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Introdução: O desenvolvimento da família é influenciado por diversos fatores de sua organização interna e de ordem ambiental, social, cultural, econômica e política. Em contexto de pobreza os riscos são maiores. Fatores de proteção, como boa organização familiar e rede social de apoio podem diminuir as consequências negativas da pobreza. São escassas as pesquisas longitudinais sobre vulnerabilidade e resiliência nas famílias. Objetivo: Este artigo descreve o desenvolvimento de três famílias ao longo de 15 anos, estudadas por meio de entrevistas em casa, parte de uma coorte populacional de um bairro de Porto Alegre (RS). Buscaram-se associações entre a qualidade das relações nessas famílias e sua saúde física e mental, especialmente a do filho, foco da pesquisa. Métodos: Selecionaram-se no arquivo da pesquisa as três primeiras famílias (do total de 148) das quais se tinham os resultados completos das cinco visitas realizadas aos quatro meses e aos dois, quatro, nove e 15 anos de um filho. Realizou-se análise qualitativa dos registros em busca de categorias para compreender a vida e as relações interpessoais nas famílias. O estudo foi realizado em conjunto por duas pesquisadoras, médicas especialistas em desenvolvimento humano. As categorias identificadas na análise e estudadas nas cinco etapas foram: configuração familiar, situação socioeconômica, situações traumáticas, saúde física, saúde relacional e mental, evolução cognitiva e escolar do filho. Resultados: As três famílias, todas de classe C, com filhos sem problemas de saúde física, tiveram evolução suficientemente boa, apesar de todas enfrentarem múltiplos problemas, inclusive separações e mortes precoces. A relação com o sistema de saúde e escola era boa e similar para as três. A jovem com menos problemas de saúde mental foi aquela que sofreu perdas mais importantes: morte dos pais. Tinha uma estrutura familiar multigeracional sólida desde a primeira infância, com relações interpessoais predominantemente colaborativas e amorosas. Conclusões: O artigo busca avançar na compreensão da resiliência nas famílias em situações de vulnerabilidade. Concluímos que essas três famílias, uma delas mais que as outras, foram suficientemente saudáveis na tarefa de educar seus filhos sem desenvolverem problemas mentais graves. Propomos que o bom desenvolvimento se associa com a adequação e amorosidade dos cuidados com a etapa do ciclo vital, mesmo enfrentando situações problemáticas. Essas qualidades precisam estar associadas à estabilidade socioeconômica básica e a bons serviços de saúde e escola.
Introduction: Family development is influenced by it's internal organization and environmental factors, socioeconomic, cultural and political. In poor contexts there are more risks to development. Protection factors like good family organization and social network may decrease the risks. Longitudinal research about vulnerability and resilience in families is scarse. Objective: This article describes the development of three families over 15 years through interviews at home. The families were part of a populational cohort of a neighborhood in Porto Alegre (RS). We looked for links between the quality of relationships and the physical and mental health of these families, especially of the child focus of the research. Methods: We selected in the research archives the first three families (of a total of 148) for which we had full results of the five interviews at four months and two, four, nine and fifteen years of a child. We did a qualitative analysis of the records looking for parameters to understand the life and interpersonal relationships of these families. This study was done by two researchers, both experts in Human Development. The categories identified in the analysis of the five phases were: family structure, socioeconomic situation, traumatic experiences, physical, mental and relational health and cognitive evolution of the child. Results: All three families belonged to economical class C. The children were in good physical health and had sufficiently good general development, having faced multiple problems, including parental separation and early parental death. The relationship with the health and school systems was good in all of them. The youth with less mental health problems was the one who suffered the heaviest loss: early death of both parents. Her family had strong multigenerational ties since her early days, with predominant collaborative and loving relationships. Conclusions: This article aims to contribute to the comprehension of resilience in families in the context of vulnerability. We can say that these three families were healthy enough in the task of bringing up children without any serious mental health problem. We suggest that healthy development is associated with loving interfamily relationships adequate to each phase of development, notwithstanding dramatic events. This needs to be supported by basic economic stability and adequate school and health systems.
