Polygenic risk scores for autoimmune related diseases are significantly different in cancer exceptional responders.

A small number of cancer patients respond exceptionally well to therapies and survive significantly longer than patients with similar diagnoses. Profiling the germline genetic backgrounds of exceptional responder (ER) patients, with extreme survival times, can yield insights into the germline polymorphisms that influence response to therapy. As ERs showed a high incidence in autoimmune diseases, we hypothesized the differences in autoimmune disease risk could reflect the immune background of ERs and contribute to better cancer treatment responses. We analyzed the germline variants of 51 ERs using polygenic risk score (PRS) analysis. Compared to typical cancer patients, the ERs had significantly elevated PRSs for several autoimmune-related diseases: type 1 diabetes, hypothyroidism, and psoriasis. This indicates that an increased genetic predisposition towards these autoimmune diseases is more prevalent among the ERs. In contrast, ERs had significantly lower PRSs for developing inflammatory bowel disease. The left-skew of type 1 diabetes score was significant for exceptional responders. Variants on genes involved in the T1D PRS model associated with cancer drug response are more likely to co-occur with other variants among ERs. In conclusion, ERs exhibited different risks for autoimmune diseases compared to typical cancer patients, which suggests that changes in a patient's immune set point or immune surveillance specificity could be a potential mechanistic link to their exceptional response. These findings expand upon previous research on immune checkpoint inhibitor-treated patients to include those who received chemotherapy or radiotherapy.

The CD8+ T cell tolerance checkpoint triggers a distinct differentiation state defined by protein translation defects.

Peripheral CD8+ T cell tolerance is a checkpoint in both autoimmune disease and anti-cancer immunity. Despite its importance, the relationship between tolerance-induced states and other CD8+ T cell differentiation states remains unclear. Using flow cytometric phenotyping, single-cell RNA sequencing (scRNA-seq), and chromatin accessibility profiling, we demonstrated that in vivo peripheral tolerance to a self-antigen triggered a fundamentally distinct differentiation state separate from exhaustion, memory, and functional effector cells but analogous to cells defectively primed against tumors. Tolerant cells diverged early and progressively from effector cells, adopting a transcriptionally and epigenetically distinct state within 60 h of antigen encounter. Breaching tolerance required the synergistic actions of strong T cell receptor (TCR) signaling and inflammation, which cooperatively induced gene modules that enhanced protein translation. Weak TCR signaling during bystander infection failed to breach tolerance due to the uncoupling of effector gene expression from protein translation. Thus, tolerance engages a distinct differentiation trajectory enforced by protein translation defects.

Primary thromboprophylaxis in cancer outpatients - real-world evidence.

INTRODUCTION: Cancer-associated thrombosis (CAT) is a significant concern among patients with malignant diseases, leading to increased mortality. While current guidelines recommend primary thromboprophylaxis for venous thromboembolism (VTE) in medium-to-high-risk outpatients, this practice remains controversial. A better understanding of primary thromboprophylaxis is crucial, yet there is a lack of Real-World Evidence (RWE) in Portugal. AIMS: This RWE study aimed to elucidate primary thromboprophylaxis practices among cancer outpatients in Portugal. METHODS: A five-year observational multicentric study in eight Portuguese health institutions enrolled 124 adult cancer outpatients under primary thromboprophylaxis for VTE. The endpoints were CAT, bleeding, cancer progression and death. RESULTS: High thrombotic risk tumours were prevalent, with 57% (71) of the patients presenting with pancreatic and gastric cancers. Regarding primary thromboprophylaxis, 55% (68) received Low-Molecular-Weight Heparin (LMWH). VTE was presented in 11% (14) of the patients and major bleeding in 2% (2). Vascular compression, elevated D-dimer and previous VTE were significantly associated with VTE occurrence under primary thromboprophylaxis. The Onkotev model was shown to be the best risk assessment model (RAM) in this population (p = 0.007). CAT patients exhibited a lower progression-free survival than non-CAT patients (p = 0.021), while thrombosis did not influence overall survival (p = 0.542). CONCLUSION: Primary thromboprophylaxis in medium-to-high-risk cancer outpatients is a safe and effective practice in real-world settings. This study is the first Portuguese RWE on primary thromboprophylaxis, highlighting evidence for improving prophylactic strategies in this population.

FOXO1 enhances CAR T cell stemness, metabolic fitness and efficacy.

Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of haematological malignancies such as acute lymphoblastic leukaemia, B cell lymphoma and multiple myeloma1-4, but the efficacy of CAR T cell therapy in solid tumours has been limited5. This is owing to a number of factors, including the immunosuppressive tumour microenvironment that gives rise to poorly persisting and metabolically dysfunctional T cells. Analysis of anti-CD19 CAR T cells used clinically has shown that positive treatment outcomes are associated with a more 'stem-like' phenotype and increased mitochondrial mass6-8. We therefore sought to identify transcription factors that could enhance CAR T cell fitness and efficacy against solid tumours. Here we show that overexpression of FOXO1 promotes a stem-like phenotype in CAR T cells derived from either healthy human donors or patients, which correlates with improved mitochondrial fitness, persistence and therapeutic efficacy in vivo. This work thus reveals an engineering approach to genetically enforce a favourable metabolic phenotype that has high translational potential to improve the efficacy of CAR T cells against solid tumours.

