Optimizing Socket-Tunnel Position for Meniscal Allograft Transplantation Combined With ACL Reconstruction: A 3D Model Analysis.

Background: Socket-tunnel overlap during meniscal allograft transplantation (MAT) combined with anterior cruciate ligament reconstruction (ACLR) may compromise graft integrity and lead to impaired fixation and treatment failure. Purpose/Hypothesis: The purpose of this study was to determine optimal socket-tunnel drilling parameters for medial and lateral MAT with concurrent ACLR using artificial tibias and computed tomography (CT) scans for 3-dimensional (3D) modeling. It was hypothesized that clinically relevant socket tunnels could be created to allow for concurrent medial or lateral MAT and ACLR without significant risk for overlap at varying tunnel guide angles. Study Design: Descriptive laboratory study. Methods: A total of 27 artificial right tibias (3 per subgroup) were allocated to 9 experimental groups based on the inclination of the socket tunnels (55°, 60°, and 65°) created for simulating medial and lateral MAT and ACLR. Five standardized socket tunnels were created for each tibia using arthroscopic guides: one for the ACL tibial insertion and one for each meniscus root insertion. CT scans were performed for all specimens and sequentially processed using computer software to produce 3D models for quantitative assessment of socket-tunnel overlap risk. Statistical analysis was performed with Kruskal-Wallis and Mann-Whitney U tests. Results: No subgroup consistently presented significantly safer distances than other subgroups for all distances measured. Three cases (11%) and 24 cases (~90%) of tunnel overlap occurred between the ACL tunnel and tunnels for medial and lateral MAT, respectively. Most socket-tunnel overlap (25 of 27; 92.6%) occurred between sockets at depths ranging between 6.3 and 10 mm from the articular surface. For ACLR and posterior root of the lateral meniscus setting, the guide set at 65° increased socket-tunnel distances. Conclusion: When combined ACLR and MAT using socket tunnels for graft fixation is performed, the highest risk for tibial socket-tunnel overlap involves the ACLR tibial socket and the lateral meniscus anterior root socket at a depth of 6 to 10 mm from the tibial articular surface. Clinical Relevance: Setting tibial guides at 65° to the tibial articular surface with the tunnel entry point anteromedial and socket aperture location within the designated anatomic "footprint" will minimize the risk for socket-tunnel overlap.

Recent Developments in the Biosynthesis of Aziridines.

Only 0.016% of all known natural products contain an aziridine ring, but this unique structural feature imparts high reactivity and cytotoxicity to the compounds in which it is found. Until 2021, no naturally occurring azirdine-forming enzymes had been identified. Since 2021, the biosynthetic enzymes for ~10% of known aziridine containing natural products have been identified and characterized. This article describes the recent advances in our understanding of enzyme-catalyzed aziridine formation in the context of historical means of azirdine formation through synthetic chemistry.

Brown spiders (Loxosceles) are taking hold in Pernambuco, Brazil: a case series, 2018-2022.

OBJECTIVE: To describe accidents involving brown spider (genus Loxosceles) bites notified by the Pernambuco Poison Information and Care Center (CIATox-PE), Brazil, from January 2018 to December 2022. METHODS: This was a case series study of brown spider bites notified by the CIATox-PE. RESULTS: The study included 22 cases with median age of 35 years, the majority being female (13); the cases occurred in rural and urban areas (12 versus 10), at night (10); Petrolina was the municipality with the highest number of notifications (6); spider bites occurred mainly in the lower (11) and upper (9) limbs, almost exclusively inside households (21); specific serum therapy was not indicated for 8 cases because the time for its effectiveness had already elapsed. CONCLUSION: Loxoscelism cases occurred more frequently in females, in both rural and urban areas and mainly at home, with delays in seeking medical care. MAIN RESULTS: The 22 cases described represent an alert for the presence of a venomous species not reported in previous studies in Pernambuco. The severity of cases may be associated with delays in seeking medical care, especially due to the population's lack of information. IMPLICATIONS FOR SERVICES: Identify the presence of brown spiders in households in the region and the potential severity of poisonings. Alert health professionals to recognize the clinical picture with a view to appropriate early treatment. PERSPECTIVES: Develop research on poisoning by venomous animals and educational actions alerting the population to prevent these accidents and updating health professionals on care.

Outcomes after Anatomic Double-Bundle Posterior Cruciate Ligament Reconstructions Using Transtibial and Tibial Inlay Techniques.

