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Objective: This study aimed to describe the histomorphologic characteristics of resected (unroofed) common wall tissue from repair of anomalous aortic origin of a coronary artery and to determine whether the histologic features correlate with clinical and imaging findings. Methods: The histology of resected tissue was analyzed and reviewed for the presence of fibrointimal hyperplasia, smooth muscle disarray, mucoid extracellular matrix accumulation, mural fibrosis, and elastic fiber disorganization and fragmentation using hematoxylin and eosin and special stains. Clinical, computed tomography imaging, and surgical data were correlated with the histopathologic findings. Results: Twenty specimens from 20 patients (age range, 7-18 years; 14 males) were analyzed. Anomalous aortic origin of a coronary artery involved the right coronary in 16 (80%), and a slit-like ostium was noted in 18 (90%). By computed tomography imaging, the median proximal coronary artery eccentricity index was 0.4 (range, 0.20-0.90). The median length of intramural course was 8.2 mm (range, 2.6-15.2 mm). The anomalous vessel was determined to be interarterial in 14 patients (93%, 15 had evaluable images). The median distance from a commissure was 2.5 mm above the sinotubular junction (STJ) (range: 2 mm below the STJ–14 mm above the STJ). Prominent histopathologic findings included elastic fiber alterations, mural fibrosis, and smooth muscle disarray. The shared wall of the aorta and intramural coronary artery is more similar to the aorta histologically. Mural fibrosis and elastic fiber abnormalities tended to be more severe in patients >10 years of age at the time of surgery, but this did not reach statistical significance. The extent of vascular changes did not appear to have a clear relationship with the imaging features. Conclusions: The findings confirm the aortic wall–like quality of the intramural segment of the coronary artery and the presence of pathologic alterations in the wall microstructure.

Parkinson's disease (PD) is a chronic and progressive neurodegenerative disorder with a higher susceptibility to occur in men. Studies suggest that this susceptibility is related to the hormonal differences observed between men and women, being a risk factor for PD. In addition, testosterone supplementation has shown controversial results in animal models of PD and parkinsonian patients. This study evaluated the effect of chronic administration of testosterone propionate (TP) on motor behavior and neurochemical parameters in the reserpine-induced rat model of parkinsonism. Male Wistar rats received 15 injections of reserpine (RES – 0.1 mg/kg) every other day and were concomitantly treated with different doses (0.1, 1.0, or 5.0 mg/kg) of daily TP for 30 days. The rats were euthanized 48 h after the 15th injection of RES or vehicle. Brains were removed and subjected to Tyrosine hydroxylase (TH) immunohistochemistry. TP at 1.0 mg/kg reduced the damages caused by reserpine in the vacuous chewing and tong protrusion behaviors and prevented dopaminergic damage in the SNpc, VTA, and Striatum. TP at 5.0 mg/kg reduced the damages caused by reserpine in the catalepsy and tong protrusion behaviors, prevented the weight loss, and prevented dopaminergic damage in the VTA. Our results suggest that chronic administration of TP has a protective effect in a rat model of parkinsonism, improving motor alterations and dopamine depletion induced by RES.

ABSTRACT: Diffusion MRI is the dominant non-invasive imaging method used to characterize white matter organization in health and disease. Increasingly, fiber-specific properties within a voxel are analyzed using fixels. While tools for conducting statistical analyses of fixel-wise data exist, currently available tools support only a limited number of statistical models. Here we introduce ModelArray, an R package for mass-univariate statistical analysis of fixel-wise data. At present, ModelArray supports linear models as well as generalized additive models (GAMs), which are particularly useful for studying nonlinear effects in lifespan data. In addition, ModelArray also aims for scalable analysis. With only several lines of code, even large fixel-wise datasets can be analyzed using a standard personal computer. Detailed memory profiling revealed that ModelArray required only limited memory even for large datasets. As an example, we applied ModelArray to fixel-wise data derived from diffusion images acquired as part of the Philadelphia Neurodevelopmental Cohort (n = 938). ModelArray revealed anticipated nonlinear developmental effects in white matter. Moving forward, ModelArray is supported by an open-source software development model that can incorporate additional statistical models and other imaging data types. Taken together, ModelArray provides a flexible and efficient platform for statistical analysis of fixel-wise data.

Introdução: Criptococose é uma micose sistêmica causada por fungos do gênero Cryptococcus. É mais comum em indivíduos com HIV/AIDS, mas um aumento de casos é observado em pacientes onco-hematológicos. Objetivo: Descrever o caso de uma paciente com Linfoma Não Hodgkin de células do manto (LNH), diagnosticada com criptococose pulmonar durante quimioterapia (QT), submetida a transplante autólogo de células-tronco hematopoiéticas (auto-TCTH) após a segunda remissão completa e tratamento da doença fúngica. Resultados: Relato: Mulher, 52 anos, diagnosticada com LNH de células do manto em 2017, estágio clínico IV XSB. Iniciou QT com CHOP. Em fevereiro de 2018, no quarto ciclo de QT, foi realizado PET CT que visualizou nódulos sólidos irregulares por todo o parênquima pulmonar. Anatomopatológico de biópsia de nódulo no lobo superior direito evidenciou numerosas leveduras, com o isolamento de Cryptococcus neoformans em cultura. Antígeno sérico para Cryptococcus foi positivo. Foi iniciado tratamento com fluconazol em março de 2018. Após o diagnóstico infeccioso, o auto-TCTH foi contraindicado e a paciente teve remissão completa do LNH após 6 ciclos de QT. Houve redução dos nódulos pulmonares nos exames de imagem e negativação do antígeno sérico para Cryptococcus. Foi reduzida a dose de fluconazol para 300 mg/dia como terapia de manutenção. Em agosto de 2020, houve recidiva tardia do linfoma, foi iniciado nova QT com (R)-DHAOX e programado auto-TCTH sequencial. Em abril de 2021, houve a remissão completa do LNH de células do manto após término da QT, realizado auto-TCTH após condicionamento com BendaEAM. Nesse momento, apresentava antígeno sérico para Cryptococcus negativo e tomografia de crânio e tórax sem evidência de doença fúngica ativa. Recebeu profilaxia com dose única de ivermectina, cotrimoxazol até D-1, aciclovir, isoniazida (PPD 8 mm) e fluconazol 400 mg por dia. Foi mantido profilaxia secundária da criptococose com fluconazol por 6 meses. Conclusão: O caso foi tratado com sucesso antes do TCTH e não houve reativação da doença durante o período de neutropenia, nem após o transplante. Embora a Criptococose seja raramente observada em receptores de TCTH, a maioria dos casos se apresenta após o transplante. Não há recomendações na literatura quanto ao manejo no diagnóstico prévio ao transplante. Este relato traz a experiência de nosso serviço neste manejo e destaca a importância da avaliação do paciente no período pré-transplante e da profilaxia farmacológica adequada.

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease associated with loss of upper and lower motor neurons in the primary motor cortex and spinal cord, respectively. Motor deficits are the main clinical features observed in patients with the disease. However, it has been suggested that the presence of neurotoxic factors in the cerebrospinal fluid (CSF) from ALS patients causes loss of motor neurons. The present study investigated the motor and histopathological changes induced by intracerebroventricular (ICV) infusion of CSF from ALS patients in middle aged male Wistar rats. Middle aged male rats were divided into three groups: (1) control group, animals injected with artificial CSF solution; (2) N-ALS group, animals injected with CSF from volunteers without neurological disease; and (3) ALS group, animals inoculated with CFS from a patient with definite ALS. After surgical and infusion procedures, animals were evaluated in different motor tests (grip strength; catalepsy and open field tests). Moreover, animals’ spinal cords were histologically investigated. We observed that ALS-CSF infusion reduced grip strength and led to motor changes and reduction in the number of motor neurons and glial cells in thoracic and lumbar regions of spinal cord. However, CSF N-ALS caused reduction of nerve and glial cells in the thoracic but not in the lumbar region. Our data suggest that ALS-CSF is associated with neurodegenerative mechanisms observed in ALS pathology.

