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PURPOSE Failure to respond to induction chemotherapy portends a poor outcome in childhood acute lymphoblastic leukemia (ALL) and is more frequent in T-cell ALL (T-ALL) than B-cell ALL. We aimed to address the limited understanding of clinical and genetic factors that influence outcome in a cohort of patients with T-ALL induction failure (IF). METHODS We studied all cases of T-ALL IF on two consecutive multinational randomized trials, UKALL2003 and UKALL2011, to define risk factors, treatment, and outcomes. We performed multiomic profiling to characterize the genomic landscape. RESULTS IF occurred in 10.3% of cases and was significantly associated with increasing age, occurring in 20% of patients age 16 years and older. Five-year overall survival (OS) rates were 52.1% in IF and 90.2% in responsive patients ( P < .001). Despite increased use of nelarabine-based chemotherapy consolidated by hematopoietic stem-cell transplant in UKALL2011, there was no improvement in outcome. Persistent end-of-consolidation molecular residual disease resulted in a significantly worse outcome (5-year OS, 14.3% v 68.5%; HR, 4.10; 95% CI, 1.35 to 12.45; P = .0071). Genomic profiling revealed a heterogeneous picture with 25 different initiating lesions converging on 10 subtype-defining genes. There was a remarkable abundance of TAL1 noncoding lesions, associated with a dismal outcome (5-year OS, 12.5%). Combining TAL1 lesions with mutations in the MYC and RAS pathways produces a genetic stratifier that identifies patients highly likely to fail conventional therapy (5-year OS, 23.1% v 86.4%; HR, 6.84; 95% CI, 2.78 to 16.78; P < .0001) and who should therefore be considered for experimental agents. CONCLUSION The outcome of IF in T-ALL remains poor with current therapy. The lack of a unifying genetic driver suggests alternative approaches, particularly using immunotherapy, are urgently needed.

Supplementary Table from Systematic Evaluation of the Immune Environment of Small Intestinal Neuroendocrine Tumors

SUPPLEMENTAL TABLE: Effect of homozygosity at the three HLA class I loci -A, -B and -C and five HLA class I loci -DRB1, DQA1, DQB1, DPA1, and DPB1 on susceptibility to four NHL subtypes (DLBCL, FL, CLL/SLL, and MZL) stratified by GWAS platform (analyses adjusted for sex, age, and ancestry/principal components)

Supplementary Data from Systematic Evaluation of the Immune Environment of Small Intestinal Neuroendocrine Tumors

A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of “heterozygote advantage” regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06–1.60; OR MZL = 1.45, 95% CI = 1.12–1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24–3.55; OR MZL = 2.10, 95% CI = 0.99–4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (P trend < 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes.Significance: HLA gene diversity reduces risk for non-Hodgkin lymphoma. Cancer Res; 78(14); 4086–96. ©2018 AACR.

Purpose:Immune dysregulation is described in multiple myeloma. While preclinical models suggest a role for altered T-cell immunity in disease progression, the contribution of immune dysfunction to clinical outcomes remains unclear. We aimed to characterize marrow-infiltrating T cells in newly diagnosed patients and explore associations with outcomes of first-line therapy.Experimental Design:We undertook detailed characterization of T cells from bone marrow (BM) samples, focusing on immune checkpoints and features of immune dysfunction, correlating with clinical features and progression-free survival.Results:We found that patients with multiple myeloma had greater abundance of BM regulatory T cells (Tregs) which, in turn, expressed higher levels of the activation marker CD25 compared with healthy donors. Patients with higher frequencies of Tregs had shorter PFS and a distinct Treg immune checkpoint profile (increased PD-1, LAG-3) compared with patients with lower frequencies of Tregs. Analysis of CD4 and CD8 effectors revealed that low CD4effector (CD4eff):Treg ratio and increased frequency of PD-1–expressing CD4eff cells were independent predictors of early relapse over and above conventional risk factors, such as genetic risk and depth of response. Ex vivo functional analysis and RNA sequencing revealed that CD4 and CD8 cells from patients with greater abundance of CD4effPD-1+ cells displayed transcriptional and secretory features of dysfunction.Conclusions:BM-infiltrating T-cell subsets, specifically Tregs and PD-1–expressing CD4 effectors, negatively influence clinical outcomes in newly diagnosed patients. Pending confirmation in larger cohorts and further mechanistic work, these immune parameters may inform new risk models, and present potential targets for immunotherapeutic strategies.

