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PI3K delta (PI3Kδ) inhibitors are used to treat lymphomas but safety concerns and limited target selectivity curbed their clinical usefulness. PI3Kδ inhibition in solid tumors has recently emerged as a potential novel anticancer therapy through the modulation of T-cell responses and direct antitumor activity. Here we report the exploration of IOA-244/MSC2360844, a first-in-class non–ATP-competitive PI3Kδ inhibitor, for the treatment of solid tumors. We confirm IOA-244’s selectivity as tested against a large set of kinases, enzymes, and receptors. IOA-244 inhibits the in vitro growth of lymphoma cells and its activity correlates with the expression levels of PIK3CD, suggesting cancer cell–intrinsic effects of IOA-244. Importantly, IOA-244 inhibits regulatory T cell proliferation while having limited antiproliferative effects on conventional CD4+ T cells and no effect on CD8+ T cells. Instead, treatment of CD8 T cells with IOA-244 during activation, favors the differentiation of memory-like, long-lived CD8, known to have increased antitumor capacity. These data highlight immune-modulatory properties that can be exploited in solid tumors. In CT26 colorectal and Lewis lung carcinoma lung cancer models, IOA-244 sensitized the tumors to anti-PD-1 (programmed cell death protein 1) treatment, with similar activity in the Pan-02 pancreatic and A20 lymphoma syngeneic mouse models. IOA-244 reshaped the balance of tumor-infiltrating cells, favoring infiltration of CD8 and natural killer cells, while decreasing suppressive immune cells. IOA-244 presented no detectable safety concerns in animal studies and is currently in clinical phase Ib/II investigation in solid and hematologic tumors. Significance: IOA-244 is a first-in-class non–ATP-competitive, PI3Kδ inhibitor with direct antitumor in vitro activity correlated with PI3Kδ expression. The ability to modulate T cells, in vivo antitumor activity in various models with limited toxicity in animal studies provides the rationale for the ongoing trials in patients with solid tumors and hematologic cancers.

O artigo trata sobre as estratégias de comunicação da Uber: a midiatização da inovação e a conjuntura de risco/Covid-19. Examinamos a circulação de sentidos das estratégias de comunicação da Uber a partir de duas matrizes interacionais: a primeira, apresentando as estratégias de comunicação utilizadas por essa organização durante a implantação de sua plataforma de mobilidade no Brasil; a segunda, permeada pelos discursos da pandemia. A pesquisa se desenvolve a partir de um estudo de caso midiatizado, indicando que a Uber acopla estratégias de ambas as matrizes interacionais, que se interpenetram e geram uma terceira matriz interacional, que oferta inovação e segurança por meio de gramáticas, contratos e operações que circulam via circuitos interacionais.

The configuration of a “modern” production structure requires there to be sufficient en-ergy supply at competitive costs. Since the last third of the nineteenth century, coal produc-tion and better natural conditions for generating electric energy at low cost explain – at least partially – the differences in favour of New Zealand with respect to Uruguay. However, in-stitutional arrangements are another relevant factor of differentiation. Our argument is based on the concept of endogeneity of natural resources, and we use it to prove the differ-ent roles of states in electricity systems: state intervention aimed at improving welfare con-ditions in Uruguay without paying enough attention to aspects related to production condi-tions; while, in New Zealand, productive development was the focus of public action. As a result, a more extensive and denser electrical network was consolidated in New Zealand which, potentially, would have created better conditions in terms of diversification and ru-ral production.