Background and Purpose: The presence of a paramagnetic rim around a white matter lesion has recently been shown to be a hallmark of a particular pathological type of multiple sclerosis lesion. Increased prevalence of these paramagnetic rim lesions is associated with a more severe disease course in MS, but manual identification is time-consuming. We present APRL, a method to automatically detect paramagnetic rim lesions on 3T T2*-phase images. Methods: T1-weighted, T2-FLAIR, and T2*-phase MRI of the brain were collected at 3T for 20 subjects with MS. The images were then processed with automated lesion segmentation, lesion center detection, lesion labelling, and lesion-level radiomic feature extraction. A total of 951 lesions were identified, 113 (12%) of which contained a paramagnetic rim. We divided our data into a training set (16 patients, 753 lesions) and a testing set (4 patients, 198 lesions), fit a random forest classification model on the training set, and assessed our ability to classify paramagnetic rim lesions on the test set. Results: The number of paramagnetic rim lesions per subject identified via our automated lesion labelling method was highly correlated with the gold standard count per subject, r = 0.86 (95% CI [0.68, 0.94]). The classification algorithm using radiomic features classified lesions with an area under the curve of 0.82 (95% CI [0.74, 0.92]). Conclusion: This study develops a fully automated technique, APRL, for the detection of paramagnetic rim lesions using standard T1 and FLAIR sequences and a T2*phase sequence obtained on 3T MR images.

Total brain white matter lesion (WML) volume is the most widely established magnetic resonance imaging (MRI) outcome measure in studies of multiple sclerosis (MS). To estimate WML volume, there are a number of automatic segmentation methods available, yet manual delineation remains the gold standard approach. Automatic approaches often yield a probability map to which a threshold is applied to create lesion segmentation masks. Unfortunately, few approaches systematically determine the threshold employed; many methods use a manually selected threshold, thus introducing human error and bias into the automated procedure. In this study, we propose and validate an automatic thresholding algorithm, Thresholding Approach for Probability Map Automatic Segmentation in Multiple Sclerosis (TAPAS), to obtain subject-specific threshold estimates for probability map automatic segmentation of T2-weighted (T2) hyperintense WMLs. Using multimodal MRI, the proposed method applies an automatic segmentation algorithm to obtain probability maps. We obtain the true subject-specific threshold that maximizes the Sørensen-Dice similarity coefficient (DSC). Then the subject-specific thresholds are modeled on a naive estimate of volume using a generalized additive model. Applying this model, we predict a subject-specific threshold in data not used for training. We ran a Monte Carlo-resampled split-sample cross-validation (100 validation sets) using two data sets: the first obtained from the Johns Hopkins Hospital (JHH) on a Philips 3 Tesla (3T) scanner (n = 94) and a second collected at the Brigham and Women's Hospital (BWH) using a Siemens 3T scanner (n = 40). By means of the proposed automated technique, in the JHH data we found an average reduction in subject-level absolute error of 0.1 mL per one mL increase in manual volume. Using Bland-Altman analysis, we found that volumetric bias associated with group-level thresholding was mitigated when applying TAPAS. The BWH data showed similar absolute error estimates using group-level thresholding or TAPAS likely since Bland-Altman analyses indicated no systematic biases associated with group or TAPAS volume estimates. The current study presents the first validated fully automated method for subject-specific threshold prediction to segment brain lesions.

Geraniol is a monoterpene alcohol that is derived from the essential oils of aromatic plants, with anti-inflammatory, antimicrobial, antioxidant and neuroprotective properties. This study characterized the effect of geraniol on behavior and brainwave patterns in rats. Male rats were submitted to administration of geraniol (25, 50 and 100 mg/kg). The hole board (HB) and open field (OF) tests were performed to evaluate anxiety and motor behavior, respectively. In addition, barbiturate-induced sleeping time (BIST) was used to analyze sedative effect. Finally, electrocorticogram (ECoG) recordings were used to characterize brain-wave patterns. The results showed that geraniol treatment in rats decreased the distance traveled, rearing numbers and lead to increase in immobility time in HB and OF tests. In BIST test, geraniol treatment increased sleep duration but not sleep latency in the animals. Furthermore, geraniol-treated animals demonstrated an increase in the percentage of delta waves in the total spectrum power. Taken together, our results suggested that geraniol exerted a depressant effect on the central nervous system of rats. Keywords: Sedation, Monoterpene, Brain waves, Hypnose, Natural product

Several studies have revealed that traditional risk factors are less effective in predicting CVD risk in the elderly, suggesting the need to identify new biomarkers. Here, we evaluated the association between serum cholesterol efflux capacity (CEC), an atheroprotective property of HDL recently identified as a novel marker of CVD risk, and atherosclerotic burden in a cohort of very old, healthy individuals. Serum CEC values were not significantly correlated either with calcium score or with markers of vulnerable plaque, such as positive remodeling, hypodensity, spotty calcification, or napking-ring sign. In addition, no association was detected between CEC and telomere length, a marker of biological aging that has been linked to atherosclerosis extent. Interestingly, elderly subjects presented a remarkably higher CEC (+30.2%; P < 0.0001) compared with values obtained from a cohort of sex-matched, cardiovascular event-free, middle-aged individuals. In conclusion, serum CEC is not related to traditional risk factors in very old, cardiovascular event-free subjects, but has significantly higher values compared with a healthy, younger population. Whether this improved HDL functionality may represent a protective factor in CVD onset must be established in future studies.

Background and purpose: Magnetic resonance imaging (MRI) is crucial for in vivo detection and characterization of white matter lesions (WML) in multiple sclerosis (MS). The most widely established MRI outcome measure is the volume of hyperintense lesions on T2-weighted images (T2L). Unfortunately, T2L are non-specific for the level of tissue destruction and show a weak relationship to clinical status. Interest in lesions that appear hypointense on T1-weighted images (T1L) (“black holes”) has grown because T1L provide more specificity for axonal loss and a closer link to neurologic disability. The technical difficulty of T1L segmentation has led investigators to rely on time-consuming manual assessments prone to inter- and intra-rater variability. This study aims to develop an automatic T1L segmentation approach, adapted from a T2L segmentation algorithm. Materials and methods: T1, T2, and fluid-attenuated inversion recovery (FLAIR) sequences were acquired from 40 MS subjects at 3 Tesla (3 T). T2L and T1L were manually segmented. A Method for Inter-Modal Segmentation Analysis (MIMoSA) was then employed. Results: Using cross-validation, MIMoSA proved to be robust for segmenting both T2L and T1L. For T2L, a Sørensen-Dice coefficient (DSC) of 0.66 and partial AUC (pAUC) up to 1% false positive rate of 0.70 were achieved. For T1L, 0.53 DSC and 0.64 pAUC were achieved. Manual and MIMoSA segmented volumes were correlated and resulted in 0.88 for T1L and 0.95 for T2L. The correlation between Expanded Disability Status Scale (EDSS) scores and manual versus automatic volumes were similar for T1L (0.32 manual vs. 0.34 MIMoSA), T2L (0.33 vs. 0.32), and the T1L/T2L ratio (0.33 vs 0.33). Conclusions: Though originally designed to segment T2L, MIMoSA performs well for segmenting T1 black holes in patients with MS.

