Linking tumor immune infiltrate and systemic immune mediators to treatment response and prognosis in advanced cervical cancer.

Cervical cancer (CC) poses a significant burden on individuals in developing regions, exhibiting heterogeneous responses to standard chemoradiation therapy, and contributing to substantial mortality rates. Unraveling host immune dynamics holds promise for innovative therapies and discovery of clinically relevant biomarkers. We studied prospectively locally advanced CC patients pre-treatment, stratifying them as responders (R) or non-responders (NR). R patients had increased tumor-infiltrating lymphocytes (TILs), while NR patients showed elevated PD-1 scores, CD8+ and PD-L2+ TILs, and PD-L1 immune reactivity. NR patients exhibited higher systemic soluble mediators correlating with TIL immune markers. R patients demonstrated functional polarization of CD4 T cells (Th1, Th2, Th17, and Treg), while CD8+ T cells and CD68+ macrophages predominated in the NR group. Receiver operating characteristic analysis identified potential CC response predictors, including PD-L1-immunoreactive (IR) area, PD-L2, CD8, FGF-basic, IL-7, IL-8, IL-12p40, IL-15, and TNF-alpha. Dysfunctional TILs and imbalanced immune mediators contribute to therapeutic insufficiency, shedding light on local and systemic immune interplay. Our study informs immunological signatures for treatment prediction and CC prognosis.

The idiopathic inflammatory myopathies module of the Rheumatic Diseases Portuguese Register.

AIMS: To characterise the idiopathic inflammatory myopathies (IIM) module of the Rheumatic Diseases Portuguese Register (Reuma.pt/myositis) and the patients in its cohort. METHODS: Reuma.pt is a web-based system with standardised patient files gathered in a registry. This was a multicentre open cohort study, including patients registered in Reuma.pt/myositis up to January 2022. RESULTS: Reuma.pt/myositis was designed to record all relevant data in clinical practice and includes disease-specific diagnosis and classification criteria, clinical manifestations, immunological data, and disease activity scores. Two hundred eighty patients were included, 71.4% female, 89.4% Caucasian, with a median age at diagnosis and disease duration of 48.9 (33.6-59.3) and 5.3 (3.0-9.8) years. Patients were classified as having definite (N=57/118, 48.3%), likely (N=23/118, 19.5%), or possible (N=2/118, 1.7%) IIM by 2017 EULAR/ACR criteria. The most common disease subtypes were dermatomyositis (DM, N=122/280, 43.6%), polymyositis (N=59/280, 21.1%), and myositis in overlap syndromes (N=41/280, 14.6%). The most common symptoms were proximal muscle weakness (N=180/215, 83.7%) and arthralgia (N=127/249, 52.9%), and the most common clinical signs were Gottron's sign (N=75/184, 40.8%) and heliotrope rash (N=101/252, 40.1%). Organ involvement included lung (N=78/230, 33.9%) and heart (N=11/229, 4.8%) involvements. Most patients expressed myositis-specific (MSA, N=158/242, 65.3%) or myositis-associated (MAA, 112/242, 46.3%) antibodies. The most frequent were anti-SSA/SSB (N=70/231, 30.3%), anti-Jo1 (N=56/236, 23.7%), and anti-Mi2 (N=31/212, 14.6%). Most patients had a myopathic pattern on electromyogram (N=101/138, 73.2%), muscle oedema in magnetic resonance (N=33/62, 53.2%), and high CK (N=154/200, 55.0%) and aldolase levels (N=74/135, 54.8%). Cancer was found in 11/127 patients (8.7%), most commonly breast cancer (N=3/11, 27.3%). Most patients with cancer-associated myositis had DM (N=8/11, 72.7%) and expressed MSA (N=6/11) and/or MAA (N=3/11). The most used drugs were glucocorticoids (N=201/280, 71.8%), methotrexate (N=117/280, 41.8%), hydroxychloroquine (N=87/280, 31.1%), azathioprine (N=85/280, 30.4%), and mycophenolate mofetil (N=56/280, 20.0%). At the last follow-up, there was a median MMT8 of 150 (142-150), modified DAS skin of 0 (0-1), global VAS of 10 (0-50) mm, and HAQ of 0.125 (0.000-1.125). CONCLUSIONS: Reuma.pt/myositis adequately captures the main features of inflammatory myopathies' patients, depicting, in this first report, a heterogeneous population with frequent muscle, joint, skin, and lung involvements.

Association of human papillomavirus (HPV), p16, p53 and p63 expression with non-bilharzia-associated squamous cell carcinoma of the bladder and algorithm construction for histopathological grading prediction.