A Case Report of Primary Aldosteronism and Extensive Hypertension-Mediated Organ Damage.

Primary aldosteronism, the most common curable form of secondary hypertension, is associated with greater hypertension-related organ damage and cardiovascular complications compared to primary essential hypertension. The authors present a case involving a 41-year-old Black male admitted to the emergency department with left hemiparesis and blurred vision persisting for one hour, accompanied by markedly elevated blood pressure (220/140 mmHg). The patient was asymptomatic by then, and, aside from a history of tobacco smoking and occasional cannabis use, lacked significant medical comorbidities. Further investigations revealed a right acute hemorrhagic stroke, bilateral grade 4 hypertensive retinopathy, chronic kidney disease with end-stage renal disease, hypokalemia, and an elevated aldosterone/renin ratio. An abdominal CT scan showed bilateral adrenal hyperplasia. The patient was diagnosed with primary aldosteronism with extensive hypertension-mediated organ damage. This case highlights the significant harm caused by undiagnosed primary aldosteronism-induced secondary hypertension, emphasizing the importance of timely diagnosis and intervention to prevent organ damage.

A Complete Response to Pembrolizumab in Malignant Peritoneal Mesothelioma: A Case Report.

Malignant peritoneal mesothelioma (MPeM) is a rare cancer of the peritoneum with a poor prognosis and nonspecific clinical course. We discuss a case of MPeM in a 59-year-old male who presented with abdominal pain and distension, without any known previous asbestos exposure. The diagnosis was made after a second biopsy finally confirmed epithelioid MPeM in an advanced stage with pleural effusion. The patient underwent six cycles of chemotherapy with cisplatin and pemetrexed, experienced disease progression, and was then started on pembrolizumab as a second-line treatment. The patient achieved a complete response after two years of treatment with pembrolizumab and has been disease-free for almost four years with an Eastern Cooperative Oncology Group (ECOG) performance status of 0. Despite the lack of evidence to support the treatment with immunotherapy for MPeM, our case report encourages its use, highlighting its ability to enable a complete response with pembrolizumab with an excellent quality of life.

Primary somesthetic cortex involvement in fibromyalgia: review of neuroimage studies / Envolvimento do córtex somestésico primário na fibromialgia: revisão de estudos de neuroimagem

ABSTRACT BACKGROUND AND OBJECTIVES: The mechanisms underlying nociplastic pain, such as fibromyalgia (FM), are not fully understood, however, it is believed that altered sensory processing and pain modulation play prominent roles in the maintenance of nociplastic pain. The hypothesis is that changes in the primary somesthetic cortex (S1) contribute to the generalized pain character of FM. The objective of this study was to evaluate the involvement of the primary somesthetic cortex in humans with fibromyalgia, as well as to investigate possible associations between S1 changes and clinical signs and symptoms of FM. CONTENTS: For this integrative review, the following databases were used: Pubmed and Web of Science, including observational studies carried out in humans with FM. In total, 541 studies were identified and four were included. The majority of studies are case-control studies, published between 2016 and 2022. In total, data from 161 individuals were included in this review. It was identified that there are morphological changes, hyperactivation and increased functional connectivity between S1 and periaqueductal gray matter and between S1 and anterior cingulate cortex. CONCLUSION: Patients with FM present morphological changes and hyperactivation in S1, as well as increased functional connectivity between S1 and periaqueductal gray matter and S1 and limbic system. Furthermore, different bilateral somatotropic subregions (legs, chest, fingers, hands, face and back) showed reduced functional connectivity in patients with FM. These regions are often presented as "tender points" in FM.

