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We used linear regression to examine cross-sectional associations of accelerometer-measured physical activity and sedentary time with extrinsic and intrinsic epigenetic age acceleration models (EEAA and IEAA) and GrimAge measured from blood samples from Framingham Heart Study participants with accelerometry and DNA methylation data (n = 2435; mean age 54.9 ± 14.3, 46.0% men). Residuals of Hannum-, Horvath-, and GrimAge-predicted epigenetic age were calculated by regressing epigenetic age on chronological age. We took into account blood cell composition for EEAA, IEAA, and AdjGrimAge. Moderate to vigorous physical activity (MVPA) was log-transformed to normalize its distribution. Adjustment models accounted for family structure, age, sex, smoking status, cohort-laboratory indicator, and accelerometer wear time. We additionally explored adjustment for body mass index (BMI).Walking 1500 more steps/day or spending 3 fewer hours sedentary was associated with10 months lower GrimAge biological age (or ~ 1 month lower AdjGrimAge, after adjusting for blood cells, p0.05). Every 5 min/day more MVPA was associated with 19-79 days lower GrimAge (4-23 days lower using EEAA or AdjGrimAge, p0.01). Adjusting for BMI attenuated these results, but all statistically significant associations with AdjGrimAge remained.Greater habitual physical activity and lower sedentary time were associated with lower epigenetic age, which was partially explained by BMI. Further research should explore whether changes in physical activity influence methylation status and whether those modifications influence chronic disease risk.

Background Dysfunction in blood vessel dynamics may contribute to changes in muscle measures. Therefore, we examined associations of vascular health measures with grip strength and gait speed in adults from the Framingham Heart Study. Methods The cross-sectional study (1998–2001) included participants with 1 measure of grip strength (kg, dynamometer) or gait speed (4-m walk, m/s) and at least 1 measure of aortic stiffness (carotid–femoral pulse wave velocity, brachial pulse pressure, and brachial flow pulsatility index) or brachial artery structure and function (resting flow velocity, resting brachial artery diameter, flow-mediated dilation %, hyperemic brachial blood flow velocity, and mean arterial pressure [MAP]) assessed by tonometry and brachial artery ultrasound. The longitudinal study included participants with ≥1 follow-up measurement of gait speed or grip strength. Multivariable linear regression estimated the association of 1 standard deviation (SD) higher level of each vascular measure with annualized percent change in grip strength and gait speed, adjusting for covariates. Results In cross-sectional analyses (n = 2 498, age 61 ± 10 years; 56% women), higher resting brachial artery diameter (β ± standard error [SE] per 1 SD: 0.59 ± 0.24, p = .01) and MAP (β ± SE: 0.39 ± 0.17, p = .02) were associated with higher grip strength. Higher brachial pulse pressure (β ± SE: −0.02 ± 0.01, p = .07) was marginally associated with slower gait speed. In longitudinal analyses (n = 2 157), higher brachial pulse pressure (β ± SE: −0.19 ± 0.07, p = .005), was associated with slowing of gait speed but not with grip strength. Conclusions Higher brachial artery pulse pressure (measure of aortic stiffness) was associated with loss of physical function over ~11 years, although we found no evidence that microvascular function contributed to the relation.

Extracorporeal membrane oxygenation (ECMO) represents an advanced option for supporting refractory respiratory and/or cardiac failure. Systemic anticoagulation with unfractionated heparin (UFH) is routinely used. However, patients with bleeding risk and/or heparin-related side effects may necessitate alternative strategies: among these, nafamostat mesilate (NM) has been reported.We conducted a systematic literature search (PubMed and EMBASE, updated 12/08/2021), including all studies reporting NM anticoagulation for ECMO. We focused on reasons for starting NM, its dose and the anticoagulation monitoring approach, the incidence of bleeding/thrombosis complications, the NM-related side effects, ECMO weaning, and mortality.The search revealed 11 relevant findings, all with retrospective design. Of these, three large studies reported a control group receiving UFH, the other were case series (n = 3) or case reports (n = 5). The main reason reported for NM use was an ongoing or high risk of bleeding. The NM dose varied largely as did the anticoagulation monitoring approach. The average NM dose ranged from 0.46 to 0.67 mg/kg/h, but two groups of authors reported larger doses when monitoring anticoagulation with ACT. Conflicting findings were found on bleeding and thrombosis. The only NM-related side effect was hyperkalemia (n = 2 studies) with an incidence of 15%-18% in patients anticoagulated with NM. Weaning and survival varied across studies.Anticoagulation with NM in ECMO has not been prospectively studied. While several centers have experience with this approach in high-risk patients, prospective studies are warranted to establish the optimal space of this approach in ECMO.

Cystic fibrosis (CF), the most common genetic disease among the Caucasian population, is caused by mutations in the gene encoding for the CF transmembrane conductance regulator (CFTR), a chloride epithelial channel whose dysfunction results in severe airway obstruction and inflammation, eventually leading to respiratory failure. The discovery of the CFTR gene in 1989 provided new insights into the basic genetic defect of CF and allowed the study of potential therapies targeting the aberrant protein. In recent years, the approval of “CFTR modulators”, the first molecules designed to selectively target the underlying molecular defects caused by specific CF-causing mutations, marked the beginning of a new era in CF treatment. These drugs have been demonstrated to significantly improve lung function and ameliorate the quality of life of many patients, especially those bearing the most common CFTR mutatant F508del. However, a substantial portion of CF subjects, accounting for ~20% of the European CF population, carry rare CFTR mutations and are still not eligible for CFTR modulator therapy, partly due to our limited understanding of the molecular defects associated with these genetic alterations. Thus, the implementation of models to study the phenotype of these rare CFTR mutations and their response to currently approved drugs, as well as to compounds under research and clinical development, is of key importance. The purpose of this review is to summarize the current knowledge on the potential of CFTR modulators in rescuing the function of rare CF-causing CFTR variants, focusing on both investigational and clinically approved molecules.

Longevity is a defining, heritable trait that varies dramatically between species. To resolve the genetic regulation of this trait, we have mined genomic variation in rockfishes, which range in longevity from 11 to over 205 years. Multiple shifts in rockfish longevity have occurred independently and in a short evolutionary time frame, thus empowering convergence analyses. Our analyses reveal a common network of genes under convergent evolution, encompassing established aging regulators such as insulin signaling, yet also identify flavonoid (aryl-hydrocarbon) metabolism as a pathway modulating longevity. The selective pressures on these pathways indicate the ancestral state of rockfishes was long lived and that the changes in short-lived lineages are adaptive. These pathways were also used to explore genome-wide association studies of human longevity, identifying the aryl-hydrocarbon metabolism pathway to be significantly associated with human survival to the 99th percentile. This evolutionary intersection defines and cross-validates a previously unappreciated genetic architecture that associates with the evolution of longevity across vertebrates.

