Perfil sociodemográfico e de saúde de diabéticos atendidos em consulta de enfermagem em ambulatório de hospital universitário

As doenças crônicas não transmissíveis (DCNT), em especial o Diabetes Mellitus (DM), são um grave problema de saúde pública, sendo a consulta de enfermagem (CE) um instrumento utilizado no controle da doença e seus agravos. Estudo baseado em experiências de CE a pacientes portadores de DM em ambulatório de estabelecimento de saúde de nível terciário, hospital universitário geral de capital do sul do Brasil. O conhecimento da situação social, econômica e de saúde dos pacientes atendidos é uma forma de auxiliar o enfermeiro na obtenção de melhor resposta as combinações e orientações melhorando o controle da doença e incrementando a qualidade de vida do paciente. Objetivo do estudo: Caracterizar perfil sociodemográfico e de saúde de pacientes adultos diabéticos atendidos em consulta de enfermagem em ambulatório de hospital universitário. Estudo de caráter quantitativo e delineamento transversal. A amostra foi constituída por pacientes adultos diabéticos com a primeira consulta marcada na agenda EAD (Enfermagem Adulto Diabético) - grade 23442 - no período de 2016 a 2017. A análise dos dados mostrou pacientes com predomínio da raça branca e sexo feminino, casados, naturais do interior do Rio Grande do Sul, residentes em Porto Alegre e região metropolitana, baixa escolaridade e com grande número de faltas a consultas. O perfil de saúde, sob a visão do controle do diabetes e DCNT tem acúmulo de comorbidades e níveis glicêmicos e de hemoglobina glicada fora das metas terapêuticas. Conclui-se que o desafio da CE em auxiliar no tratamento dos pacientes diabéticos é complexo pela longa duração das DCNT e por recebermos pacientes com inúmeras comorbidades e as limitações surgidas pelas manifestações destas patologias. A condição sociodemográfica é fator importante no planejamento e implementação do cuidado pela influência na compreensão do estado de saúde e doença pelo paciente, e na adoção das mudanças de estilo de vida e terapêuticas farmacológicas para controle e tratamento do diabetes

免疫不全ウイルスの持続感染・伝播における変異蓄積に関する研究

学位の種別: 課程博士審査委員会委員 : (主査)東京大学教授 川口 寧, 東京大学教授 岩本 愛吉, 東京大学教授 岡崎 仁, 東京大学講師 奥川 周, 東京大学講師 紙谷 尚子University of Tokyo(東京大学

Efficacy of Ebselen Against Invasive Aspergillosis in a Murine Model

Invasive aspergillosis is one of the major causes of morbidity and mortality among invasive fungal infections. The search for new antifungal drugs becomes imperative when existing drugs are not able to efficiently treat these infections. Ebselen, is an organoselenium compound, already successfully approved in clinical trials as a repositioned drug for the treatment of bipolar disorder and prevention of noise-induced hearing loss. In this study, we aimed to reposition ebselen for the treatment of invasive aspergillosis by showing ebselen effectiveness in a murine model. For this, BALB/c mice were immunosuppressed and infected systemically with Aspergillus fumigatus. Animals were divided and treated with ebselen, voriconazole, or drug-free control, for four days. The kidneys were used for CFU count and, histopathological and cytokine analysis. Ebselen was able to significantly reduce the fungal burden in the kidneys of infected mice with efficacy comparable with voriconazole treatment as both had reductions to the same extent. The absence of hyphae and intact kidney tissue structure observed in the histopathological sections analyzed from treated groups corroborate with the downregulation of IL-6 and TNF. In summary, this study brings for the first time in vivo evidence of ebselen efficacy against invasive aspergillosis. Despite these promising results, more animal studies are warranted to evaluate the potential role of ebselen as an alternative option for the management of invasive aspergillosis in humans

Autoimmunity and immunodeficiency associated with monoallelic LIG4 mutations via haploinsufficiency