Surgical reconstruction is recommended for symptomatic posterior cruciate ligament (PCL) deficiency. While anatomic double-bundle PCL reconstruction (PCLR) has been reported to be associated with biomechanical and clinical advantages over other methods, there is still debate regarding the optimal technique for tibial positioning and fixation. Based on reported advantages and disadvantages, we employed two tibial fixation techniques, transtibial (TT) and tibial inlay (TI) for anatomic double-bundle PCLR with technique selection based on body mass index, comorbidities, and primary versus revision surgery. This study aimed to compare clinical outcomes following PCLR utilizing either TT or TI techniques to validate relative advantages, disadvantages, and indications for each based on the review of prospectively collected registry data. For 37 patients meeting inclusion criteria, 26 underwent arthroscopic TT PCLR using all-soft- tissue allograft with suspensory fixation in the tibia and 11 patients underwent open TI PCLR using an allograft with calcaneal bone block and screw fixation in the tibia. There were no significant preoperative differences between cohorts. Success rates were 96% for TT and 91% for TI with all successful cases documented to be associated with good-to-excellent posterior stability and range of motion in the knee at the final follow-up. In addition, patient-reported outcome scores were within clinically meaningful ranges for pain, function, and mental health after PCLR in both cohorts, suggesting similarly favorable functional, social, and psychological outcomes. Patient-reported pain scores at 6 months postoperatively were significantly (p = 0.042) lower in the TT cohort, which was the only statistically significant difference in outcomes noted. The results of this study support the use of TT and TI techniques for double-bundle anatomic PCLR in restoring knee stability and patient function when used for the treatment of isolated and multiligamentous PCL injuries. The choice between tibial fixation methods for PCLR can be appropriately based on patient and injury characteristics that optimize respective advantages for each technique.

Brown spiders (Loxosceles) are taking hold in Pernambuco, Brazil: a case series, 2018-2022 / Las arañas marrones (Loxosceles) están instalándose en Pernambuco, Brasil: serie de casos, 2018-2022 / As aranhas-marrons (Loxosceles) estão se estabelecendo em Pernambuco: série de casos, 2018-2022

ABSTRACT Objective To describe accidents involving brown spider (genus Loxosceles) bites notified by the Pernambuco Poison Information and Care Center (CIATox-PE), Brazil, from January 2018 to December 2022. Methods This was a case series study of brown spider bites notified by the CIATox-PE. Results The study included 22 cases with median age of 35 years, the majority being female (13); the cases occurred in rural and urban areas (12 versus 10), at night (10); Petrolina was the municipality with the highest number of notifications (6); spider bites occurred mainly in the lower (11) and upper (9) limbs, almost exclusively inside households (21); specific serum therapy was not indicated for 8 cases because the time for its effectiveness had already elapsed. Conclusion Loxoscelism cases occurred more frequently in females, in both rural and urban areas and mainly at home, with delays in seeking medical care.

RESUMEN Objetivo Describir accidentes causados ​​por arañas pardas (género Loxosceles) notificados por el Centro de Información de Asistencia Toxicológica de Pernambuco (CIATox-PE), Brasil, de enero de 2018 a diciembre de 2022. Métodos Reporte de 22 casos notificados de CIATox-PE. Resultados Casos con media de idade de 35 años, predominio femenino (13); los casos ocurrieron en área rural/urbana (12 versus 10), por la noche (10); Petrolina fue el municipio con más notificaciones (6); las picaduras fueron principalmente en los miembros inferiores (11) y superiores (9), casi exclusivamente en el interior de las viviendas (21); en 8 de los casos no se indicó sueroterapia específica por haber superado el tiempo de efecto. Conclusión Los casos de loxoscelismo ocurrieron con mayor frecuencia en el sexo femenino, en áreas rurales y urbanas, y principalmente en el hogar, con demoras en la búsqueda de atención médica.

RESUMO Objetivo Descrever os acidentes por picada de aranhas-marrons (gênero Loxosceles), notificados no Centro de Informação de Assistência Toxicológica de Pernambuco (CIATox-PE), Brasil, no período de 2018 a 2022. Métodos Estudo de série, sobre casos notificados no CIATox-PE. Resultados Foram incluídos 22 casos com mediana de idade de 35 anos e houve predomínio do sexo feminino (13); os casos ocorreram nas zonas rural e urbana (12 versus 10), durante a noite (10), e Petrolina foi o município com mais notificações (6); as picadas ocorreram, principalmente, nos membros inferiores (11) e superiores (9), quase exclusivamente dentro das residências (21); para 8 acidentados, não se prescreveu soroterapia específica por terem ultrapassado o tempo de efetividade. Conclusão Os casos de loxoscelismo ocorreram com maior frequência no sexo feminino, nas zonas rural e urbana indiferentemente, quase todos foram intradomiciliares e houve demora na procura por atendimento médico.