Background: Major Depressive Disorder (MDD) is a prevalent, disruptive illness. A majority of those with MDD are at high risk for recurrence and increased risk for morbidity and mortality. This study examined whether multimodal baseline (and retest) Cognitive Control performance and neuroimaging markers (task activation and neural connectivity between key brain nodes) could differentiate between those with and without future recurrence of a major depressive (MD) episode within one year. We hypothesized that performance and neuroimaging measures of Cognitive Control would identify markers that differ between these two groups. Methods: A prospective cohort study of young adults (ages 18–23) with history (h) of early-onset MDD (N = 60), now remitted, and healthy young adults (N = 49). Baseline Cognitive Control measures of performance, task fMRI and resting state connectivity (and reliability retest 4–12 weeks later) were used to compare those with future recurrence of MDD (N = 21) relative to those without future recurrence of MDD (N = 34 with resilience). The measures tested were (1) Parametric Go/No-Go (PGNG) performance, and task activation for (2) PGNG Correct Rejections, (3) PGNG Commission errors, and (4 & 5), resting state connectivity analyses of Cognitive Control Network to and from subgenual anterior cingulate. Results: Relative to other groups at baseline, the group with MDD Recurrence had less bilateral middle frontal gyrus activation during commission errors. MDD Recurrence exhibited greater connectivity of right middle frontal gyrus to subgenual anterior cingulate (SGAC). SGAC connectivity was also elevated in this group to numerous regions in the Cognitive Control Network. Moderate to strong ICCs were present from test to retest, and highest for rs-fMRI markers. There were modest, significant correlations between task, connectivity and behavioral markers that distinguished between groups. Conclusion: Markers of Cognitive Control function could identify those with early course MD who are at risk for depression recurrence. Those at high risk for recurrence would benefit from maintenance or preventative treatments. Future studies could test and validate these markers as potential predictors, accounting for sample selection and bias in feature detection.

Introduction: The indiscriminate use of different diagnostic criteria for the definition of dyslipidemia may result in inaccurate interpretations, which could compromise diagnosis and therefore the therapeutic and prophylactic actions to be taken. Objective: To analyze possible differences in prevalence rates of dyslipidemia in adolescents based on three diagnostic definitions. Methods: A cross-sectional study was conducted of a representative sample of Brazilian adolescents between 11 and 16 years of age. Blood samples were collected from 1000 students (423 boys and 577 girls) to determine fasting total cholesterol (TC), HDL and LDL cholesterol, and triglycerides (TG). The prevalence of dyslipidemia was established according to three definitions: those of the National Cholesterol Education Program (NCEP), the Brazilian Society of Cardiology (BSC), and the National Health and Nutrition Examination Survey (NHANES). Results: Significant differences (p

Our understanding of gene regulation in plants is constrained by our limited knowledge of plant cis-regulatory DNA and its dynamics. We mapped DNase I hypersensitive sites (DHSs) in A. thaliana seedlings and used genomic footprinting to delineate ∼700,000 sites of in vivo transcription factor (TF) occupancy at nucleotide resolution. We show that variation associated with 72 diverse quantitative phenotypes localizes within DHSs. TF footprints encode an extensive cis-regulatory lexicon subject to recent evolutionary pressures, and widespread TF binding within exons may have shaped codon usage patterns. The architecture of A. thaliana TF regulatory networks is strikingly similar to that of animals in spite of diverged regulatory repertoires. We analyzed regulatory landscape dynamics during heat shock and photomorphogenesis, disclosing thousands of environmentally sensitive elements and enabling mapping of key TF regulatory circuits underlying these fundamental responses. Our results provide an extensive resource for the study of A. thaliana gene regulation and functional biology.

Summary: Small cell lung cancer (SCLC) is a lethal form of lung cancer. Here, we develop a quantitative multiplexed approach on the basis of lentiviral barcoding with somatic CRISPR-Cas9-mediated genome editing to functionally investigate candidate regulators of tumor initiation and growth in genetically engineered mouse models of SCLC. We found that naphthalene pre-treatment enhances lentiviral vector-mediated SCLC initiation, enabling high multiplicity of tumor clones for analysis through high-throughput sequencing methods. Candidate drivers of SCLC identified from a meta-analysis across multiple human SCLC genomic datasets were tested using this approach, which defines both positive and detrimental impacts of inactivating 40 genes across candidate pathways on SCLC development. This analysis and subsequent validation in human SCLC cells establish TSC1 in the PI3K-AKT-mTOR pathway as a robust tumor suppressor in SCLC. This approach should illuminate drivers of SCLC, facilitate the development of precision therapies for defined SCLC genotypes, and identify therapeutic targets.

Resumo: A asma é uma doença crónica das vias aéreas que pode levar à diminuição da força muscular respiratória pela hiperinsuflação resultante ou o uso de corticosteróides em seu tratamento. Uma das formas de avaliar essa fraqueza muscular respiratória é a pressão inspiratória máxima (PImáx). Métodos: Foi realizada uma revisão sistemática através das bases de dados PUB-MED/MEDLINE, LILACS e SCIELO, utilizando as palavras-chaves: Asthma (asma), respiratory muscle (músculos respiratórios) e muscle strength (força muscular). Resultados: Foram encontrados cinquenta e seis artigos que avaliaram a PImáx em asmáticos; desses, trinta foram excluídos, ficando um total de vinte e seis artigos. Considerações finais: Através da presente revisão comprovamos a eficácia da utilização da Pimáx na avaliação da força muscular respiratória de asmáticos; no entanto, são necessários mais estudos a este respeito, para uma melhor compreensão do indivíduo asmático.Rev Port Pneumol 2010; XVI (3): 463-470 Abstract: Asthma is a chronic illness of the airways that can reduce respiratory muscle strength due to the resulting hyperinflation or treatment with corticosteroids. One of the ways to evaluate this respiratory muscular weakness is the Maximal Inspiratory Pressure (PImax). Methods: A systematic review of the databases PUBMED/MEDLINE, LILACS and SCIELO was carried through, using the key words: Asthma, respiratory muscle and muscle strength. Results: Fifty were found and six articles that evaluated the PImax in asthmatics, from these, thirty were excluded, making a total of twenty six articles. Final considerations: Through the present revision we show the effectiveness of PImax in evaluating respiratory muscle strength in asthmatics. More studies are needed, however, fot better understanding of the asthmatic individual.Rev Port Pneumol 2010; XVI (3): 463-470 Palavras-chaves: Asma, músculo respiratório, força muscular, Key-words: Asthma, respiratory muscle, muscle strength

Background: Patient-specific 3-dimensional (3D) computational modelling offers a tailored approach with promising results, but experience using digital-twin fusion on real-time fluoroscopy to guide left atrial appendage closure (LAAC) is unreported., Objectives: To assess whether LAAC guided by fusion of a 3D computational model on real-time fluoroscopy is safe and effective., Methods: We included retrospectively through a multicenter registry all consecutive patients with non-valvular atrial fibrillation (AF) who underwent LAAC guided by artificial intelligence (AI)-enabled computer simulations (FEops, Gent, Belgium) fusion with real-time fluoroscopy. Operators selected the appropriate device size and position in relation to the LAA using FEops HEARTguide™, and a digital twin was provided for image fusion. The primary efficacy endpoint was successful LAAC with the use of a single device, without moderate or greater peri-device leak and/or device related thrombus (DRT) on follow-up imaging. The primary safety endpoint was a composite of major procedural complications including tamponade, stroke, systemic embolism, major bleeding, and device embolization., Results: A total of 106 patients underwent LAAC with an Amulet™ or Watchman FLX™ device using CT-model-fluoroscopy fusion imaging. Device implantation was successful in 100 % of cases. The primary efficacy endpoint was met in 82 patients (89 %). A single-device SINGLE-deployment LAAC procedure was observed in 49 cases (46 %). The primary safety endpoint occurred in 2 patients (1.9 %). After a median follow-up of 405 days, two patients suffered an ischemic stroke and four expired., Conclusions: Fusion of a CT-based 3D computational model on real-time fluoroscopy is a safe and effective approach that may optimize transcatheter LAAC outcomes., Competing Interests: Declaration of competing interest P. Garot is medical director and shareholder of CERC, a CRO dedicated to cardiovascular research. He is proctor for Abbott and has received Advisory/speaker's fees from Abbott, Biosensors, Boston Scientific, Cordis, GE Healthcare, and Terumo outside the submitted work. C. Skurk has received speakers fees from Abiomed and Boston Scientific. A. Gautier has received consulting fees from Abbott, Boston Scientific, GE HealthCare, Medtronic and Terumo outside the submitted work. A.M. Bavo is an employee of FEops. R. Vaillant is an employee of General Electric HealthCare. J. Horvilleur is proctor for Abbott. X. Freixa is proctor for Abbott, Boston Scientific and Lifetech Medical. J. Saw is Consultant and Proctor for Abbott and Boston Scientific. O. De Backer has received institutional research grants and consulting fees from Abbott and Boston Scientific. The other co-authors have nothing to disclose., (Copyright © 2024. Published by Elsevier B.V.)

