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O surgimento das tecnologias digitais marcou o século XXI com a era da informação e da globalização; entre essas tecnologias, dois dispositivos se destacaram e se tornaram indispensáveis na rotina moderna: o celular e o fone de ouvido. Com a popularidade desses aparelhos no Brasil, muitas pessoas passaram a utilizá-los constantemente, levando-os a diversos ambientes, incluindo locais de alto risco de propagação microbiológica. Diante desse cenário, este trabalho tem como objetivo investigar os micro-organismos patogênicos presentes em aparelhos celulares e fones ouvido por meio de uma revisão integrativa da literatura, analisar a virulência dos micro-organismos identificados, determinando sua capacidade de causar doenças em humanos e avaliar o melhor método de higienização para remoção dos patógenos nas superfícies dos dispositivos eletrônicos. Para a metodologia, foi utilizado como base bibliográfica artigos científicos disponíveis em bancos de dados online como Google Acadêmico, LILACS, MEDLINE e SciElo, estes se encontravam nas línguas portuguesa, espanhola e inglesa. Com a análise dos 15 artigos selecionados foi possível identificar uma variedade de bactérias Gram-positivas, Gram-negativas e fungos patogênicos presentes na superfície dos aparelhos celulares e fones de ouvido, destacando o Staphylococcus aureus como um patógeno recorrente, encontrado em 80% dos trabalhos analisados, além da presença de bactérias da família das enterobactérias em 27% dos artigos, como a Escherichia sp e a Klebsiella sp, que são bactérias normalmente encontradas no trato gastrointestinal humano. Ademais, 60% das pesquisas também identificaram a presença de fungos como Candida sp e 14% encontraram Aspergillus sp, que têm o potencial de causar infecções em diversas partes do corpo, incluindo a pele, unhas e ouvidos. Para higienização, é recomendado o uso do álcool 70%, por ser um dos métodos mais simples e eficazes na realização da limpeza dos aparelhos. Dessa forma, é possível concluir a importância de pesquisas e conscientização contínuas para proteger a saúde pública no contexto tecnológico atual, visto que, foi possível perceber o nível de micro-organismos presente nos dispositivos. No entanto, faz-se necessário pesquisas futuras que investiguem a resistência microbiana em dispositivos eletrônicos ao longo do tempo para o desenvolvimento de medidas de higienização mais eficazes e uma compreensão completa dos riscos potenciais à saúde associados ao uso dos aparelhos celulares e fones de ouvido.

Objective: This study aims to evaluate the response to and surgical benefits of neoadjuvant endocrine therapy (NET) in ER+/HER2-breast cancer patients who are clinically high risk, but genomic low risk according to the 70-gene signature (MammaPrint). Methods: Patients with ER+/HER2-invasive breast cancer with a clinical high risk according to MINDACT, who had a genomic low risk according to the 70-gene signature and were treated with NET between 2015 and 2023 in our center, were retrospectively analyzed. RECIST 1.1 criteria were used to assess radiological response using MRI or ultrasound. Surgical specimens were evaluated to assess pathological response. Two breast cancer surgeons independently scored the eligibility of breast conserving therapy (BCS) pre- and post- NET. Results: Of 72 included patients, 23 were premenopausal (100% started with tamoxifen of which 4 also received OFS) and 49 were postmenopausal (98% started with an aromatase inhibitor). Overall, 8 (11%) showed radiological complete response. Only 1 (1.4%) patient had a pathological complete response (RCB-0) and 68 (94.4%) had a pathological partial response (RCB-1 or RCB-2). Among the 26 patients initially considered for mastectomy, 14 (53.8%) underwent successful BCS. In all 20 clinical node-positive patients, a marked axillary lymph node was removed to assess response. Four out of 20 (20%) patients had a pathological complete response of the axilla. Conclusion: The study showed that a subgroup of patients with a clinical high risk and a genomic low risk ER+/HER2-breast cancer benefits from NET resulting in BCS instead of a mastectomy. Additionally, NET may enable de-escalation in axillary treatment.

Cervical Cancer (CC) is one of the most prevalent neoplasms among women, considered the leading cause of gynecological death worldwide, and the fourth most common type of cancer. Regional metastasis is closely related to the low effectiveness of treatment, and validating biomarkers can optimize accuracy in diagnosis and prognosis. Among the potential biomarkers associated with disease metastasis are circular RNAs (circRNAs), whose altered expression has been linked to CC progression. In this context, this systematic review aims to compile information on the clinical-pathological significance and describe the biological function of circRNAs. Inclusion and exclusion criteria were used to include relevant literature, followed by in silico analysis. Additionally, we employed the UALCAN tools to search for host genes of circRNAs and expression data, miRTargetLink 2.0 to predict interactions of microRNA target genes and the Cytoscape software to predict possible interactions of microRNA target genes. According to the research, most circRNAs were found to be overexpressed and described as regulators of processes such as invasion, cell proliferation, apoptosis and migration. They were also implicated in clinical significance, including metastasis, TNM staging and microRNA interactions. CircRNAs may participate in critical processes in tumorigenesis; therefore, understanding the underlying molecular mechanisms of gene regulation in CC can contribute to the accuracy of diagnosis, prognosis and therapy.

Breast cancer (BCa) is a highly heterogeneous disease, with hormone receptor status being a key factor in patient prognostication and treatment decision‐making. The majority of primary tumours are positive for oestrogen receptor alpha (ERα), which plays a key role in tumorigenesis and disease progression, and represents the major target for treatment of BCa. However, around one‐third of patients with ERα‐positive BCa relapse and progress into the metastatic stage, with 20% of metastatic cases characterised by loss of ERα expression after endocrine treatment, known as ERα‐conversion. It remains unclear whether ERα‐converted cancers are biologically similar to bona fide ERα‐negative disease and which signalling cascades compensate for ERα loss and drive tumour progression. To better understand the biological changes that occur in metastatic BCa upon ERα loss, we performed (phospho)proteomics analysis of 47 malignant pleural effusions derived from 37 BCa patients, comparing ERα‐positive, ERα‐converted and ERα‐negative cases. Our data revealed that the loss of ERα‐dependency in this metastatic site leads to only a partial switch to an ERα‐negative molecular phenotype, with preservation of a luminal‐like proteomic landscape. Furthermore, we found evidence for decreased activity of several key kinases, including serum/glucocorticoid regulated kinase 1 (SGK1), in ERα‐converted metastases. Loss of SGK1 substrate phosphorylation may compensate for the loss of ERα‐dependency in advanced disease and exposes a potential therapeutic vulnerability that may be exploited in treating these patients.

Abstract Background Invasive breast cancer patients are increasingly being treated with neoadjuvant chemotherapy; however, only a fraction of the patients respond to it completely. To prevent overtreatment, there is an urgent need for biomarkers to predict treatment response before administering the therapy. Methods In this retrospective study, we developed hypothesis-driven interpretable biomarkers based on deep learning, to predict the pathological complete response (pCR, i.e., the absence of tumor cells in the surgical resection specimens) to neoadjuvant chemotherapy solely using digital pathology H&E images of pre-treatment breast biopsies. Our approach consists of two steps: First, we use deep learning to characterize aspects of the tumor micro-environment by detecting mitoses and segmenting tissue into several morphology compartments including tumor, lymphocytes and stroma. Second, we derive computational biomarkers from the segmentation and detection output to encode slide-level relationships of components of the tumor microenvironment, such as tumor and mitoses, stroma, and tumor infiltrating lymphocytes (TILs). Results We developed and evaluated our method on slides from n = 721 patients from three European medical centers with triple-negative and Luminal B breast cancers and performed external independent validation on n = 126 patients from a public dataset. We report the predictive value of the investigated biomarkers for predicting pCR with areas under the receiver operating characteristic curve between 0.66 and 0.88 across the tested cohorts. Conclusion The proposed computational biomarkers predict pCR, but will require more evaluation and finetuning for clinical application. Our results further corroborate the potential role of deep learning to automate TILs quantification, and their predictive value in breast cancer neoadjuvant treatment planning, along with automated mitoses quantification. We made our method publicly available to extract segmentation-based biomarkers for research purposes.

