High volume online hemodiafiltration: a global perspective and the Brazilian experience / Hemodiafiltração on-line de alto volume: uma perspectiva global e a experiência brasileira

ABSTRACT Online hemodiafiltration (HDF) is a rapidly growing dialysis modality worldwide. In Brazil, the number of patients with private health insurance undergoing HDF has exceeded the number of patients on peritoneal dialysis. The achievement of a high convection volume was associated with better clinical imprand patient - reported outcomes confirming the benefits of HDF. The HDFit trial provided relevant practical information on the implementation of online HDF in dialysis centers in Brazil. This article aims to disseminate technical information to improve the quality and safety of this new dialysis modality.

RESUMO A hemodiafiltração (HDF) on-line é uma modalidade dialítica em rápido crescimento no mundo. No Brasil, o número de pacientes com planos de saúde privados tratados por HDF já ultrapassa aquele de pacientes em diálise peritoneal. O alcance de um alto volume convectivo associado à redução de desfechos clínicos e do risco de morte confirmam os benefícios da HDF. Dados nacionais do estudo HDFit forneceram informações práticas relevantes sobre a implementação da HDF on-line em clínicas de diálise no Brasil. O objetivo desta publicação é a disseminação de informações técnicas que possam auxiliar na utilização, com qualidade e segurança, dessa nova modalidade dialítica.

TIMP-1 is an activator of MHC-I expression in myeloid dendritic cells with implications for tumor immunogenicity.

Immune checkpoint therapies (ICT) for advanced solid tumors mark a new milestone in cancer therapy. Yet their efficacy is often limited by poor immunogenicity, attributed to inadequate priming and generation of antitumor T cells by dendritic cells (DCs). Identifying biomarkers to enhance DC functions in such tumors is thus crucial. Tissue Inhibitor of Metalloproteinases-1 (TIMP-1), recognized for its influence on immune cells, has an underexplored relationship with DCs. Our research reveals a correlation between high TIMP1 levels in metastatic melanoma and increased CD8 + T cell infiltration and survival. Network studies indicate a functional connection with HLA genes. Spatial transcriptomic analysis of a national melanoma cohort revealed that TIMP1 expression in immune compartments associates with an HLA-A/MHC-I peptide loading signature in lymph nodes. Primary human and bone-marrow-derived DCs secrete TIMP-1, which notably increases MHC-I expression in classical type 1 dendritic cells (cDC1), especially under melanoma antigen exposure. TIMP-1 affects the immunoproteasome/TAP complex, as seen by upregulated PSMB8 and TAP-1 levels of myeloid DCs. This study uncovers the role of TIMP-1 in DC-mediated immunogenicity with insights into CD8 + T cell activation, providing a foundation for mechanistic exploration and highlighting its potential as a new target for combinatorial immunotherapy to enhance ICT effectiveness.

Nutritional risk and morbidity and mortality in intensive care unit patients with Coronavirus disease 2019.

INTRODUCTION: The Coronavirus disease 2019 (COVID-19) spread rapidly, with 37 million cases and more than 699,000 deaths. Among intensive care unit (ICU) patients with COVID-19, a high incidence of acute kidney injury (AKI) has been observed, ranging from 50 to 80%; furthermore, 85.9% were calculated to have high nutritional risk, which doubled their odds of death. The aim of the present study was to evaluate possible associations between nutritional risk, acute kidney injury, and morbidity and mortality in patients with COVID-19 admitted to an ICU. METHODS: Retrospective cohort study of adult and older-adult patients hospitalized for >24 h in an ICU. The exposure was diagnosis of COVID-19, while the outcomes were mortality, acute kidney injury, dialysis, mechanical ventilation, and vasopressor use. The association of nutritional risk with outcomes was evaluated. The sample consisted of two secondary datasets. Individuals aged <18 years, those with dialytic chronic kidney disease, pregnant women, and those diagnosed with brain death were excluded. RESULTS: The sample consisted of 192 patients: 101 in the exposure group (positive for COVID-19) and 91 in the control group (no COVID-19 diagnosis). The COVID-19 and non-COVID-19 groups differed significantly in the variables weight, body mass index (BMI), nutritional risk, mNUTRIC-S score, and length of ICU stay. Our results suggest that the optimal mNUTRIC-S score cutoff to predict nutritional risk is <5 points. CONCLUSION: COVID-19 has a significant impact on patients' kidney function, increasing the incidence of AKI and the likelihood of death. Nutritional risk is a major factor in the mortality of patients with COVID-19. Therefore, use of the mNUTRIC-S scale could contribute to assessment of prognosis in this patient population.