Background: Despite evidence of substantial breast cancer risk reduction, few high-risk women adopt chemopreventive medications such as selective estrogen receptor modulators (SERMs) or aromatase inhibitors (AIs). Women with benign breast disease, such as atypical hyperplasia (AH) or lobular carcinoma in situ (LCIS), have an increased risk of developing breast cancer and derive a greater benefit from antiestrogens compared to other high-risk women. Reasons for low uptake of chemoprevention include insufficient patient and clinician knowledge about antiestrogens, time constraints during the clinical encounter, and concerns about side effects. To address these barriers, we have developed patient and provider web-based decision support tools to improve informed choice about breast cancer chemoprevention among women with AH or LCIS. Study design: We are conducting a cluster-randomized controlled trial of clinical decision support to improve chemoprevention informed choice among women with AH or LCIS and their treating providers. Twenty-six U.S. sites through the SWOG Cancer Research Network were randomly assigned 1:1 to standard educational materials alone or in combination with the patient-centered decision aid (RealRisks) and provider decision support tool (BNAV). A total of 415 patients and 200 healthcare providers will be recruited from these sites. RealRisks consists of interactive modules to calculate personalized breast cancer risk and elicit preferences on chemoprevention. The modules are available in English and Spanish. BNAV is comprised of self-directed case-based learning modules on breast cancer risk assessment and chemoprevention. Patients complete questionnaires at baseline, 6 and 12 months. Providers complete surveys at baseline and after their enrolled patient’s 6-month clinical encounter. The primary endpoint is chemoprevention informed choice at 6 months, using a measure combining knowledge, attitude, and intention scales. Secondary endpoints include perceived breast cancer risk/worry, chemoprevention knowledge/intention, decision conflict/regret, shared decision-making, and chemoprevention uptake. For patients who begin chemoprevention, adherence and reasons for discontinuation are assessed annually for up to 5 years. Barriers and facilitators to implementing RealRisks and BNAV into clinic workflow will be assessed by conducting patient and provider interviews at baseline and mid-implementation. Eligibility criteria: Eligible patients include women, age 35-74 years, with AH or LCIS, no history of breast cancer, no prior use of SERMs or AIs, no bilateral mastectomies, English or Spanish-speaking, and access to the internet. Eligible providers include breast surgeons, medical oncologists, primary care providers, and physician extenders who see patients with AH or LCIS. Statistical methods: We have 90% power to detect a 15% increase in the frequency of chemoprevention informed choice with a 1-sided 0.025 level test, assuming an intraclass correlation (ICC) of 0.02 to account for clustering, roughly equal accrual at each site, 10% loss to follow-up, and ≤10% event rate in the control arm. Current/target accrual: The trial was activated on 9/1/2020. As of 7/7/2022, all 26 sites have been randomized, 157/200 providers and 184/415 patients have been enrolled. Discussion: Our hybrid effectiveness/implementation study seeks to evaluate the effectiveness of a multi-level intervention in promoting informed decision-making about breast cancer chemoprevention. Study results will provide valuable insights on how the decision support tools are integrated in diverse clinical settings. Citation Format: Katherine D. Crew, Garnet Anderson, Kathryn Arnold, Andrew Stieb, Jacquelyn N. Amenta, Cynthia Law, Ana Sandoval-Leon, Sarah Colonna, Tari King, Debra Mangino, Sandhya Pruthi, Maria Grosse Perdekamp, Christa Braun-Inglis, Stacy Krisher, Lisa Yee, Danielle Bertoni, Samantha Seaward, Kari B. Wisinski, Justin Floyd, Corrine Zarwan, Tarah J. Ballinger, Lindi VanderWalde, Masey M. Ross, Preston Steen, Shelly Lo, Alison Conlin, Kathleen Yost, John Ellerton, Erin Lin, Holly J. Pederson, Sagar Sardesai, Cheryl Jernigan, Dawn Hershman, Marian L. Neuhouser, Banu K. Arun, Rita Kukafka. SWOG 1904: Cluster-randomized controlled trial of patient and provider decision support to increase chemoprevention informed choice among women with atypical hyperplasia or lobular carcinoma in situ (MiCHOICE) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-15-01.

Inhibitors of the Bromo- and Extra-Terminal domain (BET) family proteins have strong preclinical antitumor activity in multiple tumor models, including lymphomas. Limited single-agent activity has been reported in the clinical setting. Here, we have performed a pharmacological screening to identify compounds that can increase the antitumor activity of BET inhibitors in lymphomas. The germinal center B-cell like diffuse large B-cell lymphoma (DLBCL) cell lines OCI-LY-19 and WSU-DLCL2 were exposed to 348 compounds given as single agents at two different concentrations and in combination with the BET inhibitor birabresib. The combination partners included small molecules targeting important biologic pathways such as PI3K/AKT/MAPK signaling and apoptosis, approved anticancer agents, kinase inhibitors, epigenetic compounds. The screening identified a series of compounds leading to a stronger antiproliferative activity when given in combination than as single agents: the histone deacetylase (HDAC) inhibitors panobinostat and dacinostat, the mTOR (mechanistic target of rapamycin)inhibitor everolimus, the ABL/SRC (ABL proto-oncogene/SRC proto oncogene) inhibitor dasatinib, the AKT1/2/3 inhibitor MK-2206, the JAK2 inhibitor TG101209. The novel finding was the benefit given by the addition of the LRRK2 inhibitor LRRK2-IN-1, which was validated in vitro and in vivo. Genetic silencing demonstrated that LRRK2 sustains the proliferation of lymphoma cells, a finding paired with the association between high expression levels and inferior outcome in DLBCL patients. We identified combinations that can improve the response to BET inhibitors in lymphomas, and LRRK2 as a gene essential for lymphomas and as putative novel target for this type of tumors.

Introdução: O tratamento farmacológico da esquizofrenia com a associação de antipsicóticos é uma prática bastante comum, ainda que não haja evidências científicas consolidadas que a fundamentem, tampouco haja orientação nesse sentido, nas diretrizes de tratamento clínico. Objetivo: Avaliar os benefícios e os riscos do uso da associação de antipsicóticos em comparação ao uso de antipsicótico em monoterapia para o tratamento de esquizofrenia. Metodologia: Foi realizada uma revisão na literatura em busca de estudos científicos que comparassem o uso de antipsicóticos em monoterapia com a associação de antipsicóticos para o tratamento da esquizofrenia. Resultados: Na maioria dos estudos não houve diferenças no controle de sintomas entre os grupos. No entanto, observou-se menor frequência de reagudizações de sintomas e redução das hospitalizações nos pacientes em tratamento com antipsicótico em monoterapia. Além disso, houve menos efeitos adversos em pacientes com essa opção terapêutica. A adesão foi menor com a troca do tratamento com associação de antipsicóticos para antipsicótico em monoterapia. Porém a mudança foi bem tolerada, sendo que, em quase todos os pacientes, foram observados resultados favoráveis. Conclusões: O tratamento da esquizofrenia e do transtorno esquizoafetivo com antipsicótico em monoterapia apresenta um controle de sintomas semelhante ao tratamento com associação de antipsicóticos. Entretanto, em monoterapia é menor a ocorrência de efeitos colaterais, reagudizações e hospitalizações. Portanto, esta revisão reforça que, na prática clínica, o tratamento farmacológico da esquizofrenia, assim como do transtorno esquizoafetivo, deve priorizar uso de antipsicóticos em monoterapia.