Introducción: El desarrollo de la familia es influenciado por su organización interna y factores ambientales, sociales, culturales, económicos y políticos. En contextos pobres los riesgos son mayores. Factores de protección como buena organización familiar y red social de apoyo pueden disminuir las consecuencias negativas de la pobreza. Son pocas las investigaciones longitudinales de vulnerabilidad y resiliencia de las familias. Objetivo: Este artículo describe el estudio del desarrollo de tres familias a lo largo de 15 años, a través de entrevistas en domicilio, parte de una cohorte poblacional de un barrio de Porto Alegre (RS). Se buscaron correlaciones entre la calidad de las relaciones de esas familias y su salud física y mental, especialmente la del hijo foco de la investigación. Métodos: Fueron seleccionadas en el archivo de la investigación las tres primeras familias (de un total de 148) de las cuales se tenían los resultados completos de las cinco visitas realizadas, a los 4 meses, y a los 2, 4, 9, y 15 años de un hijo. Fue realizado un análisis cualitativo de los registros en busca de categorías para comprender la vida y las relaciones interpersonales en las familias. El estudio fue hecho en conjunto por dos investigadoras, médicas especialistas en desarrollo humano. Las categorías identificadas en el análisis y estudiadas en las cinco etapas fueron: configuración familiar, situación socioeconómica, situaciones traumáticas, salud física, salud relacional y mental, evolución cognitiva y escolar del hijo. Resultados: Las tres familias, todas de clase C, con hijos sin problemas de salud física, tuvieron evolución suficientemente buena, a pesar de que todas enfrentaron múltiples problemas, incluso separaciones y muertes precoces. La relación con el sistema de salud y escuela era buena y similar para las tres. La joven con menos problemas de salud mental fue aquella que sufrió las mayores pérdidas: muerte de los padres. Tenía una estructura familiar multigeneracional sólida desde la primera infancia, con relaciones interpersonales predominantemente colaborativas y amorosas. Conclusiones: El artículo pretende avanzar en la comprensión de la resiliencia en las familias en situaciones de vulnerabilidad. Concluimos que esas tres familias, una de ellas más que las otras, fueron suficientemente saludables en la tarea de educar a sus hijos sin que desarrollaran problemas mentales graves. Proponemos que el buen desarrollo se asocia con el amor y adecuación de los cuidados a la etapa del ciclo vital, aun enfrentando situaciones problemáticas. Esas calidades necesitan estar asociadas a la estabilidad socioeconómica básica y buenos servicios de salud y escuela.
Sujet(s)
Humains , Développement humain , Santé mentale , Résilience psychologiqueRÉSUMÉ
BACKGROUND: The COVID-19 pandemic sparked a surge of research publications spanning epidemiology, basic science, and clinical science. Thanks to the digital revolution, large data sets are now accessible, which also enables real-time epidemic tracking. However, despite this, academic faculty and their trainees have been struggling to access comprehensive clinical data. To tackle this issue, we have devised a clinical data repository that streamlines research processes and promotes interdisciplinary collaboration. OBJECTIVE: This study aimed to present an easily accessible up-to-date database that promotes access to local COVID-19 clinical data, thereby increasing efficiency, streamlining, and democratizing the research enterprise. By providing a robust database, a broad range of researchers (faculty and trainees) and clinicians from different areas of medicine are encouraged to explore and collaborate on novel clinically relevant research questions. METHODS: A research platform, called the Yale Department of Medicine COVID-19 Explorer and Repository (DOM-CovX), was constructed to house cleaned, highly granular, deidentified, and continually updated data from over 18,000 patients hospitalized with COVID-19 from January 2020 to January 2023, across the Yale New Haven Health System. Data across several key domains were extracted including demographics, past medical history, laboratory values during hospitalization, vital signs, medications, imaging, procedures, and outcomes. Given the time-varying nature of several data domains, summary statistics were constructed to limit the computational size of the database and provide a reasonable data file that the broader research community could use for basic statistical analyses. The initiative also included a front-end user interface, the DOM-CovX Explorer, for simple data visualization of aggregate data. The detailed clinical data sets were made available for researchers after a review board process. RESULTS: As of January 2023, the DOM-CovX Explorer has received 38 requests from different groups of scientists at Yale and the repository has expanded research capability to a diverse group of stakeholders including clinical and research-based faculty and trainees within 15 different surgical and nonsurgical specialties. A dedicated DOM-CovX team guides access and use of the database, which has enhanced interdepartmental collaborations, resulting in the publication of 16 peer-reviewed papers, 2 projects available in preprint servers, and 8 presentations in scientific conferences. Currently, the DOM-CovX Explorer continues to expand and improve its interface. The repository includes up to 3997 variables across 7 different clinical domains, with continued growth in response to researchers' requests and data availability. CONCLUSIONS: The DOM-CovX Data Explorer and Repository is a user-friendly tool for analyzing data and accessing a consistently updated, standardized, and large-scale database. Its innovative approach fosters collaboration, diversity of scholarly pursuits, and expands medical education. In addition, it can be applied to other diseases beyond COVID-19.
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COVID-19 , Bourses d'études et bourses universitaires , Humains , Connecticut/épidémiologie , Comportement coopératif , COVID-19/épidémiologie , Bases de données factuelles , Pandémies , Écoles de médecine/organisation et administrationRÉSUMÉ
This article aims to evaluate the adherence to antihypertensive treatment prevalence in the Brazilian population based on peer-reviewed studies which used instruments exclusively designed and/or adapted for this purpose. A systematic review with meta-analysis based on the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The search was carried out in the BDENF, SciELO, Cuiden, PsycINFOe, CINAHL, Embase, LILACS, and MEDLINE databases, as well as the AgeLine, Google Scholar and ScienceDirect academic search engines. The protocol was registered with PROSPERO (CRD42021292689). Random effects models were used for a meta-analysis of the prevalence obtained from individual studies. A total of 104 studies were included in the meta-analysis on antihypertensive treatment in the Brazilian population, totaling 38,299 patients. The most used instrument was the four-item Morisky-Green Test (49.5%). The adherence prevalence estimated by the meta-analysis was 44.4% (95%CI: 39.12%-49.94%, I2 = 91.17, p < 0.001), showing high heterogeneity. The adherence to antihypertensive treatment prevalence found in national studies was unsatisfactory, demonstrating that this problem continues to be a major challenge.