High volume online hemodiafiltration: a global perspective and the Brazilian experience.

Online hemodiafiltration (HDF) is a rapidly growing dialysis modality worldwide. In Brazil, the number of patients with private health insurance undergoing HDF has exceeded the number of patients on peritoneal dialysis. The achievement of a high convection volume was associated with better clinical imprand patient - reported outcomes confirming the benefits of HDF. The HDFit trial provided relevant practical information on the implementation of online HDF in dialysis centers in Brazil. This article aims to disseminate technical information to improve the quality and safety of this new dialysis modality.

Quality indicators in prolonged hemodialysis with regional citrate anticoagulation with the genius system: retrospective cohort of critical patients with acute kidney injury.

BACKGROUND: Prolonged hemodialysis (HD) is performed from 6 to 12 h and can last up to 24 h. To prevent system clotting some studies suggest that Regional Citrate Anticoagulation (RCA) use reduces bleeding rates relative to systemic heparin. However, there may be difficulties in the patient's clinical management and completing the prescribed HD with Genius system using RCA. OBJECTIVE: To analyze safety Quality Indicators (IQs) and follow up on prolonged HD with 4% sodium citrate solution in a Genius® hybrid system. METHODS: This is a retrospective cohort conducted in an intensive care unit. RESULTS: 53 random sessions of prolonged HD with 4% sodium citrate solution of critically ill patients with AKI assessed. Evaluated safety indicators were dysnatremia and metabolic alkalosis, observed in 15% and 9.4% of the sessions, respectively. Indicators of effectiveness were system clotting which occurred in 17.3%, and the minimum completion of the prescribed HD time, which was 75.5%. CONCLUSION: The assessment of the indicators showed that the use of RCA with a 4% sodium citrate solution in prolonged HD with the Genius system in critically ill patients with AKI can be performed in a simple, safe, and effective way.

From antimicrobial to anticancer: the pioneering works of Prof. Luiz Rodolpho Travassos on bioactive peptides.

Prof. Luiz Rodolpho Travassos, a distinguished Brazilian scientist, was instrumental in fostering an interdisciplinary research approach that seamlessly combined microbiology and oncology. This work has opened new pathways into the understanding of tumorigenesis and aided in the development of innovative therapeutic tools. One significant area of his work has been the exploration of bioactive peptides, many of which were first identified for their antimicrobial properties. These peptides demonstrate promise as potential cancer therapeutics due to their selectivity, cost-effectiveness, ease of synthesis, low antigenicity, and excellent tissue penetration. Prof. Travassos' pioneering work uncovered on the potential of peptides derived from microbiological sources, such as those obtained using phage display techniques. More importantly, in international cooperation, peptides derived from complementarity-determining regions (CDRs) that showed antimicrobial activity against Candida albicans further showed to be promising tools with cytotoxic properties against cancer cells. Similarly, peptides derived from natural sources, such as the gomesin peptide, not only had shown antimicrobial properties but could treat cutaneous melanoma in experimental models. These therapeutic tools allowed Prof. Travassos and his group to navigate the intricate landscape of factors and pathways that drive cancer development, including persistent proliferative signaling, evasion of tumor suppressor genes, inhibition of programmed cell death, and cellular immortality. This review examines the mechanisms of action of these peptides, aligning them with the universally recognized hallmarks of cancer, and evaluates their potential as drug candidates. It highlights the crucial need for more selective, microbiology-inspired anti-cancer strategies that spare healthy cells, a challenge that current therapies often struggle to address. By offering a comprehensive assessment of Prof. Travassos' innovative contributions and a detailed discussion on the increasing importance of microbiology-derived peptides, this review presents an informed and robust perspective on the possible future direction of cancer therapy.

Social Representations of Hesitant Brazilians about Vaccination against COVID-19.

