Predicting major adverse cardiovascular events after orthotopic liver transplantation using a supervised machine learning model: A cohort study.

BACKGROUND: Liver transplant (LT) patients have become older and sicker. The rate of post-LT major adverse cardiovascular events (MACE) has increased, and this in turn raises 30-d post-LT mortality. Noninvasive cardiac stress testing loses accuracy when applied to pre-LT cirrhotic patients. AIM: To assess the feasibility and accuracy of a machine learning model used to predict post-LT MACE in a regional cohort. METHODS: This retrospective cohort study involved 575 LT patients from a Southern Brazilian academic center. We developed a predictive model for post-LT MACE (defined as a composite outcome of stroke, new-onset heart failure, severe arrhythmia, and myocardial infarction) using the extreme gradient boosting (XGBoost) machine learning model. We addressed missing data (below 20%) for relevant variables using the k-nearest neighbor imputation method, calculating the mean from the ten nearest neighbors for each case. The modeling dataset included 83 features, encompassing patient and laboratory data, cirrhosis complications, and pre-LT cardiac assessments. Model performance was assessed using the area under the receiver operating characteristic curve (AUROC). We also employed Shapley additive explanations (SHAP) to interpret feature impacts. The dataset was split into training (75%) and testing (25%) sets. Calibration was evaluated using the Brier score. We followed Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis guidelines for reporting. Scikit-learn and SHAP in Python 3 were used for all analyses. The supplementary material includes code for model development and a user-friendly online MACE prediction calculator. RESULTS: Of the 537 included patients, 23 (4.46%) developed in-hospital MACE, with a mean age at transplantation of 52.9 years. The majority, 66.1%, were male. The XGBoost model achieved an impressive AUROC of 0.89 during the training stage. This model exhibited accuracy, precision, recall, and F1-score values of 0.84, 0.85, 0.80, and 0.79, respectively. Calibration, as assessed by the Brier score, indicated excellent model calibration with a score of 0.07. Furthermore, SHAP values highlighted the significance of certain variables in predicting postoperative MACE, with negative noninvasive cardiac stress testing, use of nonselective beta-blockers, direct bilirubin levels, blood type O, and dynamic alterations on myocardial perfusion scintigraphy being the most influential factors at the cohort-wide level. These results highlight the predictive capability of our XGBoost model in assessing the risk of post-LT MACE, making it a valuable tool for clinical practice. CONCLUSION: Our study successfully assessed the feasibility and accuracy of the XGBoost machine learning model in predicting post-LT MACE, using both cardiovascular and hepatic variables. The model demonstrated impressive performance, aligning with literature findings, and exhibited excellent calibration. Notably, our cautious approach to prevent overfitting and data leakage suggests the stability of results when applied to prospective data, reinforcing the model's value as a reliable tool for predicting post-LT MACE in clinical practice.

Curcumin as a Stabilizer of Macrophage Polarization during Plasmodium Infection.

Malaria is a parasitic infection responsible for high morbidity and mortality rates worldwide. During the disease, phagocytosis of infected red blood cells by the macrophages induces the production of reactive oxygen (ROS) and nitrogen species (RNS), culminating in parasite death. Curcumin (CUR) is a bioactive compound that has been demonstrated to reduce the production of pro-inflammatory cytokines and chemokines produced by macrophages but to reduce parasitemia in infected mice. Hence, the main purpose of this study is to investigate whether curcumin may interfere with macrophage function and polarization after Plasmodium berghei infection in vitro. In our findings, non-polarized macrophage (M0), classically activated (M1), and alternatively activated (M2) phenotypes showed significantly increased phagocytosis of infected red blood cells (iRBCs) when compared to phagocytosis of uninfected red blood cells (RBCs) 3 h after infection. After 24 h, M1 macrophages exposed to RBCs + CUR showed greater elimination capacity when compared to macrophages exposed to iRBCs + CUR, suggesting the interference of curcumin with the microbicidal activity. Additionally, curcumin increased the phagocytic activity of macrophages when used in non-inflammatory conditions (M0) and reduced the inducible nitric oxide synthase (iNOS) and arginase activities in all macrophage phenotypes infected (M0, M1, and M2), suggesting interference in arginine availability by curcumin and balance promotion in macrophage polarization in neutral phenotype (M0). These results support the view of curcumin treatment in malaria as an adjuvant, promoting a balance between pro- and anti-inflammatory responses for a better clinical outcome.