O objetivo do artigo é avaliar a prevalência de adesão ao tratamento anti-hipertensivo na população brasileira, com base nos estudos revisados por pares, que utilizaram instrumentos elaborados e/ou adaptados exclusivamente para este fim. Revisão sistemática com meta-análise, baseada nas recomendações do Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). A busca foi realizada nas bases BDENF, SciELO, Cuiden, PsycINFOe, CINAHL, Embase, LILACS, MEDLINE, e nos buscadores acadêmicos AgeLine, Google Scholar e ScienceDirect. O protocolo foi registrado no PROSPERO (CRD42021292689). Modelos de efeitos aleatórios foram usados para meta-análise das prevalências obtidas dos estudos individuais. Incluíram-se 104 estudos na meta-análise sobre tratamento anti-hipertensivo na população brasileira, totalizando 38.299 pacientes. O instrumento mais utilizado foi o teste de Morisky-Green de quatro itens (49,5%). A prevalência de adesão estimada pela foi de 44,4% (IC95%: 39,12%-49,94%, I2 = 91,17, p < 0,001), apresentando alta heterogeneidade. A prevalência de adesão ao tratamento anti-hipertensivo encontrada nos estudos nacionais foi insatisfatória, demonstrando que essa problemática continua sendo um grande desafio.
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Antihypertenseurs , Hypertension artérielle , Adhésion au traitement médicamenteux , Brésil , Humains , Antihypertenseurs/usage thérapeutique , Antihypertenseurs/administration et posologie , Adhésion au traitement médicamenteux/statistiques et données numériques , Hypertension artérielle/traitement médicamenteux , Hypertension artérielle/épidémiologie , PrévalenceRÉSUMÉ
Aim: The design, synthesis, docking studies and evaluation of the in vitro antifungal and cytotoxic properties of eugenol (EUG) containing 1,2,3-triazole derivatives are reported. Most of the derivatives have not been reported.Materials & methods: The EUG derivatives were synthesized, molecular docked and tested for their antifungal activity.Results: The compounds showed potent antifungal activity against Trichophyton rubrum, associated with dermatophytosis. Compounds 2a and 2i exhibited promising results, with 2a being four-times more potent than EUG. The binding mode prediction was similar to itraconazole in the lanosterol-14-α-demethylase wild-type and G73E mutant binding sites. Additionally, the pharmacokinetic profile prediction suggests good gastrointestinal absorption and potential oral administration.Conclusion: Compound 2a is a promising antifungal agent against dermatophytosis caused by T. rubrum.
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The aim of the study was to assess glucocorticoid sensitivity in survivors of childhood acute lymphoblastic leukemia using in vivo and in vitro tests. Thirty leukemia survivors of both sexes aged ≥18 years participated in the study and at least two years after therapy withdrawal. In vivo tests comprised: a) a very low dose intravenous dexamethasone suppression test for measurement of serum cortisol before, after, and % suppression, compared with 32 age-matched controls; and b) 0.25 mg overnight oral dexamethasone suppression test for assessment of salivary cortisol before, after, and % suppression. In vitro methods comprised: c) glucocorticoid receptor polymorphisms: BcI1-NR3C1 and A3669G; and d) splicing variant of glucocorticoid receptor GR-α mRNA by real-time quantitative polymerase chain reaction, compared with 32 controls. There was a reduction in salivary cortisol, and 73.3% of leukemia survivors showed high sensitivity according to % suppression after oral dexamethasone (p<0.05). Serum cortisol at baseline, after the test, % suppression after intravenous dexamethasone, and the percentage of high sensitivity were reduced in the leukemia group (%F=36.7; p<0.05). The BcI1-NR3C1 and A3669G polymorphisms were present in 11/30 (36.7%) and 5/30 (16.7%) patients, respectively. GR-α mRNA levels were lower in the leukemia group than in the controls (p<0.05). Survivors of acute lymphoblastic leukemia presented with reduced glucocorticoid sensitivity. Glucocorticoid sensitivity allows individualized treatment to avoid adverse effects and may be involved in cardiovascular disease risk among this particular group of cancer survivors.