Usefulness, Reliability, Quality, and Content of Portuguese Language YouTube Videos on COVID-19

Abstract Objective: To investigate the usefulness, reliability, quality, and content of Portuguese-language YouTube videos on COVID-19. Material and Methods: Three keywords selected on Google Trends were searched on YouTube, and the 60 first videos listed with each term were analyzed. Two calibrated researchers evaluated the reliability (DISCERN Modified Scale), the quality (Global Quality Score - GQS), and the usefulness of videos for the users (COVID-19 Specific Score - CSS). The number of views, likes, and engagement were also analyzed. The data were evaluated by the Mann-Whitney test and Spearman correlation (α=5%). Results: 59 videos were included. The average scores of quality, reliability, and usefulness were 3.0 (±1.1), 3.2 (± 0.8), and 1.5 (± 0.9), respectively. Two-thirds of the videos (64.4%) had low/moderate quality, and the majority (76.2%) were about signs and symptoms. The numbers of views (p=0.005), likes (p=0.006), and engagement (p=0.014) were significantly higher in moderate/good quality videos. The number of comments (p=0.007), duration of videos (p=0.004), and the DISCERN score (p<0.001) were significantly higher in videos made by health professionals. The general quality of the videos was positively correlated to the CSS scores, number of views, likes, and engagement (p<0.05). Conclusion: Most videos had moderate quality and reliability and low usefulness for the users.

Production of rumen- and gastrointestinal-resistant nanoparticles to deliver lysine to dairy cows.

Supplementing diets with rumen-protected lysine is a common strategy to meet the nutritional needs of high-producing dairy cows. This work addressed two separate but crucial issues: the lysine protection degree across the entire digestive tract as well as the production scalability of the proposed delivery systems. This was achieved by evaluating, in vitro or ex vivo, previously developed rumen-resistant lipid nanoparticles regarding their stability in the digestive tract and in the bloodstream of the dairy cow as well as how their production could be scaled-up. Results showed that the developed nanoparticles were able to resist digestion along the digestive tract but were degraded in the blood over 24 h. Thus, releasing their content to be used by the animal. In vitro viability assays were also performed, with the nanoparticles being found not to be inherently toxic when using nanoparticle concentrations up to 1 mg/mL. Results showed that neither the purity of the used lipids nor the production method significantly altered the nanoparticles' properties or their ruminal resistance. Furthermore, the shelf-life of these nanoparticles was assessed, and they were found to retain their properties and remain usable after at least 1 month of storage. Moreover, a pilot-scale production allowed the production of nanoparticles with similar properties to the previous ones made using standard methods. To summarize, the proposed rumen-resistant nanoparticles presented potential as orally ingested lysine delivery systems for dairy cattle supplementation, being capable of a large-scale production using cheaper components while maintaining their properties and without any efficiency loss. It should however be noted that these results were obtained mainly in vitro and further in vivo bioavailability and production experiments are needed before this technology can be confirmed as a viable way of delivering lysine to dairy cows.

Generation and validation of a classification model to diagnose familial hypercholesterolaemia in adults.

BACKGROUND AND AIMS: The early diagnosis of familial hypercholesterolaemia is associated with a significant reduction in cardiovascular disease (CVD) risk. While the recent use of statistical and machine learning algorithms has shown promising results in comparison with traditional clinical criteria, when applied to screening of potential FH cases in large cohorts, most studies in this field are developed using a single cohort of patients, which may hamper the application of such algorithms to other populations. In the current study, a logistic regression (LR) based algorithm was developed combining observations from three different national FH cohorts, from Portugal, Brazil and Sweden. Independent samples from these cohorts were then used to test the model, as well as an external dataset from Italy. METHODS: The area under the receiver operating characteristics (AUROC) and precision-recall (AUPRC) curves was used to assess the discriminatory ability among the different samples. Comparisons between the LR model and Dutch Lipid Clinic Network (DLCN) clinical criteria were performed by means of McNemar tests, and by the calculation of several operating characteristics. RESULTS: AUROC and AUPRC values were generally higher for all testing sets when compared to the training set. Compared with DLCN criteria, a significantly higher number of correctly classified observations were identified for the Brazilian (p < 0.01), Swedish (p < 0.01), and Italian testing sets (p < 0.01). Higher accuracy (Acc), G mean and F1 score values were also observed for all testing sets. CONCLUSIONS: Compared to DLCN criteria, the LR model revealed improved ability to correctly classify observations, and was able to retain a similar number of FH cases, with less false positive retention. Generalization of the LR model was very good across all testing samples, suggesting it can be an effective screening tool if applied to different populations.

