Assessment of Cardiac Troponin I Responses in Nonhuman Primates during Restraint, Blood Collection, and Dosing in Preclinical Safety Studies.

Limited information has been published on the use of cardiac troponin I (cTnI) as a biomarker of cardiac injury in monkeys. The purpose of these studies was to characterize the cTnI response seen in cynomolgus macaques during routine dosing and blood collection procedures typically used in preclinical safety studies and to better understand the pathogenesis of this response. We measured cTnI using two different methods, the Siemens Immulite cTnI assay and the more sensitive Siemens Troponin I-Ultra assay. We were able to demonstrate that after oral, subcutaneous, or intravenous dosing of common vehicles, as well as serial chair restraint for venipuncture blood collection, that minimal to mild transient increases in cTnI could be detected in monkeys with both assays. cTnI values typically peaked at 2, 3, 4, or 6 hr after sham dosing and returned to baseline at 22 or 24 hr. In addition, marked increases in heart rate (HR) and blood pressure (BP) occurred in monkeys during the restraint procedures, which likely initiated the cTnI release in these animals. Monkeys that were very well acclimated to the chairing procedures and had vascular access ports for blood sampling did not have marked increases in HRs and BP or increases in cTnI.

Reversal of the recommendations issued by the National Commission for the Incorporation of Technologies in SUS after Public Consultations. / Reversão das recomendações emitidas pela Comissão Nacional de Incorporação de Tecnologias no SUS após Consultas Públicas.

The work analyzed the effect of Public Consultations (PC) and their contributions to the recommendations of the National Commission for the Incorporation of Technologies (CONITEC). This is a descriptive and retrospective study with a qualitative-quantitative approach using a secondary data source of public access, between 2012 and 2017. A database was developed to characterize the PC of medications and their contributions, which allowed the identification of cases of reversals between the preliminary and final recommendation of CONITEC. We analyzed the contributions in cases of reversal for characterization of argumentative axes and type of basis. Of the 307 demands for incorporation of medications, 205 went through PC, with 23,894 contributions. The reversal of the recommendations occurred in 9% of the open PC (15 medications), all in the sense of non-incorporation for incorporation. Main argumentative axes dealt with clinical benefits and minor adverse events, with prevalence of the submission of clinical experiences and opinions. Advances in the processes of incorporation of technologies in the SUS by performing PC were found and the challenge that decision makers face in institutional spaces for the improvement of social participation to strengthen the public benefit was clear.

O trabalho analisou o efeito das Consultas Públicas (CP) e suas contribuições nas recomendações da Comissão Nacional de Incorporação de Tecnologias (CONITEC). Trata-se de estudo descritivo e retrospectivo, com abordagem qualiquantitativa, com fonte de dados secundárias de acesso público, entre 2012 e 2017. Elaborou-se banco de dados para caracterizar as CP de medicamentos e suas contribuições, o que permitiu identificar casos de reversões entre a recomendação preliminar e final da CONITEC. Analisou-se as contribuições nos casos de reversão para caracterização de eixos argumentativos e tipo de embasamento. Das 307 demandas de incorporação, 205 destes passaram por CP, com 23.894 contribuições. A reversão das recomendações ocorreu em 9% das CP abertas (15 medicamentos), todas no sentido da não incorporação para incorporação. Principais eixos argumentativos trataram de benefícios clínicos e menores eventos adversos, prevalecendo o envio de experiências clínicas e opiniões. Evidencia-se avanços nos processos de incorporação de tecnologias no SUS pela realização da CP e ficou claro o desafio que os tomadores de decisão enfrentam nos espaços institucionais para o aprimoramento da participação social no sentido de fortalecer o benefício público.

DEPRESSIVE AND EATING DISORDERS IN PATIENTS POST-BARIATRIC SURGERY WITH WEIGHT REGAIN: A DESCRIPTIVE OBSERVATIONAL STUDY.