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PURPOSE: To evaluate the role of multiparametric ultrasound (mpUS) in the characterization of focal breast lesions (FBLs). METHODS: This prospective study enrolled patients undergoing multiparametric breast ultrasound for FBLs. An experienced breast radiologist evaluated the following ultrasound features: US BI-RADS category, vascularization pattern (internal, vessels in rim and combined) and presence of penetrating vessels with each Doppler method (Color-Doppler, Power-Doppler, Microvascular imaging), strain ratio (SR) and Tsukuba score (TS) with Strain Elastography (SE), Emax, Emean, Emin and Eratio with 2D-shear wave elastography (2D-SWE). Core biopsy for all BI-RADS 4-5 FBLs and 24-month follow-up for all BI-RADS 2-3 FBLs were considered for standard of reference. The diagnostic performance was assessed with the area under curve (AUCs) and cut-off values were determined according to the Youden's index. RESULTS: A total of 139 FBLs were included with 75/139 (53.9%) benign and 64/139 (46.1%) malignant FBLs. Internal vascularization patterns (p < 0.001), penetrating vessels (p < 0.001), TS 4-5 (p < 0.001) and all 2D-SWE parameters (p < 0.001) were significantly different between benign and malignant FBLs. The BI-RADS score provided an AUC of 0.876 (95% CI 0.810-0.926) for the diagnosis of malignant FBLs. Among the 2D-SWE measurements, an excellent diagnostic performance was observed for Emax with an AUC of 0.915 (95% CI 0.856-0.956) and Emean of 0.908 (95% CI 0.847-0.951). Optimal cutoff for the diagnosis of malignant FBLs were US BI-RADS > 3, Strain Ratio > 2.52, Tsukuba Score > 3, Emax > 82.6 kPa, Emean > 66.0 kPa, Emin > 54.4 kPa and Eratio > 330.8. Multiparametric ultrasound, particularly SWE, can improve specificity in the characterization of FBLs.
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Acute lymphoblastic leukemia (ALL) is the most common type of leukemia in childhood and rare in adults, while acute myeloid leukemia (AML) is less common in children and more common in older adults. The aim of the study was to present our experience for the diagnostic of leukemia by using the classic and molecular cytogenetic methods. The study was conducted between 2009 and 2019 within the Classic and Molecular Genetic Laboratory of the Oncohematology Department from the Louis Turcanu Emergency Hospital for Children, Timisoara, Romania. The study group included 337 children and adults, evaluated between 2009 and 2019. By using the conventional and molecular cytogenetic technique, the cytogenetic anomalies found were 35 numerical chromosomal abnormalities, 10 (9;22)(q34;q11) [four ALL, one AML, five chronic myeloid leukemia (CML)] translocations, nine (15;17)(q24;q21) translocations, three (14;14)(q11;q32) translocations, two (4;11)(q21;q23) translocations, one (1;14)(p32;q11) translocation, one (7;14)(qter;q11) translocation, one (8;21)(q22;q22) translocation, one (9;14)(p12;q32) translocation, seven rearrangements of the MLL gene and two rearrangements of the core-binding factor subunit beta∕myosin heavy chain 11 (CBFB∕MYH11) gene. The use of conventional and molecular cytogenetic analysis is one of the most important prognostic indicators in acute leukemia patients, allowing the identification of biologically distinct subtypes of disease and selection of appropriate treatment approaches.
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Leucémies , Humains , Roumanie , Femelle , Mâle , Adulte , Enfant , Adolescent , Enfant d'âge préscolaire , Leucémies/génétique , Leucémies/anatomopathologie , Leucémies/diagnostic , Analyse cytogénétique/méthodes , Adulte d'âge moyen , Jeune adulte , Sujet âgé , Aberrations des chromosomes , NourrissonRÉSUMÉ
BACKGROUND: Sponges (phylum Porifera) constantly interact with microbes. They graze on microbes from the water column by filter-feeding and they harbor symbiotic partners within their bodies. In experimental setups, sponges take up symbionts at lower rates compared with seawater microbes. This suggests that sponges have the capacity to differentiate between microbes and preferentially graze in non-symbiotic microbes, although the underlying mechanisms of discrimination are still poorly understood. Genomic studies showed that, compared to other animal groups, sponges present an extended repertoire of immune receptors, in particular NLRs, SRCRs, and GPCRs, and a handful of experiments showed that sponges regulate the expression of these receptors upon encounter with microbial elicitors. We hypothesize that sponges may rely on differential expression of their diverse repertoire of poriferan immune receptors to sense different microbial consortia while filter-feeding. To test this, we characterized the transcriptomic response of two sponge species, Aplysina aerophoba and Dysidea avara, upon incubation with microbial consortia extracted from A. aerophoba in comparison with incubation with seawater microbes. The sponges were sampled after 1 h, 3 h, and 5 h for RNA-Seq differential gene expression analysis. RESULTS: D. avara incubated with A. aerophoba-symbionts regulated the expression of genes related to immunity, ubiquitination, and signaling. Within the set of differentially-expressed immune genes we identified different families of Nucleotide Oligomerization Domain (NOD)-Like Receptors (NLRs). These results represent the first experimental evidence that different types of NLRs are involved in microbial discrimination in a sponge. In contrast, the transcriptomic response of A. aerophoba to its own symbionts involved comparatively fewer genes and lacked genes encoding for immune receptors. CONCLUSION: Our work suggests that: (i) the transcriptomic response of sponges upon microbial exposure may imply "fine-tuning" of baseline gene expression as a result of their interaction with microbes, (ii) the differential response of sponges to microbial encounters varied between the species, probably due to species-specific characteristics or related to host's traits, and (iii) immune receptors belonging to different families of NLR-like genes played a role in the differential response to microbes, whether symbionts or food bacteria. The regulation of these receptors in sponges provides further evidence of the potential role of NLRs in invertebrate host-microbe interactions. The study of sponge responses to microbes exemplifies how investigating different animal groups broadens our knowledge of the evolution of immune specificity and symbiosis.
