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Rangel de Sousa Costa,1 Luiz Celso Hygino da Cruz Jr,2 Simone Rachid de Souza,3 Nina Ventura,1 Diogo Goulart Corrêa2 1Department of Radiology, Paulo Niemeyer State Brain Institute, Rio de Janeiro, RJ, Brazil; 2Department of Radiology, Clínica de Diagnóstico por Imagem (CDPI)/DASA, Rio de Janeiro, RJ, Brazil; 3Department of Pathology, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, BrazilCorrespondence: Diogo Goulart Corrêa, Department of Radiology, Clínica de Diagnóstico por Imagem (CDPI)/DASA, Avenida das Américas, 4666, 302A, 303, 307, 325, 326, Rio de Janeiro, RJ, Brazil, Tel +55 21 993843617, Email diogogoulartcorrea@yahoo.com.brAbstract: Paracoccidioidomycosis (PCM) is a infection caused by the thermodimorphic fungus Paracoccidioides spp. (P. lutzii and, mainly, P. brasiliensis). This infection predominantly affects rural male workers aged between 30 and 50 years old who deal with soil on daily activities. Clinically, the disease is classified as acute/subacute phase, which evolves rapidly, secondary to dissemination of the fungus through to the phagocytic-mononuclear system, leading to fever, weight loss, and anorexia, associated with hepatosplenomegaly and lymphadenopathy, which can be complicated with suppuration and fistulization; and chronic phase, which corresponds to 74% to 95% of symptomatic cases, with a common pulmonary involvement. Central nervous system involvement is almost always a characteristic of the chronic form. Inhalation is the most common route of primary infection, usually affecting the lungs, forming the primary complex. From the primary complex, hematogenic dissemination can occur to any organ, including the brain and spinal cord. Although PCM of the central nervous system diagnosis is usually based on histopathological analysis and the imaging features are not specific for PCM, computed tomography and magnetic resonance imaging can demonstrate evidences of granuloma, abscess, meningitis, or a combination of these lesions, contributing to a preoperative diagnosis, especially when considered in conjunction with epidemiology. In this article, we review the pathophysiology, clinical manifestations and imaging aspects of neuro-PCM.Keywords: paracoccidioidomycosis, neuro-PCM, magnetic resonance imaging, granuloma, meningitis

Hypertension is related to the incidence of cardiovascular diseases. Family support is essential for the patient to control the disease. This study aimed to analyze whether the family positively contributes to the patient's control of the disease. The research was carried out in 2005 in Teresina, PI, Brazil and involved people who were enrolled in the Hypertension Program of an Integrated Health Center. Data were collected through individual interviews, using the Critical Incident Technique. After the content analysis, the element Consequence was identified in 146 references, 58 positive and 88 negative, composing four categories: Family, Financial, Health and Emotional Aspects. Difficulties in family relationships, patients' concern with their descendants, and the families' little involvement in the patients' care were identified through the reports. [ABSTRACT FROM AUTHOR]

Renal biopsies of 86 patients with lupus nephritis were assessed according to the WHO classification, and according to activity and chronicity indices. The aim of the present study was to correlate clinical, and histological features (WHO class, activity and chronicity indices, and α-SM actin expression) with the progression of lupus nephritis, and identify the pathological role of α-SM actin in lupus nephritis. The median follow-up time was 75.5±57.3 months. Two patients were grouped as WHO class IIa lupus nephritis, eight patients as class IIb, 16 patients as class III, 25 patients as class IV, 15 patients as class V, and 19 patients as mixed pattern lupus nephritis. Sex, age, race, and the α-SM actin expression in glomeruli and tubulo-interstitial area in WHO class III and IV showed no correlation with clinical follow-up outcome of lupus nephritis. Unfavorable clinical outcome of lupus nephritis was correlated with WHO class IV compared to the other classes, and with the chronicity index in WHO class III patients. [ABSTRACT FROM AUTHOR]

The share of solar power in Brazil's electrical grid has rapidly increased, relieving GHG emissions and diversifying energy sources for greater energy security. Besides that, solar resource is susceptible to climate change, adding uncertainty to electrical grid resilience. This study uses satellite and reanalysis data to evaluate the performance of CMIP6 models in replicating and predicting surface solar irradiance (SSR) in Brazil. The results from the most reliable models indicate an increase in SSR by 2% to 8% in most regions, with a decrease of around 3% in the South. These findings highlight the potential for increased photovoltaic (PV) yield if backed by supportive public policies while underlining the importance of uncertainty assessment of climate models., (© 2024. The Author(s).)