Photosensitization reactions caused by ultraviolet and visible radiation (UV-vis) absorbing chemicals can induce DNA damage through direct and indirect mechanisms. In this context, the investigation of phototoxicity is an essential part of the toxicological assessment programs for drugs, cosmetics and other chemicals that may be exposed to UV-vis light. The current battery of photosafety assessment tests includes an initial investigation of their photoreactive potential followed by in vitro phototoxicity testing. The in vitro 3T3 Neutral Red Uptake (NRU) and the Reconstructed Human Epidermis phototoxicity methods are currently the only validated and recognized tests for this purpose. However, they are not suitable for detecting the photogenotoxic potential of compounds, as they are based on photocytotoxicity measurement. Although there are adaptations of genotoxicity assays in the presence of UV-vis irradiation, these methods are not validated and standardized, and their biomodels have limitations. Additionally, even though computational toxicology is an already implemented strategy for human health hazard assessment, in silico photosafety models also have limitations. The currently available in silico models are based on the 3T3 NRU assay, thus limiting their ability to reliably predict photogenotoxicity. There is evidence of chemicals that present negative results in 3T3 NRU-based in vitro and in silico tests, yet exhibit photogenotoxic potential. This is exemplified by the agrochemical glyphosate, whose photomutagenic effect was recently reported using a promising yeast-based method as a New Approach Methodology. Therefore, the need to implement a battery of phototoxicity tests, including in vitro and/or in silico photogenotoxicity assessments, to complement the existing photocytotoxicity tests should be re-discussed. Otherwise, photosafety is not completely guaranteed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: To compare the perioperative analgesic effects of an opioid-free (OFA) and an opioid-sparing (OSA) anaesthetic protocol in dogs undergoing laparoscopic ovariectomy., Study Design: Prospective, randomized, blinded, clinical trial., Animals: A group of 28 client-owned dogs., Methods: Dogs were allocated to one of two groups. The OFA group was administered intramuscular (IM) dexmedetomidine 5 μg kg -1 and ketamine 1 mg kg -1 , followed by two intraoperative constant rate infusions (CRIs) of dexmedetomidine (3 μg kg -1 hour -1 ) and lidocaine (1 mg kg -1 loading dose, 2 mg kg -1 hour -1 ). The OSA group was administered IM dexmedetomidine 5 μg kg -1 , ketamine 1 mg kg -1 and methadone 0.2 mg kg -1 , followed by two intraoperative saline CRIs. In both groups, anaesthesia was induced with intravenous (IV) propofol 2 mg kg -1 and diazepam 0.2 mg kg -1 and maintained with isoflurane. Rescue dexmedetomidine (0.5 μg kg -1 ) was administered IV if there was a 20% increase in cardiovascular variables compared with pre-stimulation values. Ketorolac (0.5 mg kg -1 ) was administered IV when the surgery ended. Postoperative analgesia was evaluated using the Short Form-Glasgow Composite Measure Pain Scale and methadone (0.2 mg kg -1 ) was administered IM if the pain score was ≥ 6/24. Statistical analysis included mixed analysis of variance, Chi-square test and Mann-Whitney U test., Results: There were no significant differences in the intraoperative monitored variables between groups. The OFA group showed a significantly lower intraoperative rescue analgesia requirement (p = 0.016) and lower postoperative pain scores at 3 (p =0.001) and 6 (p < 0.001) hours. No dogs were administered rescue methadone postoperatively., Conclusions and Clinical Relevance: Although both groups achieved acceptable postoperative pain scores with no need for further intervention, the analgesic efficacy of the OFA protocol was significantly superior to that of the OSA protocol presented and was associated with a lower intraoperative rescue analgesia requirement and early postoperative pain scores., (Copyright © 2024 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

The increased use of agrochemicals raises concerns about environmental, animal, and mainly human toxicology. The development of New Approach Methodologies (NAMs) for toxicological risk assessment including new in vitro tests and in silico protocols is encouraged. Although agrochemical mutagenicity testing is well established, a complementary alternative approach may contribute to increasing reliability, with the consequent reduction of false-positive results that lead to unnecessary use of animals in follow-up in vivo testing. Additionally, it is unreasonable to underestimate the phototoxic effects of an accidental dermal exposure to agrochemicals during agricultural work or domestic application in the absence of adequate personal protection equipment, especially in terms of photomutagenicity. In this scenario, we addressed the integration of in vitro and in silico techniques as NAMs to assess the mutagenic and phototoxic potential of agrochemicals. In the present study we used the yno1 S. cerevisiae strain as a biomodel for in vitro assessment of agrochemical mutagenicity, both in the absence and in the presence of simulated sunlight. In parallel, in silico predictions were performed using a combination of expert rule-based and statistical-based models to assess gene mutations and phototoxicity. None of the tested agrochemicals showed mutagenic potential in the two proposed approaches. The Gly and 2,4D herbicides were photomutagenic in the in vitro yeast test despite the negative in silico prediction of phototoxicity. Herein, we demonstrated a novel experimental approach combining both in silico and in vitro experiments to address the complementary investigation of the phototoxicity and (photo)mutagenicity of agrochemicals. These findings shed light on the importance of investigating and reconsidering the photosafety assessment of these products, using not only photocytotoxicity assays but also photomutagenicity assays, which should be encouraged., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Despite direct oral anticoagulants (DOACs) being safer than warfarin for stroke prevention in atrial fibrillation (AF), major bleeding concerns persist. Most bleeding risk scores predate DOAC approval., Objectives: This study aimed to compare the Age, history of Bleeding, and non-bleeding related Hospitalisation [ABH] score's performance-derived for DOAC-treated patients-with those of 5 other scores (Anticoagulation and Risk Factors in Atrial Fibrillation [ATRIA], Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly [>65 years], Drugs/alcohol concomitantly [HAS-BLED], Hepatic, Hepatic or Renal Disease, Ethanol Abuse, Malignancy, Older Age, Reduced Platelet Count or Function, Re-Bleeding, Hypertension, Anemia, Genetic Factors, Excessive Fall Risk and Stroke [HEMORR 2 HAGES], Outcomes Registry for Better Informed Treatment of Atrial Fibrillation [ORBIT-AF], and Congestive heart failure, Hypertension, Age ≥75 [doubled], Diabetes, Stroke [doubled]-Vascular disease, Age 65-74, Sex category [CHA 2 DS 2 -VASc]) in predicting DOAC-related major bleeding in patients with AF., Methods: In this retrospective study of 2364 patients with nonvalvular AF on rivaroxaban or apixaban (median age, 68.3 years; 32.1% women), International Society on Thrombosis and Haemostasis-defined major bleeding (incidence, 4.1%; n  = 97) was analyzed. C-statistics from time-dependent receiver operating characteristic (ROC) curves for continuous risk scores were the primary comparison metric, but other metrics, such as decision curves, were also compared., Results: At 100 days, C-statistics were highest for ORBIT-AF and ATRIA (0.62 and 0.61, respectively, with other scores having an area under the ROC curve of <0.60); some significant differences favored ORBIT-AF. At 1100 days, C-statistics remained highest for ORBIT-AF and ATRIA (0.62 and 0.61, respectively, with other scores having an area under the ROC curve of <0.60 again), and ORBIT-AF had significantly higher C-statistics than those for all other risk scores ( P  < .05), except for ATRIA. At 2100 days, all C-statistics were <0.60 with no significant differences. Decision curves showed the greatest net benefit for ORBIT-AF and ATRIA at 100 days and for ATRIA at 1100 days, with no discernible net benefit for any of the scores at 2100 days., Conclusion: ORBIT-AF and ATRIA provided the best bleeding risk prediction within the first 1100 days. None of the 6 bleeding risk scores provided predictive benefit over 2100 days of DOAC treatment., (© 2023 The Author(s).)

