Loss of TDP-43 function contributes to genomic instability in amyotrophic lateral sclerosis.

A common pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the cytoplasmic mislocalization and aggregation of the DNA/RNA-binding protein TDP-43, but how loss of nuclear TDP-43 function contributes to ALS and FTD pathogenesis remains largely unknown. Here, using large-scale RNAi screening, we identify TARDBP, which encodes TDP-43, as a gene whose loss-of-function results in elevated DNA mutation rate and genomic instability. Consistent with this finding, we observe increased DNA damage in induced pluripotent stem cells (iPSCs) and iPSC-derived post-mitotic neurons generated from ALS patients harboring TARDBP mutations. We find that the increase in DNA damage in ALS iPSC-derived neurons is due to defects in two major pathways for DNA double-strand break repair: non-homologous end joining and homologous recombination. Cells with defects in DNA repair are sensitive to DNA damaging agents and, accordingly, we find that ALS iPSC-derived neurons show a marked reduction in survival following treatment with a DNA damaging agent. Importantly, we find that increased DNA damage is also observed in neurons with nuclear TDP-43 depletion from ALS/FTD patient brain tissues. Collectively, our results demonstrate that ALS neurons with loss of nuclear TDP-43 function have elevated levels of DNA damage and contribute to the idea that genomic instability is a defining pathological feature of ALS/FTD patients with TDP-43 pathology.

Mature iPSC-derived astrocytes of an ALS/FTD patient carrying the TDP43A90V mutation display a mild reactive state and release polyP toxic to motoneurons.

Astrocytes play a critical role in the maintenance of a healthy central nervous system and astrocyte dysfunction has been implicated in various neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). There is compelling evidence that mouse and human ALS and ALS/FTD astrocytes can reduce the number of healthy wild-type motoneurons (MNs) in co-cultures or after treatment with astrocyte conditioned media (ACM), independently of their genotype. A growing number of studies have shown that soluble toxic factor(s) in the ACM cause non-cell autonomous MN death, including our recent identification of inorganic polyphosphate (polyP) that is excessively released from mouse primary astrocytes (SOD1, TARDBP, and C9ORF72) and human induced pluripotent stem cells (iPSC)-derived astrocytes (TARDBP) to kill MNs. However, others have reported that astrocytes carrying mutant TDP43 do not produce detectable MN toxicity. This controversy is likely to arise from the findings that human iPSC-derived astrocytes exhibit a rather immature and/or reactive phenotype in a number of studies. Here, we have succeeded in generating a highly homogenous population of functional quiescent mature astrocytes from control subject iPSCs. Using identical conditions, we also generated mature astrocytes from an ALS/FTD patient carrying the TDP43A90V mutation. These mutant TDP43 patient-derived astrocytes exhibit key pathological hallmarks, including enhanced cytoplasmic TDP-43 and polyP levels. Additionally, mutant TDP43 astrocytes displayed a mild reactive signature and an aberrant function as they were unable to promote synaptogenesis of hippocampal neurons. The polyP-dependent neurotoxic nature of the TDP43A90V mutation was further confirmed as neutralization of polyP in ACM derived from mutant TDP43 astrocytes prevented MN death. Our results establish that human astrocytes carrying the TDP43A90V mutation exhibit a cell-autonomous pathological signature, hence providing an experimental model to decipher the molecular mechanisms underlying the generation of the neurotoxic phenotype.

Moderate intrinsic phenotypic alterations in C9orf72 ALS/FTD iPSC-microglia despite the presence of C9orf72 pathological features.

While motor and cortical neurons are affected in C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), it remains largely unknown if and how non-neuronal cells induce or exacerbate neuronal damage. We differentiated C9orf72 ALS/FTD patient-derived induced pluripotent stem cells into microglia (iPSC-MG) and examined their intrinsic phenotypes. Similar to iPSC motor neurons, C9orf72 ALS/FTD iPSC-MG mono-cultures form G4C2 repeat RNA foci, exhibit reduced C9orf72 protein levels, and generate dipeptide repeat proteins. Healthy control and C9orf72 ALS/FTD iPSC-MG equally express microglial specific genes and perform microglial functions, including inflammatory cytokine release and phagocytosis of extracellular cargos, such as synthetic amyloid beta peptides and healthy human brain synaptoneurosomes. RNA sequencing analysis revealed select transcriptional changes of genes associated with neuroinflammation or neurodegeneration in diseased microglia yet no significant differentially expressed microglial-enriched genes. Moderate molecular and functional differences were observed in C9orf72 iPSC-MG mono-cultures despite the presence of C9orf72 pathological features suggesting that a diseased microenvironment may be required to induce phenotypic changes in microglial cells and the associated neuronal dysfunction seen in C9orf72 ALS/FTD neurodegeneration.

How villains are made: The translation of dipeptide repeat proteins in C9ORF72-ALS/FTD.