BACKGROUND: The control of the COVID-19 pandemic has been a great challenge. Understanding the thoughts and beliefs underlying vaccine hesitancy can help in the formulation of public policies. The present study aimed to analyze the social representations of hesitant Brazilians about vaccination against COVID-19. METHODS: Qualitative research guided by the Theory of Social Representations, carried out through an online survey among Brazilian adults living in Brazil. The data were analyzed using the IRaMuTeQ software. RESULTS: Of the 173,178 respondents, 10,928 were hesitant and declared reasons for vaccination hesitation. The analysis generated three classes: mistrust of the vaccine and underestimation of the severity of the pandemic; (dis)information and distrust of political involvement; and fear of adverse reactions to COVID-19 vaccines. CONCLUSIONS: Social knowledge, presented by the representations apprehended in this study, demonstrates difficulty in discerning the reliability of information and a social imagination full of doubts and uncertainties. Understanding the internal dynamics of these groups, with their representations of the world, is important to propose policies and actions that echo and cause changes in the understanding of the role of immunization. It is essential to shed light on the sociological imagination so that gaps filled with false information can be dismantled and confronted with scientific knowledge accessible to the population.

Resistance to immune checkpoint therapies by tumour-induced T-cell desertification and exclusion: key mechanisms, prognostication and new therapeutic opportunities.

Immune checkpoint therapies (ICT) can reinvigorate the effector functions of anti-tumour T cells, improving cancer patient outcomes. Anti-tumour T cells are initially formed during their first contact (priming) with tumour antigens by antigen-presenting cells (APCs). Unfortunately, many patients are refractory to ICT because their tumours are considered to be 'cold' tumours-i.e., they do not allow the generation of T cells (so-called 'desert' tumours) or the infiltration of existing anti-tumour T cells (T-cell-excluded tumours). Desert tumours disturb antigen processing and priming of T cells by targeting APCs with suppressive tumour factors derived from their genetic instabilities. In contrast, T-cell-excluded tumours are characterised by blocking effective anti-tumour T lymphocytes infiltrating cancer masses by obstacles, such as fibrosis and tumour-cell-induced immunosuppression. This review delves into critical mechanisms by which cancer cells induce T-cell 'desertification' and 'exclusion' in ICT refractory tumours. Filling the gaps in our knowledge regarding these pro-tumoral mechanisms will aid researchers in developing novel class immunotherapies that aim at restoring T-cell generation with more efficient priming by APCs and leukocyte tumour trafficking. Such developments are expected to unleash the clinical benefit of ICT in refractory patients.

Epigenetic control of CD1D expression as a mechanism of resistance to immune checkpoint therapy in poorly immunogenic melanomas.

Immune Checkpoint Therapies (ICT) have revolutionized the treatment of metastatic melanoma. However, only a subset of patients reaches complete responses. Deficient ß2-microglobulin (ß2M) expression impacts antigen presentation to T cells, leading to ICT resistance. Here, we investigate alternative ß2M-correlated biomarkers that associate with ICT resistance. We shortlisted immune biomarkers interacting with human ß2M using the STRING database. Next, we profiled the transcriptomic expression of these biomarkers in association with clinical and survival outcomes in the melanoma GDC-TCGA-SKCM dataset and a collection of publicly available metastatic melanoma cohorts treated with ICT (anti-PD1). Epigenetic control of identified biomarkers was interrogated using the Illumina Human Methylation 450 dataset from the melanoma GDC-TCGA-SKCM study. We show that ß2M associates with CD1d, CD1b, and FCGRT at the protein level. Co-expression and correlation profile of B2M with CD1D, CD1B, and FCGRT dissociates in melanoma patients following B2M expression loss. Lower CD1D expression is typically found in patients with poor survival outcomes from the GDC-TCGA-SKCM dataset, in patients not responding to anti-PD1 immunotherapies, and in a resistant anti-PD1 pre-clinical model. Immune cell abundance study reveals that B2M and CD1D are both enriched in tumor cells and dendritic cells from patients responding to anti-PD1 immunotherapies. These patients also show increased levels of natural killer T (NKT) cell signatures in the tumor microenvironment (TME). Methylation reactions in the TME of melanoma impact the expression of B2M and SPI1, which controls CD1D expression. These findings suggest that epigenetic changes in the TME of melanoma may impact ß2M and CD1d-mediated functions, such as antigen presentation for T cells and NKT cells. Our hypothesis is grounded in comprehensive bioinformatic analyses of a large transcriptomic dataset from four clinical cohorts and mouse models. It will benefit from further development using well-established functional immune assays to support understanding the molecular processes leading to epigenetic control of ß2M and CD1d. This research line may lead to the rational development of new combinatorial treatments for metastatic melanoma patients that poorly respond to ICT.