Background A substantial proportion of patients with macroscopic stage III melanoma do not benefit sufficiently from adjuvant anti-PD-1 therapy, as they either recur despite therapy or would never have recurred. To better inform adjuvant treatment selection, we have performed translational analyses to identify prognostic and predictive biomarkers.Patients and methods Two cohorts of patients with macroscopic stage III melanoma from an ongoing biobank study were included. Clinical data were compared between an observation cohort (cohort 1) and an adjuvant intention cohort (cohort 2). RNA sequencing for translational analyses was performed and treatment subgroups (cohort 1A and cohort 2A) were compared for possible biomarkers, using a cut-off based on the treatment-naïve patients. In addition, two validation cohorts (Melanoma Institute Australia (MIA) and University Medical Centre Utrecht (UMCU)) were obtained.Results After a median follow-up of 26 months of the 98 patients in our discovery set, median recurrence-free survival (RFS) was significantly longer for the adjuvant intention cohort (cohort 2, n=49) versus the observation cohort (cohort 1, n=49). Median overall survival was not reached for either cohort, nor significantly different. In observation cohort 1A (n=24), RFS was significantly longer for patients with high interferon-gamma (IFNγ) score (p=0.002); for adjuvant patients of cohort 2A (n=24), a similar trend was observed (p=0.086). Patients with high B cell score had a longer RFS in cohort 1A, but no difference was seen in cohort 2A. The B cell score based on RNA correlated with CD20+ cells in tumor area but was not independent from the IFNγ score. In the MIA validation cohort (n=44), longer RFS was observed for patients with high IFNγ score compared with low IFNγ score (p=0.046), no difference in RFS was observed according to the B cell score. In both the observation (n=11) and the adjuvant (n=11) UMCU validation cohorts, no difference in RFS was seen for IFNγ and B cell.Conclusions IFNγ has shown to be a prognostic marker in both patients who were and were not treated with adjuvant therapy. B cell score was prognostic but did not improve accuracy over IFNγ. Our study confirmed RFS benefit of adjuvant anti-PD-1 for patients with macroscopic stage III melanoma.

Abstract Background Despite major improvements in treatment of HER2-positive metastatic breast cancer (MBC), only few patients achieve complete remission and remain progression free for a prolonged time. The tumor immune microenvironment plays an important role in the response to treatment in HER2-positive breast cancer and could contain valuable prognostic information. Detailed information on the cancer-immune cell interactions in HER2-positive MBC is however still lacking. By characterizing the tumor immune microenvironment in patients with HER2-positive MBC, we aimed to get a better understanding why overall survival (OS) differs so widely and which alternative treatment approaches may improve outcome. Methods We included all patients with HER2-positive MBC who were treated with trastuzumab-based palliative therapy in the Netherlands Cancer Institute between 2000 and 2014 and for whom pre-treatment tissue from the primary tumor or from metastases was available. Infiltrating immune cells and their spatial relationships to one another and to tumor cells were characterized by immunohistochemistry and multiplex immunofluorescence. We also evaluated immune signatures and other key pathways using next-generation RNA-sequencing data. With nine years median follow-up from initial diagnosis of MBC, we investigated the association between tumor and immune characteristics and outcome. Results A total of 124 patients with 147 samples were included and evaluated. The different technologies showed high correlations between each other. T-cells were less prevalent in metastases compared to primary tumors, whereas B-cells and regulatory T-cells (Tregs) were comparable between primary tumors and metastases. Stromal tumor-infiltrating lymphocytes in general were not associated with OS. The infiltration of B-cells and Tregs in the primary tumor was associated with unfavorable OS. Four signatures classifying the extracellular matrix of primary tumors showed differential survival in the population as a whole. Conclusions In a real-world cohort of 124 patients with HER2-positive MBC, B-cells, and Tregs in primary tumors are associated with unfavorable survival. With this paper, we provide a comprehensive insight in the tumor immune microenvironment that could guide further research into development of novel immunomodulatory strategies. Graphical Abstract

Abstract Background Tumour hypoxia is a negative predictive and prognostic biomarker in colorectal cancer typically assessed by invasive sampling methods, which suffer from many shortcomings. This retrospective proof-of-principle study explores the potential of MRI-derived imaging markers in predicting tumour hypoxia non-invasively in patients with colorectal liver metastases (CLM). Methods A single-centre cohort of 146 CLMs from 112 patients were segmented on preoperative T2-weighted (T2W) images and diffusion-weighted imaging (DWI). HIF-1 alpha immunohistochemical staining index (high/low) was used as a reference standard. Radiomic features were extracted, and machine learning approaches were implemented to predict the degree of histopathological tumour hypoxia. Results Radiomic signatures from DWI b200 (AUC = 0.79, 95% CI 0.61–0.93, p = 0.002) and ADC (AUC = 0.72, 95% CI 0.50–0.90, p = 0.019) were significantly predictive of tumour hypoxia. Morphological T2W TE75 (AUC = 0.64, 95% CI 0.42–0.82, p = 0.092) and functional DWI b0 (AUC = 0.66, 95% CI 0.46–0.84, p = 0.069) and b800 (AUC = 0.64, 95% CI 0.44–0.82, p = 0.071) images also provided predictive information. T2W TE300 (AUC = 0.57, 95% CI 0.33–0.78, p = 0.312) and b = 10 (AUC = 0.53, 95% CI 0.33–0.74, p = 0.415) images were not predictive of tumour hypoxia. Conclusions T2W and DWI sequences encode information predictive of tumour hypoxia. Prospective multicentre studies could help develop and validate robust non-invasive hypoxia-detection algorithms. Critical relevance statement Hypoxia is a negative prognostic biomarker in colorectal cancer. Hypoxia is usually assessed by invasive sampling methods. This proof-of-principle retrospective study explores the role of AI-based MRI-derived imaging biomarkers in non-invasively predicting tumour hypoxia in patients with colorectal liver metastases (CLM). Graphical Abstract

Abstract Immune checkpoint blockade (ICB) is currently approved for patients with triple-negative breast cancer (TNBC), whereas responses to ICB are also observed in a small subgroup of Estrogen Receptor (ER)-positive breast cancer. The cut-off for ER-positivity (≥1%) is based on likelihood of endocrine treatment response, but ER-positive breast cancer represents a very heterogeneous group. This raises the question whether selection based on ER-negativity should be revisited to select patients for ICB treatment in the context of clinical trials. Stromal tumor-infiltrating lymphocytes (sTILs) and other immune parameters are higher in TNBC compared to ER-positive breast cancer, but it is unknown whether lower ER levels are associated with more inflamed tumor microenvironments (TME). We collected a consecutive series of primary tumors from 173 HER2-negative breast cancer patients, enriched for tumors with ER expression between 1 and 99% and found levels of stromal TILs, CD8 + T cells, and PD-L1 positivity in breast tumors with ER 1–9% and ER 10–50% to be comparable to tumors with ER 0%. Expression of immune-related gene signatures in tumors with ER 1–9% and ER 10–50% was comparable to ER 0%, and higher than in tumors with ER 51–99% and ER 100%. Our results suggest that the immune landscape of ER low tumors (1–9%) and ER intermediate tumors (10–50%) mimic that of primary TNBC.

