PLA2-MjTX-II from Bothrops moojeni snake venom exhibits antimetastatic and antiangiogenic effects on human lung cancer cells.

Phospholipases A2 (PLA2s) from snake venom possess antitumor and antiangiogenic properties. In this study, we evaluated the antimetastatic and antiangiogenic effects of MjTX-II, a Lys49 PLA2 isolated from Bothrops moojeni venom, on lung cancer and endothelial cells. Using in vitro and ex vivo approaches, we demonstrated that MjTX-II reduced cell proliferation and inhibited fundamental processes for lung cancer cells (A549) growth and metastasis, such as adhesion, migration, invasion, and actin cytoskeleton decrease, without significantly interfering with non-tumorigenic lung cells (BEAS-2B). Furthermore, MjTX-II caused cell cycle alterations, increased reactive oxygen species production, modulated the expression of pro- and antiangiogenic genes, and decreased vascular endothelial growth factor (VEGF) expression in HUVECs. Finally, MjTX-II inhibited ex vivo angiogenesis processes in an aortic ring model. Therefore, we conclude that MjTX-II exhibits antimetastatic and antiangiogenic effects in vitro and ex vivo and represents a molecule that hold promise as a pharmacological model for antitumor therapy.

Detection of elusive DNA copy-number variations in hereditary disease and cancer through the use of noncoding and off-target sequencing reads.

Copy-number variants (CNVs) play a substantial role in the molecular pathogenesis of hereditary disease and cancer, as well as in normal human interindividual variation. However, they are still rather difficult to identify in mainstream sequencing projects, especially involving exome sequencing, because they often occur in DNA regions that are not targeted for analysis. To overcome this problem, we developed OFF-PEAK, a user-friendly CNV detection tool that builds on a denoising approach and the use of "off-target" DNA reads, which are usually discarded by sequencing pipelines. We benchmarked OFF-PEAK on data from targeted sequencing of 96 cancer samples, as well as 130 exomes of individuals with inherited retinal disease from three different populations. For both sets of data, OFF-PEAK demonstrated excellent performance (>95% sensitivity and >80% specificity vs. experimental validation) in detecting CNVs from in silico data alone, indicating its immediate applicability to molecular diagnosis and genetic research.

Antiangiogenic properties of BthMP, a P-I metalloproteinase from Bothrops moojeni snake venom by VEGF pathway in endothelial cells.

Angiogenesis is a process that is controlled by a delicate combination of proangiogenic and antiangiogenic molecules and can be disrupted in various illnesses, including cancer. Non-cancerous diseases can also have an abnormal or insufficient vascular growth, inflammation and hypoxia, which exacerbate angiogenesis. These conditions include atherosclerosis, psoriasis, endometriosis, asthma, obesity and AIDS. Based on that, the present work assessed the in vitro and ex vivo antiangiogenic properties stemming from BthMP, a P-I metalloproteinase from Bothrops moojeni snake venom, via the VEGF pathway. BthMP at a concentration of 5 and 40 µg/mL showed no toxicity to endothelial cells (HUVEC) in the MTT assay and was not able to induce necrosis and colony proliferation. Interestingly, BthMP inhibited adhesion, migration and invasion of HUVECs in Matrigel and arrested in vitro angiogenesis by reducing the average number of nodules in toxin-treated cells by 9.6 and 17.32 at 5 and 40 µg/mL, respectively, and the number of tubules by 15.9 at 5 µg/mL and 21.6 at 40 µg/mL in a VEGF-dependent way, an essential proangiogenic property. Furthermore, BthMP inhibited the occurrence of the angiogenic process in an ex vivo aortic ring test by decreasing new vessel formation by 52% at 5 µg/mL and by 66% at 40 µg/mL and by increasing the expression of an antiangiogenic gene, SFLT-1, and decreasing the expression of the proangiogenic genes VEGFA and ANGPT-1. Finally, this toxin reduces the production of nitric oxide, a marker that promotes angiogenesis and VEGF modulation, and decreases the protein expression of VEGFA in the supernatant of the HUVEC culture by about 30 %. These results suggest that BthMP has a promising antiangiogenic property and proves to be a biotechnological mechanism for understanding the antiangiogenic responses induced by snake venom metalloproteinases, which could be applied to a variety of diseases that exhibit an imbalance of angiogenesis mechanisms.

Beyond Angiogenesis: The Multitasking Approach of the First PEGylated Vascular Endothelial Growth Factor (CdtVEGF) from Brazilian Rattlesnake Venom.