Background: Activation of the mitogen-activated protein kinase (MAPK) pathway induces uncontrolled cell proliferation in response to inflammatory stimuli. Adriamycin (ADR)-induced nephropathy (ADRN) in rats triggers MAPK activation and pro-inflammatory mechanisms by increasing cytokine secretion, similar to chronic kidney disease (CKD). Activation of the vitamin D receptor (VDR) plays a crucial role in suppressing the expression of inflammatory markers in the kidney and may contribute to reducing cellular proliferation. This study evaluated the effect of pre-treatment with paricalcitol on ADRN in renal inflammation mechanisms., Methods: Male Sprague-Dawley rats were implanted with an osmotic minipump containing activated vitamin D (paricalcitol, Zemplar, 6 ng/day) or vehicle (NaCl 0.9%). Two days after implantation, ADR (Fauldoxo, 3.5 mg/kg) or vehicle (NaCl 0.9%) was injected. The rats were divided into four experimental groups: control, n = 6; paricalcitol, n = 6; ADR, n = 7 and, ADR + paricalcitol, n = 7., Results: VDR activation was demonstrated by increased CYP24A1 in renal tissue. Paricalcitol prevented macrophage infiltration in the glomeruli, cortex, and outer medulla, prevented secretion of tumor necrosis factor-α, and interleukin-1β, increased arginase I and decreased arginase II tissue expressions, effects associated with attenuation of MAPK pathways, increased zonula occludens-1, and reduced cell proliferation associated with proliferating cell nuclear antigen expression. Paricalcitol treatment decreased the stromal cell-derived factor 1α/chemokine C-X-C receptor type 4/β-catenin pathway., Conclusions: Paricalcitol plays a renoprotective role by modulating renal inflammation and cell proliferation. These results highlight potential targets for treating CKD.

Objective: To identify the perceptions of veterinary students interested in specialization regarding veterinary anesthesiology., Study Design: Cross-sectional, multi-institutional, voluntary, anonymous, nonrandomized survey., Population: Veterinary students (303 of 557 total respondents) from 10 veterinary schools., Methods: Quantitative data were obtained via 5-point Likert scale questions about anesthesia-related topics. Open-ended questions were used to obtain qualitative data. A multivariate logistic regression model assessed the likelihood of choosing a career as an anesthesiologist. Spearman's rank correlation coefficient was used to assess the relationship between 'anesthesia is interesting' and other variables., Results: Of the respondents, 14 (6%) indicated veterinary anesthesia as their chosen specialty. There was a significant positive relationship between 'anesthesia is interesting' and the following variables: age, enjoyment in anesthesia class, belief in the importance of anesthesia for their career, belief in the importance of analgesia for their career, belief that anesthesia and analgesia have a large impact on patient care, interest in pharmacology, interest in physiology, interest in learning technical skills, belief that anesthesiologists are respected by their colleagues and belief that anesthesiologists are an important part of the health care team. More weeks on the anesthesia clinical rotation was positively and significantly associated with increased rotation enjoyment. Enjoyment in the anesthesia class [p = 0.001, Exp(β) = 2.1, 95% confidence interval (CI): 1.3-3.4] and belief that anesthesia is interesting [p = 0.013, Exp(β) = 2.6, 95% CI: 1.2-5.4] were predictors that respondents would be more likely to consider a career as a veterinary anesthesiologist., Conclusions: Those veterinary students with an interest in pharmacology and who enjoyed their anesthesia course were more likely to consider a career as a veterinary anesthesiologist. If students indicated no interest in specializing in veterinary anesthesia, they appreciated the value the specialty brings to animal care and believed that veterinary anesthesiologists are respected by their peers., (Copyright © 2024 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

Objectives: Giant cell arteritis (GCA) is the main systemic vasculitis in individuals aged ≥ 50 years. Color Doppler ultrasound (CDS) has an established role in GCA diagnosis and management. This study aims to assess the clinical characteristics associated with a positive CDS evaluation and the impact of additional axillary artery examination on diagnostic sensitivity., Material and Methods: We conducted a retrospective analysis of patients undergoing CDS of the superficial temporal arteries, with or without axillary artery assessment, at our hospital, between 2009 and 2023. Patients meeting the new 2022 diagnostic criteria for GCA were included and their characteristics were analyzed according to the presence of the halo sign on CDS., Results: Of the 135 included patients (54 % female, mean age 75 ± 8 years), the halo sign was observed in 57 %, correlating with higher systemic symptom prevalence (61 % vs 42 %, p = 0.035), lower hemoglobin (p < 0.001), and higher erythrocyte sedimentation rate (p = 0.028). The halo sign inversely related to prior corticosteroid therapy (p = 0.033). Patients with axillary halo sign had fewer external carotid symptoms and a higher vertebral halo sign prevalence. Vertebral halo sign was associated with posterior circulation ischemic stroke (65 %, p < 0.001). Axillary artery studies improved diagnostic sensitivity by 9 %., Conclusion: In our study, the halo sign correlated with higher systemic symptoms and analytical abnormalities. Axillary artery examination enhanced CDS sensitivity, linked to severe outcomes like stroke. Prior corticosteroid therapy reduced CDS sensitivity. The correlation of clinical, laboratory, and ultrasound findings provides a more comprehensive understanding of GCA pathogenesis and evolution., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier Inc.)

Objective: To determine the pharmacokinetics and physiological effects following oral and intravenous (IV) administration of gabapentin in goats., Study Design: Prospective, crossover study with a 3 week washout period between treatments., Animals: A total of eight healthy, client-owned, female goats., Methods: Gabapentin (10 mg kg -1 ) was administered to goats either orally or IV. Gabapentin concentrations were measured in serum samples collected 0-96 hours post-administration using liquid chromatography-quadrupole time-of-flight mass spectrometry. Heart rate, respiratory rate, blood pressure and temperature were recorded before and throughout the study. Correlations of the mean serum concentrations of gabapentin to those of each physiological parameter were determined using the Pearson method., Results: The mean and standard deviation of oral bioavailability for gabapentin was 60.9 ± 11.2%. Maximum serum concentration of gabapentin was lower following oral (1.19 ± 0.29 μg mL -1 ) than after IV administration (59.76 ± 14.38 μg mL -1 , p < 0.0001). Half-lives were longer following PO (8.18 ± 0.57 hours) than after IV administration (1.79 ± 0.06 hours, p < 0.0001). Time to maximum concentration was 6.86 ± 2.27 hours following oral administration. Heart rate was inversely correlated with serum gabapentin concentrations. Slight ataxia was observed in three animals, and one became recumbent following IV gabapentin., Conclusions and Clinical Relevance: Gabapentin is well-absorbed following oral administration to goats but yielded significantly lower serum concentrations than the IV route. The longer half-life of gabapentin following oral than after IV administration may result from prolonged absorption throughout the caprine gastrointestinal tract. IV gabapentin may cause slight ataxia in some goats., (Copyright © 2024 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

