Enhanced Recovery of Natural Antioxidants from Grape Waste Using Natural Eutectic Solvents-Based Microwave-Assisted Extraction.

The evaluation of sustainable solvents as alternatives to more harmful conventional solvents combined with intensification techniques to recover phenolic compounds from agri-food waste is in the spotlight. The wine industry generates large amounts of waste as a consequence of grape processing operations, which can be revalued by solvent extraction of valuable antioxidants for food and fine chemical applications. Therefore, the present study focuses on the use of natural eutectic solvents (NAESs) with benign environmental, health, and safety profiles, for valorization of grape waste in the context of a circular economy. Herein, up to 15 NAESs consisting of combinations of three hydrogen bond acceptors (choline chloride, L-proline, and betaine) and four hydrogen bond donors (1,2-propanediol, glycerol, and 1,2- and 1,3-butanediol) were evaluated for antioxidant recovery. After an initial screening of the performance of NAESs by conventional extraction, the process was intensified by microwave-assisted extraction (MAE). The extracts were analyzed by UV/VIS spectrophotometric and HPLC methods. Promising results were obtained with the solvent betaine, 1,2-butanediol [1:4], using MAE at 100 °C for 3 min. Overall, the proposed NAESs-based MAE method was successfully applied to recover target compounds from grape waste, with great prospects for the antioxidants market and sustainable development for the winery sector.

Environmental and health risk implications of unregulated emissions from advanced biofuels in a Euro 6 engine.

The use of conventional and advanced biofuels is part of the efforts to reduce greenhouse gases and harmful exhaust gaseous emissions. This study investigates the unregulated emissions in gas and particles from a Euro 6b diesel engine, operated with four unconventional and advanced biofuels (two hydrogenated terpenic biofuels, a polyoxymethylene dimethyl ether, and a glycerol-derived biofuel), blended with diesel fuel and pure hydrotreated vegetable oil as base biofuel. The engine was operated following WLTC starting from cold-engine conditions. Gas phase samples were collected at each phase of the driving cycle and particulate matter (PM) samples were collected from a dilution tunnel at the end of the driving cycle. A total of 16 PAH and 13 carbonyls were analyzed. In addition, the apoptotic index induced by gas and particle emissions was determined. In the gaseous phase, the total PAH and carbonyl emission factors were higher at the low-speed phase for all fuels. Gas-phase PAH emission factors exceeded particle-bound PAH. Carbonyl emission factors ranged from 0.12 ± 0.012 to 25.3 ± 4.2 mg/km, markedly exceeding gaseous PAH emissions, which ranged from 20.7 ± 1.5 to 51.7 ± 8.9 µg/km. Diesel fuel exhibited the highest carbonyl emissions and its blend with 20% of hydrogenated turpentine exhibited the highest PAH emissions at the end of the WLTC, both due to high emissions at the low-speed phase. Although particle-bound PAH comprise only a small fraction of total PAH emissions, both phases (gas and particles) contributed approximately equal to the toxicity associated with carcinogenic PAH. The apoptotic cells percentage increased in a dose-dependent manner and was significantly higher in cells exposed to gas phase-derived samples. The apoptotic index induced by particulate matter samples did not show a concentration-response effect for any of the fuels.

CoQ10 reduces glioblastoma growth and infiltration through proteome remodeling and inhibition of angiogenesis and inflammation.

PURPOSE: Most monotherapies available against glioblastoma multiforme (GBM) target individual hallmarks of this aggressive brain tumor with minimal success. In this article, we propose a therapeutic strategy using coenzyme Q10 (CoQ10) as a pleiotropic factor that crosses the blood-brain barrier and accumulates in cell membranes acting as an antioxidant, and in mitochondrial membranes as a regulator of cell bioenergetics and gene expression. METHODS: Xenografts of U251 cells in nu/nu mice were used to assay tumor growth, hypoxia, angiogenesis, and inflammation. An orthotopic model was used to explore microglial infiltration, tumor growth, and invasion into the brain parenchyma. Cell proliferation, migration, invasion, proteome remodeling, and secretome were assayed in vitro. Conditioned media were used to assay angiogenesis, monocyte chemoattraction, and differentiation into macrophages in vitro. RESULTS: CoQ10 treatment decreased tumor volume in xenografts and orthotopic models, although its effect on tumor cell proliferation was not direct. Tumors from mice treated with CoQ10 were less hypoxic and vascularized, having less infiltration from inflammatory cells. Treatment-induced downregulation of HIF-1α and NF-kB led to a complete remodeling of the tumor cells proteome and secretome, impacting angiogenesis, monocyte infiltration, and their differentiation into macrophages. Besides, tumor cell migration and invasion were drastically restricted by mechanisms involving modulation of the actin cytoskeleton and downregulation of matrix metalloproteases (MMPs). CONCLUSIONS: CoQ10 has a pleiotropic effect on GBM growth, targeting several hallmarks simultaneously. Thus, its integration into current treatments of this fatal disease should be considered.