Background: The variation and accuracy of computed tomography angiography (CTA) features of anomalous aortic origin of a coronary artery (AAOCA) have not been completely characterized. We evaluated anomalous right (AAORCA) and left (AAOLCA) coronary arteries by CTA, with an emphasis on reproducibility, comparison with surgical measurements, and effect of nitroglycerin., Methods: CTAs were interpreted for location of coronary origin & exit from the aorta, course, and dominance; minor & major diameters of the proximal & distal coronaries; shape of orifice; and intramural length. Relationships between vessel measurements, body surface area (BSA), and nitroglycerin use were evaluated. Comparisons between CTA and surgical measurements included intramural length, surgical probe size pre-intervention vs. CTA proximal AAOCA diameter, and surgical probe size post-intervention vs. CTA distal AAOCA diameter., Results: Of 104 patients [81 (78%) AAORCA], all but 1 were intramural. Compared to AAOLCA, AAORCA patients were more likely to have a high origin (91% vs. 31%, p ​< ​0.01), and slit-like orifice (58% vs. 26%, p ​< ​0.01). When CTAs with nitroglycerin were compared to those without, no difference in proximal AAOCA dimensions was identified; however distal AAOCA and normal-origin coronary dimensions were larger in scans with nitroglycerin. Aside from slit-like orifice, reliability of coronary CTA measurements, including proximal AAOCA minor diameter and intramural length, was moderate to good between readers. In a subgroup of 54 patients, proximal AAOCA minor diameter and intramural length had good agreement and correlation with surgery., Conclusion: Proximal AAOCA dimensions and intramural length are reproducible variables. The lack of difference in proximal AAOCA dimensions with nitroglycerin may reflect abnormal vessel mechanics. Multicenter studies are an important next step in understanding the generalizability of our findings., (Copyright © 2023 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

The rapid rise of multi-resistant bacteria is a global health threat. This is especially serious for Gram-negative bacteria in which the impermeable outer membrane (OM) acts as a shield against antibiotics. The development of new drugs with novel modes of actions to combat multi-drug resistant pathogens requires the selection of suitable processes to be targeted. The LPS export pathway is an excellent under exploited target for drug development. Indeed, LPS is the major determinant of the OM permeability barrier, and its biogenetic pathway is conserved in most Gram-negatives. Here we describe efforts to identify inhibitors of the multiprotein Lpt system that transports LPS to the cell surface. Despite none of these molecules has been approved for clinical use, they may represent valuable compounds for optimization. Finally, the recent discovery of a link between inhibition of LPS biogenesis and changes in peptidoglycan structure uncovers additional targets to develop novel therapeutic strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Three-dimensional echocardiography (3DE) evaluation of right ventricular (RV) volumes and ejection fraction (EF) is increasingly used for clinical serial assessments and management in children. This study aims to generate sex-specific reference values and z-score equations for RV volumetric parameters, independent of age and body size indices, derived from multiple populations across North America., Methods: We prospectively recruited 455 healthy children (ages 0 to 18 years) from 5 centres. 3DE of the RV were acquired using various vendors with analyses performed offline using vendor-independent software. 3DE datasets with all walls of the RV endocardium visible were included. We reported data on RV EF, and generated z scores for end-systolic volumes (ESV), end-diastolic volumes (EDV) and stroke volume (SV). Differences between the sexes were explored., Results: Of 455 3DE datasets, 312 (68%) met imaging criteria for analysis. Median age was 10.1 years (interquartile ratio [IQR]: 5.6, 14.0) with 17% being younger than 3 years of age. The mean and standard deviation for RV EDV, ESV, and SV for male and female patients were reported. We provided a downloadable z-score calculator with height and weight as independent variables to facilitate clinical utility. Although statistically significant differences between male and female RVEF was present (female 52.9 ± 3.9% vs male 51.6 ± 3.5%, P = 0.006), after adjusting for age, height, and weight, the magnitude of difference was clinically insignificant., Conclusions: Sex-specific reference values for pediatric RV volumes and EF, and z-score equations were derived from children 3DE datasets across 5 centres in North America., (Published by Elsevier Inc.)

Among intensive agricultural practices, pesticides, mowing, and heavy agricultural machineries have become an important tool to maximize harvesting and secure animal husbandry. However, they are also cause of agricultural ecosystem decline, often leading to degradation of key micro-habitat features for many species, higher predation risk and lower food availability. We investigated the diet and foraging ecology of the Italian wall lizard in agricultural areas to determine whether different management practices (conventional, organic, and control) can affect (i) the structure of the trophic niche of the species; (ii) prey diversity, the degree of individual specialization, and the overall population feeding strategy; (iii) lizards' health status. Faecal pellets were collected for diet composition analyses, while prey diversity in the environment was estimated by placing adhesive traps. Lizards' body condition did not differ among management type although males from control field resulted slightly larger than those from conventional and organic areas. The species showed a generalist (conventional and organic areas) and mixed (control area) feeding strategy with a preference for coleopterans. Although a different prey diversity was found in control areas compared to organic and conventional ones, diet composition and the importance of specific food items was similar among management types. This may suggest that management activities may have affected the overall prey availability and indirectly influenced lizard trophic behaviour. Our study provides a comprehensive knowledge on the feeding ecology of P. siculus in managed habitats, which may have useful implications for the overall conservation of lizards in agricultural environments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objectives: To assess the quality of life (QOL) and its associated factors in patients with psoriatic arthritis (PsA) who would start treatment with biologic drugs at the Brazilian Unified Health System., Methods: A cross-sectional study was performed at a single center pharmacy in Belo Horizonte, State of Minas Gerais, Brazil. EQ-5D was used to assess the patients' QOL. The functional status was assessed using the Health Assessment Questionnaire-Disability Index, whereas disease activity was evaluated through the Bath Ankylosing Spondylitis Disease Activity Index and the Clinical Disease Activity Index. Simple and multiple linear regression analyses were performed to assess the factors associated with QOL., Results: A total of 212 patients with PsA were included, of which 185 (87.3%) reported having some pain/discomfort, and 148 (69.8%) presented some level of anxiety/depression. Patients with PsA had a mean QOL score of 0.651 (SD 0.12) with a significant reduction in female patients, concomitant use of nonsteroidal anti-inflammatory drugs, comorbidity, and worse clinical and functional status. Poor QOL was associated with worse functional status by the Health Assessment Questionnaire-Disability Index, disease activity by the Bath Ankylosing Spondylitis Disease Activity Index, and with diagnoses of osteoporosis, hypothyroidism, and depression., Conclusion: PsA and its associated comorbidities negatively affect the QOL, evidencing the need for a comprehensive and effective clinical approach., (Copyright © 2021 ISPOR--The professional society for health economics and outcomes research. Published by Elsevier Inc. All rights reserved.)

