STING-Dependent Signaling in Microglia or Peripheral Immune Cells Orchestrates the Early Inflammatory Response and Influences Brain Injury Outcome.

While originally identified as an antiviral pathway, recent work has implicated that cyclic GMP-AMP-synthase-Stimulator of Interferon Genes (cGAS-STING) signaling is playing a critical role in the neuroinflammatory response to traumatic brain injury (TBI). STING activation results in a robust inflammatory response characterized by the production of inflammatory cytokines called interferons, as well as hundreds of interferon stimulated genes (ISGs). Global knock-out (KO) mice inhibiting this pathway display neuroprotection with evidence that this pathway is active days after injury; yet, the early neuroinflammatory events stimulated by STING signaling remain understudied. Furthermore, the source of STING signaling during brain injury is unknown. Using a murine controlled cortical impact (CCI) model of TBI, we investigated the peripheral immune and microglial response to injury utilizing male chimeric and conditional STING KO animals, respectively. We demonstrate that peripheral and microglial STING signaling contribute to negative outcomes in cortical lesion volume, cell death, and functional outcomes postinjury. A reduction in overall peripheral immune cell and neutrophil infiltration at the injury site is STING dependent in these models at 24 h. Transcriptomic analysis at 2 h, when STING is active, reveals that microglia drive an early, distinct transcriptional program to elicit proinflammatory genes including interleukin 1-ß (IL-1ß), which is lost in conditional knock-out mice. The upregulation of alternative innate immune pathways also occurs after injury in these animals, which supports a complex relationship between brain-resident and peripheral immune cells to coordinate the proinflammatory response and immune cell influx to damaged tissue after injury.

An Integrated Transcriptomics and Genomics Approach Detects an X/Autosome Translocation in a Female with Duchenne Muscular Dystrophy.

Duchenne and Becker muscular dystrophies, caused by pathogenic variants in DMD, are the most common inherited neuromuscular conditions in childhood. These diseases follow an X-linked recessive inheritance pattern, and mainly males are affected. The most prevalent pathogenic variants in the DMD gene are copy number variants (CNVs), and most patients achieve their genetic diagnosis through Multiplex Ligation-dependent Probe Amplification (MLPA) or exome sequencing. Here, we investigated a female patient presenting with muscular dystrophy who remained genetically undiagnosed after MLPA and exome sequencing. RNA sequencing (RNAseq) from the patient's muscle biopsy identified an 85% reduction in DMD expression compared to 116 muscle samples included in the cohort. A de novo balanced translocation between chromosome 17 and the X chromosome (t(X;17)(p21.1;q23.2)) disrupting the DMD and BCAS3 genes was identified through trio whole genome sequencing (WGS). The combined analysis of RNAseq and WGS played a crucial role in the detection and characterisation of the disease-causing variant in this patient, who had been undiagnosed for over two decades. This case illustrates the diagnostic odyssey of female DMD patients with complex structural variants that are not detected by current panel or exome sequencing analysis.

Freedom for some, but not for Mum: the reproductive injustice associated with pandemic 'Freedom Day' for perinatal women in the United Kingdom.

Introduction: Healthcare services for pregnant and postpartum ('perinatal') women were reconfigured significantly at the advent and for the duration of the SARS-CoV-2 pandemic, and despite the United Kingdom announcing 'Freedom Day' on 19 July 2021 (whereafter all legal lockdown-related restrictions were lifted), restrictions to maternity (antenatal, intrapartum, and postnatal) services remained. This study presents data from eight perinatal women about their experiences of psychosocial wellbeing and maternity care in the post-'Freedom Day' epoch. Methods: Semi-structured interviews were conducted virtually, with data recorded, transcribed, and analysed by hand. Grounded theory analysis was employed with the final theory assessing the reproductive injustice of the pandemic 'Freedom Day'. Results: Analysing iteratively and inductively led to four emergent themes: 'A Failing System, Failing Women'; 'Harm Caused by a State of Difference'; 'The Privileges (Not Rights) of Reproductive Autonomy, Agency, and Advocacy'; and 'Worried Women and Marginalised Mothers'. Together, these themes form the theory of 'Freedom for some, but not for Mum'. Discussion: Women experienced a lack of high-quality reliable information about the pandemic, vaccination against the virus, and the changes to, and decision-making surrounding, their perinatal care. Women recognised healthcare professionals and maternity services were stretched and that maternity services were failing but often reported hostility from staff and abandonment at times when they were unsure about how to navigate their care. The most singular injustice was the disparity between women having to accept continuing restrictions to their freedom whilst receiving maternity care and the (reckless) freedom being enacted by the general public.

