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Human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CM) constitute a mixed population of ventricular-, atrial-, nodal-like cells, limiting the reliability for studying chamber-specific disease mechanisms. Previous studies characterised CM phenotype based on action potential (AP) morphology, but the classification criteria were still undefined. Our aim was to use in silico models to develop an automated approach for discriminating the electrophysiological differences between hiPSC-CM. We propose the dynamic clamp (DC) technique with the injection of a specific IK1 current as a tool for deriving nine electrical biomarkers and blindly classifying differentiated CM. An unsupervised learning algorithm was applied to discriminate CM phenotypes and principal component analysis was used to visualise cell clustering. Pharmacological validation was performed by specific ion channel blocker and receptor agonist. The proposed approach improves the translational relevance of the hiPSC-CM model for studying mechanisms underlying inherited or acquired atrial arrhythmias in human CM, and for screening anti-arrhythmic agents.

DNA methylation is associated with gene silencing, but its clinical role in cardiovascular diseases (CVDs) remains to be elucidated. We hypothesized that extracellular vesicles (EVs) may carry epigenetic changes, showing themselves as a potentially valuable non-invasive diagnostic liquid biopsy. We isolated and characterized circulating EVs of acute coronary syndrome (ACS) patients and assessed their role on DNA methylation in epigenetic modifications.EVs were recovered from plasma of 19 ACS patients and 50 healthy subjects (HS). Flow cytometry, qRT-PCR, and Western blot (WB) were performed to evaluate both intra-vesicular and intra-cellular signals. ShinyGO, PANTHER, and STRING tools were used to perform GO and PPI network analyses.ACS-derived EVs showed increased levels of DNA methyltransferases (DNMTs) (p0.001) and Ten-eleven translocation (TET) genes reduction. Specifically, de novo methylation transcripts, as DNMT3A and DNMT3B, were significantly increased in plasma ACS-EVs. DNA methylation analysis on PBMCs from healthy donors treated with HS- and ACS-derived EVs showed an important role of DNMTs carried by EVs. PPI network analysis evidenced that ACS-EVs induced changes in PBMC methylome. In the most enriched subnetwork, the hub gene SRC was connected to NOTCH1, FOXO3, CDC42, IKBKG, RXRA, DGKG, BAIAP2 genes that were showed to have many molecular effects on various cell types into onset of several CVDs. Modulation in gene expression after ACS-EVs treatment was confirmed for SRC, NOTCH1, FOXO3, RXRA, DGKG and BAIAP2 (p0.05).Our data showed an important role for ACS-derived EVs in gene expression modulation through de novo DNA methylation signals, and modulating signalling pathways in target cells.

New spectroscopic experiments and state‐of‐the‐art quantum‐chemical computations of creatinine in different aggregation states unequivocally unveiled a significant tuning of tautomeric equilibrium by the environment: from the exclusive presence of the amine tautomer in the solid state and aqueous solution to a mixture of amine and imine tautomers in the gas phase. Quantum‐chemical calculations predict the amine species as the most stable tautomer by about 30 kJ mol−1 in condensed phases. On the contrary, moving to the isolated forms, both Z and E imine isomers become more stable by about 7 kJ mol−1. Since the imine isomers and one amine tautomer are separated by significant energy barriers, all of them should be present in the gas phase. This prediction has indeed been confirmed by high‐resolution rotational spectroscopy, which provides the first experimental characterization of the elusive imine tautomer. The interpretation of the complicated hyperfine structure of the rotational spectrum, originated by three 14N nuclei, makes it possible to use the spectral signatures as a sort of fingerprint for each individual tautomer in the complex sample., A journey among the aggregation states of a key biomolecule, creatinine, is reported, guided by state‐of‐the‐art quantum‐chemical computations and spectroscopic techniques. The fine tuning of the creatinine tautomeric equilibrium by different environments is unveiled and fully understood by vis‐à‐vis comparison between simulated and experimental signatures.

O artigo apresenta um estudo de caso exploratório sobre a resposta de cortes constitucionais latinoamericanas à COVID-19 em cenários políticos adversos com foco nas experiências de Brasil e México. A partir da análise da jurisprudência e de entrevistas com ativistas de Direitos Humanos e pesquisadores de think tanks latinoamericanos, busca-se refletir sobre as escolhas estratégicas que tais órgãos enfrentam sobre posicionar-se ou não em cenários de crise, frente a trade-offs como o apoio da opinião pública, desafios de implementação decisória e a manutenção de unidade e coerência de posicionamento dentro do próprio Judiciário. Conclui-se que, mesmo quando presentes desafios persistentes de implementação, tais decisões representam importante estímulo e reforçam pressões institucionais para a reação política em momentos de crise. Todavia, para as cortes, não são tão evidentes os benefícios relacionados ao fortalecimento da legitimidade social e de seus papéis institucionais.

Coronavirus disease has spread worldwide since 2019, causing important pandemic issues and various social health problems to date. Little is known about the origin of this virus and the effects it has on extra-pulmonary organs. The different mechanisms of the virus and the influence it has on humans are still being studied, with hopes of finding a cure for the disease and the pathologies associated with the infection. Liver damage caused by coronavirus disease 2019 (COVID-19) is sometimes underestimated and has been of important clinical interest in the past few years. Hepatic dysfunctions can manifest in different forms which can sometimes be mild and without specific signs and symptoms or be severe with important clinical implications. There are several studies that have tried to explain the mechanism of entry (hepatotropism) of the virus into hepatocytes and the effects the virus has on this important organ. What clearly emerges from the current literature is that hepatic injury represents an important clinical aspect in the management of patients infected with COVID-19, especially in frail patients and those with comorbidities. The aim of our brief overview is to summarize the current literature regarding the forms of hepatic damage, complications, mechanisms of pathology, clinical features of liver injury, influence of comorbidities and clinical management in patients with COVID-19 infection.

