 pacientes. A taxa de resposta completa após a primeira indução (IR) foi de 55,6%, de resposta parcial foi de 5,6%. Seis pacientes foram refratários a IR, 6,8% dos pacientes. Os dados de expressão de TERRA 10q, 15q, 20q, XqYq, XpYp, 17p, ATRX, RNaseH1, RNaseH2, TERT, TRF2 obtidos por RT-qPCR e comprimento telomérico realizados por PCR foram normalizados e utilizados para realizar a hierarquização por cluster através do cálculo por distância euclidiana. As leucemias foram classificadas em 4 clusters, denominados HCL1-4 (figura 1). O grupo 2 destaca-se pela alta expressão de TERRA e baixa expressão de ATRX, RNaseH1, RNaseH2, TERT, TRF2 e alta expressão TERRA 10q, 15, 20q e XqYq. O ensaio com MTT demonstrou que as linhagens nas linhagens NB4 (linhagem de leucemia promielocítica) e THP-1 (linhagem de leucemia mielóide aguda com diferenciação monocítica) que superexpressão RNaseH1 são mais susceptíveis a citarabina do que aquelas transfectadas com vetor vazio.

Introdução: A púrpura trombocitopênica idiopática (PTI) é uma doença autoimune adquirida caracterizada por destruição plaquetária acelerada em resposta a um estímulo desconhecido. A terapia com corticoides permanece como tratamento de primeira linha para PTI crônica e a esplenectomia é considerada opção de segunda linha para casos corticorrefratários. Caso clínico: M.A.S.R., 42 anos, feminino, com diagnóstico de PTI desde outubro de 2019 e não respondedora a terapia inicial com cursos de corticoide (dexametasona e prednisona conforme Consenso Internacional para diagnóstico e manejo de PTI). Devido a contagem plaquetária persistentemente inferior a 20.000/uL associada a sangramentos significativos com necessidade de atendimento médico frequente (epistaxe e sangramentos transvaginal), foram realizadas tentativas de tratamento com imunoglobulina humana, azatioprina, ciclofosfamida, eltrombopag, rituximabe e vincristina. No entanto, a paciente não apresentou resposta e manteve quadro hemorrágico. Dada a falta de resposta aos tratamentos instituídos, foi realizada reavaliação diagnóstica com pesquisa de causas secundárias de trombocitopenia imune e de causas não imunes (infecções virais, plaquetopatias hereditárias, colagenoses, neoplasias, síndrome mielodisplásica), com investigação negativa, reforçando hipótese diagnóstica inicial. Devido a persistência do quadro de sangramentos, optado por internação hospitalar para realização de esplenectomia. A paciente, no entanto, mantinha contagem plaquetária inferior a 10.000/uL, motivo pelo qual foi tentado novo curso de imunoglobulina antes do procedimento cirúrgico, sem reposta (melhor contagem plaquetária 35.000/uL com duração de 24 horas), inviabilizando realização segura de esplenectomia. Foi então optado pela realização de embolização de artéria esplênica como terapia ponte para esplenectomia. A embolização foi realizada sem intercorrências, com incremento rápido e progressivo da contagem plaquetária (superior a 100.000/uL após 4 dias do procedimento), possibilitando a realização de esplenectomia laparoscópica. Após esplenectomia, a paciente evoluiu com normalização da contagem plaquetária, tendo então recebido alta hospitalar para seguimento ambulatorial. Discussão: A eficácia em longo prazo das diferentes terapias de segunda linha para PTI não foi comparada diretamente, portanto, as decisões de tratamento ainda são feitas sem suporte de evidência científica de qualidade. A esplenectomia remove o sítio primário de eliminação de plaquetas e produção de autoanticorpos. Apesar da variedade de opções terapêuticas farmacológicas, ela continua sendo o único tratamento com potencial de cura para a PTI, com taxas de remissão sustentada em torno de 60% a 70%. A embolização esplênica é um procedimento pouco invasivo desenvolvido para tratamento de hiperesplenismo e é uma alternativa a esplenectomia para paciente com PTI corticorrefratária e com maior risco cirúrgico. Suas taxas de remissão a longo prazo, entretanto, são desconhecidas, motivo pelo qual optamos por realizar a esplenectomia neste caso. Conclusão: Em casos de PTI severa não respondedora a múltiplas terapias farmacológicas, a embolização esplênica pode ser uma opção de terapia ponte para realização de esplenectomia.

Extratropical cyclones and their associated extreme precipitation and winds can have a severe impact on society and the co-occurrence between the two extremes is important when assessing risk. In this study the extremal dependency measure, χ, is used to quantify the co-occurrence of extreme precipitation and wind gusts, and is investigated at individual grid points and spatially over Europe. Results using three observational datasets and a higher spatial and temporal resolution version of ERA5 than previously used confirm previous studies. Over Europe high co-occurrence is found over western coasts and low co-occurrence is found over eastern coasts. All datasets have qualitatively similar spatial patterns over most regions of Europe excluding some regions of high topography where ERA5 χ values are much larger. ERA5 represents the timings of daily extreme co-occurring events well, compared to observations. The differences in precipitation accumulation timescales are also accounted for by considering hourly, 6, 24 and 48 hourly co-occurrence. In a few regions co-occurrence changes with longer accumulations, indicating the different speeds and sizes of weather systems affecting these regions. χ in most regions has little increase by allowing a 24 h lag and lead between the precipitation and wind, with a few exceptions where χ is increased by up to 24%. Regions with the larger of these increases are on or around elevated topography. Using an objective feature tracking method, insight into the spatial pattern of extreme precipitation and wind within cyclones over Europe is given. As well as suggesting how many hours apart the extremes occur from one another in a particular location. Extreme co-occurring events are associated with cyclones far more of the time than non extreme events. Given an extreme co-occurring event the chance of a cyclone being within 1110 km is more than 70% for much of Europe. Regions with low co-occurrence have extremes caused by different weather systems and regions with large co-occurrence have both extremes caused by the same weather system. Cyclones linked to extreme events, particularly co-occurring and extreme wind, have larger intensity than those not and for most of Europe these cyclones also have faster mean speed.

Abstract Arrhythmogenic cardiomyopathy (ACM) is hallmarked by ventricular fibro‐adipogenic alterations, contributing to cardiac dysfunctions and arrhythmias. Although genetically determined (e.g., PKP2 mutations), ACM phenotypes are highly variable. More data on phenotype modulators, clinical prognosticators, and etiological therapies are awaited. We hypothesized that oxidized low‐density lipoprotein (oxLDL)‐dependent activation of PPARγ, a recognized effector of ACM adipogenesis, contributes to disease pathogenesis. ACM patients showing high plasma concentration of oxLDL display severe clinical phenotypes in terms of fat infiltration, ventricular dysfunction, and major arrhythmic event risk. In ACM patient‐derived cardiac cells, we demonstrated that oxLDLs are major cofactors of adipogenesis. Mechanistically, the increased lipid accumulation is mediated by oxLDL cell internalization through CD36, ultimately resulting in PPARγ upregulation. By boosting oxLDL in a Pkp2 heterozygous knock‐out mice through high‐fat diet feeding, we confirmed in vivo the oxidized lipid dependency of cardiac adipogenesis and right ventricle systolic impairment, which are counteracted by atorvastatin treatment. The modulatory role of oxidized lipids on ACM adipogenesis, demonstrated at cellular, mouse, and patient levels, represents a novel risk stratification tool and a target for ACM pharmacological strategies.