Novel prognostication biomarker adipophilin reveals a metabolic shift in uveal melanoma and new therapeutic opportunities.

Metastatic uveal melanoma remains incurable at present. We previously demonstrated that loss of BAP1 gene expression in tumour cells triggers molecular mechanisms of immunosuppression in the tumour microenvironment (TME) of metastatic uveal melanoma. Adipophilin is a structural protein of lipid droplets involved in fat storage within mammalian cells, and its expression has been identified in uveal melanoma. We comprehensively evaluated adipophilin expression at the RNA (PLIN2) and protein levels of 80 patients of the GDC-TCGA-UM study and in a local cohort of 43 primary uveal melanoma samples respectively. PLIN2 expression is a survival prognosticator biomarker in uveal melanoma. Loss of adipophilin expression is significantly associated with monosomy 3 status and nuclear BAP1 losses in uveal melanoma tumours. Integrative transcriptomic and secretome studies show a relationship between transient loss of adipophilin expression and increased levels of tumour-associated macrophages and hypoxia genes, suggesting PLIN2-dependent changes in oxygen and lipid metabolism in the TME of low and high-metastatic risk uveal melanoma. We designed four adipophilin-based multigene signatures for uveal melanoma prognostication using a transcriptomic and secretome survival-functional network approach. Adipophilin-based multigene signatures were validated in BAP1-positive and BAP1-negative uveal melanoma cell lines using a next-generation RNA sequencing approach. We identified existing small molecules, mostly adrenergic, retinoid, and glucocorticoid receptor agonists, MEK, and RAF inhibitors, with the potential to reverse this multigene signature expression in uveal melanoma. Some of these molecules were able to impact tumour cell viability, and carvedilol, an adrenergic receptor antagonist, restored PLIN2 levels, mimicking the expression of normoxia/lipid storage signatures and reversing the expression of hypoxia/lipolysis signatures in co-cultures of uveal melanoma cells with human macrophages. These findings open up a new research line for understanding the lipid metabolic regulation of immune responses, with implications for therapeutic innovation in uveal melanoma. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Trustworthiness of information sources on vaccines for COVID-19 prevention among Brazilians.

OBJECTIVE: This study aims to assess the trustworthiness of information sources, perception of clear information about the vaccine, and strategies to increase adherence to vaccination to provide managers with information that helps establish effective communication with the population about vaccination. METHOD: This is an online survey conducted between January 22 and 29, 2021, preceded by an Informed Consent, that aims to assess vaccine hesitancy, which corresponded to the first week of vaccination initiation to prevent COVID-19 in Brazil. Data were obtained from a questionnaire made available through a free platform and stored in Google Forms and later exported to the SPSS statistical package for analysis. The sample consisted of all questionnaires from participants who self-declared as age 18 or older, Brazilian, and residing in Brazil at the time of the survey. Incomplete records with more than 50% of blank items and duplicates were excluded. All categorical variables were analyzed from their absolute and relative frequencies. Multivariate logistic regression was performed to verify the relationship between dependent variables and independent variables. RESULTS: The results show that trust in information sources diverges between hesitant and non-hesitant. They also showed that some participants show an overall distrust that seems to have deeper foundations than issues related only to the source of information. The high rejection of television and the WHO as sources of information among hesitant suggests that integrated actions with research institutes, public figures vaccinating, and religious leaders can help to combat vaccine hesitation. Two actors become particularly important in this dynamic, both for good and bad, and their anti-vaxxer behavior must be observed: the doctor and the Ministry of Health. CONCLUSION: This study contributes to gathering valuable information to help understand the behavior and thinking relevant to the adherence to vaccination recommendations.