BRAF inhibitors have been shown in clinical trials to improve patient outcomes in non-small cell lung cancer (NSCLC) patients harbouring selected BRAF driver mutations with a limited side effect profile, and therefore show potential as therapeutics in clinical practice. To utilise BRAF inhibitors effectively, understanding the prevalence of BRAF mutations within the local patient population is crucial, especially since NSCLC driver mutation rates have been observed to vary in different populations around the world. We interrogated a clinical archive of next generation sequencing (NGS) data representative of 7 years of routine UK practice in the National Health Service (NHS) to investigate the frequency of BRAF mutations, the breakdown of mutation classes and co-occurrence of other oncogenic driver mutations. Tissue biopsies from NSCLC cases referred to the Sarah Cannon Molecular Diagnostics Laboratory between January 2015 and February 2022 from multiple centres across UK were included in this study. Somatic mutation hotspots in relevant cancer-associated genes were analysed using amplicon/ion-torrent based NGS assays, and all NSCLC samples which harboured recognised BRAF driver mutations were identified through a combination of automated and manual data retrieval. Data regarding any other detected mutations and basic demographic information were also collected. Over the 7-year period, 5384 NSCLC samples were sequenced, with BRAF mutation identified in 185 (3.44%) of cases. These 185 cases represented a total of 73 Class I BRAF mutations (39.5%), 61 Class II mutations (33.0%) and 51 Class III mutations (27.6%). Of the 73 identified Class I mutations, 69 (69/185, 37.3%) were V600E and four (4/185, 2.16%) were non-V600E mutations. Five V600E cases had co-mutations (5/185, 2.7%). Various other known driver mutations were also identified in these 185 tumour samples, with KRAS (18/185, 9.73%) and PIK3CA (7/185, 3.78%) occurring at the highest frequency. This is the first large cohort-level study in the UK to profile the breakdown of BRAF-positive NSCLC biopsy samples using NGS in routine clinical practice. This study defines the proportion of NSCLC patients that may be expected to benefit from BRAF inhibitors and highlights the utility of using NGS as a diagnostic tool to improve targeted therapy stratification for NSCLC patients.

Albeit described since 1763, cardiac contusions is still an under-recognised clinical condition in the acute care setting. This evidence-based review aims to provide an overview of the topic by focusing on etiopathogenesis, classification and clinical presentation of patients with cardiac contusions, as well as on the diagnostic work-up and therapy options available for this subset population in the acute care setting.A targeted research strategy was performed using PubMed, MEDLINE, Embase and Cochrane Central databases up to June 2022. The literature search was conducted using the following keywords (in Title and/or Abstract): ("cardiac" OR "heart" OR "myocardial") AND ("contusion"). All available high-quality resources written in English and containing information on epidemiology, etiopathogenesis, clinical findings, diagnosis and management of cardiac contusions were included in our research.Biochemical samples of cardiac troponins together with a 12‑lead ECG appear to be sufficient screening tools in hemodynamically stable subjects, while cardiac ultrasound provides a further diagnostic clue for patients with hemodynamic instability or those more likely to have a significant cardiac contusion.The management of patients with suspected cardiac contusion remains a challenge in clinical practice. For this kind of patients a comprehensive diagnostic approach and a prompt emergency response are required, taking into consideration the degree of severity and clinical impairment of associated traumatic injuries.

Background Primary antiphospholipid syndrome (PAPS) is characterized by the presence of antiphospholipid antibodies (aPL), repetitive fetal loss, and arterial/venous thrombosis and no association with other autoimmune rheumatic disease. Ocular involvement can also occur including retinal vascular thrombosis and neuro-ophthalmological manifestations, such as optic neuropathy and amaurosis fugax. Early detection of ocular changes is crucial to minimize functional loss. Purpose To perform a multimodal evaluation, including the use of Optical Coherence Angiotomography (OCTA), in patients with PAPS without ocular complaints and compare with healthy individuals. Methods We performed a complete structural and functional ophthalmological evaluation using OCTA and microperimetry exam in patients with PAPS, followed at a tertiary Rheumatology outpatient clinic. Results We included 104 eyes of 52 subjects [PAPS without ocular complaints (N = 26) and healthy individuals (N = 26)]. Among PAPS patients, 21 were female (80.8%) and 21 (80.8%) were Caucasians. PAPS manifestations were venous (65.4%), arterial thrombosis (34.6%), and obstetrical (34.6%) and all of them had lupus anticoagulant. Ophthalmologic findings were more frequent in PAPS compared to healthy individuals (19.2% vs. 0%, p = 0.05). The most common retinal change was paracentral acute middle maculopathy (PAMM) (3 patients, 5 eyes), followed by drusen (1 patient, 2 eyes) and pachychoroid pigment epitheliopathy (PPE) (1 patient, 1 eye). Hypertension and hyperlipidemia were present in 100% of the PAPS patients with PAMM, while only six patients (26.1%) with PAPS without PAMM presented these two risk factors together ( p = 0.03). Conclusions We provide novel evidence that approximately 20% of our asymptomatic PAPS patients without ocular symptoms have ophthalmologic findings that require early identification and careful surveillance focusing on minimizing systemic and vascular risk factors.