A hexanucleotide repeat expansion in the C9ORF72 gene is the most common genetic alteration associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These neurodegenerative diseases share genetic, clinical and pathological features. The mutation in C9ORF72 appears to drive pathogenesis through a combination of loss of C9ORF72 normal function and gain of toxic effects due to the repeat expansion, which result in aggregation prone expanded RNAs and dipeptide repeat (DPR) proteins. Studies in cellular and animal models indicate that the DPR proteins are the more toxic species. Thus, a large body of research has focused on identifying the cellular pathways most directly impacted by these toxic proteins, with the goal of characterizing disease pathogenesis and nominating potential targets for therapeutic development. The preventative block of the production of the toxic proteins before they can cause harm is a second strategy of intense focus. Despite the considerable amount of effort dedicated to this prophylactic approach, it is still unclear how the DPR proteins are synthesized from RNAs harboring repeat expansions. In this review, we summarize our current knowledge of the specific protein translation mechanisms shown to account for the synthesis of DPR proteins. We will then discuss how enhanced understanding of the composition of these toxic effectors could help in refining disease mechanisms, and paving the way to identify and design effective prophylactic therapies for C9ORF72 ALS-FTD.

Teamwork Is Associated with Reduced Hospital Staff Burnout at Military Treatment Facilities: Findings from the 2019 Department of Defense Patient Safety Culture Survey.

BACKGROUND: A National Academy of Medicine report emphasizes the importance of creating positive work environments to address the negative effects of burnout on health care workers. The purpose of this investigation was to determine the scope of burnout among military hospital personnel and explore the relationship between teamwork, burnout, and patient safety culture. METHODS: A logistic regression analysis investigated the relationship between teamwork and burnout using the 2019 US Department of Defense Patient Safety Culture Survey data from 15,838 military hospital workers. Additional regressions investigated teamwork/burnout relationships among individual work areas and staff positions. RESULTS: About one third of respondents (34.4%) reported experiencing burnout. Work areas most likely to report burnout included many different/other work areas (43.4%), pharmacy (41.8%), and labor and delivery/obstetrics (41.8%). Staff positions most likely to report burnout included pharmacy/pharmacists (39.7%), assistants/technicians/therapists (38.1%), and nurses/nursing (37.6%). Analysis revealed an association between lower burnout and high teamwork, both within (odds ratio [OR] 0.54, 95% confidence interval [CI] 0.48-0.60) and across (OR 0.64, 95% CI 0.57-0.72) units. Within-unit teamwork was associated with reduced odds of burnout across almost all work areas and staff positions, with the greatest odds reduction among personnel working in emergency (OR 0.25, 95% CI 0.14-0.43), radiology (OR 0.41, 95% CI 0.20-0.83), and labor and delivery/obstetrics (OR 0.42, 95% CI 0.27-0.65); and physicians/medical staff (OR = 0.44, 95% CI: 0.28-0.69), other staff positions (OR 0.48, 95% CI 0.28-0.81), and assistants/technicians/therapists (OR 0.58, 95% CI 0.46-0.73). CONCLUSION: Effective teamwork may reduce burnout in hospital workers. This association between teamwork (particularly teamwork within units) and burnout was found in all work areas, even in those with the highest levels of self-reported workplace chaos. Greater adoption of workplace interventions focused on improving teamwork, such as TeamSTEPPS, is warranted.

Direito Humano à Alimentação Adequada: um olhar para a pobreza extrema e a desnutrição infantil a partir da obra de Amartya Sen / Human Right to Adequate Food: an essay on extreme poverty and child malnutrition based on Amartya Sen

Resumo A promoção e garantia do Direito Humano à Alimentação Adequada (DHAA) é ponto central do combate à fome e à desnutrição infantil no Brasil, agravada pela situação da pobreza extrema, permitindo um aumento da expectativa de vida. O Índice de Desenvolvimento Humano (IDH) foi criado por Amartya Sen para transformar a ideia reducionista do desenvolvimento econômico, a fim de ampliar a concepção de progresso humano a partir da expansão das capacidades e das liberdades no capitalismo. O objetivo deste estudo foi relacionar as condições de pobreza, fome e desnutrição infantil à promoção da alimentação saudável, a partir do conceito de desenvolvimento como liberdade descrito na obra de Amartya Sen. A saúde e o desenvolvimento humano interligam-se e, quando analisados pela situação da extrema pobreza, intensificam os seus efeitos restritivos ao acesso à alimentação saudável. Urge a compreensão de que as políticas públicas precisam atuar em sinergia entre as áreas de saúde, alimentação, educação, renda, entre outros, considerando a intersetorialidade da segurança alimentar e nutricional.

Abstract Ensuring the Human Right to Adequate Food (HRAF) is a key point in the fight against hunger and child malnutrition in Brazil, aggravated by the context of extreme poverty, allowing an increase in life expectancy. The Human Development Index (HDI) was created by Amartya Sen to transform the reductionist idea of economic development to broaden the concept of human progress based on the expansion of capabilities and freedoms under capitalism. This study aims to relate the conditions of poverty, hunger, and child malnutrition to the healthy eating promotion, based on Amartya Sen's concept of development as freedom. Health and human development are interconnected and, when analyzed in contexts of extreme poverty, intensify their restrictive effects on access to healthy food. Public policies need to urgently act in synergy with the areas of health, food, education, income, among others, considering the intersectoriality of food and nutritional safety.

