Gestational syphilis at different health care levels: a cross-sectional study / Sífilis gestacional en diferentes niveles de atención de salud: un estudio transversal / Sífilis gestacional em diferentes níveis de atenção à saúde: um estudo transversal

Background and objectives: Syphilis is a sexually transmitted disease that can cause miscarriage, premature birth, malformations, and neonatal death. When diagnosed and treated in the first months of pregnancy, the neonatal risks are considerably reduced. This work aims to discuss the key points regarding prevention and effective treatment of gestational syphilis at different health care levels. Methods: Retrospective cross-sectional study. A survey was carried out about syphilis notifications recorded at a hospital in Porto Alegre, RS, from January to June 2021, considering the variables date of diagnosis and notification and laboratory, treatment, and prenatal care data collected in hospital records and the e-SUS system. Results: In the study period, 17 cases of gestational syphilis and 102 cases in newborns were notified. We selected the case of a patient with a history of two pregnancies without prenatal care and use of psychoactive substances. This case illustrates the patient's itinerary in Primary Care, in specialized services such as the Center for Psychosocial Care and High-Risk Prenatal Care, and hospital care, showing the availability of care and, at the same time, the fragmentation of services. Conclusion: Multidisciplinary actions are needed at different health care levels to ensure access to testing for pregnant women and their partners, family planning, and adequate syphilis treatment, which interrupts the disease transmission chain and avoids possible complications of neonatal syphilis.(AU)

Justificativa e objetivos: A sífilis é uma infecção sexualmente transmissível que pode causar aborto, parto prematuro, malformações e morte neonatal. Quando diagnosticada e tratada nos primeiros meses da gestação, os riscos neonatais são consideravelmente diminuídos. Este trabalho tem como objetivo discutir os pontos-chave na prevenção e no tratamento efetivo da sífilis gestacional no contexto dos diferentes níveis de atenção à saúde. Métodos: Estudo transversal retrospectivo. Foi realizado um levantamento das notificações de sífilis em um hospital de Porto Alegre, RS, de janeiro a junho de 2021, considerando as variáveis data do diagnóstico e da notificação e dados de exames laboratoriais, de tratamento e de atendimento pré-natal, coletadas nos registros hospitalares e no sistema e-SUS. Resultados: No período do estudo, foram notificados dezessete casos de sífilis em gestantes e 102 em recém-nascidos. Selecionamos o caso de uma paciente com histórico de duas gestações sem pré-natal e uso de substâncias psicoativas. O caso ilustra o itinerário da paciente na atenção primária, em serviços especializados, como Centro de Atenção Psicossocial e Pré-Natal de Alto Risco, além do atendimento hospitalar, demonstrando a disponibilidade dos atendimentos e, ao mesmo tempo, a fragmentação dos serviços. Conclusão: São necessárias ações multidisciplinares nos diferentes níveis de atenção à saúde para garantir acesso à testagem da gestante e seus parceiros, ao planejamento familiar e ao tratamento adequado da sífilis, que interrompa a cadeia de transmissão da doença e evite possíveis complicações da sífilis neonatal.(AU)

Justificación y objetivos: La sífilis es una infección de transmisión sexual que puede causar aborto espontáneo, parto prematuro, malformaciones y muerte neonatal. Su diagnóstico y tratamiento en los primeros meses de embarazo lleva a una considerable reducción en los riegos neonatales. Este trabajo tiene como objetivo discutir los puntos clave en la prevención y tratamiento efectivo de la sífilis gestacional en el contexto de los diferentes niveles de atención a la salud. Métodos: Estudio transversal retrospectivo. Se realizó una encuesta de notificaciones de sífilis en un hospital de Porto Alegre (Brasil), de enero a junio de 2021, considerando las siguientes variables fecha de atención y notificación, y datos de exámenes de laboratorio, de tratamiento y control prenatal, recabadas de los registros hospitalarios y del sistema e-SUS. Resultados: Durante el período de estudio se reportaron diecisiete casos de sífilis en embarazadas y 102 en recién nacidos. Seleccionamos el caso de una paciente con antecedentes de dos embarazos sin control prenatal y consumo de sustancias psicoactivas. El caso ilustra el itinerario de la paciente por la atención primaria, por servicios especializados como el Centro de Atención Psicosocial y Atención Prenatal de Alto Riesgo, además de la atención hospitalaria, lo que demostró la disponibilidad de la atención y, al mismo tiempo, la fragmentación de los servicios. Conclusiones: Son necesarias acciones multidisciplinarias en los diferentes niveles de atención a la salud para garantizar el acceso a la prueba de la embarazada y de sus parejas, a la planificación familiar y al tratamiento adecuado de la sífilis, lo que interrumpa la cadena de transmisión de la enfermedad y evite posibles complicaciones de la sífilis neonatal.(AU)