Assessment of the performance of vascular access for hemodialysis.

BACKGROUND: Life and quality of life on hemodialysis depends on adequate vascular access. An autogenous arteriovenous fistula (AVF) has the best performance, while the use of a central venous catheter (CVC) may have a negative impact on fistula performance and may be associated with increased systemic inflammation. Our objective is to evaluate the performance of vascular accesses in patients undergoing a chronic hemodialysis program. METHODS: This is an observational, cross-sectional, and descriptive study that included patients on chronic hemodialysis for more than 90 days. Patients with an acute systemic inflammatory disease and those with acute cardiovascular illness were excluded. Clinical data, dialysis session parameters, and serum levels of inflammatory markers were evaluated. RESULTS: A total of 91 patients were evaluated, 59 (65%) had an AVF and 32 patients (35%) had a CVC. The adequacy rate was 67%; being 67.8% with AVF and 65.6% with CVC. Among the causes of AVF inadequacy, the ones that presented the highest prevalence ratio (PR) were non-mature AVF (PR: 4.055; 95% CI: 2.017-8.151), pseudoaneurysm (PR: 6.580; 95% CI: 3.723-11.629) and presence of hematoma (PR: 4.360; 95% CI: 2.125-8.946), p < 0.001. Among the catheter group, the causes of inadequacy with the highest PR were the presence of access thrombosis, indicating the use of thrombolytics (PR: 11.103; 95% CI: 4.746-25.977; p < 0.001) and infection (PR: 2.984; 95% CI: 1.293-6.889; p = 0.010). Median primary AVF patency was 72 months compared to 7 months of catheters (p < 0.001). There was no significant difference in serum inflammatory markers between the two groups. CONCLUSIONS: Adequacy rates of vascular accesses did not differ between the groups, but the primary and functional patency of AVF is 10 times higher than that of catheters. Infection in dialysis catheters is associated with worse access performance. There was no association between systemic inflammation and vascular access.

Immature Platelet Fraction and Thrombin Generation: Preeclampsia Biomarkers / Fração de plaquetas imaturas e geração de trombina: Biomarcadores da pré-eclâmpsia

Abstract Preeclampsia, a human pregnancy syndrome, is characterized by elevated blood pressure and proteinuria after the 20th week of gestation. Its etiology remains unknown, and its pathophysiological mechanisms are related to placental hypoperfusion, endothelial dysfunction, inflammation, and coagulation cascade activation. Recently, the role of the complement system has been considered. This syndrome is one of the main causes of maternal and fetal mortality and morbidity. This article discusses the hypothesis of preeclampsia being triggered by the occurrence of inadequate implantation of the syncytiotrophoblast, associated with bleeding during the first stage of pregnancy and with augmented thrombin generation. Thrombin activates platelets, increasing the release of antiangiogenic factors and activating the complement system, inducing the membrane attack complex (C5b9). Immature platelet fraction and thrombin generation may be possible blood biomarkers to help the early diagnosis of preeclampsia.

Resumo A pré-eclâmpsia, uma síndrome da gestação humana, é caracterizada por elevação da pressão arterial e proteinúria patológica após a 20ª semana de gestação. Sua etiologia permanece desconhecida, e seus mecanismos fisiopatológicos estão relacionados à hipoperfusão placentária, disfunção endotelial, inflamação, e ativação da cascata de coagulação. Recentemente, o papel do sistema do complemento foi considerado. Essa síndrome é uma das principais causas de morbidade e mortalidade materna e fetal. Este artigo discute a hipótese de a pré-eclâmpsia ser desencadeada pela ocorrência da implantação inadequada do sinciciotrofoblasto, associada ao sangramento durante o primeiro trimestre da gravidez com aumento da geração de trombina. A trombina ativa plaquetas, aumentando a liberação de fatores antiangiogênicos na circulação e ativando o sistema do complemento, especialmente o complexo de ataque de membrana (C5b9). Portanto, a fração de plaquetas imaturas e a geração de trombina podem ser possíveis biomarcadores sanguíneos para auxílio no diagnóstico precoce da pré-eclâmpsia.

Immature Platelet Fraction and Thrombin Generation: Preeclampsia Biomarkers.