Inclusão social de adolescentes em situação de pobreza em um Instituto Federal: uma perspectiva psicanalítica / Inclusión social de adolescentes pobres en un Instituto Federal: una perspectiva psicoanalítica / Social inclusion of teenagers living in poverty in a federal institute: a psychoanalytic perspective / L'inclusion sociale d'adolescents en situation de pauvreté dans un Institut Fédéral: une perspective psychanalytique

A inclusão de estudantes em situação de pobreza nas instituições de ensino é uma necessidade diante das trajetórias marcadas pelo fracasso escolar. Partimos da aposta de que uma maior atenção aos laços sociais no interior das escolas é um dos elementos-chave para uma efetiva inclusão social/educacional. Esta pesquisa buscou demonstrar os processos de exclusão/inclusão de adolescentes em situação de pobreza em um Instituto Federal por meio do estudo de casos múltiplos. Os dados foram analisados mediante a leitura dirigida pela escuta e pela transferência, na perspectiva da teoria freudo-lacaniana. Os resultados apontaram que a inclusão social/educacional, quando atravessada pelo discurso do capitalista, é dificultada devido ao caráter segregador desse discurso, ao passo que a sustentação do discurso do analista no ambiente educacional favorece a inclusão social e educacional

La inclusión de los alumnos pobres en los centros educativos es una necesidad frente a las trayectorias marcadas por el fracaso escolar. Partimos de la creencia de que mayor atención a los vínculos sociales dentro de las escuelas es elemento clave para una inclusión socioeducativa eficaz. Esta investigación buscó demostrar los procesos de exclusión/inclusión de los adolescentes pobres en un Instituto Federal mediante el estudio de múltiples casos. Los datos se analizaron través de la lectura dirigida por la escucha y la transferencia, desde la perspectiva de la teoría freudiana-lacaniana. Los resultados señalaron que la inclusión social/educativa, al ser atravesada por el discurso capitalista, se ve obstaculizada debido al su carácter segregador, mientras que el apoyo del discurso del analista en el ámbito educativo favorece la inclusión social y educativa

The inclusion of students living in poverty in educational institutions is a necessity in the face of the paths marked by school failure. This work is based on the assumption that greater attention to social bonds within schools is one of the key elementsfor an effective social/educational inclusion. This research aimed to demonstrate the processes of exclusion/inclusion of teenagers living in poverty in a Federal Institute through multiple case study. The data were analyzed through reading guided by listening and transference, from the perspective of the Freudian-Lacanian theory. The results indicated that social/educational inclusion, when crossed by the capitalist discourse, is hindered due to the segregating nature of such discourse, while supporting the analyst's discourse in the educational environment favors social and educational inclusion

L'inclusion d'étudiants en situation de pauvreté dans des établissements d'enseignement est un besoin issu des parcours marqués par l'échec scolaire et une réalité historique du Brésil. Nous partons du pari que l'attention aux liens sociaux au sein des écoles est l'un des éléments clés pour une inclusion sociale/éducative efficace. Cette recherche démontre les processus d'exclusion/inclusion d'adolescents en situation de pauvreté dans un Institut Fédéral à l'aide du dispositif méthodologique de l'étude de cas multiples. Les données sont analysées à partir de la lecture dirigée par l'écoute et par le transfert, dans la perspective freudo-lacanienne. Les résultats montrent que l'inclusion sociale/éducative traversée par le discours capitaliste, est entravée par le caractère ségrégatif de ce discours, tandis que le soutien du discours de l'analyste dans l'environnement éducatif favorise l'inclusion sociale et éducative

Repertórios interculturais de mulheres sobre concepções de HIV/AIDS em cenário interétnico / Repertorios interculturales de mujeres acerca de concepciones de VIH/SIDA en un escenario interétnico / Intercultural repertories of women on HIV/AIDS conceptions in na interethnic scenario

Resumo Objetivo analisar, sob a perspectiva da interculturalidade, os significados atribuídos ao HIV/AIDS que compõem os repertórios de mulheres em situação interétnica. Método estudo descritivo, retrospectivo, desenvolvido com base no banco de dados de pesquisa primária. A amostra foi constituída por 642 registros, provenientes da aplicação do Teste de Associação Livre de Palavras, com 386 mulheres não indígenas e 256 mulheres indígenas procedentes do município de Rio Tinto-PB. As respostas apreendidas do estímulo indutor AIDS foram categorizadas segundo grupo de pertencimento, idade e conjugalidade. Os dados foram processados pelo software IraMuTeQ, e analisados pelas técnicas de Classificação Hierárquica Descendente, Especificidades Complementares e Análise Fatorial de Correspondência. As discussões apoiaram-se nas três perspectivas que abarcam a interculturalidade: relacional, funcional e crítica. Resultados foram conformadas três classes denominadas: Repertório biomédico; Repertório socioemocional; e Repertório comportamental. O biomédico foi o mais significativo para ambos os grupos, sendo liderado pelas não indígenas, e os constituintes socioemocional e comportamental foram majoritariamente representados pelas indígenas. Considerações Finais e implicações para a prática nesse cenário interétnico, o diálogo intercultural se materializa no intercâmbio de forma heterogênea de pensar-saber-fazer, que se desdobra sob a luz da interculturalidade relacional e funcional, demonstrando movimentos embrionários para a interculturalidade crítica.

