Biomarker Profiling of Upper Tract Urothelial Carcinoma Only and with Synchronous or Metachronous Bladder Cancer.

BACKGROUND: Molecular profiling in upper tract urothelial carcinoma (UTUC) with synchronous or metachronous urothelial bladder cancer (UBC) is scarce. We intended to assess immunohistochemical (IHC) and genetic differences between UTUC-only and UTUC with synchronous or metachronous UBC (UTUC + UBC) and evaluate the effect of subsequent UBC on the outcome of UTUC patients stratified by luminal-basal subtypes. METHODS: A retrospective cohort of UTUC was divided into UTUC-only (n = 71) and UTUC + UBC (n = 43). IHC expression of cytokeratin 5/6 (CK5/6), CK20, GATA3, and p53 was evaluated to assess relevant subtypes. Genetic characterization comprised TERTp, FGFR3, RAS, and TP53 status. Kaplan-Meier and Cox regression analyses estimated the effect of clinicopathological variables and molecular profiles on progression-free survival (PFS) and overall survival (OS) of UTUC patients. RESULTS: No meaningful differences were detected among both subgroups according to luminal-basal stratification and genetic analysis. UTUC + UBC was independently associated with a worse PFS when stratified by luminal-basal phenotype (HR 3.570, CI 95% 1.508-8.453, p = 0.004) but with no impact in OS (HR 1.279, CI 95% 0.513-3.190, p = 0.597). CONCLUSIONS: This study reveals that both subgroups exhibited equivalent genomic features and luminal-basal subtypes. The involvement of the bladder relates to shorter PFS but does not seem to influence the survival outcome of UTUC, independently of the IHC phenotype.

Exosomes define a local and systemic communication network in healthy pancreas and pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC), a lethal disease, requires a grasp of its biology for effective therapies. Exosomes, implicated in cancer, are poorly understood in living systems. Here we use the genetically engineered mouse model (ExoBow) to map the spatiotemporal distribution of exosomes from healthy and PDAC pancreas in vivo to determine their biological significance. We show that, within the PDAC microenvironment, cancer cells establish preferential communication routes through exosomes with cancer associated fibroblasts and endothelial cells. The latter being a conserved event in the healthy pancreas. Inhibiting exosomes secretion in both scenarios enhances angiogenesis, underscoring their contribution to vascularization and to cancer. Inter-organ communication is significantly increased in PDAC with specific organs as most frequent targets of exosomes communication occurring in health with the thymus, bone-marrow, brain, and intestines, and in PDAC with the kidneys, lungs and thymus. In sum, we find that exosomes mediate an organized intra- and inter- pancreas communication network with modulatory effects in vivo.

Indicators of functional fitness and cognitive commitment in elderly / Indicadores de aptitud funcional y compromiso cognitivo en ancianos / Indicadores de aptidão funcional e comprometimento cognitivo em idosos

ABSTRACT Introduction: Cognitive losses are among the most prevalent events in the elderly population and can cause functional deficits. Among the available non-drug prevention and treatment alternatives, the increase in functional fitness levels is presented as an important strategy suggesting improvements in the physical and cognitive function of the elderly triggered by exercise. Objective: To determine the predictive power of functional fitness indicators and establish their cutoff points as discriminators of cognitive impairment in the elderly. Methods: The sample comprised 310 elderly people who answered a questionnaire comprising sociodemographic information, lifestyle habits, hospitalization in the last 12 months, presence of comorbidity, and the Mini-Mental State Examination. Functional fitness was assessed using the Hand Grip Strength (HGS) and sitting and rising from a chair tests. To identify predictors of cognitive impairment, analysis of Receiver Operating Characteristic (ROC) curves was adopted, with a confidence interval of 95% (95%CI). Subsequently, the cut-off points with their respective sensitivities and specificities were identified. The analyses were performed respecting the significance level of 5%. Results: It was observed that some functional fitness indicators showed significant Area Under the Curve (AUC), and the sit-and-stand test (AUC=0.72; 95%CI: 0.64-0.77) showed the best results. The best cut-off points for the HGS and sit-and-stand tests were 18,8 kgf and eight repetitions, respectively. Conclusion: The results of the present study allow us to conclude that the sit-to-stand test is moderately efficient in discriminating the presence of cognitive impairment in the elderly. Level of Evidence III; Study Cross-sectional.