Comparative efficacy of amitriptyline, duloxetine and pregabalin for treating fibromyalgia in adults: an overview with network meta-analysis.

Treatment recommendations for fibromyalgia (FM) include a range of predominantly pharmacological treatment options designed to ensure the maintenance of symptoms and improvement in the quality of life of these patients. Our aim is to identify and compare the efficacy of amitriptyline (AMT), duloxetine (DLX), and pregabalin (PGB) for reducing pain intensity by 30% (R30%) and 50% (R50%) in adult patients with fibromyalgia. The review was conducted in the Medline/PubMed, Cochrane Library, and Embase databases up to February 2022. This study included systematic reviews (SR) of randomized clinical trials (RCTs) targeting adult patients over 18 years of age diagnosed with fibromyalgia according to the criteria of scientific societies, which include the basic clinical diagnosis characterized by the presence of pressure sensitivity in at least 11 of the 18 tender points, in addition to the presence of widespread musculoskeletal pain for a period longer than 3 months and a general assessment of the patient's health status. Pregnant women and children or adolescents were excluded. The Rob 2.0 tool from the Cochrane Collaboration was used to assess the risk of bias in RCTs. The quality of evidence of the reviews included was assessed according to the Grading of Recommendations Assessment, Development and Evaluation-GRADE. A meta-analysis for the evidence network was performed using the Bayesian approach, which allows simultaneous comparison of all treatment options (medication and dose). The different treatments were ranked according to the response rate according to the surface under the curve (SUCRA), which was expressed as a percentage. The results were presented in tables and figures. The protocol with the detailed methods was registered in PROSPERO (CRD42021229264). Eight systematic reviews were identified, and, from these, 15 clinical trials comparing AMT (n = 273), DLX (n = 2595), and PGB (n = 3,506) against placebo were selected. For the outcome R30%, PGB 450 mg was superior to DLX 30 mg and PGB 150 mg, while DLX 20 mg and 30 mg were not superior to placebo. For the outcome R50%, AMT 25 mg was superior to all other alternatives evaluated. The calculation of the SUCRA indicated that PGB 450 mg was the best performance option for R30% and AMT 25 mg for R50%. PGB 150 mg was the drug with the worst performance in the two outcomes evaluated. The drugs evaluated showed benefits for pain reduction in patients with fibromyalgia. In the absence of direct comparison studies, indirect comparison meta-analyses are an important resource for assisting in clinical decision-making. Our data only provide an indicator of the effectiveness of the three drugs evaluated, but as with other health conditions, tolerability and safety are important for the decision-making process and clinical management. In this regard, we encourage caution in interpreting our data.

Drug-induced liver injury and COVID-19: A review for clinical practice.

Coronavirus disease 2019 (COVID-19) consists of a systemic disease that can present many complications. The infection presents broad clinical symptoms and a high rate of transmissibility. In addition to severe acute respiratory syndrome, the patients manifest complications beyond the respiratory system. The frequency of liver damage in COVID-19 patients ranges from 14.8% to 53% of patients. One should pay attention to drug-induced liver injury (DILI) in patients with COVID-19, especially considering the off-label use of drugs in prophylactic and therapeutic regimens applied on large scales. This review aims to present relevant information on the medication used so far in COVID-19 patients and its possible hepatotoxicity. We reviewed liver damage in patients with COVID-19 on PubMed and Virtual Health Library to investigate DILI cases. Four studies were selected, involving the medicines remdesivir, tocilizumab and a pharmacovigilance analysis study. The hepatotoxicity profile of drugs presented in the literature considers use in accordance to usual posology standards for treatment. However, drugs currently used in the management of COVID-19 follow different dosages and posology than those tested by the pharmaceutical industry. The deficiency of uniformity and standardization in the assessment of hepatotoxicity cases hinders the publication of information and the possibility of comparing information among healthcare professionals. It is suggested that severe liver injury in COVID-19 patients should be reported in pharmacovigilance institutions, and physicians should pay attention to any considerable abnormal liver test elevation as it can demonstrate unknown drug hepatotoxicity. Liver disorders in COVID-19 patients and the use of several concomitant off-label medications - with a potential risk of further damaging the liver - should at least be a warning sign for rapid identification and early intervention, thus preventing liver damage from contributing to severe impairment in patients.