A pioneering study regarding the isolation, biochemical evaluation, functional assays and first PEGylation report of a novel vascular endothelial growth factor from Crotalus durissus terrificus venom (CdtVEGF and PEG-CdtVEGF). CdtVEGF was isolated from crude venom using two different chromatographic steps, representing 2% of soluble venom proteins. Its primary sequence was determined using mass spectrometry analysis, and the molecule demonstrated no affinity to heparin. The Brazilian crotalid antivenom recognized CdtVEGF. Both native and PEGylated CdtVEGF were able to induce new vessel formation and migration, and to increase the metabolic activity of human umbilical endothelial vascular cells (HUVEC), resulting in better wound closure (~50% within 12 h) using the native form. CdtVEGF induced leukocyte recruitment to the peritoneal cavity in mice, with a predominance of neutrophil influx followed by lymphocytes, demonstrating the ability to activate the immune system. The molecule also induced a dose-dependent increase in vascular permeability, and PEG-CdtVEGF showed less in vivo inflammatory activity than CdtVEGF. By unraveling the intricate properties of minor components of snake venom like svVEGF, this study illuminates the indispensable significance of exploring these molecular tools to unveil physiological and pathological processes, elucidates the mechanisms of snakebite envenomings, and could possibly be used to design a therapeutic drug.

The pro-resolving lipid mediator Maresin 1 ameliorates pain responses and neuroinflammation in the spared nerve injury-induced neuropathic pain: A study in male and female mice.

Specialized pro-resolving mediators (SPMs) have recently emerged as promising therapeutic approaches for neuropathic pain (NP). We evaluated the effects of oral treatment with the SPM Maresin 1 (MaR1) on behavioral pain responses and spinal neuroinflammation in male and female C57BL/6J mice with spared nerve injury (SNI)-induced NP. MaR1, or vehicle, was administered once daily, on post-surgical days 3 to 5, by voluntary oral intake. Sensory-discriminative and affective-motivational components of pain were evaluated with von Frey and place escape/avoidance paradigm (PEAP) tests, respectively. Spinal microglial and astrocytic activation were assessed by immunofluorescence, and the spinal concentration of cytokines IL-1ß, IL-6, IL-10, and macrophage colony-stimulating factor (M-CSF) were evaluated by multiplex immunoassay. MaR1 treatment reduced SNI-induced mechanical hypersensitivity on days 7 and 11 in both male and female mice, and appeared to ameliorate the affective component of pain in males on day 11. No definitive conclusions could be drawn about the impact of MaR1 on the affective-motivational aspects of pain in female mice, since repeated suprathreshold mechanical stimulation of the affected paw in the dark compartment did not increase the preference of vehicle-treated SNI females for the light side, during the PEAP test session (a fundamental assumption for PAEP's validity). MaR1 treatment also reduced ipsilateral spinal microglial and astrocytic activation in both sexes and marginally increased M-CSF in males, while not affecting cytokines IL-1ß, IL-6 and IL-10 in either sex. In summary, our study has shown that oral treatment with MaR1 (i) produces antinociception even in an already installed peripheral NP mouse model, and (ii) this antinociception may extend for several days beyond the treatment time-frame. These therapeutic effects are associated with attenuated microglial and astrocytic activation in both sexes, and possibly involve modulation of M-CSF action in males.

Evaluation of urinary cysteinyl leukotrienes as biomarkers of severity and putative therapeutic targets in COVID-19 patients.

BACKGROUND: Cysteinyl leukotrienes (CysLT) are potent inflammation-promoting mediators, but remain scarcely explored in COVID-19. We evaluated urinary CysLT (U-CysLT) relationship with disease severity and their usefulness for prognostication in hospitalized COVID-19 patients. The impact on U-CysLT of veno-venous extracorporeal membrane oxygenation (VV-ECMO) and of comorbidities such as hypertension and obesity was also assessed. METHODS: Blood and spot urine were collected in "severe" (n = 26), "critically ill" (n = 17) and "critically ill on VV-ECMO" (n = 17) patients with COVID-19 at days 1-2 (admission), 3-4, 5-8 and weekly thereafter, and in controls (n = 23) at a single time point. U-CysLT were measured by ELISA. Routine markers, prognostic scores and outcomes were also evaluated. RESULTS: U-CysLT did not differ between groups at admission, but significantly increased along hospitalization only in critical groups, being markedly higher in VV-ECMO patients, especially in hypertensives. U-CysLT values during the first week were positively associated with ICU and total hospital length of stay in critical groups and showed acceptable area under curve (AUC) for prediction of 30-day mortality (AUC: 0.734, p = 0.001) among all patients. CONCLUSIONS: U-CysLT increase during hospitalization in critical COVID-19 patients, especially in hypertensives on VV-ECMO. U-CysLT association with severe outcomes suggests their usefulness for prognostication and as therapeutic targets.

Mental health training programs for non-health professionals and volunteers working with asylum-seekers and refugees: scoping review / Programas de treinamento em saúde mental para profissionais, que não de saúde, e voluntários que trabalham com solicitantes de asilo e refugiados: revisão de escopo / Programas de formación en salud mental para profesionales no sanitarios y voluntarios que trabajan con solicitantes de asilo y refugiados: revisión de alcance