Transcriptomic alterations in cortical astrocytes following the development of post-traumatic epilepsy.

Post-traumatic epilepsy (PTE) stands as one of the numerous debilitating consequences that follow traumatic brain injury (TBI). Despite its impact on many individuals, the current landscape offers only a limited array of reliable treatment options, and our understanding of the underlying mechanisms and susceptibility factors remains incomplete. Among the potential contributors to epileptogenesis, astrocytes, a type of glial cell, have garnered substantial attention as they are believed to promote hyperexcitability and the development of seizures in the brain following TBI. The current study evaluated the transcriptomic changes in cortical astrocytes derived from animals that developed seizures as a result of severe focal TBI. Using RNA-Seq and ingenuity pathway analysis (IPA), we unveil a distinct gene expression profile in astrocytes, including alterations in genes supporting inflammation, early response modifiers, and neuropeptide-amidating enzymes. The findings underscore the complex molecular dynamics in astrocytes during PTE development, offering insights into therapeutic targets and avenues for further exploration.

Data from a national survey of United States primary care physicians on genetic risk scores for common disease prevention.

Genetic risk scores (GRS) are an emerging and rapidly evolving genomic medicine innovation that may contribute to more precise risk stratification for disease prevention. Inclusion of GRS in routine medical care is imminent, and understanding how physicians perceive and intend to utilize GRS in practice is an important first step in facilitating uptake. This dataset was derived from an electronic survey and comprises one of the first, largest, and broadest samples of United States primary care physician perceptions on the clinical decision-making, benefits, barriers, and utility of GRS to date. The dataset is nearly complete (<1% missing data) and contains responses from 369 PCPs spanning 58 column variables. The public repository includes minimally filtered, de-identified data, all underlying survey versions and items, a data dictionary, and associated analytic files.

Community health navigator-assisted transition of care from hospital to community: protocol for a randomised controlled trial.

INTRODUCTION: The objective of this parallel group, randomised controlled trial is to evaluate a community health navigator (CHN) intervention provided to patients aged over 40 years and living with chronic health conditions to transition from hospital inpatient care to their homes. Unplanned hospital readmissions are costly for the health system and negatively impact patients. METHODS AND ANALYSIS: Patients are randomised post hospital discharge to the CHN intervention or usual care. A comparison of outcomes between intervention and control groups will use multivariate regression techniques that adjust for age, sex and any independent variables that are significantly different between the two groups, using multiple imputation for missing values. Time-to-event analysis will examine the relationship between seeing a CHN following discharge from the index hospitalisation and reduced rehospitalisations in the subsequent 60 days and 6 months. Secondary outcomes include medication adherence, health literacy, quality of life, experience of healthcare and health service use (including the cost of care). We will also conduct a qualitative assessment of the implementation of the navigator role from the viewpoint of stakeholders including patients, health professionals and the navigators themselves. ETHICS APPROVAL: Ethics approval was obtained from the Research Ethics and Governance Office, Sydney Local Health District, on 21 January 2022 (Protocol no. X21-0438 and 2021/ETH12171). The findings of the trial will be disseminated through peer-reviewed journals and national and international conference presentations. Data will be deposited in an institutional data repository at the end of the trial. This is subject to Ethics Committee approval, and the metadata will be made available on request. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN 12622000659707). ARTICLE SUMMARY: The objective of this trial is to evaluate a CHN intervention provided to patients aged over 40 years and living with chronic health conditions to transition from hospital inpatient care to their homes.

Loss-of-function variants in JPH1 cause congenital myopathy with prominent facial involvement.

