Adsorption Mass Transfer Zone of Vancomycin in Cartridges With Styrene-Divinylbenzene Sorbent.

Cartridges for hemoadsorption containing styrene-divinylbenzene sorbent are used for multiple conditions, such as intoxication. The mass transfer zone comprises the extension along the longitudinal span of the cartridge where adsorption occurs. The aim of this experiment is to evaluate the mass transfer zone for vancomycin in the HA380 cartridge. The experiment was carried out twice. A saline solution with vancomycin passed through a HA380-modified cartridge at 100 ml/min in a single-pass fashion. The cartridge had four openings along its longitudinal dimension, at 3, 6, 9, and 12 cm. In both experiments, the collection of aliquots occurred at minute 4, in the four openings and pre- and post-cartridge, and an additional sample from the effluent bag at the end of each experiment. In the second experiment, an additional sampling of the same six sites occurred at minute 14. The sigmoidal shape of the curve for the mass transfer zone of vancomycin was similar to the theoretical one. In experiment one, at minute 4, vancomycin clearance was 98.75 ml/min. In experiment two, vancomycin clearance at minutes 4 and 14 was 93.76 and 93.20 ml/min, respectively. This implies an adequate and optimal design of the HA380 cartridge.

Hyperoxemia Induced by Oxygen Therapy in Nonsurgical Critically Ill Patients.

BACKGROUND: Hyperoxemia, often overlooked in critically ill patients, is common and may have adverse consequences. OBJECTIVE: To evaluate the incidence of hyperoxemia induced by oxygen therapy in nonsurgical critically ill patients at intensive care unit (ICU) admission and the association of hyperoxemia with hospital mortality. METHODS: This prospective cohort study included all consecutive admissions of nonsurgical patients aged 18 years or older who received oxygen therapy on admission to the Hospital Santa Luzia Rede D'Or São Luiz adult ICU from July 2018 through June 2021. Patients were categorized into 3 groups according to Pao2 level at ICU admission: hypoxemia (Pao2<60 mm Hg), normoxemia (Pao2= 60-120 mm Hg), and hyperoxemia (Pao2 >120 mm Hg). RESULTS: Among 3088 patients, hyperoxemia was present in 1174 (38.0%) and was independently associated with hospital mortality (odds ratio [OR], 1.32; 95% CI, 1.04-1.67; P=.02). Age (OR, 1.02; 95% CI, 1.02-1.02; P<.001) and chronic kidney disease (OR, 1.55; 95% CI, 1.02-2.36; P=.04) were associated with a higher rate of hyperoxemia. Factors associated with a lower rate of hyperoxemia were Sequential Organ Failure Assessment score (OR, 0.88; 95% CI, 0.83-0.93; P<.001); late-night admission (OR, 0.80; 95% CI, 0.67-0.96; P=.02); and renal/metabolic (OR, 0.22; 95% CI, 0.13-1.39; P<.001), neurologic (OR, 0.02; 95% CI, 0.01-0.05; P<.001), digestive (OR, 0.23; 95% CI, 0.13-0.41; P<.001), and soft tissue/skin/orthopedic (OR, 0.32; 95% CI, 0.13-0.79; P=.01) primary reasons for hospital admission. CONCLUSION: Hyperoxemia induced by oxygen therapy was common in critically ill patients and was linked to increased risk of hospital mortality. Health care professionals should be aware of this condition because of its potential risks and unnecessary costs.

A partial agonist of PPARγ prevents paclitaxel-induced peripheral neuropathy in mice, by inhibiting neuroinflammation.