The increasing prevalence of omics data sources is pushing the study of regulatory mechanisms underlying complex diseases such as cancer. However, the vast quantities of molecular features produced and the inherent interplay between them lead to a level of complexity that hampers both descriptive and predictive tasks, requiring custom-built algorithms that can extract relevant information from these sources of data. We propose a transformation that moves data centered on molecules (e.g., transcripts and proteins) to a new data space focused on putative regulatory modules given by statistically relevant co-expression patterns. To this end, the proposed transformation extracts patterns from the data through biclustering and uses them to create new variables with guarantees of interpretability and discriminative power. The transformation is shown to achieve dimensionality reductions of up to 99% and increase predictive performance of various classifiers across multiple omics layers. Results suggest that omics data transformations from gene-centric to pattern-centric data supports both prediction tasks and human interpretation, notably contributing to precision medicine applications., (© 2024 Wiley Periodicals LLC.)

Differently from immunocompromised patients, very little information is available in the literature regarding the clinical presentation, epidemiology, and outcomes of histoplasmosis in non-immunosuppressed individuals living in endemic areas. This retrospective case series study was carried out by reviewing the medical records of non-immunocompromised patients with histoplasmosis, residents in a hyperendemic area in northeastern Brazil, between 2011 and 2022. Thirty HIV-negative patients were identified with histoplasmosis, and 19 cases met the inclusion criteria: three had acute, five subacute and one chronic pulmonary forms; two with mediastinal picture and eight had disseminated disease (two with severe symptoms). The median age of our sample was 32.7 years old [interquartile range: 24-45]. Most of the patients were male (male-to-female ratio = 15:4) and resided in the state capital (n = 9). The majority had a previous history of exposure to well-known risk factors for Histoplasma infection. Pulmonary nodules were observed in all subacute form, two patients (acute and subacute forms) were initially treated empirically for pulmonary tuberculosis; one death was registered in the subacute form. The chronic pulmonary form of histoplasmosis was diagnosed in one patient only after the symptoms persisted despite specific treatment. The primary clinical manifestations of the moderate form of DH were enlarged lymph nodes, with histopathology being the main diagnostic method. The cases were detected as isolated occurrences and not as an outbreak, suggesting that exposure to Histoplasma can be more widespread than presumed. Despite the self-limiting nature of the disease, death can occur even in previously heathy patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

Purpose: To compare children's stereometric optic disc parameters and inner retinal thickness measured by optical coherence tomography (OCT) in two different moments in life in the same children and to establish a correlation between the optic nerve head (ONH) area and the difference of these parameters in the two observations., Methods: In this observational cohort, children were evaluated on two occasions: at 6.7 ± 1.6 and 13.2 ± 0.7 years of age. Cup volume, neuroretinal rim (NRR) area, average cup-to-disc ratio, peripapillary retinal nerve fiber layer (pRNFL), and ganglion cell inner plexiform layer (GCIPL) were measured by the Cirrus HD-OCT (Carl Zeiss Meditec AG)., Results: A total of 175 children were included, 89 boys (50.9%) and 86 girls (49.1%). There was a significant decrease of the NRR area ( P < .001) and increase of the cup volume ( P < .001) on the second observation. The pRNFL thickness and GCIPL thickness also decreased ( P < .001 and P = .002, respectively). There was a positive correlation between the ONH area and the difference of the cup volume ( P = .047; r = 0.102) and a negative correlation with the difference of the NRR area ( P < .001; r = 0.237)., Conclusions: During childhood, there is an increase of the cup volume, a decrease of the NRR area, and a decrease of inner retinal layer thickness (more significant in the superior and inferior quadrants) measured by OCT. This study demonstrates that in children with large discs the enlargement of the cup and decrease of the NRR is more evident. Considering these changes, the physiological enlargement of the cup in a child with a large disc can be misinterpreted as the development of a glaucomatous lesion. [ J Pediatr Ophthalmol Strabismus . 20XX;X(X):XXX-XXX.] .