Resumen Objetivo analizar desde la perspectiva de la interculturalidad los significados atribuidos al VIH y SIDA que componen los repertorios de mujeres en situación interétnica. Método estudio descriptivo, retrospectivo, desarrollado con base en la base de datos de investigación primaria. La muestra estuvo compuesta por 642 registros, provenientes de la aplicación del Test Libre de Asociación de Palabras, con 386 mujeres no indígenas y 256 mujeres indígenas del municipio de Rio Tinto-PB. Las respuestas aprendidas del estímulo inductor del SIDA se clasificaron según pertenencia al grupo, edad y estado civil. Los datos fueron procesados por el software IRaMuTeQ y analizados mediante las técnicas de Clasificación Jerárquica Descendente, Especificidades Complementarias y Análisis de Correspondencia Factorial. Las discusiones se basaron en las tres perspectivas que engloban la interculturalidad: relacional, funcional y crítica. Resultados se formaron tres clases: Repertorio biomédico; Repertorio socioemocional; y Repertorio conductual. El biomédico fue el más significativo para ambos grupos, siendo liderado por mujeres no indígenas, y los constituyentes socioemocionales y conductuales estuvieron mayoritariamente representados por mujeres indias. Consideraciones finales e implicaciones para la práctica en este escenario interétnico, el diálogo intercultural se materializa en el intercambio de una manera heterogénea de pensar-saber-hacer, que se despliega a la luz de la interculturalidad relacional y funcional, evidenciando movimientos embrionarios hacia una interculturalidad crítica.

Abstract Objective to analyze, from the perspective of interculturality, the meanings attributed to HIV/AIDS that make up the repertoires of women in interethnic situations. Method a descriptive, retrospective study, developed based on the primary research database. The sample consisted of 642 records, from the application of the Word Association Test, with 386 non-indigenous women and 256 indigenous women from the municipality of Rio Tinto-PB. The responses learned from the AIDS-inducing stimulus were categorized according to group belonging, age and marital status. Data were processed by the IRaMuTeQ software, and analyzed using the Descending Hierarchical Classification, complementary specificities and factorial correspondence analysis techniques. The discussions were based on the three perspectives that encompass interculturality: relational, functional and critical. Results Three classes were formed: Biomedical Repertoire, Socio-emotional Repertoire and Behavioral Repertoire. Biomedical Repertoire was the most significant for both groups, being led by non-indigenous women; the socio-emotional and behavioral constituents were mostly represented by indigenous women. Final considerations and implications for practice in this interethnic setting, intercultural dialogue materializes in the exchange of a heterogeneous way of thinking-knowing-doing, which unfolds in the light of relational and functional interculturality, demonstrating embryonic movements towards critical interculturality.

Integral health care for transgender adolescents: subsidies for nursing practice.

OBJECTIVE: to analyze the integral health care for transgender adolescents from the perspective of their guardians. METHOD: qualitative research based on the Social Network framework proposed by Lia Sanicola, developed with 22 guardians of transgender adolescents in Brazil through semi-structured individual online interviews. The empirical material was analyzed using the content analysis technique, thematic modality. RESULTS: lack of ambience was observed, in addition to technical unpreparedness of health professionals in relation to the theme at all levels of care, transphobia, centralization of care in scarce qualified services for transgender children and youth, absence of family support, lack of health promotion actions within the community, especially in the school environment, and the common support from non-governmental initiatives. CONCLUSION: the centralization of actions in scarce specialized services in the country, and the structural transphobia can compromise the integral health care for transgender adolescents. There is an urgent need for a network of care capable of assisting the joint action by multi and interdisciplinary teams, with greater proactivity of the nurse with the transgender adolescent and their guardians in individual and collective actions; ambience; health promotion in schools for visibility and support in Primary Health Care since childhood. HIGHLIGHTS: (1) Need for a network of care concerning integral health care for transgender adolescents.(2) Centralization and scarce qualified services for transgender children and youth.(3) Invisible families, lack of health promotion within the community.(4) Unpreparedness of health professionals and disarticulation of the health care network.(5) Need for qualification of nurses when caring for transgender people.

Support for Mothers, Fathers, or Guardians of Transgender Children and Adolescents: A Systematic Review on the Dynamics of Secondary Social Networks.

Mothers', fathers', or guardians' support for disclosures of diverse gender identity has significant relationships with decreased suicidality for transgender children and adolescents. They play an essential role in facing transphobia, protecting trans children, and strengthening the expression of their identity. These guardians need structural, emotional, and informative support; they need to be prepared to recognize and manage of their own feelings, as well as deal with the challenges that come with new social contexts of transphobia in schools, health institutions, and other community spaces. This study aimed to analyze the scientific evidence on the dynamics of secondary social networks to support mothers, fathers, or guardians of transgender children and adolescents. This is a systematic review of qualitative studies, guided by PRISMA guidelines. Controlled and free vocabularies were used to survey the primary studies in the following databases: EMBASE; Scopus; MEDLINE; Cumulative Index to Nursing and Allied Health Literature (CINAHL); PsycInfo; Latin American and Caribbean Literature in Health Sciences (LILACS); and Web of Science. A total of 28 articles made up the final sample of this review. Secondary social networks were described as fragile, characterized by conflicting and broken ties with healthcare services and professionals, isolation and unpreparedness from schools, and emotional and informational support from peer groups and some qualified healthcare professionals. The literature shows the potential of the dynamics of secondary social support networks; however, it presented the unpreparedness of professionals and institutional policies for welcoming transgender children and adolescents and their families, with the peer group being the main emotional and informative support network.