RESUMEN Introducción: Las pérdidas cognitivas se encuentran entre los eventos más prevalentes en la población anciana y pueden causar déficits funcionales. Entre las alternativas de prevención y tratamiento no farmacológico disponibles, el aumento de los niveles de condición física funcional se presenta como una estrategia importante que sugiere mejoras en la función física y cognitiva de los ancianos, desencadenada por la práctica de ejercicios. Objetivo: Determinar el poder predictivo de los indicadores de aptitud funcional y establecer sus puntos de corte como discriminadores del deterioro cognitivo en adultos mayores. Métodos: La muestra estuvo compuesta por 310 ancianos que respondieron un cuestionario que comprendía información sociodemográfica, hábitos de vida, hospitalización en los últimos 12 meses, presencia de comorbilidad y el Mini-Examen del Estado Mental. La condición física funcional se evaluó utilizando la fuerza de agarre manual (FAM) y las pruebas de sentarse y levantarse de una silla. Para identificar predictores de deterioro cognitivo, se adoptó el análisis de curvas Receiver Operating Characteristic (ROC), con intervalo de confianza del 95% (IC95%). Posteriormente se identificaron los puntos de corte con sus respectivas sensibilidades y especificidades. Los análisis se realizaron respetando el nivel de significancia del 5%. Resultados: Se observó que algunos indicadores de aptitud funcional mostraron un Área Bajo la Curva (ABC) significativa, y la prueba de sentarse y pararse (ABC=0,72; 95%IC: 0,64-0,77) mostró los mejores resultados. Los mejores puntos de corte para el test FAM y el sit-and-stand test fueron 18,8 kgf y 8 repeticiones, respectivamente. Conclusión: Los resultados del presente estudio permiten concluir que el test sit-to-stand es moderadamente eficiente para discriminar la presencia de deterioro cognitivo en adultos mayores. Nivel de Evidencia III; Estudio Transversal.

RESUMO Introdução: As perdas cognitivas estão entre os eventos mais prevalentes na população idosa, podendo causar déficits funcionais. Dentre as alternativas de prevenção e tratamento não medicamentosos disponíveis, o aumento dos níveis de aptidão funcional apresenta-se como uma estratégia importante sugerindo melhorias na função física e na função cognitiva de idosos, desencadeadas através da prática de exercícios. Objetivo: Determinar o poder preditivo dos indicadores de aptidão funcional e estabelecer seus pontos de corte como discriminadores do comprometimento cognitivo em idosos. Métodos: A amostra compreendeu 310 idosos que responderam a um questionário composto por informações sociodemográficas, hábitos de vida, hospitalização nos últimos 12 meses, presença de comorbidade e o Mini-Exame do Estado Mental. A aptidão funcional foi avaliada por meio dos testes de Força de Preensão Manual (FPM) e o de sentar e levantar da cadeira. Para identificação dos preditores do comprometimento cognitivo, foi adotada a análise das curvas Receiver Operating Characteristic (ROC), com intervalo de confiança de 95% (IC95%). Posteriormente, identificaram-se os pontos de corte com as respectivas sensibilidades e especificidades. As análises foram efetuadas respeitando-se o nível de significância de 5%. Resultados: Observou-se que alguns indicadores de aptidão funcional apresentaram Área Sob a Curva (ASC) significativas, sendo que o teste de sentar e levantar da cadeira (ASC=0,72; IC95%= 0,64-0,77) apresentou os melhores resultados. Os melhores pontos de corte para o teste de FPM e o teste de sentar e levantar da cadeira foram de 18,8 kgf e 8 repetições respectivamente. Conclusão: Os resultados do presente estudo permitem concluir que o teste de sentar e levantar da cadeira apresenta moderada eficiência para discriminar a presença de comprometimento cognitivo em idosos. Nível de Evidência III; Estudo Transversal.

Protein restriction impairs the response activation/responsivity of MAPK signaling pathway of hematopoietic stem cells.

Protein restriction (PR) leads to bone marrow hypoplasia with changes in stromal cellularity components of the extracellular matrix in hematopoietic stem cells (HSCs). However, the underlying signaling mechanisms are poorly understood. We hypothesize that PR impairs the HSC mitogen-activated protein kinase (MAPK) signaling pathway response activation. Our aim is to evaluate the activation of MAPK and interleukin-3 (IL-3) proteins in HSC to explain PR-induced bone marrow hypoplasia, which causes altered proliferation and differentiation. C57BL/6 male mice were subjected to a low-protein diet (2% protein) or normoproteic (12% protein). PKC, PLCγ2, CaMKII, AKT, STAT3/5, ERK1/2, JNK, and p38d phosphorylation were evaluated by flow cytometry, and GATA1/2, PU.1, C/EBPα, NF-E2, and Ikz-3 genes (mRNAs) assessed by quantitative real-time-polymerase chain reaction. Pathway proteins, such as PLCγ2, JAK2, STAT3/5, PKC, and RAS do not respond to the IL-3 stimulus in PR, leading to lower activation of ERK1/2 and Ca2+ signaling pathways, consequently lowering the production of hematopoietic transcription factors. Colony forming units granulocyte-macrophage and colony forming units macrophage formation are impaired in PR even after being stimulated with IL-3. Long-term hematopoietic stem cells, short-term hematopoietic stem cells, granulocyte myeloid progenitor, and megakaryocyte-erythroid progenitor cells were significantly reduced in PR animals. This study shows for the first time that activation of MAPK pathway key proteins in HSCs is impaired in cases of PR. Several pathway proteins, such as PLCγ2, JAK2, STAT3, PKC, and RAS do not respond to IL-3 stimulation, leading to lower activation of extracellular signal-regulated protein kinase 1/2 and consequently lower production of hematopoietic transcription factors GATA1/2, PU.1, C/EBPa, NF-E2, and Ikz3. These changes result in a reduction in colony-forming units, proliferation, and differentiation, leading to hypocellularity.