Background: Weakness of facial, ocular, and axial muscles is a common clinical presentation in congenital myopathies caused by pathogenic variants in genes encoding triad proteins. Abnormalities in triad structure and function resulting in disturbed excitation-contraction coupling and Ca 2+ homeostasis can contribute to disease pathology. Methods: We analysed exome and genome sequencing data from three unrelated individuals with congenital myopathy characterised by striking facial, ocular, and bulbar involvement. We collected deep phenotypic data from the affected individuals. We analysed the RNA-seq data of one proband and performed gene expression outlier analysis in 129 samples. Results: The three probands had remarkably similar clinical presentation with prominent facial, ocular, and bulbar features. Disease onset was in the neonatal period with hypotonia, poor feeding, cleft palate and talipes. Muscle weakness was generalised but most prominent in the lower limbs with facial weakness also present. All patients had myopathic facies, bilateral ptosis, ophthalmoplegia and fatiguability. While muscle biopsy on light microscopy did not show any obvious morphological abnormalities, ultrastructural analysis showed slightly reduced triads, and structurally abnormal sarcoplasmic reticulum. DNA sequencing identified three unique homozygous loss of function variants in JPH1 , encoding junctophilin-1 in the three families; a stop-gain (c.354C>A; p.Tyr118*) and two frameshift (c.373del p.Asp125Thrfs*30 and c.1738del; p.Leu580Trpfs*16) variants. Muscle RNA-seq showed strong downregulation of JPH1 in the F3 proband. Conclusions: Junctophilin-1 is critical to the formation of skeletal muscle triad junctions by connecting the sarcoplasmic reticulum and T-tubules. Our findings suggest that loss of JPH1 results in a congenital myopathy with prominent facial, bulbar and ocular involvement. Key message: This study identified novel homozygous loss-of-function variants in the JPH1 gene, linking them to a unique form of congenital myopathy characterised by severe facial and ocular symptoms. Our research sheds light on the critical impact on junctophilin-1 function in skeletal muscle triad junction formation and the consequences of its disruption resulting in a myopathic phenotype. What is already known on this topic: Previous studies have shown that pathogenic variants in genes encoding triad proteins lead to various myopathic phenotypes, with clinical presentations often involving muscle weakness and myopathic facies. The triad structure is essential for excitation-contraction (EC) coupling and calcium homeostasis and is a key element in muscle physiology. What this study adds and how this study might affect research practice or policy: This study establishes that homozygous loss-of-function mutations in JPH1 cause a congenital myopathy predominantly affecting facial and ocular muscles. This study also provides clinical insights that may aid the clinicians in diagnosing similar genetically unresolved cases.

Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy.

In digenic inheritance, pathogenic variants in two genes must be inherited together to cause disease. Only very few examples of digenic inheritance have been described in the neuromuscular disease field. Here we show that predicted deleterious variants in SRPK3, encoding the X-linked serine/argenine protein kinase 3, lead to a progressive early onset skeletal muscle myopathy only when in combination with heterozygous variants in the TTN gene. The co-occurrence of predicted deleterious SRPK3/TTN variants was not seen among 76,702 healthy male individuals, and statistical modeling strongly supported digenic inheritance as the best-fitting model. Furthermore, double-mutant zebrafish (srpk3-/-; ttn.1+/-) replicated the myopathic phenotype and showed myofibrillar disorganization. Transcriptome data suggest that the interaction of srpk3 and ttn.1 in zebrafish occurs at a post-transcriptional level. We propose that digenic inheritance of deleterious changes impacting both the protein kinase SRPK3 and the giant muscle protein titin causes a skeletal myopathy and might serve as a model for other genetic diseases.

Motivos da adesão de idosos às Academias da Terceira Idade / Reasons for the adherence of older adults to Gyms for Seniors

Resumo Verificar os motivos de adesão (ingresso e permanência) de idosos às Academias da Terceira Idade (ATI) da cidade do Rio de Janeiro, RJ, Brasil. Método: Foram entrevistados 396 idosos de ambos os sexos, com idade igual ou superior a 60 anos, frequentadores de 58 ATIs representativas de todas as regiões programáticas dessa cidade. Os dados foram coletados utilizando-se questionário validado e analisados por meio de estatística descritiva. Resultado: Os resultados indicaram como motivos predominantes para justificar o ingresso dos idosos nas ATIs aqueles relacionados à saúde (Evitar problemas de saúde: 26%; O médico aconselhou: 16%), enquanto que os de permanência estão mais associados com questões sociais (Gosto do professor e Me faz sentir bem: 100%) e com a percepção dos benefícios do exercício físico (É uma atividade física saudável: 100%) Conclusão: Embora os motivos ligados à saúde figurem como importantes para os idosos ingressarem no programa, a sua permanência depende do gosto que eles têm pela atividade.