BACKGROUND AND PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of paclitaxel, affecting 30-50% of patients. Increased survival and concern with patients' quality of life have encouraged the search for new tools to prevent paclitaxel-induced neuropathy. This study presents the glitazone 4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-N-phenylbenzene-sulfonamide (TZD-A1) as a partial agonist of peroxisome proliferator-activated receptor γ (PPARγ), its toxicological profile and effects on paclitaxel-induced CIPN in mice. EXPERIMENTAL APPROACH: Interactions of TZD-A1 with PPARγ were analysed using in silico docking and in vitro reporter gene assays. Pharmacokinetics and toxicity were evaluated using in silico, in vitro and in vivo (C57Bl/6 mice) analyses. Effects of TZD-A1 on CIPN were investigated in paclitaxel-injected mice. Axonal and dorsal root ganglion damage, mitochondrial complex activity and cytokine levels, brain-derived neurotrophic factor (BDNF), nuclear factor erythroid 2-related factor 2 (Nrf2) and PPARγ, were also measured. KEY RESULTS: Docking analysis predicted TZD-A1 interactions with PPARγ compatible with partial agonism, which were corroborated by in vitro reporter gene assays. Good oral bioavailability and safety profile of TZD-A1 were shown in silico, in vitro and in vivo. Paclitaxel-injected mice, concomitantly treated with TZD-A1 by i.p. or oral administration, exhibited decreased mechanical and thermal hypersensitivity, effects apparently mediated by inhibition of neuroinflammation and mitochondrial damage, through increasing Nrf2 and PPARγ levels, and up-regulating BDNF. CONCLUSION AND IMPLICATIONS: TZD-A1, a partial agonist of PPARγ, provided neuroprotection and reduced hypersensitivity induced by paclitaxel. Allied to its safety profile and good bioavailability, TZD-A1 is a promising drug candidate to prevent and treat CIPN in cancer patients.

Mouse Testicular Mkrn3 Expression Is Primarily Interstitial, Increases Peripubertally, and Is Responsive to LH/hCG.

Studies in humans and mice support a role for Makorin RING finger protein 3 (MKRN3) as an inhibitor of gonadotropin-releasing hormone (GnRH) secretion prepubertally, and its loss of function is the most common genetic cause of central precocious puberty in humans. Studies have shown that the gonads can synthesize neuropeptides and express MKRN3/Mkrn3 mRNA. Therefore, we aimed to investigate the spatiotemporal expression pattern of Mkrn3 in gonads during sexual development, and its potential regulation in the functional testicular compartments by gonadotropins. Mkrn3 mRNA was detected in testes and ovaries of wild-type mice at all ages evaluated, with a sexually dimorphic expression pattern between male and female gonads. Mkrn3 expression was highest peripubertally in the testes, whereas it was lower peripubertally than prepubertally in the ovaries. Mkrn3 is expressed primarily in the interstitial compartment of the testes but was also detected at low levels in the seminiferous tubules. In vitro studies demonstrated that Mkrn3 mRNA levels increased in human chorionic gonadotropin (hCG)-treated Leydig cell primary cultures. Acute administration of a GnRH agonist in adult mice increased Mkrn3 expression in testes, whereas inhibition of the hypothalamic-pituitary-gonadal axis by chronic administration of GnRH agonist had the opposite effect. Finally, we found that hCG increased Mkrn3 mRNA levels in a dose-dependent manner. Taken together, our developmental expression analyses, in vitro and in vivo studies show that Mkrn3 is expressed in the testes, predominantly in the interstitial compartment, and that Mkrn3 expression increases after puberty and is responsive to luteinizing hormone/hCG stimulation.

The effect of long-term exposure to nonylphenol at environmentally relevant levels on mouse liver and adipose tissue.

Exposure to the xenoestrogen nonylphenol (NP) during critical windows of development leads to metabolic abnormalities in adult life. However, less is known about NP exposure outside the developmental period on metabolic outcomes. We investigated the effect of prolonged exposure to NP after sexual maturity and at environmentally relevant concentrations below the 'no observable adverse effects level' (0.5 and 2.5 mg/kg/d). Male Swiss mice fed a normal-fat diet exposed to 2.5 mg/kg/d NP showed reduced weight gain and hepatic fat content. In male and female C57BL/6 mice fed a high-fat diet, NP exposure modified the mRNA levels of estrogen receptor α (Esr1) and adipose lineage markers in a sexually dimorphic and adipose depot-dependent pattern. Moreover, in primary female but not male stromal vascular cells from C57BL/6 mouse inguinal WAT induced to differentiate into adipocytes, NP upregulated Fabp4 expression. Low-level exposure to NP outside critical developmental windows may affect the metabolic phenotype distinctly. DATA AVAILABILITY STATEMENT: All data not included in the manuscript, such as raw results, are available upon request and should be addressed to AAA.

Rationale for Adsorption in Extracorporeal Blood Purification.