BACKGROUND: Although bariatric surgery is today's gold standard treatment for obesity, weight regain affects the success rate of the procedure. Recent studies have identified psychiatric and neurological factors as possible causes. AIMS: The aim of this study was to evaluate the influence of psychiatric diseases on the outcome and long-term success of bariatric surgeries and find a weight regain threshold that has an acceptable sensibility to mental health-related issues to be used in research and clinical studies. METHODS: This is a observational study of bariatric patients submitted to Roux-en-Y bypass or sleeve gastrectomy, with a postoperative time of 2-10 years to access weight regain, depression, and binge-eating disorder. RESULTS: Of 217 patients studied, 163 were women and 54 were men, with an average postoperative time of 5.2±2.6 years. Weight regain was experienced in 35% of the patients, binge-eating disorder in 24.9%, and depression in 24%. The greater weight before surgery, body mass index (BMI), percentage increase to maximum weight loss, and time postoperatively all have a significant positive correlation with weight regain (p=0.045, p=0.026, p<0.001, and p<0.001, respectively). A significant association between binge-eating disorder, depression, and anxiety with weight regain (p=0.004, p=0.008, and p=0.001, respectively) was found. CONCLUSIONS: The significant weight regain rates with significant impact on psychiatric disorders highlight the need for continuous postoperative monitoring focused on the psychiatric aspects of obesity to aid surgeries' long-term success.

Genetic Polymorphisms as Predictors of Survival in Breast Cancer: Future Lessons in Historical Data.

Introduction Breast cancer is the most common cancer among women worldwide and one of the main causes of death in the female sex. Genetic polymorphisms in the mu-opioid receptor (OPRM1) and catechol-o-methyltransferase (COMT) genes have been shown to increase breast cancer risk. Variants in these genes may carry a prognostic impact in breast cancer. Long follow-up intervals are critical to adequately analyze prognosis in diseases with prolonged survival times and late relapses. Objective To analyze the impact of genetic polymorphisms on the survival of a cohort of breast cancer patients with very long follow-up. Methods This was a retrospective study of patients treated at Portuguese Oncology Institute of Porto (IPO Porto), a Portuguese comprehensive cancer center, with invasive carcinoma of the breast with very long follow-up, with analysis of genetic polymorphisms OPMR1 rs1799971 (AA vs. G allele) and COMT rs4680 (CC vs T allele) on biological samples. Statistical analysis of survival was performed using the Kaplan-Meier method, log-rank test, and Cox regression method. Results A total of 143 patients with invasive breast cancer were included, with a median follow-up of 21.5 years. There was a statistically significant difference in overall survival (OS) at 30 years according to the OPMR1 polymorphism, with lower survival in patients with the AA genotype (p<0.05). The difference in OS according to the COMT polymorphism was also statistically significant, with worse survival in patients with genotype T allele (p<0.05). The genetic variants were not associated with patient age, stage at diagnosis, or tumor grade. Discussion The genetic polymorphisms of OPRM1 and COMT affected the overall survival of breast cancer patients, in concordance with previous research. Further investigation is needed in order to clarify the prognostic impact of these genetic alterations on breast cancer.

Prognostic Factors and Survival According to Tumor Subtype in Women With Breast Cancer Brain Metastases.

Breast cancer (BC) is the second most cause of central nervous system (CNS) metastases. Studies report that almost one third of patients (pts) with triple-negative, one-third with human epidermal growth factor receptor 2 (HER2)-positive and 15% of those with hormone receptor-positive, HER2-negative metastatic breast cancer will develop brain metastases. It is known that the development of symptomatic brain metastases in women with advanced breast cancer is associated with poor prognosis, irrespective of local and systemic treatments. In the present study, we aim to determine the association between BC subtypes and CNS metastases occurrence and prognosis. Retrospective analysis of 309 BC patients with CNS metastases, confirmed by pathological and/or radiological methods, treated in a Cancer Center between 2003 and 2021, was obtained to identify clinicopathologic factors associated with early onset of brain metastases and survival outcomes. For analysis purposes, 3 BC subtypes were considered according to hormone receptor status and HER-2 expression: ER and/or PR positive, HER-2 positive and triple negative. The median time between diagnosis of BC and detection of CNS metastases was 43 months, and it was significantly shorter in triple negative group (8 months). Twenty-one patients (6,8%) had CNS metastases at BC diagnosis, with CNS being the first site of recurrence in 35,3%, mainly in HER2 positive. Most of the patients had parenchymal metastases (n = 245) and 37 (12%) had leptomeningeal (LM) disease, with predominance in ER and/or PR positive subtype (70,3%). In patients submitted to CNS surgery, the concordance between primary tumor and metastases subtype was higher in triple negative (76,9%) compared to 63,2% in HER-2 positive and 38,9% in ER and/or PR positive group (P < 0.05). After CNS involvement, 25,4% (n = 34) of patients with triple negative disease did not receive any systemic therapy, compared to 30,6% (n = 41) in HER-2 positive and 44% (n = 59) in ER and/or PR positive groups (P = 0.05). Median survival after CNS metastases was 9 months, but significantly longer in HER-2 positive group (16 months) and in patients submitted to surgical resection of CNS metastases, irrespectively of subtype (22 months vs 5 months in other treatment modalities). In multivariate Cox regression analysis, having HER-2 positive tumor was an independent prognostic factor for increasing survival after CNS metastases (HR 0.60, 95% CI: 0.41-0.87, P = 0.007), regardless the therapeutic strategy. Clinical behavior and prognosis of CNS metastases varies according to BC subtype. The association between LM disease and ER and/or PR positive tumors should be explored in upcoming studies. Also, these patients' prognosis depends on the availability of specific treatment options, therefore, innovative and effective therapeutic approaches are needed, in order to improve survival and quality of life of these patients.