Prognostic Value of Bladder Involvement in the Outcome of Upper Tract Urothelial Carcinoma.

Accurately predicting the clinical prognosis of upper tract urothelial carcinoma (UTUC) seems crucial. We evaluated the effect of the involvement of urothelial bladder carcinoma (UBC) as a potential prognostic factor for overall survival (OS) and progression-free survival (PFS). The cohort included 115 patients with UTUC, subgrouped between January 2009 and December 2019 as follows: (1) only UTUC and (2) UTUC with synchronous or metachronous UBC (UTUC + UBC). Univariate and multivariate analyses were performed to identify independent prognostic factors for OS and PFS. Synchronous or metachronous UBC diagnosis in UTUC patients was an independent predictor of worse PFS (HR 3.326 CI 95% 1.474−7.503, p = 0.004), but it was not identified as a prognostic factor for OS (p > 0.05). Lymphovascular invasion (LVI) was associated with decreased PFS (HR 2.687 CI 95%1.172−6.163, p = 0.020) and OS (HR 4.980 CI 95%1.763−14.064, p = 0.002). This study indicates that concomitant or later UBC could predict a poor PFS, but it is not associated with a significantly worse OS in UTUC patients. The prognostic impact of LVI underlines its inclusion in the tumor staging system of UTUC.

The interaction between aging and protein malnutrition modulates peritoneal macrophage function: An experimental study in male mice.

Malnutrition is considered one of the most common problems in the elderly population worldwide and can significantly interfere in health evolution in these individuals, predisposing them to increased infection susceptibility. The immune response triggered by infections comprises several mechanisms, and macrophages play important roles in this response. This study aimed to evaluate mechanisms related to macrophage function in a model of protein malnutrition in the elderly. Two age groups (young: 3-5 months and elderly: 18-19 months) male C57BL/6NTac mice were subjected to protein malnutrition with a low-protein diet (2 %). The nutritional status, hemogram and number of peritoneal cells were affected by both age and nutritional status. Additionally, the spreading capacity as well as the phagocytic and fungicidal activity of peritoneal macrophages were affected by the nutritional status and age of the animal. Interestingly, the percentages of F4/80+/CD11b+ and CD86+ cells were reduced mostly in elderly animals, while the TLR-4+ population was more affected by nutritional status than by age. The production of pro-inflammatory cytokines such as TNF-α, IL-1α, and IL-6 was also influenced by nutritional status and/or by age, and malnourished animals of advanced age produced higher amounts of the anti-inflammatory cytokine IL-10. Furthermore, the phosphorylation ratio of the transcription factor NFκB (pNFκB/NFκB) was directly affected by the nutritional status, independently of age. Thus, these results allow us to conclude that aging and protein malnutrition compromise macrophage function, likely affecting their immune function, and in aged protein-malnourished animals, this impairment tends to be more pronounced.

Primary tooth restoration with colored compomer: case report / Restauração de dente decíduo com compômero colorido: relato de caso

ABSTRACT In pediatric dentistry, restorative treatment requires a material with good mechanical properties, ease of handling, and usability. For the restoration of deciduous teeth, colored compomers are an alternative material for motivating children in dental treatment and, consequently, behavior management. This study aimed to provide information about colored compomers by presenting a case of restoration in a deciduous molar with a five-year follow-up. Additionally, the study highlights the child's motivation toward dental treatment and oral care, thus offering an alternative to other restorative materials for clinicians to consider. The treatment plan for tooth 75 was selective removal of decayed tissue and restoration with compomer blue- colored Twinkly Star. The restoration was performed without anesthesia under relative isolation following the clinical protocol recommended by the manufacturer. As a result, it was observed that the restoration in colored Twinky Star compomer remained aesthetically and functionally satisfactory after five years. In addition, it was favorable for the child's collaboration in dental treatment. It is concluded that colored Twinky Star compomer can be a viable alternative for restoring deciduous teeth, contributing to children's dental treatment and oral care motivation.

RESUMO Em Odontopediatria, o tratamento restaurador exige um material que tenha boas propriedades mecânicas, facilidade de manipulação e de uso. Para a restauração de dentes decíduos, os compômeros coloridos são uma alternativa de material para a motivação de crianças no tratamento odontológico e consequentemente manejo de comportamento. Sabendo da necessidade de conhecer melhor os compômeros coloridos, o objetivo deste estudo foi relatar um caso de restauração com compômero colorido em molar decíduo com acompanhamento de cinco anos, bem como a motivação da criança perante o tratamento odontológico e cuidados bucais a fim de apresentar ao clínico uma alternativa a outros materiais restauradores. O plano de tratamento para este dente 75 foi remoção seletiva de tecido cariado e restauração com compômero colorido twinky star na cor azul. A restauração foi feita sem anestesia sob isolamento relativo seguindo o protocolo clínico preconizado pelo fabricante. Como resultado observou-se que a restauração em compômero Twinky Star colorido manteve-se satisfatória tanto estética quanto funcionalmente após cinco anos. Além disso, mostrou-se favorável para a colaboração da criança no tratamento odontológico. Conclui-se que o uso do compômero Twinky Star colorido pode ser uma alternativa viável para restauração de dente decíduo, contribuindo para a motivação de crianças no tratamento odontológico e cuidados bucais.