A strong rationale supports the development of adsorption-based extracorporeal blood purification in conditions such as sepsis, acute kidney disease, uremia, and acute liver failure. The retention of compounds as a consequence of acute or chronic organ dysfunction might have detrimental effects. When a causative effect of an accumulated compound in a pathogenic condition is demonstrated, a rationale for the removal of this solute is also established. Adsorption is a mass transfer mechanism in which a solute chemically interacts with the surface of a solid structure (sorbent) and is removed from its solvent (i.e., blood or plasma). Traditional extracorporeal blood purification techniques utilize semipermeable membranes and depend mainly on diffusion and convection as mechanisms of mass transfer. Protein-bound solutes and water-soluble compounds with molecular weight above 25 kDa are scantly removed by either diffusive or convective clearances. In contrast, recently developed resins have demonstrated safety aligned with notable adsorptive capability, which enables the extraction of endotoxins, inflammatory mediators, and uremic toxins. The understanding of the kinetics of these elements and the improvement in patient selection are key factors to propel exploratory and confirmatory trials that ultimately will lead to the expected changes in clinical practice.

ZIKV Strains Elicit Different Inflammatory and Anti-Viral Responses in Microglia Cells.

In recent years, the Zika Virus (ZIKV) has caused pandemic outbreaks associated with a high rate of congenital ZIKV syndrome (CZS). Although all strains associated with worldwide outbreaks derive from the Asian lineage, the reasons for their enhanced spread and severity are not fully understood. In this study, we conducted a comparative analysis of miRNAs (miRNA-155/146a/124) and their cellular targets (SOCS1/3, SHP1, TRAF6, IRAK1), as well as pro- and anti-inflammatory and anti-viral cytokines (IL-6, TNF-α, IFN-γ, IL-10, and IFN-ß) and peroxisome proliferator-activated receptor γ (PPAR-γ) expression in BV2 microglia cells infected with ZIKV strains derived from African and Asian lineages (ZIKVMR766 and ZIKVPE243). BV2 cells were susceptible to both ZIKV strains, and showed discrete levels of viral replication, with delayed release of viral particles without inducing significant cytopathogenic effects. However, the ZIKVMR766 strain showed higher infectivity and replicative capacity, inducing a higher expression of microglial activation markers than the ZIKVPE243 strain. Moreover, infection with the ZIKVMR766 strain promoted both a higher inflammatory response and a lower expression of anti-viral factors compared to the ZIKVPE243 strain. Remarkably, the ZIKKPE243 strain induced significantly higher levels of the anti-inflammatory nuclear receptor-PPAR-γ. These findings improve our understanding of ZIKV-mediated modulation of inflammatory and anti-viral innate immune responses and open a new avenue to explore underlining mechanisms involved in the pathogenesis of ZIKV-associated diseases.

End-to-End Detection of a Landing Platform for Offshore UAVs Based on a Multimodal Early Fusion Approach.

A perception module is a vital component of a modern robotic system. Vision, radar, thermal, and LiDAR are the most common choices of sensors for environmental awareness. Relying on singular sources of information is prone to be affected by specific environmental conditions (e.g., visual cameras are affected by glary or dark environments). Thus, relying on different sensors is an essential step to introduce robustness against various environmental conditions. Hence, a perception system with sensor fusion capabilities produces the desired redundant and reliable awareness critical for real-world systems. This paper proposes a novel early fusion module that is reliable against individual cases of sensor failure when detecting an offshore maritime platform for UAV landing. The model explores the early fusion of a still unexplored combination of visual, infrared, and LiDAR modalities. The contribution is described by suggesting a simple methodology that intends to facilitate the training and inference of a lightweight state-of-the-art object detector. The early fusion based detector achieves solid detection recalls up to 99% for all cases of sensor failure and extreme weather conditions such as glary, dark, and foggy scenarios in fair real-time inference duration below 6 ms.

Multidrug-Resistant Bacteria on Critically Ill Patients with Sepsis at Hospital Admission: Risk Factors and Effects on Hospital Mortality.