The expansion of the Internet of Things market and the proliferation of wearable technologies have generated a significant demand for textile-based energy storage systems. This work reports the engineered design of hybrid electrode nanomaterials of N-doped carbon nanotubes (CNT-N) functionalized with two types of manganese oxides (MOs)-birnessite (MnO 2 ) and hausmannite (Mn 3 O 4 )-and their application in solid-state textile-based hybrid supercapacitors (SCs). A versatile citric acid-mediated eco-friendly one-pot aqueous precipitation process is proposed for the fabrication of the hybrids. Remarkably, different types of MOs were obtained by simply changing the reaction temperature from room temperature to 100 °C, without any post -thermal treatment. Asymmetric textile SCs were developed using cotton fabrics coated with CNT-N and the hybrids as textile electrodes, and poly(vinyl) alcohol/orthophosphoric acid as the solid-gel electrolyte. The asymmetric devices presented enhanced energy storage performance relative to the symmetric device based on CNT-N and excellent cycling stability (>96%) after 8000 charge/discharge cycles owing to synergistic effects between CNT-N and the MOs, which endowed nonfaradaic and pseudocapacitive features to the SCs. The asymmetric SC based on CNT-N@MnO 2 featured 47% higher energy density and comparable power density to the symmetric CNT-N-based device (8.70 W h cm -2 at 309.01 μW cm -2 vs. 5.93 W h cm -2 at 346.58 μW cm -2 ). The engineered hybrid CNT-N@MO nanomaterials and the eco-friendly citric acid-assisted one-pot precipitation route open promising prospects not only for energy storage, but also for (photo)(electro)catalysis, wastewater treatment, and (bio)sensing., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

The role of the immune response in the pathogenesis of cutaneous leishmaniasis (CL) due to Leishmania (Viannia) braziliensis is predominantly carried out via blood cells. Here, we evaluate whether cytokine production by peripheral blood mononuclear cells (PBMCs) reflects what has been documented at the lesion site. The participants included 22 CL patients diagnosed with a positive PCR. PBMCs were stimulated for 72 h with a soluble leishmania antigen (SLA). Biopsies obtained from the edge of the ulcers were incubated for the same period. Cytokines in supernatants were assessed via ELISA. TNF, IL-1β, IL-6, IL-17, and granzyme B (GzmB) were higher in the supernatants of biopsies than in PBMCs, but IFN-γ was higher in the supernatants of PBMCs than in biopsies. There was a positive correlation between IFN-γ and TNF in PBMCs, and an inverse correlation between TNF and IL-10 in the cells from the lesion site. A strong correlation between IL-1β, IL-17, and GzmB was observed in the biopsies, and a positive correlation was detected between these cytokines and the lesion size. Our results indicate that the immune response in L. braziliensis lesions is different from that observed in peripheral blood, and our data suggest that in addition to IL-1β and GzmB, IL-17 participates in the pathology of CL., Competing Interests: The authors declare no conflicts of interest.

Recent research has revealed the significant impact of novel feed ingredients on fish gut microbiota, affecting both the immune status and digestive performance. As a result, analyzing the microbiota modulatory capabilities may be a useful method for assessing the potential functionality of novel ingredients. Therefore, this study aimed to evaluate the effects of dietary polychaete meal (PM) from Alitta virens on the autochthonous and allochthonous gut microbiota of European seabass ( Dicentrarchus labrax ). Two diets were compared: a control diet with 25% fishmeal (FM) and a diet replacing 40% of fishmeal with PM, in a 13-week feeding trial with juvenile fish (initial weight of 14.5 ± 1.0 g). The feed, digesta, and mucosa-associated microbial communities in fish intestines were analyzed using high-throughput sequencing of the 16S rRNA gene on the Illumina MiSeq platform. The results of feed microbiota analyses showed that the PM10 feed exhibited a higher microbial diversity than the FM diet. However, these feed-associated microbiota differences were not mirrored in the composition of digesta and mucosal communities. Regardless of the diet, the digesta samples consistently exhibited higher species richness and diversity than the mucosa samples. Overall, digesta samples were characterized by a higher abundance of Firmicutes in PM-fed fish. In contrast, at the gut mucosa level, the relative abundances of Mycobacterium , Taeseokella and Clostridium genera were lower in the group fed the PM10 diet. Significant differences in metabolic pathways were also observed between the FM and PM10 groups in both mucosa and digesta samples. In particular, the mucosal pathways of caffeine metabolism, phenylalanine metabolism, and sulfur relay system were significantly altered by PM inclusion. The same trend was observed in the digesta valine, leucine, and isoleucine degradation and secretion pathways. These findings highlight the potential of PM as an alternative functional ingredient in aquafeeds with microbiota modulatory properties that should be further explored in the future., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer FM declared a past collaboration with one of the author GT to the handling editor., (Copyright © 2023 Monteiro, Rimoldi, Costa, Kousoulaki, Hasan, Valente and Terova.)