Increased quality of life in patients with breakthrough cancer pain after individualized therapy: the CAVIDIOM study.

Aim: To evaluate the quality of life (QoL) in patients with breakthrough cancer pain (BTcP) in Spanish medical oncology departments. Patients & methods: In a prospective, observational, multicenter study, we assessed QoL using the EQ-5D-5L instrument at baseline and after 15 and 30 days of individualized BTcP therapy, as well as BTcP characteristics and treatment. Results: Patients (n = 118) were mainly women, over 64 years old and with advanced cancer. QoL improved at 15 (p = 0.013) and 30 days (p = 0.011) versus baseline. Individualized BTcP therapy consisted mostly of rapid-onset opioids (transmucosal fentanyl at doses of 67-800 µg) according to the physician evaluation. BTcP improved, including statistically significant reductions in intensity, duration, number of episodes in the last 24 h and time to onset of BTcP relief. Conclusion: QoL increased after individualized pain therapy in patients with advanced cancer and BTcP in medical oncology departments.

Cancer patients can experience flares of pain, called breakthrough pain (BTcP), despite treatment with painkillers. Although BTcP can be excruciating, its intensity and other characteristics depend on several factors, including its treatment. However, even if treated, BTcP can impair quality of life for cancer patients. We assessed quality of life in 118 patients with advanced cancer and BTcP treated in 13 medical oncology departments across Spain. We treated BTcP with individualized therapy, taking into account both pain-related and patient-related factors. We also measured quality of life using a specific, widely-used questionnaire at the study visits: at onset of individualized pain therapy and after 3, 15 and 30 days' treatment. At each visit, flare-up pain therapy was adjusted or maintained as necessary. Throughout the study, quality of life and sleep quality improved for all participants. Furthermore, there was a greater reduction in intensity, duration and frequency of BTcP. The most common treatments for flare-ups were low doses of rapid-onset opioids (fentanyl given by sublingual, buccal or nasal administration), which were much better tolerated than high-dose opioids. Overall, the study showed that quality of life in patients with advanced cancer and BTcP increased after individualized pain therapy, mainly with low doses of rapid-onset opioids.

Contactless Ultrasonic Cavitation for the Prevention of Shunt Obstruction in Hydrocephalus: A Proof-of-Concept Study.

BACKGROUND: Obstructive failure of implanted shunts is the most common complication in the treatment of hydrocephalus. Biological material and debris accumulate in the inner walls of the valve and catheters block the normal flow of the drained cerebrospinal fluid causing severe symptoms with high morbidity and mortality. Unfortunately, at present, there is no effective preventive protocol or cleaning procedure available. OBJECTIVE: To assess whether externally applied, focused ultrasound beams can be used to resuspend deposits accumulated in brain shunts safely. METHODS: A computational model of an implanted brain shunt was implemented to test the initial design parameters of a system comprising several ultrasound transducers. Under laboratory conditions, configurations with 3 and 4 transducers were arranged in a triangle and square pattern with their radiation axis directed towards a target model of the device, 2 catheters and a brain shunt filled with water and deposited graphite powder. The ultrasound beams were then concentrated on the device across a head model. RESULTS: The computational model revealed that by using only 3 transducers, the acoustic field intensity on the valve was approximately twice that on the brain surface suggesting that acoustic cavitation could be selectively achieved. Resuspension of graphite deposits inside the catheters and the valve were then physically demonstrated and video-recorded with no temperature increase. CONCLUSION: The technology presented here has the potential to be used routinely as a noninvasive, preventive cleaning procedure to reduce the likelihood of obstruction-related events in patients with hydrocephalus treated with an implanted shunt.

From pregnancy to breastfeeding: adequate maternal body mass index is essential to prevent a high body mass index in your children.

OBJECTIVES: To verify the associations between prenatal and perinatal factors with offspring body mass index (BMI) and the moderator role of maternal BMI in this relationship. METHODS: Cross-sectional study developed with 1,562 children and adolescents aged between 6 and 17 years, as well as their mothers, from southern Brazil. The prenatal and perinatal factors, weight, and height for the calculation of maternal BMI were self-reported. For the calculation of BMI, weight and height of the child/adolescent were measured on an anthropometric scale with a coupled stadiometer. Linear regression models were used for the moderation analysis. All analyzes were adjusted for the mother's and child's age, sex, sexual maturation, skin color/race, and educational level. RESULTS: cesarean as type of delivery (ß=0.66; 95% CI=0.22 1.04; p=0.002) and pregnancy complications (ß=0.60; 95% CI=0.15 1.04; p=0.002) were positively associated with offspring BMI. Schoolchildren who were breastfed for 4-6 months showed -0.56 kg/m2 of BMI (95% CI=-1.06-0.06; p=0.02). Birth weight was also associated with BMI, with low weight being inversely (ß=-0.59; 95% CI=-1.03-0.15; p=0.008), while overweight was positively related (ß=0.84; 95% CI=0.08 1.60; p=0.02). The moderation analysis indicated a positive interaction between the mother's BMI and cesarean, pregnancy complications, and smoking with the offspring's BMI. On the other hand, there was an inverse association between breastfeeding from 7 to 12 months and the offspring BMI, only in mothers with high BMI. CONCLUSIONS: Adequate maternal BMI is essential to prevent a high BMI in their children, especially when considering the influence of prenatal and perinatal risk factors.