RESUMO JUSTIFICATIVA E OBJETIVOS: Os mecanismos subjacentes à dor nociplástica, como a fibromialgia (FM), não são totalmente compreendidos, contudo acredita-se que o processamento sensorial e a modulação da dor alterados desempenham papéis proeminentes para a manutenção da dor nociplástica. Com a hipótese de que alterações no córtex somestésico primário (S1) contribuam para o caráter de dor generalizada da FM, o objetivo deste estudo foi avaliar o envolvimento do córtex somestésico primário em humanos com FM, bem como investigar possíveis associações entre alterações de S1 com sinais e sintomas clínicos da FM. CONTEÚDO: Para esta revisão integrativa, foram utilizadas as seguintes bases de dados: Pubmed e Web of Science, incluindo estudos observacionais realizados em humanos com FM. No total, 541 estudos foram identificados e quatro foram incluídos. A maioria dos estudos são do tipo caso-controle, publicados entre 2016 e 2022. Ao todo, dados de 161 indivíduos foram incluídos. Foi identificado que há alterações morfológicas, hiperativação e aumento da conectividade funcional entre S1 e substância cinzenta periaquedutal e entre S1 e córtex cingulado anterior. CONCLUSÃO: Pacientes com FM apresentam alterações morfológicas e hiperativação em S1, bem como aumento da conectividade funcional entre S1 e substância cinzenta periaquedutal e S1 e sistema límbico. Ademais, diferentes sub-regiões somatotrópicas bilaterais (pernas, tórax, dedos, mãos, face e costas) apresentaram redução da conectividade funcional em pacientes com FM. Essas regiões são frequentemente apresentadas como "tender points" na FM.

A2AR eGFP reporter mouse enables elucidation of A2AR expression dynamics during anti-tumor immune responses.

There is significant clinical interest in targeting adenosine-mediated immunosuppression, with several small molecule inhibitors having been developed for targeting the A2AR receptor. Understanding of the mechanism by which A2AR is regulated has been hindered by difficulty in identifying the cell types that express A2AR due to a lack of robust antibodies for these receptors. To overcome this limitation, here an A2AR eGFP reporter mouse is developed, enabling the expression of A2AR during ongoing anti-tumor immune responses to be assessed. This reveals that A2AR is highly expressed on all tumor-infiltrating lymphocyte subsets including Natural Killer (NK) cells, NKT cells, γδ T cells, conventional CD4+ and CD8+ T lymphocytes and on a MHCIIhiCD86hi subset of type 2 conventional dendritic cells. In response to PD-L1 blockade, the emergence of PD-1+A2AR- cells correlates with successful therapeutic responses, whilst IL-18 is identified as a cytokine that potently upregulates A2AR and synergizes with A2AR deficiency to improve anti-tumor immunity. These studies provide insight into the biology of A2AR in the context of anti-tumor immunity and reveals potential combination immunotherapy approaches.

Avaliação da fixação dos avanços maxilares pela técnica de osteotomia Le Fort I / Evaluación de la fijación de avances maxilar mediante la técnica de osteotomía Le Fort I / Evaluation of the fixation of maxillary advancements by the Le Fort I osteotomy technique

Introdução: A osteotomia Le Fort I possibilita a correção de deformidades dentofaciais que envolvem o terço médio da face. Para sua fixação, convencionou-se o emprego de quatro mini-placas nos pilares zigomático-maxilar e nasomaxilar. Propôs-se então, a dispensa da fixação do segmento posterior, surgindo questionamentos relacionados à capacidade biomecânica do sistema. Objetivos: Comparar o estresse biomecânico gerado em três meios distintos de fixação da osteotomia Le Fort I frente ao movimento de avanço sagital linear maxilar de 7mm. Metodologia: Trata-se de uma pesquisa experimental laboratorial, utilizando-se da análise de elementos finitos como ferramenta analítica, a fim de constatar qual das técnicas sofrerá maior estresse biomecânico. Resultados: Constatou-se que o estresse biomecânico gerado é maior quando aplicado em 4 pontos do que quando aplicado em apenas 2 pontos. Conclusão: Os resultados obtidos fornecem informações aos cirurgiões sobre a real necessidade do uso de fixação adicional de acordo com o método de fixação planejado. No entanto, deve ser interpretado de forma cautelosa, considerando-se as limitações deste estudo. Sendo assim, uma análise incipiente, que tem como intuito o fornecimento de evidência científica de grande significância.

Introducción: La osteotomía Le Fort I permite la corrección de deformidades dentofaciales que involucran el tercio medio de la cara. Para su fijación se acordó utilizar cuatro miniplacas en los pilares cigomaticomaxilar y nasomaxilar. Entonces se propuso prescindir de la fijación del segmento posterior, planteando interrogantes relacionados con la capacidad biomecánica del sistema. Objetivos: Comparar el estrés biomecánico generado en tres medios diferentes de fijación de la osteotomía Le Fort I frente a un movimiento de avance sagital lineal maxilar de 7mm. Metodología: Se trata de una investigación experimental de laboratorio, utilizando como herramienta analítica el análisis de elementos finitos, con el fin de comprobar cuál de las técnicas sufrirá un mayor estrés biomecánico. Resultados: Se encontró que el estrés biomecánico generado es mayor cuando se aplica en 4 puntos que cuando se aplica solo en 2 puntos. Conclusión: Los resultados obtenidos brindan información a los cirujanos sobre la necesidad real de utilizar fijación adicional de acuerdo al método de fijación planificado. Sin embargo, debe interpretarse con cautela, considerando las limitaciones de este estudio. Por tanto, un análisis incipiente, que pretende aportar evidencias científicas de gran trascendencia.