BACKGROUND Takotsubo syndrome (TS) represents a form of nonischemic cardiomyopathy characterized by sudden and temporary weakening of the myocardium. Many data suggest a primary role for sympathetic overstimulation in its pathogenesis. Nevertheless, these correlates are less easily identified during anesthesia. OBSERVATIONS A 50-year-old female patient with a 4-year history of drug-resistant left trigeminal neuralgia. She was scheduled for surgical microvascular decompression. In the operating room, after induction of general anesthesia and oral intubation, the electrocardiogram revealed a significant ST segment elevation along with a sudden decrease in systolic blood pressure and heart rate. Administration of atropine caused a conversion into ventricular tachycardia. The advanced cardiac life support protocols were applied with prompt defibrillation and rapid recovery at sinus rhythm. A transthoracic echocardiogram revealed apical akinesia with ballooning of the left ventricle with a reduction of systolic function. An emergency coronary arteriography was performed, showing normal epicardial coronary vessels. After 4 days, echocardiography revealed normalization of the left ventricular function with improvement of the ejection fraction. LESSONS In patients affected by trigeminal neuralgia, chronic pain can lead to a state of adrenergic hyperactivation, which can promote TS during the induction of general anesthesia, probably through the trigeminocardiac reflex.

BACKGROUND Few studies examined the association between depressive symptom trajectories and objectively measured physical activity. OBJECTIVE We aimed to investigate if antecedent depressive symptoms predict subsequent daily step counts among participants in the electronic Framingham Heart Study (eFHS). METHODS We performed group-based multi-trajectory modeling to construct depressive symptom trajectory groups using both depressive symptoms (CES-D >16) and antidepressant use in eFHS participants who attended three FHS research exams over fourteen years. At the third exam, eFHS participants were provided with a study smartwatch for measuring daily step counts. We performed linear mixed models to examine the association between depressive symptom trajectories and daily step counts over one-year follow-up adjusting for age, sex, wear-hour, body mass index, and smoking status. RESULTS We identified two depressive symptom trajectory groups from 724 eFHS participants (mean age 53 years, 60% women). The low symptom group (n=566; mean follow-up 286±111 days) consisted of ≤5% of participants with depressive symptoms and ≤1% reporting antidepressant medication use, and the high symptom group (n = 158; 269±113 days) consisted of ≥28% of participants with depressive symptoms and ≥47% reporting antidepressant medication use across the three exams. Compared to those in the low symptom group, participants in the high symptom group walked fewer daily steps during one-year follow-up (690 fewer; 95% CI: 254-1125). CONCLUSIONS Antecedent depressive symptoms/anti-depressive medication use was associated with lower subsequent daily step counts in eFHS. Our findings suggest that adding interventions to improve mood via mHealth technologies may help promote people’s daily physical activity.

Longevity is a defining, heritable trait that varies dramatically between species. To resolve the genetic regulation of this trait, we have mined genomic variation in rockfishes, ranging in longevity from 11 to over 205 years. Multiple shifts in rockfish longevity have occurred independently, and in a short evolutionary time frame, thus empowering convergence analyses. Our analyses reveal a common network of genes under convergent restricted evolution in long-lived lineages, encompassing established aging regulators such as insulin-signaling, yet also identify flavonoid (aryl-hydrocarbon) metabolism as a novel pathway modulating longevity. Further, these genes were used to refine human longevity GWAS, identifying the aryl-hydrocarbon metabolism pathway to be significantly associated with human survival to the 99th percentile. This evolutionary intersection defines and cross-validates a novel, conserved genetic architecture that associates with the evolution of longevity across vertebrates.

Longevity is a defining, heritable trait that varies dramatically between species. To resolve the genetic regulation of this trait, we have mined genomic variation in rockfishes, which range in longevity from 11 to over 205 years. Multiple shifts in rockfish longevity have occurred independently, and in a short evolutionary time frame, thus empowering convergence analyses. Our analyses reveal a common network of genes under convergent evolution, encompassing established aging regulators such as insulin-signaling, yet also identify flavonoid (aryl-hydrocarbon) metabolism as a novel pathway modulating longevity. The selective pressures on these pathways indicate the ancestral state of rockfishes was long-lived, and that the changes in short-lived lineages are adaptive. Further, these pathways were used to explore GWAS of human longevity, identifying the aryl-hydrocarbon metabolism pathway to be significantly associated with human survival to the 99th percentile. This evolutionary intersection defines and cross-validates a novel, conserved genetic architecture that associates with the evolution of longevity across vertebrates.

Cyclic adenosine 3′,5′-monophosphate (cAMP)–elevating agents, such as β 2 -adrenergic receptor (β 2 -AR) agonists and phosphodiesterase (PDE) inhibitors, remain a mainstay in the treatment of obstructive respiratory diseases, conditions characterized by airway constriction, inflammation, and mucus hypersecretion. However, their clinical use is limited by unwanted side effects because of unrestricted cAMP elevation in the airways and in distant organs. Here, we identified the A-kinase anchoring protein phosphoinositide 3-kinase γ (PI3Kγ) as a critical regulator of a discrete cAMP signaling microdomain activated by β 2 -ARs in airway structural and inflammatory cells. Displacement of the PI3Kγ-anchored pool of protein kinase A (PKA) by an inhaled, cell-permeable, PI3Kγ mimetic peptide (PI3Kγ MP) inhibited a pool of subcortical PDE4B and PDE4D and safely increased cAMP in the lungs, leading to airway smooth muscle relaxation and reduced neutrophil infiltration in a murine model of asthma. In human bronchial epithelial cells, PI3Kγ MP induced unexpected cAMP and PKA elevations restricted to the vicinity of the cystic fibrosis transmembrane conductance regulator (CFTR), the ion channel controlling mucus hydration that is mutated in cystic fibrosis (CF). PI3Kγ MP promoted the phosphorylation of wild-type CFTR on serine-737, triggering channel gating, and rescued the function of F508del-CFTR, the most prevalent CF mutant, by enhancing the effects of existing CFTR modulators. These results unveil PI3Kγ as the regulator of a β 2 -AR/cAMP microdomain central to smooth muscle contraction, immune cell activation, and epithelial fluid secretion in the airways, suggesting the use of a PI3Kγ MP for compartment-restricted, therapeutic cAMP elevation in chronic obstructive respiratory diseases.

Aims While greater physical activity (PA) is associated with improved health outcomes, the direct links between distinct components of PA, their changes over time, and cardiorespiratory fitness are incompletely understood. Methods and results Maximum effort cardiopulmonary exercise testing (CPET) and objective PA measures [sedentary time (SED), steps/day, and moderate-vigorous PA (MVPA)] via accelerometers worn for 1 week concurrent with CPET and 7.8 years prior were obtained in 2070 Framingham Heart Study participants [age 54 ± 9 years, 51% women, SED 810 ± 83 min/day, steps/day 7737 ± 3520, MVPA 22.3 ± 20.3 min/day, peak oxygen uptake (VO2) 23.6 ± 6.9 mL/kg/min]. Adjusted for clinical risk factors, increases in steps/day and MVPA and reduced SED between the two assessments were associated with distinct aspects of cardiorespiratory fitness (measured by VO2) during initiation, early-moderate level, peak exercise, and recovery, with the highest effect estimates for MVPA (false discovery rate Conclusions Our findings provide a detailed assessment of relations of different types of PA with multidimensional cardiorespiratory fitness measures and suggest favourable longitudinal changes in PA (and MVPA in particular) are associated with greater objective fitness.

