Microglia jointly degrade fibrillar alpha-synuclein cargo by distribution through tunneling nanotubes.

Microglia are the CNS resident immune cells that react to misfolded proteins through pattern recognition receptor ligation and activation of inflammatory pathways. Here, we studied how microglia handle and cope with α-synuclein (α-syn) fibrils and their clearance. We found that microglia exposed to α-syn establish a cellular network through the formation of F-actin-dependent intercellular connections, which transfer α-syn from overloaded microglia to neighboring naive microglia where the α-syn cargo got rapidly and effectively degraded. Lowering the α-syn burden attenuated the inflammatory profile of microglia and improved their survival. This degradation strategy was compromised in cells carrying the LRRK2 G2019S mutation. We confirmed the intercellular transfer of α-syn assemblies in microglia using organotypic slice cultures, 2-photon microscopy, and neuropathology of patients. Together, these data identify a mechanism by which microglia create an "on-demand" functional network in order to improve pathogenic α-syn clearance.

Microglial PD-1 stimulation by astrocytic PD-L1 suppresses neuroinflammation and Alzheimer's disease pathology.

Chronic neuroinflammation is a pathogenic component of Alzheimer's disease (AD) that may limit the ability of the brain to clear amyloid deposits and cellular debris. Tight control of the immune system is therefore key to sustain the ability of the brain to repair itself during homeostasis and disease. The immune-cell checkpoint receptor/ligand pair PD-1/PD-L1, known for their inhibitory immune function, is expressed also in the brain. Here, we report upregulated expression of PD-L1 and PD-1 in astrocytes and microglia, respectively, surrounding amyloid plaques in AD patients and in the APP/PS1 AD mouse model. We observed juxtamembrane shedding of PD-L1 from astrocytes, which may mediate ectodomain signaling to PD-1-expressing microglia. Deletion of microglial PD-1 evoked an inflammatory response and compromised amyloid-ß peptide (Aß) uptake. APP/PS1 mice deficient for PD-1 exhibited increased deposition of Aß, reduced microglial Aß uptake, and decreased expression of the Aß receptor CD36 on microglia. Therefore, ineffective immune regulation by the PD-1/PD-L1 axis contributes to Aß plaque deposition during chronic neuroinflammation in AD.

NLRP3 inflammasome activation drives tau pathology.

Alzheimer's disease is characterized by the accumulation of amyloid-beta in plaques, aggregation of hyperphosphorylated tau in neurofibrillary tangles and neuroinflammation, together resulting in neurodegeneration and cognitive decline1. The NLRP3 inflammasome assembles inside of microglia on activation, leading to increased cleavage and activity of caspase-1 and downstream interleukin-1ß release2. Although the NLRP3 inflammasome has been shown to be essential for the development and progression of amyloid-beta pathology in mice3, the precise effect on tau pathology remains unknown. Here we show that loss of NLRP3 inflammasome function reduced tau hyperphosphorylation and aggregation by regulating tau kinases and phosphatases. Tau activated the NLRP3 inflammasome and intracerebral injection of fibrillar amyloid-beta-containing brain homogenates induced tau pathology in an NLRP3-dependent manner. These data identify an important role of microglia and NLRP3 inflammasome activation in the pathogenesis of tauopathies and support the amyloid-cascade hypothesis in Alzheimer's disease, demonstrating that neurofibrillary tangles develop downstream of amyloid-beta-induced microglial activation.

A land plant phylogenetic framework for GLABROUS INFLORESCENCE STEMS (GIS), SUPERMAN, JAGGED and allies plus their TOPLESS co-repressor.