The anti-infective crotalicidin peptide analog RhoB-Ctn[1-9] is harmless to bovine oocytes and able to induce parthenogenesis in vitro.

Crotalicidin is a cathelicidin-related anti-infective (antimicrobial) peptide expressed in the venom glands of the South American rattlesnake Crotalus durissus terrificus. Congener peptides of crotalicidin, named vipericidins, are found in other pit vipers inhabiting South America. Crotalicidin is active against bacteria and pathogenic yeasts and has anti-proliferative activity for some cancer cells. The structural dissection of crotalicidin produced fragments (e.g., Ctn [15-34]) with multiple biological functionalities that mimic the native peptide. Another structural characteristic of crotalidicin and congeners is a unique repetitive stretch of amino acid sequences in tandem embedded in their primary structures. One of the encrypted vipericidn peptides (Ctn [1-9]) was synthesized, and the analog covalently conjugated with rhodamine B (RhoB-Ctn [1-9]) displayed considerable antimicrobial activity and selective cytotoxicity. Methods to evaluate antimicrobial peptides' toxicity include lysis of red blood cells (hemolysis) in vitro and cytotoxicity of healthy cultured cells (e.g., fibroblasts). Here, as a non-conventional model of toxicity, the bovine oocytes were exposed to two standardized concentrations of RhoB-Ctn [1-9], and embryo viability and development at its first stage of cleavage (division of cells) and blastocyst formation were evaluated. Oocytes treated with peptide at 10 and 40 µM induced cleavage rates of 44.94% and 51.53%, resulting in the formation of blastocysts of 7.07% and 11.73%, respectively. Light sheet microscopy and in silico prediction analysis indicated that RhoB-Ctn [1-9] peptide interacts with zona pellucida and internalizes into bovine oocytes and developing embryos. The ADMET prediction estimated good bioavailability of RhoB-Ctn [1-9]. In conclusion, the peptide appeared harmless to bovine oocytes and, remarkably, activated the parthenogenesis in vitro.

A spatio-temporal analysis investigating completeness and inequalities of global urban building data in OpenStreetMap.

OpenStreetMap (OSM) has evolved as a popular dataset for global urban analyses, such as assessing progress towards the Sustainable Development Goals. However, many analyses do not account for the uneven spatial coverage of existing data. We employ a machine-learning model to infer the completeness of OSM building stock data for 13,189 urban agglomerations worldwide. For 1,848 urban centres (16% of the urban population), OSM building footprint data exceeds 80% completeness, but completeness remains lower than 20% for 9,163 cities (48% of the urban population). Although OSM data inequalities have recently receded, partially as a result of humanitarian mapping efforts, a complex unequal pattern of spatial biases remains, which vary across various human development index groups, population sizes and geographic regions. Based on these results, we provide recommendations for data producers and urban analysts to manage the uneven coverage of OSM data, as well as a framework to support the assessment of completeness biases.

Alternative Analysis Approaches for the Assessment of Pilot Bioavailability/Bioequivalence Studies.

Pilot bioavailability/bioequivalence (BA/BE) studies are usually conducted and analysed similarly to pivotal studies. Their analysis and interpretation of results usually rely on the application of the average bioequivalence approach. However, due to the small study size, pilot studies are inarguably more sensitive to variability. The aim of this work is to propose alternative approaches to the average bioequivalence methodology, in a way to overcome and reduce the uncertainty on the conclusions of these studies and on the potential of test formulations. Several scenarios of pilot BA/BE crossover studies were simulated through population pharmacokinetic modelling. Each simulated BA/BE trial was analysed using the average bioequivalence approach. As alternative analyses, the centrality of the test-to-reference geometric least square means ratio (GMR), bootstrap bioequivalence analysis, and arithmetic (Amean) and geometric (Gmean) mean ƒ2 factor approaches were investigated. Methods performance was measured with a confusion matrix. The Gmean ƒ2 factor using a cut-off of 35 was the most appropriate method in the simulation conditions frame, enabling to more accurately conclude the potential of test formulations, with a reduced sample size. For simplification, a decision tree is also proposed for appropriate planning of the sample size and subsequent analysis approach to be followed in pilot BA/BE trials.