Age-related changes to the genome-wide DNA methylation (DNAm) pattern observed in blood are well-documented. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by the age-related acquisition and expansion of leukemogenic mutations in hematopoietic stem cells (HSCs), is associated with blood cancer and coronary artery disease (CAD). Epigenetic regulators DNMT3A and TET2 are the two most frequently mutated CHIP genes. Here, we present results from an epigenome-wide association study for CHIP in 582 Cardiovascular Health Study (CHS) participants, with replication in 2655 Atherosclerosis Risk in Communities (ARIC) Study participants. We show that DNMT3A and TET2 CHIP have distinct and directionally opposing genome-wide DNAm association patterns consistent with their regulatory roles, albeit both promoting self-renewal of HSCs. Mendelian randomization analyses indicate that a subset of DNAm alterations associated with these two leading CHIP genes may promote the risk for CAD.

Blood pressure (BP) measures in women more sharply increase with age compared with men, with a widening disparity in older women. The use of home blood pressure monitoring (HBPM) among women may improve this inequity. However, sex-related differences in adherence to HBPM are not well understood. We analyzed data from electronic Framingham Heart Study participants who were given a Withings digital BP cuff and instructed to perform HBPM weekly for 1 year. Adherence was defined as ≥1 BP measurement per week, averaged over 4-week segments. HTN status was self-reported. Group-based trajectory modeling (GBTM) was used to identify trajectory patterns of adherence. We investigated the association of 3 adherence patterns with HTN status stratified by sex using multinomial logistic models adjusting for age group, marital status, education, employment status, income, non-BP cardiac medication use, subjective health, depression and anxiety. Among 1,048 participants (59% female, mean age 53±9 years, 25% with HTN), we identified 3 trajectory groups corresponding to distinct patterns of HBPM adherence: early discontinuation (N = 458, 58% female, 21% HTN), gradual decrease (N = 360, 60% female, 27% HTN), and high adherence (N = 230, 57% female, 31% HTN, Figure 1 ). Women with HTN compared to women without HTN had 80% higher odds of being in the high adherence group versus early discontinuation group (aOR 1.80; 95% CI 1.02-3.17). This pattern was not observed for men (aOR 1.12; 95% CI 0.68-1.63). In this middle-aged eCohort, HTN was associated with high adherence to HBPM in women but not men. The targeted prescription of HBPM for woman should be studied to see if it can reduce sex disparities in BP control.

Long-term use of digital devices is critical for successful clinical or research use, but digital health studies are challenged by a rapid drop-off in participation. A nested e-cohort (eFHS) is embedded in the Framingham Heart Study and uses three system components: a new smartphone app, a digital blood pressure (BP) cuff, and a smartwatch. This study aims to identify factors associated with the use of individual eFHS system components over 1-year. Among 1948 eFHS enrollees, we examine participants who returned surveys within 90 days (n = 1918), and those who chose to use the smartwatch (n = 1243) and BP cuff (n = 1115). For each component, we investigate the same set of candidate predictors for usage and use generalized linear mixed models to select predictors (P P value from Z test statistic), adjusting for age, sex, and time (app use: 3-month period, device use: weekly). A multivariable model with the predictors selected from initial testing is used to identify factors associated with use of components (P P value from Z test statistic) adjusting for age, sex, and time. In multivariable models, older age is associated with higher use of all system components. Female sex and higher education levels are associated with higher completion of app-based surveys whereas higher scores for depressive symptoms, and lower than excellent self-rated health are associated with lower use of the smartwatch over the 12-month follow-up. Our findings show that sociodemographic and health related factors are significantly associated with long-term use of digital devices. Future research is needed to test interventional strategies focusing on these factors to evaluate improvement in long-term engagement.

Rationale: The association between aging and idiopathic pulmonary fibrosis has been established. The associations between aging-related biomarkers and interstitial lung abnormalities (ILA) have not...

We analysed state-of-the-art observations of the solar atmosphere to investigate the dependence of the \ca brightness of several solar features on spectral bandwidth and spatial resolution of the data. Specifically, we study data obtained at the Swedish Solar Telescope with the CRiSP and CHROMIS instruments. The analyzed data, which are characterized by spectral bandwidth of 0.12 \AA \ and spatial resolution of 0.078\arcsec, were acquired close to disc center by targeting a quiet Sun area and an active region. We convolved the original observations with Gaussian kernels to degrade their spectral bandwidth and spatial resolution to the instrumental characteristics of the most prominent series of \ca observations available to date. We then studied the effect of data degradation on the observed regions and on parameters derived from \ca line measurements that are largely employed as diagnostics of the solar and stellar chromospheres. We find that the effect of degrading the spectral resolution of \ca observations and line profiles depends on both the employed bandwidth and observed solar region. Besides, we found that the spatial degradation impacts the data characterized by a broad bandwidth to a larger extent compared to those acquired with a narrow band. However, the appearance of the observed solar regions is only slightly affected by the spatial resolution of data with bandwidths up to 1 \AA \ and in the range [3,10] \AA. Finally, we derived relationships that can be used to intercalibrate results from observations taken with different instruments in diverse regions of the solar atmosphere., Comment: 26 pages, 17 figures, ApJ accepted

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes)1. In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%., The goals, resources and design of the NHLBI Trans-Omics for Precision Medicine (TOPMed) programme are described, and analyses of rare variants detected in the first 53,831 samples provide insights into mutational processes and recent human evolutionary history.

Neuroinflammation is an important contributor to the pathogenesis of dementia, but the role of circulating inflammatory markers is unclear. The aim of the study is to identify circulating inflammatory biomarkers associated with cognitive function in the Framingham Heart Study Offspring cohort. We used OLINK inflammation panel to measure 92 inflammation protein biomarkers using stored plasma samples at Offspring examination 7 (1998-2001) from 879 participants (52% female, mean 61 years range 40 to 88 years, 22% APOE e4 carrier). Cognitive function was assessed with seven tests derived from a neuropsychological (NP) testing battery representing four cognitive domains collected closest to the 7th examination. 68 proteins with at least 50% values above the limit of detection (LOD) were clustered with hierarchical clustering, and data below LOD were replaced with LOD/√2. We identified nine clusters of highly correlated proteins and created cluster composite scores on the first principal component of each. Adjusting for age, sex and education, five of the seven NP tests are nominally associated (p < 0.05) with at least one of the protein clusters, and five of the nine clusters are associated with at least one of the NP tests. The executive function test Trails B–Trails A is nominally associated with three clusters, and the Boston Naming Test 30 items version with two clusters, both sharing one common cluster which includes IFN-γ-inducible chemokines involved in inflammatory conditions. Future analyses will explore individual protein associations with cognitive test performance and incident dementia and will investigate the biological relevance of the identified clusters.