O uso de LEDs, como fonte de radiação no cultivo de plantas, tem despertado considerável interesse nos últimos anos, por estes também possuírem vasto potencial para a aplicação comercial. O objetivo deste trabalho foi avaliar a qualidade da luz na produção de mudas de Physalis. As sementes foram semeadas em bandejas contendo substrato vegetal e mantidas em câmara de crescimento com fotoperíodo de 16 horas e intensidade luminosa de 25 µmol m-2 s-1. Os tratamentos foram constituídos por LEDs azuis, LEDs verdes, LEDs vermelhos e controle (ausência de luz artificial). O delineamento experimental utilizado foi inteiramente casualizado com dez repetições. Após 30 dias foi avaliado a altura das plantas, número de folhas, comprimento das raízes e massa fresca da planta. Os dados obtidos foram submetidos a análise de variância, sendo as médias comparadas pelo teste de Tukey. As plantas com maior altura foram obtidas sob LEDs verdes (7,02 cm) e controle (6,52 cm), e as de menor altura sob LEDs azuis. As plantas cultivadas sob os LEDs vermelhos (5,32 cm) apresentaram raízes maiores do que aquelas mantidas sob LEDs verdes; não houve diferença entre os LEDs vermelhos, LEDs azuis e controle. O maior número de folhas foi obtido sob os LEDs azuis e os menores sob os LEDs vedes e controle. Quanto a massa fresca, a média obtida sob os LEDs vermelhos foram superiores a dos LEDs verdes.

Context: Despite increasing use of reference values in isokinetic measurements and increasing importance, there is no systematic review of the reference values for lower and upper limb isokinetic muscle strength. Objective: A systematic review to analyze studies on the reference values and protocols for the measurement for upper and lower limb isokinetic muscle strength in an untrained and noninjured healthy population. Data Sources: MEDLINE, Scopus, Scielo, and CINAHL (from the earliest date available to June 2020). Study Selection: Studies that measured a set of reference values for isokinetic muscle strength. Study Design: Systematic review. Level of Evidence: Level 3. Data Extraction: Two reviewers selected studies independently. Data related to participants characteristics, outcomes of interest, isokinetic parameters, reference values for isokinetic muscle strength, and quality of evidence assessment were systematically reviewed independently by 2 authors. Results: A total of 31 studies met the study criteria. The included studies were used to synthesize the isokinetic muscle strength data according to age-group and sex. We extracted 1845 normative data related to isokinetic strength. Of these, 1181 items referred to lower limbs and 664 items to upper limbs. Conclusion: In general, agonist muscle groups are stronger than antagonist muscles, and the men tend to obtain higher strength values than women. The angular velocity varied from 10 to 300 deg/s. The reference values identified can be useful for professionals to obtain during the isokinetic evaluation of the diagnostic parameters of muscle deficiency.

Serum collected from multiparous Holsteins (n = 73) in a previous experiment was used to determine the effect of prepartum plane of energy intake on metabolites related to inflammation and liver function in periparturient cows. Prepartum diets were in a 3 × 2 factorial arrangement over the far-off (d -65 to -26 before expected parturition) and close-up (d -25 relative to parturition until parturition) dry periods. During the far-off period, 2 diets were fed for ad libitum intake (ADLIB) to supply either 100% (100E) or 150% (150E) of National Research Council recommendations for net energy for lactation for mature cows in late gestation. For the third dietary far-off treatment, the 150E diet was fed at restricted intake (REST) to supply 80% (80E) of recommendations. During the close-up period, cows were fed a diet either at ADLIB or REST to supply 150% of net energy for lactation or 80% of net energy for lactation requirements, respectively. Beginning at parturition, all cows were fed a lactation diet through 56 d in milk. Cows fed 150E tended to accumulate more liver lipid postpartum; peak lipid accumulation occurred in all groups on d 14 postpartum. Cows fed 150E tended to have lower serum Ca on d 1 after calving, and cows fed REST had higher Ca than those fed ADLIB. Cows fed 150E tended to have higher serum bilirubin prepartum compared with other groups. Feeding REST in the close-up period resulted in higher bilirubin prepartum compared with ADLIB; bilirubin was positively associated (r = 0.34) with lipid accumulation postpartum. Feeding REST resulted in lower serum vitamin A (an indirect measure of retinol binding protein) prepartum compared with ADLIB, especially when coupled with 80E. Postpartum paraoxonase was negatively associated (r = -0.27) and ceruloplasmin was positively associated (r = 0.21) with liver lipid accumulation postpartum. A larger spike in haptoglobin was observed on d 1 and 7 postpartum for cows fed 100E and 150E during the far-off period followed by REST during the close-up period. The ratio of albumin to globulin in serum was higher for cows fed 100E than for those fed 150E both prepartum and postpartum. Liver activity index indicated poorer liver function for cows fed 150E in the far-off period regardless of close-up diet. Negative liver function was also noted for cows fed 80E and REST. Cows in the 100E group fed ADLIB or REST had positive liver activity index postpartum. Avoidance of gross overconsumption of energy prepartum, particularly during the far-off period, appears best to reduce systemic inflammatory signals and improve liver function.