Laboratory diagnosis of leishmaniasis shows variable efficacy in detecting infected mammalian hosts and there is a need to identify suitable antigens to improve the accuracy of diagnostic tests. In the present study, a L. infantum hypothetical protein called LiHyQ was evaluated for the diagnosis of tegumentary (TL) and visceral (VL) leishmaniasis using canine and human samples. A collection of dog sera (n=155) were tested and contained samples from asymptomatic (n=20) and symptomatic (n=25) VL animals, from healthy dogs living in endemic (n=25) or non-endemic (n=25) areas of disease, from Leish-Tec® vaccinated dogs (n=20) or from dogs infected with Ehrlichia canis (n=15), Babesia canis (n=10) and Trypanosoma cruzi (n=15). Sensitivity (Se), Specificity (Sp), Positive Predictive Value (PPV) and Negative Predictive Value (NPV) of 100% were observed for rLiHyQ with these samples, whereas the Se, Sp, PPV and NPV values with L. infantum Soluble Leishmania Antigen (SLA) preparation were 60.0%, 99.0%, 96.0% and 86.0%, respectively. A collection of human sera (n=305) were tested and contained samples from TL (n=50) and VL (n=40) patients, from VL/HIV co-infected patients (n=35), from patients infected with HIV alone (n=30), Chagas Disease (n=30), malaria (n=10), tuberculosis (n=10), paracoccidioidomycosis (n=15), leprosy (n=30) or aspergillosis (n=15); and from healthy subjects (n=40). Se, Sp, PPV and NPV values of 100% were observed for rLiHyQ with these samples, whereas the Se, Sp, PPV and NPV values with SLA were 58.0%, 76.0%, 50.0% and 82.0%, respectively. The antibody reactivity against the protein was compared with commercial kits, and the kappa index varied from 0.95 to 1.00 for rLiHyQ, and of 0.55 to 0.82 for the kits. In addition, the serological follow-up of treated patients showed a significant reduction in rLiHyQ-specific IgG antibody levels. All canine and human samples were tested at the same time using the same reagents, in order to reduce experimental variation and interference in data interpretation. In conclusion, our preliminary data suggest a diagnostic and prognostic role for rLiHyQ against leishmaniasis., (Copyright © 2021. Published by Elsevier B.V.)

Background and Aims: Multivariable algorithms have been developed to predict the risk of atherosclerotic cardiovascular disease (ASCVD) to identify high-risk patients. Shortly after the introduction of the AHA/ACC Pooled Cohort Equations (PCE), a systematic overestimation of risk was identified. As such, a revised PCE was proposed to more accurately assess ASCVD risk. This study aims to compare the accuracy of both PCE in predicting ASCVD risk within a large, real-world patient sample in the US., Methods: This retrospective cohort study identified 20,843 patients aged between 40 and 75 years with no previous ASCVD in an academic healthcare system. Model fit, calibration, and discrimination were compared between PCE using Bayesian Information Criterion (BIC), Hosmer-Lemeshow test, area under the ROC curves (AUC), Brier score, and precision-recall analysis. In addition, we examined race and sex subgroups for effect modification., Results: Both PCE showed poor calibration (Hosmer-Lemeshow χ 2  > 20; p < 0.05) and discrimination (AUC<0.7). The lack of improvement in discrimination of the revised PCE (AUC: 0.677 vs 0.679; p = 0.357) was confirmed with the AUC precision-recall curves (AUC PR : 0.0717 vs 0.0698). In contrast, the AHA/ACC PCE showed a strong positive risk prediction (ΔBIC>10) compared to the revised PCE, although calibration curves had overlapped., Conclusions: In this single center analysis, both PCE had poor calibration and discrimination of ASCVD risk in a large, real-world patient sample followed up for over 2 years. There was no evidence of improvement in the accuracy of the revised PCE in assessing the risk of ASCVD in relation to the AHA/ACC PCE., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Clinical and experimental studies have described eosinophil infiltration in Leishmania amazonensis infection sites, positioning eosinophils strategically adjacent to the protozoan-infected macrophages in cutaneous leishmaniasis. Here, by co-culturing mouse eosinophils with L. amazonensis-infected macrophages, we studied the impact of eosinophils on macrophage ability to regulate intracellular L. amazonensis infection. Eosinophils prevented the increase in amastigote numbers within macrophages by a mechanism dependent on a paracrine activity mediated by eosinophil-derived prostaglandin (PG) D 2 acting on DP2 receptors. Exogenous PGD 2 mimicked eosinophil-mediated effect on managing L. amazonensis intracellular infection by macrophages and therefore may function as a complementary tool for therapeutic intervention in L. amazonensis-driven cutaneous leishmaniasis., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background and Purpose: The presence of a paramagnetic rim around a white matter lesion has recently been shown to be a hallmark of a particular pathological type of multiple sclerosis lesion. Increased prevalence of these paramagnetic rim lesions is associated with a more severe disease course in MS, but manual identification is time-consuming. We present APRL, a method to automatically detect paramagnetic rim lesions on 3T T2*-phase images., Methods: T1-weighted, T2-FLAIR, and T2*-phase MRI of the brain were collected at 3T for 20 subjects with MS. The images were then processed with automated lesion segmentation, lesion center detection, lesion labelling, and lesion-level radiomic feature extraction. A total of 951 lesions were identified, 113 (12%) of which contained a paramagnetic rim. We divided our data into a training set (16 patients, 753 lesions) and a testing set (4 patients, 198 lesions), fit a random forest classification model on the training set, and assessed our ability to classify paramagnetic rim lesions on the test set., Results: The number of paramagnetic rim lesions per subject identified via our automated lesion labelling method was highly correlated with the gold standard count per subject, r = 0.86 (95% CI [0.68, 0.94]). The classification algorithm using radiomic features classified lesions with an area under the curve of 0.82 (95% CI [0.74, 0.92])., Conclusion: This study develops a fully automated technique, APRL, for the detection of paramagnetic rim lesions using standard T1 and FLAIR sequences and a T2*phase sequence obtained on 3T MR images., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Most studies evaluating vaccine candidates against visceral leishmaniasis (VL) have used parasite promastigote-expressed antigens; however, Leishmania proteins expressed in the amastigote forms should be considered, since few hours after infection this stage comes into contact with the host immune system and is responsible for the development of the disease. In this context, in the present study, a Leishmania amastigote-specific hypothetical protein, called LiHyJ, was evaluated as a recombinant protein plus saponin as an adjuvant or DNA vaccine to protect against VL. The vaccine effect was evaluated by means of the evaluation of immunological and parasitological analyses performed in BALB/c mice against Leishmania infantum infection. Results showed that rLiHyJ/saponin and DNA LiHyJ induced significantly higher levels of anti-protein and anti-parasite IFN-γ, IL-12, GM-CSF, and IgG2a isotype antibodies, which were associated with a low presence of IL-4 and IL-10. DNA vaccination induced higher IFN-γ production, mainly by CD8 + T cells, while rLiHyJ/saponin stimulated the production of this cytokine, mainly by CD4 + T cells. The parasite load evaluated in distinct organs showed that both immunization schedules significantly reduced organic parasitism, when compared to the controls. Similar results were found in the immunological and parasitological assays when using the recombinant protein or DNA, although the vaccination with rLiHyJ plus saponin induced a slightly higher Th1 response and lower parasite load, when compared to the use of DNA plasmid. The protein also proved to be immunogenic when peripheral blood mononuclear cells of treated VL patients and healthy subjects were in vitro stimulated, since higher IFN-γ and lower IL-4 and IL-10 levels were found in the culture supernatants. In conclusion, LiHyJ should be considered in future studies as a vaccine candidate to protect against VL., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To evaluate the effect of alfaxalone and methadone administered intramuscularly (IM), with or without ketamine, on sedation and echocardiographic measurements in healthy cats., Study Design: A randomized, blinded, clinical study., Animals: A group of 24 client-owned cats., Methods: Baseline echocardiographic evaluation (bEchoCG) was performed. Cats were given IM alfaxalone (2 mg kg -1 ) and methadone (0.3 mg kg -1 ) with (AMK group) or without (AM group) ketamine (1 mg kg -1 ). A sedation score (0-5, indicating none to good sedation) was assigned at 5 (T5), 10 (T10) and 15 (T15) minutes after IM injection. At T15, a second echocardiographic evaluation (sEchoCG) was performed. Data are shown as median (range). Significance was p < 0.05., Results: Finally, 21 cats were included. Sedation score was significantly higher in the AMK (11 cats) than in the AM group (10 cats): 4 (1-5) versus 0.5 (0-4) at T5 (p = 0.003); 4 (1-5) versus 1.5 (0-5) at T10 (p = 0.043); and 4 (1-5) versus 2 (0-5) at T15 (p = 0.024). All echocardiographic measurements obtained were within reference ranges. Between the groups, aortic root area (p = 0.009) and end-diastolic aortic dimension (p = 0.011) were significantly higher in the AM group at bEchoCG and sEchoCG, respectively. Within each group, values at bEchoCG and sEchoCG showed no significant differences, except for pulmonary peak velocity (0.85 m second -1 ; p = 0.028) in the AMK group and ejection time (154 m second; p = 0.03) in the AM group; both variables decreased after sedation., Conclusions and Clinical Relevance: In this population of healthy cats, neither protocol produced clinically meaningful effects on the echocardiographic variables evaluated. Alfaxalone with methadone produced mild sedation, whereas the addition of 1 mg kg -1 ketamine induced adequate sedation for diagnostic procedures., (Copyright © 2020 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