Perception of lower back pain associated with use of body armor in police officers of the countryside specialized battalion of Ceará, Brazil.

Introduction: The strict demands of the military environment, associated with the increase in violence, as well as the frequent use of body armor, can further aggravate health problems. Objectives: To investigate the perception of police officers of the Countryside Specialized Police Battalion in relation to comfort, fatigue, and lower back pain, resulting from the use of body armor. Methods: This was a cross-sectional study conducted with 260 male military police officers (34.62 ± 5.83 years old) belonging to the ostensive rural police battalion in the state of Ceará, Brazil. The questionnaire related to comfort, fatigue, and lower back pain was used to identify the perception of pain from the use of body armor, with staggered responses, and the results were analyzed using the SPSS 21.0 software. Results: Regarding the use of body armor, 41.5% of participants perceived it to be little comfortable in general; furthermore, 45 and 47.5% of military police officers considered it little comfortable in relation to weight and use during operational activities, respectively. With regard to body measurements, 48.5% reported being little comfortable, and 70% perceived that the body armor is adjustable to the body. At the end of the work shift, 37.3% complained of lower back pain, and 45.8% felt moderate fatigue. Moreover, 70.1% felt pain in the lower back after the work shift. Conclusions: Military police officers reported lower back pain at the end and after the work shift due to use of body armor, as well as little comfort of the protective equipment and moderate fatigue at the end of the work shift.

Introdução: As rigorosas exigências do ambiente militar associadas ao aumento da violência, bem como ao uso frequente do colete balístico, podem agravar ainda mais os problemas de saúde. Objetivos: Investigar a associação do uso de colete balístico em relação ao conforto, à fadiga e à queixa de lombalgia em policiais do batalhão especializado do Ceará. Métodos: Tratou-se de um estudo transversal realizado com 260 policiais militares do sexo masculino (34,62 ± 5,83 anos) pertencentes ao batalhão de policiamento ostensivo rural do estado do Ceará. O questionário relacionado a conforto, fadiga e dores na região lombar foi utilizado para identificar a percepção de dor pelo uso do colete balístico, com respostas escalonadas, e seus resultados foram analisados no software SPSS 21.0. Resultados: Quanto ao uso do colete, 41,5% perceberam ser pouco confortável no geral; e 45 e 47,5% dos policiais militares consideraram ser pouco confortável em relação ao peso e em relação ao uso durante as atividades operacionais, respectivamente. No que se refere às medidas corporais, 48,5% reportaram ser confortável, e 70% percebem o colete como ajustável ao corpo. No momento da finalização do turno de trabalho, 37,3% apresentam dores na região lombar e 45,8% sentem fadiga moderada. Após o encerramento do turno de trabalho, 70,1% sentem dores na região lombar. Conclusões: Os policiais militares perceberam dores na região lombar ao final e depois do turno de trabalho pelo uso do colete balistico, além de relatarem sobre o pouco conforto do equipamento de proteção e sobre a fadiga moderada ao fim do turno de trabalho.

Perfil Clínico-Epidemiológico e Sobrevida dos Casos de Retinoblastoma em um Hospital Referência em Oncologia do Estado de Goiás / Clinical-Epidemiological Profile and Survival of the Cases of Retinoblastoma in a Reference Hospital in Oncology in the State of Goiás / Perfil Clínico-Epidemiológico y Sobrevida de los Casos de Retinoblastoma en un Hospital de Referencia en Oncología del Estado de Goiás