Validation of Questionnaire to Assess the Impact of Dementia on the Family.

OBJECTIVE: To validate a questionnaire to assess the impact of dementia on one of the household members. METHODS: Methodological study. The instrument was designed based on literature review, expert opinion, and researchers' experience and then applied to a non-probability convenience sample consisting of 262 family members who live daily with a person with dementia. The construct validity was studied by exploratory factor analysis, principal components method, with varimax rotation of the items. RESULTS: An instrument with 30 items was obtained, distributed in four dimensions: "Emotional dimension," "Economic dimension," "Family relations dimension," and "Support-seeking dimension." Factor analysis revealed a total explained variance of 54.96% and a total Cronbach's alpha of .899. CONCLUSIONS: The instrument presents high internal consistency, grouped into four dimensions, all closely related to the family's adaptation to the onset of dementia in one of its members.

Efeitos da pandemia e fatores associados à saúde mental de profissionais de saúde: revisão integrativa / Efectos de la pandemia y factores asociados en la salud mental de los profesionales de la salud: revisión integradora / The effects of the pandemic and factors associated with the mental health of healthcare professionals: integrative review

RESUMO Objetivo: identificar, na literatura científica, os efeitos da pandemia e fatores associados àsaúde mental de profissionais de saúde que atuam no enfrentamento da COVID-19. Método: revisão integrativa da literatura, através das bases de dados Web of Science, LILACS, Medline e CINAHL, realizada em novembro de 2020.A busca se deu de forma ampla, criteriosa e independente por dois pesquisadores; em casos de divergência, houve a participação de um terceiro pesquisador. Resultados: 12 artigos compuseram a amostra. Ansiedade, depressão e distúrbios do sono foram os efeitos na saúde mental mais prevalentes em profissionais de saúde durante a pandemia de COVID-19. O setor de trabalho, a falta de Equipamentos de Proteção Individual (EPIs) e o aumento da carga horária de trabalho foram os principais fatores desencadeantes desses efeitos. Considerações Finais: faz-se necessária a implantação de estratégias e intervenções eficazes que garantam um suporte psicológico a curto, médio e longo prazo para os profissionais de saúde.

RESUMEN Objetivo: identificar en la literatura científica los efectos de la pandemia y los factores asociados a la salud mental de los profesionales de la salud que trabajan frente al COVID-19. Método: revisión bibliográfica integradora, a través de las bases de datos Web of Science, LILACS, Medline y CINAHL, realizada en noviembre de 2020. La búsqueda fue llevada a cabo de forma amplia, cuidadosa e independiente por dos investigadores y, en caso de desacuerdo, se contó con la participación de un tercer investigador. Resultados: 12 artículos componían la muestra. La ansiedad, la depresión y los trastornos del sueño fueron los efectos de salud mental más prevalentes en los profesionales de la salud durante la pandemia de COVID-19. El sector laboral, la falta de Equipos de Protección Individual y el aumento de la carga de trabajo fueron los principales factores desencadenantes de estos efectos. Consideraciones finales: es necesario poner en marcha estrategias e intervenciones eficaces que garanticen el apoyo psicológico a corto, medio y largo plazos de los profesionales de la salud.

ABSTRACT Objective: to identify, in the scientific literature, the effects of the pandemic and factors associated with the mental health of healthcare professionals who work in the fight against COVID-19. Method: integrative literature review, through the Web of Science, LILACS, Medline and CINAHL databases, carried out in November 2020. The search was carried out in a broad, thorough, and independent way by two researchers; in cases of divergence, there was the participation of a third researcher. Results: 12 articles made up the sample. Anxiety, depression, and sleep disorders were the most prevalent mental health effects in healthcare workers during the COVID-19 pandemic. The work sector, the lack of Personal Protective Equipment (PPE) and the increase in working hours were the main triggering factors for these effects. Final Considerations: it is necessary to implement effective strategies and interventions that guarantee short, medium, and long-term psychological support for healthcare professionals.

Excessive release of inorganic polyphosphate by ALS/FTD astrocytes causes non-cell-autonomous toxicity to motoneurons.