Purpose: To evaluate the effect of MDRO infection on hospital mortality and the risk factors among critically ill patients with sepsis at hospital admission. Patients and Methods: A cross-sectional study was performed between April 2019 and May 2020, followed by a cohort to evaluate hospital mortality that prospectively included all consecutive patients 18 years or older with sepsis admitted within 48 hours of hospital admission to an adult ICU in Brazil. Patients' characteristics, blood samples within one hour of ICU admission, and microbiological results within 48h of hospital admission were collected. In addition, descriptive statistics, binary logistic regression, and propensity score matching were performed. Results: At least one MDRO was isolated in 85 patients (9.8%). The extended-spectrum beta-lactamase-producing Enterobacterales are the most frequent organism (56.1%). Hypoxemic acute respiratory failure (OR 1.87, 95% CI 1.02-3.40, p = 0.04), Glasgow Coma Score below 15 (OR 2.57, 95% CI 1.38-4.80, p < 0.01), neoplasm (OR 2.66, 95% CI 1.04-6.82, p = 0.04) and hemoglobin below 10.0 g/dL (OR 1.82, 95% CI 1.05-3.16, p = 0.03) were associated with increased MDRO. Admission from the Emergency Department (OR 0.25, 95% CI 0.14-0.43, p < 0.01) was associated with decreased MDRO. In the multivariate analysis, MDRO at hospital admission increased hospital mortality (OR 2.80, 95% CI 1.05-7.42, p = 0.04). After propensity score-matching adjusted to age, APACHE II, SOFA, and dementia, MDRO at hospital admission was associated with significantly high hospital mortality (OR 2.80, 95% CI 1.05-7.42, p = 0.04). The E-value of adjusted OR for the effect of MDRO infection on hospital mortality was 3.41, with a 95% CI of 1.31, suggesting that unmeasured confounders were unlikely to explain the entirety of the effect. Conclusion: MDRO infection increased hospital mortality, and MDRO risk factors should be accessed even in patients admitted to ICU within 48 hours of hospital admission.

Rationale for a New Classification of Solutes of Interest in Chronic Kidney Disease and Hemodialysis.

A hallmark of chronic kidney disease is the retention of solutes that normally are eliminated by the kidneys. The current classification defines uremic toxins based on molecular weight and protein affinity. The retention of solutes is already detected in the early stages of the disease when patients are pauci-symptomatic or asymptomatic but the role of therapies to retard the loss of kidney function in patients with chronic kidney disease (e.g., modulators of the renin-angiotensin-aldosterone system, sodium-glucose cotransporter inhibitors) in reducing uremic toxins is poorly understood. Most of the research evaluating the impact of therapies to lower serum concentrations of those toxic compounds is carried out in patients with kidney failure already undergoing kidney replacement therapy. The removal of those molecules relies in physicochemical mass transfer phenomena, i.e., adsorption, diffusion, and convection. In the past 2 decades, the rise and broad adoption of blood purification strategies with enhanced convective properties, such as high-volume online hemodiafiltration and expanded hemodialysis, considerably amplified the ability to mechanically extract middle molecules (molecular weight >0.5 kDa) from the blood compartment. Nonetheless, the classification of uremic toxins has not evolved in parallel with dialysis advancements. Mounting evidence demonstrates the link between middle molecules with uremic symptoms, cardiovascular and mortality risks. An urgent need for updating the classification exists. Defining the causative relationship between specific solutes and specific clinical outcomes will promote the development of targeted therapies. In parallel, the inclusion of new pertinent dimensions to the classification like the influence of new dialysis membranes, sorbents, and intestinal chelators in the concentration of uremic toxins would improve the understanding of the pathogenesis of chronic kidney disease, setting the pace for future research in nephrology.

Cisplatin-induced changes in calcitonin gene-related peptide or TNF-α release in rat dorsal root ganglia in vitro model of neurotoxicity are not reverted by rosiglitazone.

INTRODUCTION: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of anticancer drugs which affect the peripheral nervous system, as occurs with cisplatin treatment. Nowadays, one strategy in development to prevent, minimize and/or revert CIPN is neuroprotection. Therefore, we have evaluated the signaling pathways involved in CIPN and the effect of rosiglitazone, a peroxisome proliferator-activated receptor γ (PPAR-γ) agonist. METHODS: Dorsal Root Ganglia (DRG) were harvested from Wistar rats (Rattus norvegicus), the cells were dissociated, plated, and maintained with nerve growth factor for 9 days. On day 8, the cells were treated with cisplatin, rosiglitazone and/or T0070907 (PPAR-γ antagonist) for 24 h. The cell viability was measured by trypan blue exclusion method, the mRNA was quantified by real-time RT-PCRq and the release of TNF-α and calcitonin gene-related peptide (CGRP) was evaluated by ELISA. RESULTS: Cisplatin, rosiglitazone or T0070907 treatments did not decreased the cell viability on the primary DRG cultures cells. Cisplatin treatment induced a decrease of PPAR-γ and -ß/δ mRNA, while the co-treatment with rosiglitazone inhibited this cisplatin-induced effect. Moreover, T0070907 did not change the observed results, indicating that the rosiglitazone's effect could be due to mechanisms beyond PPAR-γ activation. Also, the rosiglitazone effect is not exclusively to DRG cells since there was an increase of PPAR-γ mRNA expression in 3T3-L1 cells. Furthermore, rosiglitazone did not modulate the cisplatin decrease neuronal function of DRG cells (TNF-α and CGRP release). CONCLUSION: Cisplatin decreased the gene expression of PPAR-γ and -ß/δ, while the rosiglitazone treatment inhibited these effects via PPAR-γ independent pathway. Rosiglitazone did not show improvement in modulation of TNF-α or CGRP release impaired by cisplatin.