Impacts of Curcumin Treatment on Experimental Sepsis: A Systematic Review.

Background and Aims: Sepsis is defined as a life-threatening organ dysfunction due to a dysregulated host immune response to an infection. Curcumin is a yellow polyphenol derived from the rhizome of Curcuma longa with anti-inflammatory and antioxidant properties scientifically proven, a condition that allowed its use as a tool in the treatment of sepsis. Thus, the purpose of this article was to systematically review the evidence on the impact of curcumin's anti-inflammatory effect on experimental sepsis. Methods: For this, the PubMed, MEDLINE, EMBASE, Scopus, Web of Science, and LILACS databases were used, and the research was not limited to a specific publication period. Only original articles in English using in vivo experimental models (rats or mice) of sepsis induction performed by administration of lipopolysaccharide (LPS) or cecal ligation and perforation surgery (CLP) were included in the study. Studies using curcumin in dry extract or with a high degree of purity were included. At initial screening, 546 articles were selected, and of these, 223 were eligible for primary evaluation. Finally, 12 articles with full text met all inclusion criteria. Our results showed that curcumin may inhibit sepsis-induced complications such as brain, heart, liver, lungs, and kidney damage. Curcumin can inhibit inflammatory factors, prevent oxidative stress, and regulate immune responses in sepsis. Additionally, curcumin increased significantly the survival rates after experimental sepsis in several studies. The modulation of the immune response and mortality by curcumin reinforces its protective effect on sepsis and indicates a potential therapeutic tool for the treatment of sepsis.

Polymethylmethacrylate Microspheres are Immunologically Inert in Mouse Tissues.

Nowadays, aesthetic concerns have gained attention, especially by patients looking for a less invasive alternative to minor facial corrections. Polymethylmethacrylate (PMMA) is widely used as a soft tissue filler; the demand for this polymer has increased, and along with it, there are some reports of adverse reactions. Such adverse reactions stem from consequences of immune and inflammatory reactions to PMMA. Some animal models have been used to unravel the causes of these reactions, among other factors involving the management of PMMA. The aim of this study was to determine the immunogenic profile of PMMA implantation in different anatomical planes of mice, over up to 360 experimental days. In this study, BALB/c mice were divided into 30 groups for immune evaluation of the interaction between the organism and the polymer; 2% PMMA was implanted subcutaneously, 10% intramuscularly and 30% in periosteal juxtaposition and followed during five experimental days (7, 30, 90, 180 and 360 days after implantation-DAI). Pro- and anti-inflammatory cytokines (IL-2, IL-4, IL-6, IFN-gamma, TNF, IL-17A, IL-10 and TGF-beta) were quantified in all experimental days. There was no statistical difference between the groups analyzed considering the evaluated parameters. Therefore, at all implanted depths, PMMA behaved inertly in a murine model.No Level Assigned This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Tissue Remodeling After Implantation with Polymethylmethacrylate: An Experimental Study in Mice.