Mobile technology offers a remote method to monitor health in older adults and it may provide a platform for early detection of cognitive decline. We aimed to examine attributes of smartphone survey use in the electronic Framingham Heart Study (eFHS) cohort in relation to cognitive testing performed at the time of enrollment. eFHS participants who returned smartphone surveys and underwent cognitive testing were considered in the study (n=1810). The CERAD recall score, Victoria Stroop test interference score, and dichotomous AD8 and MOCA (MOCA score ≤ 19, AD8 score ≥2) were considered as primary exposures. App-based survey adherence was defined as a dichotomous outcome based on whether at least one survey was completed at each 3-month period from baseline to 12 months. Several time attributes were considered including survey return time, touch time, step time, and question completion time. Linear mixed models (LMM for time attributes outcomes and generalized LMM for adherence outcome) were fitted for each cognitive score as the predictor adjusting for age, sex, race/ethnicity, and education level. Results suggest that higher CERAD recall scores were associated with higher odds of completing surveys. There was a significant association between all cognitive exposures and survey time attributes. Participants with poorer cognitive function (lower CERAD, higher stroop interference, MOCA score ≤ 19, AD8 score ≥2) had delayed survey return times, higher touch time, higher step time and higher question completion time. This study contributes to the growing body of evidence that smartphones may be an important tool to identify cognitive decline.

Although measures of physical function such as walking speed and time to complete chair-rises are highly heritable, the genetic architecture underlying these phenotypes remains poorly defined. To identify potentially novel genes and pathways underlying physical performance in older adults, we conducted a genome-wide association meta-analysis of the short physical performance battery (SPPB) (Score 0-12) and one of its components, chair-rise time (seconds) in 24,033 Caucasian adults aged 60+ from 13 cohorts (mean cohort age 66.2 ± 5.3 to 84.3 ± 4.1 years; 56.5% women). Cohorts had a genome wide scan imputed to either the Haplotype Reference Consortium or Trans-Omics for Precision Medicine imputation panels. Single nucleotide polymorphism (SNPs) with a minor allele frequency ≥0.1% and imputation quality score ≥0.7 were included (range 7.5-10.5 million per cohort). Analyses were adjusted for age, sex, height, and population substructure. Meta-analysis was performed using a fixed-effects model. Although no genome-wide significant loci were identified, 67 and 60 suggestive loci (p< 5*10-5) were detected for SPPB score and chair-rises time, respectively. Pathway-based analyses indicated significant enrichment of genes affecting negative regulation of calcium channel activity (Bonferroni corrected p-value < 0.05). Sex-stratified gene-based analyses identified clathrin vesicle-associated sec14 protein 1 (CLVS1), significantly associated with chair-rise time in women (p= -1.5*10-7). CLVS1 is highly expressed in the cerebellum, which is involved in postural and motor function control. A larger sample size is needed to confirm and extend our findings, but our results potentially implicate a novel pathway and locus for physical performance in older women.

Background Non-genetic factors contribute to differences in diabetes risk across race/ethnic and socioeconomic groups, which raises the question of whether effects of predictors of diabetes are similar across populations. We studied diabetes incidence in the primarily non-Hispanic White Framingham Heart Study (FHS, N = 4066) and the urban, largely immigrant Hispanic Community Health Study/Study of Latinos (HCHS/SOL, N = 6891) Please check if the affiliations are captured and presented correctly. Methods Clinical, behavioral, and socioeconomic characteristics were collected at in-person examinations followed by seven-day accelerometry. Among individuals without diabetes, Cox proportional hazards regression models (both age- and sex-adjusted, and then multivariable-adjusted for all candidate predictors) identified predictors of incident diabetes over a decade of follow-up, defined using clinical history or laboratory assessments. Results Four independent predictors were shared between FHS and HCHS/SOL. In each cohort, the multivariable-adjusted hazard of diabetes increased by approximately 50% for every ten-year increment of age and every five-unit increment of body mass index (BMI), and was 50–70% higher among hypertensive than among non-hypertensive individuals (all P Conclusions The same four independent predictors – age, body mass index, hypertension and employment status – were associated with diabetes risk across two disparate US populations. While the reason for elevated diabetes risk in full-time workers is unclear, the findings suggest that diabetes may be part of the work-related burden of disease. Our findings also support prior evidence that differences by gender and socioeconomic position in diabetes risk are not universally present across populations.

OBJECTIVE: Women have a higher lifetime risk of AD than men. Among cognitively normal (CN) older adults, women exhibit elevated tau positron emission tomography (PET) signal compared with men. We explored whether menopause exacerbates sex differences in tau deposition in middle-aged adults.METHODS: 328 CN participants from the Framingham Study (mean age=57yrs(±10yrs), 161 women, of whom, 104 were post-menopausal) underwent tau and β-amyloid (Aβ)-PET neuroimaging. We examined global Aβ-PET, and tau-PET signal in five regions identified a priori as demonstrating significant sex differences in older adults (in temporal, inferior parietal, middle frontal, and lateral occipital regions). We examined sex and menopause status-related differences in each region-of-interest, using linear regressions, as well as interactions with Aβ and APOEε4 genotype.RESULTS: Women exhibited higher tau-PET signal (pINTERPRETATION: Clear divergence in tauopathy between the sexes are apparent approximately 20 years earlier than previously reported. Menopause status moderated sex differences in Aβ and tau-PET burden, with tau first appearing post-menopause. Sex and menopause differences consistently appeared in middle frontal and parieto-occipital regions but were not moderated by Aβ burden or APOEε4, suggesting that menopause-related tau vulnerability may be independent of AD-related pathways. This article is protected by copyright. All rights reserved.

Early de-tethering procedures are performed on spinal dysraphisms to prevent neuro-urological deterioration caused by growth. Partial lipoma removal may cause delayed deterioration by re-tethering, while complete removal may increase the risk of postoperative worsening. The present study evaluates the risk of postoperative deterioration and the protective potential of intraoperative neurophysiological monitoring (IOM), with a special reference to the conus lipomas treated with the radical approach. Forty toddlers (

DNA methylation has fundamental roles in gene programming and aging that may help predict mortality. However, no large-scale study has investigated whether site-specific DNA methylation predicts all-cause mortality. We used the Illumina-HumanMethylation450-BeadChip to identify blood DNA methylation sites associated with all-cause mortality for 12, 300 participants in 12 Cohorts of the Heart and Aging Research in Genetic Epidemiology (CHARGE) Consortium. Over an average 10-year follow-up, there were 2,561 deaths across the cohorts. Nine sites mapping to three intergenic and six gene-specific regions were associated with mortality (P < 9.3x10-7) independently of age and other mortality predictors. Six sites (cg14866069, cg23666362, cg20045320, cg07839457, cg07677157, cg09615688)—mapping respectively to BMPR1B, MIR1973, IFITM3, NLRC5, and two intergenic regions—were associated with reduced mortality risk. The remaining three sites (cg17086398, cg12619262, cg18424841)—mapping respectively to SERINC2, CHST12, and an intergenic region—were associated with increased mortality risk. DNA methylation at each site predicted 5%¬¬–15% of all deaths. We also assessed the causal association of those sites to age-related chronic diseases by using Mendelian randomization, identifying weak causal relationship between cg18424841 and cg09615688 with coronary heart disease. Of the nine sites, three (cg20045320, cg07839457, cg07677157) were associated with lower incidence of heart disease risk and two (cg20045320, cg07839457) with smoking and inflammation in prior CHARGE analyses. Methylation of cg20045320, cg07839457, and cg17086398 was associated with decreased expression of nearby genes (IFITM3, IRF, NLRC5, MT1, MT2, MARCKSL1) linked to immune responses and cardiometabolic diseases. These sites may serve as useful clinical tools for mortality risk assessment and preventative care.