Asthma is a respiratory disease caused by the interaction of genetic and environmental factors. The adenylyl cyclase type 9 (ADCY9) enzyme produces the cyclic-adenosinemonophosphate (cAMP), important mediator involved in bronchodilation and immunomodulatory response. The aim of this study was to investigate if rs2601796 and rs2532019 variants in the ADCY9 gene are associated with asthma and lung function. The study comprised 1,052 subjects. Logistic regressions were done using PLINK 1.9 adjusted by sex, age, BMI, smoke and principal components. Bronchodilator responsiveness was assessed using the percentage of difference in FEV1 before and after the bronchodilator use. The in silico analysis for gene expression was performed in the GTEx Portal. The variant rs2601796 (AA/AG genotype) was positively associated with asthma severity (OR: 1.60 IC95%: 1.08-2.39) and with obstruction in individuals with severe asthma (OR: 3.10, IC95%: 1.11-8.62). Individuals with severe asthma and the AA/AG genotype of rs2601796 had less responsiveness to bronchodilators and also a lower expression of ADCY9 in lung and whole blood. The variant rs2532019 (TT/GT genotype) also downregulated the ADCY9 gene expression, but no significant association with the studied phenotypes was found. Thus, the variant in ADCY9 was associated with worse asthma outcomes, including a lower response to bronchodilators, likely due to the impact on its gene expression rate. This variant may be useful in the future to assist in personalized management of patients with asthma., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Álvaro A. Cruz: Reports grants from: i. CNPq (Brazil) - National Research Council; ii. FAPESB - State agency for research in Bahia; iii. GSK, during the conduct of the study (Investigator initiated grant). Reports personal fees from: i. SANOFI (Advisor, lecturer and conduction of clinical trial); ii. AstraZeneca (Advisor, lecturer and conduction of clinical trial); iii. GSK (Advisor); iv. Boehringer-Ingelheim (Advisor, lecturer and developer of educational materials); v. Novartis (Lecturer and developer of educational materials); vi. Mantecorp (Advisor, lecturer and developer of educational materials); vii. EUROFARMA (Lecturer and developer of educational materials); viii. Mylan (Advisor, lecturer and developer of educational materials). The other authors declare that have no relevant conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Gastric neoplasms have different histological subtypes. Mixed neuroendocrine/non neuroendocrine neoplasms (MiNEN), as defined by the World Health Organization (WHO) 2019 Classification of Tumours of the Digestive System, are rare composite tumours bearing morphological characteristics of more than one histological type. Historically, the diagnosis requires that each component accounts for at least 30% of the total tumour burden. We present the case of a 70-year-old male, who was referred to our endoscopy unit for resection of a depressed lesion (Paris classification type 0 IIc) of 40mm in largest diameter, located on the lesser curvature of the gastric body. The lesion was submitted to en bloc resection by endoscopic submucosal dissection. Histological examination revealed a poorly differentiated intramucosal adenocarcinoma and a grade G3 well differentiated neuroendocrine tumour (NET), on a background of chronic atrophic gastritis. Unfortunately, examination of the NET component revealed intercepted margins. The patient is currently undergoing tumour staging and will be discussed by a multidisciplinary team to determine subsequent management.

The accurate prediction of phenotypes in microorganisms is a main challenge for systems biology. Genome-scale models (GEMs) are a widely used mathematical formalism for predicting metabolic fluxes using constraint-based modeling methods such as flux balance analysis (FBA). However, they require prior knowledge of the metabolic network of an organism and appropriate objective functions, often hampering the prediction of metabolic fluxes under different conditions. Moreover, the integration of omics data to improve the accuracy of phenotype predictions in different physiological states is still in its infancy. Here, we present a novel approach for predicting fluxes under various conditions. We explore the use of supervised machine learning (ML) models using transcriptomics and/or proteomics data and compare their performance against the standard parsimonious FBA (pFBA) approach using case studies of Escherichia coli organism as an example. Our results show that the proposed omics-based ML approach is promising to predict both internal and external metabolic fluxes with smaller prediction errors in comparison to the pFBA approach. The code, data, and detailed results are available at the project's repository[1]., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could influence the work reported in this paper. Any opinions, findings, conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the funding bodies. Therefore, the authors declare that they have no conflicts of interest., (© 2023 The Authors.)

Introduction: Hybrid modeling combining First-Principles with machine learning is becoming a pivotal methodology for Biopharma 4.0 enactment. Chinese Hamster Ovary (CHO) cells, being the workhorse for industrial glycoproteins production, have been the object of several hybrid modeling studies. Most previous studies pursued a shallow hybrid modeling approach based on three-layered Feedforward Neural Networks (FFNNs) combined with macroscopic material balance equations. Only recently, the hybrid modeling field is incorporating deep learning into its framework with significant gains in descriptive and predictive power. Methods: This study compares, for the first time, deep and shallow hybrid modeling in a CHO process development context. Data of 24 fed-batch cultivations of a CHO-K1 cell line expressing a target glycoprotein, comprising 30 measured state variables over time, were used to compare both methodologies. Hybrid models with varying FFNN depths (3-5 layers) were systematically compared using two training methodologies. The classical training is based on the Levenberg-Marquardt algorithm, indirect sensitivity equations and cross-validation. The deep learning is based on the Adaptive Moment Estimation Method (ADAM), stochastic regularization and semidirect sensitivity equations. Results and conclusion: The results point to a systematic generalization improvement of deep hybrid models over shallow hybrid models. Overall, the training and testing errors decreased by 14.0% and 23.6% respectively when applying the deep methodology. The Central Processing Unit (CPU) time for training the deep hybrid model increased by 31.6% mainly due to the higher FFNN complexity. The final deep hybrid model is shown to predict the dynamics of the 30 state variables within the error bounds in every test experiment. Notably, the deep hybrid model could predict the metabolic shifts in key metabolites (e.g., lactate, ammonium, glutamine and glutamate) in the test experiments. We expect deep hybrid modeling to accelerate the deployment of high-fidelity digital twins in the biopharma sector in the near future., Competing Interests: Authors SR and PD were employed by GSK group of companies. The authors declare that this study received funding from GlaxoSmithKline Biologicals SA, Rixensart, Belgium. The funder had the following involvement in the study: bioreactor cultivations, data acquisition and analytics were performed at the funder laboratories. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Pinto, Ramos, Costa, Rossell, Dumas and Oliveira.)