Polymethylmethacrylate (PMMA) is a filler used for aesthetic and/or repair purposes. The response to the implantation of biomaterials varies according to factors related to the patient, the professional responsible for the application and the material used. In vitro and in vivo experimental models have been used to study aspects such as the organism/biomaterial interface and the role of macrophages, dendritic cells and neutrophils. This study aimed to characterize the inflammatory reactions related to polymer concentration, implantation depth and exposure time. Different concentrations of PMMA were implanted in different anatomical planes in mice. The consequences of contact with PMMA, from structural changes to the inflammatory characteristic of tissue damage, were histologically evaluated. The implantation interfered in the morphological structure of the region where it was implanted, expanding it and due to the inflammatory reaction generated, by the presence of the vehicle in the initial phase and by the collagen produced in the chronic phase. The 30% concentration of PMMA induced a greater presence of foreign body giant cells both subcutaneously, at 7, 30 and 90 days after implantation (DAI), and intramuscular at 30DAI. Tissue remodeling was more expressive in the subcutaneous region with significant density of the extracellular matrix at 90DAI. In conclusion, the foreign body reaction resulting from the implantation process acquires different characteristics depending on the anatomical plane and the concentration of implanted product, where the more superficial the implantation plane, the greater the inflammatory reaction. Moreover, PMMA concentration and the depth of implantation did not influence the collagen production.No Level Assigned This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors https://www.springer.com/00266.

Doxorubicin-induced Cardiotoxicity and Cardioprotective Agents: Classic and New Players in the Game.

Doxorubicin (DOX) is a cytostatic antibiotic from the class of anthracyclines widely used in chemotherapeutic cancer treatments. Despite the efficiency against several types of cancer, the use of DOX remains limited due to the side effects, especially cardiotoxicity. Among the DOX administration strategies, there are the "classic players" such as nanoparticles and polymers, which are capable of DOX delivery directly to interesting neoplastic regions. On the other hand, the "new players" such as phytochemicals and probiotics emerged with the proposal to react with DOX free radicals, reducing the oxidative stress, inflammatory and apoptotic process. Thus, this review aims to report the studies involving these classics and new players along the years that focus on improved administration and reduction of DOX-induced cardiotoxicity.

Influence of sucrose on growth and sensitivity of Candida albicans alone and in combination with Enterococcus faecalis and Streptococcus mutans to photodynamic therapy.

This study has evaluated the effects of photodynamic inactivation (PDI) using erythrosine as photosensitizer and green light-emitting diode (LED) on biofilms of Candida albicans alone and in combination with Enterococcus faecalis and Streptococcus mutans. We have also evaluated the effect of sucrose on biofilm formation and bacterial growth and sensitivity to PDI. Biofilms were formed in suspension of 106 cells/ml on plates before being grown in broth culture with and without sucrose and incubated for 48 h. Next, the treatment was applied using erythrosine at a concentration of 400 µM for 5 min and green LED (532 ± 10 nm) for 3 min on biofilms alone and in combination. The plates were washed and sonicated to disperse the biofilms, and serial dilutions were carried and aliquots seeded in Sabouraud agar before incubation for 48 h. Next, the colony-forming units per milliliter (CFU/ml; log10) were counted and analyzed statistically (ANOVA, Tukey test, P ≤ 0.05). Results show that S. mutans favors the growth of C. albicans in biofilms with sucrose, with treatment not being effective. However, when the biofilm was grown without sucrose, we found a reduction in biofilm formation and a significant decrease in the PDI treatment (P < 0.0001). In conclusion, both growth and sensitivity to PDI in biofilms of C. albicans are strongly influenced by bacterial combination, and the presence of sucrose affected directly the growth and sensitivity of the biofilm to PDI as sucrose is the substrate for construction of the exopolysaccharide matrix.

Leishmania (Viannia) braziliensis amastigotes from patients with mucosal leishmaniasis have increased ability to disseminate and are controlled by nitric oxide at the early stage of murine infection.

Mucosal leishmaniasis (ML) caused by Leishmania (Vianna) braziliensis usually appears after the healing of the primary lesion when amastigotes disseminate from the infection site to the mucosal area. Here, we investigated murine infection with amastigotes obtained from patients with ML or localized cutaneous leishmaniasis (LCL). Amastigotes were used to infect wild type, IFN-γ KO and inducible nitric oxide synthase (iNOS) KO mice. Amastigotes from patients with LCL induced lesions that appeared earlier in IFN-γ KO than parasites from ML. The lesion after infection with ML appeared early in iNOS KO than in IFN-γ KO mice and in iNOS KO mice parasites from ML and LCL cause similar lesions at the initial phase of infection, while parasites from ML induced greater lesions than the ones from LCL at the late phase. A greater number of parasites were observed in spleen of IFN-γ KO and iNOS KO mice infected with amastigotes from patients with ML than those with LCL. Parasites from ML infect a lower percentage of macrophages and are killed independent on IFN-γ and dependent on NO. The data suggest that amastigotes responsible for mucosal lesion in humans develop slowly on the initial phase of infection due to high susceptibility to NO and they have an increased ability to disseminate.