ABSTRACT Objective: To identify and describe the mental health training programs for non-health professionals and volunteers who work, have worked, or would work with asylum seekers and/or refugees. Method: Scoping review following JBI methodology. Search carried out in MEDLINE, CINAHL, ERIC, SCOPUS, PsycINFO, Psychology & Behavioral Sciences Collection, RCAAP, ProQuest, and websites of Clinical Trials, UNHCR, International Organization for Migration, WHO, Save the Children, International Migration, Integration and Social Cohesion in Europe, and International Federation of Red Cross and Red Crescent Societies. Studies written in English, Portuguese, French, Spanish and Swedish. Results: Of the 8954 articles identified, 16 were included reporting on 11 training programs: Mind-Spring, PM+, MHFA, Cognitive-Behavioral Training for Community and Religious Leaders, EmpaTeach, Suicide Prevention Education Program, Teaching Recovery Techniques, Handbook for Teachers of Vietnamese Refugee Students, PFA, Psychosocial support of volunteers and CBP&MHPSS. Conclusion: Training programs from scientific literature focus on mental health disorders, while non-governmental organizations' documents focus on resilience and self-care. The current mental health training programs might be insufficient.

RESUMEN Objetivo: Identificar y describir los programas de formación en salud mental para profesionales no sanitarios y voluntarios que trabajan, han trabajado o gustarían de trabajar con solicitantes de asilo y/o refugiados. Método: Revisión de alcance según la metodología JBI. Búsqueda realizada en MEDLINE, CINAHL, ERIC, SCOPUS, PsycINFO, Psychology & Behavioral Sciences Collection, RCAAP, ProQuest, y sitios web de ClinicalTrials, ACNUR, Organización Internacional para las Migraciones, OMS, Save the Children, Migración Internacional, Integración y Cohesión Social en Europa, y Federación Internacional de Sociedades de la Cruz Roja y de la Media Luna Roja. Estudios escritos en inglés, portugués, francés, español y sueco. Resultados: De los 8954 artículos identificados, se incluyeron 16 que informan sobre 11 programas de capacitación: Mind-Spring, PM+, MHFA, Capacitación cognitiva conductual para líderes comunitarios y religiosos, EmpaTeach, Programa de educación para la prevención del suicidio, Enseñanza de técnicas de recuperación, Manual para maestros de Estudiantes refugiados vietnamitas, PFA, apoyo psicosocial de voluntarios y CBP&MHPSS. Conclusión: Los programas de formación en la literatura científica se centran en los trastornos de salud mental, mientras que los documentos de las organizaciones no gubernamentales se centran en la resiliencia y el autocuidado. Los actuales programas de formación en salud mental pueden ser insuficientes.

Antileishmanial effects of γCdcPLI, a phospholipase A2 inhibitor from Crotalus durissus collilineatus snake serum, on Leishmania (Leishmania) amazonensis

BACKGROUND Leishmaniasis, a neglected disease caused by the parasite Leishmania, is treated with drugs associated with high toxicity and limited efficacy, in addition to constant reports of the emergence of resistant parasites. In this context, snake serums emerge as good candidates since they are natural sources with the potential to yield novel drugs. OBJECTIVES We aimed to show the antileishmanial effects of γCdcPLI, a phospholipase A2 inhibitor from Crotalus durissus collilineatus snake serum, against Leishmania (Leishmania) amazonensis. METHODS Promastigotes forms were exposed to γCdcPLI, and we assessed the parasite viability and cell cycle, as well as invasion and proliferation assays. FINDINGS Despite the low cytotoxicity effect on macrophages, our data indicate that γCdcPLI has a direct effect on parasites promoting an arrest in the G1 phase and reduction in the G2/M phase at the highest dose tested. Moreover, this PLA2 inhibitor reduced the parasite infectivity when promastigotes were pre-treated. Also, we demonstrated that the γCdcPLI treatment modulated the host cell environment impairing early and late steps of the parasitism. MAIN CONCLUSIONS γCdcPLI is an interesting tool for the discovery of new essential targets on the parasite, as well as an alternative compound to improve the effectiveness of the leishmaniasis treatment.

Therapeutic Leukapheresis: Experience of a Single Oncologic Centre.

Introduction: Leukostasis refers to clinical symptoms caused by hyperleukocytosis seen in some haematological diseases such as leukaemia. Cytoreduction can be achieved by therapeutic leukapheresis. The aim of this study was to retrospectively analyse the procedures performed in our Centre and to evaluate their efficacy and safety. Methods: This was a retrospective study of all the therapeutic leukapheresis procedures carried out in our Centre between January 1998 and December 2020. The sample collection was obtained through the review of the clinical files of the respective patients. Statistical analysis was performed using the software R v.4.0.1. A total of 54 therapeutic leukapheresis procedures were performed in 31 patients in our Centre. Results: After these procedures clinical improvement was observed in 16 patients and we verify that there was a significant difference in survival between the group that improved and the group that maintained the same clinical condition or worsened. The lack of immediate clinical improvement was a sign of a poor prognosis. Laboratory efficacy occurred in 16 patients who had a reduction in white blood cell count, with a 39.1% reduction after 24 h, and did not succeed in 15 patients, who had no reduction. However, in this case there is no significant difference in survival between the two groups. There was some complication in 53.9% of the procedures, with hypocalcaemia being the most frequent, which was observed in 22 procedures. Only 4 patients experienced serious side effects but these adverse reactions cannot be attributed to the procedures carried out. The overall survival rate 6 months after this treatment was 51.6%. Conclusion: Despite the reduced number of patients, we conclude that therapeutic leukapheresis is a safe and effective option that may still have a therapeutic role in some cases.