In this work we propose a chemically-informed data-driven approach to benchmark the approximate density-functional tight-binding (DFTB) excited state (ES) methods that are currently available within the DFTB+ suite. By taking advantage of the large volume of low-detail ES-data in the machine learning (ML) dataset, QM8, we were able to extract valuable insights regarding the limitations of the benchmarked methods in terms of the approximations made to the parent formalism, density-functional theory (DFT), while providing recommendations on how to overcome them. For this benchmark, we compared the first singlet-singlet vertical excitation energies ($E_1$) predicted by the DFTB-approximate methods with predictions of less approximate methods from the reference ML-dataset. For the nearly 21,800 organic molecules in the GDB-8 chemical space, we were able to identify clear trends in the $E_1$ prediction error distributions, with respect to second-order approximate coupled cluster (CC2), showing a strong dependence on chemical identity., Comment: This article has been submitted to the Physical Chemistry Chemical Physics (PCCP) journal

Hot-pressing leads to low temperature densification of garnet type Li5La3Bi2O12 solid electrolyte and density functional theory calculations allow to explore its metastable properties under the formation of impurities.

Knowledge of the global reservoir of submarine gas hydrates is of great relevance for understanding global climate dynamics, submarine geohazards, and unconventional hydrocarbon energy resources. Despite the expected presence of gas hydrates from modeling studies, the land-locked Mediterranean Basin displays a lack of evidence of extensive gas hydrate presence from samples and seismic data. We modeled the theoretical Mediterranean distribution of methane hydrate below the seafloor and in the water column using available geological information provided by 44 Deep Sea Drilling Project (DSDP) and Ocean Drilling Program (ODP) boreholes, measured geothermal gradients, and thermohaline characteristics of the water masses. We find that the pervasive presence of high-salinity waters in sediments, coupled with the unique warm and salty water column, limit the thickness of the theoretical methane hydrate stability zone in the subsurface and deepen its top surface to 1163–1391 m water depth. The theoretical distribution of methane hydrates coincides well with the distribution of shallow, low-permeability Messinian salt deposits, further limiting the formation of pervasive gas hydrate fronts and controlling their or distribution due to the prevention of upward hydrocarbon gas migration. We conclude that the Mediterranean Basin, hosting the youngest salt giant on Earth, is not prone to the widespread formation and preservation of gas hydrates in the subsurface and that the gas hydrate potential of salt-bearing rifted continental margins may be considerably decreased by the presence of subsurface brines.

A Leishmaniose Tegumentar Americana (LTA) é uma doença infecciosa negligenciada por apresentar caráter emergencial e uma imediata urgência de controle do vetor e disponibilidade de tratamento. Esta patologia vem aumentando nos últimos vinte anos, sendo a leishmaniose cutânea (LC) sua manifestação clínica mais frequente e a Leishmaniose mucosa (LM) sua manifestação grave. Constitui um problema de saúde pública em mais 85 países. Portanto, O presente estudo será uma revisão bibliográfica sobre atividade Antileishmania da folha de Artemisia annua L. (Asterolacea) no tratamento da Leishmaniose Tegumentar em humanos como potenciais agentes utilizados como forma de tratamento contra o referido parasita.

Este estudo buscou investigar as dificuldades enfrentadas pelos professores e professoras dos anos iniciais do ensino fundamental I em relação ao ensino durante a pandemia ocasionada pela Covid-19. Como metodologia, utilizou-se a análise qualitativa e coleta de dados por meio do questionário aplicado à professores e professoras de duas escolas, uma da rede pública e a outra da rede privada, ambas localizadas no município de Ponta Grossa-PR. Como resultado, constatou-se que a maioria dos professores e professoras pesquisados não receberam formação acadêmica sobre o ensino não presencial, bem como se perceberam despreparados para ministrar aulas e atividades nesse modo, evidenciando o quão a abordagem de ensino tradicional está incutida nos sujeitos.