In vitro effects of European and Latin-American medicinal plants in CYP3A4 gene expression, glutathione levels, and P-glycoprotein activity.

Many medicinal plants species from European -such as Artemisia absinthium, Equisetum arvense, Lamium album, Malva sylvestris, Morus nigra, Passiflora incarnata, Frangula purshiana, and Salix alba- as well as Latin American traditions -such as Libidibia ferrea, Bidens pilosa, Casearia sylvestris, Costus spicatus, Monteverdia ilicifolia, Persea americana, Schinus terebinthifolia, Solidago chilensis, Syzygium cumini, Handroanthus impetiginosus, and Vernonanthura phosphorica- are shortlisted by the Brazilian National Health System for future clinical use. However, they lack many data on their action upon some key ADME targets. In this study, we assess non-toxic concentrations (up to100 µg/ml) of their infusions for in vitro ability to modulate CYP3A4 mRNA gene expression and intracellular glutathione levels in HepG2 cells, as well as P-glycoprotein (P-gp) activity in vincristine-resistant Caco-2 cells (Caco-2 VCR). We further investigated the activation of human pregnane X receptor (hPXR) in transiently co-transfected HeLa cells and the inhibition of Gamma-glutamyl transferase (GGT) in HepG2 cells. Our results demonstrate L. ferrea, C. sylvestris , M. ilicifolia, P. americana, S. terebinthifolia, S. cumini, V. phosphorica, E. arvense, P. incarnata, F. purshiana, and S. alba can significantly increase CYP3A4 mRNA gene expression in HepG2 cells. Only F. purshiana shown to do so likely via hPXR activation. P-gp activity was affected by L. ferrea, F. purshiana, S. terebinthifolia, and S. cumini. Total intracellular glutathione levels were significantly depleted by exposure to all extracts except S. alba and S. cumini This was accompanied by a lower GGT activity in the case of C. spicatus, P. americana, S. alba, and S. terebinthifolia, whilst L. ferrea, P. incarnata and F. purshiana increased it. Surprisingly, S. cumini aqueous extract drastically decreased GGT activity (-48%, p < 0.01). In conclusion, this preclinical study shows that the administration of some of these herbal medicines causes in vitro disturbances to key drug metabolism mechanisms. We recommend active pharmacovigilance for Libidibia ferrea (Mart.) L. P. Queiroz, Frangula purshiana Cooper, Schinus terebinthifolia Raddi, and Salix alba L. which were able to alter all targets in our preclinical study.

The Inflammatory Status of Soluble Microenvironment Influences the Capacity of Melanoma Cells to Control T-Cell Responses.

The development of immunotherapeutic approaches for the treatment of melanoma requires a better understanding of immunoescape mechanisms of tumor cells and how they interact with other tumor-resident cell types. Here, we evaluated how the conditioned media of resting (rCM) and immune-activated PBMCs (iCM) influence the ability of a metastatic melanoma cell line (MeWo) to control T-cells function. MeWo cells were expanded in RPMI, rCM, or iCM and the secretome generated after cell expansion was identified as MeSec (RPMI), niSec (non-inflammatory), or iSec (inflammatory secretome), respectively. Then, the immunomodulatory potential of such secretomes was tested in PHA-activated PBMCs. iCM induced higher levels of IFN-γ and IL-10 in treated melanoma cells compared to rCM, as well as higher IDO and PD-L1 expression. The iSec was able to inhibit T-cell activation and proliferation. Interestingly, PBMCs treated with iSec presented a reduced expression of the regulators of Th1 and Th2 responses T-BET and GATA-3, as well as low expression of IFN-γ, and co-stimulatory molecules TIM-3 and LAG-3. Importantly, our findings show that melanoma may benefit from an inflammatory microenvironment to enhance its ability to control the T-cell response. Interestingly, such an immunomodulatory effect involves the inhibition of the checkpoint molecules LAG-3 and TIM-3, which are currently investigated as important therapeutic targets for melanoma treatment. Further studies are needed to better understand how checkpoint molecules are modulated by paracrine and cell contact-dependent interaction between melanoma and immune cells. Such advances are fundamental for the development of new therapeutic approaches focused on melanoma immunotherapy.