Biodistribution and Tolerability of AAV-PHP.B-CBh-SMN1 in Wistar Han Rats and Cynomolgus Macaques Reveal Different Toxicologic Profiles.

Recombinant adeno-associated viruses (AAVs) have emerged as promising vectors for human gene therapy, but some variants have induced severe toxicity in Rhesus monkeys and piglets following high-dose intravenous (IV) administration. To characterize biodistribution, transduction, and toxicity among common preclinical species, an AAV9 neurotropic variant expressing the survival motor neuron 1 (SMN1) transgene (AAV-PHP.B-CBh-SMN1) was administered by IV bolus injection to Wistar Han rats and cynomolgus monkeys at doses of 2 × 1013, 5 × 1013, or 1 × 1014 vg/kg. A dose-dependent degeneration/necrosis of neurons without clinical manifestations occurred in dorsal root ganglia (DRGs) and sympathetic thoracic ganglia in rats, while liver injury was not observed in rats. In monkeys, one male at 5 × 1013 vg/kg was found dead on day 4. Clinical pathology data on days 3 and/or 4 at all doses suggested liver dysfunction and coagulation disorders, which led to study termination. Histologic evaluation of the liver in monkeys showed hepatocyte degeneration and necrosis without inflammatory cell infiltrates or intravascular thrombi, suggesting that hepatocyte injury is a direct effect of the vector following hepatocyte transduction. In situ hybridization demonstrated a dose-dependent expression of SMN1 transgene mRNA in the cytoplasm and DNA in the nucleus of periportal to panlobular hepatocytes, while quantitative polymerase chain reaction confirmed the dose-dependent presence of SMN1 transgene mRNA and DNA in monkeys. Monkeys produced a much greater amount of transgene mRNA compared with rats. In DRGs, neuronal degeneration/necrosis and accompanying findings were observed in monkeys as early as 4 days after test article administration. The present results show sensory neuron toxicity following IV delivery of AAV vectors at high doses with an early onset in Macaca fascicularis and after 1 month in rats, and suggest adding the autonomic system in the watch list for preclinical and clinical studies. Our data also suggest that the rat may be useful for evaluating the potential DRG toxicity of AAV vectors, while acute hepatic toxicity associated with coagulation disorders appears to be highly species-dependent.

Reversão das recomendações emitidas pela Comissão Nacional de Incorporação de Tecnologias no SUS após Consultas Públicas / Reversal of the recommendations issued by the National Commission for the Incorporation of Technologies in SUS after Public Consultations

Resumo O trabalho analisou o efeito das Consultas Públicas (CP) e suas contribuições nas recomendações da Comissão Nacional de Incorporação de Tecnologias (CONITEC). Trata-se de estudo descritivo e retrospectivo, com abordagem qualiquantitativa, com fonte de dados secundárias de acesso público, entre 2012 e 2017. Elaborou-se banco de dados para caracterizar as CP de medicamentos e suas contribuições, o que permitiu identificar casos de reversões entre a recomendação preliminar e final da CONITEC. Analisou-se as contribuições nos casos de reversão para caracterização de eixos argumentativos e tipo de embasamento. Das 307 demandas de incorporação, 205 destes passaram por CP, com 23.894 contribuições. A reversão das recomendações ocorreu em 9% das CP abertas (15 medicamentos), todas no sentido da não incorporação para incorporação. Principais eixos argumentativos trataram de benefícios clínicos e menores eventos adversos, prevalecendo o envio de experiências clínicas e opiniões. Evidencia-se avanços nos processos de incorporação de tecnologias no SUS pela realização da CP e ficou claro o desafio que os tomadores de decisão enfrentam nos espaços institucionais para o aprimoramento da participação social no sentido de fortalecer o benefício público.

