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Background Physical inactivity is a known risk factor for atrial fibrillation (AF). Wearable devices, such as smartwatches, present an opportunity to investigate the relation between daily step count and AF risk. Objective The objective of this study was to investigate the association between daily step count and the predicted 5-year risk of AF. Methods Participants from the electronic Framingham Heart Study used an Apple smartwatch. Individuals with diagnosed AF were excluded. Daily step count, watch wear time (hours and days), and self-reported physical activity data were collected. Individuals’ 5-year risk of AF was estimated, using the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE)–AF score. The relation between daily step count and predicted 5-year AF risk was examined via linear regression, adjusting for age, sex, and wear time. Secondary analyses examined effect modification by sex and obesity (BMI≥30 kg/m2), as well as the relation between self-reported physical activity and predicted 5-year AF risk. Results We examined 923 electronic Framingham Heart Study participants (age: mean 53, SD 9 years; female: n=563, 61%) who had a median daily step count of 7227 (IQR 5699-8970). Most participants (n=823, 89.2%) had a Conclusions Higher daily step counts were associated with a lower predicted 5-year risk of AF, and this relation was stronger in men and participants with obesity. The utility of a wearable daily step counter for AF risk reduction merits further investigation.

Background Post-operative pulmonary complications (PPC) can develop in up to 13% of patients undergoing neurosurgical procedures and may adversely affect clinical outcome. The use of intraoperative lung protective ventilation (LPV) strategies, usually including the use of a low Vt, low PEEP and low plateau pressure, seem to reduce the risk of PPC and are strongly recommended in almost all surgical procedures. Nonetheless, feasibility of LPV strategies in neurosurgical patients are still debated because the use of low Vt during LPV might result in hypercapnia with detrimental effects on cerebrovascular physiology. Aim of our study was to determine whether LPV strategies would be feasible compared with a control group in adult patients undergoing cranial or spinal surgery. Methods This single-centre, pilot randomized clinical trial was conducted at the University Hospital “Maggiore della Carità” (Novara, Italy). Adult patients undergoing major cerebral or spinal neurosurgical interventions with risk index for pulmonary post-operative complications > 2 and not expected to need post-operative intensive care unit (ICU) admission were considered eligible. Patients were randomly assigned to either LPV (Vt = 6 ml/kg of ideal body weight (IBW), respiratory rate initially set at 16 breaths/min, PEEP at 5 cmH2O and application of a recruitment manoeuvre (RM) immediately after intubation and at every disconnection from the ventilator) or control treatment (Vt = 10 ml/kg of IBW, respiratory rate initially set at 6–8 breaths/min, no PEEP and no RM). Primary outcomes of the study were intraoperative adverse events, the level of cerebral tension at dura opening and the intraoperative control of PaCO2. Secondary outcomes were the rate of pulmonary and extrapulmonary complications, the number of unplanned ICU admissions, ICU and hospital lengths of stay and mortality. Results A total of 60 patients, 30 for each group, were randomized. During brain surgery, the number of episodes of intraoperative hypercapnia and grade of cerebral tension were similar between patients randomized to receive control or LPV strategies. No difference in the rate of intraoperative adverse events was found between groups. The rate of postoperative pulmonary and extrapulmonary complications and major clinical outcomes were similar between groups. Conclusions LPV strategies in patients undergoing major neurosurgical intervention are feasible. Larger clinical trials are needed to assess their role in postoperative clinical outcome improvements. Trial registration registered on the Australian New Zealand Clinical Trial Registry (www.anzctr.org.au), registration number ACTRN12615000707561.

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.

Background All-cause mortality following atrial fibrillation (AF) has decreased over time. Data regarding temporal trends in causes of death among individuals with AF are scarce. The aim of our study was to analyze temporal trends in cause-specific mortality and predictors for cardiovascular (CVD) and non-CVD deaths among participants with incident AF in the Framingham Heart Study. Methods We categorized all newly diagnosed AF cases according to age at AF diagnosis ( Results We included 2125 newly diagnosed AF cases (mean age 75.5 years, 47.8% women). During a median follow-up of 4.8 years, 1657 individuals with AF died. There was evidence of decreasing CVD mortality among AF cases diagnosed trend < 0.001) but not ≥ 80 years (p = 0.76). Among the cases diagnosed Conclusions In this community-based cohort, CVD mortality among AF cases decreased over time. Most deaths in individuals with AF are no longer CVD-related, regardless of age at AF diagnosis.

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...

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.

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.

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.

Mitochondrial DNA copy number (mtDNA-CN) measured from blood specimens is a minimally invasive marker of mitochondrial function that exhibits both inter-individual and intercellular variation. To identify genes involved in regulating mitochondrial function, we performed a genome-wide association study (GWAS) in 465,809 White individuals from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (UKB). We identified 133 SNPs with statistically significant, independent effects associated with mtDNA-CN across 100 loci. A combination of fine-mapping, variant annotation, and co-localization analyses was used to prioritize genes within each of the 133 independent sites. Putative causal genes were enriched for known mitochondrial DNA depletion syndromes (p = 3.09 × 10–15) and the gene ontology (GO) terms for mtDNA metabolism (p = 1.43 × 10–8) and mtDNA replication (p = 1.2 × 10–7). A clustering approach leveraged pleiotropy between mtDNA-CN associated SNPs and 41 mtDNA-CN associated phenotypes to identify functional domains, revealing three distinct groups, including platelet activation, megakaryocyte proliferation, and mtDNA metabolism. Finally, using mitochondrial SNPs, we establish causal relationships between mitochondrial function and a variety of blood cell-related traits, kidney function, liver function and overall (p = 0.044) and non-cancer mortality (p = 6.56 × 10–4).