Identifying individuals and factors associated with severe cases of COVID-19 is crucial as the pandemic continues to spread globally. Effective biomarkers for predicting severe cases are essential for optimizing clinical management, therapy, and preventing unfavorable outcomes. This exploratory observational study aimed to investigate the expression of dysregulated immune response genes (ARG1, NOS2, ITGA4, and SELPLG) in total leukocytes, plasmatic levels of P-selectin and PSGL-1, and their clinical associations in patients with mild and severe COVID-19. Data from 117 confirmed COVID-19 patients (severe = 58, mild = 59) were collected upon admission. Gene expression was measured using RT-qPCR, and plasma protein levels assessed with ELISA assay. The severe COVID-19 patient group had a higher median age of 62.0 (p = 0.0001), a higher proportion of black individuals (86.2%, p < 0.0001), and more males (65.5%, p = 0.007). The neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) were significantly higher in the severe COVID-19 patient group (p < 0.0001), indicating ongoing systemic inflammation. Severe COVID-19 patients also exhibited increased expression of ARG1 (p < 0.05) and SELPLG (p < 0.0001) genes, as well as higher concentrations of soluble P-selectin (p < 0.005) and PSGL-1 (p < 0.05) proteins. Multivariate analysis revealed that NLR, PLR, the expression of SELPLG and sPSGL-1 were independent predictors of COVID-19 severity. In conclusion, this study suggests that biomarkers of endothelial dysfunction and dysregulated leukocyte responses are associated with COVID-19 severity, serving as promising predictive tools for optimizing clinical management and patient monitoring., 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.)

This study evaluated the technological viability of yogurt with the addition of green-banana biomass (Musa spp.) considering the resistant starch (BBV) as a potential prebiotic ingredient and texture agent. Four yogurt formulations were prepared: control; 3% BBV; 5% BBV; and 10% BBV. They were subjected to analysis of resistant starch, lactose, fat, total dry extract, defatted dry extract, moisture, ash, proteins, pH and titratable acidity; syneresis analysis, instrumental texture and instrumental color. All four formulations met the requirements of the identity and quality regulation for fermented milks regarding the physicochemical and microbiological parameters. In the instrumental color analysis, in all treatments with added BBV, darkening was observed after 21 days, with a reduction of a* coordinate and an increase of b* coordinate. In the instrumental texture analysis, the yogurt in the Control treatment had the highest firmness (0.430 N) at 21 days among these treatments. Among the treatments with added BBV, the yogurt with 5% added BBV showed the best results for increasing the viability of lactic bacteria. It was found that yogurt with added BBV is a promising alternative in the elaboration of functional dairy products, adding value to the banana production chain by reducing the green fruit waste.

Objective: To evaluate sedative and behavioral effects of a client-administered preappointment protocol with PO gabapentin and melatonin and oral-transmucosal acepromazine (GMA protocol)., Animals: 45 client-owned dogs between 1 and 12 years old that underwent standardize examinations between February and August 2021., Methods: In this clinical trial, dogs with a history of anxiety, fearfulness, and/or aggression during hospital visits were assessed and videotaped before (baseline) and after administration of the GMA protocol. For the second visit, owners administered PO gabapentin (20 to 25 mg/kg) in the evening prior to the next visit and PO gabapentin (20 to 25 mg/kg), PO melatonin (3 to 5 mg/dog), and oral-transmucosal acepromazine (0.05 mg/kg) 90 to 120 minutes prior to the second appointment. Examinations were performed, and behavioral stress and sedation levels were evaluated with semiquantitative rating scales. Randomized videos were analyzed, and a paired t test was used to compare stress and sedation scores between baseline and GMA. A Pearson correlation coefficient was used to evaluate the effect of age on the scores., Results: Stress scores were significantly lower after the GMA protocol, and sedation scores were significantly higher when compared to baseline (21.84 vs 27.11 and 1.39 vs 0.68, respectively). A significant correlation between increasing age and lower stress scores post-GMA and higher sedation scores post-GMA were observed., Clinical Relevance: Preappointment administration of the GMA protocol reduced signs of stress, fear, and fear-based aggression during hospital visits and provided sedation in this dog population. This protocol could represent an adjunct tool for veterinarians to improve quality of care and reduce animal-related injury.

Background: The presence of food insecurity in households headed by older people is related to social inequalities. The objective of this study was to analyze the prevalence and factors associated with moderate/severe food insecurity in households headed by older people., Methods: A cross-sectional study based on a nationally representative sample of older adults aged ≥ 60 years was conducted using data from the 2017/2018 Family Budget Survey. In the study, moderate/severe food insecurity was the dependent variable, with food insecurity assessed with the Brazilian Household Food Insecurity Measurement Scale. Prevalence and odds ratio estimates were generated with 99% confidence intervals. Data analysis was performed using STATA software., Findings: A total of 16,314 households headed by older people were identified. Approximately 10.1% of these households were in the moderate/severe range for food insecurity. The majority are female (11.9%)and self-declared indigenous people (25.5%), with a lack of schooling (18.3%) and a per capita income of up to half of one minimum wage (29.6%). The analysis model found that color/race, region, schooling, per capita household income, and social benefits received in the household were statistically significant factors (p value < 0.01)., Conclusion: Moderate/severe food insecurity in households headed by older people is associated with the pronounced social inequalities present in Brazil, and these findings intensify the need for additional study of the challenges faced by this age group., (© 2023. The Author(s).)