Background.The extraction-free HTG Edge-Seq protocols are recent techniques for a time- and cost-effective characterisation of tumors and their microenvironment composition, by profiling a predefined set of genes and measuring their gene expressions. Despite positive and control genes are provided, little indication is given with respect to the assessment of the technical success of each sample within the run. Findings.We have developed HTGQC, a R package for the quality control of HTG Edge-Seq protocols, and shinyHTGQC, a shiny application for users without computing knowledge, that provides an easy-to-use interface for the the quality control of the data. The quality check can be performed directly from the raw output of the sequencing machine, and provides summary, tables and plots for the assessment of the quality of the samples. Samples are flagged as FAIL or ALERT based on the expression levels of the positive and negative control genes. In the shiny application basic visualisation (PCA and heatmap) is provided for assessing the different pre vs post quality control. The code is freely availabe on the web athttps://github.com/LodovicoTerzi/HTGQC(R package) and athttps://lodovico.shinyapps.io/shinyHTGQC/(shiny application), including test datasets. Conclusions.HTGQC allows to perform quality control for HTG Edge-Seq protocols, an unmet need at the moment. A user-friendly web tool allows the visualisation of the effect of data cleaning.

The paper addresses the issue of complexity in the administrative processes of public institutions: in particular, accounting routines and processes are examined. Back-office activities, although having a mere supporting role in the delivery of public services, absorb a relevant part of the resources of public institutions. The aim of the paper is to analyse the factors that contribute to the enhancement of complexity of these activities. The paper is based on an in-depth analysis of two Italian public organisations: a university and an ASP (agency for services to persons). Italy is an interesting context since simplification policies have been adopted in the country at central government level and in specific sectors of public administration, however, at the institutional level, simplification initiatives depend on the initiative of the single organisation. The cases described in this paper show that complexity stems from the need for inspectory controls (which is typical of the law) as well as from the volume of information requested (which is typical of management studies) for different stakeholders and at different, yet correlated, levels. The paper suggests that public management scholars have the opportunity and the burden of a contribution in this field.

Neisseria gonorrhoeae é um agente etiológico da gonorreia, uma das doenças sexualmente transmissíveis mais comuns causadas por bactérias. Por muitos anos, as infecções causadas por N. gonorrhoeae foram consideradas relativamente fáceis de tratar, no entanto, a resistência emergiu sucessivamente a todos os agentes terapêuticos usados ​​no tratamento da doença, por exemplo, penicilina, ciprofloxacina ou azitromicina. Atualmente, o problema global é o surgimento e a ameaça de disseminação de cepas de N. gonorrhoeae resistentes. A presença de diferentes mecanismos de resistência aos medicamentos afeta significativamente a prática clínica e força mudanças nos regimes de tratamento e a introdução de novos medicamentos. O controle da gonorreia tem sido difícil na maioria das populações. Algumas explicações para essa incidência se dão por fatores sociais, comportamentais e demográficos. O manejo da gonorreia e de outras doenças sexualmente transmissíveis requer tanto o tratamento do paciente e de seu parceiro sexual como medidas de saúde pública para interromper a transmissão da infecção e evitar complicações de longo prazo.

Es imprescindible explorar alternativas para producir alimentos a través de modelos de bajo consumo de energía y reducida emisión de gases invernadero, pero con rendimientos elevados. En este artículo se analizan resultados de investigaciones que documentan la viabilidad de los sistemas de producción de búfalos de agua en un ambiente propicio y exigente como el trópico mexicano, siguiendo los preceptos de la agroecología. Se examinan los principios básicos de la agroecología aplicada a la ganadería, para identificar la interacción suelovegetación-búfalos y potenciar procesos de resiliencia. Se caracterizaron los aspectos físico-bióticos de la región tropical, en especial sus recursos forrajeros. También se estudian las características anatómicas y fisiológicas de los búfalos para prosperar en este ambiente, bajo la modalidad de doble propósito, produciendo carne y leche. Finalmente, se aportan elementos para diseñar sistemas de pastoreo intensivo, incluyendo los silvopastoriles, en los cuales los búfalos responden de manera sobresaliente. Se concluye que es factible implementar sistemas sustentables de búfalos en el trópico, mediante un proceso de intensificación planificado, que puede suponer el acompañamiento de asistencia técnica especializada para que se puedan adoptar con éxito.

The aim is to elucidate other key aspects of these dual-purpose systems in wetland areas, including labor, markets, the conditions of facilities, machinery and equipment indices, and zootechnical indicators. The health management values determined for production units (PU) PU2, 3, and 4 were similar (50%) but higher at PU1 (75%). Three scheduled milkings once a day (1x), but PU3 performed it twice a day (2x). Most workers are permanent, but PU1 and PU2 hire temporary laborers. The average workday was 7.69 ± 2.84 hours/animal unit at a mean wage of $11.43 ± $1.27. Unit prices per kg of meat from fattening animals and liter of milk were $1.83 ± $0.03 and $0.51 ± $0.08, respectively. Production variables showed an average calving interval of 371.25 ± 7.50 days, a mean parturition index of 89% ± 1%, and mean mortality of 1.8% ± 0.5% and 0.6% ± 0.8% for young and adult animals, respectively. Milk production per lactation was 1240 ± 211.66 liters. The mean daily production for sale was 5.17 ± 0.88 liters. Individual calves consumed 2.13 ± 0.63 liters of milk per day on average. Mean productive life was 17 ± 2.45 years. Average scores on the facilities conditions and machinery and equipment indices were 68% ± 14% and 57% ± 26%, respectively.