Supplementary tables and figures

Purpose:The immune tumor microenvironment and the potential therapeutic opportunities for immunotherapy in small intestinal neuroendocrine tumors (siNET) have not been fully defined.Experimental Design:Herein, we studied 40 patients with primary and synchronous metastatic siNETs, and matched blood and normal tissue obtained during surgery. We interrogated the immune checkpoint landscape using multi-parametric flow cytometry. In addition, matched FFPE tissue was obtained for multi-parametric IHC to determine the relative abundance and distribution of T-cell infiltrate. Tumor mutational burden (TMB) was also assessed and correlated with immune infiltration.Results:Effector tumor-infiltrating lymphocytes (TIL) had a higher expression of PD-1 in the tumor microenvironment compared with the periphery. In addition, CD8+ TILs had a significantly higher co-expression of PD-1/ICOS and PD-1/CTLA-4 (cytotoxic T lymphocyte antigen-4) and higher levels of PD-1 expression compared with normal tissue. IHC revealed that the majority of cases have ≤10% intra-tumoral T cells but a higher number of peri-tumoral T cells, demonstrating an “exclusion” phenotype. Finally, we confirmed that siNETs have a low TMB compared with other tumor types in the TCGA database but did not find a correlation between TMB and CD8/Treg ratio.Conclusions:Taken together, these results suggest that a combination therapy approach will be required to enhance the immune response, using PD-1 as a checkpoint immunomodulator backbone in combination with other checkpoint targeting molecules (CTLA-4 or ICOS), or with drugs targeting other pathways to recruit “excluded” T cells into the tumor microenvironment to treat patients with siNETs.

Single-cell profiling of circulating tumor cells (CTCs) as part of a minimally invasive liquid biopsy presents an opportunity to characterize and monitor tumor heterogeneity and evolution in individual patients. In this study, we aimed to compare single-cell copy number variation (CNV) data with tissue and define the degree of intra- and inter-patient genomic heterogeneity. We performed next-generation sequencing (NGS) whole-genome CNV analysis of 125 single CTCs derived from seven patients with neuroendocrine neoplasms (NEN) alongside matched white blood cells (WBC), formalin-fixed paraffin-embedded (FFPE), and fresh frozen (FF) samples. CTC CNV profiling demonstrated recurrent chromosomal alterations in previously reported NEN copy number hotspots, including the prognostically relevant loss of chromosome 18. Unsupervised hierarchical clustering revealed CTCs with distinct clonal lineages as well as significant intra- and inter-patient genomic heterogeneity, including subclonal alterations not detectable by bulk analysis and previously unreported in NEN. Notably, we also demonstrated the presence of genomically distinct CTCs according to the enrichment strategy utilized (EpCAM-dependent vs size-based). This work has significant implications for the identification of therapeutic targets, tracking of evolutionary change, and the implementation of CTC-biomarkers in cancer.

"Nowadays, technology and digital screens have become an essential part of our routine. At the same time, young children are being exposed to these screens at an earlier age. Literature suggests that there is a digital gap between those children who have been trained to use technology critically and effectively and those who have not. Considering the relevance of the topic in developed societies, we will analyze the current national (Spain) and international literature on the issue. The objective of the study is to recognize the needs and weaknesses of Spanish research with the aim to offer an effective data collection tool for future research. The literature review reveals that as a result of COVID-19 pandemic, several new articles have been produced with the aim of analyzing the situation, anticipating possible consequences and providing action strategies and healthy routines for families and schools. On the international scene, during the last 10 years the number of studies about experts' recommendations, health concerns and the benefits of educational Apps has increased consistently. Focusing on national research, most Spanish studies exclude young children (0-6 years) and those who include them, focus on a specific field or analyze a small sample. To cover the research gap from 0-6 years old, we have designed two surveys, one for caregivers and one for preschool teachers. Some semi-structured interviews are also being considered to complement the quantitative data with qualitative information related to the perceptions, experiences, beliefs and practices of parents and teachers. The sample is divided into the main caregivers of young children and early education tutors of preschools in the Metropolitan Area of Barcelona. To include different socioeconomic status (SES), should be conducted in at least 30 preschool education centers distributed as follows: 10 schools located in low-income neighborhoods, 10 schools located in middle-income neighborhoods and 10 schools located in high-income neighborhoods."