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Consortiums microbiens , Porifera , Symbiose , Transcriptome , Symbiose/génétique , Porifera/microbiologie , Porifera/génétique , Animaux , Consortiums microbiens/génétique , Analyse de profil d'expression de gènes , Mer MéditerranéeRÉSUMÉ
BACKGROUND: Patients with COVID-19 often experience severe long-term sequelae. This study aimed to assess resilience and Quality of Life (QoL) of patients who underwent mechanical ventilation due to COVID-19, one year after discharge. METHODS: This cross-sectional study enrolled patients who received mechanical ventilation for severe COVID-19 and were assessed one-year post-discharge. Participants completed a structured questionnaire via telephone comprising the Connor-Davidson Resilience Scale (CD-RISC) and the Post-COVID-19 Functional Status scale (PCFS). To establish the association between QoL and resilience, Spearman correlations were calculated between the PCFS and the CD-RISC. Linear regression models were adjusted to evaluate which factors were associated with QoL, with the total score of PCFS as the dependent variable. RESULTS: A total of 225 patients were included in the analysis. The CD-RISC had a median score of 83 (IQR 74-91). The PCFS results showed that 61.3% (n = 138) of the patients were able to resume their daily activities without limitations. Among them, 37.3% (n = 84) were classified as Grade 0 and 24% (n = 54) as Grade 1. Mild and moderate functional limitations were found in 33.7% of the patients, with 24.8% (n = 56) classified as Grade 2 and 8.8% (n = 20) as Grade 3. Severe functional limitations (Grade 4) were observed in 4.8% (n = 11) of the patients. High CD-RISC scores were associated with lower levels of PCFS score (p < 0.001). CONCLUSIONS: In this cohort of critically ill patients who underwent mechanical ventilation due to COVID-19, 38% of patients experienced a significant decline in their QoL one year after hospital discharge. Finally, a high level of resilience was strongly associated with better QoL one year after discharge.
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COVID-19 , Sortie du patient , Qualité de vie , Résilience psychologique , Ventilation artificielle , Humains , COVID-19/psychologie , Qualité de vie/psychologie , Mâle , Femelle , Études transversales , Adulte d'âge moyen , Sujet âgé , SARS-CoV-2 , Enquêtes et questionnairesRÉSUMÉ
Skeletal muscle regeneration after injury is a complex process involving inflammatory signaling and myoblast activation. Pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF-α) are key mediators, but their effects on gene expression in proliferating myoblasts are unclear. We performed the RNA sequencing of TNF-α treated C2C12 myoblasts to elucidate the signaling pathways and gene networks regulated by TNF-α during myoblast proliferation. The TNF-α (10 ng/mL) treatment of C2C12 cells led to 958 differentially expressed genes compared to the controls. Pathway analysis revealed significant regulation of TNF-α signaling, along with the chemokine and IL-17 pathways. Key upregulated genes included cytokines (e.g., IL-6), chemokines (e.g., CCL7), and matrix metalloproteinases (MMPs). TNF-α increased myogenic factor 5 (Myf5) but decreased MyoD protein levels and stimulated the release of MMP-9, MMP-10, and MMP-13. TNF-α also upregulates versican and myostatin mRNA. Overall, our study demonstrates the TNF-α modulation of distinct gene expression patterns and signaling pathways that likely contribute to enhanced myoblast proliferation while suppressing premature differentiation after muscle injury. Elucidating the mechanisms involved in skeletal muscle regeneration can aid in the development of regeneration-enhancing therapeutics.
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Prolifération cellulaire , Myoblastes , Transduction du signal , Facteur de nécrose tumorale alpha , Myoblastes/métabolisme , Facteur de nécrose tumorale alpha/métabolisme , Facteur de nécrose tumorale alpha/pharmacologie , Prolifération cellulaire/effets des médicaments et des substances chimiques , Animaux , Souris , Lignée cellulaire , Chimiokines/métabolisme , Chimiokines/génétique , Cytokines/métabolisme , Cytokines/génétique , Régulation de l'expression des gènes/effets des médicaments et des substances chimiquesRÉSUMÉ
Combining multiple drugs broadens the window of therapeutic opportunities and is crucial for diseases that are currently lacking fully curative treatments. A powerful emerging tool for selecting effective drugs and combinations is the high-throughput drug screening (HTP). The histone deacetylase inhibitor (HDACi) givinostat (ITF2357) has been shown to act effectively against CRLF2-rearranged pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL), a subtype characterized by poor outcome and enriched in children with Down Syndrome, very fragile patients with a high susceptibility to treatment-related toxicity. The aim of this study is to investigate possible synergies with givinostat for these difficult-to-treat patients by performing HTP screening with a library of 174 drugs, either approved or in preclinical studies. By applying this approach to the CRLF2-r MHH-CALL-4 cell line, we identified 19 compounds with higher sensitivity in combination with givinostat compared to the single treatments. Next, the synergy between givinostat and the promising candidates was further validated in CRLF2r cell lines with a broad matrix of concentrations. The combinations with trametinib (MEKi) or venetoclax (BCL2i) were found to be the most effective and with the greatest synergy across three metrics (ZIP, HAS, Bliss). Their efficacy was confirmed in primary blasts treated ex vivo at concentration ranges with a safe profile on healthy cells. Finally, we described givinostat-induced modifications in gene expression of MAPK and BCL-2 family members, supporting the observed synergistic interactions. Overall, our study represents a model of drug repurposing strategy using HTP screening for identifying synergistic, efficient, and safe drug combinations.