Introduction: The Le Fort I osteotomy allows the correction of dentofacial deformities involving the middle third of the face. For its fixation, it was agreed to use four mini plates on the zygomaticomaxillary and nasomaxillary pillars. It was then proposed to dispense with the fixation of the posterior segment, raising questions related to the biomechanical capacity of the system. Objectives: To compare the biomechanical stress generated in three different means of fixation of the Le Fort I osteotomy against a 7mm maxillary linear sagittal advancement movement. Methodology: This is an experimental laboratory research, using finite element analysis as an analytical tool, in order to verify which of the techniques will suffer greater biomechanical stress. Results: It was found that the biomechanical stress generated is greater when applied to 4 points than when applied to only 2 points. Conclusion: The results obtained provide information to surgeons about the real need to use additional fixation according to the planned fixation method. However, it should be interpreted with caution, considering the limitations of this study. Therefore, an incipient analysis, which aims to provide scientific evidence of great significance.

Occurrence of plasmid-mediated fosfomycin resistance (fos genes) among Escherichia coli isolates, Portugal.

OBJECTIVES: To evaluate the occurrence of plasmid-mediated fos genes among fosfomycin-resistant Escherichia coli isolates collected from patients in Lisbon, Portugal, and characterize the fos-positive strains. METHODS: A total of 19 186 E. coli isolates were prospectively collected between April 2022 and January 2023 from inpatients and outpatients at a private laboratory in Lisbon. Fosfomycin resistance was initially assessed by semi-automated systems and further confirmed by the disc diffusion method. Resistant isolates were investigated for plasmid-mediated fos genes (fosA1-fosA10, fosC and fosL1-fosL2) and extended-spectrum beta-lactamases (ESBLs) by PCR and sequencing. Multilocus sequence typing was performed to evaluate the clonal relationship among fos-carrying isolates. RESULTS: Out of the 19 186 E. coli isolates, 100 were fosfomycin-resistant (0.5%), out of which 15 carried a fosA-like gene (15%). The most prevalent fosfomycin-resistant determinant was fosA3 (n = 11), followed by fosA4 (n = 4). Among the 15 FosA-producing isolates, 10 co-produced an ESBL (67%), being either of CTX-M-15 (n = 8) or CTX-M-14 (n = 2) types. The fosA3 gene was carried on IncFIIA-, IncFIB-, and IncY-type plasmids, whereas fosA4 was always located on IncFIB-type plasmids. Most FosA4-producing isolates belonged to a single sequence type ST2161, whereas isolates carrying the fosA3 gene were distributed into nine distinct genetic backgrounds. CONCLUSION: The prevalence of fosfomycin-resistant E. coli isolates is still low in Portugal. Notably, 15% of fosfomycin-resistant isolates harbour a transferable fosA gene, among which there is a high rate of ESBL producers, turning traditional empirical therapeutical options used in Portugal (fosfomycin and amoxicillin-clavulanic acid) ineffective.

Contribution of HLA-G and FOXP3 genes and proteins in the severity of cervical intraepithelial neoplasia during HPV infection.

Human Papillomavirus (HPV) persistence leads to the chronification of cervical inflammation, where HLA-G and Foxp3; immunomodulatory molecules, may contribute to the aggravation of the lesion and cancerization. Here, we evaluated the synergic effect of these two molecules in the worsening of the lesion in presence of HPV infection. Hundred and eighty (180) women cervical cells and biopsies were collected for (i) HLAG Sanger sequencing and gene expression, and (ii) HLA-G and Foxp3 molecule expressions by immunohistochemistry. 53 women were HPV+ against 127 women HPV-. HPV+ women were more at risk of having cytological changes (p ≤ 0.0123), histological changes (p < 0.0011), and cervical lesion (p = 0.0004). The HLA-G + 3142CC genotype predisposed women to infection (p = 0.0190), while HLA-G + 3142C and +3035 T alleles were associated with HLA-G5 transcript expression. Both sHLA-G (p = 0.030) and Foxp3 (p = 0.0002) proteins were higher in cervical lesion as well as in high-grade lesion. In addition, sHLA-G+ cells were positively correlated to Foxp3+ cells in presence of HPV infection and in cervical grade II/III injuries. In conclusion, HPV may use HLA-G and Foxp3 as a way of host immune escape contributing to the persistence of infection and inflammation, leading to the cervical lesion and the worsening of lesions.

Breast Cancer Survivors and Healthy Women: Could Gut Microbiota Make a Difference?-"BiotaCancerSurvivors": A Case-Control Study.