Performance of pre-transplant criteria in prediction of hepatocellular carcinoma progression and waitlist dropout.

BACKGROUND & AIM: Liver transplantation (LT) selection models for hepatocellular carcinoma (HCC) have not been proposed to predict waitlist dropout because of tumour progression. The aim of this study was to compare the alpha-foetoprotein (AFP) model and other pre-LT models in their prediction of HCC dropout. METHODS: A multicentre cohort study was conducted in 20 Latin American transplant centres, including 994 listed patients for LT with HCC from 2012 to 2018. Longitudinal tumour characteristics, and patterns of progression were recorded at time of listing, after treatments and at last follow-up over the waitlist period. Competing risk regression models were performed, and model's discrimination was compared estimating Harrell's adapted c-statistics. RESULTS: HCC dropout rate was significantly higher in patients beyond (24% [95% CI 16-28]) compared to those within Milan criteria (8% [95% IC 5%-12%]; p < .0001), with a SHR of 3.01 [95% CI 2.03-4.47]), adjusted for waiting list time and bridging therapies (c-index 0.63 [95% CI 0.57; 0.69). HCC dropout rates were higher in patients with AFP scores >2 (adjusted SHR of 3.17 [CI 2.13-4.71]), c-index of 0.71 (95% CI 0.65-0.77; p = .09 vs Milan). Similar discrimination power for HCC dropout was observed between the AFP score and the Metroticket 2.0 model. In patients within Milan, an AFP score >2 points discriminated two populations with a higher risk of HCC dropout (SHR 1.68 [95% CI 1.08-2.61]). CONCLUSIONS: Pre-transplant selection models similarly predicted HCC dropout. However, the AFP model can discriminate a higher risk of dropout among patients within Milan criteria.

Usuários de substâncias psicoativas: desafios à assistência de enfermagem na Estratégia Saúde da Família / Usuarios de sustancias psicoactivas: desafíos para la atención de enfermería en la Estrategia de Salud de la Familia / Users of psychoactive substances: challenges to nursing care in the Family Health Strategy

RESUMO Objetivo analisar a assistência de Enfermagem ao usuário de substâncias psicoativas na Estratégia Saúde da Família. Método estudo descritivo e qualitativo realizado com sete enfermeiros da Estratégia Saúde da Família de Juiz de Fora, Minas Gerais. Os dados foram obtidos por meio de entrevistas guiadas por um roteiro semiestruturado e a Análise Temática de Conteúdo foi utilizada para o seu tratamento. Resultados a assistência prestada pelos entrevistados é pautada na demanda espontânea, sem estratégias de busca ativa, com a valorização de práticas orientadas pela medicalização da pessoa e o encaminhamento aos serviços especializados. A inclusão da família no processo de reabilitação, o atendimento imediato e o exercício da escuta terapêutica foram mencionados como estratégias que podem ser adotadas para uma assistência integral. Os desafios mencionados referiram-se à falta de formação em saúde mental, à fragmentação do conhecimento acerca da especialidade, à ausência de capacitações e ao desejo do paciente em participar do tratamento. Considerações finais e implicações para a prática os enfermeiros referiram um cuidado insuficiente para a garantia da integralidade da assistência permeado pela falta de conhecimentos e habilidades para lidar com esse público, o que leva ao encaminhamento para serviços especializados como principal intervenção, reforçando a necessidade de capacitação desses profissionais.

RESUMEN Objetivo analizar la atención de Enfermería a usuarios de sustancias psicoactivas en la Estrategia Salud de la Familia. Método estudio descriptivo y cualitativo realizado con siete enfermeros de la Estrategia Salud de la Familia en Juiz de Fora, Minas Gerais. Los datos fueron obtenidos a través de entrevistas guiadas por un guion semiestructurado y se utilizó el Análisis de Contenido Temático para su tratamiento. Resultados la asistencia proporcionada por los entrevistados se basa en la demanda espontánea, sin estrategias de búsqueda activa, con la valoración de prácticas guiadas por la medicalización de la persona y la derivación a servicios especializados. La inclusión de la familia en el proceso de rehabilitación, la atención inmediata y el ejercicio de la escucha terapéutica fueron mencionadas como estrategias que pueden ser adoptadas para la atención integral. Los desafíos mencionados se refirieron a la falta de formación en salud mental, la fragmentación del conocimiento sobre la especialidad, la falta de formación y el deseo del paciente de participar en el tratamiento. Consideraciones finales e implicaciones para la práctica los enfermeros mencionaron cuidados insuficientes para garantizar una atención integral permeada por la falta de conocimientos y habilidades para el trato con este público, lo que lleva a la derivación a servicios especializados como principal intervención, reforzando la necesidad de formación de estos profesionales.