Anti-MDA5 dermatomyositis after COVID-19 vaccination: a case-based review.

Anti-MDA5 (Melanoma differentiation-associated protein 5) myositis is a rare subtype of dermatomyositis (DM) characterized by distinct ulcerative, erythematous cutaneous lesions and a high risk of rapidly progressive interstitial lung disease (RP-ILD). It has been shown that SARS-CoV-2 (COVID-19) replicates rapidly in lung and skin epithelial cells, which is sensed by the cytosolic RNA-sensor MDA5. MDA5 then triggers type 1 interferon (IFN) production, and thus downstream inflammatory mediators (EMBO J 40(15):e107826, 2021); (J Virol, 2021, https://doi.org/10.1128/JVI.00862-21 ); (Cell Rep 34(2):108628, 2021); (Sci Rep 11(1):13638, 2021); (Trends Microbiol 27(1):75-85, 2019). It has also been shown that MDA5 is triggered by the mRNA COVID-19 vaccine with resultant activated dendritic cells (Nat Rev Immunol 21(4):195-197, 2021). Our literature review identified one reported case of MDA5-DM from the COVID-19 vaccine (Chest J, 2021, https://doi.org/10.1016/j.chest.2021.07.646 ). We present six additional cases of MDA5-DM that developed shortly after the administration of different kinds of COVID-19 vaccines. A review of other similar cases of myositis developing from the COVID-19 vaccine was also done. We aim to explore and discuss the evidence around recent speculations of a possible relation of MDA5-DM to COVID-19 infection and vaccine. The importance of vaccination during a worldwide pandemic should be maintained and our findings are not intended to discourage individuals from receiving the COVID-19 vaccine.

Immunogenicity and Safety of SARS-CoV-2 Vaccination in Patients With Rheumatic Diseases: A Systematic Review and Meta-analysis.

OBJECTIVE: The aim of this study was to conduct a systematic review and meta-analysis examining the immunogenicity and safety of SARS-CoV-2 vaccination in patients with RD. METHODS: We systematically searched PubMed/MEDLINE and Scopus to identify observational studies that examined the immunogenicity and safety of SARS-CoV-2 vaccination in RD patients. Information on disease, immunosuppressant, vaccine type, and proportion of patients with serologic response was obtained from each study. RESULTS: There were 25 eligible studies. The pooled rate of seroconversion was 0.79 (95% confidence interval [CI], 0.72-0.86). Compared with control subjects, the odds of seroconversion were significantly lower (odds ratio, 0.11; 95% CI, 0.05-0.24). Users of rituximab showed the lowest rate of seroconversion (0.39; 95% CI, 0.29-0.51) followed by mycophenolate (0.56; 95% CI, 0.40-71). On the other hand, users of interleukin 17 (0.94; 95% CI, 0.78-0.98) and tumor necrosis factor inhibitors (0.94; 95% CI, 0.84-0.98) showed high seroconversion rate. Regarding safety of COVID-19 vaccine, approximately 2% of patients reported severe adverse events and 7% reported diseases flares following the first or second dose. CONCLUSION: Vaccination against SARS-CoV-2 appears to be safe. Most RD patients developed humoral immune response following vaccination. However, the odds of seroconversion were significantly lower in RD patients compared with controls. This is likely driven by certain immunosuppressants including rituximab and mycophenolate. Future studies need to identify strategies to improve vaccine response in these patients.

Subchronic Graphene Exposure Reshapes Skin Cell Metabolism.

In recent years, the toxicity of graphene-related materials (GRMs) has been evaluated in diverse models to guarantee their safety. In most applications, sublethal doses of GRMs contact human barriers such as skin in a subchronic way. Herein, the subchronic effect (30 day exposure) of three GRMs (GO 1, GO 2, and FLG) with different oxidation degrees and sizes was studied. The effects of these materials on human skin cells, HaCaTs, were assayed through high-throughput metabolic-based readout and other cell-based assays. A differential effect was found between the different GRMs. GO 2 induced a metabolic remodeling in epithelial cells, increasing the level of tricarboxylic acid components, mirrored by increased cell proliferation and changes in cell phenotype. The oxidation degree, size, and method of manufacture of GRMs dictated harmful effects on cell metabolism and behavior generated by nontoxic exposures. Therefore, a "safe by design" procedure is necessary when working with these nanomaterials.