Abstract Objective: to verify the reasons behind the adherence (entry and permanence) of older adults to Gyms for Seniors (GFSs) in the city of Rio de Janeiro. Method: a total of 396 men and women over the age of 60 were interviewed for this study. The subjects frequented 58 different GFSs from all the administrative regions of the city of Rio de Janeiro. The data was collected with a validated questionnaire and analyzed through descriptive statistics. Results: the results indicated that the main reasons which explain the older population entering the GFSs are to do with health (Avoiding health problems: 26%; Doctor's orders: 16%) while their permanence is more associated with social factors (I like the teacher and It makes me feel good, both with 100%) and their perception of the benefits of exercise (It is a healthy physical activity: 100%). Conclusion: although health reasons are important for the older adults who enter the program, they mostly remain due to how much they like the activities.

Free exercise programs for the elderly: a systematic review on adherence and abandonment / Programas gratuitos de exercício físico para idosos: uma revisão sistemática sobre adesão e desistência

ABSTRACT The elderly population in Brazil is on the rise. As a consequence, there is an equal growth in the number of free public exercise programs directed to this group. Considering the benefits of exercising and the importance of adherence to this behavior so that the benefits can be perceived, we conducted a systematic review of the existing literature on the topic, aiming to identify the reasons that lead to adherence to free public exercise programs, as well as those that lead to abandoning the same programs. Searches were conducted on SciElo, SPORTdiscus and Pubmed databases, with search phrases in Portuguese and in English. After a triage, ten studies were analyzed regarding sample characteristics, program type, data collection method and the reasons behind the subjects' adherence and abandonment. We verified that elderly people tend to enter the projects for health-related reasons, but they remain due to other factors, such as socialization and the perception of the benefits brought on by exercising. As for abandonment, it occurs due to health problems, muscle pain due to exercising, dislike for the classes and family business.

RESUMO A população idosa cresce cada vez mais no Brasil. Como consequência, há um crescimento equivalente no número de programas públicos de exercícios físicos direcionados a esse grupo. Considerando os benefícios dos exercícios físicos e a importância de se aderir a esse comportamento para que os benefícios possam ser percebidos, foi realizada uma revisão sistemática da literatura existente sobre esse assunto com o objetivo de identificar os motivos que levam à adesão a programas gratuitos de exercícios, assim como aqueles que levam à desistência dos mesmos programas. Foram realizadas buscas nas bases de dados SciElo, SPORTdiscus e Pubmed, com frases de busca em português e em inglês. Após uma triagem, dez estudos foram analisados em relação às características das amostras, tipos de programas, método de coleta de dados e as razões por trás da adesão e da desistência dos sujeitos. Verificamos que as pessoas idosas tendem a entrar nos projetos por motivos relacionados à saúde, mas permanecem devido a outros fatores, como a socialização e a percepção dos benefícios provenientes da prática de exercícios. Quanto ao abandono, o mesmo ocorreu devido a problemas de saúde, dor muscular causada pelo exercício, o desgosto pelas aulas e questões relacionadas à família.

A mídia impressa e o polo aquático brasileiro: o mito de Aladar Szabo / Los medios impresos y el polo acuático brasileño: el mito de Aladar Szabo / Printed media and brazilian water polo: the myth of Aladar Szabo

Este artigo objetiva analisar a visão da mídia impressa sobre um jogador de polo aquático brasileiro, o húngaro naturalizado Aladar Szabo, e também sobre o polo aquático nos anos 1960. Buscamos identificar como os relatos midiáticos contribuíram para a consolidação da imagem do jogador-mito, como eram relatados os acontecimentos sobre o esporte e ainda de que forma a mídia impressa participou da construção de sua imagem e sua relação com o mito da masculinidade. Metodologicamente, combinamos pesquisa documental e bibliográfica. Verificou-se construção de uma imagem violenta do esporte, aproximando as atitudes e fatos do jogador com o mito da masculinidade.

