RESUMO
BACKGROUND: Hematopoiesis in mammal is a complex and highly regulated process in which hematopoietic stem cells (HSCs) give rise to all types of differentiated blood cells. Previous studies have shown that hairy and enhancer of split (HES) repressors are essential regulators of adult HSC development downstream of Notch signaling. METHODS: In this study, we investigated the role of HES1, a member of HES family, in fetal hematopoiesis using an embryonic hematopoietic specific Hes1 conditional knockout mouse model by using phenotypic flow cytometry, histopathology analysis, and functional in vitro colony forming unit (CFU) assay and in vivo bone marrow transplant (BMT) assay. RESULTS: We found that loss of Hes1 in early embryonic stage leads to smaller embryos and fetal livers, decreases hematopoietic stem progenitor cell (HSPC) pool, results in defective multi-lineage differentiation. Functionally, fetal hematopoietic cells deficient for Hes1 exhibit reduced in vitro progenitor activity and compromised in vivo repopulation capacity in the transplanted recipients. Further analysis shows that fetal hematopoiesis defects in Hes1fl/flFlt3Cre embryos are resulted from decreased proliferation and elevated apoptosis, associated with de-repressed HES1 targets, p27 and PTEN in Hes1-KO fetal HSPCs. Finally, pharmacological inhibition of p27 or PTEN improves fetal HSPCs function both in vitro and in vivo. CONCLUSION: Together, our findings reveal a previously unappreciated role for HES1 in regulating fetal hematopoiesis, and provide new insight into the differences between fetal and adult HSC maintenance.
Assuntos
Feto , Hematopoese , Células-Tronco Hematopoéticas , Camundongos Knockout , Fatores de Transcrição HES-1 , Animais , Fatores de Transcrição HES-1/metabolismo , Fatores de Transcrição HES-1/genética , Camundongos , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/citologia , Feto/citologia , Feto/metabolismo , Diferenciação Celular , Apoptose , Proliferação de Células , PTEN Fosfo-Hidrolase/metabolismo , PTEN Fosfo-Hidrolase/genética , Transdução de Sinais , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/genéticaRESUMO
ABSTRACT: Medical journals from the 1800s described differences in disease susceptibility, skin thickness, and pain tolerance among races. These misconceptions about biologic differences, the historical exploitation of minorities in research, and implicit biases among healthcare workers have all affected patient care. Discrepancies still exist in pain assessment and management for minority patients compared with their White counterparts and lead to poor health outcomes. By implementing specific changes in policy and practice, including standardization, implicit bias training, and building a diverse workforce, clinicians can begin to provide care that more equitably manages pain for all patients, regardless of race.
Assuntos
Disparidades em Assistência à Saúde , Dor , Humanos , Atitude do Pessoal de Saúde , Pessoal de Saúde , Grupos MinoritáriosRESUMO
The cross talk between extrinsic niche-derived and intrinsic hematopoietic stem cell (HSC) factors controlling HSC maintenance remains elusive. Here, we demonstrated that amphiregulin (AREG) from bone marrow (BM) leptin receptor (LepR+) niche cells is an important factor that mediates the cross talk between the BM niche and HSCs in stem cell maintenance. Mice deficient of the DNA repair gene Brca2, specifically in LepR+ cells (LepR-Cre;Brca2fl/fl), exhibited increased frequencies of total and myeloid-biased HSCs. Furthermore, HSCs from LepR-Cre;Brca2fl/fl mice showed compromised repopulation, increased expansion of donor-derived, myeloid-biased HSCs, and increased myeloid output. Brca2-deficient BM LepR+ cells exhibited persistent DNA damage-inducible overproduction of AREG. Ex vivo treatment of wild-type HSCs or systemic treatment of C57BL/6 mice with recombinant AREG impaired repopulation, leading to HSC exhaustion. Conversely, inhibition of AREG by an anti-AREG-neutralizing antibody or deletion of the Areg gene in LepR-Cre;Brca2fl/fl mice rescued HSC defects caused by AREG. Mechanistically, AREG activated the phosphoinositide 3-kinases (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, promoted HSC cycling, and compromised HSC quiescence. Finally, we demonstrated that BM LepR+ niche cells from other DNA repair-deficient and aged mice also showed persistent DNA damage-associated overexpression of AREG, which exerts similar negative effects on HSC maintenance. Therefore, we identified an important factor that regulates HSCs function under conditions of DNA repair deficiency and aging.