Abstract The work analyzed the effect of Public Consultations (PC) and their contributions to the recommendations of the National Commission for the Incorporation of Technologies (CONITEC). This is a descriptive and retrospective study with a qualitative-quantitative approach using a secondary data source of public access, between 2012 and 2017. A database was developed to characterize the PC of medications and their contributions, which allowed the identification of cases of reversals between the preliminary and final recommendation of CONITEC. We analyzed the contributions in cases of reversal for characterization of argumentative axes and type of basis. Of the 307 demands for incorporation of medications, 205 went through PC, with 23,894 contributions. The reversal of the recommendations occurred in 9% of the open PC (15 medications), all in the sense of non-incorporation for incorporation. Main argumentative axes dealt with clinical benefits and minor adverse events, with prevalence of the submission of clinical experiences and opinions. Advances in the processes of incorporation of technologies in the SUS by performing PC were found and the challenge that decision makers face in institutional spaces for the improvement of social participation to strengthen the public benefit was clear.

Depressive and eating disorders in patients post-bariatric surgery with weight regain: a descriptive observational study / Transtorno depressivo e alimentar em pacientes pós-bariátricos cirurgia bariátrica com reganho de peso: um estudo observacional descritivo

ABSTRACT BACKGROUND: Although bariatric surgery is today's gold standard treatment for obesity, weight regain affects the success rate of the procedure. Recent studies have identified psychiatric and neurological factors as possible causes. AIMS: The aim of this study was to evaluate the influence of psychiatric diseases on the outcome and long-term success of bariatric surgeries and find a weight regain threshold that has an acceptable sensibility to mental health-related issues to be used in research and clinical studies. METHODS: This is a observational study of bariatric patients submitted to Roux-en-Y bypass or sleeve gastrectomy, with a postoperative time of 2-10 years to access weight regain, depression, and binge-eating disorder. RESULTS: Of 217 patients studied, 163 were women and 54 were men, with an average postoperative time of 5.2±2.6 years. Weight regain was experienced in 35% of the patients, binge-eating disorder in 24.9%, and depression in 24%. The greater weight before surgery, body mass index (BMI), percentage increase to maximum weight loss, and time postoperatively all have a significant positive correlation with weight regain (p=0.045, p=0.026, p<0.001, and p<0.001, respectively). A significant association between binge-eating disorder, depression, and anxiety with weight regain (p=0.004, p=0.008, and p=0.001, respectively) was found. CONCLUSIONS: The significant weight regain rates with significant impact on psychiatric disorders highlight the need for continuous postoperative monitoring focused on the psychiatric aspects of obesity to aid surgeries' long-term success.

RESUMO INTRODUÇÃO: Embora a cirurgia bariátrica atualmente é considerada o tratamento padrão ouro para a obesidade, o reganho de peso afeta a taxa de sucesso do procedimento. Estudos recentes identificaram fatores psiquiátricos e neurológicos como possíveis causas. OBJETIVOS: Avaliar a influência de transtornos psiquiátricos no resultado a longo prazo das cirurgias bariátricas; testar a sensibilidade e correlação das fórmulas de reganho de peso e de seus respectivos pontos de corte para questões relacionadas à saúde mental. MÉTODOS: Estudo observacional de pacientes pós bariátricos submetidos à by-pass em Y de Roux ou gastrectomia vertical com pós-operatório de 2 a10 anos avaliados quanto a reganho de peso, depressão e transtorno da compulsão alimentar. RESULTADOS: Foram avaliados 217 pacientes, 163 mulheres e 54 homens com pós-operatório de 5,2±2,6 anos. O reganho de peso foi registrado em 35% dos pacientes, o transtorno da compulsão alimentar (TCA) foi encontrado em 24,9% e depressão em 24%. O ganho de peso pré-operatório, o índice de massa corporea (IMC), o aumento percentual para perda máxima de peso e tempo de pós-operatório, apresentaram correlação positiva significativa com o reganho de peso (p=0,045), (p=0,026), (<0,001), (<0,001). Foi encontrada associação significativa entre TCA, depressão e ansiedade com reganho de peso (p=0,004), (p=0,008) e (p=0,001). CONCLUSÕES: As taxas significativas de reganho de peso associado ao impacto dos transtornos psiquiátricos reforçam a necessidade de acompanhamento pós-operatório contínuo focado nos aspectos psiquiátricos da obesidade, para sucesso do tratamento cirúrgico em longo prazo.