OBJECTIVE: To investigate the expression of human papillomavirus (HPV), p16, p53, and p63 in non-schistosomiasis-related squamous cell carcinoma of the bladder and to develop an accurate and automated tool to predict histological classification based on clinicopathological features. METHODS: Twenty-eight patients with primary bladder pure squamous cell carcinoma who underwent cystectomy or transurethral resection of bladder tumor (TURBT) for bladder cancer between January 2011 and July 2017 were evaluated. Clinical data and follow-up information were obtained from medical records. Formalin-fixed, paraffin-embedded surgical specimens were used for immunohistochemical staining for p16, p53, and p63. Human papillomavirus detection was evaluated by PCR. Statistical analysis was performed, and statistical significance was set at p<0.05. Finally, decision trees were built to classify patients' prognostic features. Leave-one-out cross-validation was used to test the generalizability of the model. RESULTS: Neither direct HPV detection nor its indirect marker (p16 protein) was identified in most cases. The absence of p16 was correlated with less aggressive histological grading (p=0.040). The positive p16 staining detection found only in pT1 and pT2 cases in our sample suggests a possible role for this tumor suppressor protein in the initial stages of bladder squamous cell carcinoma. The decision trees constructed described the relationship between clinical features, such as hematuria/dysuria, the level of tumor invasion, HPV status, lymphovascular invasion, gender, age, compromised lymph nodes, and tumor degree differentiation, with high classification accuracy. CONCLUSION: The algorithm classifier approach established decision pathways for semi-automatic tumor histological classification, laying the foundation for tailored semi-automated decision support systems for pathologists.

Assessment of calcinosis in Portuguese patients with systemic sclerosis - a multicenter study.

INTRODUCTION/OBJECTIVES: The study aims to define the clinical and subclinical calcinosis prevalence, the sensitivity of radiographed site and clinical method for its diagnosis, and the phenotype of Portuguese systemic sclerosis (SSc) patients with calcinosis. METHOD: A cross-sectional multicenter study was conducted with SSc patients fulfilling Leroy/Medsger 2001 or ACR/EULAR 2013 classification criteria, registered in the Reuma.pt. Calcinosis was assessed through clinical examination and radiographs of hands, elbows, knees, and feet. Independent parametric or non-parametric tests, multivariate logistic regression, and sensitivity calculation of radiographed site and clinical method for calcinosis detection were performed. RESULTS: We included 226 patients. Clinical calcinosis was described in 63 (28.1%) and radiological calcinosis in 91 (40.3%) patients, of which 37 (40.7%) were subclinical. The most sensitive location to detect calcinosis was the hand (74.7%). Sensitivity of the clinical method was 58.2%. Calcinosis patients were more often female (p = 0.008) and older (p < 0.001) and had more frequently longer disease duration (p < 0.001), limited SSc (p = 0.017), telangiectasia (p = 0.039), digital ulcers (p = 0.001), esophageal (p < 0.001) and intestinal (p = 0.003) involvements, osteoporosis (p = 0.028), and late capillaroscopic pattern (p < 0.001). In multivariate analysis, digital ulcers (OR 2.63, 95% CI 1.02-6.78, p = 0.045) predicted overall calcinosis, esophageal involvement (OR 3.52, 95% CI 1.28-9.67, p = 0.015) and osteoporosis (OR 4.1, 95% CI 1.2-14.2, p = 0.027) predicted hand calcinosis, and late capillaroscopic pattern (OR 7.6, 95% CI 1.7-34.9, p = 0.009) predicted knee calcinosis. Anti-nuclear antibody positivity was associated with less knee calcinosis (OR 0.021, 95% CI 0.001-0477, p = 0.015). CONCLUSIONS: Subclinical calcinosis high prevalence suggests that calcinosis is underdiagnosed and radiographic screening might be relevant. Multifactorial pathogenesis may explain calcinosis predictors' variability. Key Points • Prevalence of subclinical calcinosis in SSc patients is substantial. • Hand radiographs are more sensitive to detect calcinosis than other locations or clinical method. • Digital ulcers were associated with overall calcinosis, esophageal involvement and osteoporosis were associated with hand calcinosis, and late sclerodermic pattern in nailfold capillaroscopy was associated with knee calcinosis. • Anti-nuclear antibody positivity may be a protective factor for knee calcinosis.

Interaction of a Homologous Series of Amphiphiles with P-glycoprotein in a Membrane Environment-Contributions of Polar and Non-Polar Interactions.

The transport of drugs by efflux transporters in biomembranes limits their bioavailability and is a major determinant of drug resistance development by cancer cells and pathogens. A large number of chemically dissimilar drugs are transported, and despite extensive studies, the molecular determinants of substrate specificity are still not well understood. In this work, we explore the role of polar and non-polar interactions on the interaction of a homologous series of fluorescent amphiphiles with the efflux transporter P-glycoprotein. The interaction of the amphiphiles with P-glycoprotein is evaluated through effects on ATPase activity, efficiency in inhibition of [125I]-IAAP binding, and partition to the whole native membranes containing the transporter. The results were complemented with partition to model membranes with a representative lipid composition, and details on the interactions established were obtained from MD simulations. We show that when the total concentration of amphiphile is considered, the binding parameters obtained are apparent and do not reflect the affinity for P-gp. A new formalism is proposed that includes sequestration of the amphiphiles in the lipid bilayer and the possible binding of several molecules in P-gp's substrate-binding pocket. The intrinsic binding affinity thus obtained is essentially independent of amphiphile hydrophobicity, highlighting the importance of polar interactions. An increase in the lipophilicity and amphiphilicity led to a more efficient association with the lipid bilayer, which maintains the non-polar groups of the amphiphiles in the bilayer, while the polar groups interact with P-gp's binding pocket. The presence of several amphiphiles in this orientation is proposed as a mechanism for inhibition of P-pg function.