BACKGROUND: Biallelic mutations in LIG4 encoding DNA-ligase 4 cause a rare immunodeficiency syndrome manifesting as infant-onset life-threatening and/or opportunistic infections, skeletal malformations, radiosensitivity and neoplasia. LIG4 is pivotal during DNA repair and during V(D)J recombination as it performs the final DNA-break sealing step. OBJECTIVE: We explored whether monoallelic LIG4 missense mutations may underlie immunodeficiency and autoimmunity with autosomal dominant inheritance. METHODS: Extensive flow-cytometric immune-phenotyping was performed. Rare variants of immune system genes were analyzed by whole exome sequencing. DNA repair functionality and T cell-intrinsic DNA damage tolerance was tested with an ensemble of in vitro and in silico tools. Antigen-receptor diversity and autoimmune features were characterized by high-throughput sequencing and autoantibody arrays. Reconstitution of wild-type vs. mutant LIG4 were performed in LIG4 knock-out Jurkat T cells and DNA damage tolerance was subsequently assessed. RESULTS: A novel heterozygous LIG4 loss-of-function mutation (p.R580Q), associated with a dominantly inherited familial immune-dysregulation consisting of autoimmune cytopenias, and in the index patient with lymphoproliferation, agammaglobulinemia and adaptive immune cell infiltration into nonlymphoid organs. Immunophenotyping revealed reduced naïve CD4$^{+}$ T cells and low TCR-Vα7.2$^{+}$ T cells, while T/B-cell receptor repertoires showed only mild alterations. Cohort screening identified two other non-related patients with the monoallelic LIG4 mutation p.A842D recapitulating clinical and immune-phenotypic dysregulations observed in the index family and displaying T cell-intrinsic DNA damage intolerance. Reconstitution experiments and molecular dynamics simulations categorize both missense mutations as loss-of-function and haploinsufficient. CONCLUSION: We provide evidence that certain monoallelic LIG4 mutations may cause human immune dysregulation via haploinsufficiency

Development and Psychometric Evaluation of a Japanese Version of Newly Graduated Nurses’ Difficulties with End-of-Life Care for Cancer Patients (NDEC Scale)

(1) Background: End-of-life care (EoL care) for cancer patients is stressful for nurses and can easily lead to burnout. Newly graduated nurses (NGNs) have a particularly difficult time, but no scale or inventory has been designed to evaluate their difficulties. This study developed and tested the reliability and validity of a scale to measure NGNs’ difficulties with EoL care for cancer patients (NDEC scale). (2) Methods: This study population consisted of 1000 NGNs and 1000 nurses with at least five years of clinical experience (GNs) that were working in hospitals in Japan. The initial scale consisted of six factors and 28 items. The reliability and validity of the scale were tested. (3) Results: A total of 171 NGNs and 194 GNs responded to the survey. The scale consisted of five factors and 25 items with the factors including “Feeling painful”, “Can’t deal with patients and their families”, “Don’t know the answer”, “Cannot afford”, and “Being afraid of death”. The criteria validity, known population validity, and internal consistency were confirmed. (4) Conclusions: The scale was validated to have a certain level of reliability and validity. The NDEC scale is expected to be used for self-care for NGNs and as an effectiveness indicator for educational programs

Identification of new putative inhibitors of Mycobacterium tuberculosis 3-dehydroshikimate dehydratase from a combination of ligand- and structure-based and deep learning in silico approaches

International audienceThe development of new drugs against Mycobacterium tuberculosis is an essential strategy for fighting drug resistance. Although 3-dehydroquinate dehydratase (MtDHQ) is known to be a highly relevant target for M. tuberculosis , current research shows new putative inhibitors of MtDHQ selected by a large-scale ensemble-docking strategy combining ligand- and target-based chemoinformatic methods to deep learning. Initial chemical library was reduced from 216 million to approximately 460 thousand after pharmacophore, toxicity and molecular weight filters. Final library was subjected to an ensemble-docking protocol in GOLD which selected the top 300 molecules (GHITS). GHITS displayed different structures and characteristics when compared to known inhibitors (KINH). GHITS were further screened by post-docking analysis in AMMOS2 and deep learning virtual screening in DeepPurpose. DeepPurpose predicted that a number of GHITS had comparable or better affinity for the target than KINH. The best molecule was selected by consensus ranking using GOLD, AMMOS2 and DeepPurpose scores. Molecular dynamics revealed that the top hit displayed consistent and stable binding to MtDHQ, making strong interactions with active-site loop residues. Results forward new putative inhibitors of MtDHQ and reinforce the potential application of artificial intelligence methods for drug design. This work represents the first step in the validation of these molecules as inhibitors of MtDHQ

Dysbiotic Fecal Microbiome in HIV-1 Infected Individuals in Ghana.