Optical imaging spectroscopy for rapid, primary screening of SARS-CoV-2: a proof of concept.

Effective testing is essential to control the coronavirus disease 2019 (COVID-19) transmission. Here we report a-proof-of-concept study on hyperspectral image analysis in the visible and near-infrared range for primary screening at the point-of-care of SARS-CoV-2. We apply spectral feature descriptors, partial least square-discriminant analysis, and artificial intelligence to extract information from optical diffuse reflectance measurements from 5 µL fluid samples at pixel, droplet, and patient levels. We discern preparations of engineered lentiviral particles pseudotyped with the spike protein of the SARS-CoV-2 from those with the G protein of the vesicular stomatitis virus in saline solution and artificial saliva. We report a quantitative analysis of 72 samples of nasopharyngeal exudate in a range of SARS-CoV-2 viral loads, and a descriptive study of another 32 fresh human saliva samples. Sensitivity for classification of exudates was 100% with peak specificity of 87.5% for discernment from PCR-negative but symptomatic cases. Proposed technology is reagent-free, fast, and scalable, and could substantially reduce the number of molecular tests currently required for COVID-19 mass screening strategies even in resource-limited settings.

Modeling chronic cervical spinal cord injury in aged rats for cell therapy studies.

With an expanding elderly population, an increasing number of older adults will experience spinal cord injury (SCI) and might be candidates for cell-based therapies, yet there is a paucity of research in this age group. The objective of the present study was to analyze how aged rats tolerate behavioral testing, surgical procedures, post-operative complications, intra-spinal cell transplantation and immunosuppression, and to examine the effectiveness of human iPSC-derived Neural Progenitor Cells (IMR90-hiPSC-NPCs) in a model of SCI. We performed behavioral tests in rats before and after inducing cervical hemi-contusions at C4 level with a fourth-generation Ohio State University Injury Device. Four weeks later, we injected IMR90-hiPSC-NPCs in animals that were immunosuppressed by daily cyclosporine injection. Four weeks after injection we analyzed locomotor behavior and mortality, and histologically assessed the survival of transplanted human NPCs. As rats aged, their success at completing behavioral tests decreased. In addition, we observed high mortality rates during behavioral training (41.2%), after cervical injury (63.2%) and after cell injection (50%). Histological analysis revealed that injected cells survived and remained at and around the grafted site and did not cause tumors. No locomotor improvement was observed in animals four weeks after IMR90-hiPSC-NPC transplantation. Our results show that elderly rats are highly vulnerable to interventions, and thus large groups of animals must be initially established to study the potential efficacy of cell-based therapies in age-related chronic myelopathies.

The benefit of a neoadjuvant instillation of chemotherapy in non-muscle invasive bladder cancer: Interim analysis of the PRECAVE randomized clinical trial. / El beneficio de una instilación neoadyuvante de quimioterapia en el carcinoma vesical no músculo invasivo: análisis intermedio del ensayo clínico aleatorizado PRECAVE.

OBJECTIVE: Although an immediate postoperative instillation of chemotherapy (IPOIC) after transurethral resection of bladder tumors (TURBT) is recommended for the prevention of recurrences of non-muscleinvasive bladder cancer (NMIBC), evidence shows there is an important compliance failure worldwide. We believe that an immediate neoadjuvant instillation of chemotherapy (INAIC) can act similarly, reducing the recurrence risk of NMIBC. Here we present the interim analysis of the PRECAVE clinical trial. MATERIAL AND METHODS: Patients with clinically diagnosed NMIBC were randomized to receive an INAIC with mitomycin C before TURBT (Group A) or to a control group with TURBT only (Group B). Primary end point was to compare the efficacy of an INAIC in the early recurrence-free survival (RFS). Secondary end points were: RFS in patients who did not receive adjuvant treatments, toxicity, and feasibility. RESULTS: A total of 124 patients with Ta/T1 G1-G3NMIBC were included in the initial analysis (Group A:64, Group B: 60). Demographics, risk classification, complications, and adjuvant treatments were balanced between groups. Eighty-four patients (Group A: 45, Group B: 39) who completed a one-year follow-up were included in the efficacy analysis and no difference was observed in the RFS between groups (p=0.3). In the subgroup of patients who did not receive adjuvant treatments, we found a significant difference in favor of an INAIC (p=0.009) and an 80% reduction in the risk of early recurrences (Hazard Ratio: 0.20; 95% confidence interval: 0.05-0.81; p=0.0024). No differences were observed in adverse events. Only 4 patients did not receive an INAIC despite being planned. CONCLUSIONS: In this interim analysis, although we could not demonstrate a reduction in the RFS of all patients, we did find a significant decrease of recurrences in patients who did not receive adjuvant treatments. The administration of an INAIC seems to be safe and our protocol appears feasible and reproductive.