Whole bone subcutaneous transplantation as a strategy to study precisely the bone marrow niche.

Hematopoietic stem cells are maintained in a specialized microenvironment, known as the 'niche', within the bone marrow. Understanding the contribution of cellular and molecular components within the bone marrow niche for the maintenance of hematopoietic stem cells is crucial for the success of therapeutic applications. So far, the roles of crucial mechanisms within the bone marrow niche have been explored in transgenic animals in which genetic modifications are ubiquitously introduced in the whole body. The lack of precise tools to explore genetic alterations exclusively within the bone marrow prevents our determination of whether the observed outcomes result from confounding effects from other organs. Here, we developed a new method - 'whole bone subcutaneous transplantation'- to study the bone marrow niche in transgenic animals precisely. Using immunolabeling of CD45.1 (donor) vs. CD45.2 (recipient) hematopoeitic stem cells, we demonstrated that hematopoeitic stem cells from the host animals colonize the subcutaneously transplanted femurs after transplantation, while the hematopoietic stem cells from the donor disappear. Strikinlgy, the bone marrow niche of these subcutaneously transplanted femurs remain from the donor mice, enabling us to study specifically cells of the bone marrow niche using this model. We also showed that genetic ablation of peri-arteriolar cells specifically in donor femurs reduced the numbers of hematopoietic stem cells in these bones. This supports the use of this strategy as a model, in combination with genetic tools, to evaluate how bone marrow niche specific modifications may impact non-modified hematopoietic stem cells. Thus, this approach can be utilized for genetic manipulation in vivo of specific cell types only within the bone marrow. The combination of whole bone subcutaneous transplantation with rodent transgenic models will facilitate a more precise, complex and comprehensive understanding of existing problems in the study of the hematopoietic stem cell bone marrow niche.

Impairment of adenosine signaling disrupts early embryo development: unveiling the underlying mechanisms.

Purinergic signaling has been implicated in many biological functions, including development. In this study, we investigate the functions of extracellular adenosine and adenosine receptors using a mouse embryonic stem cell (ESC) line and morula stages isolated from mouse embryos. Feeder-free mouse ESC was investigated in the absence and presence of the leukemia inhibitory factor (LIF), configuring undifferentiated cells and cells undergoing spontaneous differentiation. High alkaline phosphatase (ALPL) and low CD73 levels resulting in low adenosine (eADO) levels were characteristic for pluripotent cells in the presence of the LIF, while LIF deprivation resulted in augmented adenosine levels and reduced pluripotency marker expression, which indicated differentiation. Tracing ESC proliferation by BrdU labeling revealed that the inhibition of ALPL by levamisole resulted in a decrease in proliferation due to less eADO accumulation. Furthermore, caffeine and levamisole treatment, inhibiting adenosine receptor and eADO accumulation, respectively, reduced ESC migration, similar to that observed in the absence of the LIF. Pharmacological approaches of selective adenosine receptor subtype inhibition triggered specific adenosine receptor activities, thus triggering calcium or MAP kinase pathways leading to differentiation. In line with the in vitro data, mouse embryos at the morula stage were sensitive to treatments with A1 and A3 receptor antagonists, leading to the conclusion that A1 receptor and A3 receptor inhibition impairs proliferation and self-renewal and triggers inappropriate differentiation, respectively. The findings herein define the functions of eADO signaling in early development with implications for developmental disorders, in which adenosine receptors or ectonucleotidase dysfunctions are involved, and which could lead to malformations and miscarriages, due to exposure to caffeine.

Association of human papillomavirus (HPV), p16, p53 and p63 expression with non-bilharzia-associated squamous cell carcinoma of the bladder and algorithm construction for histopathological grading prediction

ABSTRACT Objective To investigate the expression of human papillomavirus (HPV), p16, p53, and p63 in non-schistosomiasis-related squamous cell carcinoma of the bladder and to develop an accurate and automated tool to predict histological classification based on clinicopathological features. Methods Twenty-eight patients with primary bladder pure squamous cell carcinoma who underwent cystectomy or transurethral resection of bladder tumor (TURBT) for bladder cancer between January 2011 and July 2017 were evaluated. Clinical data and follow-up information were obtained from medical records. Formalin-fixed, paraffin-embedded surgical specimens were used for immunohistochemical staining for p16, p53, and p63. Human papillomavirus detection was evaluated by PCR. Statistical analysis was performed, and statistical significance was set at p<0.05. Finally, decision trees were built to classify patients' prognostic features. Leave-one-out cross-validation was used to test the generalizability of the model. Results Neither direct HPV detection nor its indirect marker (p16 protein) was identified in most cases. The absence of p16 was correlated with less aggressive histological grading (p=0.040). The positive p16 staining detection found only in pT1 and pT2 cases in our sample suggests a possible role for this tumor suppressor protein in the initial stages of bladder squamous cell carcinoma. The decision trees constructed described the relationship between clinical features, such as hematuria/dysuria, the level of tumor invasion, HPV status, lymphovascular invasion, gender, age, compromised lymph nodes, and tumor degree differentiation, with high classification accuracy. Conclusion The algorithm classifier approach established decision pathways for semi-automatic tumor histological classification, laying the foundation for tailored semi-automated decision support systems for pathologists.