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BACKGROUND: In 2020, the prevalence of cancer rose to 844,778 cases among the population aged 0-19 years. Approximately 90% of individuals under 18 years of age reside in low- and middle-income countries, where cancer survivors report adverse outcomes that negatively impact their general health, emotional state, and external factors such as academic performance due to the effect of these outcomes on executive functions. The Wisconsin Cart Sorting Test (WCST) is the gold standard for evaluating executive functioning. Therefore, this article (1) reports the performance of the Wisconsin Card Sorting Test (WCST) in oncopediatric patients from Cali, Colombia; (2) indicates the reliability of the WCST; (3) describes the association between cancer type and executive functioning in patients; (4) describes the differences between patients with various executive deficits and their executive total scores; and (5) describes the association between cancer type and the presence of brain deficits based on the WCST. METHODS: In this cross-sectional observational study, 24 oncopediatric patients were interviewed and evaluated via the WCST. RESULTS: The mean age was 12.08 years (SD 3.98); 20.8% of the patients were women, 70.8% had a primary diagnosis of leukemia, 8% exhibited acquired brain deficits, and more than 75% displayed adequate functional indicators of executive functions. Robust statistics were employed to explore the differences between the types of diagnosis and performance in executive functions, and no statistically significant differences were found (p = 0.156). We found that the WCST has a reliable Cronbach's α of 0.804. Oncopediatric patients without brain deficits presented strong results in terms of executive functions (p = 0.002), with a moderate effect size (0.727). CONCLUSIONS: The WCST is reliable for discriminating executive functioning among pediatric cancer patients. The evidence suggests that there were no differences in the executive functioning of the participants based on the types of cancer being evaluated.
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Decision-making regarding limb amputation represents a significant clinical challenge, especially when the initial evaluation does not coincide with the criteria established in scales used worldwide, as is the case of the MESS scale. This article presents the case of a 24-year-old female patient who was transferred to a university hospital after a road traffic accident with severe and large lesions in the left lower limb. Despite a poor initial prognosis and in-hospital complications, including multiple surgical procedures and foot drop, a favorable recovery was achieved with complete anatomical salvage of the limb at risk. The multidisciplinary approach and intensive rehabilitation were instrumental in achieving a satisfactory functional recovery. This case highlights the importance of considering factors beyond amputation scale scores, as well as the need for comprehensive care to improve outcomes in patients with complex extremity injuries.
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We report that ~1.8% of all mesothelioma patients and 4.9% of those younger than 55, carry rare germline variants of the BRCA1 associated RING domain 1 (BARD1) gene that were predicted to be damaging by computational analyses. We conducted functional assays, essential for accurate interpretation of missense variants, in primary fibroblasts that we established in tissue culture from a patient carrying the heterozygous BARD1V523A mutation. We found that these cells had genomic instability, reduced DNA repair, and impaired apoptosis. Investigating the underlying signaling pathways, we found that BARD1 forms a trimeric protein complex with p53 and SERCA2 that regulates calcium signaling and apoptosis. We validated these findings in BARD1-silenced primary human mesothelial cells exposed to asbestos. Our study elucidated mechanisms of BARD1 activity and revealed that heterozygous germline BARD1 mutations favor the development of mesothelioma and increase the susceptibility to asbestos carcinogenesis. These mesotheliomas are significantly less aggressive compared to mesotheliomas in asbestos workers.
Sujet(s)
Signalisation calcique , Réparation de l'ADN , Prédisposition génétique à une maladie , Mutation germinale , Mésothéliome , Protéines suppresseurs de tumeurs , Ubiquitin-protein ligases , Humains , Réparation de l'ADN/génétique , Protéines suppresseurs de tumeurs/génétique , Protéines suppresseurs de tumeurs/métabolisme , Ubiquitin-protein ligases/génétique , Ubiquitin-protein ligases/métabolisme , Mésothéliome/génétique , Signalisation calcique/génétique , Femelle , Mâle , Adulte d'âge moyen , Protéine p53 suppresseur de tumeur/génétique , Protéine p53 suppresseur de tumeur/métabolisme , Apoptose/génétique , Fibroblastes/métabolisme , Amiante/toxicité , Instabilité du génomeRÉSUMÉ
Sulfonamides are one of the oldest groups of antibacterial agents with a broad-spectrum, used as first line treatment in bacterial infections. Their widespread use produced a selective pressure on bacteria, as observed by the high incidence of sulfonamides resistance mainly in Gram negative bacteria isolated from animals. In this research, the presence of sulfonamide resistance genes (sul1, sul2, sul3, and sul4) in phenotypically resistant Escherichia coli isolates has been studied. These genes were amplified in isolates recovered from five animal species, with different interactions to humans: cattle, swine, poultry as livestock, and dogs and cats as companion animals. Isolates were collected according to their phenotypic resistance, and the magnetic bead-based Luminex technology was applied to simultaneously detect sul target genes. The frequency of sul genes was highest in swine, among livestock isolates. The sul1 and sul2 were the most frequently sulfonamide resistance genes detected in all phenotypically resistant isolates. Notably, in companion animals, with a closest interaction with human, sul4 gene was detected. To our knowledge, this is the first report of the presence of sul4 gene in E. coli collected from animals, whereas previously the presence of this gene was reported in environmental, municipal wastewater and human clinical isolates. These results highlighted the importance of continuous antimicrobial resistant genes monitoring in animal species, with a special care to companion animals.