Consumo de bebidas açucaradas e imagem corporal de adolescentes na Pandemia de Covid-19 / Consumption of sugary drinks and body image of adolescents in the Covid-19 Pandemic

O isolamento social promovido pela pandemia do COVID-19 alterou os comportamentos da população, principalmente de adolescentes que com o fechamento das escolas passaram a ficar em casa. Neste contexto, o consumo de alimentos e de bebidas açucaradas aumentou, podendo acarretar alterações na composição e na imagem corporal desses jovens. Este estudo avaliou o consumo de bebidas açucaradas, imagem corporal e estado nutricional de adolescentes antes e durante a pandemia do COVID-19. Tratou-se de um estudo quali-quantitativo, que avaliou 62 estudantes de 13 a 18 anos de idade na cidade de Canaã-MG. Investigou-se o consumo de bebidas açucaradas (volume e frequência) por meio do formulário de recordatório alimentar, a imagem corporal usando a escala de silhueta de 9 imagens, e o estado nutricional por meio de parâmetros antropométricos. Os resultados mostram que a maioria dos estudantes era eutrófica e relatou mudar o consumo dos tipos de bebida, a frequência e o volume consumido, sendo suco natural e refrigerante comum as bebidas mais consumidas antes e durante a pandemia. Também relataram alto índice de insatisfação corporal por magreza, que foi reduzido durante a pandemia. O motivo dessa insatisfação relacionou-se à saúde e estética, sendo que as garotas exibiram maiores alterações na insatisfação corporal entre o período antes e durante a pandemia. Os parâmetros antropométricos confirmaram o alto índice de insatisfação corporal dos estudantes, quando comparados a sua classificação por estado nutricional. Conclui-se que durante a pandemia, os estudantes alteraram o consumo de bebidas e a percepção da imagem corporal.

The social isolation promoted by the COVID-19 pandemic changed the behavior of the population, especially teenagers who, with the closing of schools, started to stay at home. In this context, the consumption of sugary foods and beverages increased, which may lead to changes in the composition and body image of these young people. This study evaluated the consumption of sugary drinks, body image, and nutritional status of adolescents before and during the COVID-19 pandemic. It was a quali-quantitative study, which evaluated 62 students from 13 to 18 years old in the city of Canaã-MG. The consumption of sugary drinks (volume and frequency) was investigated using the dietary recall form, the 9-image silhouette scale for body image, and anthropometric parameters for measuring nutritional status. The results show that most students were eutrophic and reported changing their consumption of types of beverages, frequency, and volume consumed. Natural juice and common soft drinks were the most consumed beverages before and during the pandemic. They also reported a high rate of body dissatisfaction due to thinness, which was reduced during the pandemic. The reason for this dissatisfaction was related to health and aesthetics, with girls exhibiting greater changes in body dissatisfaction between the period before and during the pandemic. Anthropometric parameters confirmed the high rate of body dissatisfaction among students, when compared to their classification by nutritional status. It is concluded that during the pandemic, students changed their consumption of beverages and their perception of their body image.

Bioluminescent Salmonella reverse mutation assay: a screen for detecting mutagenicity with high throughput attributes.

Here, we describe the development and evaluation of a novel bioluminescent high-throughput Salmonella reverse mutation assay applicable to the screening of large numbers of small molecules. The bioluminescent Salmonella assay utilizes genetically engineered standard Salmonella tester strains TA98 and TA100 expressing the lux(CDABE) operon from Xenorhabdus luminescence. In principle, the assay employs bioluminescence as a sensor of changes in bacterial metabolism associated with starvation or energy depletion effectively identifying colonies of histidine-independent revertant cells in a high-throughput fashion. The assay provides highly concordant data with the outcome in the standard Salmonella plate incorporation reverse mutation assay. Since the results of the standard Salmonella plate assay are required by various regulatory agencies for approval of new drugs, the bioluminescent Salmonella assay can be effectively used for prioritization of compounds in pharmaceutical drug discovery as well as the evaluation of environmental and industrial chemicals. Because of its high throughput attributes, the assay permits effective, fast and economical screening of a large series of structural analogs enabling the investigation of structure-activity relationships.