Members of the plant specific family of C1-1i zincfinger transcriptionfactors (ZF-TFs), such as SUPERMAN, JAGGED, KNUCKLES or GIS,regulatediversedevelopmental processes including sexual reproduction. C1-1is consist of one zinc-finger and one to two EAR domains, connected by large intrinsically disordered regions (IDR). While the role of C1-i1 ZF-TFs in development processes is well known for some genes in Arabidopsis, rice or tomatoa comprehensive and broadphylogenetic background is lacking, yet knowledge of orthology is a requirement for a better understanding of C1-1i-Zf-TFs diverse roles in plants. Here, we provide a fine-grained and land plant wide classification of C1-1i sub-families and their known co-repressors TOPLESS and TOPLESS RELATED. Our work combines the identification of orthologous groups with Maximum-Likelihood phylogeny reconstructions and digital gene expression analyses mining high quality land plant genomes and transcriptomes to generate a comprehensive framework of C1-1i ZF-TF evolution. We show that C1-1i's are low to moderate copy genesand that orthologous genesonly partiallyhaveconserved sub-family and life cycle stage dependent expression pattern across land plants while others are highly diverged. Our workprovides the phylogenetic framework for C1-1i ZF-TFs, s and strengthen C1-1 ZF-TFs as a potential model for IDR-research in plants.

Does physical activity and inflammation mediate the job stress-headache relationship? A sequential mediation analysis in the ELSA-Brasil study.

BACKGROUND: Evidence indicates that physical activity reduces stress and promote a myriad of health-enhancing effects through anti-inflammatory mechanisms. However, it is unknown whether these mechanisms interfere in the association between psychosocial job stress and headache disorders. OBJECTIVE: To test whether physical activity and its interplay with the systemic inflammation biomarkers high-sensitivity C-reactive protein (hs-CRP) and acute phase glycoproteins (GlycA) would mediate the associations between job stress and headache disorders. METHODS: We cross-sectionally evaluated the baseline data from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) regarding job stress (higher demand and lower control and support subscales), migraine and tension-type headache (ICHD-2 criteria), self-reported leisure-time physical activity, and plasma hs-CRP and GlycA levels. Conditional process analyses with a sequential mediation approach were employed to compute path coefficients and 95 % confidence intervals (CI) around the indirect effects of physical activity and biomarkers on the job stress-headache relationship. Separate models were adjusted for sex, age, and depression and anxiety. Further adjustments added BMI smoking status, and socioeconomic factors. RESULTS: In total, 7,644 people were included in the study. The 1-year prevalence of migraine and tension-type headache were 13.1 % and 49.4 %, respectively. In models adjusted for sex, age, anxiety, and depression, the association between job stress (lower job control) and migraine was mediated by physical activity [effect = -0.039 (95 %CI: -0.074, -0.010)] but not hs-CRP or GlycA. TTH was associated with higher job control and lower job demand, which was mediated by the inverse associations between physical activity and GlycA [Job Control: effect = 0.0005 (95 %CI: 0.0001, 0.0010); Job Demand: effect = 0.0003 (95 %CI: 0.0001, 0.0007]. Only the mediating effect of physical activity in the job stress-migraine link remained after further adjustments including socioeconomic factors, BMI, smoking, and the exclusion of major chronic diseases. CONCLUSION: In the ELSA-Brasil study, physical activity reversed the link between job stress and migraine independently of systemic inflammation, while the LTPA-mediated downregulation of GlycA was associated with lower job stress-related TTH.

Racial inequalities in the development of multimorbidity of chronic conditions: results from a Brazilian prospective cohort.

BACKGROUND: The occurrence of multimorbidity and its impacts have differentially affected population subgroups. Evidence on its incidence has mainly come from high-income regions, with limited exploration of racial disparities. This study investigated the association between racial groups and the development of multimorbidity and chronic conditions in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). METHODS: Data from self-reported white, brown (pardos or mixed-race), and black participants at baseline of ELSA-Brasil (2008-2010) who were at risk for multimorbidity were analysed. The development of chronic conditions was assessed through in-person visits and self-reported diagnosis via telephone until the third follow-up visit (2017-2019). Multimorbidity was defined when, at the follow-up visit, the participant had two or more morbidities. Cumulative incidences, incidence rates, and adjusted incidence rate ratios (IRRs) were estimated using Poisson models. RESULTS: Over an 8.3-year follow-up, compared to white participants: browns had a 27% greater incidence of hypertension and obesity; and blacks had a 62% and 45% greater incidence, respectively. Blacks also had 58% more diabetes. The cancer incidence was greater among whites. Multimorbidity affected 41% of the participants, with a crude incidence rate of 57.5 cases per 1000 person-years (ranging from 56.3 for whites to 63.9 for blacks). Adjusted estimates showed a 20% higher incidence of multimorbidity in black participants compared to white participants (IRR: 1.20; 95% CI: 1.05-1.38). CONCLUSIONS: Significant racial disparities in the risk of chronic conditions and multimorbidity were observed. Many associations revealed a gradient increase in illness risk according to darker skin tones. Addressing fundamental causes such as racism and racial discrimination, alongside considering social determinants of health, is vital for comprehensive multimorbidity care. Intersectoral, equitable policies are essential for ensuring health rights for historically marginalized groups.