Introdução: O retinoblastoma é a malignidade primária intraocular mais comum na infância, é raro e corresponde de 2% a 4% dos tumores malignos pediátricos. Objetivo: Descrever o perfil clínico-epidemiológico e a sobrevida dos casos de retinoblastoma em um hospital de referência em oncologia do Estado de Goiás, entre 2008 a 2014. Método: Estudo observacional analítico do tipo transversal, construído com base na análise de prontuários de pacientes diagnosticados com retinoblastoma entre 2008 e 2014. Realizaram-se análises por estatística descritiva e teste de associação qui-quadrado. Adotou-se o nível de significância de 5%. A sobrevida foi avaliada por meio do método de Kaplan-Meier. Resultados: Foram atendidos 55 pacientes com retinoblastoma, permitindo identificar o predomínio do sexo feminino (54,5%); na faixa etária de 1 a 4 anos (27,3%); com etnia parda (50,9%). As características clínicas mais prevalentes foram: acometimento intraocular (74,5%); unilateral (65,5%); sem histórico familiar (56,4%); e com sinal clínico de leucocoria (80%). A maioria não apresentou metástases ao diagnóstico (87,3%), sendo o principal tratamento a enucleação unilateral (72,7%). Verificou-se associação quanto à evolução clínica do paciente em relação à localização extraocular (p = 0,001), presença de metástase (p = 0,001) e estádio IV de Chantada et al. (p = 0,001). Pacientes classificados como E foram submetidos a maior número de enucleações (olho direito ­ p = 0,05 e olho esquerdo ­ p = 0,001). A sobrevida global em cinco anos foi de 72,7%. Conclusão: Tais achados são relevantes para o planejamento de ações de prevenção, pois o diagnóstico precoce é um dos principais aliados na determinação da cura e na preservação da visão.

Introduction: Retinoblastoma is the most common intraocular primary malignancy in childhood, it is rare and accounts for 2% to 4% of pediatric malignant tumors. Objective: To describe the clinical-epidemiological profile and survival of cases of retinoblastoma in a reference hospital in oncology in the state of Goiás, between 2008 and 2014. Method: Crosssectional analytical observational study built from the analysis of medical records of patients diagnosed with retinoblastoma between 2008 and 2014. Analyzes were performed using descriptive statistics and chi-square association test. A significance level of 5% was adopted. Survival was assessed using the Kaplan-Meier method. Results: 55 patients with retinoblastoma were treated, with predominance of females (54.5%), in the age group of 1 to 4 years (27.3%) and of brown ethnicity (50.9%). The most prevalent clinical characteristics were intraocular involvement (74.5%), unilateral (65.5%), with no family history (56.4%) and with clinical signs of leukocoria (80%). Most of them did not present metastases at diagnosis (87.3%), the main treatment being unilateral enucleation (72.7%). Association between the clinical evolution of the patient and extraocular location (p = 0.001) was found, presence of metastasis (p = 0.001), and stage IV classified by Chantada et al. (p = 0.001). Patients classified as E were submitted to higher volume of enucleation (right eye ­ p = 0.05 and left eye ­ p = 0.001). The 5-year overall survival was 72.7%. Conclusion: These findings are relevant for planning preventive actions, as early diagnosis is one of the main allies in determining the cure and preserving vision

Introducción: El retinoblastoma es la neoplasia maligna primaria intraocular más frecuente en la infancia, es raro y corresponde del 2% al 4% de los tumores malignos pediátricos. Objetivo: Describir el perfil clínicoepidemiológico y la sobrevida de los casos de retinoblastoma en un hospital de referencia en oncología en el Estado de Goiás, entre 2008 y 2014. Método: Estudio observacional analítico transversal, construido a partir del análisis de las historias clínicas de los pacientes diagnosticados con retinoblastoma entre 2008 y 2014. Los análisis se realizaron mediante estadística descriptiva y prueba de asociación ji cuadrada. Se adoptó un nivel de significancia del 5%. La sobrevida se evaluó mediante el método de Kaplan-Meier. Resultados: Fueron tratados 55 pacientes con retinoblastoma, lo que permitió identificar un predominio femenino (54,5%); en el grupo de edad de 1 a 4 años (27,3%); con etnia parda (50,9%). Las características clínicas más prevalentes fueron: afectación intraocular (74,5%); unilateral (65,5%); y sin antecedentes familiares (56,4%) y con signos clínicos de leucocoria (80%). La mayoría no presentaba metástasis al diagnóstico (87,3%); siendo el principal tratamiento la enucleación unilateral (72,7%). Hubo asociación entre la evolución clínica del paciente y la localización extraocular (p = 0,001), presencia de metástasis (p = 0,001) y estadio IV de Chantada et al. (p = 0,001). Los pacientes clasificados como E tenían más ojos enucleados (ojo derecho ­ p = 0,05 y ojo izquierdo ­ p = 0,001). La sobrevida global a los 5 años fue del 72,7%. Conclusión: Estos hallazgos son relevantes para la planificación de acciones preventivas, ya que el diagnóstico precoz es uno de los principales aliados para determinar la cura y preservar la visión.