Overview of drug induced liver injury in Brazil: What is the role of public health policy on the evidence?

BACKGROUND: Adverse drug reactions are responsible for increased costs and morbidity in the health system. Hepatotoxicity can be induced both by non-prescription drugs and by those used for chronic diseases. It is the main cause of safety-related drug marketing withdrawals and could be responsible for irreversible and fatal injuries. AIM: To identify and to summarize Brazilian studies reporting the drug-induced liver injury. METHODS: A systematic review of Brazilian studies was carried out until June 2020. It was found 32 studies, being 10 retrospective cohorts, 12 prospective cohorts, 5 cross-sectional, 3 case-control, one case series and one randomized clinical trial. In most studies were investigated tuberculosis patients followed by other infectious conditions like human immunodeficiency virus (HIV) and hepatitis C virus. The hepatotoxicity ranged from one to 57%, led by isoniazid, rifampicin, and pyrazinamide. Few studies reported algorithm to assess causality. In most studies, there were moderate outcomes and it was necessary drug interruption. However, few severe outcomes, such as chronic liver damage and liver transplantation were reported. RESULTS: Twenty-two different criteria for hepatotoxicity were found. The great heterogeneity did not allow a meta-analysis. Standardization of parameter of drug-induced liver injury and greater effort in pharmacovigilance could contribute to learn more about drug-induced liver injury (DILI)'s epidemiology in Brazil. CONCLUSION: The development of strategic public health policies seems to have an influence on the DILI scientific evidence in Brazil due to main studies are in HIV and tuberculosis line care, two strategic health policies in Brazil.

Hospital expenses and liver disease in Brazil / Gastos hospitalares e doença hepática no Brasil

Objective: This study aims at describing the values and morbimortality of hospital admissions for liver disease in the Brazilian public health system. Methods: The study was carried out in the DATASUS, for a period of five years. The number, causes, time, mortality rate and values of hospitalizations in the period were investigated. Results: In five years, there were 67,561,584 hospitalizations, of which 461,431 were due to liver diseases. The value of hospitalizations in the period was US$ 23 billion, and liver diseases accounted for US$ 384 million, which corresponds to 76 million per year. In liver diseases, the mean length of hospital stay was 8 days whereas for other hospitalizations the mean time was 5 days. The mortality rate from liver diseases was 14% while the general mortality rate was 4%. The average cost of hospitalizations was US$ 531 for liver diseases and US$ 84 for other causes of hospitalization. Conclusion: In the Brazilian public health system, liver diseases have a higher average value, a longer average hospital stay, and a higher mortality rate when compared to all causes of hospitalization.

Objetivo: Este estudo tem como objetivo descrever os valores e a morbimortalidade das internações por doenças hepáticas no sistema público de saúde brasileiro. Métodos: O estudo foi realizado no Sistema de Informações Hospitalares do Datasus, por um período de cinco anos. Foram investigados o número, as causas, o tempo, a taxa de mortalidade e os valores das internações no período. Resultados: Em cinco anos houve 67.561.584 internações, das quais 461.431 foram por hepatopatias. O valor das internações no período foi de US$ 23 bilhões, e as doenças do fígado representaram US$ 384 milhões, o que corresponde a 76 milhões por ano. Nas hepatopatias, o tempo médio de internação hospitalar foi de 8 dias, enquanto para outras internações o tempo médio foi de 5 dias. A taxa de mortalidade por doenças do fígado foi de 14%, enquanto a taxa geral de mortalidade foi de 4,0%. O custo médio das hospitalizações foi de US$ 531 para doenças do fígado, enquanto para outras causas de hospitalização foi de US$ 84. Conclusão: No sistema público de saúde brasileiro, as hepatopatias têm maior valor médio, maior tempo de internação e maior mortalidade quando comparadas a todas as causas de internação.