Purpose: Immune dysregulation is described in multiple myeloma. While preclinical models suggest a role for altered T-cell immunity in disease progression, the contribution of immune dysfunction to clinical outcomes remains unclear. We aimed to characterize marrow-infiltrating T cells in newly diagnosed patients and explore associations with outcomes of first-line therapy. Experimental Design: We undertook detailed characterization of T cells from bone marrow (BM) samples, focusing on immune checkpoints and features of immune dysfunction, correlating with clinical features and progression-free survival. Results: We found that patients with multiple myeloma had greater abundance of BM regulatory T cells (Tregs) which, in turn, expressed higher levels of the activation marker CD25 compared with healthy donors. Patients with higher frequencies of Tregs had shorter PFS and a distinct Treg immune checkpoint profile (increased PD-1, LAG-3) compared with patients with lower frequencies of Tregs. Analysis of CD4 and CD8 effectors revealed that low CD4effector (CD4eff):Treg ratio and increased frequency of PD-1–expressing CD4eff cells were independent predictors of early relapse over and above conventional risk factors, such as genetic risk and depth of response. Ex vivo functional analysis and RNA sequencing revealed that CD4 and CD8 cells from patients with greater abundance of CD4effPD-1+ cells displayed transcriptional and secretory features of dysfunction. Conclusions: BM-infiltrating T-cell subsets, specifically Tregs and PD-1–expressing CD4 effectors, negatively influence clinical outcomes in newly diagnosed patients. Pending confirmation in larger cohorts and further mechanistic work, these immune parameters may inform new risk models, and present potential targets for immunotherapeutic strategies.

RESUMO A educação popular em saúde é uma estratégia de fortalecimento da participação popular na rearticulação da Reforma Sanitária Brasileira. Como efetivação da Política Nacional de Educação Popular em Saúde, tem-se o Curso Livre de Educação Popular em Saúde (EdPopSUS). Os educadores do EdPopSUS passam por uma seleção pública composta de um curso de 40 horas. A coordenação do Ceará realizou, autonomamente, processo de educação permanente após a etapa seletiva. Este artigo objetivou constituir um olhar sobre a formação inicial e sobre a educação permanente vivenciadas pelos/as educadores/as, analisando os conflitos desses processos à luz da educação popular, em diálogo com as superações produzidas a partir de atos-limites. Nesta pesquisa de abordagem qualitativa, baseada no estudo de caso, realizou-se análise de conteúdo de um corpus constituído por 23 entrevistas. Foram evidenciadas quatro categorias: processo inicial, princípios da educação popular, situações-limites e ação-reflexão-ação. O curso possibilitou a concretização dos princípios da educação popular. A competição para a seleção, a não participação em todos os momentos e a constituição das duplas foram algumas das situações-limites experienciadas pelos/as educadores/as. Tais situações foram mediadas pela vivência dos princípios da educação popular, apontando atos-limites para o seu exercício na conjuntura atual, especialmente no âmbito do Sistema Único de Saúde. ABSTRACT Popular education in health is a strategy to strengthen popular participation in the rearticulation of the Brazilian Sanitary Reform. As a result of the National Policy for Popular Education in Health, there is the Free Course of Popular Education in Health (EdPopSUS). EdPopSUS educators go through a public selection made up of a 40-hour course. The coordination of Ceará carried out, independently, a permanent education process after the selective stage. This article aimed to constitute a look at the initial formation and permanent education experienced by the educators, analyzing the conflicts of these processes in the light of popular education, in dialogue with the overcoming produced from limiting-acts. In this qualitative research, based on the case study, content analysis of a corpus consisting of 23 interviews was carried out. Four categories were highlighted: initial process, principles of popular education, limit-situations and action-reflection-action. The course made it possible to implement the principles of popular education. The competition for selection, the non-participation at all times and the formation of pairs were some of the limit situations experienced by educators. Such situations were mediated by the experience of the principles of popular education, pointing out limiting-acts for its exercise in the current situation, especially within the scope of the Unified Health System.