Modelling premature cardiac aging with induced pluripotent stem cells from a hutchinson-gilford Progeria Syndrome patient.

Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare genetic disorder that causes accelerated aging and a high risk of cardiovascular complications. However, the underlying mechanisms of cardiac complications of this syndrome are not fully understood. This study modeled HGPS using cardiomyocytes (CM) derived from induced pluripotent stem cells (iPSC) derived from a patient with HGPS and characterized the biophysical, morphological, and molecular changes found in these CM compared to CM derived from a healthy donor. Electrophysiological recordings suggest that the HGPS-CM was functional and had normal electrophysiological properties. Electron tomography showed nuclear morphology alteration, and the 3D reconstruction of electron tomography images suggests structural abnormalities in HGPS-CM mitochondria, however, there was no difference in mitochondrial content as measured by Mitotracker. Immunofluorescence indicates nuclear morphological alteration and confirms the presence of Troponin T. Telomere length was measured using qRT-PCR, and no difference was found in the CM from HGPS when compared to the control. Proteomic analysis was carried out in a high-resolution system using Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS). The proteomics data show distinct group separations and protein expression differences between HGPS and control-CM, highlighting changes in ribosomal, TCA cycle, and amino acid biosynthesis, among other modifications. Our findings show that iPSC-derived cardiomyocytes from a Progeria Syndrome patient have significant changes in mitochondrial morphology and protein expression, implying novel mechanisms underlying premature cardiac aging.

Hypothalamic AgRP neurons exert top-down control on systemic TNF-α release during endotoxemia.

Loss of appetite and negative energy balance are common features of endotoxemia in all animals and are thought to have protective roles by reducing nutrient availability to host and pathogen metabolism. Accordingly, fasting and caloric restriction have well-established anti-inflammatory properties. However, in response to reduced nutrient availability at the cellular and organ levels, negative energy balance also recruits distinct energy-sensing brain circuits, but it is not known whether these neuronal systems have a role in its anti-inflammatory effects. Here, we report that hypothalamic AgRP neurons-a critical neuronal population for the central representation of negative energy balance-have parallel immunoregulatory functions. We found that when endotoxemia occurs in fasted mice, the activity of AgRP neurons remains sustained, but this activity does not influence feeding behavior and endotoxemic anorexia. Furthermore, we found that endotoxemia acutely desensitizes AgRP neurons, which also become refractory to inhibitory signals. Mimicking this sustained AgRP neuron activity in fed mice by chemogenetic activation-a manipulation known to recapitulate core behavioral features of fasting-results in reduced acute tumor necrosis factor alpha (TNF-α) release during endotoxemia. Mechanistically, we found that endogenous glucocorticoids play an important role: glucocorticoid receptor deletion from AgRP neurons prevents their endotoxemia-induced desensitization, and importantly, it counteracts the fasting-induced suppression of TNF-α release, resulting in prolonged sickness. Together, these findings provide evidence directly linking AgRP neuron activity to the acute response during endotoxemia, suggesting that these neurons are a functional component of the immunoregulatory effects associated with negative energy balance and catabolic metabolism.

Comparative study on the performance of different classification algorithms, combined with pre- and post-processing techniques to handle imbalanced data, in the diagnosis of adult patients with familial hypercholesterolemia.

Familial Hypercholesterolemia (FH) is an inherited disorder of cholesterol metabolism. Current criteria for FH diagnosis, like Simon Broome (SB) criteria, lead to high false positive rates. The aim of this work was to explore alternative classification procedures for FH diagnosis, based on different biological and biochemical indicators. For this purpose, logistic regression (LR), naive Bayes classifier (NB), random forest (RF) and extreme gradient boosting (XGB) algorithms were combined with Synthetic Minority Oversampling Technique (SMOTE), or threshold adjustment by maximizing Youden index (YI), and compared. Data was tested through a 10 × 10 repeated k-fold cross validation design. The LR model presented an overall better performance, as assessed by the areas under the receiver operating characteristics (AUROC) and precision-recall (AUPRC) curves, and several operating characteristics (OC), regardless of the strategy to cope with class imbalance. When adopting either data processing technique, significantly higher accuracy (Acc), G-mean and F1 score values were found for all classification algorithms, compared to SB criteria (p < 0.01), revealing a more balanced predictive ability for both classes, and higher effectiveness in classifying FH patients. Adjustment of the cut-off values through pre or post-processing methods revealed a considerable gain in sensitivity (Sens) values (p < 0.01). Although the performance of pre and post-processing strategies was similar, SMOTE does not cause model's parameters to loose interpretability. These results suggest a LR model combined with SMOTE can be an optimal approach to be used as a widespread screening tool.