Background: Percutaneous left atrial appendage (LAA) closure can be optimised through diligent preprocedural planning. Cardiac computational tomography (CCT) is increasingly recognised as a valuable tool in this process. A CCT-based computational model (FEops HEARTguide™, Belgium) has been developed to simulate the deployment of the two most commonly used LAA closure devices into patient-specific LAA anatomies., Objective: The aim of this study was to validate this computational model based on real-life percutaneous LAA closure procedures and post-procedural CCT imaging., Methods: Thirty patients having undergone LAA closure (Amulet™ n = 15, Watchman™ n = 15) and having a pre- and post-procedural CCT-scan were selected for this validation study. Virtually implanted devices were directly compared to actual implants for device frame deformation and LAA wall apposition., Results: The coefficient of determination (R 2 ) and the difference in measurements between model and actual device (area, perimeter, minimum diameter, maximum diameter) were ≥0.91 and ≤ 5%, respectively. For both device types, the correlation coefficient between predicted and observed measurements was higher than 0.90. Furthermore, predicted device apposition correlated well with observed leaks based on post-procedural CCT., Conclusion: Computational modelling accurately predicts LAA closure device deformation and apposition and may therefore potentiate more accurate LAA closure device sizing and better preprocedural planning., (Copyright © 2020 Society of Cardiovascular Computed Tomography. All rights reserved.)

Background and Aims: Osteoporosis and coronary heart disease (CHD) are very common conditions among elderly people, and both represent a public health concern due to their prognostic consequences. Osteoporosis and CHD share many risk factors and pathophysiological mechanisms, such as calcification pathways. Clinical evidence associates lower bone mass with cardiovascular diseases and endothelial dysfunction. Hence, this study aims to investigate whether bone mass density is associated with subclinical atherosclerosis and/or endothelial dysfunction in the very elderly., Methods: We performed a cross-sectional study of cohort enrolled individuals, ages 80 years or older (n = 208), who had never manifested cardiovascular diseases. Medical evaluation, blood tests, flow-mediated dilation (FMD), carotid intimal-media thickness (IMT), Dual Energy X-ray Absorptiometry (DEXA) and Coronary Calcium Score (CCS) were obtained. Odds Ratio (OR) was calculated by multivariate logistic regression models using CCS, FMD and IMT categories. Adjustments for covariates were done., Results: Overall bone mass was independently and inversely associated with CCS categories [OR:1.68(1.16-8.85); p = 0.024] and IMT categories [OR:2.97(1.11-7.90); p = 0.030]. Conversely, overall bone mass was independent and directly associated with FMD categories [OR:2.73(1.36-70.39); p = 0.023]., Conclusions: This study indicates that overall bone mass is independently and inversely associated with subclinical atherosclerosis, endothelial dysfunction and thickness of carotid in the very elderly., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Exposure to environmental toxins, including hydrocarbon solvents, increases the risk of developing Parkinson's disease. An emergent hypothesis considers microtubule dysfunction as one of the crucial events in triggering neuronal degeneration in Parkinson's disease. Here, we used 2,5-hexanedione (2,5-HD), the toxic metabolite of n-hexane, to analyse the early effects of toxin-induced neurodegeneration on the cytoskeleton in multiple model systems. In PC12 cells differentiated with nerve growth factor for 5 days, we found that 2,5-HD treatment affected all the cytoskeletal components. Moreover, we observed alterations in microtubule distribution and stability, in addition to the imbalance of post-translational modifications of α-tubulin. Similar defects were also found in vivo in 2,5-HD-intoxicated mice. Interestingly, we also found that 2,5-HD exposure induced significant changes in microtubule stability in human skin fibroblasts obtained from Parkinson's disease patients harbouring mutations in PRKN gene, whereas it was ineffective in healthy donor fibroblasts, suggesting that the genetic background may really make the difference in microtubule susceptibility to this environmental Parkinson's disease-related toxin. In conclusion, by showing the imbalance between dynamic and stable microtubules in hydrocarbon-induced parkinsonism, our data support the crucial role of microtubule defects in triggering neurodegeneration., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Total brain white matter lesion (WML) volume is the most widely established magnetic resonance imaging (MRI) outcome measure in studies of multiple sclerosis (MS). To estimate WML volume, there are a number of automatic segmentation methods available, yet manual delineation remains the gold standard approach. Automatic approaches often yield a probability map to which a threshold is applied to create lesion segmentation masks. Unfortunately, few approaches systematically determine the threshold employed; many methods use a manually selected threshold, thus introducing human error and bias into the automated procedure. In this study, we propose and validate an automatic thresholding algorithm, Thresholding Approach for Probability Map Automatic Segmentation in Multiple Sclerosis (TAPAS), to obtain subject-specific threshold estimates for probability map automatic segmentation of T2-weighted (T2) hyperintense WMLs. Using multimodal MRI, the proposed method applies an automatic segmentation algorithm to obtain probability maps. We obtain the true subject-specific threshold that maximizes the Sørensen-Dice similarity coefficient (DSC). Then the subject-specific thresholds are modeled on a naive estimate of volume using a generalized additive model. Applying this model, we predict a subject-specific threshold in data not used for training. We ran a Monte Carlo-resampled split-sample cross-validation (100 validation sets) using two data sets: the first obtained from the Johns Hopkins Hospital (JHH) on a Philips 3 Tesla (3T) scanner (n = 94) and a second collected at the Brigham and Women's Hospital (BWH) using a Siemens 3T scanner (n = 40). By means of the proposed automated technique, in the JHH data we found an average reduction in subject-level absolute error of 0.1 mL per one mL increase in manual volume. Using Bland-Altman analysis, we found that volumetric bias associated with group-level thresholding was mitigated when applying TAPAS. The BWH data showed similar absolute error estimates using group-level thresholding or TAPAS likely since Bland-Altman analyses indicated no systematic biases associated with group or TAPAS volume estimates. The current study presents the first validated fully automated method for subject-specific threshold prediction to segment brain lesions., Competing Interests: Declaration of competing interest Ms. Alessandra Valcarcel has nothing to disclose. Dr. John Muschelli has nothing to disclose. Dr. Dzung Pham has nothing to disclose. Ms. Melissa Martin has nothing to disclose. Dr. Paul Yushkevich has nothing to disclose. Dr. Kristina Patterson has served on the advisory board for Alexion. Dr. Peter Calabresi has received personal consulting fees for serving on SABs for Biogen and Disarm Therapeutics. He is PI on grants to JHU from Biogen, Novartis, Sanofi, Annexon and MedImmune. Dr. Rohit Bakshi has received consulting fees from Bayer, Biogen, Celgene, EMD Serono, Genentech, Guerbet, Sanofi-Genzyme, and Shire and research support from EMD Serono and Sanofi-Genzyme. Dr. Russell (Taki) Shinohara has received consulting fees from Genentech and Roche., (Published by Elsevier Inc.)