Sex and population differences in the cardiometabolic continuum: a machine learning study using the UK Biobank and ELSA-Brasil cohorts.

BACKGROUND: The temporal relationships across cardiometabolic diseases (CMDs) were recently conceptualized as the cardiometabolic continuum (CMC), sequence of cardiovascular events that stem from gene-environmental interactions, unhealthy lifestyle influences, and metabolic diseases such as diabetes, and hypertension. While the physiological pathways linking metabolic and cardiovascular diseases have been investigated, the study of the sex and population differences in the CMC have still not been described. METHODS: We present a machine learning approach to model the CMC and investigate sex and population differences in two distinct cohorts: the UK Biobank (17,700 participants) and the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) (7162 participants). We consider the following CMDs: hypertension (Hyp), diabetes (DM), heart diseases (HD: angina, myocardial infarction, or heart failure), and stroke (STK). For the identification of the CMC patterns, individual trajectories with the time of disease occurrence were clustered using k-means. Based on clinical, sociodemographic, and lifestyle characteristics, we built multiclass random forest classifiers and used the SHAP methodology to evaluate feature importance. RESULTS: Five CMC patterns were identified across both sexes and cohorts: EarlyHyp, FirstDM, FirstHD, Healthy, and LateHyp, named according to prevalence and disease occurrence time that depicted around 95%, 78%, 75%, 88% and 99% of individuals, respectively. Within the UK Biobank, more women were classified in the Healthy cluster and more men in all others. In the EarlyHyp and LateHyp clusters, isolated hypertension occurred earlier among women. Smoking habits and education had high importance and clear directionality for both sexes. For ELSA-Brasil, more men were classified in the Healthy cluster and more women in the FirstDM. The diabetes occurrence time when followed by hypertension was lower among women. Education and ethnicity had high importance and clear directionality for women, while for men these features were smoking, alcohol, and coffee consumption. CONCLUSIONS: There are clear sex differences in the CMC that varied across the UK and Brazilian cohorts. In particular, disadvantages regarding incidence and the time to onset of diseases were more pronounced in Brazil, against woman. The results show the need to strengthen public health policies to prevent and control the time course of CMD, with an emphasis on women.

Clinical Predictors of Major Intrathoracic Injury in Pediatric Blunt Trauma.

OBJECTIVES: Blunt trauma in pediatric patients accounts for a significant proportion of pediatric death from traumatic injury. Currently, there are no clinical decision-making tools available to guide imaging choice in the evaluation of pediatric patients with blunt thoracic trauma (BTT). This study aimed to analyze the rates of missed major intrathoracic injuries on chest x-ray (CXR) and identify clinical risk factors associated with major intrathoracic injuries to formulate a clinical decision-making tool for computed tomography (CT) use in pediatric patients with BTT. METHODS: We performed a retrospective single-center study using an institutional trauma database of pediatric patients. Inclusion criteria included age, blunt trauma, and patients who received a CXR and thoracic CT within 24 hours of presentation. Thoracic CT findings were graded as major, minor, or none, and comparison CXR was used to determine the rate of missed thoracic injuries. Eighty-four patient variables were then collected, and clinically relevant variables associated with major intrathoracic injuries were placed in a logistic regression model to determine the best predictors of major injury in pediatric BTT patients. RESULTS: A total of 180 patients (48.3%) had CXR that missed an injury that was seen on thoracic CT. In our cohort, 20 patients (5.4%) had major injuries that were missed on CXR. Characteristics correlating with major thoracic injuries were older age (odds ratio [OR], 1.125; 95% confidence interval [CI], 1.015-1.247), chest pain (OR, 4.907; 95% CI, 2.173-11.083), abnormal chest auscultation (OR, 3.564; 95% CI, 1.406-9.035), and tachycardia (OR, 2.876; 95% CI, 1.256-6.586). Using these 4 variables, receiver operating characteristic analysis revealed an area under the curve of 0.7903. CONCLUSIONS: Pediatric BTT patients older than 15 years with tachycardia, chest pain, or abnormal chest auscultation are at increased risk for major intrathoracic injuries and may benefit from thoracic CT.