Physical exercise improves mitochondrial function in ovariectomized rats.

Estrogen deficiency causes metabolic disorders in humans and rodents, including in part due to changes in energy expenditure. We have shown previously that skeletal muscle mitochondrial function is compromised in ovariectomized (Ovx) rats. Since physical exercise is a powerful strategy to improve skeletal muscle mitochondrial content and function, we hypothesize that exercise training would counteract the deficiency-induced skeletal muscle mitochondrial dysfunction in Ovx rats. We report that exercised Ovx rats, at 60-65% of maximal exercise capacity for 8 weeks, exhibited less fat accumulation and body weight gain compared with sedentary controls. Treadmill exercise training decreased muscle lactate production, indicating a shift to mitochondrial oxidative metabolism. Furthermore, reduced soleus muscle mitochondrial oxygen consumption confirmed that estrogen deficiency is detrimental to mitochondrial function. However, exercise restored mitochondrial oxygen consumption in Ovx rats, achieving similar levels as in exercised control rats. Exercise-induced skeletal muscle peroxisome proliferator-activated receptor-γ coactivator-1α expression was similar in both groups. Therefore, the mechanisms by which exercise improves mitochondrial oxygen consumption appears to be different in Ovx-exercised and sham-exercised rats. While there was an increase in mitochondrial content in sham-exercised rats, demonstrated by a greater citrate synthase activity, no induction was observed in Ovx-exercised rats. Normalizing mitochondrial respiratory capacity by citrate synthase activity indicates a better oxidative phosphorylation efficiency in the Ovx-exercised group. In conclusion, physical exercise sustains mitochondrial function in ovarian hormone-deficient rats through a non-conventional mitochondrial content-independent manner.

Subacute and sublethal ingestion of microcystin-LR impairs lung mitochondrial function by an oligomycin-like effect.

Microcystin-LR (MC-LR) is a potent cyanotoxin that can reach several organs. However subacute exposure to sublethal doses of MC-LR has not yet well been studied. Herein, we evaluated the outcomes of subacute and sublethal MC-LR exposure on lungs. Male BALB/c mice were exposed to MC-LR by gavage (30 µg/kg) for 20 consecutive days, whereas CTRL mice received filtered water. Respiratory mechanics was not altered in MC-LR group, but histopathology disclosed increased collagen deposition, immunological cell infiltration, and higher percentage of collapsed alveoli. Mitochondrial function was extensively affected in MC-LR animals. Additionally, a direct in vitro titration of MC-LR revealed impaired mitochondrial function. In conclusion, MC-LR presented an intense deleterious effect on lung mitochondrial function and histology. Furthermore, MC-LR seems to exert an oligomycin-like effect in lung mitochondria. This study opens new perspectives for the understanding of the putative pulmonary initial mechanisms of damage resulting from oral MC-LR intoxication.

Performance comparison of different classification algorithms applied to the diagnosis of familial hypercholesterolemia in paediatric subjects.

Familial Hypercholesterolemia (FH) is an inherited disorder of lipid metabolism, characterized by increased low density lipoprotein cholesterol (LDLc) levels. The main purpose of the current work was to explore alternative classification methods to traditional clinical criteria for FH diagnosis, based on several biochemical and biological indicators. Logistic regression (LR), decision tree (DT), random forest (RF) and naive Bayes (NB) algorithms were developed for this purpose, and thresholds were optimized by maximization of Youden index (YI). All models presented similar accuracy (Acc), specificity (Spec) and positive predictive values (PPV). Sensitivity (Sens) and G-mean values were significantly higher in LR and RF models, compared to the DT. When compared to Simon Broome (SB) biochemical criteria for FH diagnosis, all models presented significantly higher Acc, Spec and G-mean values (p < 0.01), and lower negative predictive value (NPV, p < 0.05). Moreover, LR and RF models presented comparable Sens values. Adjustment of the cut-off point by maximizing YI significantly increased Sens values, with no significant loss in Acc. The obtained results suggest such classification algorithms can be a viable alternative to be used as a widespread screening method. An online application has been developed to assess the performance of the LR model in a wider population.