ABSTRACT Objective to analyze the nursing care provided to users of psychoactive substances in the Family Health Strategy. Method a descriptive and qualitative study carried out with seven nurses from the Family Health Strategy of Juiz de Fora, Minas Gerais. Data was obtained through interviews guided by a semi-structured script and the Thematic Content Analysis was used for its treatment. Results the care provided by the interviewees is based on spontaneous demand, without active search strategies, with the valorization of practices guided by the medicalization of the person and the referral to specialized services. The inclusion of the family in the rehabilitation process, immediate care, and therapeutic listening were mentioned as strategies that can be adopted for an integral assistance. The challenges mentioned referred to the lack of training in mental health, the fragmentation of knowledge about the specialty, the absence of training, and the patient's desire to participate in the treatment. Final considerations and implications for the practice the nurses reported insufficient care to ensure comprehensive care permeated by a lack of knowledge and skills to deal with this public, which leads to referral to specialized services as the main intervention, reinforcing the need to train these professionals.

Transcriptional Regulation of Congocidine (Netropsin) Biosynthesis and Resistance.

The production of specialized metabolites by Streptomyces bacteria is usually temporally regulated. This regulation is complex and frequently involves both global and pathway-specific mechanisms. Streptomyces ambofaciens ATCC23877 produces several specialized metabolites, including spiramycins, stambomycins, kinamycins and congocidine. The production of the first three molecules has been shown to be controlled by one or several cluster-situated transcriptional regulators. However, nothing is known regarding the regulation of congocidine biosynthesis. Congocidine (netropsin) belongs to the family of pyrrolamide metabolites, which also includes distamycin and anthelvencins. Most pyrrolamides bind into the minor groove of DNA, specifically in A/T-rich regions, which gives them numerous biological activities, such as antimicrobial and antitumoral activities. We previously reported the characterization of the pyrrolamide biosynthetic gene clusters of congocidine (cgc) in S. ambofaciens ATCC23877, distamycin (dst) in Streptomyces netropsis DSM40846, and anthelvencins (ant) in Streptomyces venezuelae ATCC14583. The three gene clusters contain a gene encoding a putative transcriptional regulator, cgc1, dst1, and ant1, respectively. Cgc1, Dst1, and Ant1 present a high percentage of amino acid sequence similarity. We demonstrate here that Cgc1, an atypical orphan response regulator, activates the transcription of all cgc genes in the stationary phase of S. ambofaciens growth. We also show that the cgc cluster is constituted of eight main transcriptional units. Finally, we show that congocidine induces the expression of the transcriptional regulator Cgc1 and of the operon containing the resistance genes (cgc20 and cgc21, coding for an ABC transporter), and propose a model for the transcriptional regulation of the cgc gene cluster. IMPORTANCE Understanding the mechanisms of regulation of specialized metabolite production can have important implications both at the level of specialized metabolism study (expression of silent gene clusters) and at the biotechnological level (increase of the production of a metabolite of interest). We report here a study on the regulation of the biosynthesis of a metabolite from the pyrrolamide family, congocidine. We show that congocidine biosynthesis and resistance are controlled by Cgc1, a cluster-situated regulator. As the gene clusters directing the biosynthesis of the pyrrolamides distamycin and anthelvencin encode a homolog of Cgc1, our findings may be relevant for the biosynthesis of other pyrrolamides. In addition, our results reveal a new type of feed-forward induction mechanism, in which congocidine induces its own biosynthesis through the induction of the transcription of cgc1.

Aggressive Neuroblastoma in a Pediatric Patient with Severe Hemophilia A.

Despite the extensive information regarding hemophilia's hemorrhagic complications, the literature on cancer in hemophilia is scarce, especially in pediatric patients. Many uncertainties remain concerning diagnosis and workup. We report a rare case of two severe diseases (neuroblastoma and hemophilia A (HA)) concomitantly present in the same pediatric patient. We highlight that the diagnosis of severe HA did not have a negative impact on the patient's oncologic course. This case also illustrates the significance of the cooperation among different specialties and hospitals when caring for the same patient.

Liver transplantation for hepatocellular carcinoma: impact of expansion criteria in a multicenter cohort study from a high waitlist mortality region.

This study aimed to compare liver transplantation (LT) outcomes and evaluate the potential rise in numbers of LT candidates with hepatocellular carcinoma (HCC) of different allocation policies in a high waitlist mortality region. Three policies were applied in two Latin American cohorts (1085 HCC transplanted patients and 917 listed patients for HCC): (i) Milan criteria with expansion according to UCSF downstaging (UCSF-DS), (ii) the AFP score, and (iii) restrictive policy or Double Eligibility Criteria (DEC; within Milan + AFP score ≤2). Increase in HCC patient numbers was evaluated in an Argentinian prospective validation set (INCUCAI; NCT03775863). Expansion criteria in policy A showed that UCSF-DS [28.4% (CI 12.8-56.2)] or "all-comers" [32.9% (CI 11.9-71.3)] had higher 5-year recurrence rates compared to Milan, with 10.9% increase in HCC patients for LT. The policy B showed lower recurrence rates for AFP scores ≤2 points, even expanding beyond Milan criteria, with a 3.3% increase. Patients within DEC had lower 5-year recurrence rates compared with those beyond DEC [13.3% (CI 10.1-17.3) vs 24.2% (CI 17.4-33.1; P = 0.0006], without significant HCC expansion. In conclusion, although the application of a stricter policy may optimize the selection process, this restrictive policy may lead to ethical concerns in organ allocation (NCT03775863).