Assuntos
Distúrbios no Reparo do DNA , Receptores para Leptina , Camundongos , Animais , Anfirregulina/genética , Anfirregulina/metabolismo , Receptores para Leptina/genética , Receptores para Leptina/metabolismo , Camundongos Endogâmicos C57BL , Células-Tronco Hematopoéticas/metabolismo , Envelhecimento/genética , Distúrbios no Reparo do DNA/metabolismo , Nicho de Células-Tronco/genética , Mamíferos/metabolismoRESUMO
Abstract How do governments distribute resources across economic sectors during a crisis? And why do some sectors receive more than others? The recent COVID-19 pandemic has highlighted the urgency of these questions. In this paper, we explore the extent to which a political economy perspective can help explain the characteristics of sector-specific state aid in the Netherlands, a traditionally corporatist country. While KLM, the biggest player in the Dutch aviation sector, was promised loans worth €3.4 billion, the horeca (hospitality) sector was denied a similar deal. Limited cross-case analysis eliminates purely economic accounts. We employed process-tracing and analyzed hundreds of national media articles to understand the influence of elected leaders, interest groups, and experts. We find that, against the backdrop of economic concerns, vote-seeking behavior by elected leaders as well as the strength and organization of interest groups influenced how much each sector could expect. Meanwhile, policy-seeking behavior helps explain the form that aid took. Our findings highlight the need to consider fiscal support in political economy terms, even during crises, and to explore the composition of state aid, not just its presence or amount.
Resumo Como são distribuídos os recursos de auxílio governamental entre os vários setores econômicos durante uma crise? E por que alguns sectores recebem mais do que outros? A recente pandemia da COVID-19 sublinhou a urgência destas questões. Neste artigo, discutimos como uma perspectiva de economia política pode ajudar a explicar as caraterísticas do auxílio estatal setorial nos Países Baixos, uma nação tradicionalmente corporativista. Enquanto o governo prometeu à KLM, o maior ator no setor da aviação holandês, empréstimos no valor de 3,4 mil milhões de euros, o horeca (sector da hotelaria) não recebeu um pacote de auxílio semelhante. A análise de casos elimina explicações puramente técnicas para esse fenômeno. Utilizamos process-tracing e fizemos uma análise de centenas de artigos publicados na mídia do país para compreender a influência dos líderes políticos, lobbies e peritos. Descobrimos que, num contexto de crise econômica, o comportamento eleitoreiro dos líderes políticos e a força e organização dos lobbies, determinaram a quantia que cada setor poderia esperar receber. Entretanto, os interesses no campo das políticas públicas ajudam a explicar a forma específica do auzílio. Nossas conclusões sublinham a necessidade de considerar o apoio fiscal em termos de economia política, mesmo durante crises, e de explorar não somente a existência ou o montante dos auxílios oferecidos pelo estado, mas também sua composição.
Resumen ¿Cómo se distribuyen los recursos de ayuda gubernamental entre los diferentes sectores económicos durante una crisis? ¿Y por qué algunos sectores reciben más que otros? La reciente pandemia de COVID-19 puso de relieve la importancia de estas cuestiones. En este artículo, exploramos cómo una perspectiva de economía política puede ayudar a entender la distribución del apoyo estatal en diferentes sectores en los Países Bajos, un país de tradición corporativista. Mientras que a KLM ‒el actor más importante del sector de aviación holandés‒ el gobierno le prometió préstamos de alrededor de 3.400 millones de euros, al sector HORECA (que congrega hoteles, restaurantes y cafeterías) se le denegó una ayuda similar. A través de un análisis cruzado de casos eliminamos razones puramente técnicas para este fenómeno. A continuación, utilizamos la metodología process-tracing y analizamos cientos de artículos de medios de comunicación holandeses para entender la influencia de líderes políticos, lobbies y expertos. Descubrimos que, en un contexto de crisis económica, el comportamiento electorero de los líderes políticos y el poder y organización de los lobbies determinaron la suma que cada sector podría esperar. Por otro lado, la estructura de dichas ayudas se explica a través del alineamiento político de los decisores políticos. Nuestros resultados subrayan la necesidad de estudiar el apoyo gubernamental en términos de economía política, inclusive durante crisis, y de explorar no solo la existencia o la cuantía de dichas ayudas sino también su composición.