Fundação, implementação, consolidação e ações de uma liga acadêmica interdisciplinar de gerontologia / Foundation, implementation, consolidation and actions of an interdisciplinary academic league of gerontology

Objetivo: relatar a experiência sobre a fundação, implementação, consolidação e ações de uma liga acadêmica interdisciplinar de gerontologia. Método: relato de experiência construído durante os meses de abril a maio de 2022 acerca da história e trajetória da Liga Acadêmica Interdisciplinar de Gerontologia da URI Santiago. Os dados que embasaram a escrita do relato de experiência foram extraídos do livro ata da Liga e das verbalizações dos integrantes. Resultados: fundar, implementar e consolidar uma Liga em tempos pandêmicos ascendeu uma maior responsabilidade na escolha da fundamentação teórica; fontes seguras para seleção; e na diversidade de conteúdos (complexidade do envelhecimento), em atenção às questões econômicas, sociais, culturais e de gênero que possuem relação direta com a saúde e a longevidade, sem esquecer da inclusão social (acesso e acessibilidade à tecnologia digital, literacia em saúde, territórios vulneráveis, condições individuais e familiares dos idosos). Conclusão: as atividades realizadas durante o percurso inicial da Liga, além de proporcionar aos discentes a autonomia em atuar de forma prática no contexto da gerontologia, despertou outros membros da comunidade acadêmica para o trabalho interdisciplinar e de engajamento.

Eficácia in sílico do florfenicol no tratamento de pododermatite infecciosa por Fusobacterium necrophorum em ovelhas / In sílico efficacy of florfenicol in the treatment of Fusobacterium necrophorum infectious pododermatitis in sheep

Objetivou-se comparar o efeito in silico do florfenicol nas doses de 20 e 30 mg/Kg em ovinos pelas vias intravenosa (IV) e intramuscular (IM), usando a modelagem PK/PD. Realizou-se uma simulação de Monte Carlo com base nos dados de concentração plasmática de um estudo publicado anteriormente. Calculou-se a área sob a curva (ASC) e as taxas de eficácia do florfenicol para os efeitos bacteriostático, bactericida e de erradicação bacteriológica. A dose de 20 mg/Kg IV demonstrou efeitos de erradicação de 100, 93 e 0% para CIM de 0,5, 1 e acima, respectivamente. O efeito bacteriostático foi de 99 e 90% para CIM de 4 e 2 µg/ml, enquanto o bactericida foi de 14% para CIM de 2 µg/ml. A dose de 30 mg/Kg IV apresentou 100% de erradicação para CIM de 1 µg/mL e 100% de efeito bactericida para CIM de 2 µg/mL. Há 100% de efeito bacteriostático em CIM de 4 µg/ml. As doses de 20 e 30 mg/Kg IM mostraram 100% de erradicação para CIM até 1 µg/mL e 0% para CIM maiores. O efeito bacteriostático foi mantido em 100% para uma CIM de 4 µg/mL em ambas as doses. Este estudo mostra o efeito de erradicação bacteriológica do florfenicol nas doses de 20 e 30 mg/Kg, IV e IM. Recomenda-se que seja feito um estudo de eficácia in vivo com a dose de 30mg/Kg IM em ovinos infectados por F. necrophorum com MIC superior a 2 µg/mL.

We aimed to compare the in silico effect of florfenicol at doses of 20 and 30 mg/Kg in sheep by intravenous (IV) and intramuscular (IM) routes, using PK/PD modeling. We performed a Monte Carlo simulation based on plasma concentration data from a previously published study. We calculated the area under the curve (AUC) and the efficacy rates of florfenicol to bacteriostatic, bactericidal, and bacteriological eradication effects. The dose of 20 mg/Kg IV demonstrated 100, 93, and 0% eradication effects for MICs of 0.5, 1, and above, respectively. The bacteriostatic effect was 99 and 90% for MIC of 4 and 2 µg/ml, while the bactericide was 14% for MIC of 2 µg/ml. The 30 mg/Kg IV dose showed 100% eradication for MIC of 1 µg/mL and 100% bactericidal effect for MIC of 2 µg/mL. There is a 100% of bacteriostatic effect at MIC of 4 µg/ml. Doses of 20 and 30 mg/Kg IM showed 100% eradication for MIC up to 1 µg/mL and 0% for MIC above. The bacteriostatic effect was maintained at 100% for a MIC of 4 µg/mL at both doses. This study shows the bacteriological eradication effect of florfenicol at doses of 20 and 30 mg/Kg, IV, and IM. Therefore, we recommend an in vivo efficacy study with a dose of 30mg/Kg IM in sheep infected with F. necrophorum with MIC greater than two µg/mL.