Direct-Acting Antivirals and Hepatocellular Carcinoma: No Evidence of Higher Wait-List Progression or Posttransplant Recurrence.

The association between direct-acting antivirals (DAAs) and hepatocellular carcinoma (HCC) wait-list progression or its recurrence following liver transplantation (LT) remains uncertain. We evaluated the impact of DAAs on HCC wait-list progression and post-LT recurrence. This Latin American multicenter retrospective cohort study included HCC patients listed for LT between 2012 and 2018. Patients were grouped according to etiology of liver disease: hepatitis C virus (HCV) negative, HCV+ never treated with DAAs, and HCV+ treated with DAAs either before or after transplantation. Multivariate competing risks models were conducted for both HCC wait-list progression adjusted by a propensity score matching (pre-LT DAA effect) and for post-LT HCC recurrence (pre- or post-LT DAA effect). From 994 included patients, 50.6% were HCV-, 32.9% were HCV+ never treated with DAAs, and 16.5% were HCV+ treated with DAAs either before (n = 66) or after LT (n = 98). Patients treated with DAAs before LT presented similar cumulative incidence of wait-list tumor progression when compared with those patients who were HCV+ without DAAs (26.2% versus 26.9%; P = 0.47) and a similar HCC-related dropout rate (12.1% [95% CI, 0.4%-8.1%] versus 12.9% [95% CI, 3.8%-27.2%]), adjusted for baseline tumor burden, alpha-fetoprotein values, HCC diagnosis after listing, bridging therapies, and by the probability of having received or not received DAAs through propensity score matching (subhazard ratio [SHR], 0.9; 95% CI, 0.6-1.6; P = 0.95). A lower incidence of posttransplant HCC recurrence among HCV+ patients who were treated with pre- or post-LT DAAs was observed (SHR, 0.7%; 95% CI, 0.2%-4.0%). However, this effect was confounded by the time to DAA initiation after LT. In conclusion, in this multicenter cohort, HCV treatment with DAAs did not appear to be associated with an increased wait-list tumor progression and HCC recurrence after LT.

Disease Progression in Patients With Hepatitis C Virus Infection Treated With Direct-Acting Antiviral Agents.

BACKGROUND & AIMS: Little is known about how a sustained virologic response (SVR) to treatment of hepatitis C virus infection with direct-acting antivirals (DAAs) affects patient mortality and development of new liver-related events. We aimed to evaluate the incidence of disease progression in patients treated with DAAs. METHODS: We performed a prospective multicenter cohort study of 1760 patients who received DAA treatment at 23 hospitals in Latin America, from May 1, 2016, through November 21, 2019. We excluded patients with a history of liver decompensation, hepatocellular carcinoma (HCC), or solid-organ transplantation. Disease progression after initiation of DAA therapy included any of the following new events: liver decompensation, HCC, liver transplantation, or death. Evaluation of variables associated with the primary outcome was conducted using a time-dependent Cox proportional hazards models. RESULTS: During a median follow-up period of 26.2 months (interquartile range, 15.3-37.5 mo), the overall cumulative incidence of disease progression was 4.1% (95% CI, 3.2%-5.1%), and after SVR assessment was 3.6% (95% CI, 2.7%-4.7%). Baseline variables associated with disease progression were advanced liver fibrosis (hazard ratio [HR], 3.4; 95% CI, 1.2-9.6), clinically significant portal hypertension (HR, 2.1; 95% CI, 1.2-3.8), and level of albumin less than 3.5 mg/dL (HR, 4.1; 95% CI, 2.3-7.6), adjusted for SVR achievement as a time covariable. Attaining an SVR reduced the risk of liver decompensation (HR, 0.3; 95% CI, 0.1-0.8; P = .016) and de novo HCC (HR, 0.2; 95% CI, 0.1%-0.8%; P = .02) in the overall cohort. CONCLUSIONS: Treatment of hepatitis C virus infection with DAAs significantly reduces the risk of new liver-related complications and should be offered to all patients, regardless of disease stage. Clinicaltrials.gov: NCT03775798.