This investigation verified the relationship of spirituality and religiosity associated with quality of life in chronic renal patients who underwent hemodialysis. Cross-sectional study conducted in the State of Ceará, northeastern Brazil, using a sample of 192 participants. The following instruments were used in the interviews: sociodemographic and clinical questionnaire, kidney disease and quality of life short-form (KDQOL-SF TM) and WHOQOL-SRPB. The collection took place in 2019. All analyses were performed on the SPSS. The results showed that the participants were between 50 and 51 years old (30.1%); male (69.8%); married (54.7%); receiving between 1 and 2 minimum wages (67.2%); incomplete elementary school (47.9%); unemployed (19.8%); live accompanied (93.2%); dialysis time from 1 to 5 years (39.6%). Patients were aware that their state of health makes it difficult to "perform activities that require physical exertion" showed a significant increase of about three times more spirituality/religiosity (OR=4.096, 95% CI: 1.33 – 12.608, p= 0.014). It was found that religiosity and spirituality interferes in the quality of life of chronic renal patients. Esta investigación verificó la relación de espiritualidad y religiosidad asociada con la calidad de vida en pacientes renales crónicos que se sometieron a hemodiálisis. Estudio transversal realizado en el Estado de Ceará, nordeste de Brasil, utilizando una muestra de 192 participantes. En las entrevistas se utilizaron los siguientes instrumentos: cuestionario sociodemográfico y clínico, enfermedad renal y calidad de vida de forma corta (KDQOL-SF TM) y WHOQOL-SRPB. La colección tuvo lugar en 2019. Todos los análisis se realizaron en el SPSS. Los resultados mostraron que los participantes tenían entre 50 y 51 años (30,1%); hombres (69,8%); casados (54,7%); recibir entre 1 y 2 salarios mínimos (67,2%); escuela primaria incompleta (47,9%); desempleados (19,8%); en vivo acompañados (93,2%); tiempo de diálisis de 1 a 5 años (39,6%). Los pacientes eran conscientes de que su estado de salud dificulta la "realización de actividades que requieren esfuerzo físico" mostraron un aumento significativo de aproximadamente tres veces más espiritualidad/religiosidad (OR=4,096, IC 95%: 1,33 – 12,608, p= 0,014). Se encontró que la religiosidad y la espiritualidad interfieren en la calidad de vida de los pacientes renales crónicos. Essa investigação verificou a relação da espiritualidade e religiosidade associada à qualidade de vida em pacientes renais crônicos que fazem hemodiálise. Estudo transversal realizado no Estado do Ceará, nordeste do Brasil, utilizando uma amostra de 192 participantes. Nas entrevistas foram utilizados os seguintes instrumentos: questionário sociodemográfico e clínico, o Kidney Disease and Quality of Life Short-Form (KDQOL-SF TM) e WHOQOL-SRPB. A coleta ocorreu em 2019. Todas as análises foram realizadas no SPSS. Os resultados demonstraram que os participantes tinham entre 50 a 51 anos (30,1%); masculino (69,8%); casado (54,7%); recebendo entre 1 a 2 salários mínimos (67,2%); com ensino fundamental incompleto (47,9%); desempregados (19,8%); moram acompanhados (93,2%); tempo de diálise de 1 a 5 anos (39,6%). Os pacientes tinham ciência de que seu estado de saúde dificulta “a realização de atividades que requerem esforço físico” apresentaram aumento significativo de cerca de três vezes mais espiritualidade/religiosidade (OR=4,096, IC 95%: 1,33 – 12,608, p= 0,014). Constatado que a religiosidade e espiritualidade interfere na qualidade de vida dos renais crônicos.