Treatment for severe acute kidney injury (AKI) typically involves the use of acute kidney replacement therapy (AKRT) to prevent or reverse complications.We aimed to determine the prevalence of successful discontinuation of AKRT and its predictive factors. A retrospective cohort study was performed with 316 patients hospitalized at a public Brazilian university hospital between January 2011 and June 2020.Success and hospital discharge were achieved for most patients (85% and 74%, respectively). Multivariable logistic regression analysis showed that C-reactive protein (CRP), urine output, and need mechanical ventilation at the time of interruption were variable associated with discontinuation success (OR 0.969, CI 0.918-0.998, p = 0.031; OR 1.008, CI 1.001-1.012, p = 0.041 and OR 0.919, CI 0.901-0.991, p = 0.030; respectively), while the absence of comorbidities such as chronic kidney disease (OR 0.234, CI 0.08-0.683, p = 0.008), cardiovascular disease (OR 0.353, CI 0.134-0.929, p = 0.035) and hypertension (OR 0.278, CI 0.003-0.882, p = 0.009), as well as pH values at the time of AKRT indication (OR 1.273, CI 1.003-1.882, p = 0.041), mechanical ventilation at the time of interruption (OR 0.19, CI 0.19-0.954, p = 0.038) and successful discontinuation (OR 8.657, CI 3.135-23.906, p 0.001) were identified as variables associated with hospital discharge.These results show that clinical conditions such as comorbidities, urine output, and mechanical ventilation, and laboratory variables such as pH and CRP are factors associated with hospital discharge and AKRT discontinuation success, requiring larger studies for confirmation.

Through an aesthetic and a historical-philological lens, this essay analyses the complex relationship between Wassily Kandinsky’s work and its critical interpretations by Carl Einstein and Clement Greenberg in the first half of the 20th century. Within two different and paradigmatic modernisms — the European and the North American one, the German-speaking and the English-speaking one —, both authors read Kandinsky’s abstraction both as a negative (in its deviation from modernist orthodoxy) and positive (a chance to project through Kandisky’s work an unprecedented image of modernism, as well as their critical vision) form of art., CoSMo | Comparative Studies in Modernism, N. 22 (2023): 1922/2022: Total Modernism - Vol. 1

To assess the number of life-bearing worlds in astrophysical environments, it is necessary to take the intertwined processes of abiogenesis (birth), extinction (death), and transfer of life (migration) into account. We construct a mathematical model that incorporates this trio of mechanisms and accordingly derive the probability distribution function and other statistical properties (e.g., mean) for the number of worlds with biospheres. We show that a given astrophysical setting may become eventually saturated with life if the rate of successful transfers of organisms is higher than the extinction rate of biospheres. Based on the available data, we suggest that this criterion might be fulfilled for star-forming clusters (and perhaps the Galactic bulge under optimal circumstances), thereby indicating that such regions could constitute promising abodes for hosting and detecting life., 8 pages, 3 figures. Published on 28 October 2021 in MNRAS

Photosynthesis is a plausible pathway for the sustenance of a substantial biosphere on an exoplanet. In fact, it is also anticipated to create distinctive biosignatures detectable by next-generation telescopes. In this work, we explore the excitation features of photopigments that harvest electromagnetic radiation by constructing a simple quantum-mechanical model. Our analysis suggests that the primary Earth-based photopigments for photosynthesis may not function efficiently at wavelengths $> 1.1$ $\mu$m. In the context of (hypothetical) extrasolar photopigments, we calculate the potential number of conjugated $\pi$-electrons ($N_\star$) in the relevant molecules, which can participate in the absorption of photons. By hypothesizing that the absorption maxima of photopigments are close to the peak spectral photon flux of the host star, we utilize the model to estimate $N_\star$. As per our formalism, $N_\star$ is modulated by the stellar temperature, and is conceivably higher (lower) for planets orbiting stars cooler (hotter) than the sun; exoplanets around late-type M-dwarfs might require an $N_\star$ twice that of the Earth. We conclude the analysis with a brief exposition of how our model could be empirically tested by future observations., Comment: 9 pages, 2 figures. Published 2021 November 11 in ApJ Letters

BACKGROUND: Catheter-related bloodstream infections (CRBSI) represent a frequent complication of vascular catheterization, with high morbidity, mortality, and associated costs. Most infections are caused by Gram-positive bacteria; thus dalbavancin, a new long-acting lipoglicopeptide, may have a role in early patient discharge strategies optimizing treatment and reducing overall costs. METHODS: In this small pilot feasibility study, we assessed the efficacy and safety of a “single step” treatment strategy combining dalbavancin administration (1500 mg IV single dose), catheter removal, and early discharge in adult patients admitted to medical wards in a three-year period. RESULTS: We enrolled sixteen patients with confirmed Gram-positive CRBSI, with a mean age of 68 years and relevant comorbidities (median Charlson Comorbidity index=7). The most frequent causative agents were staphylococci, with 25% of methicillin-resistant strains, and the majority of infected devices were short term central venous catheter (CVC) and peripherally inserted central catheter (PICC). Ten out of sixteen patients had been treated empirically before dalbavancin administration. The mean time from dalbavancin administration to discharge was 2 days; none of the patients had adverse drug-related reactions; at 30- and 90-day follow-up, no patients have been readmitted to the hospital due to bacteraemia recurrence. CONCLUSIONS: Our results indicate that single-dose dalbavancin is highly effective, well-tolerated, and cost-saving for Gram-positive CRBSI.