Prioritization of ICU beds with renal replacement therapy support by court order and mortality in a Brazilian metropolitan area.

The shortage of intensive care unit (ICU) resources, including equipment and supplies for renal replacement therapy (RRT), is a critical problem in several countries. This study aimed to assess hospital mortality and associated factors in patients treated in public hospitals of the Federal District, Brazil, who requested admission to ICU with renal replacement therapy support (ICU-RRT) in court. Retrospective cohort study that included 883 adult patients treated in public hospitals of the Federal District who requested ICU-RRT admission in court from January 2017 to December 2018. ICU-RRT was denied to 407 patients, which increased mortality (OR 3.33, 95% CI 2.39-4.56, p ≪ 0.01), especially in patients with priority level I/II (OR 1.02, 95% CI 1.01-1.04, p ≪ 0.01). Of the requests made in court, 450 were filed by patients with priority levels III/IV, and 44.7% of these were admitted to ICU-RRT. In admitted patients, priority level III priority level I/II was associated with a low mortality (OR 0.47, 95% CI 0.32-0.69, p < 0.01), and not. The admission of patients classified as priority levels III/IV to ICU-RRT considerably jeopardized the admission of patients with priority levels I/II to these settings. The results found open new avenues for organizing public policies and improving ICU-RRT triage.

Nursing students admitted through the affirmative action system display similar performance in professional and academic trajectories to those from the regular path in a public school in Brazil.

OBJECTIVES: Affirmative action providing higher education access for socially vulnerable students has been implemented in several countries. However, these policies remain controversial. This study compares the performance of students admitted through the regular path and social quota systems, during and after completion of nursing education, in a public nursing school in Brazil. METHODS: This retrospective cohort study included all students admitted to nursing school at the School of Health Sciences (ESCS), Brazil, between 2009 and 2014, who were followed until May 2020. The first phase involved document analysis from the ESCS academic management system and Brazilian government agencies. In the second phase, a survey was conducted among the alumni. The social quota system criterion was public school attendance across all primary and secondary education levels. RESULTS: Of the 448 students included in the study, 178 (39.7%) were from the affirmative action and 270 (60.3%) from the regular path systems. Affirmative action students were older at the time of nursing school admission (p < 0.001) and took longer to be admitted to the nursing school (p < 0.001) after completing high school. There were no significant differences in the dropout rates and years to complete nursing school. In the second phase, 108 alumni answered the survey. No significant differences were found in their participation in the undergraduate scientific research program and university extension projects, attending residency programs, getting a master's degree and doctoral degree, monthly income, teaching activity, joining public service through a government job competition process, participation in management activities in the private and public health sector, and degree of job satisfaction. CONCLUSION: Our results revealed that affirmative action is a policy that contributes to the reduction of inequalities and guarantees the training of nursing professionals with a similar professional qualification received through affirmative action and regular path systems.

Comparison Between Students Admitted Through Regular Path and Affirmative Action Systems in a Brazilian Public Medical School.

Purpose: Affirmative action policies to provide access to higher education for socially vulnerable students have been implemented in several countries and have faced many questions nowadays. The aim of the study was to compare the socioeconomic background and performance during and after completing the undergraduate course of students admitted through the regular path and social quota systems in a public medical school in Brazil. Methods: A retrospective cohort study including students admitted to a medical school within the School of Health Sciences (ESCS), in Brazil, between 2005 and 2012, and followed until May 2020. In the first phase, data collection was performed by analyzing documents from the ESCS academic management system and Brazilian government agencies. In the second phase, a survey with 12 questions was sent to the medical school alumni. The social quota system criteria were the public school attendance in all primary and secondary education levels. Results: Among 707 students, 204 (28.9%) were from the social quota and 503 (78.5%) from the regular path system. The place of residence of social quota students had a lower Human Development Index (p < 0.001) and per capita income (p < 0.001) when compared to regular path students. Regular path students were associated with the highest dropout from medical school (OR: 50.552, 95% CI: 12.438-205.453, p < 0.001). There was no difference between regular path and social quota students attending medical residency programs (OR: 1.780, 95% CI: 0.957-3.309, p = 0.069). Out of the 308 alumni who completed the survey, regular path students had more family members who were health professionals than social quota students (p < 0.001). There were no significant differences regarding monthly income, job satisfaction, employment, or management activities. Conclusion: Affirmative action targeted students with a disadvantaged socioeconomic background. Regular path students had a higher dropout rate than social quota students.