The novel coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is sorely testing health care systems and economies around the world and is rightly considered as the major health emergency in a century. Despite the course of the disease appearing to be mild in many cases, a significant proportion of symptomatic patients develop pneumonia requiring hospitalisation or progress to manifest respiratory complications leading to intensive care treatment. Potential interventions for SARS-CoV2-associated pneumonia are being tested, some of which holding promise, but as of today none of these has yet demonstrated outstanding efficacy in treating COVID-19. In this article, we discuss fresh perspectives and insights into the potential role of immune dysregulation in COVID-19 as well as similarities with systemic inflammatory response in sepsis and the rationale for exploring novel treatment options affecting host immune response.

Radium-223 prolongs overall survival (OS) and delays time to the first symptomatic skeletal events in patients with symptomatic metastatic castration-resistant prostate cancer (mCRPC). There is a lack of evidence on the safety and efficacy of Radium-223 treatment in the very elderly population. Aim of this multicentre study is to analyze mCRPC patients treated with Radium-223 in terms of OS and to assess whether there are differences between young and elderly, as well as to verify efficacy and safety in patients ≥ 75 years of age. 430 mCRPC patients of six Italian Centres were analyzed in this multicenter retrospective study. At baseline and after each cycle were collected clinical and diagnostic patients’ parameters. The whole cohort was divided into two groups based on the age of the patients (

Backgrounds and aims: Several genes are known to contribute to the levels and metabolism of HDL-C, however, their protective effects in cardiovascular disease (CVD), healthy aging, and longevity are complex and poorly understood. It is also unclear if these genes predict longitudinal HDL-C change. We aimed to identify loci influencing HDL-C change. Methods: We performed a genome-wide association study (GWAS) with harmonized HDL-C and imputed genotype in three family-based studies recruited for exceptional survival (Long Life Family Study), from community-based (Framingham Heart Study) and enriched for CVD (Family Heart Study). In 7738 individuals with at least 2 visits, we employed a growth curve model to estimate the random linear trajectory parameter of age-sex-adjusted HDL-C for each person. GWAS was performed using a linear regression model on HDL-C change accounting for kinship correlations, population structure, and differences among studies. Results: We identified a novel association for HDL-C with GRID1 (p = 5.43 × 10−10), which encodes a glutamate receptor channel subunit involved in synaptic plasticity. Seven suggestive novel loci (p < 1.0 × 10−6; MBOAT2, LINC01876-NR4A2, NTNG2, CYSLTR2, SYNE2, CTXND1-LINC01314, and CYYR1) and a known lipid gene (ABCA10) showed associations with HDL-C change. Two additional sex-specific suggestive loci were identified in women (DCLK2 and KCNJ2). Several of these genetic variants are associated with lipid-related conditions influencing cardiovascular and metabolic health, have predictive regulatory function, and are involved in lipid-related pathways. Conclusions: Modeling longitudinal HDL-C in prospective studies, with differences in healthy aging, longevity and CVD risk, contributed to gene discovery and provided insights into mechanisms of HDL-C regulation.

Social isolation might be considered as a marker of poor health and higher mortality. The aim of our analysis was to assess the association of social network index (SNI) with incident AF and death. We selected participants aged ≥ 55 years without prevalent AF from the Framingham Heart Study. We evaluated the association between social isolation measured by the Berkman-Syme Social Network Index (SNI), incident AF, and mortality without diagnosed AF. We assessed the risk factor-adjusted associations between SNI (the sum of 4 components: marriage status, close friends/relatives, religious service attendance, social group participation), incident AF, and mortality without AF by using Fine-Gray competing risk regression models. We secondarily examined the outcome of all-cause mortality. We included 3454 participants (mean age 67 ± 10 years, 58% female). During 11.8 ± 5.2 mean years of follow-up, there were 686 incident AF cases and 965 mortality without AF events. Individuals with fewer connections had lower rates of incident AF (P = 0.04) but higher rates of mortality without AF (P = 0.03). Among SNI components, only social group participation was associated with higher incident AF (subdistribution hazards ratio [sHR] 1.35, 95% CI 1.16–1.57, P = 0.0001). For mortality without AF, social group participation (sHR = 0.81, 95% CI 0.71–0.93, P = 0.002) and regular religious service attendance sHR = 0.76, 95% CI 0.67–0.87, P

Background The electronic Framingham Heart Study (eFHS) is an ongoing nested study, which includes FHS study participants, examining associations between health data from mobile devices with cardiovascular risk factors and disease. Objective To describe application (app) design, report user characteristics, and describe usability and survey response rates. Methods Eligible FHS participants were consented and offered a smartwatch (Apple Watch), a digital blood pressure (BP) cuff, and the eFHS smartphone app for administering surveys remotely. We assessed usability of the new app using 2 domains (functionality, aesthetics) of the Mobile App Rating Scale (MARS) and assessed survey completion rates at baseline and 3 months. Results A total of 196 participants were recruited using the enhanced eFHS app. Of these, 97 (49.5%) completed the MARS instrument. Average age of participants was 53 ± 9 years, 51.5% were women, and 93.8% were white. Eighty-six percent of participants completed at least 1 measure on the baseline survey, and 50% completed the 3-month assessment. Overall subjective score of the app was 4.2 ± 0.7 on a scale from 1 to 5 stars. Of those who shared their health data with others, 46% shared their BP and 7.7% shared their physical activity with a health care provider. Conclusion Participants rated the new, enhanced eFHS app positively overall. Mobile app survey completion rates were high, consistent with positive in-app ratings from participants. These mobile data collection modalities offer clinicians new opportunities to engage in conversations about health behaviors.