Background: Despite the advancements in multiagent chemotherapy in the past years, up to 10% of Hodgkin's Lymphoma (HL) cases are refractory to treatment and, after remission, patients experience an elevated risk of death from all causes. These complications are dependent on the treatment and therefore an increase in the prognostic accuracy of HL can help improve these outcomes and control treatment-related toxicity. Due to the low incidence of this cancer, there is a lack of works comprehensively assessing the predictability of treatment response, especially by resorting to machine learning (ML) advances and high-throughput technologies., Methods: We present a methodology for predicting treatment response after two courses of Adriamycin, Bleomycin, Vinblastine and Dacarbazine (ABVD) chemotherapy, through the analysis of gene expression profiles using state-of-the-art ML algorithms. We work with expression levels of tumor samples of Classical Hodgkin's Lymphoma patients, obtained through the NanoString's nCounter platform. The presented approach combines dimensionality reduction procedures and hyperparameter optimization of various elected classifiers to retrieve reference predictability levels of refractory response to ABVD treatment using the regulatory profile of diagnostic tumor samples. In addition, we propose a data transformation procedure to map the original data space into a more discriminative one using biclustering, where features correspond to discriminative putative regulatory modules., Results: Through an ensemble of feature selection procedures, we identify a set of 14 genes highly representative of the result of an fuorodeoxyglucose Positron Emission Tomography (FDG-PET) after two courses of ABVD chemotherapy. The proposed methodology further presents an increased performance against reference levels, with the proposed space transformation yielding improvements in the majority of the tested predictive models (e.g. Decision Trees show an improvement of 20pp in both precision and recall)., Conclusions: Taken together, the results reveal improvements for predicting treatment response in HL disease by resorting to sophisticated statistical and ML principles. This work further consolidates the current hypothesis on the structural difficulty of this prognostic task, showing that there is still a considerable gap to be bridged for these technologies to reach the necessary maturity for clinical practice., (© 2023. The Author(s).)

Background: Diabetic kidney disease (DKD) remains one of the main causes of end-stage renal disease (ESRD) and mortality in diabetic patients worldwide. Vitamin D deficiency (VitDD) is one of the main consequences of different chronic kidney disease (CKD) types and is associated with rapid progression to ESRD. Nevertheless, the mechanisms that lead to this process are poorly understood. This study aimed to characterize a model of diabetic nephropathy progression in VitDD and the epithelial-mesenchymal-transition (EMT) role in these processes., Methods: Wistar Hannover rats received a diet with or without VitD before type 1 diabetes (T1D) induction. After this procedure, the rats were accompanied for 12 and 24 weeks after T1D induction and the renal function, structure, cell transdifferentiating markers and zinc finger e-box binding homeobox 1/2 (ZEB1/ZEB2) contribution to kidney damage were evaluated during the DKD progression., Results: The results showed an increase in glomerular tuft, mesangial and interstitial relative areas and renal function impairment in VitD-deficient diabetic rats compared to diabetic rats that received a VitD-containing diet. These alterations can be associated with increased expression of EMT markers, ZEB1 gene expression, ZEB2 protein expression and TGF-β1 urinary excretion. Decreased miR-200b expression, an important post-transcriptional regulator of ZEB1 and ZEB2 was also observed., Conclusion: Our data demonstrated that VitD deficiency contributes to the rapid development and progression of DKD in diabetic rats induced by increase ZEB1/ZEB2 expressions and miR-200b downregulation., (© 2023. The Author(s).)

Understanding the effects of diabetes and hyperglycemia on hydration, acid-base status, and immune function is paramount to safely anesthetizing diabetic cats and dogs. Preoperative stabilization of glucose concentrations, hydration, and electrolyte imbalances is key to minimizing morbidity and mortality. Blood glucose monitoring perioperatively will help guide insulin and dextrose administration. Specific anesthetic considerations, and peri-anesthetic management of animals with diabetes mellitus, including anesthetic drugs and recommended insulin protocols are discussed., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: Pain assessment in veterinary medicine is challenging. Uncertainty in the ability to recognise pain in animals contributes to suboptimal analgesia. Pain scales have been developed to aid in pain recognition. It is unknown if such scales are routinely utilised in veterinary practices., Materials and Methods: A survey using RedCap software was emailed to veterinarians and veterinary technicians working in practices across the USA. This study aimed to investigate whether pain scoring was routinely performed and reasons to use or not use pain scales. One hundred and forty-four participants were required to estimate prevalence (95% confidence level, 5% precision) with hypothesised prevalence of approximately 10%., Results: One hundred and forty-seven participants completed the survey. Seventy (47.6%) responded that pain scoring was performed in their practices, 24 (16.3%), reported "sometimes" and 53 (36.1%) reported pain scores were not performed. Reasons for not pain scoring included no training (51.9%) and busy caseload (48.1%). Disadvantages of pain scales were unreliability (16/82; 20%), duration required for completion (14/82; 17%) and vocalisation (14/82; 17%)., Clinical Significance: Almost 50% of the small animal practices surveyed reported the use of pain scales as part of their routine workflow. However, many practices still do not consistently utilise pain scales to assess pain in dogs and cats. Perceived unreliability and lack of compliance were reasons for this result. Improvement of training and proper pain scale introduction and implementation in small animal practices in the USA appears to be required., (© 2022 British Small Animal Veterinary Association.)