Drug and herb-induced liver injury: A critical review of Brazilian cases with proposals for the improvement of causality assessment using RUCAM.

INTRODUCTION AND OBJECTIVES: Although hepatotoxicity accounts for 10% of adverse drug reactions, it remains poorly understood and underreported. This study aimed to summarize case reports of herb- and drug-induced liver injury in Brazil. METHODOLOGY: Systematic review in the following databases: PubMed, SciELO, Science Direct, CAPES, and gray literature. RESULTS: Twenty-seven studies reporting 32 cases were identified. Brazilian cases were primarily detected in hospitals, and occurred mainly in young males suffering from chronic diseases. Drugs (n=29) were a more frequent cause of liver injury than herbs (n=3). Almost a third of these drugs were anticonvulsants, and 15 appear in the Brazilian List of Essential Medicines. In 50% of the cases, clinical manifestations started within 30 days of drug ingestion. Regarding the decline of liver enzymes, 50% of the cases reached normality after drug withdrawal. However, 7 deaths and 2 liver transplantations were reported. Only one study assessed causality using RUCAM. CONCLUSION: Given the severe outcomes of DILI and HILI, early detection and management of hepatotoxicity to increase drug safety are necessary, as well as pharmacotherapeutic monitoring of patients with chronic diseases. Moreover, the application of the RUCAM algorithm in clinical practice has to be further disseminated.

Liver transplantation and the use of KAVA: Case report.

BACKGROUND: Self-medication and the belief that herbal products are free of health risks are common in Brazil. The kava (Piper methysticum), known for its anxiolytic action, has a widespread popular use. Hepatotoxicity of kava is reported, including cases of liver transplantation and death. The kava had its use prohibited or restricted in countries like Germany, France, among others. Toxicity may be related to overdosage; however, factors such as botanical characteristics of the plant, the harvesting, storage, and production process may be associated with the development of hepatotoxic substances, such as triggering idiosyncratic reactions. HYPOTHESIS: In this case, there is a suspicion that the toxicide is intrinsic to the drug; however, the possibility of adulterants and contaminants must be ruled out. STUDY DESIGN: This study reports the case of a patient who, after using the herbal kava for 52 days, evolved into acute liver failure and liver transplantation. METHODS: The data were collected directly with the patient and compared with their clinical records. Causality was determined through the RUCAM algorithm. In addition, a phytochemical analysis of the drug used was performed. RESULTS: According to the patient's report, there is no evidence of overdosage. Results from RUCAM algorithm infer causality between liver damage and the use of kava. The analysis chemical constituents did not find any possible contaminants and major changes in the active compounds. Seven months after transplantation, the patient is well and continues to be followed up by a medical team. CONCLUSION: Our investigation indicates that there was kava-induced hepatotoxicity at standard dosages. In Brazil, self-medication by herbal medicines is frequent and many patients and health professionals do not know the risks associated with their use. Diagnosing and notifying cases in which plants and herbal medicine induce liver damage is of paramount importance to increase the knowledge about DILI and to prevent or treat similar cases quickly.

Depression and Mania Induce Pro-inflammatory Activation of Macrophages Following Application of Serum from Individuals with Bipolar Disorder.

OBJECTIVE: Evidence has suggested that immune imbalance is involved with bipolar disorder (BD); however, its precise mechanism is poorly understood. This study investigated whether biochemical changes in the serum from BD patients could modulate the phenotype of cultured macrophages. METHODS: Eighteen subjects with BD and five healthy individuals were included in this study. The human monocyte cell line U-937 was activated with phorbol 12-myristate 13-acetate (PMA) and polarization was induced with RPMI-1640 media supplemented with 10% serum from each patient for 24 hours. Gene expression of selected M1 and M2 markers was assessed by quantitative PCR. RESULTS: Macrophages exposed to serum of manic and depressive BD patients displayed an increase of interleukin-1ß (6.40±3.47 and 9.04±5.84 vs. 0.23±0.11; p＜0.05) and tumor necrosis factor-α (2.23±0.91 and 2.03±0.45 vs. 0.62±0.24; p=0.002 and p=0.004, respectively) compared to euthymic group (there was no difference between euthymic and controls). In parallel, U-937 macrophages treated with serum of patients in acute episode displayed a down-regulation of CXCL9 (0.29±0.20 vs. 1.86±1.61; p=0.006) and CXCL10 expression (0.36±0.15 and 0.86±0.24 vs. 1.83±0.88; p＜0.000 and p=0.04) compared to the euthymia group. CONCLUSION: Our results are consistent with previous studies showing that changes in peripheral blood markers could modulate M1/M2 polarization in BD. The evidence of macrophages as source of inflammatory cytokines might be helpful to unravel how the mononuclear phagocyte system is involved in the etiology of BD.