In this first analysis, samples from 23 BC survivors (group 1) and 291 healthy female controls (group 2) were characterised through the V3 and V4 regions that encode the "16S rRNA" gene of each bacteria. The samples were sequenced by next-generation sequencing (NGS), and the taxonomy was identified by resorting to Kraken2 and improved with Bracken, using a curated database called 'GutHealth_DB'. The α and ß-diversity analyses were used to determine the richness and evenness of the gut microbiota. A non-parametric Mann-Whitney U test was applied to assess differential abundance between both groups. The Firmicutes/Bacteroidetes (F/B) ratio was calculated using a Kruskal-Wallis chi-squared test. The α-diversity was significantly higher in group 1 (p = 0.28 × 10-12 for the Chao index and p = 1.64 × 10-12 for the ACE index). The Shannon index, a marker of richness and evenness, was not statistically different between the two groups (p = 0.72). The microbiota composition was different between the two groups: a null hypothesis was rejected for PERMANOVA (p = 9.99 × 10-5) and Anosim (p = 0.04) and was not rejected for ß-dispersion (p = 0.158), using Unifrac weighted distance. The relative abundance of 14 phyla, 29 classes, 25 orders, 64 families, 116 genera, and 74 species differed significantly between both groups. The F/B ratio was significantly lower in group 1 than in group 2, p < 0.001. Our study allowed us to observe significant taxonomic disparities in the two groups by testing the differences between BC survivors and healthy controls. Additional studies are needed to clarify the involved mechanisms and explore the relationship between microbiota and BC survivorship.

Epidemiological profile of gestational syphilis and congenital syphilis in a reference center in Northeast Brazil: risk factors and trend from 2019 to 2021 / Perfil epidemiológico de sífilis gestacional e sífilis congênita em centro de referência no Nordeste do Brasil: fatores de risco e tendência de 2019 a 2021

Introduction: Syphilis is an infectious systemic disease caused by the bacterium Treponema pallidum. The Amaury de Medeiros Integrated University Health Center in Recife is a reference maternity hospital for high-risk pregnancies and the management of the most common Sexually Transmitted Infections during prenatal care, including Gestational Syphilis and Congenital Syphilis. Objective: To determine the epidemiological profile of the population exposed to these conditions, the rate of Gestational Syphilis detection, the incidence of Congenital Syphilis, and the associated unfavorable outcomes in Amaury de Medeiros Integrated University Health Center between January 2019 and December 2021. Methods: This retrospective cohort study included pregnant women and neonates diagnosed with syphilis at Amaury de Medeiros Integrated University Health Center. Data were collected from the Notification/Investigation Forms for Gestational Syphilis and Congenital Syphilis, between January 2019 and December 2021. Results: At Amaury de Medeiros Integrated University Health Center, 463 cases of Gestational Syphilis and 296 of Congenital Syphilis were reported. During the three-year study, 4444, 4360, and 4265 live births were recorded, confirming the Gestational Syphilis detection rates ­ 33.30, 36.92, and 36.10 per 1000 live births, with the incidence of Congenital Syphilis being 26.1, 21.33, and 20.39 per 1000 live births. Pregnant women in their third trimester who were brown, had incomplete primary education, and lived in an urban area were the main sociodemographic variables. In total, 217 (73.3%) patients were diagnosed with Gestational Syphilis during or after delivery, indicating a low prenatal coverage (70.6%). In terms of the progression of Congenital Syphilis, unfavorable outcomes was found in 40 (13.5%) patients, including 16 (40%) abortions, 10 (25%) stillbirths, nine (22.5%) deaths from Congenital Syphilis, and 5 (12.5%) deaths from other causes. Conclusion: Gestational Syphilis detection rates and Congenital Syphilis incidence remain alarming, with abortions and stillbirths being the most common unfavorable outcomes. To change the dramatic situation of Congenital Syphilis in Brazil, the associated factors point to a poor quality of prenatal care and an urgent need to change public policies for pregnant women and newborns, in conjunction with socioeconomic assistance

Prevalence of HPV infection and cervical intraepithelial lesions in HIV positive and negative women in the city of Florianopolis / Prevalência da infecção pelo HPV e lesões intraepiteliais cervicais em mulheres HIV positivas e negativas na cidade de Florianópolis

Introduction: HPV infection is the most frequent sexually transmitted infection in women. The high oncogenic risk HPV, associated with others factors, there are a risk of progressing to a precancerous lesion of the cervix and even cancer. This evolution is related to the persistence of the infection and other factors, mainly those that interfere with the woman's immunity. The immunosuppression caused by HIV infection is an important factor for viral persistence and the appearance of these lesions. Objectives: To compare the prevalence of HPV infection and cervical intraepithelial lesions in HIV-positive and negative women and describe the possible associated risk factors. Methods: The sample consisted of 50 HIV positive women (study group) and 50 HIV negative women (control group) recruited from the public health system of Florianópolis during the months of January to April 2022. Cervical samples were collected for cytological analysis and for detection of high-risk oncogenic HPV DNA by polymerase chain reaction (PCR). Categorical variables were compared using the chi-square test, with a significance level set at 5% Results: HPV infection was more prevalent in the control group, however, HIV positive women had a higher frequency of intraepithelial lesions diagnosed on cytology. Factors such as greater number of sexual partners, depression and smoking were more frequent in the group of HIV positive women. The number of CD4 T cells less than 200 cels/mm3 was associated with a higher number of altered Pap smears and a positive HPV DNA test. The use of combination antiretroviral therapy and undetectable viral load were associated with a greater number of normal cytology and undetected HPV DNA. Conclusion: The prevalence of cervical intraepithelial lesions in HIV-infected women is higher than in women without infection. The presence of HIV infection was the most important risk factor associated with the development of cervical lesions. (AU)