Anestesia multimodal para ressecção de tumor cerebral com monitorização eletroneurofisiológica: relato de caso / Multimodal anesthesia for brain tumor resection with electroneurophysiological monitoring: case report

Introdução: O monitoramento neurofisiológico intraoperatório (MNIO) é uma técnica valiosa, empregada durante procedimentos neurocirúrgicos complexos. Ao monitorar continuamente as vias neurais, o MNIO fornece feedback em tempo real aos cirurgiões durante o procedimento, permitindo tomada de decisões críticas e redução do risco de déficits neurológicos. O papel do anestesiologista na identificação e correção dos fatores de risco modificáveis é fundamental para a prevenção de lesões neurológicas e otimização dos resultados. Sendo assim, a compreensão das limitações do MNIO e das evidências que orientam seu uso é de fundamental importância. Objetivo: Descrever o manejo de uma anestesia multimodal, realizada em conjunto com a equipe de neurofisiologia, para ressecção de um tumor cerebral recidivante e o seu desfecho clinico. Método: Trata-se de relato de caso atendido no Hospital do Servidor Público Municipal de São Paulo. Os dados para realização deste trabalho foram coletados durante a cirurgia, sendo a coleta autorizada pelo paciente por meio da assinatura de termo de consentimento livre e esclarecido. Relato do Caso: Paciente, sexo masculino, 64 anos, ASA II, hipertenso, com história prévia de meningioma atípico, submetido a neurocirurgia e radioterapia em 2021, em uso de anticonvulsivante oral para profilaxia de crises convulsivas. Apresenta lesão tumoral cerebral recidivante em região frontal bilateral. Após a indução anestésica, foi realizada passagem de acesso venoso central em veia jugular interna direita com auxílio de ultrassonografia, monitoração da pressão arterial invasiva após cateterização de artéria radial direita, sondagem vesical de demora, termômetro esofágico, otimização do posicionamento na mesa cirúrgica, índice bispectral e Scalp Block com 20 ml de ropicavaína a 0,375%. Realizou- se manutenção da anestesia com propofol (4-6 mg/kg/h) e remifentanil (0,1 mcg/kg/min) em infusão contínua associado a dexmedetomidina (0,2-0,6 mcg/kg/h) mantendo valores do índice bispectral entre 40-60. As respostas dos potenciais evocados foram obtidas nas extremidades superiores e inferiores durante todo o procedimento pela equipe de neurofisiologia. Durante a manipulação tumoral, foi detectada queda superior a 40% do potencial evocado motor em dimídio corporal esquerdo, e emitido o alerta à equipe cirúrgica. Nenhuma outra intercorrência foi registrada durante o procedimento. Conclusões: Propofol, dexmedetomidina, lidocaína, opioides e anestésicos voláteis potentes de baixa dosagem (menos de 0,5 CAM) associado a técnicas de bloqueios periféricos, fornecem condições compatíveis com monitoramento neurofisiológico intraoperatório. O MNIO contínuo é um complemento indispensável no período perioperatório para pacientes com alto risco de desenvolver complicações neurológicas. Os anestesistas devem fornecer um meio fisiológico e anestésico estável para facilitar a interpretação significativa das mudanças de sinal e precisa orientação cirúrgica. Palavras-chave: Adjuvantes Anestésicos. Potenciais Evocados. Neurocirurgia. Monitorização Neurofisiológica Intraoperatória.

Análise espacial dos casos de COVID-19 notificados no estado da Bahia, Brasil / Spatial analysis of COVID-19 cases notified in the state of Bahia, Brazil

Resumo Introdução Estudos que utilizam georreferenciamento se mostram úteis para tomada de decisão nas ações em saúde. Objetivo Analisar a distribuição espacial de Coronavirus Disease-2019 (COVID-19) no estado da Bahia e unidades de saúde geridas pela rede. Método Estudo ecológico com análise da distribuição espacial dos casos notificados em boletins epidemiológicos da Secretária de Saúde entre 6 de março e 6 de junho de 2020. Na análise espacial foram utilizados os "I de Moran" bruto e ajustado pelo Estimador Bayesiano Global e criados mapas para visualização dos resultados. Foi realizada regressão espacial multivariável, sendo que a variável dependente esteve relacionada com os coeficientes de incidência de COVID-19, ao passo que para as independentes, identificaram-se o Índice de Desenvolvimento Humano, renda per capita, densidade demográfica, quantidade de leitos, profissionais e unidades de saúde. Resultados Foram identificados 26.823 casos em 322 municípios, totalizando 58,2% na capital; municípios com maior coeficiente de incidência foram Ipiaú (718,0), Itajuípe (678,2) e Uruçuca (638,0), em macrorregiões diversas e 42 unidades de saúde em diversos níveis de complexidade, sendo 18 na capital. Conclusão Métodos de análise espacial são evidenciados como meio essencial para compreensão da espacialização da COVID-19, sendo útil como ferramenta no planejamento das ações de prevenção e controle do COVID-19.