The Fate of the Tumor in the Hands of Microenvironment: Role of TAMs and mTOR Pathway.

Since 2000, written with elegance and accuracy, Hanahan and Weinberg have proposed six major hallmarks of cancer and, together, they provide great advances to the understanding of tumoral biology. Our knowledge about tumor behavior has improved and the investigators have now recognized that inflammatory microenvironment may be a new feature for the tumor entities. Macrophages are considered as an important component of tumoral microenvironment. Biologically, two forms of activated macrophages can be observed: classically activated macrophages (M1) and alternative activated macrophages (M2). Despite the canonical pathways that control this puzzle of macrophages polarization, recently, mTOR signaling pathway has been implicated as an important piece in determining the metabolic and functional differentiation of M1 and M2 profiles. Currently, it is believed that macrophages related to tumoral microenvironment present an "M2-like" feature promoting an immunosuppressive microenvironment enhancing tumoral angiogenesis, growth, and metastasis. In the present review we discuss the role of macrophages in the tumor microenvironment and the role of mTOR pathway in M1 and M2 differentiation. We also discuss the recent findings in M1 and M2 polarization as a possible target in the cancer therapy.

The association of fractional CO2 laser 10.600nm and photodynamic therapy in the treatment of onychomycosis.

BACKGROUND: Onychomycosis is a fungal infection of the nails caused in most cases by dermatophytes Trichophyton rubrum and Trichophyton mentagrophytes. Despite numerous available antifungal drugs for therapy of this infection, the cure rate is low, with high rates of relapse after treatment and side effects. OBJECTIVES: To present a new option for the treatment of onychomycosis, in search of a more effective and rapid method than conventional ones. METHODS: Patients underwent two sessions of CO2 fractional laser 10.600nm associated with photodynamic therapy. Mycological and digital photography were performed before and after the treatment. RESULTS: McNemar test with continuity correction and degrees of freedom = 1: for clinical cure rate, 13.06, with p=0.00005; for mycological cure, 17.05, with p=0.00005; 72% felt fully satisfied with the procedure. CONCLUSIONS: The use of fractional CO2 laser 10.600nm associated with photodynamic therapy can be effective in the treatment of onychomycosis, decreasing the risk of systemic lesions that may be triggered with prolonged use of oral antifungals.

The association of fractional CO2 laser 10.600nm and photodynamic therapy in the treatment of onychomycosis

AbstractBACKGROUND:Onychomycosis is a fungal infection of the nails caused in most cases by dermatophytes Trichophyton rubrum and Trichophyton mentagrophytes. Despite numerous available antifungal drugs for therapy of this infection, the cure rate is low, with high rates of relapse after treatment and side effects.OBJECTIVES:To present a new option for the treatment of onychomycosis, in search of a more effective and rapid method than conventional ones.METHODS:Patients underwent two sessions of CO2 fractional laser 10.600nm associated with photodynamic therapy. Mycological and digital photography were performed before and after the treatment.RESULTS:McNemar test with continuity correction and degrees of freedom = 1: for clinical cure rate, 13.06, with p=0.00005; for mycological cure, 17.05, with p=0.00005; 72% felt fully satisfied with the procedure.CONCLUSIONS:The use of fractional CO2 laser 10.600nm associated with photodynamic therapy can be effective in the treatment of onychomycosis, decreasing the risk of systemic lesions that may be triggered with prolonged use of oral antifungals.