Characterizing microglial senescence: Tau as a key player.

The highest risk factor for the development of neurodegenerative diseases like tauopathies is aging. Many physiological decrements underlying aging are linked to cellular senescence. Senescent cells are characterized by an irreversible growth arrest and formation of a senescence-associated secretory phenotype (SASP), a proinflammatory secretome that modifies the cellular microenvironment and contributes to tissue deterioration. Microglia, the innate immune cells in the brain, can enter a senescent state during aging. In addition, senescent microglia have been identified in the brains of tau-transgenic mice and patients suffering from tauopathies. While the contribution of senescent microglia to the development of tauopathies and other neurodegenerative diseases is a growing area of research, the effect of tau on microglial senescence remains elusive. Here, we exposed primary microglia to 5 and 15 nanomolar (nM) of monomeric tau for 18 h, followed by a recovery period of 48 h. Using multiple senescence markers, we found that exposure to 15 nM, but not 5 nM of tau increased levels of cell cycle arrest and a DNA damage marker, induced loss of the nuclear envelope protein lamin B1 and the histone marker H3K9me3, impaired tau clearance and migration, altered the cell morphology and resulted in formation of a SASP. Taken together, we show that exposure to tau can lead to microglial senescence. As senescent cells were shown to negatively impact tau pathologies, this suggests the presence of a vicious circle, which should be further investigated in the future.

NLRP3-directed antisense oligonucleotides reduce microglial immunoactivities in vitro.

Alzheimer's disease (AD) is associated with the cerebral deposition of Amyloid-ß (Aß) peptide, which leads to NLRP3 inflammasome activation and subsequent release of interleukin-1ß (IL-1ß) and interleukin-18 (IL-18). NLRP3 reduction has been found to increase microglial clearance, protect from synapse loss, and suppress both the changes to synaptic plasticity and spatial memory dysfunction observed in murine AD models. Here, we test whether NLRP3-directed antisense oligonucleotides (ASOs) can be harnessed as immune modulators in primary murine microglia and human THP-1 cells. NLRP3 mRNA degradation was achieved at 72 h of ASO treatment in primary murine microglia. Consequently, NLRP3-directed ASOs significantly reduced the levels of cleaved caspase-1 and mature IL-1ß when microglia were either activated by LPS and nigericin or LPS and Aß. In human THP-1 cells NLRP3-targeted ASOs also significantly reduced the LPS plus nigericin- or LPS plus Aß-induced release of mature IL-1ß. Together, NLRP3-directed ASOs can suppress NLRP3 inflammasome activity and subsequent release of IL-1ß in primary murine microglia and THP-1 cells. ASOs may represent a new and alternative approach to modulate NLRP3 inflammasome activation in neurodegenerative diseases, in addition to attempts to inhibit the complex pharmacologically.

Three-month tapering and discontinuation of long- term, low-dose glucocorticoids in senior patients with rheumatoid arthritis is feasible and safe: placebo-controlled double blind tapering after the GLORIA trial.