OBJETIVO: Aunque el uso de una instilación postoperatoria inmediata de quimioterapia (IPOIQ) tras una resección transuretral vesical (RTUV) esta recomendada para prevenir recurrencias de carcinoma vesical no músculo invasivo (CVNMI), no se llega a realizar en muchos casos debido a fallos en su cumplimiento. Nosotros creemos que una instilación neoadyuvante inmediata de quimioterapia (INAIQ) puede actuar de manera similar reduciendo el riesgo de recurrencias. Presentamos el análisis intermedio del ensayo clínico PRECAVE.MATERIAL Y MÉTODOS: Se aleatorizó a pacientes diagnosticados de CVNMI a recibir una INAIQ con mitomicina C antes de la RTUV (Grupo A) o a un grupo control con RTUV solamente (Grupo B). El objetivo primario fue comparar la eficacia de una INAIQ en la supervivencia libre de recurrencia (SLR) temprana. Los objetivos secundarios fueron la SLR en pacientes que no recibieron tratamientos adyuvantes, toxicidad y viabilidad. RESULTADOS: Analizamos un total de 124 pacientes con CVNMI Ta/T1G1-G3 fueron analizados (Grupo A:64, Grupo B: 60). No se encontraron diferencias entre datos demográficos, grupos de riesgo, complicaciones o tratamientos adyuvantes. Para el análisis de eficacias e incluyeron 84 pacientes (Grupo A: 45, Grupo B:39) con al menos un año de seguimiento, sin observar diferencias en la SLR (p=0,3). Sin embargo, en el subgrupo que no recibió tratamientos adyuvantes, sí encontramos una diferencia significativa a favor de la INAIQ (p=0,009), y una reducción del riesgo de recurrencias tempranas del 80% (Hazard Ratio: 0,20; intervalo de confianza 95%: 0,05-0,81; p=0,0024). No se observaron diferencias en la aparición de eventos adversos. Solo 4 pacientes no recibieron un INAIC a pesar de estar planificado. CONCLUSIONES: En este análisis intermedio, aunque no pudimos demostrar una reducción en la SLR de todos los pacientes, sí encontramos una diferencia en el subgrupo que no recibió tratamientos adyuvantes. La administración de una INAIC parece ser segura, y nuestro protocolo parece factible y reproducible.

Supervised Exercise Immediately After Bariatric Surgery: the Study Protocol of the EFIBAR Randomized Controlled Trial.

BACKGROUND: Previous studies have investigated weight loss caused by exercise following bariatric surgery. However, in most cases, the training program is poorly reported; the exercise type, volume, and intensity are briefly mentioned; and the sample size, selection criteria, and follow-up time vary greatly across studies. PURPOSE: The EFIBAR study aims to investigate over 1 year the effects of a 16-week supervised exercise program, initiated immediately after bariatric surgery, on weight loss (primary outcome), body composition, cardiometabolic risk, physical fitness, and quality of life in patients with severe/extreme obesity. MATERIAL AND METHODS: The EFIBAR study is a parallel-group, superiority, randomized controlled trial (RCT), comprising 80 surgery patients. Half of the participants, randomly selected, perform a 16-week supervised exercise program, including both strength and aerobic training, starting immediately after the surgery (7-14 days). For each participant, all primary and secondary outcomes are measured at three different time points: (i) before the surgery, (ii) after the intervention (≈4 months), and (iii) 1 year after the surgery. CONCLUSION: The EFIBAR study will provide new insights into the multidimensional benefits of exercise in adults with severe/extreme obesity following bariatric surgery. TRIAL REGISTRATION: EFIBAR randomized controlled trial was prospectively registered at Clinicaltrials.gov (NCT03497546) on April 13, 2018.

The Use of Coenzyme Q10 in Cardiovascular Diseases.

CoQ10 is an endogenous antioxidant produced in all cells that plays an essential role in energy metabolism and antioxidant protection. CoQ10 distribution is not uniform among different organs, and the highest concentration is observed in the heart, though its levels decrease with age. Advanced age is the major risk factor for cardiovascular disease and endothelial dysfunction triggered by oxidative stress that impairs mitochondrial bioenergetic and reduces NO bioavailability, thus affecting vasodilatation. The rationale of the use of CoQ10 in cardiovascular diseases is that the loss of contractile function due to an energy depletion status in the mitochondria and reduced levels of NO for vasodilatation has been associated with low endogenous CoQ10 levels. Clinical evidence shows that CoQ10 supplementation for prolonged periods is safe, well-tolerated and significantly increases the concentration of CoQ10 in plasma up to 3-5 µg/mL. CoQ10 supplementation reduces oxidative stress and mortality from cardiovascular causes and improves clinical outcome in patients undergoing coronary artery bypass graft surgery, prevents the accumulation of oxLDL in arteries, decreases vascular stiffness and hypertension, improves endothelial dysfunction by reducing the source of ROS in the vascular system and increases the NO levels for vasodilation.