Selective modulator of nuclear receptor PPARγ with reduced adipogenic potential ameliorates experimental nephrotic syndrome.

Glomerular disease manifests as nephrotic syndrome (NS) with high proteinuria and comorbidities, and is frequently refractory to standard treatments. We hypothesized that a selective modulator of PPARγ, GQ-16, will provide therapeutic advantage over traditional PPARγ agonists for NS treatment. We demonstrate in a pre-clinical NS model that proteinuria is reduced with pioglitazone to 64%, and robustly with GQ-16 to 81% of nephrosis, comparable to controls. Although both GQ-16 and pioglitazone restore glomerular-Nphs1, hepatic-Pcsk9 and serum-cholesterol, only GQ-16 restores glomerular-Nrf2, and reduces hypoalbuminemia and hypercoagulopathy. GQ-16 and pioglitazone restore common and distinct glomerular gene expression analyzed by RNA-seq and induce insulin sensitizing adipokines to various degrees. Pioglitazone but not GQ-16 induces more lipid accumulation and aP2 in adipocytes and white adipose tissue. We conclude that selective modulation of PPARγ by a partial agonist, GQ-16, is more advantageous than pioglitazone in reducing proteinuria, NS associated comorbidities, and adipogenic side effects of full PPARγ agonists.

Differential peripheral blood mononuclear cell reactivity against SARS-CoV-2 proteins in naïve and previously infected subjects following COVID-19 vaccination.

The decline in vaccine efficacy and the risk of reinfection by SARS-CoV-2 make new studies important to better characterize the immune response against the virus and its components. Here, we investigated the pattern of activation of T-cells and the expression of inflammatory factors by PBMCs obtained from naïve and previously infected subjects following COVID-19 vaccination, after PBMCs stimulation with S1, RBD, and N-RBD SARS-CoV-2 proteins. PBMCs showed low levels of ACE2 and TMPRSS2 transcripts, which were not modulated by the exposure of these cells to SARS-CoV-2 proteins. Compared to S1 and RBD, N-RBD stimulation showed a greater ability to stimulate T-cell reactivity, according to CD25 and CD69 markers. Interestingly, T-cell reactivity was more pronounced in vaccinated subjects with prior SARS-CoV-2 infection than in vaccinated donors who never had been diagnosed with COVID-19. Finally, N-RBD stimulation promoted greater expression of IL-6 and IFN-γ in PBMCs, which reinforces the greater immunogenic potential of this protein in the vaccinated subjects. These data suggest that PBMCs from previously infected and vaccinated subjects are more reactive than those derived from just vaccinated donors. Moreover, the N-RBD together viral proteins showed a greater stimulatory capacity than S1 and RBD viral proteins.

Antiproliferative effects of metformin in cellular models of pheochromocytoma.

Pheochromocytomas (PCCs) are rare neuroendocrine tumors derived from adrenal medulla chromaffin cells. Malignancy and recurrence are rare but demand effective treatment. Metformin exerts antiproliferative effects in several cancer cell lines. We thus evaluated the effects of metformin on cell viability and proliferation, cellular respiration and AMPK-AKT-mTOR-HIFA proliferation pathway on a rat PCC cell line (PC12-Adh). We then addressed metformin's effects on the AMPK-AKT-mTOR-HIFA pathway on two human primary cultures: one from a VHL-mutant PCC and other from a sporadic PCC. Metformin (20 mM) inhibited PC12-Adh cell proliferation, and decreased oxygen consumption, ATP production and proton leak, in addition to loss of mitochondrial membrane potential. Further, metformin induced AMPK phosphorylation and impaired AMPK-PI3k-AKT-mTOR pathway activation. The mTOR pathway was also inhibited in human VHL-related PCC cells, however, in an AMPK-independent manner. Metformin-induced decrease of HIF1A levels was likely mediated by proteasomal degradation. Altogether our results suggest that metformin impairs PCC cellular proliferation.