Non-cell-autonomous mechanisms contribute to neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), in which astrocytes release unidentified factors that are toxic to motoneurons (MNs). We report here that mouse and patient iPSC-derived astrocytes with diverse ALS/FTD-linked mutations (SOD1, TARDBP, and C9ORF72) display elevated levels of intracellular inorganic polyphosphate (polyP), a ubiquitous, negatively charged biopolymer. PolyP levels are also increased in astrocyte-conditioned media (ACM) from ALS/FTD astrocytes. ACM-mediated MN death is prevented by degrading or neutralizing polyP in ALS/FTD astrocytes or ACM. Studies further reveal that postmortem familial and sporadic ALS spinal cord sections display enriched polyP staining signals and that ALS cerebrospinal fluid (CSF) exhibits increased polyP concentrations. Our in vitro results establish excessive astrocyte-derived polyP as a critical factor in non-cell-autonomous MN degeneration and a potential therapeutic target for ALS/FTD. The CSF data indicate that polyP might serve as a new biomarker for ALS/FTD.

Ribosome profiling reveals novel regulation of C9ORF72 GGGGCC repeat-containing RNA translation.

GGGGCC (G4C2) repeat expansion in the first intron of C9ORF72 causes amyotrophic lateral sclerosis and frontotemporal dementia. Repeat-containing RNA is translated into dipeptide repeat (DPR) proteins, some of which are neurotoxic. Using dynamic ribosome profiling, we identified three translation initiation sites in the intron upstream of (G4C2) repeats; these sites are detected irrespective of the presence or absence of the repeats. During translocation, ribosomes appear to be stalled on the repeats. An AUG in the preceding C9ORF72 exon initiates a uORF that inhibits downstream translation. Polysome isolation indicates that unspliced (G4C2) repeat-containing RNA is a substrate for DPR protein synthesis. (G4C2) repeat-containing RNA translation is 5' cap-independent but inhibited by the initiation factor DAP5, suggesting an interplay with uORF function. These results define novel translational mechanisms of expanded (G4C2) repeat-containing RNA in disease.

Validation of Questionnaire to Assess the Impact of Dementia on the Family / Validación de encuesta de evaluación del impacto de la demencia en la familia / Validação do questionário de avaliação do impacto da demência na família

ABSTRACT Objective: To validate a questionnaire to assess the impact of dementia on one of the household members. Methods: Methodological study. The instrument was designed based on literature review, expert opinion, and researchers' experience and then applied to a non-probability convenience sample consisting of 262 family members who live daily with a person with dementia. The construct validity was studied by exploratory factor analysis, principal components method, with varimax rotation of the items. Results: An instrument with 30 items was obtained, distributed in four dimensions: "Emotional dimension," "Economic dimension," "Family relations dimension," and "Support-seeking dimension." Factor analysis revealed a total explained variance of 54.96% and a total Cronbach's alpha of .899. Conclusions: The instrument presents high internal consistency, grouped into four dimensions, all closely related to the family's adaptation to the onset of dementia in one of its members.

RESUMEN Objetivo: Validar encuesta de evaluación del impacto de la demencia en uno de los miembros del agregado familiar. Métodos: Estudio metodológico. El instrumento fue construido basado en la revisión de la literatura, opinión de peritos y experiencia de los investigadores y, en seguida, aplicado a una muestra no probabilística de conveniencia constituida por 262 familiares que cohabitan diariamente con una persona con demencia. La validez de constructo fue estudiada por análisis factorial exploratorio, método de los componentes principales, con rotación varimax de los ítems. Resultados: Obtuvo un instrumento con 30 ítems, distribuidos en cuatro dimensiones: "Emocional", "Económica", "Relaciones familiares" y "Búsqueda de soporte". El análisis factorial reveló variancia explicada total de 54.96% y alfa de Cronbach total de .899. Conclusiones: El instrumento presenta consistencia interna elevada agrupándose en cuatro dimensiones, todas íntimamente relacionadas a la adaptación de la familia delante el aparecimiento de la demencia en uno de sus miembros.

RESUMO Objetivo: Validar um questionário de avaliação do impacto da demência num dos membros do agregado familiar. Métodos: Estudo metodológico. O instrumento foi construído, com base na revisão da literatura, na opinião de peritos e na experiência dos investigadores. Foi aplicado a uma amostra não probabilística de conveniência constituída por 262 familiares de pessoas que coabitam diariamente com a pessoa com demência. A validade de constructo foi estudada pela análise fatorial exploratória, método dos componentes principais, com rotação varimax dos itens. Resultados: Obteve-se um instrumento com 30 itens distribuídos por quatro dimensões "Dimensão emocional", "Dimensão económica", "Dimensão relações familiares" e "Dimensão procura de suporte". A análise fatorial revelou uma variância explicada total de 54,96% e um alfa de Cronbach total de ,899. Conclusões: O instrumento apresenta uma consistência interna elevada agrupando-se em quatro dimensões, todas elas intimamente ligadas à adaptação da família ao aparecimento da demência num dos seus membros.