Retinopatía del prematuro: resultados de un programa de prevención, detección y tratamiento

RESUMEN Introducción: La Retinopatía del Prematuro (ROP) es una de las principales causas de ceguera prevenibles en la infancia. La Fundación Visión implementa; el Programa de Prevención, Detección y Tratamiento en el año 2015. Objetivos: Describir los resultados de implementación y los resultados alcanzados por un programa de ROP en su accesibilidad, efectividad y calidad de atención. Materiales y Métodos: Estudio descriptivo, ambispectivo, de casos consecutivos de recién nacidos prematuros con criterios de evaluación; de una población evaluada en el año 2009 y del 2015 al 2019. Resultados: Las unidades neonatales incluidas aumentaron de 3 a 7; cubriendo Asunción, área Central, Caaguazú y Alto Paraná. De los registros se constato que la cobertura aumento de 36% en el año 2009 a 97% en el 2019. Desde que se instaló el programa; en el primer año la proporción del número de evaluaciones aumento entre el 28 y el 216%; y los resultados globales de julio 2015 a diciembre 2019 fueron: número totales de pacientes con criterio: 2397 pacientes; número totales de pacientes evaluados: 2080 (86,8%), número de pacientes con ROP: 416/2080 pacientes (20%), número de pacientes con ROP que requirieron tratamiento: 76/416 pacientes (18,2%), proporción global de ROP grave con tratamiento: 76/2080 pacientes (3,4%). Conclusiones: El programa a través de un equipo multidisplinario y la inovación con telemedicina logró aumentar la proporción de cobertura y la disminución de los casos graves que requirieron tratamiento.

ABSTRACT Introduction: Retinopathy of Prematurity (ROP) is one of the main preventable causes of blindness in childhood. The Vision Foundation implemented the Prevention, Detection and Treatment Program in 2015. Objective: To describe the implementation results and the outcomes achieved by a ROP program regarding its accessibility, effectiveness and quality of care. Materials and Methods: This was a descriptive and ambispective study of consecutive cases of premature newborns with criteria for evaluation, of a population evaluated in the year 2009 and from 2015 to 2019. Results: The participating neonatal units increased from 3 to 7; covering Asunción, the Central, Caaguazú and Alto Paraná Departments. From the records, it was found that program coverage increased from 36% in 2009 to 97% in 2019. Since the beginning of the program, during the first year the proportion of the number of evaluations increased between 28 and 218%; the global results from July 2015 to December 2019 were: total number of patients with criteria: 2397 patients; total number of patients evaluated: 2,080 (88%), number of patients with ROP: 416/2080 patients (20 %), number of patients with ROP requiring treatment: 76/416 patients (18.3%), overall proportion of severe ROP with treatment: 76/2080 patients (3.4%). Conclusions: The program, using a multidisciplinary team and the innovation of telemedicine, managed to increase the proportion of coverage and the reduction of serious cases that require treatment.

NGS of microRNAs Involved in Cardioprotection Induced by Sevoflurane Compared to Propofol in Myocardial Revascularization Surgery: The ACDHUVV-16 Clinical Trial.