Clinical characterisation of a multicentre nationwide cohort of patients with antisynthetase syndrome.

BACKGROUND: Antisynthetase syndrome (ASyS) is characterised by the association of inflammatory myopathy, interstitial lung disease (ILD), arthritis, Raynaud's phenomenon (RP) or mechanic's hands (MH), with the presence of anti-aminoacyl-tRNA-synthetase antibodies (anti-ARS). It has been suggested that different anti-ARS may be associated with distinct clinical pictures. OBJECTIVE: To characterise the clinical and immunological features of a multicentric nationwide cohort of ASyS patients. METHODS: This is a multicentre retrospective cohort study including patients with ASyS from nine Portuguese rheumatology centres. Data on patients' demographics, signs and symptoms, laboratory results, pulmonary imaging findings and treatment with immunomodulators were collected. Comparison between patients with different anti-ARS antibodies was made using the Chi-square test for categorical variables and Student's t-test or Man-Whitney test for continuous variables, considering anti-Jo1 positive patients as the reference group. RESULTS: Seventy patients were included (70% female) with a median age in years at disease onset of 52 (15-75) years and median follow-up time of 3 years (range 0-32). The three most common clinical manifestations were ILD (n=53, 75.7%), followed by arthritis (n=43, 61.4%) and myositis (n=37, 52.9%). Forty-three patients were positive for anti-Jo1 (61.4%), 11 for anti-PL12 (15.7%), 10 for anti-PL7 (14.3%), 4 for anti-EJ (5.7%), and 2 for anti-OJ (2.9%) antibodies. Antibody co-positivity with anti-Ro52 antibodies was found in 15 patients (21.4%) and was more prevalent in anti-Jo1 patients. ILD prevalence was similar in the different anti-ARS subgroups, without statistically significant differences. Patients positive for anti-PL7 antibodies had significantly lower risk of presenting arthritis (p =< 0.05) and those positive for anti-PL-12 antibodies had a significantly lower risk of presenting myositis than the reference group of anti-Jo1 positive patients (p =< 0.05). RP was more frequently found in patients positive for anti-PL-12 than in anti-Jo1-positive patients (p =< 0.05). Malignancies were reported in four (5.7%) patients, none of whom were anti-Ro52-positive, and one of such patients had a double malignancy. Only three deaths were reported. Corticosteroids were the most frequently prescribed therapy and the use of immunosuppressive drugs was decided according to the type of predominant clinical manifestation. CONCLUSION: The three most common clinical manifestations were ILD, followed by arthritis and myositis. Patients positive for anti-PL7 antibodies had significantly lower risk of presenting arthritis and those positive for anti-PL-12 antibodies had a significantly lower risk of presenting myositis than the reference group of anti-Jo1 positive patients. RP was more frequently found in patients positive for anti-PL-12 than in anti-Jo1-positive patients. Corticosteroids were the most frequently prescribed therapy. These results are generally concordant with data retrieved from international cohorts.

Gender differences in clinical features and outcomes of a Portuguese systemic sclerosis cohort.

Evidence for the role of sex in the clinical manifestations of systemic sclerosis (SSc) patients is emerging. Some multicenter cohorts have shown that male SSc patients have more severe disease and worse survival. To assess the differences in clinical manifestations and survival in Portuguese SSc patients according to gender. Data from male and female adult SSc patients included in the Rheumatic Diseases Portuguese Register (Reuma.pt) were analysed and compared. Survival was calculated for patients included in Reuma.pt. within the first two years of diagnosis (inception cohort). In total, 1054 adult patients with SSc were included, 12.5% males. No differences in demographic features and comorbidities were found between the sexes, except for a higher rate of cigarette smokers among men. Diffuse cutaneous SSc and anti-topoisomerase antibodies were more prevalent in males than females. Additionally, male patients presented significantly more myositis, interstitial lung disease and gastric involvement. There were no differences in the patterns of drug use between the sexes. During follow-up, more deaths were reported in men than women (12.1% vs 7.3%, p = 0.04). The overall 1-, 3-, and 5-year survivals from diagnosis of the inception cohort (N = 469) for men vs women were 96.4% vs 98.2%, 93% vs 95.9%, and 75.8% vs 93.2%, respectively, with statistically significant differences (p < 0.01). This study confirms the existence of gender differences in clinical and immunological SSc features. Although SSc is less common in men than women, men have a more severe expression of skin and internal organ involvement and worse survival. Key Points • There are differences in SSc disease manifestations between sexes. • Males more commonly have diffuse cutaneous SSc, anti-topoisomerase antibodies, pulmonary and musculoskeletal involvement. • In the inception cohort, men had worse survival rates than women.