Carditis in childhood is a rare disease with several etiologies. We report a case of infant death due to pericarditis and myocarditis after the mRNA vaccine against COVID-19 (COVIDmRNAV). A 7-year-old male child received the first dose of the COVIDmRNAV and presented with monoarthritis and a fever non-responsive to oral antibiotics. The laboratory investigation showed signs of infection (leukocytosis, high levels of c-reactive protein). His condition rapidly deteriorated, and the patient died. The autopsy identified pericardial fibrin deposits, hemorrhagic areas in the myocardium, and normal valves. A diffuse intermyocardial inflammatory infiltrate composed of T CD8+ lymphocytes and histiocytes was identified. An antistreptolysin O (ASO) dosage showed high titers. The presence of arthritis, elevated ASO, and carditis fulfills the criteria for rheumatic fever. However, valve disease and Aschoff’s nodules, present in 90% of rheumatic carditis cases, were absent in this case. The temporal correlation with mRNA vaccination prompted its inclusion as one of the etiologies. In cases of myocardial damage related to COVID-19mRNAV, it appears to be related to the expression of exosomes and lipid nanoparticles, leading to a cytokine storm. The potential effects of the COVID-19mRNAV must be considered in the pathogenesis of this disease, whether as an etiology or a contributing factor to a previously initiated myocardial injury.

Background While linked to obesity and associated with an increased cardiovascular morbidity, non-alcoholic fatty liver disease (NAFLD) is an often-asymptomatic cause of chronic liver disease in children. Early detection provides opportunity for interventions to curb progression. Childhood obesity is on the rise in low/middle-income countries, but cause-specific mortality data associated with liver disease are scanty. Establishing the prevalence of NAFLD in overweight and obese Kenyan children would guide in public health policies aimed at early screening and intervention.Objectives To investigate prevalence of NAFLD in overweight and obese children aged 6–18 years using liver ultrasonography.Methodology This was a cross-sectional survey. After obtaining informed consent, a questionnaire was administered, and blood pressure (BP) measured. Liver ultrasonography was performed to assess fatty changes. Categorical variables were analysed using frequency and percentages. χ2 test and multiple logistic regression model were used to determine relationship between exposure and outcome variables.Results Prevalence of NAFLD was 26.2% (27/103, 95% CI=18.0% to 35.8%). There was no association between sex and NAFLD (OR1.13, p=0.82; 95% CI=0.4 to 3.2). Obese children were four times more likely to have NAFLD compared with overweight children (OR=4.52, p=0.02; 95% CI=1.4 to 19.0). About 40.8% (n=41) had elevated BP, but there was no association with NAFLD (OR=2.06; p=0.27; 95% CI=0.6 to 7.6). Older children (13–18 years) were more likely to have NAFLD (OR 4.42; p=0.03; 95% CI=1.2 to 17.9).Conclusion Prevalence of NAFLD was high in overweight and obese school children in Nairobi. Further studies are needed to identify modifiable risk factors to arrest progression and prevent sequelae.

Abstract Background Although penile cancer (PC) is uncommon in developed countries, it is widespread in developing countries. The state of Maranhão (Northeast, Brazil) has the highest global incidence recorded for PC, and, despite its socioeconomic vulnerability, it has been attributed to human papillomavirus (HPV) infection. This study aimed to determine the histopathological features, the prevalence of HPV infection, and the immunohistochemical profile of PC in Maranhão. Methods A retrospective cohort of 200 PC cases were evaluated. HPV detection was performed using nested-PCR followed by direct sequencing for genotyping. Immunohistochemistry (IHC) was performed using monoclonal antibodies anti-p16INK4a, p53, and ki-67. Results Our data revealed a delay of 17 months in diagnosis, a high rate of penile amputation (96.5%), and HPV infection (80.5%) in patients from Maranhão (Molecular detection). We demonstrated the high rate of HPV in PC also by histopathological and IHC analysis. Most patients presented koilocytosis (75.5%), which was associated with those reporting more than 10 different sexual partners during their lifetime (p = 0.001). IHC revealed frequent p16INK4a overexpression (26.0%) associated with basaloid (p

Background: Pathologic complete response (pCR) rates in early stage HER2-positive breast cancer improved after pertuzumab was added to neoadjuvant treatment. However, survival benefit is less-well established and seems mostly limited to node-positive patients. We used national cancer registry data to compare outcomes of patients treated with and without pertuzumab. Methods: We identified stage II-III HER2-positive breast cancer patients treated with neoadjuvant trastuzumab-based chemotherapy between November 2013 until January 2016 from the Netherlands Cancer Registry. During that period pertuzumab was only available in the 37 hospitals that participated in the TRAIN-2 study. Missing grade and pCR-status were obtained from the Dutch Pathology Registry (PALGA) and cause of death from Statistics Netherlands. We used multiple imputation to impute missing data, multivariable logistic regression to evaluate the association between pertuzumab and pCR (ypT0/is, ypN0) and multivariable Cox regression models for overall survival and breast cancer specific survival (BCSS). Results: We identified 1124 patients of whom 453 received pertuzumab. Baseline characteristics were comparable, although tumor grade was missing more often in patients treated without pertuzumab (12% vs. 2%). Pertuzumab improved pCR rates (41% vs 65%, adjusted odds ratio [aOR] 2.91; 95% CI:2.20–3.94). After a median follow-up of 6.0 years, 5-year BCSS rates were 95% and 98% respectively (adjusted hazard ratio [aHR]: 0.58; 95% CI:0.36–0.95). Younger patients derived more benefit from pertuzumab, but no other significant interactions were found. Conclusion: These results support earlier data of a small survival benefit with the addition of pertuzumab to trastuzumab-based neoadjuvant chemotherapy which is most meaningful in younger patients.

Abstract Background Information on HRQOL can enhance patient diagnosis and management but it is rarely available in routine clinical practice. This mixed-method study evaluated the feasibility and acceptability of the electronic EQ-5D-5L measurement of HRQOL in patients with chronic musculoskeletal problems in primary care. Methods In three primary care clinics, 665 patients with musculoskeletal problems completed the electronic EQ-5D-5L and Visual Analogue Scale (e-EQ-5D-5L/VAS), and a questionnaire on socio-demographics, perceived ease of use (PEOU), and perceived usefulness (PU) at baseline and two follow-ups. Patient completion and response rates, and time to complete the e-EQ-5D-5L/VAS were measured. During the same consultations, 49 doctors reviewed the e-EQ-5D-5L/VAS reports and completed a clinician questionnaire on PEOU, PU, and time spent to address each report. Individual interviews along with focus group discussions were conducted on patients, doctors, and research assistants for further exploration. Results Mean completion time reduced from baseline to first and second follow-up (120.66, 83.99, and 105.22 s, respectively). Completion and response rates were high at each follow-up visit (> 99.8% and > 91.11%, respectively). Doctors needed less than 2 min to read the report but felt the time required to address the report was a significant barrier. Some patients had difficulties using e-platforms, in understanding or answering questions; but, PEOU improved with time (p 85.3%). Clinicians agreed a great majority of the reports were easy to use (76.0–85.1%) and useful (69.2–72.0%), particularly aiding with a holistic view of the patient's musculoskeletal problem. Conclusion The e-EQ-5D-5L/VAS is a feasible and acceptable measurement of HRQOL of patients with chronic musculoskeletal problems in routine primary care in Hong Kong which can assist real-time management decisions. Trial registration: NCT03609762.