Preeclampsia, a human pregnancy syndrome, is characterized by elevated blood pressure and proteinuria after the 20th week of gestation. Its etiology remains unknown, and its pathophysiological mechanisms are related to placental hypoperfusion, endothelial dysfunction, inflammation, and coagulation cascade activation. Recently, the role of the complement system has been considered. This syndrome is one of the main causes of maternal and fetal mortality and morbidity. This article discusses the hypothesis of preeclampsia being triggered by the occurrence of inadequate implantation of the syncytiotrophoblast, associated with bleeding during the first stage of pregnancy and with augmented thrombin generation. Thrombin activates platelets, increasing the release of antiangiogenic factors and activating the complement system, inducing the membrane attack complex (C5b9). Immature platelet fraction and thrombin generation may be possible blood biomarkers to help the early diagnosis of preeclampsia.

A pré-eclâmpsia, uma síndrome da gestação humana, é caracterizada por elevação da pressão arterial e proteinúria patológica após a 20ª semana de gestação. Sua etiologia permanece desconhecida, e seus mecanismos fisiopatológicos estão relacionados à hipoperfusão placentária, disfunção endotelial, inflamação, e ativação da cascata de coagulação. Recentemente, o papel do sistema do complemento foi considerado. Essa síndrome é uma das principais causas de morbidade e mortalidade materna e fetal. Este artigo discute a hipótese de a pré-eclâmpsia ser desencadeada pela ocorrência da implantação inadequada do sinciciotrofoblasto, associada ao sangramento durante o primeiro trimestre da gravidez com aumento da geração de trombina. A trombina ativa plaquetas, aumentando a liberação de fatores antiangiogênicos na circulação e ativando o sistema do complemento, especialmente o complexo de ataque de membrana (C5b9). Portanto, a fração de plaquetas imaturas e a geração de trombina podem ser possíveis biomarcadores sanguíneos para auxílio no diagnóstico precoce da pré-eclâmpsia.

Efficacy and safety of neuromuscular electrical stimulation in the prevention of pressure injuries in critically ill patients: a randomized controlled trial.

BACKGROUND: Pressure injuries (PIs), especially in the sacral region are frequent, costly, and increase morbidity and mortality of patients in an intensive care unit (ICU). These injuries can occur as a result of prolonged pressure and/or shear forces. Neuromuscular electrical stimulation (NMES) can increase muscle mass and improve local circulation, potentially reducing the incidence of PI. METHODS: We performed a randomized controlled trial to assess the efficacy and safety of NMES in preventing PI in critically ill patients. We included patients with a period of less than 48 h in the ICU, aged ≥ 18 years. Participants were randomly selected (1:1 ratio) to receive NMES and usual care (NMES group) or only usual care (control group-CG) until discharge, death, or onset of a PI. To assess the effectiveness of NMES, we calculated the relative risk (RR) and number needed to treat (NNT). We assessed the muscle thickness of the gluteus maximus by ultrasonography. To assess safety, we analyzed the effects of NMES on vital signs and checked for the presence of skin burns in the stimulated areas. Clinical outcomes were assessed by time on mechanical ventilation, ICU mortality rate, and length of stay in the ICU. RESULTS: We enrolled 149 participants, 76 in the NMES group. PIs were present in 26 (35.6%) patients in the CG and 4 (5.3%) in the NMES group (p ˂ 0.001). The NMES group had an RR = 0.15 (95% CI 0.05-0.40) to develop a PI, NNT = 3.3 (95% CI 2.3-5.9). Moreover, the NMES group presented a shorter length of stay in the ICU: Δ = - 1.8 ± 1.2 days, p = 0.04. There was no significant difference in gluteus maximus thickness between groups (CG: Δ = - 0.37 ± 1.2 cm vs. NMES group: Δ = 0 ± 0.98 cm, p = 0.33). NMES did not promote deleterious changes in vital signs and we did not detect skin burns. CONCLUSIONS: NMES is an effective and safe therapy for the prevention of PI in critically ill patients and may reduce length of stay in the ICU. Trial registration RBR-8nt9m4. Registered prospectively on July 20th, 2018, https://ensaiosclinicos.gov.br/rg/RBR-8nt9m4.