Stress represents a main risk factor for psychiatric disorders. Whereas it is known that even a single trauma may induce psychiatric disorders in humans, the mechanisms of vulnerability to acute stressors have been little investigated. In this study, we generated a new animal model of resilience/vulnerability to acute footshock (FS) stress in rats and analyzed early functional, molecular, and morphological determinants of stress vulnerability at tripartite glutamate synapses in the prefrontal cortex (PFC). We found that adult male rats subjected to FS can be deemed resilient (FS-R) or vulnerable (FS-V), based on their anhedonic phenotype 24 h after stress exposure, and that these two populations are phenotypically distinguishable up to two weeks afterwards. Basal presynaptic glutamate release was increased in the PFC of FS-V rats, while depolarization-evoked glutamate release and synapsin I phosphorylation at Ser9 were increased in both FS-R and FS-V. In FS-R and FS-V rats the synaptic expression of GluN2A and apical dendritic length of prelimbic PFC layers II–III pyramidal neurons were decreased, while BDNF expression was selectively reduced in FS-V. Depolarization-evoked (carrier-mediated) glutamate release from astroglia perisynaptic processes (gliosomes) was selectively increased in the PFC of FS-V rats, while GLT1 and xCt levels were higher and GS expression reduced in purified PFC gliosomes from FS-R. Overall, we show for the first time that the application of the sucrose intake test to rats exposed to acute FS led to the generation of a novel animal model of resilience/vulnerability to acute stress, which we used to identify early determinants of maladaptive response related to behavioral vulnerability to stress.

PRAME (PReferentially expressed Antigen in MElanoma), a cancer-testis antigen expressed in normal and neoplastic tissues with several functions, proved to be a useful diagnostic tool in the differential diagnosis between benign and malignant melanocytic lesions. The current study aims to perform PRAME stain on a retrospective case series of mucosal melanocytic tumors of the head and neck region to compare 3 different scores and evaluate the most reliable one in this diagnostic set. Immunohistochemical analysis for PRAME was performed in 54 benign and malignant mucosal melanocytic tumors of the head and neck region collected from 41 patients. The best-performing cutoff of PRAME-positive cells (nuclear stain) to differentiate benign and malignant mucosal melanocytic tumors of the head and neck region is that proposed by Raghavan and colleagues (

Both progression from the early pathogenic events to clinically manifest cardiovascular diseases (CVD) and cancer impact the integrity of the vascular system. Pathological vascular modifications are affected by interplay between endothelial cells and their microenvironment. Soluble factors, extracellular matrix molecules and extracellular vesicles (EVs) are emerging determinants of this network that trigger specific signals in target cells. EVs have gained attention as package of molecules with epigenetic reversible activity causing functional vascular changes, but their mechanisms are not well understood. Valuable insights have been provided by recent clinical studies, including the investigation of EVs as potential biomarkers of these diseases. In this paper, we review the role and the mechanism of exosomal epigenetic molecules during the vascular remodeling in coronary heart disease as well as in cancer-associated neoangiogenesis.

Background: Management of infections due to carbapenemase-resistant Enterobacterales (CRE) in solid organ transplant (SOT) recipients remains a difficult challenge. The INCREMENT-SOT-CPE score has been specifically developed from SOT recipients to stratify mortality risk, but an external validation is lacking.Methods: Multicenter retrospective cohort study of liver transplant (LT) recipients colonized with CRE infection who developed infection after transplant over 7-year period. Primary endpoint was all-cause 30-day mortality from infection onset. A comparison between INCREMENT-SOT-CPE and other selected scores was performed. A two-level mixed effects logistic regression model with random effects for the center was fitted. Performance characteristics at optimal cut-point were calculated. Multivariable Cox regression analysis of risk factors for all-cause 30-day mortality was carried out.Results: Overall, 250 CRE carriers developed infection after LT and were analyzed. The median age was 55 years (interquartile range [IQR]: 46-62) and 157 were males (62.8%). All-cause 30-day mortality was 35.6%. A sequential organ failure assessment (SOFA) score >= 11 showed a sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of 69.7%, 76.4%, 62.0%, 82.0%, and 74.0%, respectively. An INCREMENT-SOT-CPE >= 11 reported a sensitivity, specificity, PPV, NPV, and accuracy of 73.0%, 62.1%, 51.6%, 80.6% and 66.0%, respectively. At multivariable analysis acute renal failure, prolonged mechanical ventilation, INCREMENT-SOT-CPE score >= 11 and SOFA score >= 11 were independently associated with all-cause 30-day mortality, while a tigecycline-based targeted regimen was found to be protective.Conclusions: Both INCREMENT-SOT-CPE >= 11 and SOFA >= 11 were identified as strong predictors of all-cause 30-day mortality in a large cohort of CRE carriers developing infection after LT.