Abstract Background Studies using georeferencing are useful for decision-making in health actions. Objective To analyze the spatial distribution of Coronavirus Disease-2019 (COVID-19) in the state of Bahia and health units managed by the network. Method Ecological study consisted of an analysis regarding the spatial distribution of cases reported in epidemiological bulletins of the Health Secretary between March 6 and June 6, 2020. In the spatial analysis, the crude "I de Moran" was used and adjusted by the Bayesian Global Estimator and maps were created to visualize the results. Multivariate spatial regression was performed, since the dependent variable was associated with the incidence coefficients of COVID-19, whereas the independent one was related to the Human Development Index, per capita income, demographic density, number of beds, professionals and health units were dependent. Results This study could identify 26,823 cases in 322 municipalities, comprising 58.2% in the capital; i.e., municipalities with the highest incidence coefficient were Ipiaú (718.0), Itajuípe (678.2) and Uruçuca (638.0), in diverse macroregions and 42 health units at various levels of complexity, 18 in the capital. Conclusion Spatial analysis methods are evidenced as an essential tool to understand the spatialization of COVID-19, thus being useful as a tool in planning the prevention and controlling actions of COVID-19.

The influence of association between aging and reduced protein intake on some immunomodulatory aspects of bone marrow mesenchymal stem cells: an experimental study.

PURPOSE: Dietary protein deficiency is common in the elderly, compromising hematopoiesis and the immune response, and may cause a greater susceptibility to infections. Mesenchymal stem cells (MSCs) have immunomodulatory properties and are essential to hematopoiesis. Therefore, this study aimed to investigate, in an aging model subjected to malnutrition due a reduced protein intake, aspects related to the immunomodulatory capacity of MSCs. METHODS: Male C57BL/6 mice from young and elderly groups were fed with normoproteic or hypoproteic diets (12% and 2% of protein, respectively) and nutritional, biochemical and hematological parameters were evaluated. MSCs from bone marrow were isolated, characterized and their secretory parameters evaluated, along with gene expression. Additionally, the effects of aging and protein malnutrition on MSC immunomodulatory properties were assessed. RESULTS: Malnourished mice lost weight and demonstrated anemia, leukopenia, and bone marrow hypoplasia. MSCs from elderly animals from both groups showed reduced CD73 expression and higher senescence rate; also, the malnourished state affected CD73 expression in young animals. The production of IL-1ß and IL-6 by MSCs was affected by aging and malnutrition, but the IL-10 production not. Aging also increased the expression of NFκB, reducing the expression of STAT-3. However, MSCs from malnourished groups, regardless of age, showed decreased TGF-ß and PGE2 production. Evaluation of the immunomodulatory capacity of MSCs revealed that aging and malnutrition affected, mainly in lymphocytes, the production of IFN-γ and IL-10. CONCLUSION: Aging and reduced protein intake are factors that, alone or together, influence the immunomodulatory properties of MSCs and provide basic knowledge that can be further investigated to explore whether MSCs' therapeutic potential may be affected.

Direct ionizing radiation and bystander effect in mouse mesenchymal stem cells.

Purpose: This study aimed to evaluate the radiation-induced direct and bystander (BYS) responses of mesenchymal stem cells (MSCs) and to characterize these cells radiobiologically.Methods and materials: MSCs were irradiated (IR) and parameters related to DNA damage and cellular signaling were verified in a dose range from 0.5 to 15 Gy; also a transwell insert co-culture system was used to study medium-mediated BYS effects.Results: The main effects on directly IR cells were seen at doses higher than 6 Gy: induction of cell death, cell cycle arrest, upregulation of p21, and alteration of redox status. Irrespective of a specific dose, induction of micronuclei formation, H2AX phosphorylation, and decreased Akt expression also occurred. Thus, mTOR expression, cell senescence, nitric oxide generation, and calcium levels, in general were not significantly modulated by radiation. Data from the linear-quadratic model showed a high alpha/beta ratio, which is consistent with a more exponential survival curve. BYS effects from the unirradiated MSCs placed into companion wells with the directly IR cells, were not observed.Conclusions: The results can be interpreted as a positive outcome, meaning that the radiation damage is restricted to the directed IR MSCs not leading to off-target cell responses.

Low Mg content on Ti-Nb-Sn alloy when in contact with eBMMSCs promotes improvement of its biological functions.