OBJECTIVE: The randomised placebo-controlled GLORIA (Glucocorticoid LOw-dose in RheumatoId Arthritis) trial evaluated the benefits and harms of prednisolone 5 mg/day added to standard care for 2 years in patients aged 65+ years with rheumatoid arthritis (RA). Here, we studied disease activity, flares and possible adrenal insufficiency after blinded withdrawal of study medication. METHODS: Per protocol, patients successfully completing the 2-year trial period linearly tapered and stopped blinded study medication in 3 months. We compared changes in disease activity after taper between treatment groups (one-sided testing). Secondary outcomes (two-sided tests) comprised disease flares (DAS28 (Disease Activity Score 28 joints) increase >0.6, open-label glucocorticoids or disease-modifying antirheumatic drug (DMARD) increase/switch after week 4 of tapering) and symptoms/signs of adrenal insufficiency. In a subset of patients from 3 Dutch centres, cortisol and ACTH were measured in spot serum samples after tapering. RESULTS: 191 patients were eligible; 36 met treatment-related flare criteria and were only included in the flare analysis. Mean (SD) DAS28 change at follow-up: 0.2 (1.0) in the prednisolone group (n=76) vs 0.0 (1.2) in placebo (n=79). Adjusted for baseline, the between-group difference in DAS28 increase was 0.16 (95% confidence limit -0.06, p=0.12). Flares occurred in 45% of prednisolone patients compared with 33% in placebo, relative risk (RR) 1.37 (95% CI 0.95 to 1.98; p=0.12). We found no evidence for adrenal insufficiency. CONCLUSIONS: Tapering prednisolone moderately increases disease activity to the levels of the placebo group (mean still at low disease activity levels) and numerically increases the risk of flare without evidence for adrenal insufficiency. This suggests that withdrawal of low-dose prednisolone is feasible and safe after 2 years of administration.

Association between objective sleep measures and cognitive performance: a cross-sectional analysis in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) study.

Sleep disturbances often co-exist, which challenges our understanding of their potential impact on cognition. We explored the cross-sectional associations of insomnia and objective measures of sleep with cognitive performance in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) study stratified by middle-aged and older adults. Participants aged ≥55 years underwent cognitive evaluations, polygraphy for 1 night, and actigraphy for 7 days. Insomnia was evaluated using the Clinical Interview Scheduled Revised. Obstructive sleep apnea (OSA) and short sleep duration (SSD) were defined by an apnea-hypopnea index (AHI) of ≥15 events/h and <6 h/ night, respectively. In 703 participants (mean [SD] age 62 [6] years, 44% men), cognition was evaluated using a 10-word list, verbal fluency, and trail-making tests. The frequencies of insomnia, SSD, and OSA were 11%, 24%, and 33%, respectively. In all, 4% had comorbid OSA and insomnia, and 11% had both OSA and SSD. Higher wake after sleep onset (ß = -0.004, 95% confidence interval [CI] -0.008, -0.001) and the number of awakenings (ß = -0.006, 95% CI -0.012, -0.001) were associated with worse verbal fluency performance. Compared to those without insomnia, older participants with insomnia had worse global performance (ß = -0.354, 95% CI -0.671, -0.038). Insomnia was an effect modifier in the associations between AHI and executive function performance (p for the interaction between insomnia and AHI = 0.004) and between oxygen saturation <90% and memory performance (p for the interaction between insomnia and oxygen saturation = 0.02). Although some associations between sleep measures and cognition were significant, they should be considered with caution due to the large sample size and multiple testing performed in this study.

Microglial NLRP3 Inflammasome Activation upon TLR2 and TLR5 Ligation by Distinct α-Synuclein Assemblies.

Parkinson's disease (PD) is the second most common age-related neurodegenerative disorder and is characterized by the formation of cellular inclusions inside neurons that are rich in an abnormal form of the protein α-synuclein (α-syn). Microglia are the CNS resident immune cells that react to misfolded proteins through pattern recognition receptor ligation and activation of signaling transduction pathways. Here, we studied activation of primary microglia isolated from wild-type mouse by distinct α-syn forms and their clearance. Internalization of α-syn monomers and oligomers efficiently activated the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome via TLR2 and TLR5 ligation, thereby acting on different signaling checkpoints. We found that primary microglia effectively engulf α-syn but hesitate in its degradation. NLRP3 inhibition by the selective inhibitor CRID3 sodium salt and NLRP3 deficiency improved the overall clearance of α-syn oligomers. Together, these data show that distinct α-syn forms exert different microglial NLRP3 inflammasome activation properties, thereby compromising its degradation, which can be prevented by NLRP3 inhibition.

Microglia-derived ASC specks cross-seed amyloid-ß in Alzheimer's disease.