Purpose: The immune tumor microenvironment and the potential therapeutic opportunities for immunotherapy in small intestinal neuroendocrine tumors (siNET) have not been fully defined. Experimental Design: Herein, we studied 40 patients with primary and synchronous metastatic siNETs, and matched blood and normal tissue obtained during surgery. We interrogated the immune checkpoint landscape using multi-parametric flow cytometry. In addition, matched FFPE tissue was obtained for multi-parametric IHC to determine the relative abundance and distribution of T-cell infiltrate. Tumor mutational burden (TMB) was also assessed and correlated with immune infiltration. Results: Effector tumor-infiltrating lymphocytes (TIL) had a higher expression of PD-1 in the tumor microenvironment compared with the periphery. In addition, CD8+ TILs had a significantly higher co-expression of PD-1/ICOS and PD-1/CTLA-4 (cytotoxic T lymphocyte antigen-4) and higher levels of PD-1 expression compared with normal tissue. IHC revealed that the majority of cases have ≤10% intra-tumoral T cells but a higher number of peri-tumoral T cells, demonstrating an “exclusion” phenotype. Finally, we confirmed that siNETs have a low TMB compared with other tumor types in the TCGA database but did not find a correlation between TMB and CD8/Treg ratio. Conclusions: Taken together, these results suggest that a combination therapy approach will be required to enhance the immune response, using PD-1 as a checkpoint immunomodulator backbone in combination with other checkpoint targeting molecules (CTLA-4 or ICOS), or with drugs targeting other pathways to recruit “excluded” T cells into the tumor microenvironment to treat patients with siNETs.

Este estudo tem o objetivo de analisar as experiências da avaliação formativa em cursos de graduação da saúde a partir de evidências latino-americanas. Trata-se de uma revisão integrativa que utilizou 26 artigos selecionados nas bases de dados da Biblioteca Virtual em Saúde (BVS), Scielo e LILACS, a partir da adoção de critérios de elegibilidade pré-estabelecidos. A análise desses artigos revelou conceitos, atividades e desafios da avaliação formativa. Verificou-se que a avaliação formativa ainda não é bem interpretada por docentes e discentes, o que compromete a sua efetividade. Foram identificadas como principais estratégias o feedback e o portfólio interpretativo, que possibilitam a autoavaliação independente do facilitador/docente. O mapa conceitual também foi indicado como uma das estratégias. Este estudo revelou que a avaliação formativa, apesar de um tema em constante discussão nos espaços educacionais, ainda é incipiente na literatura científica latino-americana, dessa forma, suscita-se a necessidade de mais estudos de campo relacionados ao tema.

Integrative analysis of multi-omics data is a powerful approach for gaining functional insights into biological and medical processes. Conducting these multifaceted analyses on human samples is often complicated by the fact that the raw sequencing output is rarely available under open access. The Personal Genome Project UK (PGP-UK) is one of few resources that recruits its participants under open consent and makes the resulting multi-omics data freely and openly available. As part of this resource, we describe the PGP-UK multi-omics reference panel consisting of ten genomic, methylomic and transcriptomic data. Specifically, we outline the data processing, quality control and validation procedures which were implemented to ensure data integrity and exclude sample mix-ups. In addition, we provide a REST API to facilitate the download of the entire PGP-UK dataset. The data are also available from two cloud-based environments, providing platforms for free integrated analysis. In conclusion, the genotype-validated PGP-UK multi-omics human reference panel described here provides a valuable new open access resource for integrated analyses in support of personal and medical genomics., Measurement(s)DNA methylation profiling data • whole genome sequencing assay • bisulfite sequencing assay • transcription profiling assayTechnology Type(s)DNA methylation profiling assay • DNA sequencing • RNA sequencingFactor Type(s)age • sex • smoking statusSample Characteristic - OrganismHomo sapiens Machine-accessible metadata file describing the reported data: 10.6084/m9.figshare.9896405