Abstract Secretory leukocyte protease inhibitor (SLPI) is a pleiotropic protein produced by healthy intestinal epithelial cells. SLPI regulates NF-κB activation, inhibits neutrophil proteases and has broad antimicrobial activity. Recently, increased SLPI expression was found in various types of carcinomas and was suggested to increase their metastatic potential. Indeed, we demonstrated that SLPI protein expression in colorectal cancer (CRC) liver metastases and matched primary tumors is associated with worse outcome, suggesting that SLPI promotes metastasis in human CRC. However, whether SLPI plays a role in CRC before distant metastases have formed is unclear. Therefore, we examined whether SLPI expression is associated with prognosis in CRC patients with localized disease. Using a cohort of 226 stage II and 160 stage III CRC patients we demonstrate that high SLPI protein expression is associated with reduced disease recurrence in patients with stage III micro-satellite stable tumors treated with adjuvant chemotherapy, independently of established clinical risk factors (hazard rate ratio 0.54, P-value 0.03). SLPI protein expression was not associated with disease-free survival in stage II CRC patients. Our data suggest that the role of SLPI in CRC may be different depending on the stage of disease. In stage III CRC, SLPI expression may be unfavorable for tumors, whereas SLPI expression may be beneficial for tumors once distant metastases have established.

Abstract Background COVID-19 pandemic is the major public health problem in the world actually. It’s associated with high morbidity and mortality. To date, no therapeutic measure has a curative potential. Hydroxychloroquine (HCQ) is a drug with immunomodulatory properties that has demonstrated antiviral efficacy in in vitro experiments, with conflicting results in in vivo studies. Methods A single-center, prospective and interventional study, that evaluates the impact on mortality of the HCQ use in 154 patients hospitalized with COVID-19 in a Brazilian public hospital. The study also aims to determine prognostic factors that predict mortality, ICU admission and endotracheal intubation in this population. Results 154 patients diagnosed with COVID-19 confirmed by RT-PCR and hospitalized were included. There was a male predominance (87/154, 56.5%), median age 60 years and 88% (136/154) had comorbidities. Among these, 76% (117/154) were admitted to the ICU and 29.2% (45/154) experienced EOT. The OMR was 51.3% (79/154). There was no difference in mortality between patients treated with HCQ (N = 95) and non-HCQ (N = 59) (44.1% × 55.8%, p = 0.758). In univariate analysis, age ≥ 60 years (HR 3.62, p

Abstract Background Electronic measurement of health-related quality of life (HRQOL) may facilitate timely and regular assessments in routine clinical practice. This study evaluated the validity and psychometric properties of an electronic version of the EQ-5D-5L (e-EQ-5D-5L) in Chinese patients with chronic knee and/or back problems. Methods 151 Chinese subjects completed an electronic version of the Chinese (Hong Kong) EQ-5D-5L when they attended a primary care or orthopedics specialist out-patient clinic in Hong Kong. They also completed the Chinese Western Ontario and McMaster University Osteoarthritis Index (WOMAC), a Pain Rating Scale, and a structured questionnaire on socio-demographics, co-morbidities and health service utilization. 32 subjects repeated the e-EQ-5D-5L two weeks after the baseline. 102 subjects completed e-EQ-5D-5L and 99 completed the Global Rating on Change Scale at three-month clinic follow up. Construct validity was assessed by the association of EQ-5D-5L scores with external criterion of WOMAC scores. We tested mean differences of WOMAC scores between adjacent response levels of the EQ-5D-5L dimensions by one-way ANOVA, test–retest reliability by intra-class correlation, sensitivity by known group comparisons and responsiveness by changes in EQ-5D-5L scores over 3 months. Results There was an association between EQ-5D-5L and WOMAC scores. Mean WOMAC scores increased with the increase in adjacent response levels of EQ-5D-5L dimensions. Test–retest intraclass correlation coefficient (ICC) of EQ-5D-5L utility and EQ-VAS scores were 0.76 and 0.83, respectively, indicating good reliability. There were significant differences in the proportions reporting limitations in the EQ-5D-5L dimensions, the utility and VAS scores between the mild and severe pain groups (utility = 0.28, p = 0.001; VAS = 11.46, p

Abstract The low-grade inflammation is pivotal in obesity and its comorbidities; however, the inflammatory proteins are out of target for traditional drug therapy. Omega-3 (ω3) fatty acids can modulate the downstream signaling of Toll-like receptor (TLR) and tumor necrosis factor-α receptor (TNFα) through GPR120, a G-protein-coupled receptor, a mechanism not yet elucidated in humans. This work aims to investigate if the ω3 supplementation, at a feasible level below the previously recommended level in the literature, is enough to disrupt the inflammation and endoplasmic reticulum stress (ER-stress), and also if in acute treatment (3 h) ω3 can activate the GPR120 in peripheral blood mononuclear cells (PBMC) and leukocytes from overweight non-alcoholic fatty liver disease (NAFLD) participants. The R270H variant of the Ffar4 (GPR120 gene) will also be explored about molecular responses and blood lipid profiles. A triple-blind, prospective clinical trial will be conducted in overweight men and women, aged 19–75 years, randomized into placebo or supplemented (2.2 g of ω3 [EPA+DHA]) groups for 28 days. For sample calculation, it was considered the variation of TNFα protein and a 40% dropout rate, obtaining 22 individuals in each group. Volunteers will be recruited among patients with NAFLD diagnosis. Anthropometric parameters, food intake, physical activity, total serum lipids, complete fatty acid blood profile, and glycemia will be evaluated pre- and post-supplementation. In the PBMC and neutrophils, the protein content and gene expression of markers related to inflammation (TNFα, MCP1, IL1β, IL6, IL10, JNK, and TAK1), ER-stress (ATF1, ATF6, IRE1, XBP1, CHOP, eIF2α, eIF4, HSP), and ω3 pathway (GPR120, β-arrestin2, Tab1/2, and TAK1) will be evaluated using Western blot and RT-qPCR. Participants will be genotyped for the R270H (rs116454156) variant using the TaqMan assay. It is hypothesized that attenuation of inflammation and ER-stress signaling pathways in overweight and NAFLD participants will be achieved through ω3 supplementation through binding to the GPR120 receptor. Trial registration ClinicalTrials.gov #RBR-7x8tbx. Registered on May 10, 2018, with the Brazilian Registry of Clinical Trials.

Immunotherapies, in particular immune checkpoint blockade (ICB), have improved the clinical outcome of cancer patients, although many fail to mount a durable response. Several resistance mechanisms have been identified, but our understanding of the requirements for a robust ICB response is incomplete. We have engineered an MHC I/antigen: TCR-matched panel of human NSCLC cancer and T cells to identify tumor cell-intrinsic T cell resistance mechanisms. The top differentially expressed gene in resistant tumor cells was SERPINB9. This serine protease inhibitor of the effector T cell-derived molecule granzyme B prevents caspase-mediated tumor apoptosis. Concordantly, we show that genetic ablation of SERPINB9 reverts T cell resistance of NSCLC cell lines, whereas its overexpression reduces T cell sensitivity. SERPINB9 expression in NSCLC strongly correlates with a mesenchymal phenotype. We also find that SERPINB9 is commonly amplified in cancer, particularly melanoma in which it is indicative of poor prognosis. Single-cell RNA sequencing of ICB-treated melanomas revealed that SERPINB9 expression is elevated not only in cells from post- versus pre-treatment cancers, but also in ICB-refractory cancers. In NSCLC we commonly observed rare SERPINB9-positive cancer cells, possibly accounting for reservoirs of ICB-resistant cells. While underscoring SERPINB9 as a potential target to combat immunotherapy resistance, these results suggest its potential to serve as a prognostic and predictive biomarker.