Integrated Transcriptomics Establish Macrophage Polarization Signatures and have Potential Applications for Clinical Health and Disease.

Growing evidence defines macrophages (Mφ) as plastic cells with wide-ranging states of activation and expression of different markers that are time and location dependent. Distinct from the simple M1/M2 dichotomy initially proposed, extensive diversity of macrophage phenotypes have been extensively demonstrated as characteristic features of monocyte-macrophage differentiation, highlighting the difficulty of defining complex profiles by a limited number of genes. Since the description of macrophage activation is currently contentious and confusing, the generation of a simple and reliable framework to categorize major Mφ phenotypes in the context of complex clinical conditions would be extremely relevant to unravel different roles played by these cells in pathophysiological scenarios. In the current study, we integrated transcriptome data using bioinformatics tools to generate two macrophage molecular signatures. We validated our signatures in in vitro experiments and in clinical samples. More importantly, we were able to attribute prognostic and predictive values to components of our signatures. Our study provides a framework to guide the interrogation of macrophage phenotypes in the context of health and disease. The approach described here could be used to propose new biomarkers for diagnosis in diverse clinical settings including dengue infections, asthma and sepsis resolution.

Potential crosstalk between cofilin-1 and EGFR pathways in cisplatin resistance of non-small-cell lung cancer.

Current challenge in oncology is to establish the concept of personalized medicine in clinical practice. In this context, non-small-cell lung cancer (NSCLC) presents clinical, histological and molecular heterogeneity, being one of the most genomically diverse of all cancers. Recent advances added Epidermal Growth Factor Receptor (EGFR) as a predictive biomarker for patients with advanced NSCLC. In tumors with activating EGFR mutations, tyrosine kinase inhibitors (TKI) are indicated as first-line treatment, although restricted to a very small target population. In this context, cofilin-1 (a cytosolic protein involved with actin dynamics) has been widely studied as a biomarker of an aggressive phenotype in tumors, and overexpression of cofilin-1 is associated with cisplatin resistance and poor prognosis in NSCLC. Here, we gather information about the predictive potential of cofilin-1 and reviewed the crosstalk between cofilin-1/EGFR pathways. We aimed to highlight new perspectives of how these interactions might affect cisplatin resistance in NSCLC. We propose that cofilin-1 quantification in clinical samples in combination with presence/absence of EGFR mutation could be used to select patients that would benefit from TKI's treatment. This information is of paramount importance and could result in a possibility of guiding more effective treatments to NSCLC patients.

High cofilin-1 levels correlate with cisplatin resistance in lung adenocarcinomas.

High cofilin-1 levels have been shown to be an accurate prognostic biomarker in non-small cell lung cancer (NSCLC) and a predictive factor in drug resistance. Herein we explore the role of cofilin-1 in cis-diamminedichloroplatinum(II) (cisplatin) resistance. We evaluated cofilin-1 levels in intrinsically cisplatin-resistant A549 (ICR-A549) cells and determined the cisplatin toxicity in A549 cells transiently transfected and overexpressing CFL1 plasmid. Moreover, expression levels (activity) of the CFL1 gene network were analyzed in a cisplatin-resistant human lung adenocarcinoma cell panel. ICR-A549 cells, selected by challenging parental cells with 10-fold drug GI50 value, presented a sixfold increase in cisplatin GI50 value and an increased cofilin-1 immunocontent (P < 0.01). In addition, cells transfected with cofilin-1 became more resistant to cisplatin (P < 0.01). High activity of the CFL1 gene network was found in a cisplatin-resistant adenocarcinoma cell panel (P < 0.01). In vitro evidences suggest that cofilin-1 is a biological predictor of cisplatin resistance, supporting new treatment initiatives based on cofilin-1 levels to guide chemotherapeutic interventions in NSCLC patients.