Collective Health is considered a field of investigation and knowledge production, being understood as a social practice and of an interdisciplinary nature that brings together three areas: Epidemiology, Social and Human Sciences in Health and Health Policy, Planning and Management. To describe the experiences, challenges and contributions of the discipline of Health Policy, Management and Planning for the training of masters in Public Health, in the current period of pandemic by Covid-19. This is a descriptive study, of the experience report type, carried out from February to June 2020, during the development of activities carried out in the aforementioned discipline in the Graduate Program in Public Health at the State University of Ceará. The course provided a remote space for experiences rich in new knowledge and practices, in addition to providing an environment for discussion and sharing of knowledge, as well as leading students to produce more critical and reflective thoughts. The subject was, therefore, an enriching experience of great relevance for the training of Master's students in Public Health. In addition, it enabled the master's students to (de)construction and consolidation of concepts, overcoming obstacles and difficulties. La Salud Colectiva es considerada un campo de investigación y producción de conocimiento, entendiéndose como una práctica social y de carácter interdisciplinario que aglutina tres áreas: Epidemiología, Ciencias Sociales y Humanas en Salud y Política de Salud, Planificación y Gestión. Para describir las experiencias, Retos y aportes de la disciplina de Política, Gestión y Planificación Sanitaria para la formación de Maestros en Salud Pública, en el actual período de pandemia por Covid-19. Se trata de un estudio descriptivo, del tipo informe de experiencia, realizado de febrero a junio de 2020, durante el desarrollo de las actividades realizadas en la referida disciplina en el Programa de Posgrado en Salud Pública de la Universidad Estatal de Ceará. El curso proporcionó un espacio remoto para experiencias ricas en nuevos conocimientos y prácticas, además de proporcionar un entorno para la discusión y el intercambio de conocimientos, además de llevar a los estudiantes a producir pensamientos más críticos y reflexivos. La asignatura supuso, por tanto, una experiencia enriquecedora y de gran relevancia para la formación de los estudiantes de Máster en Salud Pública. Además, permitió a los alumnos del máster la (des)construcción y consolidación de conceptos, superando obstáculos y dificultades. A Saúde Coletiva é considerada um campo de investigação e produção de conhecimento, sendo compreendida como uma prática social e de natureza interdisciplinar que congrega três áreas: a Epidemiologia, as Ciências Sociais e Humanas em Saúde e a Política, Planejamento e Gestão em Saúde. Objetivou-se descrever as experiências, desafios e contribuições da disciplina de Política, Gestão e Planejamento em Saúde para a formação de mestres em Saúde Coletiva, no período atual de pandemia por Covid-19. Trata-se de um estudo descritivo, do tipo relato de experiência, realizado no período de fevereiro a junho de 2020, durante o desenvolvimento das atividades realizadas na disciplina supracitada no Programa de Pós-Graduação em Saúde Coletiva da Universidade Estadual do Ceará. A disciplina propiciou um espaço remoto de experiências, rico em novos saberes e práticas, além de oportunizar um ambiente de discussão e compartilhamento de conhecimentos, assim como conduzir os discentes a produzirem pensamentos mais críticos e reflexivos. A disciplina constituiu-se, portanto, como uma experiência enriquecedora e de grande relevância para a formação dos mestrandos em Saúde Coletiva. Além disso, possibilitou aos mestrandos a (des)construção e consolidação de conceitos, a superação de obstáculos e dificuldades.

RESUMO Canais de pactuação intergovernamental são instâncias de fortalecimento da descentralização e regionalização no Sistema Único de Saúde. A descentralização apresenta-se como importante dispositivo para a produção do poder regional. O artigo tem por objetivo refletir sobre a importância da Comissão Intergestores Regional na governança da saúde, na Primeira Região de Saúde do Ceará, considerando o processo de descentralização e regionalização. Trata-se de uma pesquisa social qualitativa, um estudo de caso, cujas técnicas de produção de dados foram: a entrevista semiestruturada e a observação simples. Projeto aprovado pelo Comitê de Ética em Pesquisa da Universidade Estadual do Ceará. Alguns resultados mostraram que a Comissão Intergestores Regional é uma instância importante para a governança regional da saúde, através da qual os gestores locais expressam as necessidades do município, pactuam e deliberam sobre a política de saúde da região, mostrando que não são passivos quanto às decisões pactuadas para a organização dessa área. Antes, são sujeitos que se movem em uma arena de disputa pelo melhor desenvolvimento das ações de saúde de seus munícipes, influenciando a governança desta área no estado do Ceará. Verificou-se que a Comissão Intergestores Regional é, também, um local de disputa de poder e de conflitos de interesses. ABSTRACT The channels of intergovernmental agreement are instances of the decentralization and regionalization strengthening in the Unified Health System. Decentralization is an important device for the production of regional power. The article aims to reflect on the importance of the Regional Intergovernmental Commission in health governance in the First Health Region of Ceará, considering the process of decentralization and regionalization. It is a qualitative social research, a case study, whose techniques of data production were semi-structured interviews and simple observation. Project approved by the Research Ethics Committee of the State University of Ceará. Some results showed that the Regional Intergovernmental Commission is an important instance for regional health governance, where local managers express the needs of the municipality, agree and deliberate on the region’s health policy, showing that they are not passive regarding the decisions agreed upon for the organization of this area. Prior to that, they are subjects that move in an arena of dispute for the better development of the health actions of their citizens, influencing the governance of this area in the State of Ceará. It was found that the Regional Intergovernmental Commission is also a place of dispute for power and interests, of conflicts.