Análise de padrão da razão de mortalidade materna por hipertensão / Analysis of maternal mortality ratio pattern by hypertension / Análisis de estándar de la razón de mortalidad materna por hipertensión

Objetivo: Analisar o padrão da razão de mortalidade materna através dos óbitos por hipertensão associados à gestação nos municípios do Estado do Piauí, dos anos 2012 a 2016. Método: Trata-se de um estudo epidemiológico descritivo, comparativo, longitudinal de abordagem quantitativa, realizado a partir de registros de óbitos maternos ocorridos por distúrbios hipertensivos no Piauí, de 2012 à 2016. Resultados: Foram identificados 46 óbitos maternos por hipertensão, destes 12 mulheres possuíam escolaridade de 8 a 11 anos de estudo (26,1%), 19 (41,3%) tinham de 30 a 39 anos, eram 33 (71,7%) pardas e 12 (26,1%) solteiras. Conclusão: É fundamental que haja comprometimento de gestores e profissionais, para desenvolver ações de promoção a saúde das mulheres no ciclo gravídico-puerperal nos diversos serviços de saúde, de forma descentralizado, por meio de uma atenção qualificada, humanizada e integral

Objective: analyze the pattern of the maternal mortality ratio through gestational hypertension deaths in the counties of the State of Piauí from the years 2012 to 2016. Method: epidemiological study of a descriptive, comparative, longitudinal quantitative approach, carried out from records of maternal deaths caused by hypertensive disorders in Piauí, from 2012 to 2016. Results: a total of 46 maternal deaths from hypertension were identified. Of these, 12 were women with 8 to 11 years of schooling (26.1%), 19 (41.3%) were between 30 and 39 years of age, 33 (71.7%) were brown and 12 (26.1%) were single. Conclusion: it is fundamental that there is a commitment of managers and professionals to develop actions to promote women's health in the pregnancy-puerperal cycle in the various health services, in a decentralized way, through a qualified, humanized and integral care

Objetivo: analizar el patrón de la razón de mortalidad materna a través de las muertes por hipertensión asociadas a la gestación en los municipios del Estado de Piauí, de los años 2012 a 2016. Método: se trata de un estudio epidemiológico descriptivo, comparativo, longitudinal de abordaje cuantitativo, realizado a partir de registros de muertes maternas ocurridas por disturbios hipertensivos en Piauí, de 2012 a 2016. Resultados: se identificaron 46 muertes por hipertensión, de estas 12 mujeres tenían escolaridad de 8 a 11 años de estudio (26,1%), 19 (41,3%) tenían de 30 a 39 años, eran 33 (71,7%) pardas y 12 (26,1%) solteras. Conclusión: es fundamental que haya compromiso de gestores y profesionales, para desarrollar acciones de promoción a la salud de las mujeres en el ciclo gravídico-puerperal en los diversos servicios de salud, de forma descentralizada, por medio de una atención cualificada, humanizada e integral

Burnout, estresse, depressão e suporte laboral em professores universitários / Burnout, stress, depression, and job support in university professors / Burnout, estrés, depresión y soporte laboral en profesores universitarios

A síndrome de burnout é um conjunto de sintomas relacionados ao esgotamento, e afeta professores universitários. O objetivo do estudo foi investigar variáveis que se associam ao burnout em professores universitários, possíveis preditores e diferenças de média nos níveis de burnout entre docentes de universidades públicas e privadas. A amostra foi constituída por 99 professores universitários de instituições públicas e privadas do Estado de São Paulo. Os instrumentos aplicados avaliavam a SB, os eventos estressores no trabalho, a depressão e o suporte laboral. Foram realizadas correlações, regressões e o teste t para comparação de média. Idade, eventos estressantes, suporte laboral e depressão foram as variáveis que apresentaram correlações com a SB e suas categorias. De forma geral, os eventos estressores e a sintomatologia depressiva foram os preditores significativos da SB na amostra e professores de universidade pública demonstram maior nível de desgaste psicológico em comparação aos de universidades privadas.

Burnout Syndrome (BS) is a set of symptoms related to emotional exhaustion, lack of personal fulfillment at work, and depersonalization. University professors are among the most vulnerable groups for BS. The objective of the study was to investigate variables associated with burnout in university professors, possible predictors and differences in mean burnout levels among teachers from public and private universities. The sample consisted of 99 university professors from public and private institutions in the state of São Paulo. The instruments applied evaluated BS, stressful events at work, depression, and work support. Correlations, regressions, and t-tests were performed to compare means. Age, stressful events, work support, and depression were the variables that presented correlations with BS and its categories. In general, stressors and depression symptoms were the significant predictors of BS in the sample, and public university professors demonstrated a higher level of psychological exhaustion compared to those from private universities.

El síndrome de burnout es un conjunto de síntomas relacionados con el agotamiento, y afecta a los profesores universitarios. El objetivo de este estudio fue investigar variables que se asocian al burnout en profesores universitarios, posibles predictores y diferencias de promedio en los docentes de universidades públicas y privadas. La muestra fue constituida por 99 profesores de instituciones del Estado de São Paulo. Los instrumentos aplicados evaluaban la SB, los eventos estresores en el trabajo, la depresión y el soporte laboral. Se realizaron correlaciones, regresiones y la prueba t para comparación de media. Edad, eventos estresantes, soporte laboral y depresión fueron las variables que presentaron correlaciones con la SB y sus categorías. En general, los eventos estresores y la sintomatología depresiva fueron los predictores significativos de la SB en la muestra; y profesores de universidad pública demuestran mayor nivel de desgaste psicológico en comparación con los de universidades privadas