The prognostic impact of tumor-associated macrophages and intra-tumoral apoptosis in non-small cell lung cancer.

Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for 80% of all lung malignancies. Tumor-associated macrophages (TAM) are abundant components of NSCLC. Although under certain conditions TAM can kill tumor cells, they can also act as tumor promoters secreting a variety of factors that directly stimulate tumor invasion and metastasis. TAM presents two distinct phenotypes: the classically activated (or M1) phenotype, which is highly pro-inflammatory (phagocytic and cytotoxic), and the alternatively activated (or M2) phenotype, which has anti-inflammatory and pro-tumoral properties. The polarization status of TAM depends on stimulating factors from the tumor microenvironment, and some in vitro evidence implies that the phagocytosis of apoptotic bodies derived from tumoral cells is a key factor in M1/M2 modulation, raising the question of whether the evaluation of the apoptotic index (AI) and macrophage polarization have a prognostic role in NSCLC patient survival. The present article systematically reviewed the published series of clinical data that correlated the AI and/or macrophage densities and polarization status (M1/M2) with the outcome of non-small cell lung cancer patients. Even though an overwhelming body of clinical data support that TAM's density, micro-anatomical localization, phenotype and intra-tumoral AI are independent predictors of survival time, no study to date has been conducted to evaluate the impact of these parameters altogether in NSCLC patient outcome. Joint analysis of these biologic factors in future studies might reveal their prognostic value in the management of NSCLC cases.

Implantação de um método de seguimento farmacoterapêutico para pacientes gestantes HIV+ aplicado em famácias de medicamentos especiais do Sistema Único de Saúde

A diminuição da população infectada pelo HIV é um dos principais desafios dos gestores da saúde atualmente. O tratamento medicamentoso das gestantes infectadas, quando corretamente realizado, diminui a taxa de infecção vertical para menos de 1%. Desta forma se voltam as atenções à determinação de um método de seguimento farmacoterapêutico ideal na adesão dos pacientes ao tratamento. Este trabalho tem como objetivo comparar as principais metodologias utilizadas em seguimento farmacoterapêutico promovendo a inserção das tecnologias de informação na assistência farmacêutica no SUS. Será realizada uma revisão sistemática comparando os principais resultados alcançados com as metodologias de seguimento farmacoterapêutico e determinando a que mais se adequaria as necessidades locais.

The pharmacological NFkappaB inhibitors BAY117082 and MG132 induce cell arrest and apoptosis in leukemia cells through ROS-mitochondria pathway activation.

A growing body of evidence suggests the inhibition of NFkappaB as a strategy to induce cell death in tumor cells. In this work, we evaluated the effects of the pharmacological NFkappaB inhibitors BAY117082 and MG132 on leukemia cells apoptosis. BAY117082 and MG132 presented potent apoptotic effects compared to inhibitors of MAPKs, EGFR, PI3K/Akt, PKC and PKA signaling pathways. Non-tumor peripheral blood cells were insensitive to BAY117082 and MG132 apoptotic effects. BAY117082 and MG132-induced apoptosis was dependent on their ability to increase ROS as a prelude to mitochondria membrane potential (MMP) depolarization, permeability transition pore opening and cytochrome c release. Antioxidants blocked MG132 and BAY117082 effects on ROS, MMP and cell death. Although apoptotic markers as phosphatidylserine externalization, chromatin condensation and sub-G1 were detected in BAY117082-treated cells, caspases activation did not occur and apoptosis was insensitive to caspase inhibitors, suggesting a caspase-independent mechanism. In contrast, MG132 induced classical apoptosis through ROS-mitochondria and subsequent caspase-9/caspase-3 activation. At sub-apoptotic concentrations, BAY117082 and MG132 arrested cells in G2/M phase of the cell cycle and blocked doxorubicin-induced NFkappaB, which sensitized doxorubicin-resistant cells. Data suggest that the NFkappaB inhibitors MG132 and BAY117082 are potential anti-leukemia agents.