BACKGROUND: Numerous studies have demonstrated that halogenated agents elicit myocardial conditioning effects when administered perioperatively in cardiac surgery. Recent evidence has been published on the benefits of maintaining exposure to halogenated agents during the early postoperative period. The enzymatic mechanisms by which this beneficial effect is exerted were explained recently. OBJECTIVES: Our study was performed to investigate whether this phenomenon is mediated by either the activation or suppression of miRNAs targeted by halogenated anesthetics. METHODS: A double-blind, two-stage trial was conducted. The results of the first stage of the trial are presented in this paper. The sample was composed of patients undergoing off-pump myocardial revascularization surgery. Patients were randomized to receive either sevoflurane [S] or propofol [P] during the intraoperative and early postoperative period (during the first six hours after the intervention). Hemodynamics (heart rate, blood pressure, central venous pressure, cardiac index, systolic volume index, LVEF) and myocardial enzymes (troponin I) were monitored at six hour intervals during the first 48 hours. In the first stage of the trial, blood was drawn for gene sequencing from eight patients (four per group) at baseline and at 24 h. In the second stage of the study, a qPCR analysis was performed of the miRNAs identified as significant by gene sequencing. Levels of cardioprotective enzymes (serine/threonine protein kinase (Akt), tumor necrosis factor alpha (TNFα), extracellular regulated protein kinase (ERK 1/2), and caspase 3) were measured to assess their role in myocardial conditioning pathways. The purpose was to identify the miRNAs that play a major role in myocardial conditioning induced by halogenated agents. Concentrations of cardioprotective enzymes were higher in patients who received sevoflurane than the patients who were administered propofol. RESULTS: NGS differences were observed between baseline and 24-h values in the two study groups. In group P, miRNA 197-3p was overexpressed, whereas miRNAs 4443 and 1294, 708-3p were underexpressed. In group S, miRNAs 615-3p, 4466, 29, 937-3p, 636, 197-3P, 184, 4685, 296-3p, 147b, 3199, 6815, 1294 and 3176 were underexpressed; whereas 708-3p was overexpressed. qPCR showed significant variations in miRNAs 197-3p, 4443, 708-3p and 1294 in the P group, and in miRNAs 937-3p, 636, 197- 3p, 296-3p and 708-3p in the S group. CONCLUSION: In the P Group, changes in the expression of some miRNAs were associated with lower concentrations of the enzymes involved in myocardial pre- and postconditioning. In contrast, in Group S, variations in miRNAs were associated with the activation of mediators of anesthetic-induced pre- and post-conditioning, a reduction in cell apoptosis, and a decrease in caspase and TnBF alpha concentrations. Changes in these miRNAs were associated with better prognosis in patients with ischemic heart disease. The main limitation of this study will be overcome in the second stage of the trial, where the specific role of each miRNA will be determined.

Cranial expansion and aqueductoplasty for combined isolated fourth ventricle and slit-ventricle syndrome: a surgical alternative.

INTRODUCTION: An isolated fourth ventricle (IFV) is a rare entity observed in shunted patients and its treatment is still uncertain. Endoscopic aqueductoplasty has shown good results for restoring CSF flux between the third and fourth ventricles. However, it needs some grade of ventricular dilation to be performed. Some patients affected by IFV show slit-ventricle morphology in CT/MRI. Usually, the rise of opening pressure or the shunt externalization gets enough ventricular dilation. However, the lack of intracranial compliance in some patients makes these options unsuitable and high-ICP symptoms are developed without ventricular dilation. METHODS: We present a two cases series affected by IFV with no ventricular dilation in radiological exams. ICP sensors were implanted, observing high-ICP and establishing the diagnosis of craniocerebral disproportion. A two-stage surgical plan based on a dynamic cranial expansion followed by a supratentorial endoscopic aqueductoplasty was performed. A physical and mathematical model explaining our approach was also provided. RESULTS: Chess-table cranial expansion technique was performed in both patients. Six/seven days after the first surgery, respectively, ventricular dilation was observed in CT. Endoscopic precoronal aqueductoplasty was then performed. No postoperative complications were described. IFV symptoms improved in both patients. Eighteen and 12 months after the two-stage surgical plan, the patients remain symptom-free and void of flow is still observed between the third and the fourth ventricles in MRI. CONCLUSION: The two-stage approach was a suitable option for the treatment of these complex patients affected by both craniocerebral disproportion and isolated fourth ventricle.

Mediation role of residential density on the association between perceived environmental factors and active commuting to school in Brazilian adolescents / O papel de mediação da densidade residencial na associação entre fatores ambientais percebidos e deslocamento ativo à escola em adolescentes brasileiros / El papel mediador de la densidad poblacional en la asociación entre los factores ambientales percibidos y el desplazamiento activo a la escuela en adolescentes brasileños

Abstract: The objective of this study was to verify whether residential density and connectivity between streets are mediators on the association between perceived environmental factors and active commuting to school (ACS) in Brazilian adolescents. This is a cross-sectional study with a random sample of 1,130 adolescents (52.7% girls) aged between 14 to 20 years, from Porto Alegre, Rio Grande do Sul State, Brazil. Adolescents' self-reported their usual mode of commuting to and from school using a questionnaire and the perceived environmental attributes by Neighborhood Environment Walkability Scale for Youth (NEWS-Y). Residential density and connectivity between streets were measured by gographic information systems (GIS), within 1km road network buffers around the participant's residential address. Regression models were fitted according to mediation analyses procedures. The results showed that residential density is a mediator on the association between ACS and perceived environmental factors, including land-use mix diversity (IE = 0.114; 95%CI: 0.130, 0.311; 32% mediation), neighborhood recreation facilities (IE = 0.064; 95%CI: 0.034, 0.105; 15% mediation), and access to services (IE = 0.045; 95%CI: 0.006, 0.104; 14% mediation). Connectivity between streets did not correlate with ACS, thus it was not tested in the mediation model. In conclusion, residential density is a mediator on the relationship between perceived environmental factors and ACS.