Integral health care for transgender adolescents: subsidies for nursing practice / Atenção integral à saúde dos adolescentes transgêneros: subsídios para a prática da Enfermagem / Atención integral a la salud de los adolescentes transgénero: subsidios para la práctica de la Enfermería

Abstract Objective: to analyze the integral health care for transgender adolescents from the perspective of their guardians. Method: qualitative research based on the Social Network framework proposed by Lia Sanicola, developed with 22 guardians of transgender adolescents in Brazil through semi-structured individual online interviews. The empirical material was analyzed using the content analysis technique, thematic modality. Results: lack of ambience was observed, in addition to technical unpreparedness of health professionals in relation to the theme at all levels of care, transphobia, centralization of care in scarce qualified services for transgender children and youth, absence of family support, lack of health promotion actions within the community, especially in the school environment, and the common support from non-governmental initiatives. Conclusion: the centralization of actions in scarce specialized services in the country, and the structural transphobia can compromise the integral health care for transgender adolescents. There is an urgent need for a network of care capable of assisting the joint action by multi and interdisciplinary teams, with greater proactivity of the nurse with the transgender adolescent and their guardians in individual and collective actions; ambience; health promotion in schools for visibility and support in Primary Health Care since childhood.

Resumo Objetivo: analisar a atenção integral à saúde dos adolescentes transgêneros na perspectiva dos seus responsáveis. Método: estudo qualitativo fundamentado no referencial Rede Social proposto por Lia Sanicola, desenvolvido com 22 responsáveis por adolescentes transgêneros no Brasil por meio de entrevistas online individuais semiestruturadas. O material empírico foi analisado com a utilização da técnica de análise de conteúdo na modalidade temática. Resultados: Foram evidenciados a falta de ambiência e despreparo técnico de profissionais da saúde em relação à temática em todos os níveis de atenção, transfobia, centralização do cuidado em escassos serviços habilitados para pessoas trans no período infantojuvenil, invisibilidade do apoio à família, ausência de ações de promoção da saúde no âmbito comunitário, sobretudo, escolar, e, ainda, o acolhimento promovido, comumente, pelas iniciativas não governamentais. Conclusão: a centralização de ações em escassos serviços especializados no país e a transfobia estrutural podem comprometer a atenção integral à saúde dos adolescentes trans. Urge a necessidade de uma linha de cuidado capaz de auxiliar a atuação conjunta por equipe multi e interdisciplinar com maior proatividade do enfermeiro junto ao adolescente trans e seus responsáveis por meio de ações individuais e coletivas; ambiência; promoção da saúde nas escolas para visibilidade e acolhimento na Atenção Primária à Saúde desde a infância.

Resumen Objetivo: analizar la atención integral a la salud de los adolescentes transgénero desde la perspectiva de sus responsables. Método: estudio cualitativo basado en el marco de la Red Social propuesto por Lia Sanicola, desarrollado con 22 responsables de adolescentes transgénero en Brasil a partir de entrevistas en línea individuales semiestructuradas. El material empírico fue analizado mediante la técnica de análisis de contenido, modalidad temática. Resultados: se ha evidenciado la falta de ambiente y preparación técnica de los profesionales de la salud con relación al tema en todos los niveles de atención, transfobia, centralización del cuidado en los pocos servicios habilitados para personas trans en el período infantojuvenil, invisibilidad del apoyo a la familia, ausencia de acciones de promoción de la salud en el ámbito comunitario, especialmente en la escuela, y la acogida comúnmente por las iniciativas no gubernamentales. Conclusión: la centralización de acciones en los pocos servicios especializados del país y la transfobia estructural pueden comprometer la atención integral en salud de los adolescentes trans. Urge una línea de cuidado capaz de auxiliar la acción conjunta de un equipo multi e interdisciplinario, con mayor proactividad del enfermero con el adolescente transgénero y sus responsables en acciones individuales y colectivas; ambiente; promoción de la salud en las escuelas para la visibilidad y acogida en la Atención Primaria de la Salud desde la infancia.

[Community Therapy and psychic distress in the family system: an approach based on the new paradigm of science]. / Terapia Comunitária e sofrimento psíquico no sistema familiar: um enfoque baseado no novo paradigma da ciência.

The scope of this study was to analyze the behavior patterns adopted by family members dealing with individuals in psychological distress within the scope of the relationships established in the family system, after participating in Community Therapy sessions. It was based on research with a qualitative approach using the research-action-intervention method. The intervention used centered around twelve Community Therapy sessions. Ten family members of people in psychological distress monitored by a Psychosocial Care Center took part in the study. Field notebook records, videos obtained with the tapes of the Community Therapy sessions, the interview material and Community Therapy itself were used as the empirical material production technique. The study revealed that the family members' understanding of psychological distress could be transformed as they attributed new meanings and performed fundamental actions to balanced living in the family. Community Therapy was seen as a practice that facilitated changes in the lives of its participants, as it contributed to generate social and individual interactions that stimulated family members to rethink concepts and to create spaces of coexistence and human and respectful care that permeated the family unit.

O presente estudo buscou analisar os comportamentos adotados por familiares que lidam com entes em sofrimento psíquico, no âmbito das relações estabelecidas no sistema familiar, depois de participarem de rodas de Terapia Comunitária. Pesquisa de abordagem qualitativa que utilizou o método da pesquisa-ação-intervenção. A intervenção utilizada foram doze rodas de Terapia Comunitária. Fizeram parte do estudo dez familiares de pessoas em sofrimento psíquico acompanhadas em um Centro de Atenção Psicossocial. Como técnicas de produção do material empírico foram utilizados os registros do caderno de campo, os vídeos obtidos com a gravação das rodas de Terapia Comunitária, o material das entrevistas e a própria Terapia Comunitária. O estudo revelou que a compreensão dos familiares acerca do sofrimento psíquico pôde ser transformada na medida que atribuíam novos significados e realizavam ações fundamentais ao convívio equilibrado na família. A Terapia Comunitária pôde ser elucidada como uma prática que facilitou mudanças na vida de seus participantes, pois contribuiu para gerar interações sociais e individuais que estimularam os familiares a repensarem conceitos e a criarem espaços de convivência e cuidado humanos e respeitosos que se difundiram para o sistema familiar.