Abstract Window studies are gaining traction to assess (molecular) changes in short timeframes. Decreased tumor cell positivity for the proliferation marker Ki67 is often used as a proxy for treatment response. Immunohistochemistry (IHC)-based Ki67 on tissue from neo-adjuvant trials was previously reported to be predictive for long-term response to endocrine therapy for breast cancer in postmenopausal women, but none of these trials enrolled premenopausal women. Nonetheless, the marker is being used on this subpopulation. We compared pathologist assessed IHC-based Ki67 in samples from pre- and postmenopausal women in a neo-adjuvant, endocrine therapy focused trial (NCT00738777), randomized between tamoxifen, anastrozole, or fulvestrant. These results were compared with (1) IHC-based Ki67 scoring by AI, (2) mitotic figures, (3) mRNA-based Ki67, (4) five independent gene expression signatures capturing proliferation, and (5) blood levels for tamoxifen and its metabolites as well as estradiol. Upon tamoxifen, IHC-based Ki67 levels were decreased in both pre- and postmenopausal breast cancer patients, which was confirmed using mRNA-based cell proliferation markers. The magnitude of decrease of Ki67 IHC was smaller in pre- versus postmenopausal women. We found a direct relationship between post-treatment estradiol levels and the magnitude of the Ki67 decrease in tumors. These data suggest IHC-based Ki67 may be an appropriate biomarker for tamoxifen response in premenopausal breast cancer patients, but anti-proliferative effect size depends on estradiol levels.

Objetiva-se analisar as evidências científicas sobre o exercício da espiritualidade em pacientes com câncer, tendo em vista suas contribuições para o tratamento oncológico. Realizou-se uma revisão integrativa da literatura nas bases de dados MEDLINE, LILACS, BDENF e literatura cinzenta. Foram selecionados 15 artigos em português, inglês e espanhol, publicados entre os anos de 2010 e 2020, que abordaram o papel da espiritualidade durante o tratamento oncológico. Para discussão dos resultados estabeleceu-se três categorias: (1) a espiritualidade e o bem-estar físico e emocional, (2) a espiritualidade na construção da resiliência, e (3) a espiritualidade ressignificando a vida. Notou-se que o aumento de aspectos positivos relacionados à prática espiritual como otimismo, esperança, adoção de hábitos saudáveis e redução do estresse e da ansiedade refletem no bem-estar e na qualidade de vida; o exercício espiritual oferece mecanismos para construção da resiliência, como resistência, força e superação das adversidades; e ajudam os pacientes a enxergar a vida sob uma perspectiva mais otimista. Poucos estudos abordam que não há benefícios relacionados à pratica da espiritualidade. Conclui-se, conforme a maioria das pesquisas, que a prática espiritual é relevante para o bem-estar, enfrentamento da doença e ressignificação da existência durante o tratamento oncológico. Palavras-chave: Espiritualidade; Oncologia; Adaptação Psicológica.

Membranous nephropathy (MN) is a form of kidney disease that is idiopathic in 70%–80% of cases. Glomerular involvement in autoimmune thyroiditis can occur in 10%–30% of patients, and MN manifests in association with Hashimoto thyroiditis in up to 20% of the cases with glomerular involvement. Reports of MN associated with Graves’ disease (GD) are extremely rare in the current literature. Herein, we report the case of a 46-year-old man admitted to the hospital with nephrotic syndrome and symptomatic hyperthyroidism due to GD. Kidney biopsy revealed a secondary MN pattern. Immunohistochemical staining for PLA2R was negative, and thyroglobulin showed weak and segmental staining along the glomerular capillary. Anti-thyroid peroxidase (TPO) antibody test was not performed. The patient was treated for GD with methimazole and prednisone, and despite reaching clinical improvement after 8 months, proteinuria remained close to nephrotic levels. In this scenario, the patient was submitted to radioactive iodine, and there was a dramatic reduction in proteinuria levels after treatment. In conclusion, GD association with MN is rare, and when present, diagnosis using PLA2R and immunohistochemistry can be useful in determining association. In addition, radioactive iodine therapy can be an effective treatment modality when preceded with immunosuppressive corticosteroid therapy.

Abstract Although ductal carcinoma in situ (DCIS) is a non-obligate precursor to ipsilateral invasive breast cancer (iIBC), most DCIS lesions remain indolent. Hence, overdiagnosis and overtreatment of DCIS is a major concern. There is an urgent need for prognostic markers that can distinguish harmless from potentially hazardous DCIS. We hypothesised that features of the breast adipose tissue may be associated with risk of subsequent iIBC. We performed a case–control study nested in a population-based DCIS cohort, consisting of 2658 women diagnosed with primary DCIS between 1989 and 2005, uniformly treated with breast conserving surgery (BCS) alone. We assessed breast adipose features with digital pathology (HALO®, Indica Labs) and related these to iIBC risk in 108 women that developed subsequent iIBC (cases) and 168 women who did not (controls) by conditional logistic regression, accounting for clinicopathological and immunohistochemistry variables. Large breast adipocyte size was significantly associated with iIBC risk (odds ratio (OR) 2.75, 95% confidence interval (95% CI) = 1.25–6.05). High cyclooxygenase (COX)-2 protein expression in the DCIS cells was also associated with subsequent iIBC (OR 3.70 (95% CI = 1.59–8.64). DCIS with both high COX-2 expression and large breast adipocytes was associated with a 12-fold higher risk (OR 12.0, 95% CI = 3.10–46.3, P

Abstract Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune inflammatory disease. However, some patients may exhibit a histological pattern of kidney injury, with characteristics indistinguishable from lupus nephritis, but without presenting any extrarenal symptoms or serologies suggestive of SLE. Such involvement has recently been called non-lupus full-house nephropathy. The objective is to report a series of clinical cases referred to the Laboratory of the Federal University of Maranhão that received the diagnosis of "full-house" nephropathy unrelated to lupus, upon immunofluorescence and to discuss its evolution and outcomes. Non-lupus full-house nephropathy represents a diagnostic and therapeutic challenge, because it is a new entity, which still needs further studies and may be the initial manifestation of SLE, isolated manifestation of SLE or a new pathology unrelated to SLE.

Collapsing glomerulopathy (CG) is a clinicopathologic entity characterized by segmentar or global collapse of the glomerulus and hypertrophy and hyperplasia of podocytes. The Columbia classification of 2004 classified CG as a histological subtype of focal segmental glomerulosclerosis (FSGS). A growing number of studies have demonstrated a high prevalence of CG in many countries, especially among populations with a higher proportion of people with African descent. The present study is a narrative review of articles extracted from PubMed, Medline, and Scielo databases from September 1, 2020 to December 31, 2021. We have focused on populational studies (specially cross-sectional and cohort articles). CG is defined as a podocytopathy with a distinct pathogenesis characterized by strong podocyte proliferative activity. The most significant risk factors for CG include APOL1 gene mutations and infections with human immunodeficiency virus and severe acute respiratory syndrome coronavirus 2. CG typically presents with more severe symptoms and greater renal damage. The prognosis is notably worse than that of other FSGS subtypes.

Anti-androgen therapy inhibits prostate cancer (PC) progression, and is thought to act directly on cancer cells. Here the authors show that androgen receptor is expressed on normal and PC-associated macrophages, and its stimulation alters macrophage secretome to promote migration of cultured PC cell lines.