The spreading of pathology within and between brain areas is a hallmark of neurodegenerative disorders. In patients with Alzheimer's disease, deposition of amyloid-ß is accompanied by activation of the innate immune system and involves inflammasome-dependent formation of ASC specks in microglia. ASC specks released by microglia bind rapidly to amyloid-ß and increase the formation of amyloid-ß oligomers and aggregates, acting as an inflammation-driven cross-seed for amyloid-ß pathology. Here we show that intrahippocampal injection of ASC specks resulted in spreading of amyloid-ß pathology in transgenic double-mutant APPSwePSEN1dE9 mice. By contrast, homogenates from brains of APPSwePSEN1dE9 mice failed to induce seeding and spreading of amyloid-ß pathology in ASC-deficient APPSwePSEN1dE9 mice. Moreover, co-application of an anti-ASC antibody blocked the increase in amyloid-ß pathology in APPSwePSEN1dE9 mice. These findings support the concept that inflammasome activation is connected to seeding and spreading of amyloid-ß pathology in patients with Alzheimer's disease.

Food consumption by degree of processing is associated with nocturnal dipping and blood pressure variability: The ELSA-Brasil study.

BACKGROUND AND AIMS: Ambulatory blood pressure monitoring (ABPM) allows the assessment of cardiovascular risk markers that cannot be obtained by casual measurements; however, the evidence on the association between food consumption and blood pressure (BP) assessed by ABPM is scarce. We aimed to evaluate the association between food consumption by degree of processing and ambulatory BP. METHODS AND RESULTS: Cross-sectional analysis (2012-2014) of data from a subsample (n = 815) of ELSA-Brasil cohort participants who performed 24-h ABPM was conducted. Systolic (SBP) and diastolic (DBP) BP means and variability during the 24 h and subperiods (sleep and wake), nocturnal dipping, and morning surge were evaluated. Food consumption was classified according to NOVA. Associations were tested by generalized linear models. The consumption of unprocessed, minimally processed foods, and culinary ingredients (U/MPF&CI) was 63.1% of daily caloric intake, 10.8% of processed (PF), and 24.8% of ultraprocessed (UPF). A negative association was found between U/MPF&CI consumption and extreme dipping (T2: odds ratio [OR] = 0.56, 95% confidence interval [CI] = 0.55-0.58; T3: OR = 0.55; 95% CI = 0.54-0.57); and between UPF consumption and nondipping (T2: OR = 0.68, 95% CI = 0.55-0.85) and extreme dipping (T2: OR = 0.63, 95% CI = 0.61-0.65; T3: OR = 0.95, 95% CI = 0.91-0.99). There was a positive association between PF consumption and extreme dipping (T2: OR = 1.22, 95% CI = 1.18-1.27; T3: OR = 1.34, 95% CI = 1.29-1.39) and sleep SBP variability (T3: Coef = 0.56, 95% CI = 0.03-1.10). CONCLUSIONS: The high consumption of PF was associated with greater BP variability and extreme dipping, while the U/MPF&CI and UPF consumption were negatively associated with alterations in nocturnal dipping.

Body shape trajectories are associated with birth weight, body mass index and sociodemographic conditions in participants of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil): a multiple correspondence analysis.

BACKGROUND: Evaluating lifelong weight trajectories is challenging due to the high costs of studies that follow individuals from childhood to adulthood. The use of silhouette scales has been a new approach to assess the body shape trajectory across life as a proxy for body weight trajectory. Depending on body shape trajectories, individuals may be more prone to develop diseases in adulthood. Therefore, identifying factors related to them is essential for public health. This study aimed to evaluate body shape trajectories across the lifespan and to verify associations between them, birth weight, body mass index, and sociodemographic conditions in a Brazilian cohort. METHODS: This is a cross-sectional analysis conducted with 14,014 participants of first follow-up data collection of Longitudinal Study of Adult Health (ELSA-Brasil). ELSA-Brasil is a multicentric prospective cohort study initiated in 2008 with civil servants of six public institutions in the Northeast, South and Southeast regions of Brazil. We applied a clustering method to longitudinal data to identify body shape trajectories from 5 to 40 years of age and assessed the associations between these trajectories and birth weight, body mass index and sociodemographic conditions (race, education, maternal education and monthly per capita family income) using multiple correspondence analysis. RESULTS: We found five body shape trajectories for women and three for men. Low birth weight was associated with a slight to moderate increase in shape. High birth weight was associated with maintaining large body size in both sexes and markedly increased body shape in women. Higher sociodemographic status and white race were associated with marked increases in body shape in men and maintenance of medium body shape in women. CONCLUSIONS: The study shows that variables related to worse lifetime weight status (evaluated by anthropometry), such as presence of obesity, are also associated with worse body shape trajectories, as assessed with silhouette scales. Our results suggest that body shape trajectories are a good indicator of body weight trajectories and may be used when cohort studies are not possible.