Introduction: Depression is a common and serious medical illness world-wide. Studies have demonstrated a protective effect of physical activity on depression, but few studies have examined the prospective association between depressive symptoms and objectively measured physical activity. Objective: To investigate if antecedent depressive symptoms predict subsequent daily step counts among participants enrolled in the electronic Framingham Heart Study (eFHS). We hypothesize that the trajectory group with a larger proportion of participants having depressive symptoms and antidepressant use is associated with a lower level of physical activity. Methods: We used group-based multi-trajectory modeling to construct depressive symptom trajectory patterns using both depressive symptoms and antidepressant use collected from eFHS participants who attended three FHS health exams over fourteen years. The presence of depressive symptoms was defined at each exam with a Center for Epidemiological Studies-Depression (CES-D) score > 16. At the final exam, participants were provided with a study smartwatch to measure daily step counts. We excluded: a) person-day records with less than 5 hours of wear-time, or less than 1000 steps recorded in a day; b) participants who failed to return data for ≥1 day per week in the first month. We performed linear mixed effects models to examine the association between depressive symptom trajectories and average daily step counts during the first 30 days of smartwatch use and one-year of follow-up adjusting for age, sex, wear-hour, BMI, and smoking status. We used p Results: We identified two depressive symptom trajectory groups for the 724 eFHS participants (mean age 53 years, 60% women). The “low-stable” group (n=578; mean follow-up 286±110 days) consisted of n = 146; 269±114 days) consisted of >21% of participants with depressive symptoms and >46% of those with antidepressant medication use across the three exams. Compared to the low-stable trajectory group, the participants in the high-increasing depressive symptoms group walked 475 (95% CI: 24-927) fewer daily steps during the first 30 days of smartwatch use ( p = 0.04) and walked 550 (95% CI: 109-991) fewer daily steps during one-year of follow-up ( p = 0.01). Conclusion: Participants in the group with a larger proportion of antecedent depression and anti-depressant use walked significantly fewer steps compared to the group with a smaller proportion of antecedent depression and anti-depressant use. Our findings suggest that interventions via mHealth technologies that target mood may play an important role in promoting physical activity.

Introduction: Depressive symptoms are common and share many biopsychosocial mechanisms with hypertension, but cross-sectional studies on their association have produced inconsistent results. The emergence of digital home blood pressure (BP) measurements may provide additional insight into the relationship. Hypothesis: We hypothesized that depressive symptoms would be modestly associated with higher home BP and hypertension prevalence in participants of the electronic Framingham Heart Study (eFHS). Methods: FHS participants who attended research exam 3 (2016-2019) were invited to enroll in eFHS. They downloaded a smartphone app and were provided a digital BP cuff to measure their weekly BP for up to 1 year. Participants who had at least 3 home BPs were included. Depressive symptoms were measured at the exam using the Center for Epidemiological Studies Depression Scale (CES-D) scored 0-60. We used linear mixed regression models to test the association of CES-D score (independent) with home SBP and DBP (dependent) and a logistic regression model to evaluate the association of depressive symptoms (defined as CES-D ≥16) with prevalent hypertension, adjusting for age, sex, cohort, lifestyle factors, diabetes, and CVD. Results: The study sample included 855 eFHS participants (mean age 53 years, 59% women, 9% multi-ethnic). The prevalence of depressive symptoms was 7% (CES-D score mean±SD, 5.7±6.6). The mean SBP and DBP were 119 and 76 mmHg; the prevalence of hypertension was 48%. CES-D score was modestly associated with home BP; a 1 SD higher CES-D corresponded with 0.9 and 0.6 mmHg higher mean SBP and DBP respectively (Table). Depressive symptoms were not significantly associated with home BP or hypertension prevalence (OR=3.16, 95% CI, 0.96-10.43). Antidepressant use attenuated the relationship. Conclusion: CES-D score had a small positive association with digital home BP, but it was not clinically substantive. The association of depression and hypertension risk warrants more data, which may be supported by mobile health.

Background Although new approaches for data collection, such as mobile technology and teleresearch, have demonstrated new opportunities for the conduct of more timely and less costly surveys in community-based studies, literature on the feasibility of conducing cardiovascular disease research using mobile health (mHealth) platforms among middle-aged and older African Americans has been limited. Objective The purpose of this study was to contribute to the knowledge regarding the penetrance of internet and mobile technologies, such as cellphones or smartphones in existing large cohort studies of cardiovascular disease. Methods A digital connectedness survey was conducted in the Jackson Heart Study (JHS), a Mississippi-based African American cohort study, as part of the annual follow-up calls with participants from July 2017 to February 2019. Results Of the 4024 participants contacted, 2564 (63.7%) completed the survey. Among survey respondents, 2262 (88.2%) reported use of internet or cellphone, and 1593 (62.1%) had a smartphone. Compared to nonusers (n=302), internet or cellphone users (n=2262) were younger (mean age 80.1, SD 8.0 vs 68.2, SD 11.3 years), more likely to be affluent (n=778, 40.1% vs n=39, 15.4%), and had greater than high school education (n=1636, 72.5% vs n=85, 28.1%). Internet or cellphone users were less likely to have cardiovascular disease history compared to nonusers (136/2262, 6.6% vs 41/302, 15.8%). The prevalence of current smoking and average BMI were similar between internet or cellphone users and nonusers. Among internet or cellphone users, 1316 (58.3%) reported use of email, 504 (22.3%) reported use of apps to track or manage health, and 1269 (56.1%) expressed interest in using JHS-developed apps. Conclusions Our findings suggest that it is feasible to use mHealth technologies to collect survey data among African Americans already enrolled in a longitudinal study. Our findings also highlight the need for more efforts to reduce the age and education divide in access and use of internet and smartphones for tracking health and research in African American communities.

BACKGROUND Although new approaches for data collection such as mobile technology and tele-research have demonstrated new opportunities for the conduct of more timely and less costly surveys in community-based studies, literature on the feasibility of conducing mHealth research among African Americans has been limited. OBJECTIVE - METHODS A digital connectedness survey was conducted in the Jackson Heart Study (JHS), a Mississippi-based African American cohort study, as part of the annual follow-up calls with participants from July 2017 to February 2019. RESULTS Of the 4024 participants contacted, 2564 (63.7%) completed the survey. Among survey respondents, 2262 (88.2%) reported use of internet/cellphone and 1593 (62.1%) had a smartphone. Compared to non-users, internet/cellphone users were younger (68.2 vs. 80.1 years), more likely to be affluent (40.1% vs. 15.4%), and had greater than high school education (72.5% vs. 28.1%). Internet/cellphone users were less likely to have cardiovascular disease history than non-users (6.6% vs. 15.8%). The prevalence of current smoking and average body mass index were similar between internet/cellphone users and non-users. Among internet/cellphone users, 1316 (58.3%) reported use of email, 504 (22.3%) reported use of apps to track/manage health, and 1269 (56.1%) expressed interest in using JHS-developed apps. CONCLUSIONS Our findings suggest that it is feasible to use mHealth technologies to collect survey data among African Americans already enrolled in a longitudinal study. Our findings also highlight the need for more efforts to reduce the age and education divide in access and use of internet and smartphones for tracking health and research in African American communities.