Brangus is a composite cattle breed developed with the objective of combining the advantages of Angus and Zebuine breeds (Brahman, mainly) in tropical climates. The aim of this work was to estimate breed composition both genome-wide and locally, at the chromosome level, and to uncover genomic regions evidencing positive selection in the Argentinean Brangus population/nucleus. To do so, we analysed marker data from 478 animals, including Brangus, Angus and Brahman. Average breed composition was 35.0% ± 9.6% of Brahman, lower than expected according to the theoretical fractions deduced by the usual cross-breeding practice in this breed. Local ancestry analysis evidenced that breed composition varies between chromosomes, ranging from 19.6% for BTA26 to 56.1% for BTA5. Using approaches based on allelic frequencies and linkage disequilibrium, genomic regions with putative selection signatures were identified in several chromosomes (BTA1, BTA5, BTA6 and BTA14). These regions harbour genes involved in horn development, growth, lipid metabolism, reproduction and immune response. We argue that the overlapping of a chromosome segment originated in one of the parental breeds and over-represented in the sample with the location of a signature of selection constitutes evidence of a selection process that has occurred in the breed since its take off in the 1950s. In this regard, our results could contribute to the understanding of the genetic mechanisms involved in cross-bred cattle adaptation and productivity in tropical environments.

Purpose: The purpose of this systematic review is to identify and evaluate systemic racism interventions in academic medicine. Methods: Studies were identified through the use of the PubMed database, using the keywords ‘systemic racism’ and ‘academic medicine’. Of the 18 publications generated, 6 highlighted systemic racism interventions. Results: Ultimately, 6 studies were selected in this review including multiple interventions: virtual training modules, a department wide cultural competency curriculum, a hospital-wide breastfeeding initiative, and a fellowship program for underrepresented minorities interested in surgery. Conclusion: The findings of this systematic review indicate a dearth of systemic racism interventions. While the data is limited, there is some evidence that department/hospital-wide commitments, virtual curricula, and programming/mentorship directed at underrepresented minorities (URM) in medicine may be effective tools in combating systemic racism.

Background and ObjectivesThere have been numerous reports of neurologic manifestations identified in hospitalized patients infected with SARS-CoV-2, the virus that causes COVID-19. Here, we identify the spectrum of associated neurologic symptoms and diagnoses, define the time course of their development, and examine readmission rates and mortality risk posthospitalization in a multiethnic urban cohort.MethodsWe identify the occurrence of new neurologic diagnoses among patients with laboratory-confirmed SARS-CoV-2 infection in New York City. A retrospective cohort study was performed on 532 cases (hospitalized patients with new neurologic diagnoses within 6 weeks of positive SARS-CoV-2 laboratory results between March 1, 2020, and August 31, 2020). We compare demographic and clinical features of the 532 cases with 532 controls (hospitalized COVID-19 patients without neurologic diagnoses) in a case-control study with one-to-one matching and examine hospital-related data and outcomes of death and readmission up to 6 months after acute hospitalization in a secondary case-only analysis.ResultsAmong the 532 cases, the most common new neurologic diagnoses included encephalopathy (478, 89.8%), stroke (66, 12.4%), and seizures (38, 7.1%). In the case-control study, cases were more likely than controls to be male (58.6% vs 52.8%, p = 0.05), had baseline neurologic comorbidities (36.3% vs 13.0%, p < 0.0001), and were to be treated in an intensive care unit (62.0% vs 9.6%, p < 0.0001). Of the 394 (74.1%) cases who survived acute hospitalization, more than half (220 of 394, 55.8%) were readmitted within 6 months, with a mortality rate of 23.2% during readmission.DiscussionHospitalized patients with SARS-CoV-2 and new neurologic diagnoses have significant morbidity and mortality postdischarge. Further research is needed to define the effect of neurologic diagnoses during acute hospitalization on longitudinal post-COVID-19–related symptoms including neurocognitive impairment.

Here we present an open access GIS project associated to a structural database which includes the geo-structural measurements (over 6000) collected in the field during the past Italian PNRA (National Antarctic Research Program) scientific expeditions from the year 1988 to 2021. The targeted research area is the North Victoria Land (NVL), Antarctica, between the 70°-76° S latitude and the 159°-171° E longitude.NVL is an area difficult to be accessed for direct geological studies on rocks due to the extensive ice/snow coverage (~5%) and few published studies with complete structural datasets are available so far.Our database is organized in various fields which include: number/code of the expedition, date, code of the site of field structural measurement, geographical coordinates of the field measurement site, elevation, toponyms, lithological classification, geological unit, description of any collected sample, name of the field data collector, classification, attitude of measured structural element (strike/trend, dip/plunge, dip/plunge direction), local magnetic declination at the date of the field survey. Fault attributes include fault type (normal, reverse, strike-slip), rake of the slickenlines and sense of motion. Attributes of the extensional fractures/joints also include their dimension (height, H) and spacing (S).Moreover, the GIS project includes basic georeferenced maps such as: i) geological maps of NVL available in literature at 1:250.000 and 1:500.000 scale; ii) DEM of the bedrock and of the ice surface (from Bedmap 2); iii) the Radarsat mosaic of Antarctica; and iv) the MODIS mosaic of Antarctica.This queryable database allows to perform multiple geostatistical analyses and realise geothematic maps such as: i) the spatial variability of the main azimuthal structural trends at the regional scale; ii) the intensity of brittle deformation quantified by the H/S parameter (see contribution of Cianfarra et al. in this meeting); and iii) thematic geostructural maps (e.g: maps of the foliation traces, of strain partitioning or fractures distribution).These analyses, pivotal to better understand the tectonic framework of complex regions such as the NVL and to provide constraints supporting any geodynamic modelling, will greatly benefit from the extreme pliability and interoperability of such a database, which can be easily modified and expanded according to different scientific research needs by the production of newly derived data.