Sujet(s)
Antibactériens , Résistance bactérienne aux médicaments , Escherichia coli , Animaux de compagnie , Volaille , Sulfonamides , Animaux , Chiens , Chats , Sulfonamides/pharmacologie , Escherichia coli/effets des médicaments et des substances chimiques , Escherichia coli/génétique , Suidae , Bovins , Antibactériens/pharmacologie , Animaux de compagnie/microbiologie , Résistance bactérienne aux médicaments/génétique , Volaille/microbiologie , Tests de sensibilité microbienne , Protéines Escherichia coli/génétique , Infections à Escherichia coli/médecine vétérinaire , Infections à Escherichia coli/microbiologie , Infections à Escherichia coli/traitement médicamenteux , Humains , Bétail/microbiologieRÉSUMÉ
BACKGROUND AND AIMS: Unlike other malignancies, hepatic functional reserve competes with tumor progression in determining the risk of mortality from hepatocellular carcinoma (HCC). However, the relative contribution of hepatic decompensation over tumor progression in influencing overall survival (OS) has not been assessed in combination immunotherapy recipients. APPROACH AND RESULTS: From the AB-real observational study (n = 898), we accrued 571 patients with advanced/unresectable hepatocellular carcinoma, Child-Pugh A class treated with frontline atezolizumab + bevacizumab (AB). Hepatic decompensation and tumor progression during follow-up were studied in relationship to patients' OS using a time-dependent Cox model. Baseline characteristics were evaluated as predictors of decompensation in competing risks analysis. During a median follow-up of 11.0 months (95% CI: 5.1-19.7), 293 patients (51.3%) developed tumor progression without decompensation, and 94 (16.5%) developed decompensation. In multivariable time-dependent analysis, decompensation (HR: 19.04, 95% CI: 9.75-37.19), hepatocellular carcinoma progression (HR: 9.91, 95% CI: 5.85-16.78), albumin-bilirubin (ALBI) grade 2/3 (HR: 2.16, 95% CI: 1.69-2.77), and number of nodules >3(HR: 1.63, 95% CI: 1.28-2.08) were independently associated with OS. Pretreatment ALBI grade 2/3 (subdistribution hazard ratio [sHR]: 3.35, 95% CI: 1.98-5.67) was independently associated with decompensation, whereas viral etiology was protective (sHR: 0.55, 95% CI: 0.34-0.87). Among patients with viral etiology, effective antiviral treatment was significantly associated with a lower risk of decompensation (sHR: 0.48, 95% CI: 0.25-0.93). CONCLUSIONS: Hepatic decompensation identifies patients with the worst prognosis following AB and is more common in patients with baseline ALBI >1 and nonviral etiology. Effective antiviral treatment may protect from decompensation, highlighting the prognostic disadvantage of patients with nonviral etiologies and the importance of multidisciplinary management to maximize OS.
RÉSUMÉ
Ethnobotany approached through ethnoeducation allows for the preservation of the cultural heritage of indigenous communities. In this way, the ethnobotanical knowledge of primary school students from the Paniquita Indigenous Community was recognized, regarding the cultural knowledge of medicinal plants and their significance in the conservation of the biocultural heritage. This research had a qualitative, ethnographic approach. The sample consisted of ten students who were part of a focus group, ethnobotanical walks, and participatory workshops with drawings since they stimulate students' creative and dynamic thinking and strengthen interculturality. Twenty-one plants were reported, which are used to relieve sore throats, headaches, and stomach aches, as well as to treat diarrhea and fever, to prevent flu, and as a purgative. All the medicinal plants mentioned grow in the community and are either cultivated or wild, which also shows the students' knowledge of the ir territory. These findings reflect the importance of ethno-education and ethnobotany at school and how historical reconstruction processes are generated from these settings, where indigenous ancestral knowledge is made visible.
La etnobotánica abordada desde la etnoeducación permite mantener el legado cultural de los pueblos originarios. De esta manera, se reconoció el conocimiento etnobotáni co de los estudiantes de primaria de la Comunidad Indígena Paniquita, sobre el conocimiento cultural de las plantas medicinales y su importancia para la conservación del patrimonio biocultural. La investigación tuvo un enfoque cualitativo y etnográfico. La muestra estuvo conformada por diez estudiantes que formaron parte de un grupo focal, caminatas etnobotánicas y talleres participativos con dibujos, ya que estimulan el pensamiento creativo y dinámico de los estudiantes y fortalecen la interculturalidad. Se reportaron 21 plantas que se utilizan para aliviar dolores de garganta, cabeza y estómago, así como para tratar la diarrea y la fiebre, para prevenir la gripe y como purgante. Todas las plantas medicinales mencionadas crecen en la comunidad y son cultivadas o silvestres, lo que también demuestra el conocimiento que los estudiantes tienen de su territorio. Estos hallazgos reflejan la importancia de la etnoeducación y la etnobotánica en la escuela y cómo se generan procesos de reconstrucción histórica desde estos escenarios, donde se visibiliza el conocimiento ancestral indígena.