Full list of authors: Noda, C. Quintero; Schlichenmaier, R.; Bellot Rubio, L. R.; Lofdahl, M. G.; Khomenko, E.; Leenaarts, J.; Kuckein, C.; Gonzalez Manrique, S. J.; Gunar, S.; Nelson, C. J.; Rodriguez, J. de la Cruz; Tziotziou, K.; Tsiropoula, G.; Aulanier, G.; Aboudarham, J.; Allegri, D.; Alsina Ballester, E.; Amans, J. P.; Asensio Ramos, A.; Bailen, F. J.; Balaguer, M.; Baldini, V; Balthasar, H.; Barata, T.; Barczynski, K.; Barreto Cabrera, M.; Baur, A.; Bechet, C.; Beck, C.; Belio-Asin, M.; Bello-Gonzalez, N.; Belluzzi, L.; Bentley, R. D.; Berdyugina, S., V; Berghmans, D.; Berlicki, A.; Berrilli, F.; Berkefeld, T.; Bettonvil, F.; Bianda, M.; Bienes Perez, J.; Bonaque-Gonzalez, S.; Brajsa, R.; Bommier, V; Bourdin, P-A; BurgosMartin, J.; Calchetti, D.; Calcines, A.; Calvo Tovar, J.; Campbell, R. J.; Carballo-Martin, Y.; Carbone, V; Carlin, E. S.; Carlsson, M.; Castro Lopez, J.; Cavaller, L.; Cavallini, F.; Cauzzi, G.; Cecconi, M.; Chulani, H. M.; Cirami, R.; Consolini, G.; Coretti, I; Cosentino, R.; Cozar-Castellano, J.; Dalmasse, K.; Danilovic, S.; Ovelar, M. De Juan; Del Moro, D.; del Pino Aleman, T.; del Toro Iniesta, J. C.; Denker, C.; Dhara, S. K.; Di Marcantonio, P.; Baso, C. J. Diaz; Diercke, A.; Dineva, E.; Diaz-Garcia, J. J.; Doerr, H-P; Doyle, G.; Erdelyi, R.; Ermolli, I; Escobar Rodriguez, A.; Esteban Pozuelo, S.; Faurobert, M.; Felipe, T.; Feller, A.; Feijoo Amoedo, N.; Femenia Castella, B.; Fernandes, J.; Ferro Rodriguez, I; Figueroa, I; Fletcher, L.; Franco Ordovas, A.; Gafeira, R.; Gardenghi, R.; Gelly, B.; Giorgi, F.; Gisler, D.; Giovannelli, L.; Gonzalez, F.; Gonzalez, J. B.; Gonzalez-Cava, J. M.; Gonzalez Garcia, M.; Gomory, P.; Gracia, F.; Grauf, B.; Greco, V; Grivel, C.; Guerreiro, N.; Guglielmino, S. L.; Hammerschlag, R.; Hanslmeier, A.; Hansteen, V; Heinzel, P.; Hernandez-Delgado, A.; Hernandez Suarez, E.; Hidalgo, S. L.; Hill, F.; Hizberger, J.; Hofmeister, S.; Jagers, A.; Janett, G.; Jarolim, R.; Jess, D.; Jimenez Mejias, D.; Jolissaint, L.; Kamlah, R.; Kapitan, J.; Kasparova, J.; Keller, C. U.; Kentischer, T.; Kiselman, D.; Kleint, L.; Klvana, M.; Kontogiannis, I; Krishnappa, N.; Labrosse, N.; Lagg, A.; Degl'Innocenti, E. Landi; Langlois, M.; Lafon, M.; Laforgue, D.; Le Men, C.; Lepori, B.; Lepreti, F.; Lindberg, B.; Lilje, P. B.; Ariste, A. Lopez; Lopez Fernandez, V. A.; Lopez Jimenez, A. C.; Lopez Lopez, R.; Sainz, R. Manso; Marassi, A.; Marco de la Rosa, J.; Marino, J.; Marrero, J.; Martin, A.; Martin Galvez, A.; Martin Hernando, Y.; Masciadri, E.; MartinezGonzalez, M.; Matta-Gomez, A.; Mato, A.; Mathioudakis, M.; Matthews, S.; Mein, P.; Merlos Garcia, F.; Moity, J.; Montilla, I; Molinaro, M.; Molodij, G.; Montoya, L. M.; Munari, M.; Murabito, M.; Nunez Cagigal, M.; Oliviero, M.; Orozco Suarez, D.; Ortiz, A.; Padilla-Hernandez, C.; Paez Mana, E.; Paletou, F.; Pancorbo, J.; Pastor Canedo, A.; Yabar, A. Pastor; Peat, A. W.; Pedichini, F.; Peixinho, N.; Penate, J.; Perez de Taoro, A.; Peter, H.; Petrovay, K.; Piazzesi, R.; Pietropaolo, E.; Pleier, O.; Poedts, S.; Potzi, W.; Podladchikova, T.; Prieto, G.; Quintero Nehrkorn, J.; Ramelli, R.; Ramos Sapena, Y.; Rasilla, J. L.; Reardon, K.; Rebolo, R.; Regalado Olivares, S.; Reyes Garcia-Talavera, M.; Riethmuller, T. L.; Rimmele, T.; Rodriguez Delgado, H.; Rodriguez Gonzalez, N.; Rodriguez-Losada, J. A.; Rodriguez Ramos, L. F.; Romano, P.; Roth, M.; vander Voort, L. Rouppe; Rudawy, P.; Ruiz de Galarreta, C.; Rybak, J.; Salvade, A.; Sanchez-Capuchino, J.; Sanchez Rodriguez, M. L.; Sangiorgi, M.; Sayede, F.; Scharmer, G.; Scheiffelen, T.; Schmidt, W.; Schmieder, B.; Scire, C.; Scuderi, S.; Siegel, B.; Sigwarth, M.; Simoes, P. J. A.; Snik, F.; Sliepen, G.; Sobotka, M.; Socas-Navarro, H.; Sola La Serna, P.; Solanki, S. K.; Soler Trujillo, M.; Soltau, D.; Sordini, A.; Sosa Mendez, A.; Stangalini, M.; Steiner, O.; Stenflo, J. O.; Stepan, J.; Strassmeier, K. G.; Sudar, D.; Suematsu, Y.; Sutterlin, P.; Tallon, M.; Temmer, M.; Tenegi, F.; Tritschler, A.; Trujillo Bueno, J.; Turchi, A.; Utz, D.; van Harten, G.; VanNoort, M.; van Werkhoven, T.; Vansintjan, R.; Vaz Cedillo, J. J.; Vega Reyes, N.; Verma, M.; Veronig, A. M.; Viavattene, G.; Vitas, N.; Vogler, A.; von der Luhe, O.; Volkmer, R.; Waldmann, T. A.; Walton, D.; Wisniewska, A.; Zeman, J.; Zeuner, F.; Zhang, L. Q.; Zuccarello, F.; Collados, M.--This is an Open Access article, published by EDP Sciences, under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited., The European Solar Telescope (EST) is a project aimed at studying the magnetic connectivity of the solar atmosphere, from the deep photosphere to the upper chromosphere. Its design combines the knowledge and expertise gathered by the European solar physics community during the construction and operation of state-of-the-art solar telescopes operating in visible and near-infrared wavelengths: the Swedish 1m Solar Telescope, the German Vacuum Tower Telescope and GREGOR, the French Télescope Héliographique pour l’Étude du Magnétisme et des Instabilités Solaires, and the Dutch Open Telescope. With its 4.2 m primary mirror and an open configuration, EST will become the most powerful European ground-based facility to study the Sun in the coming decades in the visible and near-infrared bands. EST uses the most innovative technological advances: the first adaptive secondary mirror ever used in a solar telescope, a complex multi-conjugate adaptive optics with deformable mirrors that form part of the optical design in a natural way, a polarimetrically compensated telescope design that eliminates the complex temporal variation and wavelength dependence of the telescope Mueller matrix, and an instrument suite containing several (etalon-based) tunable imaging spectropolarimeters and several integral field unit spectropolarimeters. This publication summarises some fundamental science questions that can be addressed with the telescope, together with a complete description of its major subsystems. © C. Q. Noda et al. 2022., C.Q.N. was supported by the EST Project Office, funded by the Canary Islands Government (file SD 17/01) under a direct grant awarded to the IAC on ground of public interest. This project has received funding from the European Union’s Horizon 2020 Research and Innovation programme under Grant Agreements No 739500 (PRE-EST) and 653982 (GREST). This project was supported by the European Commission’s FP7 Capacities Programme under Grant Agreements No 212482 (EST Design Study) and No. 312495 (SOLARNET). It was also supported by the European Union’s Horizon 2020 Research and Innovation programme under Grant Agreement No. 824135 (SOLARNET). This work has been partially funded by the Spanish Ministry of Science and Innovation through project RTI2018-096886-B-C51, including a percentage from FEDER funds, and through the Centro de Excelencia Severo Ochoa grant SEV-2017-0709 awarded to the Instituto de Astrofísica de Andalucía in the period 2018-2022. The EST preparatory phase was supported by a grant for research infrastructures of national importance from the Swedish Research Council (registration number 2017-00625). J.J. was supported by the Ministry of Education, Youth and Sports of the Czech Republic through the EST-CZ project (LM2018095). C.K. acknowledges funding received from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 895955. Queen’s University Belfast acknowledges support from the Science and Technology Facilities Council (STFC) under grant No. ST/V003739/1. This work was supported by Fundação para a Ciência e a Tecnologia (FCT) through the research grants [UID/FIS/04434/2019], UIDB/04434/2020, UIDP/04434/2020, UIDB/00611/2020 and UIDP/00611/2020. This work was partly funded by a grant of the Austrian Science Fund (FWF): P 32958-N. J.C.R., C.J.D.B. and A.P.Y. gratefully acknowledge financial support from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (SUNMAG, grant agreement 759548). J.A. was supported by Centre National d’Etudes Spatiales (CNES). G.A., M.C., L.F., V.H., A.O. and L.R.V.V acknowledge support by the Research Council of Norway through its Centres of Excellence scheme, project number 262622. L.B., M.B., R.R. acknowledge State Secretariat for Education, Research, and Innovation (SERI), Canton Ticino and Swiss National Science Foundation (grants 200020_184952, 200021_175997, CRSII5_180238) for the financial support. R. Brajša and D. Sudar acknowledge the support by the Croatian Science Foundation under project 7549 ‘Millimeter and submillimeter observations of the solar chromosphere with ALMA’. The NSO is operated by the Association of Universities for Research in Astronomy, Inc., under cooperative agreement with the National Science Foundation. The work of A.B. was partially supported by the programme ‘Excellence Initiative – Research University’ for years 2020–2026 for University of Wrocław, project no. BPIDUB.4610.15.2021.KP.B. E.S.C. acknowledges financial support from the Spanish Ministry of Science and Innovation (MICINN) through the Spanish State Research Agency, under Severo Ochoa Centres of Excellence Programme 2020-2023 (CEX2019-000920-S). L.F. and N.L. would like to acknowledge support from UK Research and Innovation Science and Technology Facilities Council grants ST/L006200/1 and ST/T000422/1. J.F. acknowledges visiting facilities at Rosseland Centre for Solar Physics (University of Oslo), in 2019. P. Gömöry, A.K. and J.R. were supported by the Science Grant Agency project VEGA 2/0048/20. I. Kontogiannis is supported by KO 6283/2-1 of the Deutsche Forschungsgemeinschaft (DFG). C.J.N. is thankful to the Science and Technology Facilities Council (STFC), for support received through grant ST/T00021X/1, and ESA, for support as an ESA Research Fellow. K.P. was supported by the Hungarian National Research, Development and Innovation Fund (grants no. NKFI K-128384 and TKP2021-NKTA-64). P.J.A. Simões acknowledges support from CNPq (contract 307612/2019-8). J.T.B. acknowledges the funding received from the European Research Council (ERC) under de European Union’s Horizon 2020 research and innovation programme (ERC Advanced Grant Agreement No. 742265). M.V. is supported by VE 1112/1-1 of the Deutsche Forschungsgemeinschaft (DFG). L.Q.Z. acknowledges that this work was supported by the National Natural Science Foundation of China (Grant No. 11727805, No. 1210030348). F.Z. acknowledges that this work was supported by the Italian MIUR-PRIN grant 2017APKP7T and by the Università degli Studi di Catania (Piano per la Ricerca Università di Catania 2020-2022, Linea di intervento 2).