In this study, researchers reviewed electronic health record data to assess whether the coronavirus disease 2019 pandemic was associated with disruptions in diabetes care processes of A1C testing, retinal screening, and nephropathy evaluation among patients receiving care with Wake Forest Baptist Health in North Carolina. Compared with the pre-pandemic period, they found an increase of 13–21 percentage points in the proportion of patients delaying diabetes care for each measure during the pandemic. Alarmingly, delays in A1C testing were greatest for individuals with the most severe disease and may portend an increase in diabetes complications.

O artigo propõe-se a refletir sobre a história do ensino de teatro na Universidade Federal do Rio Grande do Sul (UFRGS), tendo por base registros memoriais da trajetória acadêmica de seis profissionais formados no Curso de Arte Dramática (CAD)/Departamento de Arte Dramática (DAD) no período compreendido entre os anos de 1960 e 1973. Através da metodologia da História Oral, são produzidos, organizados e analisados depoimentos obtidos por meio de entrevistas, que revelam diferentes aspectos da formação em teatro dentro da universidade.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may result in a severe pneumonia associated with elevation of blood inflammatory parameters, reminiscent of cytokine storm syndrome. Steroidal anti-inflammatory therapies have shown efficacy in reducing mortality in critically ill patients; however, the mechanisms by which SARS-CoV-2 triggers such an extensive inflammation remain unexplained.To dissect the mechanisms underlying SARS-CoV-2-associated inflammation in patients with severe coronavirus disease 2019 (COVID-19), we studied the role of IL-1β, a pivotal cytokine driving inflammatory phenotypes, whose maturation and secretion are regulated by inflammasomes.We analyzed nod-like receptor protein 3 pathway activation by means of confocal microscopy, plasma cytokine measurement, cytokine secretion following in vitro stimulation of blood circulating monocytes, and whole-blood RNA sequencing. The role of open reading frame 3a SARS-CoV-2 protein was assessed by confocal microscopy analysis following nucleofection of a monocytic cell line.We found that circulating monocytes from patients with COVID-19 display ASC (adaptor molecule apoptotic speck like protein-containing a CARD) specks that colocalize with nod-like receptor protein 3 inflammasome and spontaneously secrete IL-1β in vitro. This spontaneous activation reverts following patient's treatment with the IL-1 receptor antagonist anakinra. Transfection of a monocytic cell line with cDNA coding for the ORF3a SARS-CoV-2 protein resulted in ASC speck formation.These results provide further evidence that IL-1β targeting could represent an effective strategy in this disease and suggest a mechanistic explanation for the strong inflammatory manifestations associated with COVID-19.

Este artículo se propone como objetivo analizar las estrategias securitarias de mujeres de sectores populares de La Plata, Argentina. La hipótesis que lo guía es que la innovación y rutinización de estrategias, entendidas como rituales de la vida cotidiana que posibilitan seguir adelante y proyectar una dimensión de futuro, se tornan fundamentales para la autonomía de las mujeres. El análisis se basa en información recolectada mediante observaciones y entrevistas semiestructuradas a mujeres de dos asentamientos periféricos del municipio de La Plata. Los resultados muestran que las estrategias logran dotar la vida cotidiana de cierta certidumbre y colonización del futuro, pero que principalmente despliegan prácticas de evitación y autorrestricción en el uso del espacio urbano. Además, dichas estrategias están mediadas por experiencias sedimentadas previas, tanto propias como ajenas.

Neste artigo, analisamos as representações sociais que os profissionais de saúde mental têm acerca dos usos de substâncias psicoativas. Para tanto, foram realizadas entrevistas com os profissionais de saúde de um Centro de Atenção Psicossocial Álcool e Outras Drogas (CAPS AD), sendo os dados analisados com base na Análise de Conteúdo. Dessas análises, emergiram três categorias reflexivas: a) “Drogas: um olhar dos profissionais do CAPS AD”; b) “Legalização versus criminalização das drogas: o que os profissionais de saúde mental têm a dizer?”; c) “Modelos de tratamento: Redução de Danos versus abstinência”. Os profissionais revelaram dificuldades em trabalhar com a abordagem da Redução de Danos e não apresentam uma posição consolidada a respeito da legalização e criminalização das drogas. Apesar das limitações, este estudo serve como um objeto de reflexão, tendo em vista que propõe uma reorientação das práticas assistenciais em saúde mental.

With the advances of telemetries and computational power, the question for firms is no longer what can be collected but what shall be collected. It is easy to add sensors and gather a vast amount of data but without knowing their purpose, the gains are marginal. In the field of Value-Driven Design, value is quantified and measured to ensure an overall higher output, something crucial for complex and ambiguous domains such as Product-Service Systems. This paper aims at finding the connection between PSS value and operational data from an industrial perspective. By using Participatory Action Research in a manufacturing firm, a value-data framework and method were developed that succeed in connecting these two extremities as well as visualize them with the support of network graph theory. open access