Candidate immune biomarkers have been proposed for predicting response to immunotherapy in urothelial cancer (UC). Yet, these biomarkers are imperfect and lack predictive power. A comprehensive overview of the tumor immune contexture, including Tertiary Lymphoid structures (TLS), is needed to better understand the immunotherapy response in UC. We analyzed tumor sections by quantitative multiplex immunofluorescence to characterize immune cell subsets in various tumor compartments in tumors without pretreatment and tumors exposed to preoperative anti-PD1/CTLA-4 checkpoint inhibitors (NABUCCO trial). Pronounced immune cell presence was found in UC invasive margins compared to tumor and stroma regions. CD8+PD1+ T-cells were present in UC, particularly following immunotherapy. The cellular composition of TLS was assessed by multiplex immunofluorescence (CD3, CD8, FoxP3, CD68, CD20, PanCK, DAPI) to explore specific TLS clusters based on varying immune subset densities. Using a k-means clustering algorithm, we found five distinct cellular composition clusters. Tumors unresponsive to anti-PD-1/CTLA-4 immunotherapy showed enrichment of a FoxP3+ T-cell-low TLS cluster after treatment. Additionally, cluster 5 (macrophage low) TLS were significantly higher after pre-operative immunotherapy, compared to untreated tumors. We also compared the immune cell composition and maturation stages between superficial (submucosal) and deeper TLS, revealing that superficial TLS had more pronounced T-helper cells and enrichment of early TLS than TLS located in deeper tissue. Furthermore, superficial TLS displayed a lower fraction of secondary follicle like TLS than deeper TLS. Taken together, our results provide a detailed quantitative overview of the tumor immune landscape in UC, which can provide a basis for further studies.

The ascorbyl methylsilanol pectinate (AMP) presents the same functional properties of ascorbic acid (AA). Besides antioxidant and depigmentant activity, the AMP presents silanol in its chemical structure. The aim of this work was to characterize and indentify the AMP alone and in cosmetic formulations. The following techniques were employed: Fourier Transform Infrared Spectrophotometry, particle size distributions, in vitro antioxidant activity with 2.2-diphenyl-1-picrylhydrazyl (DPPH) and Oxigen Radical Absorbance Capacity Assay and High Performace Liquid Chromatography (HPLC) (developed and validated method) for the active ingredient; Microscopy, HPLC and Normal Stability Assay (NSA) for the emulsions. Particle size distributions results showed that the average size of AMP was 1.0 µm and polydispersity index was 0.1. In DPPH assay AA and AMP were statistically the same. The value of ORAC obtained for AMP was 0.74 and for AA in the literature was 0.95. In the NSA the formulations were stable in conditions of 5.0 and 45.0 ± 2.0 ºC for 90 days. Adequate stability at ambient temperature out of reach of light was also observed. Thus, this works presented an acceptable method for quantification of AMP alone and in cosmetic formulations. AMP was an adequate choice for the incorporation in emulsions with antioxidant efficacy.

O objetivo deste artigo é analisar a formação sócio-histórica da Amazônia, destacando o (não) lugar ocupado pelas comunidades ribeirinhas e por outros povos amazônicos, bem como problematizar o uso do território e a inserção da região amazônica no mundo globalizado. Trata-se de um ensaio teórico, com base em livros, revistas e artigos publicados, fundamentado em perspectiva crítica. No qual, evidencia-se essa trajetória socioeconômica e histórica da Amazônia marcada por uma intensa exploração dos seus recursos naturais que visa atender aos interesses do capital. O plano de modernização da região culminou contraditoriamente no adensamento das expressões da questão social e marginalização dos povos amazônicos, em especial, as comunidades ribeirinhas, historicamente excluídas nesse processo.

Clinical presentations of the novel coronavirus (SARS-CoV-2) infection are quite varied, ranging from asymptomatic conditions to potentially fatal disease. The kidney is one of the affected targets of coronavirus disease (COVID-19) complications, and renal dysfunction is a significant prognostic factor for mortality. This report describes a series of clinical complications in a previously healthy child who developed nephritic syndrome with a concomitant SARS-CoV-2 infection. These complications include acute kidney injury that progressed to chronicity, multisystemic inflammatory syndrome, Kawasaki-like syndrome, and thrombotic microangiopathy.

To verify the efficiency of Brazilian municipalities in the application of public resources disaggregated in the quality of public education, from 2009 to 2013, the Stochastic Frontier Analysis method was used, according to Battese and Coelli (1995). The results showed that social aspects (health and infrastructure expenditures) were not drivers of efficiency, despite the greater allocation of resources by the most efficient. Of the disaggregated public educational expenditures, the infrastructure, outsourced services by legal entities and other expenses were positive. In addition, the most efficient municipalities were those with the fewest students in the classroom and, especially, with 90% of the students enrolled in the age-consistent grade.

Para verificar a eficiência dos municípios brasileiros na aplicação dos recursos públicos desagregados na qualidade da educação pública, de 2009 a 2013, utilizou-se o método de Análise de Fronteira Estocástica, conforme Battese e Coelli (1995). Os resultados apontaram que aspectos sociais (gastos com saúde e infraestrutura) não foram propulsores da eficiência, apesar da maior destinação de recursos por parte dos mais eficientes. Dos gastos públicos educacionais desagregados, foram positivos os com infraestrutura, serviços terceirizados por pessoas jurídicas e com outras despesas. Ainda, os municípios mais eficientes foram os com menos alunos em sala de aula e, principalmente, com 90% dos alunos matriculados na série coerente à idade.

Introdução: Insatisfação corporal é comumente observada na adolescência, resultando em inadequações nutricionais, todavia poucos estudos com essa vertente são realizados em adolescentes em treinamento esportivo. Objetivo: Associar a imagem corporal com parâmetros do estado nutricional (antropometria e ingestão alimentar) de adolescentes em treinamento de futebol. Materiais e métodos: Trata-se de um estudo observacional, de corte transversal realizado com 60 adolescentes do sexo masculino, praticantes de futebol. Foram aplicados questionários sobre o estado geral de saúde e, outro auto aplicado com a Escada de desenhos de silhuetas nos adolescentes. Para avaliação do estado nutricional foram aferidas medidas antropométricas (peso, altura, circunferências e dobras cutâneas) e a avaliação da ingestão alimentar por recordatório alimentar de 24h. Foi considerado α=5%. Resultados: A média de idade foi 13,55 (1,61) anos entre os adolescentes. Aproximadamente 67% (n=40) dos adolescentes demonstraram insatisfação corporal para magreza, mesmo com a maioria estando eutrófico, segundo o índice de Massa Corporal (IMC). A ingestão de lipídios foi maior no grupo de adolescentes insatisfeitos com o excesso de peso, que também apresentou IMC para sobrepeso e obesidade. Discussão: Os resultados mostram elevado número de adolescentes, que mesmo praticando atividade física, estão insatisfeitos com a aparência corporal. Conclusão: A insatisfação corporal está relacionada a fatores como distorção da imagem corporal, excesso de peso e inadequações da dieta. Assim, é necessária a associação da prática de esporte com hábitos alimentares saudáveis.

Abstract Introduction The presence of tumor-infiltrating lymphocytes (TILs) is correlated with good prognosis and outcome after (immuno)therapy in triple-negative and HER2-positive breast cancer. However, the role of TILs in luminal breast cancer is less clear. Emerging evidence has now demonstrated that genetic aberrations in malignant cells influence the immune landscape of tumors. Phosphatidylinositol 3-kinase (PI3K) is the most common altered pathway in ER-positive breast cancer. It is unknown whether changes in the PI3K pathway result in a different composition of the breast tumor microenvironment. Here we present the retrospective analysis of a prospective randomized trial in ER-positive breast cancer on the prognostic and predictive value of specific tumor-associated lymphocytes in the context of PI3K alterations. Methods We included 563 ER-positive tumors from a multicenter trial for stage I to III postmenopausal breast cancer patients, who were randomized to tamoxifen or no adjuvant therapy. The amount of CD8-, CD4-, and FOXP3-positive cells was evaluated by immunohistochemistry and quantified by imaging-analysis software. We analyzed the associations between PIK3CA hotspot mutations, PTEN expression, phosphorylated proteins of the PI3K and MAPK pathway (p-AKT, p-ERK1/2, p-4EBP1, p-p70S6K), and recurrence-free interval after adjuvant tamoxifen or no adjuvant treatment. Results CD8-positive lymphocytes were significantly more abundant in PIK3CA-mutated tumors (OR = 1.65; 95% CI 1.03–2.68). While CD4 and FOXP3 were not significantly associated with prognosis, patients with tumors classified as CD8-high had increased risk of recurrence (HR = 1.98; 95% CI 1.14–3.41; multivariable model including PIK3CA status, treatment arm, and other standard clinicopathological variables). Lymphocytes were more often present in tumors with increased PI3K downstream phosphorylation. This was most pronounced for FOXP3-positive cells. Conclusion These exploratory analyses of a prospective trial in luminal breast cancer suggest high CD8 infiltration is associated with unfavorable outcome and that PI3K pathway alterations might be associated with the composition of the tumor microenvironment.