Computational simulators of complex physical processes, such as inundations, require a robust characterization of the uncertainties involved to be useful for flood hazard and risk analysis. While flood extent data, as obtained from synthetic aperture radar (SAR) imagery, has become widely available, no methodologies have been implemented that can robustly assimilate this information source into fully probabilistic estimations of the model parameters, model structural deficiencies, and model predictions. This paper proposes a fully Bayesian framework to calibrate a 2D physics-based inundation model using a single observation of flood extent, explicitly including uncertainty in the floodplain and channel roughness parameters, simulator structural deficiencies, and observation errors. The proposed approach is compared to the current state-of-practice Generalized Likelihood Uncertainty Estimation (GLUE) framework for calibration and with a simpler Bayesian model. We found that discrepancies between the computational simulator output and the flood extent observation are spatially correlated, and calibration models that do not account for this, such as GLUE, might consistently mispredict flooding over large regions. The added structural deficiency term succeeds in capturing and correcting for this spatial behavior, improving the rate of correctly predicted pixels. We also found that binary data does not have information relative to the magnitude of the observed process (e.g. flood depths), raising issues in the identifiability of the roughness parameters, and the additive terms of structural deficiency and observation errors. The proposed methodology, while computationally challenging, is proven to perform better than existing techniques. It also has the potential to consistently combine observed flood extent data with other data such as sensor information and crowd-sourced data, something which is not currently possible using GLUE calibration framework.

Therapy and prognosis of several solid and hematologic malignancies, including non-small cell lung cancer (NSCLC), have been favourably impacted by the introduction of immune checkpoint inhibitors (ICIs). Their mechanism of action relies on the principle that some cancers can evade immune surveillance by expressing surface inhibitor molecules, known as “immune checkpoints”. ICIs aim to conceal tumoural checkpoints on the cell surface and reinvigorate the ability of the host immune system to recognize tumour cells, triggering an antitumoural immune response. In this review, we will focus on the imaging patterns of different responses occurring in patients treated by ICIs. We will also discuss imaging findings of immune-related adverse events (irAEs), along with current and future perspectives of metabolic imaging. Finally, we will explore the role of radiomics in the setting of ICI-treated patients.

Accumulating evidence suggests that maternal overnutrition can result in a higher development risk of obesity and renal disease in the offspring’s adulthood. The present study tested different lipid levels in the maternal diet during pregnancy and lactation and its repercussions on the offspring of Wistar rats. Offspring of 1, 7, 30 and 90-d-old were divided into the following groups: Control (CNT) – offspring of dams that consumed a standard chow diet (3.5% of lipids); Experimental 1 (EXP1) – offspring of dams exposed to a high-fat diet (HFD) (28% of lipids); and Experimental 2 (EXP2) – offspring of dams exposed to a HFD (40% of lipids). Regarding maternal data, there was a decrease in the amount of diet ingested by EXP2. Daily caloric intake was higher in EXP1, while protein and carbohydrate intakes were lower in EXP2. While lipid intake was higher in the experimental groups, EXP1 consumed more lipids than EXP2, despite the body weight gain being higher in EXP2. Adult offspring from EXP1 presented higher blood glucose. Regarding morphometric analysis, in both experimental groups, there was an increase in the glomerular tuft and renal corpuscle areas, but an increase in the capsular space area only in EXP1. There was a decrease in the glomerular filtration rate (GFR) in EXP1, in contrast to an increase in GFR of EXP2, along with an increase in urinary protein excretion. In conclusion, the maternal HFDs caused significant kidney damage in offspring, but had different repercussions on the type and magnitude of recorded change.

Objectives To describe the frequency and investigate potential associations of unemployment, need of financial assistance and health-related quality of life in adult patients with childhood-onset Systemic Lupus Erythematosus (cSLE). Methods In this multicenter cross-sectional retrospective cohort study including cSLE adult patients, questionnaires were applied evaluating demographic characteristics, medical history, treatment, receipt of government financial assistance, work status, quality of life, economic classification, disease activity, and damage accrual. Disease activity and disease damage were measured at the study visit. Results Sixty-nine cSLE patients with a median age of 21 years from two Brazilian tertiary centers were included (median disease duration 9 years). Twenty-eight (40.6%) patients were unemployed and 16 (23.2%) were receiving financial assistance or retirement pension. Work unemployment was associated with higher damage scores (OR 1.83, 95% CI 1.08 to 3.09, p = 0.024), and the need of financial assistance was associated with longer disease duration (OR 1.15, 95% CI 1.00 to 1.31, p = 0.045) and worse economic score (OR 0.87, 95% CI 0.77 to 0.99, p = 0.038). Emotional health and body image perception were the most compromised domains of quality of life but showed no association with disease parameters. Disease activity, on the other hand, was inversely associated with symptoms scores (β = −1.377, p = 0.014) and scores of adverse effects of medications (β = −1.286, p = 0.020). Conclusion cSLE is a disease with severe outcomes and high social burden that profoundly impacts patients. Damage accrual is a major contributor to unemployment during adulthood and its prevention must be central in the management of cSLE.