O presente estudo tem por finalidade analisar o perfil epidemiológico dos casos de notificações de acidentes de trabalho com exposição a material biológico no quinquênio de 2018 a 2022 no estado de Rondônia, região norte do país. Trata-se de estudo transversal, descritivo com abordagem quantitativa, do tipo retrospectivo realizado a partir de recorte temporal de dados analisados entre o período de 2018 a 2022 registrados no SINAN e disponibilizados na plataforma do DATASUA/TABNET. Observou-se que ao longo dos cinco anos analisados foram registradas 1737 notificações de acidentes de trabalho com exposição a material biológico, destes os trabalhadores de 30 anos ou mais foram os mais acometidos com 1173 casos, os quais as mulheres corresponderam a (76,05%) dos casos notificados, quanto à escolaridade os portadores de nível médio e superior completo estiveram em maior número. Notou-se também importante registro para os casos notificados que não fizeram emissão do Comunicado de Acidente de Trabalho. Conclui-se que é importante o levantamento de dados de casos existentes para estimular a reflexão da necessidade de implantação de protocolos de notificações e comunicação de acidentes de trabalho com fluídos biológicos bem esclarecidos em instituições públicas e privadas.

Background Autoimmune disorders, including Systemic Lupus Erythematosus (SLE), are associated with increased incidence of hematological malignancies. The matricellular protein osteopontin (OPN) has been linked to SLE pathogenesis, as SLE patients show increased serum levels of OPN and often polymorphisms in its gene. Although widely studied for its pro-tumorigenic role in different solid tumours, the role of OPN in autoimmunity-driven lymphomagenesis has not been investigated yet. Methods To test the role of OPN in the SLE-associated lymphomagenesis, the SLE-like prone Faslpr/lpr mutation was transferred onto an OPN-deficient background. Spleen from Faslpr/lpr and OPN-/-Faslpr/lpr mice, as well as purified B cells, were analysed by histopathology, flow cytometry, Western Blot, immunohistochemistry, immunofluorescence and gene expression profile to define lymphoma characteristics and investigate the molecular mechanisms behind the observed phenotype. OPN cellular localization in primary splenic B cells and mouse and human DLBCL cell lines was assessed by confocal microscopy. Finally, gain of function experiments, by stable over-expression of the secreted (sOPN) and intracellular OPN (iOPN) in OPN-/-Faslpr/lpr -derived DLBCL cell lines, were performed for further validation experiments. Results Despite reduced autoimmunity signs, OPN-/-Faslpr/lpr mice developed splenic lymphomas with higher incidence than Faslpr/lpr counterparts. In situ and ex vivo analysis featured such tumours as activated type of diffuse large B cell lymphoma (ABC-DLBCL), expressing BCL2 and c-MYC, but not BCL6, with activated STAT3 signaling. OPN-/-Faslpr/lpr B lymphocytes showed an enhanced TLR9-MYD88 signaling pathway, either at baseline or after stimulation with CpG oligonucleotides, which mimic dsDNA circulating in autoimmune conditions. B cells from Faslpr/lpr mice were found to express the intracellular form of OPN. Accordingly, gene transfer-mediated re-expression of iOPN, but not of its secreted isoform, into ABC-DLBCL cell lines established from OPN-/-Faslpr/lpr mice, prevented CpG-mediated activation of STAT3, suggesting that the intracellular form of OPN may represent a brake to TLR9 signaling pathway activation. Conclusion These data indicate that, in the setting of SLE-like syndrome in which double strand-DNA chronically circulates and activates TLRs, B cell intracellular OPN exerts a protective role in autoimmunity-driven DLBCL development, mainly acting as a brake in the TLR9-MYD88-STAT3 signaling pathway.

Store-operated Ca2+-entry is a cellular mechanism that governs the replenishment of intracellular stores of Ca2+ upon depletion caused by the opening of intracellular Ca2+-channels. Gain-of-function mutations of the 2 key proteins of store-operated Ca2+-entry, STIM1 and ORAI1, are associated with several ultra-rare diseases clustered as tubular aggregate myopathies. Our group has previously demonstrated that a mouse model bearing the STIM1 p.I115F mutation recapitulates the main features of the STIM1 gain-of-function disorders: muscle weakness and thrombocytopenia. Similar findings have been found in other mice bearing different mutations on STIM1. At present, no valid treatment is available for these patients. In the present contribution, we report that CIC-39Na, a store-operated Ca2+-entry inhibitor, restores platelet number and counteracts the abnormal bleeding that characterizes these mice. Subtle differences in thrombopoiesis were observed in STIM1 p.I115F mice, but the main difference between wild-type and STIM1 p.I115F mice was in platelet clearance and in the levels of platelet cytosolic basal Ca2+. Both were restored on treatment of animals with CIC-39Na. This finding paves the way to a pharmacological treatment strategy for thrombocytopenia in tubular aggregate myopathy patients.