Quedas em idosos comunitários atendidos por uma estratégia de saúde da família do município de São Leopoldo: prevalência e fatores associados / Falls in community dwelling elderly assisted by a family health strategy in the municipality of São Leopoldo: prevalence and associated factors

Idosos ocupam espaço significativo em nossa sociedade gerando uma modificação na estrutura de gastos em diversas áreas. Um dos fatores que mais colaboram para gastos em saúde é a queda acidental/recorrente, evento responsável por altas taxas de mortalidade e desenvolvimento de morbidades na terceira idade. Objetivo: Identificar a prevalência de quedas em idosos e realizar um rastreio epidemiológico dos fatores de risco encontrados nesta faixa etária. Método: Trata-se de estudo observacional do tipo descritivo transversal realizado com idosos pertencentes a uma Estratégia de Saúde da Família de São Leopoldo/RS, entre fevereiro e março de 2020. A coleta de dados se deu através de cinco instrumentos: questionário de histórico de quedas; Timed Up & Go (TUG); Teste de Alcance Funcional (TAF); Dinamometria de Preensão Palmar (DPP); e Mini Exame do Estado Mental (MEEM). Para análise de dados, utilizou-se teste QuiQuadrado de Pearson, resíduos ajustados e Odds Ratio. Resultados: Amostra foi composta por 125 idosos comunitários, 66,4% do sexo feminino e com média de idade de 70,39±6,56 anos. Mais da metade sofreu queda no último ano, sendo as de tipo recorrentes as mais prevalentes (61,6%) e 53,4% destes fraturaram algum osso como resultado da queda. O histórico de quedas demonstrou associação positiva (p<0,05) ao sexo feminino, faixa etária mais elevada, viuvez, viver sozinho, polimedicação, medo de cair, ao TAF e à DPP. Conclusão: Idosos comunitários apresentam alta prevalência de quedas e diversos fatores causais associados. Reconhece-se a importância de uma avaliação multidimensional para rastrear os riscos e identificar idosos mais suscetíveis.

Elderly are a significant portion of our society, causing a change in expenses in many fields. One of the factors that collaborate the most for health expenses is the accidental/recurrent fall, responsible event for high mortality rate and the development of morbidity in the third age. Objective: Identify the prevalence of falls in elderly and make an epidemiologic tracing of the risk factors present in that age group. Method: This is an observational and cross-sectional descriptive study carried with elderly people of ESF of São Leopoldo/RS, in the period between February and March of 2020. The data collection was held by five instruments: questionnaire about falls history; Timed Up & Go (TUG); Functional Reach Teste (FRT); Handgrip Dinamometry (HGD); and Mini-Mental State Examination (MMSE). For the data analysis, the Qui-Square test, adjusted residual and Odds Ratio was used. Results: The sample consisted of 125 community elderly, 66,4% of the female sex and at the average age of 70,39±6,56 years old. More than half of them have felt in the last year, being the ones of recurrent kind the most prevalent (61,6%) and 53,4% had broken a bone because of it. The history of falls demonstrated positive association (p<0,05) to the female sex, higher group age, widowhood, living alone, polypharmacy, fear of falling, to the FRT and HGD. Conclusion: Community elderly present a high prevalence rate of falls and various causes of it. It is important to recognize the importance of a multidimensional assessment to trace the risks and to identify the more susceptible seniors to falling.

Effect of the Brazilian Cardioprotective Nutritional Program on the Quality of Life of Atherosclerotic Disease Patients

Abstract Background Cardiovascular diseases (CVD) accounted for 27% of deaths in Brazil in 2017. Most of the recorded deaths caused by CVD would be preventable if patients controlled risk factors including inadequate diet. The Brazilian Cardioprotective Nutritional Program (Dica Br) adapted the Mediterranean diet pattern to Brazilian typical foods and evaluated the effectiveness of a nutritional program based on cardioprotective foods on cardiovascular events and death of patients with cardiovascular diseases. Objectives To evaluate the effect of Dica Br on the QoL of patients with atherosclerotic disease from two health centers in the city of Rio de Janeiro. Method Randomized clinical trial with 273 participants of both sexes, over 45 years old, followed for four years. The intervention group (IG) received individualized dietary prescription, educational program, individual and group consultations, and phone calls. The control group (CG) received general dietary guidance. The SF-36 was used to assess QoL. The Student's t-test and the Mann-Whitney test was used to compare means between the groups. The mixed model test was used to compare the course of variables over time between the groups. Statistical significance was set at 5%. Result Most patients were male, with an average age of 64.2 ± 8.2 years in the IG and 65±9.5 years in the CG. Most were physically inactive, overweight, and had incomplete elementary school. The most prevalent comorbidity was systemic arterial hypertension, followed by dyslipidemia. QoL improved in both groups at four years. Waist circumference decreased in both groups over time, and low-density lipoprotein cholesterol (LDL-C) levels decreased in the IG but not in the CG after four years of follow-up. Conclusion The cardioprotective diet was effective in reducing LDL-C in the IG, and an improvement in QoL was observed in both intervention and control groups.