Abstract Background Breast cancer surgeons struggle with differentiating healthy tissue from cancer at the resection margin during surgery. We report on the feasibility of using diffuse reflectance spectroscopy (DRS) for real-time in vivo tissue characterization. Methods Evaluating feasibility of the technology requires a setting in which measurements, imaging and pathology have the best possible correlation. For this purpose an optical biopsy needle was used that had integrated optical fibers at the tip of the needle. This approach enabled the best possible correlation between optical measurement volume and tissue histology. With this optical biopsy needle we acquired real-time DRS data of normal tissue and tumor tissue in 27 patients that underwent an ultrasound guided breast biopsy procedure. Five additional patients were measured in continuous mode in which we obtained DRS measurements along the entire biopsy needle trajectory. We developed and compared three different support vector machine based classification models to classify the DRS measurements. Results With DRS malignant tissue could be discriminated from healthy tissue. The classification model that was based on eight selected wavelengths had the highest accuracy and Matthews Correlation Coefficient (MCC) of 0.93 and 0.87, respectively. In three patients that were measured in continuous mode and had malignant tissue in their biopsy specimen, a clear transition was seen in the classified DRS measurements going from healthy tissue to tumor tissue. This transition was not seen in the other two continuously measured patients that had benign tissue in their biopsy specimen. Conclusions It was concluded that DRS is feasible for integration in a surgical tool that could assist the breast surgeon in detecting positive resection margins during breast surgery. Trail registration NIH US National Library of Medicine–clinicaltrails.gov, NCT01730365. Registered: 10/04/2012 https://clinicaltrials.gov/ct2/show/study/NCT01730365

Group C Streptococcus (GCS) is part of the normal commensal flora of the upper airway, as well as frequently colonizes the skin, gastrointestinal tract, and female genital tract. It can also be implicated in mono- and polymicrobial infections of the skin and soft tissue, pharyngitis, bacteremia, endocarditis, septic arthritis, osteomyelitis, and meningitis. Our case study features a previously healthy 65-year-old male, who retired as a veterinarian one month prior, with Group C Streptococcus bacteremia complicated by septic polyarthritis, native mitral valve endocarditis, and lumbar discitis/osteomyelitis.

Overlapping commonalities between coronavirus disease of 2019 (COVID-19) and cardio-oncology regarding cardiovascular toxicities (CVT), pathophysiology, and pharmacology are special topics emerging during the pandemic. In this perspective, we consider an array of CVT common to both COVID-19 and cardio-oncology, including cardiomyopathy, ischemia, conduction abnormalities, myopericarditis, and right ventricular (RV) failure. We also emphasize the higher risk of severe COVID-19 illness in patients with cardiovascular disease (CVD) or its risk factors or cancer. We explore commonalities in the underlying pathophysiology observed in COVID-19 and cardio-oncology, including inflammation, cytokine release, the renin-angiotensin-aldosterone-system, coagulopathy, microthrombosis, and endothelial dysfunction. In addition, we examine common pharmacologic management strategies that have been elucidated for CVT from COVID-19 and various cancer therapies. The use of corticosteroids, as well as antibodies and inhibitors of various molecules mediating inflammation and cytokine release syndrome, are discussed. The impact of angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) is also addressed, since these drugs are used in cardio-oncology and have received considerable attention during the COVID-19 pandemic, since the culprit virus enters human cells via the angiotensin converting enzyme 2 (ACE2) receptor. There are therefore several areas of overlap, similarity, and interaction in the toxicity, pathophysiology, and pharmacology profiles in COVID-19 and cardio-oncology syndromes. Learning more about either will likely provide some level of insight into both. We discuss each of these topics in this viewpoint, as well as what we foresee as evolving future directions to consider in cardio-oncology during the pandemic and beyond. Finally, we highlight commonalities in health disparities in COVID-19 and cardio-oncology and encourage continued development and implementation of innovative solutions to improve equity in health and healing.

Summary: We describe an RT-PCR protocol that allows high-resolution mapping of splicing products and isoforms using fluorescently labeled primers. Each species contains one fluorescent group allowing a direct comparison of the different isoforms despite size differences. A custom-size ladder enables the precise determination of cDNA lengths and discrimination of isoforms differing by less than five nucleotides on polyacrylamide gels. This protocol also allows the detection of products from in vitro splicing reactions, circumventing the need to use radiolabeled transcripts.For complete details on the use and execution of this protocol, please refer to Gabunilas and Chanfreau (2016).

Kidney involvement appears to be frequent in coronavirus disease 2019 (COVID-19). Despite this, information concerning renal involvement in COVID-19 is still scarce. Several mechanisms appear to be involved in the complex relationship between the virus and the kidney. Also, different morphological patterns have been described in the kidneys of patients with COVID-19. For some authors, however, this association may be just a coincidence. To investigate this issue, we propose assessing renal morphology associated with COVID-19 at the renal pathology reference center of federal university hospitals in Brazil. Data will come from a consortium involving 17 federal university hospitals belonging to Empresa Brasileira de Serviços Hospitalares (EBSERH) network, as well as some state hospitals and an autopsy center. All biopsies will be sent to the referral center for renal pathology of the EBSERH network. The data will include patients who had coronavirus disease, both alive and deceased, with or without pre-existing kidney disease. Kidney biopsies will be analyzed by light, fluorescence, and electron microscopy. Furthermore, immunohistochemical (IHC) staining for various inflammatory cells (i.e., cells expressing CD3, CD20, CD4, CD8, CD138, CD68, and CD57) as well as angiotensin-converting enzyme 2 (ACE2) will be performed on paraffinized tissue sections. In addition to ultrastructural assays, in situ hybridization (ISH), IHC and reverse transcription-polymerase chain reaction (RT-PCR) will be used to detect Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) in renal tissue. For the patients diagnosed with Collapsing Glomerulopathy, peripheral blood will be collected for apolipoprotein L-1 (APOL1) genotyping. For patients with thrombotic microangiopathy, thrombospondin type 1 motif, member 13 (ADAMTS13), antiphospholipid, and complement panel will be performed. The setting of this study is Brazil, which is second behind the United States in highest confirmed cases and deaths. With this complete approach, we hope to help define the spectrum and impact, whether immediate or long-term, of kidney injury caused by SARS-CoV-2.