This article looks into the view of printed media on Hungarian-born Braziliannaturalized water polo player Aladar Szabo and also on water polo itself in the 1960s. We sought to identify how media relationships contributed to consolidate the mythical player’s image, how sport-related occurrences were narrated, and how printed media participated in the construction of Szabo’s image and its relation with the myth of masculinity. Methodologically speaking, we combined documental and bibliographical research. We found the construction of a violent image of the sport, bringing together facts about the player and his attitudes with the myth of masculinity.

Este artículo se propone analizar la visión de los medios impresos sobre un jugador de polo acuático brasileño, el húngaro naturalizado Aladar Szabo, y también sobre el polo acuático en los años 1960. Buscamos identificar cómo los relatos hechos por los medios contribuyeron a la consolidación de la imagen del jugador-mito, saber cómo eran relatados los acontecimientos sobre el deporte y de qué forma los medios impresos participaron en la construcción de su imagen y su relación con el mito de la masculinidad. Metodológicamente, combinamos la investigación documental con la bibliográfica. Se constato la construcción de una imagen violenta del deporte, aproximando las actitudes y hechos del jugador al mito de la masculinidad.

Promoção da saúde: análise imagética e textual de programas desenvolvidos por operadoras de planos de assistência à saúde / Health Promotion: imagetic and textual analysis of programs developed by Health Insurance Operators

A Promoção da Saúde (PS) apresenta-se em diferentes roupagens, podendo ter diversos significados, o que denota sua maleabilidade a diferentes projetos de sociedade. Objetivo: o objetivo deste estudo foi identificar a abordagem de PS veiculada nos materiais imagéticos e textuais de programas de PS desenvolvidos por Operadoras de Plano de Assistência à Saúde (OPS), baseados em resoluções da Agência Nacional de Saúde Suplementar. Metodologia: para tal, foram analisados materiais imagéticos de programas de PS desenvolvidos por seis OPS de 2005 a 2011. A análise ocorreu por meio do método do saber indiciário (Ginzburg, 1989). Resultados/discussão: durante as análises, percebeu-se que os materiais de muitas das OPS alinhavam-se a mais de uma abordagem de PS e que ainda há uma grande predominância da 1ª PS nos materiais de algumas OPS, enquanto a 2ª PS tende a aparecer em menor escala. Foram feitas sugestões de modificações a serem feitas pelas OPS em materiais com predominância de 1ª PS, como a substituição de imagens que possam transmitir temas recorrentes da 1ª PS e a modificação do texto dos materiais. Conclusões: após a análise dos materiais, percebeu-se que alguns materiais passam imagens contraditórias de seu alinhamento à 1ª ou 2ª PS e questionou-se se as OPS realizaram estudos sobre a PS quando o material foi elaborado. Como muitos materiais mostram alinhamento à 1ª PS, a interpretação crítica dos mesmos é importante para evitar a sensação de culpabilidade dos leitores...

Health promotion presents itself in different manners and can have diverse meanings, denoting its conformity to different society projects. Objectives: the objective of this study was to identify which health promotion approach was used in imagetic and textual materials from health promotion programs developed by health insurance operators based on National Supplementary Health Agency resolutions. Methodology: in order to achieve this goal, imagetic and textual materials from health promotion programs developed between 2005 and 2011 by six health insurance operators were analyzed. The method used for analysis was the Indiciary Knowledge Method. Results/discussion: during the analysis, it was noted that materials from many of the health insurance operators were aligned to more than one type of health promotion and there is still a predominance of the first health promotion approach in some of the six operator's materials. The second health promotion approach tended to show on a lesser scale. Suggestions were made for changes in materials with a predominance of the first health promotion approach, like switching images that transmit recurrent themes of said approach. Conclusions: after analysis, it was perceived that many materials show contradictions regarding their alignment to the 1st or 2 nd health promotion approach. It was questioned whether the operators had studies done about health promotion when the materials were elaborated. Considering the ample presence of the first approach, critical interpretation is deemed vital for readers to avoid a sensation of culpability...