Magnesium is a metal used in the composition of titanium alloys and imparts porosity. Due to its osteoconductive, biocompatible and biodegradable characteristics, its application in the development of biomedical materials has become attractive. This study aimed to evaluate the influence of magnesium present in porous Ti-Nb-Sn alloys, which have a low elastic modulus in adhesive, osteogenic properties and the amount of reactive intracellular oxygen species released in mesenchymal stem cells derived from bone marrow equine bone (eBMMSCs). Mechanical properties of the alloy, such as hardness, compressive strength and elastic modulus, were analyzed, as well as surface morphological characteristics through scanning electron microscopy. The evaluation of magnesium ion release was performed by atomic force spectroscopy. The biological characteristics of the alloy, when in contact with the alloy surface and with the culture medium conditioned with the alloy, were studied by SEM and optical microscopy. Confirmation of osteogenic differentiation by alizarin red and detection of ROS using a Muse® Oxidative Stress Kit based on dihydroetide (DHE). The alloy showed an elastic modulus close to cortical bone values. The hardness was close to commercial Ti grade 2, and the compressive strength was greater than the value of cortical bone. The eBMMSCs adhered to the surface of the alloy during the experimental time. Osteogenic differentiation was observed with the treatment of eBMMMSCs with conditioned medium. The eBMMSCs treated with conditioned medium decreased ROS production, indicating a possible antioxidant defense potential of magnesium release.

Evidence-based public policy making for medicines across countries: findings and implications for the future.

Aim: Global expenditure on medicines is rising up to 6% per year driven by increasing prevalence of non-communicable diseases (NCDs) and new premium priced medicines for cancer, orphan diseases and other complex areas. This is difficult to sustain without reforms. Methods: Extensive narrative review of published papers and contextualizing the findings to provide future guidance. Results: New models are being introduced to improve the managed entry of new medicines including managed entry agreements, fair pricing approaches and monitoring prescribing against agreed guidance. Multiple measures have also successfully been introduced to improve the prescribing of established medicines. This includes encouraging greater prescribing of generics and biosimilars versus originators and patented medicines in a class to conserve resources without compromising care. In addition, reducing inappropriate antibiotic utilization. Typically, multiple measures are the most effective. Conclusion: Multiple measures will be needed to attain and retain universal healthcare.

TERTp mutations and p53 expression in head and neck cutaneous basal cell carcinomas with different aggressive features.

Cutaneous basal cell carcinoma (cBCC) is an economic burden to health services, due to its great morbidity and increasing incidence in old people. Infiltrative cBCCs and cBCCs with micronodular pattern are considered as more aggressive. The role of p53 expression and TERTp mutation on cBCC behavior remains to be clarified. We aimed to assess TERTp mutations and p53 expression in relation to the cBCC histological subtype in a cohort of patients referred to an ENT Department of a tertiary Hospital of Northern Portugal. We performed a retrospective clinicopathological and histological review of the head and neck cBCCs followed-up at the otorhinolaryngology department of Trás-os-Montes e Alto Douro hospital (January 2007-June 2018). We assessed TERTp mutations in 142 cBCCs and p53 protein expression, through immunohistochemistry, in 157 cBCCs. We detected TERTp mutations in 43.7% of cBCCs and p53 overexpression in 60.5% of cBCCs. We spotted association of p53 overexpression and TERTp mutation with necrosis. In the infitrative-growth pattern cBCCs, there was no significant association with the clinical and histological features evaluated, except for necrosis. In the indolent-growth cBCCs, we identified a significant association of TERTp mutation status with female sex, necrosis, multiple cBCCs, and p53 positive expression. Our results suggest that TERTp mutation may be useful to identify more aggressive features in the indolent-growth pattern cBCCs (nodular and superficial subtypes). Further studies with larger cohorts are warranted to clarify the relevance of TERTp mutation in cBCCs.

Association between TNF-α and IFN-γ levels and severity of acute viral bronchiolitis.

Acute bronchiolitis caused by the respiratory syncytial virus triggers an inflammatory response with the production and release of several pro-inflammatory cytokines. Evidence suggests that their levels are associated with the severity of the infection. This systematic review and meta-analysis aim to assess whether the levels of TNF-α and IFN-γ are associated with the severity of acute viral bronchiolitis. We searched MEDLINE libraries (via PUBMED), EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), Scientific Electronic Library Online (SciELO), Latin American Caribbean Health Sciences Literature (LILACS), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Science, and the gray literature through April 2020. Random effect models were used for general and subgroup analysis. In total, six studies were included with a total of 744 participants. The mean TNF-α levels between the severe group did not differ from the control group 0.14 (95% CI: -0.53 to 0.82, I2 = 91%, p < 0.01); the heterogeneity was high. The results remained insignificant when the analyses were performed including only studies with high quality 0.25 (95% CI: -0.46 to 0.96, I2 = 92%, p < 0.01) I2 = 95%, p = 0.815), when TNF-α was nasal 0.60 (95% CI: -0.49 to 1.69), I2 = 94%, p < 0.01), or serum -0.08 (95% CI: -0.48 to 0.31), I2 = 29%, p = 0.24). In the analysis of studies measuring IFN-γ, there was also no significance of -0.67 (95% CI: -1.56 to 0.22, I2 = 76%, p = 0.04). In conclusion, this meta-analysis suggests that the most severe patients do not have different mean TNF-α and IFN-γ values ​than patients with mild disease, but the heterogeneity of the studies was high. Supplemental data for this article is available online at https://doi.org/10.1080/08830185.2021.1889534.