Resumo A educação é direito de todos, sendo papel do Estado garanti-la com qualidade, ainda que os parâmetros de qualidade sejam diferentes para os indivíduos. Para assegurar que os recursos sejam destinados a atividades educacionais, a Constituição Federal brasileira de 1988 determina percentuais mínimos de aplicação, assim como os fundos de manutenção do ensino, como o vigente Fundo de Manutenção e Desenvolvimento da Educação Básica (Fundeb). Portanto, este estudo verificou a influência de transferências intergovernamentais, enquanto característica financeira dos municípios, e dos valores repassados ao Fundeb, na qualidade da educação dos municípios das regiões brasileiras Norte e Nordeste. Assim, utilizou-se de modelo de regressão com dados em painel, para o período de 2007 a 2013, cujos resultados indicaram que a maioria das transferências intergovernamentais recebidas pelos municípios impactaram positivamente no desenvolvimento educacional. Além disso, destacou-se a importância dos recursos do Fundeb, ainda que com magnitude baixa. Entretanto, o ponto mais importante refere-se à contribuição expressiva do fato de o município receber a complementação financeira da União no Fundo, indicando que a premissa de minimizar as diversidades regionais através deste recurso tenha sido efetiva. Desse modo, a complementação financeira da União feita ao Fundeb foi de grande valia para equalizar as destoantes divergências existentes no setor educacional.

The purpose of this study was to quantify and evaluate the quality standard of education of Brazilian municipalities, by means of an indicator of the quality of municipal basic education, and to verify the relation between headings of the public educational budget and this quality of education. Through the Principal Components Analysis, the General Quality Index of Municipal Education (IQGEM) was created, which included micro and macrostructural aspects, between 2009 and 2013. Subsequently, an Inflation Beta Regression model was used to verify the relationships between the disaggregated educational budget and social factors and the IQGEM. Ranging from 0 (minimum) to 1 (maximum), the index showed an average quality of 0.61 points, being the highest values of municipalities in the South and Southeast. In addition, the factors that were positively related to the IQGEM were investments in school infrastructure and social aspects. On the other hand, expenses with personnel and consumables influenced it negatively. In general, these results indicate that investments in school infrastructure and social promotion policies are relevant to the quality of education in the municipalities of the country. On the other hand, although they have been negatively related to the IQGEM in the short term, it is possible that in the medium- and long-term investments in personnel and consumables can have positive influences.

Secretory leukocyte protease inhibitor (SLPI), a pleiotropic protein expressed by healthy intestinal epithelial cells, functions as an inhibitor of NF-κB and neutrophil proteases and exerts antimicrobial activity. We previously showed SLPI suppresses intestinal epithelial chemokine production in response to microbial contact. Increased SLPI expression was recently detected in various types of carcinoma. In addition, accumulating evidence indicates SLPI expression is favorable for tumor cells. In view of these findings and the abundance of SLPI in the colonic epithelium, we hypothesized SLPI promotes colorectal cancer (CRC) growth and metastasis. Here, we aimed to establish whether SLPI expression in CRC is related to clinical outcome. Using a cohort of 507 patients with CRC who underwent resection of liver metastases, we show that high SLPI protein expression in both liver metastases and primary CRC is associated with significantly shorter overall survival after resection of liver metastases. The prognostic value of SLPI in CRC patients with liver metastases implies a role for SLPI in the formation of metastasis of human CRC. Based on the immune regulatory functions of SLPI, we anticipate that expression of SLPI provides tumors with a mechanism to evade infiltration by immune cells.

Ethnicity appears to play an important role in the prevalence and severity of hypertension, renal disease, and atherosclerosis. A cross-sectional study was conducted, including 206 Afro-descendants with hypertension, living in the remaining quilombo communities. These subjects underwent a carotid intima-media thickness (CIMT) assessment. The presence of renal injury was assessed by: (1) The glomerular filtration rate (GFR) estimated by the formula CKD-EPI using creatinine and cystatin C and (2) Albuminuria (ACR ≥30 mg/g). The Poisson distribution model was set with robust variance to identify factors associated with carotid atherosclerosis. The statistical analysis was performed using the Stata 12.0 software, adopting a significance level of 5%. Most subjects were women (61.65%); the average age was 61.32 (±12.44) years. Subjects (12.62%) were identified with GFR

In most countries, salt intake has been excessive and constitutes one of the main risk factors for disease development, especially hypertension. Factors such as age, gender, sedentary lifestyle, smoking, African descent, obesity, dietary habits and family history of hypertension may be associated with high blood pressure. Studies show a positive association between the excretion of sodium and increased blood pressure. We evaluated the urinary excretion of sodium and associated factors in isolated urine samples of African descendants from remaining Quilombos. We performed a cross-sectional, population-based study with 1162 African descendants living in remaining quilombos in Alcântara, Maranhão, Brazil. Demographic, nutritional, clinical and laboratory data were analyzed. Urinary sodium excretion was estimated using the Kawasaki equation. A multivariate linear regression model was used to identify the variables related to sodium excretion. The average age was 37.6 ± 11.8 years and 51.2% were women. The prevalence of hypertension was 21.3%. The average urinary excretion of sodium was high, especially among the hypertensive (217.9 ± 90.1 vs. 199.2 ± 83.0 mmol/d; p = .002). After an adjusted analysis, only the waist circumference (odds ratios (OR) = 1.16; confidence intervals(CI)95%: 1.03–1.30), triglyceride (OR = 1.13; CI95%: 1.05–1.22), systolic blood pressure (OR = 1.19; CI95%: 1.08–1.32) and Chronic Kidney Disease Epidemiology (CKD-EPI;OR = 1.24; CI95%: 1.15–1.35) remained related to urinary sodium excretion. African descendants had a high rate of sodium excretion, especially among those who had hypertension. Abdominal adiposity, triglyceride and systolic blood pressure levels and renal function by CKD-EPI equation were associated to urinary sodium excretion.

Abstract Background Controversy exists for the use of Ki67 protein expression as a predictive marker to select patients who do or do not derive benefit from adjuvant endocrine therapy. Whether other proliferation markers, like Cyclin D1, and mitotic count can also be used to identify those estrogen receptor α (ERα) positive breast cancer patients that derive benefit from tamoxifen is not well established. We tested the predictive value of these markers for tamoxifen benefit in ERα positive postmenopausal breast cancer patients. Methods We collected primary tumor blocks from 563 ERα positive patients who had been randomized between tamoxifen (1 to 3 years) vs. no adjuvant therapy (IKA trial) with a median follow-up of 7.8 years. Mitotic count, Ki67 and Cyclin D1 protein expression were centrally assessed by immunohistochemistry on tissue microarrays. In addition, we tested the predictive value of CCND1 gene copy number variation using MLPA technology. Multivariate Cox proportional hazard models including interaction between marker and treatment were used to test the predictive value of these markers. Results Patients with high Ki67 (≥5%) as well as low (

Abstract Background The objectives of this study were to determine the minimum incidence of penile cancer in the poorest Brazilian state, and to describe the epidemiologic and clinical characteristics of patients diagnosed with the disease. Methods A retrospective study of 392 patients diagnosed with penile cancer in the three most important referral center in the state was conducted during 2004–2014. Results The age-standardized incidence was 6.15 per 100,000 and the crude annual incidence was 1.18 per 100,000. More than half (61.1%) of the tumors were histological grades 2 and 3, and 66.4% of tumors were classified as at least stage T2. The average age of patients was 58.6 ± 15.7 years (range, 18 to 103 years), with 20.8% of patients ≤40 years of age at diagnosis. The vast majority underwent penectomy (93%). Only 41.8% underwent lymphadenectomy, 58 patients (14.8%) received chemotherapy, and 54 patients (13.8%) received radiotherapy. Stage 3/4 and vascular invasion were statically significant at disease-free survival analysis. Conclusion The state of Maranhão has the highest incidence of penile cancer in Brazil and globally. Tumors are locally advanced and at the time of diagnosis, and there is a high frequency among young individuals. Patients have a low socioeconomic status, making it difficult to complete treatment and receive appropriate follow-up.