Colombian experience in the treatment of hepatitis C with direct-acting antiviral agents

There are few published real-world studies on hepatitis C in Latin America. This paper describes a cohort of Colombian subjects treated with direct-acting antiviral agents. A total of 195 patients from 5 hepatology centers in 4 Colombian cities were retrospectively studied. For each patient, serum biomarkers were obtained, and Child-Pugh, MELD, cirrhosis and fibrosis stage were calculated. Additionally, viral load was quantified at initiation, end of treatment and at 12 weeks of completion. Adverse effects were recorded. Patients with liver transplant were compared with non-transplanted patients in terms of serum biomarkers. The patients had received 9 different regimes. The most prevalent viral genotype was 1b (81.5%). Overall, 186 patients (95.4%) attained sustained virologic response. When comparing transplanted vs. non-transplanted patients, those in the non-transplanted group were more likely to have cirrhosis (52.6% vs. 12.5%, p = 0.0004). Pre-treatment viral load was higher in the transplant group (1 743 575 IQR = 1 038 062-4 252 719 vs. 345 769 IQR = 125 806-842 239; p < 0.0001) as well as ALT and AST levels (82.5 IQR 43.5-115.5 vs. 37.0 IQR = 24.7-73.3; p = 0.0009 and 70 IQR = 41-140 vs. 37 IQR = 24-68; p = 0.004 respectively). Adverse events were reported by 28.7% of the patients; asthenia (5.6%) was the most prevalent. Our results are comparable with those from other countries in terms of therapy and biomarkers. However, our cohort reported less adverse events. Further research is needed in the region.

Existen pocas publicaciones de evidencias del mundo real sobre hepatitis C en América Latina. En este estudio presentamos una cohorte colombiana de pacientes tratados con agentes antivirales de acción directa. Fueron analizados retrospectivamente 195 pacientes seleccionados en 5 centros de hepatología en 4 ciudades de Colombia. Dos tercios fueron mujeres y la mitad tenía ≥ 62 años. De cada uno se cuantificaron biomarcadores séricos, escala de Child-Pugh, MELD y grado de cirrosis y fibrosis. Se cuantificó carga viral al inicio, al final y a las 12 semanas después de completado el tratamiento. Se comparó la frecuencia de efectos adversos de medicamentos en trasplantados vs. no trasplantados. Los pacientes recibieron 9 esquemas de tratamiento diferentes. El genotipo más prevalente fue 1b (81.5%). La respuesta viral sostenida fue alcanzada por 186 pacientes (95.4%). El grupo no trasplantado tenía mayor frecuencia de cirrosis (52.6% vs. 12.5%, p = 0.0004). En los trasplantados, la carga viral pre-tratamiento era mayor (1 743 575 IQR = 1 038 062-4 252 719 vs. 345 769 IQR = 125 806-842 239; p = < 0.0001) igual que la ALT y la AST (82.5 IQR 43.5-115.5 vs. 37.0 IQR = 24.7-73.3; p = 0.0009 and 70 IQR = 41-140 vs. 37 IQR = 24-68; p = 0.004 respectivamente). El 28.7% refirió efectos adversos, siendo el más prevalente la astenia (5.6%). Nuestros resultados fueron comparables a los de estudios publicados en términos de terapia y biomarcadores pero nuestra cohorte presentó menos efectos adversos. Se requiere más investigación en la región.

Treatment with direct-acting antivirals for HCV decreases but does not eliminate the risk of hepatocellular carcinoma.

BACKGROUND & AIMS: Data from Europe and North America have been published regarding the risk of developing hepatocellular carcinoma (HCC) after treatment with direct antiviral agents (DAA). We proposed to evaluate cumulative incidence and associated risk factors for de novo HCC. METHODS: This was a prospective multicentre cohort study from Latin America including 1400 F1-F4-treated patients with DAAs (F3-F4 n = 1017). Cox proportional regression models (hazard ratios, HR and 95% CI) were used to evaluate independent associated variables with HCC. Further adjustment with competing risk regression and propensity score matching was carried out. RESULTS: During a median follow-up of 16 months (IQR 8.9-23.4 months) since DAAs initiation, overall cumulative incidence of HCC was 0.02 (CI 0.01; 0.03) at 12 months and 0.04 (CI 0.03; 0.06) at 24 months. Cumulative incidence of HCC in cirrhotic patients (n = 784) was 0.03 (CI 0.02-0.05) at 12 months and 0.06 (CI 0.04-0.08) at 24 months of follow-up. Failure to achieve SVR was independently associated with de novo HCC with a HR of 4.9 (CI 1.44; 17.32), after adjusting for diabetes mellitus, previous interferon non-responder, Child-Pugh and clinically significant portal hypertension. SVR presented an overall relative risk reduction for de novo HCC of 73% (CI 15%-91%), 17 patients were needed to be treated to prevent one case of de novo HCC in this cohort. CONCLUSIONS: Achieving SVR with DAA regimens was associated with a significant risk reduction in HCC. However, this risk remained high in patients with advanced fibrosis, thus demanding continuous surveillance strategies in this population.