Terapia Comunitária e sofrimento psíquico no sistema familiar: um enfoque baseado no novo paradigma da ciência / Community Therapy and psychic distress in the family system: an approach based on the new paradigm of science

Resumo O presente estudo buscou analisar os comportamentos adotados por familiares que lidam com entes em sofrimento psíquico, no âmbito das relações estabelecidas no sistema familiar, depois de participarem de rodas de Terapia Comunitária. Pesquisa de abordagem qualitativa que utilizou o método da pesquisa-ação-intervenção. A intervenção utilizada foram doze rodas de Terapia Comunitária. Fizeram parte do estudo dez familiares de pessoas em sofrimento psíquico acompanhadas em um Centro de Atenção Psicossocial. Como técnicas de produção do material empírico foram utilizados os registros do caderno de campo, os vídeos obtidos com a gravação das rodas de Terapia Comunitária, o material das entrevistas e a própria Terapia Comunitária. O estudo revelou que a compreensão dos familiares acerca do sofrimento psíquico pôde ser transformada na medida que atribuíam novos significados e realizavam ações fundamentais ao convívio equilibrado na família. A Terapia Comunitária pôde ser elucidada como uma prática que facilitou mudanças na vida de seus participantes, pois contribuiu para gerar interações sociais e individuais que estimularam os familiares a repensarem conceitos e a criarem espaços de convivência e cuidado humanos e respeitosos que se difundiram para o sistema familiar.

Abstract The scope of this study was to analyze the behavior patterns adopted by family members dealing with individuals in psychological distress within the scope of the relationships established in the family system, after participating in Community Therapy sessions. It was based on research with a qualitative approach using the research-action-intervention method. The intervention used centered around twelve Community Therapy sessions. Ten family members of people in psychological distress monitored by a Psychosocial Care Center took part in the study. Field notebook records, videos obtained with the tapes of the Community Therapy sessions, the interview material and Community Therapy itself were used as the empirical material production technique. The study revealed that the family members' understanding of psychological distress could be transformed as they attributed new meanings and performed fundamental actions to balanced living in the family. Community Therapy was seen as a practice that facilitated changes in the lives of its participants, as it contributed to generate social and individual interactions that stimulated family members to rethink concepts and to create spaces of coexistence and human and respectful care that permeated the family unit.

Limiting factors of face shield use for health professionals during the COVID-19 pandemic.

BACKGROUND: Coronavirus disease (COVID-19) is caused by SARS-COV2, a highly transmissible and pathogenic viral infection, and was identified in December 2019 in Wuhan, China. Three months later, it became a severe pandemic. OBJECTIVE: To identify scientific evidence on the use of face shields by health professionals during the COVID-19 pandemic period. METHOD: An integrative literature review of articles obtained from PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Web of Science databases was undertaken. For the search, controlled, non-controlled descriptors and specific keywords: "face shield," "fluid resistance procedure," "respiratory infections," "healthcare workers," "COVID-19," "aerosols," and "personal protection infection" were used. RESULTS: The sample comprised seven studies. The available evidence has shown that face shields do not have a defined standard for their production-their effectiveness depends on the quality of the visor, structure, and fixation system. They must be used as adjuvants to other personal protective equipment (PPE), and their isolated use is not recommended due to the fragilities of peripheral face sealing, especially during the COVID-19 pandemic period. CONCLUSION: Due to the shortage of this equipment, domestic face shields can be indicated if they meet production requirements, based on scientific evidence for their efficient use.

Translation of the poly(GR) frame in C9ORF72-ALS/FTD is regulated by cis-elements involved in alternative splicing.

GGGGCC (G4C2) repeat expansion in the first intron of C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia, two devastating age-dependent neurodegenerative disorders. Both sense and antisense repeat RNAs can be translated into 5 different dipeptide repeat proteins, such as poly(GR), which is toxic in various cellular and animal models. However, it remains unknown how poly(GR) is synthesized in patient neurons. Using a reporter construct containing 70 G4C2 repeats flanked by human intronic and exonic sequences, we show that translation of the poly(GR) frame does not depend on repeats or the CUG start codon in the poly(GA) frame, suggesting poly(GR) is not produced after ribosomal frameshifting in the poly(GA) frame. However, deletion analysis suggests that translation of the poly(GR) frame depends on the length of the intronic sequence 5' adjacent to G4C2 repeats. Moreover, several 5´ cis elements that are predicted to be involved in alternative splicing regulates poly(GR) synthesis. These results suggest that translation of repeat RNAs in the poly(GR) frame is regulated by multiple cis elements, likely through RNA secondary structures and/or associated RNA binding proteins.