Potential approaches for the pricing of cancer medicines across Europe to enhance the sustainability of healthcare systems and the implications.

Introduction: There are growing concerns among European health authorities regarding increasing prices for new cancer medicines, prices not necessarily linked to health gain and the implications for the sustainability of their healthcare systems.Areas covered: Narrative discussion principally among payers and their advisers regarding potential approaches to the pricing of new cancer medicines.Expert opinion: A number of potential pricing approaches are discussed including minimum effectiveness levels for new cancer medicines, managed entry agreements, multicriteria decision analyses (MCDAs), differential/tiered pricing, fair pricing models, amortization models as well as de-linkage models. We are likely to see a growth in alternative pricing deliberations in view of ongoing challenges. These include the considerable number of new oncology medicines in development including new gene therapies, new oncology medicines being launched with uncertainty regarding their value, and continued high prices coupled with the extent of confidential discounts for reimbursement. However, balanced against the need for new cancer medicines. This will lead to greater scrutiny over the prices of patent oncology medicines as more standard medicines lose their patent, calls for greater transparency as well as new models including amortization models. We will be monitoring these developments.

A pandemia de COVID-19 e a saúde mental de idosos: possibilidades de atividade física por meio dos Exergames / The COVID-19 pandemic and the mental health of the elderly: possibilities of physical activity through Exergames

Este ensaio teórico foi elaborado com o objetivo de discutir sobre os reflexos da pandemia na saúde mental de idosos e a contribuição dos exergames como terapia não medicamentosa para o cuidado à saúde neste grupo em tempos de pandemia de COVID-19. Apesar de compreender que as medidas restritivas para aglomerações são estratégias importantes no controle da pandemia, o distanciamento social pode aumentar ainda mais a vulnerabilidade dos idosos, principalmente no que diz respeito ao agravamento das morbidades psíquicas. Nesse sentido, apresentar possibilidades de atividades físicas, já comprovadamente aceitas, como modalidades terapêuticas efetivas, frente a essas condições, e indicar possibilidades de movimentar-se com os exergames, contribui para o aumento do nível de atividade física e, consequentemente, para a melhoria da saúde mental dessa população

This theoretical essay was prepared with the aims to discuss the effects of the pandemic on mental health of elderly people and the contribution of exergames as non-drug therapy for health care in this group in times of the COVID-19 pandemic. Despite understanding that restrictive measures for agglomerations are important strategies in controlling the pandemic, social isolation can further increase the vulnerability of the elderly, especially the worsening of psychic morbidities. In this sense, presenting possibilities of physical activities, already proven accepted, as effective therapeutic modalities, in the face of these conditions, and indicating possibilities of moving with exergames, contributes to the increase in the level of physical activity and, consequently, to the improvement mental health of this population

Integrative Review of Managed Entry Agreements: Chances and Limitations.

BACKGROUND AND OBJECTIVE: Managed entry agreements (MEAs) consist of a set of instruments to reduce the uncertainty and the budget impact of new high-priced medicines; however, there are concerns. There is a need to critically appraise MEAs with their planned introduction in Brazil. Accordingly, the objective of this article is to identify and appraise key attributes and concerns with MEAs among payers and their advisers, with the findings providing critical considerations for Brazil and other high- and middle-income countries. METHODS: An integrative review approach was adopted. This involved a review of MEAs across countries. The review question was 'What are the health technology MEAs that have been applied around the world?' This review was supplemented with studies not retrieved in the search known to the senior-level co-authors including key South American markets. It also involved senior-level decision makers and advisers providing guidance on the potential advantages and disadvantages of MEAs and ways forward. RESULTS: Twenty-five studies were included in the review. Most MEAs included medicines (96.8%), focused on financial arrangements (43%) and included mostly antineoplastic medicines. Most countries kept key information confidential including discounts or had not published such data. Few details were found in the literature regarding South America. Our findings and inputs resulted in both advantages including reimbursement and disadvantages including concerns with data collection for outcome-based schemes. CONCLUSIONS: We are likely to see a growth in MEAs with the continual launch of new high-priced and often complex treatments, coupled with increasing demands on resources. Whilst outcome-based MEAs could be an important tool to improve access to new innovative medicines, there are critical issues to address. Comparing knowledge, experiences, and practices across countries is crucial to guide high- and middle-income countries when designing their future MEAs.