HIV-1 infected individuals under antiretroviral therapy can control viremia but often develop non-AIDS diseases such as cardiovascular and metabolic disorders. Gut microbiome dysbiosis has been indicated to be associated with progression of these diseases. Analyses of gut/fecal microbiome in individual regions are important for our understanding of pathogenesis in HIV-1 infections. However, data on gut/fecal microbiome has not yet been accumulated in West Africa. In the present study, we examined fecal microbiome compositions in HIV-1 infected adults in Ghana, where approximately two-thirds of infected adults are females. In a cross-sectional case-control study, age- and gender-matched HIV-1 infected adults (HIV+; n = 55) and seronegative controls (HIV-; n = 55) were enrolled. Alpha diversity of fecal microbiome in HIV+ was significantly reduced compared to HIV- and associated with CD4 counts. HIV+ showed reduction in varieties of bacteria including Faecalibacterium, the most abundant in seronegative controls, but enrichment of Proteobacteria. Ghanaian HIV+ exhibited enrichment of Dorea and Blautia; bacteria groups whose depletion has been reported in HIV-1 infected individuals in several other cohorts. Furthermore, HIV+ in our cohort exhibited a depletion of Prevotella, a genus whose enrichment has recently been shown in men having sex with men (MSM) regardless of HIV-1 status. The present study revealed the characteristics of dysbiotic fecal microbiome in HIV-1 infected adults in Ghana, a representative of West African populations

Two New 1,3,4-Oxadiazoles With Effective Antifungal Activity Against Candida albicans

International audienceCandidainfections have become a serious public health problem with high mortalityrates, especially in immunocompromised patients, sinceCandida albicansis the majoropportunistic pathogen responsible for systemic or invasive candidiasis. Commerciallyavailable antifungal agents are restricted and fungal resistance to such drugs hasincreased; therefore, the development of a more specific antifungal agent is necessary.Using assays for antifungal activity, here we report that two new compounds of1,3,4-oxadiazoles class (LMM5 and LMM11), which were discovered byin silicomethodologies as possible thioredoxin reductase inhibitors, were effective againstC. albicans. Both compounds hadin vitroantifungal activity with MIC 32μg/ml.Cytotoxicityin vitrodemonstrated that LMM5 and LMM11 were non-toxic in the cell linesevaluated. The kinetic of the time-kill curve suggested a fungistatic profile and showedan inhibitory effect of LMM5 and LMM11 in 12 h that remained for 24 and 36 h, whichis better than fluconazole. In the murine systemic candidiasis model byC. albicans, thetwo compounds significantly reduced the renal and spleen fungal burden. Accordingto the SEM and TEM images, we hypothesize that the mechanism of action of LMM5and LMM11 is directly related to the inhibition of the enzyme thioredoxin reductaseand internally affect the fungal cell. In view of allin vitroandin vivoresults, LMM5and LMM11 are effective therapeutic candidates for the development of new antifungaldrugs addressing the treatment of human infections caused byC. albicans

Fungicidal Activity of a Safe 1,3,4-Oxadiazole Derivative Against <i>Candida albicans</i>

Candida albicans is the most common species isolated from nosocomial bloodstream infections. Due to limited therapeutic arsenal and increase of drug resistance, there is an urgent need for new antifungals. Therefore, the antifungal activity against C. albicans and in vivo toxicity of a 1,3,4-oxadiazole compound (LMM6) was evaluated. This compound was selected by in silico approach based on chemical similarity. LMM6 was highly effective against several clinical C. albicans isolates, with minimum inhibitory concentration values ranging from 8 to 32 µg/mL. This compound also showed synergic effect with amphotericin B and caspofungin. In addition, quantitative assay showed that LMM6 exhibited a fungicidal profile and a promising anti-biofilm activity, pointing to its therapeutic potential. The evaluation of acute toxicity indicated that LMM6 is safe for preclinical trials. No mortality and no alterations in the investigated parameters were observed. In addition, no substantial alteration was found in Hippocratic screening, biochemical or hematological analyzes. LMM6 (5 mg/kg twice a day) was able to reduce both spleen and kidneys fungal burden and further, promoted the suppresses of inflammatory cytokines, resulting in infection control. These preclinical findings support future application of LMM6 as potential antifungal in the treatment of invasive candidiasis