Sujet(s)
Humains , Plantes médicinales , Étudiants , Indien Amérique Sud , Ethnobotanique , Colombie , Médecine traditionnelleRÉSUMÉ
INTRODUCTION: In highly multiracial populations with inadequate newborn screening, knowledge of the various phenotypic presentations of Cystic Fibrosis (CF) can help reach an early diagnosis. This study aims to describe phenotypes and genotypes at the time of CF diagnosis in a state in the Northeast Region of Brazil. METHODS: Retrospective cross-sectional study. Clinical data were extracted from the medical records of CF patients. Clinical, laboratory, and genotypic characteristics were described for patients admitted to a tertiary referral center between 2007 and 2021. RESULTS: Fifty-eight (58) patients were included in the study, 53.5% of whom were diagnosed through clinical suspicion. The median age at diagnosis was 4.7 months (IQR: 1.5-14.8 months). Five patients had false-negative results in the newborn screening. Faltering growth was the most frequent clinical manifestation. Bronchiectasis and a history of pneumonia predominated in those older than ten, while thinness, underweight, and electrolyte imbalances were more frequent in children under two. Sequencing of the CFTR gene identified 27 genotypes, with at least one class I-III variant in all patients, and nine variants that are rare, previously undescribed, or have uncertain significance (619delA, T12991, K162Q, 3195del6, 1678del > T, 124del123bp, 3121-3113 A > T). The most frequent alleles were p.Phe508del, p.Gly542*, p.Arg334Trp, and p.Ser549Arg. CONCLUSIONS: Malnutrition and electrolyte imbalances were the most frequent phenotypes for children < 2 years and were associated with genotypes including 2 class I-III variants. Rare and previously undescribed variants were identified. The p.Gly542*, p.Arg334Trp, and p.Ser549Arg alleles were among the most frequent variants in this population.
Sujet(s)
Protéine CFTR , Mucoviscidose , Génotype , Phénotype , Humains , Mucoviscidose/génétique , Mucoviscidose/diagnostic , Brésil , Études transversales , Études rétrospectives , Mâle , Femelle , Nourrisson , Protéine CFTR/génétique , Nouveau-né , Dépistage néonatal , Enfant d'âge préscolaire , MutationRÉSUMÉ
Importance: Whether patients with Child-Pugh class B (CP-B) cancer with unresectable hepatocellular carcinoma (uHCC) benefit from active anticancer treatment vs best supportive care (BSC) is debated. Objective: To evaluate the association of immune checkpoint inhibitor (ICI)-based therapies vs BSC with overall survival (OS) of patients with uHCC and CP-B liver dysfunction. Design, Setting, and Participants: This retrospective, multicenter, international clinical case series examined data of patients with CP-B with uHCC who were receiving first-line ICI-based regimens from September 2017 to December 2022 whose data were extracted from an international consortium and compared with a cohort of patients with CP-B receiving BSC. Patients were treated in tertiary care centers across Europe, US, and Asia in routine clinical practice. After applying the inclusion criteria, 187 and 156 patients were left in the ICI and BSC groups, respectively. The propensity score was calculated for the following variables: age, alpha-fetoprotein levels, Child-Pugh score, extrahepatic spread, portal vein tumor thrombosis, cirrhosis, ascites, and baseline Eastern Cooperative Oncology Group performance status. Exposures: Patients in the ICI group received first-line systemic therapy with either atezolizumab plus bevacizumab (A+B) (n = 141) or nivolumab (n = 46). Main Outcomes and Measures: OS in the inverse probability of treatment weighting (IPTW) populations was the main outcome, and it was estimated with Kaplan-Meier method; univariable Cox regression test was used to make comparisons between the 2 groups. Results: The median age was 66 (IQR, 61-72) and 73 (IQR, 66-81) years in the ICI (33 women [18%]) and BSC groups (41 women [26%]), respectively. In the IPTW populations, median OS was significantly longer in the ICI group (7.50 months; 95% CI, 5.62-11.15) compared with BSC (4.04 months; 95% CI, 3.03-5.03; hazard ratio, 0.59; 95% CI, 0.43-0.80; P < .001). Multivariable analysis confirmed that ICI exposure was associated with a reduction of approximately 50% in the risk of death (hazard ratio, 0.55; 95% CI, 0.35-0.86; P < .001), and the presence of portal vein tumor thrombosis, an Eastern Cooperative Oncology Group performance score of greater than 1, and alpha-fetoprotein levels of 400 ng/mL or greater were associated with increased risk of death. Conclusions and Relevance: The results of this case series provide comparative evidence of improved survival in association with ICI treatment compared with BSC in patients with uHCC with CP-B liver dysfunction.