Assuntos
Humanos , Masculino , Feminino , Política Pública , Apoio Financeiro , Políticas , Pandemias , COVID-19 , Manobras PolíticasRESUMO
BACKGROUND: There is a lack of appropriate tools for assessing the effectiveness of teaching evidence-based practice in nursing. OBJECTIVES: The objective of the study was to develop the instrument evaluating the students' perception of the effectiveness of EBP courses and to verify its psychometric properties. DESIGN: A descriptive cross-sectional study design was used to verify psychometric properties of the questionnaire measuring the students' perception of the effectiveness of EBP courses. PARTICIPANTS: The psychometric properties were evaluated in a group of 129 graduate nursing students who completed EBP courses. METHODS: The instrument for measuring the students' perception of the effectiveness of EBP courses was inspired by Kirkpatrick's evaluation model, which advocates evaluating interventions at four levels - reaction (satisfaction), learning, behavior change (transfer) and results (benefits). A web-based survey was used for data collection. Data was collected from the middle of January 2013 through the end of March 2013. RESULTS: A thirteen item instrument was developed for measuring the students' perception of the effectiveness of EBP courses. The internal consistency of the scale, based on standardized Cronbach's alpha, was .93. The results of factor analysis identified three factors of the instrument. The highest rated items on a scale of 1 (strongly disagree) to 7 (strongly agree) were 'implementation of EBP can improve clinical care' (mean 6.16), 'EBP instructors had a thorough knowledge of EBP' (6.13), 'EBP instructors were enthusiastic about teaching EBP' (5.65), and 'I can use my EBP knowledge and skills in my practice' (5.58). CONCLUSIONS: The results of testing of the psychometric properties of the questionnaire showed at least satisfactory validity and reliability. The majority of students perceived EBP courses as effective. The instrument may be used to assess the students' perception of the effectiveness of EBP courses.
Assuntos
Educação de Pós-Graduação em Enfermagem , Enfermagem Baseada em Evidências/educação , Estudantes de Enfermagem/psicologia , Inquéritos e Questionários , Adulto , Estudos Transversais , Avaliação Educacional/métodos , Feminino , Humanos , Masculino , Pesquisa em Avaliação de Enfermagem , Psicometria/normas , Reprodutibilidade dos Testes , Adulto JovemRESUMO
BACKGROUND: Effective teaching is key in preparing students to become successful evidence-based healthcare professionals. The effectiveness of graduate evidence-based practice (EBP) pedagogy is not often a subject of research studies. PURPOSE: The purpose of this study was to determine how faculty from the 50 top graduate nursing schools in the United States perceived the effectiveness of EBP courses for graduate nursing students. METHODS: A descriptive cross-sectional design was used to explore faculty perception of the effectiveness of EBP courses. A web-based survey was used for data collection. A total of 45 questionnaires were subjected to statistical analysis. RESULTS: The mean perception of the effectiveness of EBP courses for the whole sample, on a scale from 1 to 7, was 5.58 (min. 4.29; max. 6.73), a higher score signifying higher perceived effectiveness. The highest rated item concerned a school's access to different databases. The strongest correlations were found between the total score and the scores for items describing students' opportunities to strengthen and apply their EBP skills (rs = .66). The internal consistency of the Perception of Effectiveness of EBP Courses scale, based on standardized Cronbach's alpha, was .84, which signifies strong internal consistency. Faculty perceived themselves as most competent at the following EBP skills: (a) "Asking questions regarding patients' care" (6.56), (b) "Considering patient preferences when implementing EBP" (6.40), and (c) "Critically appraising the relevant body of evidence to address clinical questions" (6.40). DISCUSSION: To strengthen the effectiveness of EBP courses, students should have more opportunities to implement their EBP knowledge and skills after completing EBP courses. LINKING EVIDENCE TO ACTION: Evaluation of faculty perceptions of the effectiveness of EBP courses can help to guide the development of nursing school curricula that better integrate EBP. Further evaluation of the psychometric properties of the instrument used to measure perception of the effectiveness of EBP courses is required along with objective measures of faculty knowledge and skills in teaching EBP.