Introdução: O Papilomavírus Humano (HPV) é a infecção de transmissão sexual mais frequente na mulher. O HPV de alto risco oncogênico, associado a outros fatores, apresenta risco de evoluir para uma lesão pré-cancerosa do colo de útero e até mesmo para o câncer. Essa evolução está relacionada à persistência da infecção e outros fatores, principalmente os que interferem na imunidade da mulher. A imunossupressão causada pela infecção HIV é um fator importante para a persistência viral e o aparecimento destas lesões. Objetivos: Comparar a prevalência da infecção pelo HPV e das lesões intraepiteliais do colo de útero em mulheres HIV positivas e negativas, e descrever os possíveis fatores de risco associados. Métodos: A amostra foi composta por 50 mulheres HIV positivas (grupo de estudo) e 50 mulheres HIV negativas (grupo controle) recrutadas no sistema público de saúde de Florianópolis durante os meses de janeiro a abril de 2022. Foram coletadas amostras cervicais para análise citológica e para detecção do DNA HPV de alto risco oncogênico por reação em cadeia da polimerase (PCR). As variáveis categóricas foram comparadas pelo teste qui-quadrado, com nível de significância estabelecido em 5%. Resultados: A infecção pelo HPV foi mais prevalente no grupo controle, entretanto, as mulheres HIV positivas tiveram uma maior frequência de lesões intraepiteliais diagnosticadas na citologia. Os fatores como maior número de parceiros sexuais, depressão e tabagismo foram mais frequentes no grupo de mulheres HIV positivas. O número de células TCD4 inferior a 200 células/mm3 esteve associado a maior número de colpocitologias alteradas e teste DNA HPV positivo. O uso da terapia antirretroviral combinada e a carga viral indetectável estiveram associadas a um número elevado de citologias normais e DNA HPV não detectado. Conclusão: A prevalência de lesões intraepiteliais do colo do útero em mulheres infectadas pelo HIV foi maior que em mulheres soronegativas. A presença de infecção pelo HIV foi o fator de risco mais importante associado ao desenvolvimento de lesões cervicais.Palavras-chave: HPV. HIV. coinfecção. lesões intraepiteliais escamosas cervicais. prevalência.. (AU)

Acute kidney injury after allogeneic hematopoietic stem cell transplantation - Predictors and survival impact: A single center retrospective study.

INTRODUCTION AND OBJECTIVES: Acute kidney injury (AKI) is a frequent complication of hematopoietic stem cell transplantation (HSCT) and appears to be linked to increased morbidity and mortality. The aim of this study was to evaluate the incidence, etiology, predictors and survival impact of early AKI in the post-allogeneic HSCT setting. PATIENTS AND METHODS: We performed a retrospective single center study that included 155 allogeneic transplant procedures from June 2017 through September 2019. RESULTS: AKI was observed in 50 patients (32%). In multivariate analysis, age (OR 31.55, 95% CI [3.42; 290.80], p=0.002), evidence of disease at the time of transplant (OR 2.54, 95% CI [1.12; 5.75], p=0.025), cytomegalovirus reactivation (OR 5.77, 95% CI [2.43; 13.72], p<0.001) and hospital stay >35 days (OR 2.66, 95% CI [1.08; 6.52], p=0.033) were independent predictors for AKI. Increasing age (HR 1.02, 95% CI [1.00; 1.04], p=0.029), increasing length of hospital stay (HR 1.02, 95% CI [1.01; 1.03], p=0.002), matched unrelated reduced intensity conditioning HSCT (HR 1.91, 95% CI [1.10; 3.33], p=0.022), occurrence of grade III/IV acute graft-versus-host disease (HR 2.41, 95% CI [1.15; 5.03], p=0.019) and need for mechanical ventilation (HR 3.49, 95% CI [1.54; 7.92], p=0.003) predicted an inferior survival in multivariate analysis. Early AKI from any etiology was not related to worse survival. CONCLUSION: Patients submitted to HSCT are at an increased risk for AKI, which etiology is often multifactorial. Due to AKI incidence, specialized nephrologist consultation as part of the multidisciplinary team might be of benefit.

PARP Inhibitors for Breast Cancer: Germline BRCA1/2 and Beyond.