Pragmatic biomarkers of preclinical dementia would allow for easy and large-scale screening of risk in populations. Physical function measures like grip strength and gait speed are potential predictive biomarkers but their relationship with plasma markers of Alzheimer's Disease and neurodegeneration have not been elucidated.To examine association between physical function measures and plasma markers of Alzheimer's Disease (AD) and neurodegeneration.Cross-sectional and longitudinal analyses.Community-based cohort in the city of Framingham, Massachusetts.2336 participants of the Framingham Heart Study Offspring cohort with an average age of 61.Plasma Aβ40 and Aβ42 were measured in 1998-2001 (Exam-7) and plasma total tau measured 5 years later (Exam-8). Grip strength, fast walk speed and chair stand speed were measured at both exams. Quantification of Aβ isoforms in plasma was performed using INNO-BIA assays and plasma total-tau was measured using Quanterix Simoa HD-1 assay. Confounder-adjusted linear regression models examined associations between physical function and plasma markers, Results: Grip strength at Exam-7 was associated with plasma Aβ40 (β -0.006, p-value 0.032) at Exam-7 and plasma total-tau (β -0.010, p-value 0.001) at Exam-8. Grip strength and fast walk speed at Exam-8 were associated with plasma total-tau at Exam-8 (GS: β -0.009, p 0.0005; FWS: β -0.226, p-value0.0001). Chair stand speed was not associated with plasma markers; Aβ42 was not associated with function.Grip strength and fast walk speed are associated with plasma markers of neurodegeneration in dementia-free middle aged and older individuals. Both these measures could be used as potential screening tools for identifying individuals at a higher risk for AD and related dementias alongside other validated markers.

Additional file 1: Supplemental Figure 1. Flow diagram of participant inclusion and exclusion.