Distúrbios do sono e estados de humor em pilotos civis / Sleep disorders and mood states in civilian pilots

Distúrbios do sono e as alterações do estado de humor, quando não tratados, estão associados à perda de produtividade e acidentes de trabalho, resultando em lesões e fatalidade. Esses distúrbios são subdiagnosticados e subtratados em contextos clínicos, porque podem ser assintomáticos e o exame de polissonografia tem custo elevado. Por isso, questionários são usados para realizar uma triagem e detectar profissionais com alto risco de síndrome da apneia obstrutiva do sono, de sonolência diurna excessiva e fadiga. Este estudo teve como objetivo aplicar questionários validados para triagem dos distúrbios do sono e do humor em pilotos civis e analisar os resultados obtidos com a aplicação desses instrumentos. Foram coletados dados de 44 pilotos civis por meio de quatro instrumentos: um questionário para a caracterização sociodemográfica e ocupacional da amostra, a Escala de Sonolência de Epworth para avaliar a presença de sonolência diurna excessiva, o Questionário de Berlim para avaliar a Síndrome da Apneia Obstrutiva do Sono e a Escala de Humor de Brunel para avaliar o estado de humor. A Escala de Sonolência de Epworth mostrou que 25% dos pilotos apresentaram pontuação para sonolência diurna excessiva. De acordo com o Questionário de Berlim, 29,5% apresentaram alto risco para a Síndrome da Apneia Obstrutiva do Sono e pela Escala de Humor de Brunel, o domínio vigor, teve a média mais alta (5,09 ±4,06). Portanto, a utilização dos questionários nos exames de admissão e nos periódicos, pode auxiliar na identificação precoce e no monitoramento de distúrbios do sono e dos estados de humor ao longo do tempo em pilotos civis, priorizando aqueles que deverão ser encaminhados para realizarem estudos do sono.

Sleep disorders and mood state changes, when untreated, are associated with loss of productivity and accidents at work, resulting in injuries and fatality. These disorders are underdiagnosed and undertreated in clinical contexts due to them being asymptomatic and the prohibitive cost of polysomnography exams. For this reason, questionnaires are used to screen and detect professionals at high risk for obstructive sleep apnea syndrome, excessive daytime sleepiness, and fatigue. This study aimed at applying validated questionnaires for screening sleep and mood disorders in civilian pilots and analyzing the results obtained with the application of these instruments. Data were collected from 44 civilian pilots using four instruments: a questionnaire for sociodemographic and occupational characterization of the sample; the Epworth Sleepiness Scale to assess the presence of excessive daytime sleepiness; the Berlin Questionnaire to assess Obstructive Sleep Apnea Syndrome; and the Brunel Mood Scale to assess the mood state. The Epworth Sleepiness Scale showed that 25% of the pilots presented scores for excessive daytime sleepiness. According to the Berlin Questionnaire, 29.5% were at high risk for Obstructive Sleep Apnea Syndrome, and according to the Brunel Mood Scale, the vigor domain presented the highest mean (5.09 ± 4.06). Therefore, the use of questionnaires in admission and periodic exams can assist in the early identification and monitoring of sleep disorders and mood states over time in civilian pilots, prioritizing those who should be referred to sleep studies.

Gastric Adenocarcinoma Presenting as a Rheumatoid Factor and Anti-cyclic Citrullinated Protein Antibody-Positive Polyarthritis: A Case Report and Review of Literature.

A 64-year-old male presented with a 6-month history of symmetric polyarthritis involving proximal interphalangeal joints and metacarpophalangeal joints of the hands, wrists, and ankles. Associated symptoms included vomiting, progressive fatigue, and weight loss. Laboratory results showed microcytic anemia, leukocytosis, thrombocytosis, elevated C-reactive protein and erythrocyte sedimentation rate, and rheumatoid factor (RF) and anti-cyclic citrullinated protein (ACPA) antibody positivity. Joints radiographs were normal, without erosions. Upper endoscopy and gastric endoscopic ultrasonography showed a gastric adenocarcinoma with lymphatic involvement. Intraoperatively, peritoneal carcinomatosis was documented, and the patient started palliative chemotherapy. A paraneoplastic seropositive arthritis was assumed, and treatment with low-dose prednisolone and hydroxychloroquine was started. Arthritis remission was achieved and sustained up to 18 months of follow-up, although gastric cancer progression was documented. We describe a unique phenotype of paraneoplastic arthritis (PA) presenting as a seropositive (RF and ACPA positivity) rheumatoid arthritis (RA) with a good response to both low dose corticosteroids and hydroxychloroquine therapy. We also review the literature of PA, mostly the RA-like pattern, and the association between PA and ACPA positivity. This case highlights the importance of considering underlying cancer in elderly male patients, presenting with polyarthritis and systemic symptoms, even in those with ACPA-positive RA-like arthritis.

Cervical Cancer Stem-Like Cell Transcriptome Profiles Predict Response to Chemoradiotherapy.