Poly-adenosine diphosphate ribose polymerase (PARP) inhibitors (PARPi) are approved for BRCA1/2 carriers with HER2-negative breast cancer in the adjuvant setting with a high risk of recurrence as well as the metastatic setting. However, the indications for PARPi are broader for patients with other cancer types (e.g., prostate and ovarian cancer), involving additional biomarkers (e.g., ATM, PALB2, and CHEK) and genomic instability scores. Herein, we summarize the data on PARPi and breast cancer and discuss their use beyond BRCA carriers.

Evaluation of the Antimicrobial Effect of Photodynamic Therapy and Er:YAG Laser Irradiation on Root Canals Infected with Enterococcus faecalis.

Objective: To carry out a histological and morphometric analysis of the antimicrobial effect of Er:YAG laser irradiation combined with photodynamic therapy (PDT) on root canals infected with Enterococcus faecalis. Background: PDT and Er:YAG laser irradiation may be alternatives for effective endodontic disinfection but there are no data on the combination of these therapies. Materials and methods: Forty single-rooted bovine teeth had their roots contaminated with E. faecalis for 72 h. The teeth were randomly divided into four groups (n = 10): group 1, irrigation with 2.5% sodium hypochlorite (NaOCl); group 2, Er:YAG laser (λ2940 nm, 15 Hz, 100 mJ); group 3, PDT with 0.07% methylene blue as photosensitizer and laser irradiation (λ660 nm, power 40 mW, 5 min); and group 4, Er:YAG laser + PDT. After treatment, the teeth were examined by confocal laser scanning microscopy to verify bacterial viability, and morphometric analysis of the images was performed. Results: The PDT and Er:YAG + PDT treatments promoted the greatest reduction in bacteria among the proposed therapies, whereas 2.5% NaOCl was the least effective in bacterial elimination. A statistically significant difference (p < 0.05) was observed among the groups studied, except between the group combining Er:YAG and PDT and the group treated with PDT alone. Conclusions: PDT combined or not with Er:YAG laser was found to be more effective in root canal disinfection when compared with the other groups.

Genital infection by Human Papillomavirus (HPV) in women from Santa Catarina/Brazil / Infecção genital pelo Papilomavírus Humano (HPV) em mulheres de Santa Catarina/Brasil

Human Papillomavirus (HPV) infection is the most common sexually transmitted infection in women. About 80% of sexually active women will have contact with this virus at some point in their lives. Most infections will be transient, but when the infection becomes persistent and associated with a high oncogenic risk of Human Papillomavirus, there may be progression to cancer, especially cervical cancer. The best way to prevent Human Papillomavirus infection is through the use of vaccines, which have been available to the public in Brazil since 2014. Objective: This study aimed to assess the most prevalent types of Human Papillomavirus in the state of Santa Catarina, Brazil, and its mesoregions and if the majority of diagnosed types are contained in the Human Papillomavirus vaccines currently available on the market. Methods: A total of 20,000 Human Papillomavirus tests were evaluated for the diagnosis of genital Human Papillomavirus infection in women from the state of Santa Catarina, Brazil. The prevalence of infection was evaluated according to age and the city of origin of the exams. Human Papillomavirus detection was performed using molecular biology tests, such as hybrid capture (for diagnosis of the Human Papillomavirus group, high or low oncogenic risk) and polymerase chain reaction (viral genotyping) techniques. Results: The diagnosis of Human Papillomavirus infection was performed on women between 1 and 102 years of age. The age with the highest Human Papillomavirus positivity, as expected, was 20­25 years (45.6%) and the lowest after 70 years (7.1%). The highest Human Papillomavirus positivity of the exams was observed in the Serrana region of Santa Catarina state (58.9% of the exams). A high-oncogenic-risk Human Papillomavirus was detected in 93% of positive samples and was the most frequent in all age groups. Mixed infection (high- and low-risk Human Papillomavirus) was more prevalent in the 66­70 age group (29.3%) and in the Southern Region of Santa Catarina (26.4%). The most frequent genotypes in the state of Santa Catarina were non-16/18 high oncogenic risk Human Papillomavirus (76.9% of positive cases). Human Papillomavirus 16 was found in 17.1% of positive cases and Human Papillomavirus 18 in 6.6%. Conclusion: The most prevalent types of Human Papillomavirus in the state of Santa Catarina in the past 6 years are the non-16/18 high oncogenic risk Human Papillomavirus types, which are viral types not covered by the current Human Papillomavirus vaccines available in Brazil.