En Paraguay, así como en las Américas, la leishmaniasis constituye una de las problemáticas de salud pública importante, debido a su complejidad tanto epidemiológica, clínica y biológica, afectando especialmente a los más pobres y en los países en vía de desarrollo. Polygonum punctatum Elliot. pertenece a la familia Polygonaceae, la medicina popular le atribuye varias propiedades, por medio de estudios anteriores se confirma que diferentes extractos de esta planta presentan actividad antibacteriana, antiinflamatoria y antifúngica. En este trabajo, se evaluó la actividad citotóxica del extracto etanólico de Polygonum punctatum de la familia Polygonaceae en concentraciones de 100, 50 y 25 µg/ml en células de macrófagos de ratones, en los cuales no se encontró actividad citotóxica. Además, se evaluó la actividad leishmanicida por medio de estudios experimentales in vitro a concentraciones de 100, 75, 50, 25, 20 y 10 µg/ml frente a tres cepas de parásitos: Leishmania infantum, L. amazonensis y L. braziliensis, en los cuales se observó una actividad de 58 y 56% de lisis de parásitos con el extracto de 100µg/ml frente a las cepas de L. braziliensis y L. infantum, respectivamente y 51% para L. amazonensis. Estos resultados son prometedores, y aportan una base para el desarrollo y búsqueda de nuevos tratamientos para la leishmaniasis, sin embargo, son necesarios estudios posteriores en cuanto a aislamiento e identificación del compuesto y evaluación en modelos animales in vivo.

PURPOSE The first convincing evidence for a causal relationship between bacterial infection and lymphomagenesis came from the link between gastric lymphoma and chronic Helicobacter pylori gastritis. This review will summarize the current epidemiological, clinical, and biological evidence of a causative role of bacteria in the development of malignant lymphomas, particularly, the extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue type. RECENT FINDINGS Other microorganisms have been associated with specific extranodal lymphoma sites with variable and not always definitive, evidence, including Chlamydia psittaci, Borrelia burgdorferi, Campylobacter jejuni and, most recently, Coxiella Burnetii. According to most plausible models, lymphoma growth is a consequence of continuous antigenic stimulation induced by chronic infection. However, some evidence of a direct oncogenic role of H. pylori has been provided, too. SUMMARY Lymphomas are not the result of a single cause but multifactorial diseases, influenced by a variety of genetic and environmental elements. Hence, ascertaining the specific contribution of bacterial infections is not always easy. Nevertheless, the eradication of the associated chronic infection may result in sustained lymphoma regression. Moreover, the association between infections and lymphoma may offer opportunities for reducing lymphoma incidence by preventing the predisposing infections or treating them early.

Background: Diabetes and prediabetes are common among African Americans (AA), but the frequency and predictors of transition between normal, impaired glucose metabolism, and diabetes are not well-described. The aim of this study was to examine glucometabolic transitions and their association with the development of type 2 diabetes (T2D).Methods: AA participants of the Jackson Heart Study who attended baseline exam (2000-2004) and at least one of two subse­quent exams (2005-2008 and 2009-2013, ~8 years) were classified according to glycemic status. Transitions were defined as progression (deterioration) or remission (im­provement) of glycemic status. Multinomial logistic regression models with repeated measures were used to estimate the odds ratios (OR) for remission and progression with adjustment for demographic, anthro­pometric, behavioral, and biochemical factors.Results: Among 3353 participants, (mean age 54.6±12.3 years), 43% were normogly­cemic, 32% were prediabetes, and 25% had diabetes at baseline. For those with normal glucose at a visit, the probability at the next visit (~4years) of having prediabetes or diabetes was 38.5% and 1.8%, respectively. For those with prediabetes, the probability was 9.9% to improve to normal and 19.9% to progress to diabetes. Progression was as­sociated with baseline BMI, diabetes status, triglycerides, family history of diabetes, and weight gain (OR 1.04 kg, 95% CI:1.03-1.06, P=

Objetivo: O presente estudo visa apresentar um panorama do perfil dos profissionais de perícia contábil no Brasil e de suas atividades. Metodologia: Foi desenvolvida uma pesquisa de levantamento (survey) com 556 peritos cujos dados foram obtidos por meio do Cadastro Nacional de Peritos (CNPC), de todas regiões do Brasil. A pesquisa teve enfoque quali-quanti, ao analisar os dados do questionário, bem como as declarações efetudas pelos profissionais. Resultados: O perito contador brasileiro atua, principalmente de forma individual principalmente na esfera judicial, e de forma concentrada nas áreas Financeira, Contábil e Trabalhista. Mais da metade dos profissionais, não tem a perícia como sua atividade profissional principal, e esta é a principal fatia de profissionais que não está satisfeita com os rendimentos que a atividade proporciona. A atuação profissional se da principalmente por meio perícias judiciais e de apuração de cálculos, principalmente em perícias financeiras, contábeis e trabalhistas. Entre os principais problemas enfrentados pelos peritos está a falta de apoio dos conselhos de classe para o desenvolvimento e defesa da atividade e a dificuldade de compreensão do processo de nomeação dos peritos, que não foi resolvida com a implantação do CNPC. Os peritos, de maneira geral, acreditam que a atividade é pouco valorizada nas universidades, e que os estudantes aprendem pouco sobre ela no curso de graduação. Contribuições do estudo: Os resultados contribuem para a literatura visto não haver estudos que avaliem de forma ampla a profissão de perito contador no Brasil, tanto no contexto de seu perfil quanto de suas atividades. E no que se refere ao aspecto prático, os dados do estudo fornecem subsídios para que órgãos de classe, associações e o sistema judiciário possam melhorar aspectos do trabalho e da valorização do períto no Brasil.