Cervical cancer (CC) represents a major global health issue, particularly impacting women from resource constrained regions worldwide. Treatment refractoriness to standard chemoradiotheraphy has identified cancer stem cells as critical coordinators behind the biological mechanisms of resistance, contributing to CC recurrence. In this work, we evaluated differential gene expression in cervical cancer stem-like cells (CCSC) as biomarkers related to intrinsic chemoradioresistance in CC. A total of 31 patients with locally advanced CC and referred to Mário Penna Institute (Belo Horizonte, Brazil) from August 2017 to May 2018 were recruited for the study. Fluorescence-activated cell sorting was used to enrich CD34+/CD45- CCSC from tumor biopsies. Transcriptome was performed using ultra-low input RNA sequencing and differentially expressed genes (DEGs) using Log2 fold differences and adjusted p-value < 0.05 were determined. The analysis returned 1050 DEGs when comparing the Non-Responder (NR) (n=10) and Responder (R) (n=21) groups to chemoradiotherapy. These included a wide-ranging pattern of underexpressed coding genes in the NR vs. R patients and a panel of lncRNAs and miRNAs with implications for CC tumorigenesis. A panel of biomarkers was selected using the rank-based AUC (Area Under the ROC Curve) and pAUC (partial AUC) measurements for diagnostic sensitivity and specificity. Genes overlapping between the 21 highest AUC and pAUC loci revealed seven genes with a strong capacity for identifying NR vs. R patients (ILF2, RBM22P2, ACO16722.1, AL360175.1 and AC092354.1), of which four also returned significant survival Hazard Ratios. This study identifies DEG signatures that provide potential biomarkers in CC prognosis and treatment outcome, as well as identifies potential alternative targets for cancer therapy.

ATP and spontaneous calcium oscillations control neural stem cell fate determination in Huntington's disease: a novel approach for cell clock research.

Calcium, the most versatile second messenger, regulates essential biology including crucial cellular events in embryogenesis. We investigated impacts of calcium channels and purinoceptors on neuronal differentiation of normal mouse embryonic stem cells (ESCs), with outcomes being compared to those of in vitro models of Huntington's disease (HD). Intracellular calcium oscillations tracked via real-time fluorescence and luminescence microscopy revealed a significant correlation between calcium transient activity and rhythmic proneuronal transcription factor expression in ESCs stably expressing ASCL-1 or neurogenin-2 promoters fused to luciferase reporter genes. We uncovered that pharmacological manipulation of L-type voltage-gated calcium channels (VGCCs) and purinoceptors induced a two-step process of neuronal differentiation. Specifically, L-type calcium channel-mediated augmentation of spike-like calcium oscillations first promoted stable expression of ASCL-1 in differentiating ESCs, which following P2Y2 purinoceptor activation matured into GABAergic neurons. By contrast, there was neither spike-like calcium oscillations nor responsive P2Y2 receptors in HD-modeling stem cells in vitro. The data shed new light on mechanisms underlying neurogenesis of inhibitory neurons. Moreover, our approach may be tailored to identify pathogenic triggers of other developmental neurological disorders for devising targeted therapies.

Equações brasileiras: força muscular inspiratória / Ecuaciones brasileñas: fuerza muscular inspiratoria / Brazilian equations: inspiratory muscle force

RESUMO A força dos músculos respiratórios (FMR) - pressão inspiratória máxima [PImáx] e pressão expiratória máxima [PEmáx] - apresentam variação quando estimadas por equações de predição. O objetivo deste estudo foi verificar se a classificação da PImáx obtida pelas equações de predição propostas por autores brasileiros é semelhante e concordante. A amostra foi constituída por 18 pacientes estáveis com disfunções cardiorrespiratória, neurológica e fraqueza muscular respiratória. A PImáx foi medida pelo manovacuômetro analógico e comparada com as equações de predição de autores brasileiros. Apenas dois autores detectaram fraqueza muscular inspiratória (p<0,0001). Ao avaliar a concordância entre autores (Bias), verificou-se baixa concordância entre os valores preditos pelas equações, exceto entre os autores que detectaram fraqueza muscular inspiratória nos pacientes avaliados.

RESUMEN La fuerza muscular respiratoria (MRF) (presión inspiratoria máxima [MMAX] y presión espiratoria máxima [Mepmax]) varían cuando se estima por ecuaciones de predicción. El objetivo de este estudio era verificar si la clasificación del MIP obtenida por las ecuaciones de predicción propuestas por los autores brasileños es similar y concordante. La muestra consistió en 18 pacientes estables con debilidad cardiorrespiratoria, neurológica y muscular respiratoria. Mmax fue medido por el manovacuómetro analógico y comparado con las ecuaciones de predicción de autores brasileños. Solo dos autores debilidad muscular inspiradora (p<0.0001). Al evaluar la concordancia entre los autores (Bias), hubo una baja concordancia entre los valores predichos por las ecuaciones a excepción de los autores que detectaron debilidad de los músculos inspiratorios en los pacientes evaluados.

ABSTRACT Respiratory muscle strength (RMS) (maximal inspiratory pressure [MIP] and maximal expiratory pressure [MEP]) vary when estimated by prediction equations. This study will verify whether the classification of MIP obtained by the prediction equations proposed by Brazilian authors is similar and concordant. The sample consisted of 18 stable patients with cardiorespiratory and neurological dysfunctions and respiratory muscle weakness. The MIP was measured by the analog compound gauge and compared to the prediction equations of Brazilian authors. Only two authors found inspiratory muscle weakness (p<0.0001). Assessing the agreement among authors (BIAS), there was a low agreement between the values predicted by the equations, except among the authors who detected inspiratory muscle weakness in the evaluated patients.