A infecção por Papilomavírus Humano é a infecção sexualmente transmissível mais frequente na mulher. Cerca de 80% das mulheres sexualmente ativas entrarão em contato com esse vírus em algum momento. A maioria das infecções será transitória, mas quando ela é persistente, associada aos Papilomavírus Humano de alto risco oncogênico, poderá progredir para câncer, principalmente de colo de útero. A melhor forma de se prevenir da contaminação pelo vírus é por meio de vacina, disponível no sistema público do Brasil desde 2014. Objetivo: Avaliar os tipos de Papilomavírus Humano mais prevalentes no estado de Santa Catarina e suas mesorregiões, e se a maioria dos tipos diagnosticados estão contidos nas vacinas contra o Papilomavírus Humano atualmente disponíveis no mercado. Métodos: Foram avaliados 20 mil exames para diagnóstico da infecção genital pelo Papilomavírus Humano em mulheres de todo o estado. A prevalência da infecção foi comparada de acordo com a idade e a procedência dos exames. A detecção do Papilomavírus Humano deu-se pelos exames de biologia molecular pelas técnicas de captura híbrida (para diagnóstico do grupo de Papilomavírus Humano, alto ou baixo riscos oncogênicos) e de PCR (genotipagem viral). Resultados: Foram avaliados exames para diagnóstico da infecção de mulheres entre um e 102 anos de idade. A faixa etária de maior positividade, como era de ser esperado, foi dos 20 aos 25 anos (45.6%) e a menor depois dos 70 anos (7.1%). A maior positividade dos exames foi observada na região Serrana do estado (58.9% dos exames). O Papilomavírus Humano de alto risco oncogênico foi detectado em 93% dos casos positivos e foi o mais frequente em todas as faixas etárias. A infecção mista (Papilomavírus Humano de alto e baixo riscos) foi mais prevalente na faixa etária dos 66 aos 70 anos (29.3%) e na região Sul Catarinense (26.4%). Os genótipos mais frequentes no estado foram os Papilomavírus Humano de alto risco oncogênico não 16/18 (76.9% dos casos positivos). O Papilomavírus Humano 16 foi encontrado em 17.1% dos casos positivos e o Papilomavírus Humano 18 em 6.6%. Conclusão:Os tipos de Papilomavírus Humano mais prevalentes no estado de Santa Catarina, nos últimos seis anos, são os Papilomavírus Humano de alto risco oncogênico não 16/18, tipos virais não cobertos pelas atuais vacinas contra o Papilomavírus Humano disponíveis no Brasil.

The antigen processing-associated transporter gene polymorphism: Role on gene and protein expression in HPV-infected pre-cancerous cervical lesion.

Human papillomavirus (HPV) is the major pathogen for cervical lesions. The evasion mechanism of the immune response and persistence of HPV infection can be influenced by polymorphisms (SNPs) in genes associated with transporter associated with antigen processing (TAP), which may change the peptide binding affinity or the TAP expression impacting the efficiency of peptide transport in the secretory pathway, and the presentation of peptides to cytotoxic T lymphocytes. This study aimed to evaluate the role of the TAP1 and TAP2 polymorphisms, TAP1, and TAP2 genes expressions, and protein levels in cervical cells presenting different degrees of pre-cancerous lesions in 296 immunocompetent women infected or not by HPV. TAP SNPs were genotyped by Sanger sequencing, and gene expression by real-time PCR. Aneuploidy was determined by DNA index using flow cytometry. TAP-1 and TAP-2 tissue expressions were evaluated by immunohistochemistry. The Asp697Gly SNP of TAP1 presented a risk for cellular aneuploidy (P=0.0244). HPV+ women had higher TAP-2 mRNA (P=0.0212) and protein (P<0.0001) levels. The TAP2D and TAP2E haplotypes were associated with the risk for aneuploidy and pre-cancerous lesions. In conclusion, nucleotide variability at the peptide binding region of peptide transporter genes, particularly of the TAP2 gene, may influence the HPV-peptide transportation from the cytosol to the endoplasmic reticulum, increasing the susceptibility to the development of high-grade cervical lesions.

Validation of blood gas analysis in arteriovenous fistula for hemodialysis.

INTRODUCTION: Arterial blood gas analysis is a minimally invasive technique used in our daily practice but is not a complication free technique. The aim of this study was to validate results from blood gas analysis obtained from the arteriovenous fistula (AVF)/graft as a surrogate marker of the arterial blood gas analysis. METHODS: A prospective observational study was made in 45 patients. We performed arterial and AVF/graft blood gas analysis and results were compared by a paired sample t Student test. RESULTS: Most of our subjects was male (68.9%) and the mean age was 67 years (±14). Hemodialysis vintage was 63 months (±66), and vascular access age was 62 months (±56). The more prevalent vascular access was left radiocephalic AVF (n = 16; 35.6%) and the main puncture artery was right radial artery (n = 27; 60.0%). There were no statistically significant differences between the samples collected. CONCLUSIONS: Our results suggest a possible alternative of arterial blood gas analysis in AVF/graft for hemodialysis patients. This could result in making an uncomfortable procedure almost painless and reducing complications. Future research should take place to include anatomical characteristics of the AVF or the circulation of recirculation.