Resumo: O estudo teve como objetivo verificar se a densidade residencial e a conectividade entre ruas são mediadores da associação entre fatores ambientais percebidos e deslocamento ativo casa-escola (DAE) em adolescentes brasileiros. Foi um estudo transversal com uma amostra randomizada de 1.130 adolescentes (52,7% do sexo feminino) entre 14 e 20 anos de idade, de Porto Alegre, Rio Grande do Sul, Brasil. Os adolescentes informaram seu modo de deslocamento casa-escola (ida e volta) através de um questionário, além dos atributos ambientais percebidos, de acordo com a Neighborhood Environment Walkability Scale for Youth (NEWS-Y). A densidade residencial e a conectividade entre ruas foram medidas por sistemas de informação geográfica (SIG), dentro de um raio de 1km da rede viária em torno do endereço residencial do participante. Foram ajustados modelos de regressão de acordo com os procedimentos para análises de mediação. Os resultados mostraram que a densidade residencial é um mediador da associação entre os fatores ambientais percebidos e o DAE, inclusive a diversidade do uso do solo (EI = 0,114; IC95%: 0,130, 0,311; 32% de mediação), infraestrutura para atividades de lazer na vizinhança (EI = 0,064; IC95%: 0,034, 0,105; 15% de mediação) e acesso a serviços (EI = 0,045; IC95%: 0,006, 0,104; 14% de mediação). A conectividade entre ruas não mostrou correlação com DAE, portanto não foi testado no modelo de mediação. Conclui-se que a densidade residencial é um mediador da relação entre fatores ambientais percebidos e DAE.

Resumen: El objetivo fue verificar si la densidad poblacional y la conectividad entre calles son mediadores en la asociación entre los factores ambientales percibidos y el desplazamiento activo a la escuela (DAE) en adolescentes brasileños. Se trata de un estudio transversal, con una muestra aleatoria de 1.130 adolescentes (52,7% chicas), con una edad comprendida entre los 14 y los 20 años de edad, de Porto Alegre, Río Grande do Sul, Brasil. Los adolescentes autoinformaron su modo habitual de desplazamiento "a" y "desde" la escuela, usando un cuestionario y las características ambientales percibidas mediante el Neighborhood Environment Walkability Scale for Youth (NEWS-Y). La densidad poblacional y conectividad entre las calles se midieron mediante los sistemas de información geográfica (GIS), dentro de una red vial delimitada por un radio de 1km alrededor de la dirección residencial del participante. Los modelos de regresión se ajustaron según los procedimientos para el análisis de mediación. Los resultados mostraron que la densidad poblacional es un a mediador en la asociación entre los factores ambientales percibidos y la DAE, incluyendo el uso del suelo para diversos fines (EI = 0,114; IC95%: 0,130, 0,311; 32% mediación), instalaciones recreativas en el barrio (EI = 0,064; IC95%: 0,034, 0,105; 15% mediación), y acceso a los servicios (EI = 0,045; IC95%: 0,006, 0,104; 14% mediación). Conectividad entre calles que no mostraron correlación con DAE, por consiguiente, no fue probado en el modelo de mediación. En conclusión, la densidad poblacional es un mediador en la relación entre los factores ambientales percibidos con DAE.

Tumor stem cells fuse with monocytes to form highly invasive tumor-hybrid cells.

The 'cancer cell fusion' theory is controversial due to the lack of methods available to identify hybrid cells and to follow the phenomenon in patients. However, it seems to be one of the best explanations for both the origin and metastasis of primary tumors. Herein, we co-cultured lung cancer stem cells with human monocytes and analyzed the dynamics and properties of tumor-hybrid cells (THC), as well as the molecular mechanisms beneath this fusion process by several techniques: electron-microscopy, karyotyping, CRISPR-Cas9, RNA-seq, immunostaining, signaling blockage, among others. Moreover, mice models were assessed for in vivo characterization of hybrids colonization and invasiveness. Then, the presence of THCs in bloodstream and samples from primary and metastatic lesions were detected by FACS and immunofluorescence protocols, and their correlations with TNM stages established. Our data indicate that the generation of THCs depends on the expression of CD36 on tumor stem cells and the oxidative state and polarization of monocytes, the latter being strongly influenced by microenvironmental fluctuations. Highly oxidized M2-like monocytes show the strongest affinity to fuse with tumor stem cells. THCs are able to proliferate, colonize and invade organs. THC-specific cell surface signature CD36+CD14+PANK+ allows identifying them in matched primary tumor tissues and metastases as well as in bloodstream from patients with lung cancer, thus functioning as a biomarker. THCs levels in circulation correlate with TNM classification. Our results suggest that THCs are involved in both origin and spread of metastatic cells. Furthermore, they might set the bases for future therapies to avoid or eradicate lung cancer metastasis.