Before the need of knowing the past to understand the present and plan for the future, we elaborated a memory to explain the participation of civil society and the State in the formulation of the State Policy on Food and Nutrition Security in Ceará. This paper presents the results of a bibliographic survey conducted in books, articles, and newspapers addressing the theme of drought and famine in Ceará, as well as of a semi-structured interview with the Councilors of the Food and Nutrition Security Council and members of the Human Right to Food. The (re)told story begins by recovering facts that are still unknown to most of Ceará’s inhabitants, such as concentration camps during droughts, the formulation of the state policy on food security interspersed with social movements, strengthening of social participation, and the conquest of the right to food as a human right in Brazil and in Ceará. Despite these advancements, the continuity of this history still has to overcome some challenges, such as investing in the quality of social participation, strengthening participation spaces, gaining political support, guaranteeing financing, giving visibility to legislation, and enforcing mechanisms that ensure the human right to adequate food. Este estudo visa descrever a participação da sociedade civil e do Estado na construção da Política Estadual de Segurança Alimentar e Nutricional no estado do Ceará, conhecendo o passado para compreender o presente e as perspectivas futuras. Para tanto, foi realizado levantamento bibliográfico sobre a seca e a fome no Ceará em livros, artigos e jornais, além disso, foram realizadas entrevistas semiestruturadas junto aos conselheiros do Conselho de Segurança Alimentar e Nutricional e militantes pelo direito humano a alimentação. As ações de combate à fome no Ceará tiveram início com a criação dos campos de concentração durante as secas, fato desconhecido pela maioria dos cearenses. A trajetória da formulação da política estadual de segurança alimentar foi entremeada com os movimentos de luta e o fortalecimento da participação social, que levou à conquista dos marcos legais do direito humano à alimentação no Ceará. No entanto, alguns desafios precisam ser enfrentados para a para a continuidade dessa política: investir na qualidade da participação social, no fortalecimento dos espaços de participação, conquistar apoio político, lutar pela garantia de financiamento, dar visibilidade à legislação e mecanismos de exigibilidade.

Aim: Recessive genetic variation is thought to play a role in non-Hodgkin lymphoma (NHL) etiology. Runs of homozygosity (ROH), defined based on long, continuous segments of homozygous SNPs, can be used to estimate both measured and unmeasured recessive genetic variation. We sought to examine genome-wide homozygosity and NHL risk.Methods: We used data from eight genome-wide association studies of four common NHL subtypes: 3061 chronic lymphocytic leukemia (CLL), 3814 diffuse large B-cell lymphoma (DLBCL), 2784 follicular lymphoma (FL), and 808 marginal zone lymphoma (MZL) cases, as well as 9374 controls. We examined the effect of homozygous variation on risk by: (1) estimating the fraction of the autosome containing runs of homozygosity (FROH); (2) calculating an inbreeding coefficient derived from the correlation among uniting gametes (F3); and (3) examining specific autosomal regions containing ROH. For each, we calculated beta coefficients and standard errors using logistic regression and combined estimates across studies using random-effects meta-analysis.Results: We discovered positive associations between FROH and CLL (β = 21.1, SE = 4.41, P = 1.6 × 10 -6) and FL (β = 11.4, SE = 5.82, P = 0.02) but not DLBCL ( P = 1.0) or MZL ( P = 0.91). For F3, we observed an association with CLL (β = 27.5, SE = 6.51, P = 2.4 × 10 -5). We did not find evidence of associations with specific ROH, suggesting that the associations observed with FROH and F3 for CLL and FL risk were not driven by a single region of homozygosity. Conclusion: Our findings support the role of recessive genetic variation in the etiology of CLL and FL; additional research is needed to identify the specific loci associated with NHL risk.