Work from home and the association with sedentary behaviors, leisure-time and domestic physical activity in the ELSA-Brasil study.

BACKGROUND: Work from home (WFH) can impact workers´ sedentary behaviors and levels of physical activity. The aim of this study was to estimate the association between WFH and workers´ sedentary behaviors, leisure-time and domestic physical activities during the COVID-19 pandemic and verify whether age and sex may act as effect modifiers. METHODS: We conducted a cross-sectional study of 2544 participants in the supplementary study on COVID-19 in the Longitudinal Study of Adult Health (ELSA-Brasil) from July 2020 to February 2021. We assessed screen time (≤ 8 h/day versus > 8 h/day), accumulated sitting time (≤ 8 h/day versus > 8 h/day) as sedentary behaviors on a typical day, and leisure-time (active versus inactive, according to World Health Organization recommendations) and domestic (low versus high, according to median) physical activity, using the International Physical Activity Questionnaire (IPAQ), before and during social distancing. Logistic regression models were used. RESULTS: Participants that were working from home during social distancing showed increased odds of screen time and sitting time greater than 8 h/day (OR = 3.12; 95%CI: 2.32-4.20 and OR = 2.68; 95%CI: 2.02-3.56, respectively) and higher odds of high domestic physical activity (OR = 1.29; 95%CI: 0.99-1.67) when compared to those not working from home. There was no association between WFH and leisure-time physical activity (OR = 0.99, 95%CI: 0.75,1.31). Age was an effect modifier in the association between WFH and leisure-time physical activity and domestic activity. Older people working from home showed higher odds of physical inactivity (OR = 1.84, 95%CI: 1.07,3.16) and high domestic physical activity (OR = 1.92, 95%CI: 1.12,3.27) compared to older people not working from home. CONCLUSION: WFH was associated with sedentary behavior > 8 h/day and high domestic physical activity. In the older people, WFH was associated with physical inactivity and high domestic physical activity. As sedentary behavior and physical inactivity are consistently negatively associated with health, it is important to discuss policies to manage WFH that allow pauses from physical activities and performance of hours of work within preestablished limits to reduce sedentary behavior. In addition, individuals working from home, especially the older people, should be encouraged to engage in leisure-time physical activity as a form of health promotion.

Gender, race/skin colour and incidence of hypertension in ELSA-Brasil: an intersectional approach.

OBJECTIVE: Race and gender inequities in the incidence of hypertension (HTN) are well documented; however, few empirical investigations looked into these associations, considering the synergies and heterogeneous experiences of intersectional gender and race/skin colour groups. This study investigated the association of intersectional identities defined by gender and race/skin colour with HTN incidence, and verified whether they are affected by educational level in adulthood. DESIGN: We used the Longitudinal Study of Adult Health (ELSA-Brasil) data to estimate the incidence of HTN between visits 1 (2008-2010) and 2 (2012-2014), in 8528 participants without hypertension at visit 1. HTN was defined as systolic blood pressure ≥140 mmHg, or diastolic blood pressure ≥90 mmHg, or use of antihypertensive drugs. Generalized linear models with Poisson distribution and log link function were used to assess the associations. RESULTS: The incidence of HTN was 43.4/1000 person-years, ranging from 30.5/1000 in White women to 59.4/1000 in Black men. After adjusting by age and family history of HTN, the incidence rate ratio (IRR) was higher in Black men (2.25; 95%CI: 1.65-3.08), Brown (Pardo) men (1.89; 95%CI: 1.59-2.25), Black women (1.85; 95%CI: 1.50-2.30), Brown (Parda) women (1.47; 95%CI: 1.31-1.67) and White men (1.76; 95%CI: 1.49-2.08), compared to White women. These associations were maintained even after considering socioeconomic, behavioural and health mediators in the model. No interaction was found between education level and intersectional identities in the IRRs observed. CONCLUSION: By using an intersectional approach, we showed the complex relations between race/skin colour and gender inequities in the incidence of HTN, pointing not only that Black men have the highest risk of developing HTN, but also that the risk of HTN is greater in Black women than in White men, when compared to White women.