The new generation of vaccines for Chagas disease, are focused to induce both humoral and cellular response to effectively control Trypanosoma cruzi parasites. The administration of vaccine formulations intranasally has the advantage over parenteral routes that can induce a specific response at mucosal and systemic levels. This study aimed to evaluate and compare the immunogenicity and prophylactic effectiveness of two Trans-sialidase (TS)-based mucosal vaccines against T. cruzi administered intranasally. Vaccines consisted of a recombinant fragment of TS expressed in Lactococcus lactis formulated in two different adjuvants. The first, was an immunostimulant particle (ISPA, an ISCOMATRIX-like adjuvant), while the second was the dinucleotide c-di-AMP, which have shown immunostimulant properties at the mucosal level. BALB/c mice were immunized intranasally (3 doses, one every two weeks) with each formulation (TS + ISPA or TS + c-di-AMP) and with TS alone or vehicle (saline solution) as controls. Fifteen days after the last immunization, both TS + ISPA or TS + c-di-AMP induced an evident systemic humoral and cellular response, as judged by the increased plasma anti-TS IgG2a titers and IgG2a/IgG1 ratio and enhanced cellular response against TS. Plasma derived antibodies from TS + c-di-AMP also inhibit in vitro the invasion capacity of T. cruzi. Furthermore, specific secretory IgA was more enhanced in TS + c-di-AMP group. Protective efficacy was proved in vaccinated animals by an oral T. cruzi-challenge. Parasitemia control was only achieved by animals vaccinated with TS + c-di-AMP, despite all vaccinates groups showed enhanced CD8

ObjectiveTo determine the immunogenicity of the third dose of CoronaVac vaccine in a large population of patients with autoimmune rheumatic diseases (ARD) and the factors associated with impaired response.MethodsAdult patients with ARD and age-balanced/sex-balanced controls (control group, CG) previously vaccinated with two doses of CoronaVac received the third dose at D210 (6 months after the second dose). The presence of anti-SARS-CoV-2 S1/S2 IgG and neutralising antibodies (NAb) was evaluated previously to vaccination (D210) and 30 days later (D240). Patients with controlled disease suspended mycophenolate mofetil (MMF) for 7 days or methotrexate (MTX) for 2 weekly doses after vaccination.ResultsARD (n=597) and CG (n=199) had comparable age (p=0.943). Anti-S1/S2 IgG seropositivity rates significantly increased from D210 (60%) to D240 (93%) (pConclusionsWe provide novel data on a robust response to the third dose of CoronaVac in patients with ARD, even in those with prevaccination COVID-19 seronegative status. Drugs implicated in reducing immunogenicity after the regular two-dose regimen were associated with non-responsiveness after the third dose, except for MTX.Trial registration numberNCT04754698.

Introduction The standard of care for thrombotic antiphospholipid syndrome (APS) is anticoagulation with vitamin K antagonists (VKAs). Prothrombin time, and its corresponding international normalized ratio (INR), is the laboratory test routinely performed to assess anticoagulation. Self-management of VKA therapy using point-of-care (POC) devices seems to be an attractive option. Purpose/objective To evaluate the accuracy of a POC device (CoaguChek XS) in APS patients by comparing it with venous laboratory INR. Furthermore, we analyzed whether other clinical and laboratory features could interfere with the CoaguChek XS results. Patients and methods This is a single-center cross-sectional study with 94 APS patients from a tertiary rheumatology clinic performed from August 2014 to March 2015. The comparison between CoaguChek XS and venous laboratory INR results was evaluated using the coefficient of determination (r) followed by the Bland–Altman test. A paired t-test was also applied. A difference of up to ±0.5 INR unit between the two systems was considered clinically acceptable. Results The mean CoaguChek-INR was 2.94 ± 1.41 and venous laboratory INR was 2.43±0.86, with a correlation coefficient (r) of 0.95. Categorizing INR values in ranges (INR 4), we found that the INR >4 group presented a lower correlation (r = 0.64) compared to the other ranges ( p < 0.05). Although both methods were highly correlated, CoaguChek XS showed higher values than the venous laboratory INR, with an increased average of 0.42 ± 0.54. Therefore, we proposed a simple linear regression model to predict the venous laboratory INR values, using results obtained from CoaguChek XS. A difference ≤0.5 INR unit between the two systems was observed in 57.4% of patients, and the aPL profile did not influence the results. Conclusion Although CoaguChek XS and venous laboratory INR demonstrated a good linear correlation in the group of INR ≤4, extra caution should be taken in APS patients, since a reasonable proportion of patients can present differences in INR results that are not acceptable. We do not recommend routine POC in APS patients.

Despite major advances in pharmacologic treatment, patients with pulmonary arterial hypertension (PAH) still have a considerably reduced life expectancy. In this context, chronic hyperactivity of the neurohormonal axis has been shown to be detrimental in PAH, thus providing novel insights on the role of neurohormonal blockade as a potential therapeutic target.To evaluate the application and prognostic effect of neurohormonal inhibitors (NEUi) in a single-center sample of patients with idiopathic PAH and risk factors for left heart disease.We analyzed data retrospectively collected from our register of right heart catheterizations performed consecutively from January 1, 2005 to October 31, 2018. Patients on beta-blocker, angiotensin-converting enzyme inhibitor, angiotensin receptor blocker or mineralocorticoid receptor antagonist at the time of right heart catheterization were classified as NEUi users and compared to NEUi non-recipients.Complete data were available for 57 PAH subjects: 27 of those (47.4%) were taking at least one NEUi at the time of right heart catheterization and were compared with the remaining 36 NEUi non-recipients. NEUi users were older and had a higher cardiovascular risk profile compared to non-recipients. Additionally, NEUi non-users had a higher probability of dying during the course of follow-up than NEUi recipients (56.7%The above data highlighted a subgroup of patients with PAH and comorbidities for left heart disease in which NEUi use has shown to be associated with improved survival. Future prospective studies are needed to identify the most appropriate therapeutic strategies in this subset population.