The surface of the outer membrane of Gram-negative bacteria is covered by a tightly packed layer of lipopolysaccharide molecules which provide a barrier against many toxic compounds and antibiotics. Lipopolysaccharide, synthesized in the cytoplasm, is assembled in the periplasmic leaflet of the inner membrane where the intermembrane Lpt system mediates its transport to the cell surface. The first step of lipopolysaccharide transport is its extraction from the outer leaflet of inner membrane powered by the atypical LptB 2 FGC ABC transporter. Here we review latest advances leading to understanding at molecular level how lipopolysaccharide is transported irreversibly to the outer membrane., (Copyright © 2019 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.)

Lectins are carbohydrate binding proteins with many physiological and biotechnological applications. Isolation of proteins is normally time-consuming and encompasses multiple and, sometimes, complicated steps that hinder reproducibility and yield. Affinity chromatography is an efficient way to simplify and improve protein purification, however often requiring an expensive and fragile stationary phase. In this regard, automated flow-based systems minimize the time for extraction of species from solid samples without hindering the features of batch procedures. In this work, a new inexpensive affinity-based stationary phase was developed for in-line separation of jacalin, a galactose-binding lectin from jackfruit seeds. In the flow manifold, in-line extraction of proteins was also carried out with continuous monitoring using the spectrophotometric Biuret assay. For protein determination, linear response was observed from 3.0 to 15 g L -1 . The results of the analysis of protein extracts from jackfruit seeds obtained with the herein described procedure and batch procedure agreed with 95% confidence level. Quantitative extraction of proteins from jackfruit seed powder required recirculation of extraction buffer for 15 min through a lab-made polymethylmethacrylate (PMMA) column containing 200 mg of the crude seed powder. In the chromatographic step, jacalin was isolated after 300 s. Therefore, three essential steps for jacalin isolation were performed in one manifold in a fast way, minimizing sample consumption and solution handling. Additionally, the versatile and multi-task developed flow manifold can be useful for routine analysis and preparative procedures, being adaptable for the extraction and separation of other species from solid matrixes with continuous monitoring of the processes., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: Evidence is lacking concerning the myriad surgical techniques for type 1 Chiari malformation. This study evaluated the impact of arachnoid violation with tonsil thermocoagulation during surgical craniovertebral junction decompression., Methods: The evaluation included aspects of the neurologic examination and parameters of cerebrospinal fluid flow on magnetic resonance imaging during preoperative and postoperative periods. All patients underwent craniovertebral junction decompression and opening of the dura mater. Patients were divided into 2 study groups. Patients in group 1 did not undergo arachnoid violation. Patients in group 2 underwent tonsil manipulation and systematic opening of the fourth ventricle outlet., Results: There were 16 patients enrolled in each group (total of 32 patients). Regarding clinical improvement, there were no significant differences between groups in the postoperative period. Group 2 had more adverse events (relative risk 2.45, 95% confidence interval 1.55-3.86). In terms of cerebrospinal fluid flow parameter analyses, patients in group 1 achieved better results (P < 0.05)., Conclusions: For treatment of symptomatic type 1 Chiari malformation, craniovertebral junction decompression with arachnoid preservation (i.e., without tonsillar manipulation) seems more suitable than the addition of arachnoid opening and thermocoagulation of the tonsils., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Geraniol is a monoterpene alcohol that is derived from the essential oils of aromatic plants, with anti-inflammatory, antimicrobial, antioxidant and neuroprotective properties. This study characterized the effect of geraniol on behavior and brainwave patterns in rats. Male rats were submitted to administration of geraniol (25, 50 and 100 mg/kg). The hole board (HB) and open field (OF) tests were performed to evaluate anxiety and motor behavior, respectively. In addition, barbiturate-induced sleeping time (BIST) was used to analyze sedative effect. Finally, electrocorticogram (ECoG) recordings were used to characterize brain-wave patterns. The results showed that geraniol treatment in rats decreased the distance traveled, rearing numbers and lead to increase in immobility time in HB and OF tests. In BIST test, geraniol treatment increased sleep duration but not sleep latency in the animals. Furthermore, geraniol-treated animals demonstrated an increase in the percentage of delta waves in the total spectrum power. Taken together, our results suggested that geraniol exerted a depressant effect on the central nervous system of rats., (Copyright © 2018 Chang Gung University. Published by Elsevier B.V. All rights reserved.)

The aim of the present work was to develop a novel in-house mixed-mode SPE sorbent to be used for the HPLC-Ion TrapMS determination of 16 basic drugs in urine. By using a computational modelling, a virtual monomer library was screened identifying three suitable functional monomers, methacrylic acid (MAA), itaconic acid (IA) and 2-acrylamide-2-methylpropane sulfonic acid (AMPSA), respectively. Three different sorbents were then synthetized based on these monomers, and using as cross-linker trimethylolpropane trimethacrylate (TMPTMA). The sorbent characterization analyses brought to the selection of the AMPSA based phase. Using this novel in-house sorbent, a SPE-HPLC-Ion TrapMS method for drug analysis in urine was validated proving to be selective and accurate and showing a sensitivity adequate for toxicological urine analysis. The comparison of the in-house mixed-mode SPE sorbent with two analogous commercial mixed-mode SPE phases showed that the first one was better not only in terms of process efficiency, but also in terms of quality-price rate. To the best of our knowledge, this is the first time in which an in-house SPE procedure has been applied to the toxicological analysis of a complex matrix, such as urine., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Several studies have revealed that traditional risk factors are less effective in predicting CVD risk in the elderly, suggesting the need to identify new biomarkers. Here, we evaluated the association between serum cholesterol efflux capacity (CEC), an atheroprotective property of HDL recently identified as a novel marker of CVD risk, and atherosclerotic burden in a cohort of very old, healthy individuals. Serum CEC values were not significantly correlated either with calcium score or with markers of vulnerable plaque, such as positive remodeling, hypodensity, spotty calcification, or napking-ring sign. In addition, no association was detected between CEC and telomere length, a marker of biological aging that has been linked to atherosclerosis extent. Interestingly, elderly subjects presented a remarkably higher CEC (+30.2%; P < 0.0001) compared with values obtained from a cohort of sex-matched, cardiovascular event-free, middle-aged individuals. In conclusion, serum CEC is not related to traditional risk factors in very old, cardiovascular event-free subjects, but has significantly higher values compared with a healthy, younger population. Whether this improved HDL functionality may represent a protective factor in CVD onset must be established in future studies., (Copyright © 2018 by the American Society for Biochemistry and Molecular Biology, Inc.)