Assuntos
Atitude do Pessoal de Saúde , Educação de Pós-Graduação em Enfermagem/métodos , Avaliação Educacional , Prática Clínica Baseada em Evidências/educação , Docentes de Enfermagem/estatística & dados numéricos , Conhecimentos, Atitudes e Prática em Saúde , Ensino/métodos , Adulto , Competência Clínica , Estudos Transversais , Currículo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Psicometria , Inquéritos e Questionários , Estados UnidosRESUMO
BACKGROUND: In 2011, an outbreak of measles in Minnesota was traced back to an unvaccinated Somali child. The purpose of this project was to (1) ascertain whether Somali parents are more likely than non-Somalis to refuse childhood vaccinations, particularly the measles-mumps-rubella (MMR) vaccine and (2) determine what factors influence the decision not to vaccinate. METHODS: We explored parental perceptions and utilization of vaccines through a survey distributed to a convenience sample of Somali and non-Somali parents of children ≤5 years old in a family medicine clinic in Minneapolis, MN. RESULTS: A total of 99 surveys were completed, 28% (n = 27) by Somali parents. Somali parents were more likely than non-Somali parents to have refused the MMR vaccine for their child (odds ratio, 4.6; 95% confidence interval, 1.2-18.0). Most of them refused vaccines because they had heard of adverse effects associated with the vaccine or personally knew someone who suffered an adverse effect. Somali parents were significantly more likely to believe that autism is caused by vaccines (35% vs. 8% of non-Somali parents). Somalis were also more likely to be uncomfortable with administering multiple vaccines at one visit (odds ratio, 4.0; 95% confidence interval, 1.4-11.9) and more likely to believe that children receive too many vaccines. CONCLUSIONS: Statistically significant differences in perceptions and use of vaccines were reported by Somali and non-Somali participants. Somali parents are more likely to believe that the MMR vaccine causes autism and more likely to refuse the MMR vaccine than non-Somali parents. These beliefs have contributed to an immunization gap between Somali and non-Somali children.
Assuntos
Cultura , Conhecimentos, Atitudes e Prática em Saúde , Vacina contra Sarampo-Caxumba-Rubéola , Pais/psicologia , Vacinação/psicologia , Adulto , Transtorno Autístico/etiologia , Feminino , Humanos , Masculino , Somália/etnologia , Vacinação/efeitos adversos , Vacinação/estatística & dados numéricosRESUMO
CONTEXT: Soft drink consumption in the United States has tripled in recent decades, paralleling the dramatic increases in obesity prevalence. The purpose of this clinical review is to evaluate the extent to which current scientific evidence supports a causal link between sugar-sweetened soft drink consumption and weight gain. EVIDENCE ACQUISITION: MEDLINE search of articles published in all languages between 1966 and December 2006 containing key words or medical subheadings, such as "soft drinks" and "weight." Additional articles were obtained by reviewing references of retrieved articles, including a recent systematic review. All reports with cross-sectional, prospective cohort, or clinical trial data in humans were considered. EVIDENCE SYNTHESIS: Six of 15 cross-sectional and 6 of 10 prospective cohort studies identified statistically significant associations between soft drink consumption and increased body weight. There were 5 clinical trials; the two that involved adolescents indicated that efforts to reduce sugar-sweetened soft drinks slowed weight gain. In adults, 3 small experimental studies suggested that consumption of sugar-sweetened soft drinks caused weight gain; however, no trial in adults was longer than 10 weeks or included more than 41 participants. No trial reported the effects on lipids. CONCLUSIONS: Although observational studies support the hypothesis that sugar-sweetened soft drinks cause weight gain, a paucity of hypothesis-confirming clinical trial data has left the issue open to debate. Given the magnitude of the public health concern, larger and longer intervention trials should be considered to clarify the specific effects of sugar-sweetened soft drinks on body weight and other cardiovascular risk factors.