Low dose, add-on prednisolone in patients with rheumatoid arthritis aged 65+: the pragmatic randomised, double-blind placebo-controlled GLORIA trial.

BACKGROUND: Low-dose glucocorticoid (GC) therapy is widely used in rheumatoid arthritis (RA) but the balance of benefit and harm is still unclear. METHODS: The GLORIA (Glucocorticoid LOw-dose in RheumatoId Arthritis) pragmatic double-blind randomised trial compared 2 years of prednisolone, 5 mg/day, to placebo in patients aged 65+ with active RA. We allowed all cotreatments except long-term open label GC and minimised exclusion criteria, tailored to seniors. Benefit outcomes included disease activity (disease activity score; DAS28, coprimary) and joint damage (Sharp/van der Heijde, secondary). The other coprimary outcome was harm, expressed as the proportion of patients with ≥1 adverse event (AE) of special interest. Such events comprised serious events, GC-specific events and those causing study discontinuation. Longitudinal models analysed the data, with one-sided testing and 95% confidence limits (95% CL). RESULTS: We randomised 451 patients with established RA and mean 2.1 comorbidities, age 72, disease duration 11 years and DAS28 4.5. 79% were on disease-modifying treatment, including 14% on biologics. 63% prednisolone versus 61% placebo patients completed the trial. Discontinuations were for AE (both, 14%), active disease (3 vs 4%) and for other (including covid pandemic-related disease) reasons (19 vs 21%); mean time in study was 19 months. Disease activity was 0.37 points lower on prednisolone (95% CL 0.23, p<0.0001); joint damage progression was 1.7 points lower (95% CL 0.7, p=0.003). 60% versus 49% of patients experienced the harm outcome, adjusted relative risk 1.24 (95% CL 1.04, p=0.02), with the largest contrast in (mostly non-severe) infections. Other GC-specific events were rare. CONCLUSION: Add-on low-dose prednisolone has beneficial long-term effects in senior patients with established RA, with a trade-off of 24% increase in patients with mostly non-severe AE; this suggests a favourable balance of benefit and harm. TRIAL REGISTRATION NUMBER: NCT02585258.

Body image distortion among Brazilian and Portuguese women with children: A comparative study between the ELSA-Brasil and Generation XXI cohorts.

Solid evidence indicates that body image distortion is associated with various physical and mental health problems in women (e.g. Lee and Lee, 2016; Mölbert et al., 2017; Raj and Ploriya, 2020; Sagar, 2005; Shin et al., 2015). Furthermore, body image has been shown to vary according to life context and stage, particularly after a woman has had children. This scenario justifies the comparison between different countries and cultures. The objective of the present study was to evaluate the prevalence and associated factors of body image distortion/accuracy in Brazilian and Portuguese women with children. The study assessed women selected from two epidemiological cohorts: ELSA-Brasil in Brazil (n = 1468) and Generation XXI in Portugal (n = 3380). The data analyzed were based on multidimensional questionnaires from which sociodemographic and family characteristics as well as data associated with lifestyle and health were obtained. The results show that most women in both cohorts had an accurate perception of their own body size. In cases of distorted self-perception, the likelihood of the Brazilian women perceiving themselves as being heavier was greater if they had had cancer, whereas the Portuguese women were less likely to perceive themselves as heavier when they had less schooling. Perceiving themselves as thinner than they actually are, was associated with poorer self-perception of their own state of health in the Brazilian women and with poorer schooling in both the Brazilian and Portuguese women. The present findings contribute towards improving understanding of the influence of body image distortion on the health and wellbeing of Brazilian and Portuguese women, possibly leading to the implementation of health-promoting policies in both countries.