Background Identification of COPD patients with a rapid decline in FEV1 is of particular interest for prognostic and therapeutic reasons. Objective To determine the expression of markers of inflammation in COPD patients with rapid functional decline in comparison to slow or no decliners. Methods In COPD patients monitored for at least 3 years (mean ± SD: 5.8 ± 3 years) for lung functional decline, the expression and localization of inflammatory markers was measured in bronchial biopsies of patients with no lung functional decline (FEV1% + 30 ± 43 ml/year, n = 21), slow (FEV1% ml/year, − 40 ± 19, n = 14) and rapid decline (FEV1% ml/year, − 112 ± 53, n = 15) using immunohistochemistry. ELISA test was used for polymeric immunoglobulin receptor (pIgR) quantitation “in vitro”. Results The expression of secretory IgA was significantly reduced in bronchial epithelium (p = 0.011) and plasma cell numbers was significantly reduced in the bronchial lamina propria (p = 0.017) of rapid decliners compared to no decliners. Bronchial inflammatory cell infiltration, CD4, CD8, CD68, CD20, NK, neutrophils, eosinophils, mast cells, pIgR, was not changed in epithelium and lamina propria of rapid decliners compared to other groups. Plasma cells/mm2 correlated positively with scored total IgA in lamina propria of all patients. “In vitro” stimulation of 16HBE cells with LPS (10 μg/ml) and IL-8 (10 ng/ml) induced a significant increase while H2O2 (100 μM) significantly decreased pIgR epithelial expression. Conclusion These data show an impaired humoral immune response in rapid decliners with COPD, marked by reduced epithelial secretory IgA and plasma cell numbers in the bronchial lamina propria. These findings may help in the prognostic stratification and treatment of COPD.

The purposes of this study were to describe the endoscopic-assisted orbital exenteration surgical techniques, to report preliminary outcomes and to discuss advantages, indications and limitations of this approach. All patients who underwent endoscopic-assisted orbital exenteration at a single tertiary-care center were retrospectively reviewed. A concomitant reconstruction was performed in all cases. The extent of surgical resection was tailored to the size and location of tumor and was classified into four subtypes. A total of 40 patients were included in this series. Orbital exenteration type 1 was performed in 7 cases, type 2 in 11 cases, type 3 in 19 cases, and type 4 in 3 cases. The reconstruction was performed with a pedicled temporal flap in 5 patients and with a free vascularized flap in 34 cases. A radical resection of disease was obtained in 32 cases. After a mean follow-up of 36 months, 14 patients died of disease, one patient died of other causes, 7 are alive with disease, and 18 patients are currently alive without evidence of disease. The preliminary data emerging from this case-series support the feasibility and safety of endoscopic-assisted orbital exenteration.

In dense indoor wireless networks, handoffs occur frequently. The criteria to trigger handoffs are not defined by the IEEE 802.11 standard, thus being specific to each manufacturer’s implementation. Current handoff implementations typically use RSSI (Received Signal Strength Indicator) as a performance metric and commonly cause association instability in dense environments, a well-known problem referred to as the ping-pong effect. In this paper, we present a deep analysis of RSSI traces collected in dense indoor environments using the FIBRE testbed. Based on that, we conclude that the RSSI time series presents deep fast fades that occur frequently in bursts of small sizes, which can cause ping-pongs. Motivated by this behavior, we propose a new and simple filtering mechanism called Maximum which targets to eliminate these valleys in the RSSI time series. In a nutshell, this filter chooses the maximum RSSI value from a sliding window containing the last few RSSI samples of the series. We conduct simulations based on real RSSI traces from static and mobile scenarios to evaluate Maximum with respect to other filtering mechanisms found in the literature. Additionally, we present a simplified model of the behavior of Maximum that allows us to study the probability of unwanted handoffs as a function of the RSSI of the available access points. Our analysis reveals that Maximum is able to offer a better tradeoff between handoff triggering delay and stability in mobile scenarios, while also performing well in static scenarios, effectively avoiding the occurrence of ping-pongs in most cases.

The ‘Balbi model’ is a simplified rate of fire spread model aimed at providing computationally fast and accurate simulations of fire propagation that can be used by fire managers under operational conditions. This model describes the steady-state spread rate of surface fires by accounting for both radiation and convection heat transfer processes. In the present work the original Balbi model developed for laboratory conditions is improved by addressing specificities of outdoor fires, such as fuel complexes with a mix of live and dead materials, a larger scale and an open environment. The model is calibrated against a small training dataset (n = 25) of shrubland fires conducted in Turkey. A sensitivity analysis of model output is presented and its predictive capacity against a larger independent dataset of experimental fires in shrubland fuels from different regions of the world (Europe, Australia, New Zealand and South Africa) is tested. A comparison with older versions of the model and a generic empirical model is also conducted with encouraging results. The improved model remains physics-based, faster than real time and fully predictive.