Electroacupuncture at the ST36 acupoint increases interleukin-4 responsiveness in macrophages, generation of alternatively activated macrophages and susceptibility to Leishmania major infection.

BACKGROUND: Electroacupuncture (EA) has been used to treat inflammatory diseases. Alternatively activated macrophages (AAMo) stimulated by cytokines such as interleukin (IL)-4, IL-10 and IL-13 are anti-inflammatory and mildly microbicidal. This study aimed to evaluate whether EA at the Zusanli acupoint (ST36) would change the profile of healthy murine macrophages, particularly the generation of AAMo and susceptibility to Leishmania major infection. METHODS: BALB/c mice were treated with EA (15/30 Hz) at the ST36 acupoint for 20 min/d for 5 d. After the final EA session, the mice were euthanized and their peritoneal cells were harvested and counted for determination of arginase activity, nitric oxide (NO) production and microbicidal activity after culture in the presence or absence of IL-4, interferon-γ (IFNγ) or lipopolysaccharide (LPS) or both IFNγ and LPS. Twelve mice were infected with L. major promastigotes into the footpads after the final EA session and the infection course was monitored. RESULTS: Peritoneal cells freshly obtained from EA-treated mice had similar arginase and microbicidal activities to cells from sham-treated mice. After culture with IL-4, cells from EA-treated mice exhibited significant increases in the arginase activity (sham: 58 ± 11.3 vs. EA: 80.7 ± 4.6%, P = 0.025) and number of parasites/infected cell (sham: 2.5 ± 0.4 vs. EA: 4.3 ± 0.8 cells, P = 0.007). The NO production was lower in cells from EA-treated mice cultured in the presence of a combination of IFNγ and LPS (sham: 31.6 ± 6.5 vs. EA: 22.3 ± 2.1 µM, P = 0.025). The lesion size in mice infected with L. major promastigotes was larger in EA-treated mice (sham: 3.26 ± 0.29 vs. EA: 2.23 ± 0.4 mm, P = 0.039). CONCLUSION: EA at the ST36 acupoint increases IL-4 responsiveness in macrophages, Generation of AAMo and susceptibility to L. major infection.

O que eles fazem depois da aula? As atividades extracurriculares dos alunos de Ciências Médicas da FMRP-USP / What do they do after class? Extra curriculum activities of medical students of Ribeirão Preto-University of São Paulo

Em 1999, O Programa Especial de Treinamento da Faculdade de Medicina de Ribeirão Preto, da Universidade de São Paulo realizou um estudo com 326 alunos, do primeiro ao quarto ano, com o objetivo de identificar e descrever as atividades extracurriculares desses alunos. Em 2002, o estudo foi repetido, utilizando-se o mesmo instrumento, aplicado em 360 alunos. Trata-se, portanto, de estudo transversal, cujas variáveis estudadas são: idade, sexo, ano do curso, atividades extracurriculares ligadas à FMRP-USP, motivo da pratica de tais atividades, horas despendidas com elas, grau de satisfação e motivo de satisfação e insatisfação. Do total de entrevistados, 64 por cento são homens e 36 por cento são mulheres. A média da idade é 20,7 anos e apenas 8por cento (29) não estavam engajados em nenhuma atividade extracurricular na época da entrevista. Das atividades mais freqüentadas estão as ligas (73 por cento), os treinos esportivos (53 por cento), os estágios em laboratório de iniciação cientifica (31,5 por cento) e os plantões voluntários (31 por cento). Das atividades não relacionadas à Faculdade, 36 por cento referiram-se ao estudo de uma língua estrangeira e 24,5 por cento, à música ou ao teatro. A maioria gasta, pelo menos, cinco horas semanais com essas atividades. Maior número de atividades foi encontrado, associado ao maior o tempo de permanência do aluno no curso médico (p=0,002), embora a carga horária da grade curricular também aumente com o passar do tempo. Embora não tenham sido encontradas grandes diferenças, ao compararmos os alunos entrevistados em 1999 e 2002, houve aumento significativo de participação em ligas, já que novas foram criadas no período