Protocolo de exercícios terapêuticos em grupo para pessoas com doença de Alzheimer / Protocol of group therapeutic exercises of people with Alzheimer's Disease

O envelhecimento gera diversas alterações biológicas que dão origens a condições de saúde como a Doença de Alzheimer (DA) que pode prejudicar a funcionalidade dos idosos. OBJETIVO: Verificar o efeito de um programa de exercícios fisioterapêuticos sobre a saúde dos idosos com DA. MÉTODOS: Foi realizado um estudo longitudinal, em idosos com DA frequentadores de um Centro-Dia. Os participantes foram selecionados por meio de características demográficos e condições de saúde. Para análise das variáveis de desfecho foram avaliados pré e pós intervenção com os testes: Timed Up and Go (TUG), Caixa e Blocos, Escala de Berg e Alcance funcional em pé e sentado. Em seguida foram submetidos a um protocolo de intervenção em grupo dividido em três fases: fase preparatória, fase ativa e fase de desaquecimento. Utilizou-se para análise estatística o Teste T-Student Pareado e a correlação de Pearson. Foi estabelecido Intervalo de Confiança (IC) e p<0,05. RESULTADOS: Foram realizadas 28 sessões com 11 idosas, com idade média de 88 (± 4) anos, frequência semanal no Centro Dia de 4 (± 1) vezes e pontuação média no MEEM de 12 (± 5). Obtiveram significância estatística no teste Alcance Sentado pré 22,3 (±10,4) e pós 28,2 (±9,0), com p = 0,003 e, no teste de TUG pré 16,9 (±5,8) e pós 2,5 (± 3,9), com p = 0,009. Além disso, o teste Berg e TUG apresentaram correlação negativa, classificada como boa p= 0,020. CONCLUSÃO: O protocolo proposto contribuiu para melhora na saúde funcional observadas no aumento do alcance funcional e da mobilidade das idosas.

Aging generates several biological changes that give rise to diseases such as Alzheimer's Disease (AD) that can result in the functionality of the elderly. OBJECTIVE: To verify the effect of a physical therapy exercise program on the health of elderly people with AD. MATERIALS AND METHODS: A longitudinal study was carried out in elderly people with AD who attended a Day Care Center. Participants were selected using demographic characteristics and health conditions. For the analysis of the outcome variables, the pre and post intervention were evaluated with the tests: Timed Up and Go (TUG), Box and Blocks, Berg Scale and Functional reach in standing and sitting. Then they underwent a group intervention protocol divided into three phases: the preparatory phase, the active phase and the cooling down phase. Paired T-Student Test and Pearson's correlation were used for statistical analysis. Confidence Interval (CI) was established and p <0.05. RESULTS: We performed 28 sessions, with 11 elderly women, mean age of 88 (± 4) years, weekly attendance at the Center on Day 4 (± 1) times and mean score on the MMSE of 12 (± 5). They obtained statistical significance in the Seated Reach test pre 22.3 (± 10.4) and post 28.2 (± 9.0), with p = 0.003 and, in the TUG test pre 16.9 (± 5.8) and powders 2.5 (± 3.9), with p = 0.009. In addition, the Berg and TUG test showed a negative correlation, classified as good p = 0.020. CONCLUSION: The proposed protocol contributed to the improvement in functional health observed in the increase in the functional range and mobility of the elderly.

Fin whale (Balaenoptera physalus) mitogenomics: A cautionary tale of defining sub-species from mitochondrial sequence monophyly.

The advent of massive parallel sequencing technologies has resulted in an increase of studies based upon complete mitochondrial genome DNA sequences that revisit the taxonomic status within and among species. Spatially distinct monophyly in such mitogenomic genealogies, i.e., the sharing of a recent common ancestor among con-specific samples collected in the same region has been viewed as evidence for subspecies. Several recent studies in cetaceans have employed this criterion to suggest subsequent intraspecific taxonomic revisions. We reason that employing intra-specific, spatially distinct monophyly at non-recombining, clonally inherited genomes is an unsatisfactory criterion for defining subspecies based upon theoretical (genetic drift) and practical (sampling effort) arguments. This point was illustrated by a re-analysis of a global mitogenomic assessment of fin whales, Balaenoptera physalus spp., published by Archer et al. (2013), which proposed to further subdivide the Northern Hemisphere fin whale subspecies, B. p. physalus. The proposed revision was based upon the detection of spatially distinct monophyly among North Atlantic and North Pacific fin whales in a genealogy based upon complete mitochondrial genome DNA sequences. The extended analysis conducted in this study (1676 mitochondrial control region, 162 complete mitochondrial genome DNA sequences and 20 microsatellite loci genotyped in 380 samples) revealed that the apparent monophyly among North Atlantic fin whales reported by Archer et al. (2013) to be due to low sample sizes. In conclusion, defining sub-species from monophyly (i.e., the absence of para- or polyphyly) can lead to erroneous conclusions due to relatively "trivial" aspects, such as sampling. Basic population genetic processes (i.e., genetic drift and migration) also affect the time to the most recent common ancestor and hence the probability that individuals in a sample are monophyletic.