Background: Acute kidney injury is a frequent cause of hospital readmission in kidney transplant recipients (KTR), usually associated with infections and graft rejection. Herein, we report a case of an unusual cause of acute kidney injury in a KTR (massive histiocytes renal interstitial infiltration)., Case Presentation: A 40-year-old woman was submitted to a second kidney transplant. One year after surgery, she presented asthenia, myalgia, and fever, haemoglobin 6.1 g/dL; neutrophils: 1.3 × 109/µL; platelets: 143 × 109/µL; blood creatinine 11.8 mg/dL, requiring dialysis. A kidney biopsy revealed diffuse histiocytic infiltration, which was assumed due to dysregulated immunological activation triggered by infections. The patient had multiple infections, including cytomegalovirus infection (CMV), aspergillosis, bacteraemia, and urinary tract infections, which could trigger the immune response. Haemophagocytic lymphohistiocytosis (HLH) was ruled out. The present case highlights the occurrence of isolated massive renal interstitial infiltration of histiocytes that does not meet the criteria for HLH or other related pathologies., Conclusions: Renal histiocyte activation and infiltration may have been initiated by an immunological mechanism similar to what occurs in HLH and infectious processes. The present case highlights the occurrence of isolated massive renal interstitial infiltration of histiocytes that does not meet the criteria for HLH or other related pathologies., (© 2023. The Author(s).)

Niemann-Pick type C1 (NPC1) is an endolysosomal transmembrane protein involved in the export of cholesterol and sphingolipids to other cellular compartments such as the endoplasmic reticulum and plasma membrane. NPC1 loss of function is the major cause of NPC disease, a rare lysosomal storage disorder characterized by an abnormal accumulation of lipids in the late endosomal/lysosomal network, mitochondrial dysfunction, and impaired autophagy. NPC phenotypes are conserved in yeast lacking Ncr1, an orthologue of human NPC1, leading to premature aging. Herein, we performed a phosphoproteomic analysis to investigate the effect of Ncr1 loss on cellular functions mediated by the yeast lysosome-like vacuoles. Our results revealed changes in vacuolar membrane proteins that are associated mostly with vesicle biology (fusion, transport, organization), autophagy, and ion homeostasis, including iron, manganese, and calcium. Consistently, the cytoplasm to vacuole targeting (Cvt) pathway was increased in ncr1 ∆ cells and autophagy was compromised despite TORC1 inhibition. Moreover, ncr1 ∆ cells exhibited iron overload mediated by the low-iron sensing transcription factor Aft1. Iron deprivation restored the autophagic flux of ncr1 ∆ cells and increased its chronological lifespan and oxidative stress resistance. These results implicate iron overload on autophagy impairment, oxidative stress sensitivity, and cell death in the yeast model of NPC1.

Summary: Here, we present sbml2hyb, an easy-to-use standalone Python tool that facilitates the conversion of existing mechanistic models of biological systems in Systems Biology Markup Language (SBML) into hybrid semiparametric models that combine mechanistic functions with machine learning (ML). The so-formed hybrid models can be trained and stored back in databases in SBML format. The tool supports a user-friendly export interface with an internal format validator. Two case studies illustrate the use of the sbml2hyb tool. Additionally, we describe HMOD, a new model format designed to support and facilitate hybrid models building. It aggregates the mechanistic model information with the ML information and follows as close as possible the SBML rules. We expect the sbml2hyb tool and HMOD to greatly facilitate the widespread usage of hybrid modeling techniques for biological systems analysis., Availability and Implementation: The Python interface, source code and the example models used for the case studies are accessible at: https://github.com/r-costa/sbml2hyb., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2023. Published by Oxford University Press.)

Objective: To evaluate the effects of alfaxalone administered IM with or without buprenorphine or hydromorphone in healthy rabbits (Oryctolagus cuniculus)., Animals: 24 male rabbits undergoing elective orchiectomy between August 21, 2021, and November 6, 2021., Procedures: In this controlled clinical trial, rabbits were randomly assigned to receive alfaxalone (4 mg/kg, IM) alone (group A; n = 8) or with buprenorphine (0.03 mg/kg, IM; group BA; 8) or hydromorphone (0.1 mg/kg, IM; group HA; 8). Vital signs and sedation scores were recorded immediately prior to (T0) and 10 minutes after (T1) treatment. Ease of IV catheter placement and pain scores were also evaluated. All rabbits received ketamine (2.5 mg/kg, IV), midazolam (0.13 mg/kg, IV), and meloxicam (0.5 mg/kg, SC) before orchiectomy but after IM treatments. Results were compared across groups with ANOVA or Fisher exact tests and across time with paired t tests., Results: Sedation score, median time to recumbency, and ease of catheter placement did not differ among groups. Supraglottic airway device placement was possible for 1 rabbit in group A, 1 in group BA, and 2 in group HA. Mean respiratory rate at T1 versus T0 was significantly decreased for groups BA (63.8 vs 128.6 breaths/min) and HA (66.7 vs 123.2 breaths/min). Mean postoperative pain scores were significantly lower for rabbits in group HA (0.58), compared with those in groups A (2.25) and BA (2.06)., Clinical Relevance: All 3 treatments provided reliable sedation; however, alfaxalone (4 mg/kg, IM) combined with hydromorphone (0.1 mg/kg, IM) may be a better choice for painful procedures.