Background: Peripheral inflammation is associated with increased risk for dementia. Neutrophil to lymphocyte ratio (NLR), red cell distribution width (RDW), and mean platelet volume (MPV), are easily measured circulating blood cell phenotypes reflecting chronic peripheral inflammation, but their association with dementia status is unclear. Objective: We sought to investigate the cross-sectional association of these inflammatory measures with neuropsychological (NP) test performance, and brain magnetic resonance imaging (MRI) measures in the Framingham Heart Study (FHS) Offspring, Third-generation, and Omni cohorts. Methods: We identified FHS participants who attended an exam that included a complete blood cell count (CBC) and underwent NP testing (n = 3,396) or brain MRI (n = 2,770) within five years of blood draw. We investigated the association between NLR, RDW, and MPV and NP test performance and structural MRI-derived volumetric measurements using linear mixed effect models accounting for family relationships and adjusting for potential confounders. Results: Participants were on average 60 years old, 53% female, and about 80% attended some college. Higher NLR was significantly associated with poorer performance on visual memory, and visuospatial abilities, as well as with larger white matter hyperintensity volume. We also observed associations for higher RDW with poorer executive function and smaller total cerebral brain volume. Conclusion: Chronic peripheral inflammation as measured by NLR and RDW was associated with worse cognitive function, reduced brain volume, and greater microvascular disease in FHS participants. If confirmed in other samples, CBC may provide informative and cost-effective biomarkers of abnormal brain aging in the community.

Background Smartphone apps and mobile health devices offer innovative ways to collect longitudinal cardiovascular data. Randomized evidence regarding effective strategies to maintain longitudinal engagement is limited. Objective This study aimed to evaluate smartphone messaging interventions on remote transmission of blood pressure (BP) and heart rate (HR) data. Methods We conducted a 2 × 2 × 2 factorial blinded randomized trial with randomization implemented centrally to ensure allocation concealment. We invited participants from the Electronic Framingham Heart Study (eFHS), an e-cohort embedded in the FHS, and asked participants to measure their BP (Withings digital cuff) weekly and wear their smartwatch daily. We assessed 3 weekly notification strategies to promote adherence: personalized versus standard; weekend versus weekday; and morning versus evening. Personalized notifications included the participant’s name and were tailored to whether or not data from the prior week were transmitted to the research team. Intervention notification messages were delivered weekly automatically via the eFHS app. We assessed if participants transmitted at least one BP or HR measurement within 7 days of each notification after randomization. Outcomes were adherence to BP and HR transmission at 3 months (primary) and 6 months (secondary). Results Of the 791 FHS participants, 655 (82.8%) were eligible and randomized (mean age 53, SD 9 years; 392/655, 59.8% women; 596/655, 91% White). For the personalized versus standard notifications, 38.9% (126/324) versus 28.8% (94/327) participants sent BP data at 3 months (difference=10.1%, 95% CI 2.9%-17.4%; P=.006), but no significant differences were observed for HR data transmission (212/324, 65.4% vs 209/327, 63.9%; P=.69). Personalized notifications were associated with increased BP and HR data transmission versus standard at 6 months (BP: 107/291, 36.8% vs 66/295, 22.4%; difference=14.4%, 95% CI 7.1- 21.7%; P Conclusions Personalized notifications increased longitudinal adherence to BP and HR transmission from mobile and digital devices among eFHS participants. Our results suggest that personalized messaging is a powerful tool to promote adherence to mobile health systems in cardiovascular research. Trial Registration ClinicalTrials.gov NCT03516019; https://clinicaltrials.gov/ct2/show/NCT03516019

Background: Cholesterol has a pivotal role in human physiology, exerting both structural and functional activity. However, higher blood cholesterol levels, especially low-density lipoprotein cholesterol (LDL-C), are a major cardiovascular risk factor. Therefore, special attention has been given to the effect of dietary factors in influencing LDL-C blood levels. In particular, much research has focused on dairy products, since they are a main component of different dietary patterns worldwide. A large body of evidence did not support the hypothesis that dairy products significantly increase circulating LDL-C, but no definitive data are available. Hence, we aimed to assess the relationships among LDL-C, habitual dairy food intake and anthropometric variables in a cohort representative of the general population in a Mediterranean area. Methods: We evaluated 802 healthy adults included in the ABCD_2 (Alimentazione, Benessere Cardiovascolare e Diabete) study (ISRCTN15840340), a longitudinal observational single-center study of a cohort representative of the general population of Palermo, Sicily. The habitual intake of dairy products was assessed with a validated food frequency questionnaire, and LDL-C serum levels and several anthropometric parameters were measured. Results: The group with high LDL-C serum concentrations (≥130 vs. &lt, 130 mg/dL) exhibited higher age, body mass index (BMI), waist-to-hip ratio (WHR), body fat percentage, systolic and diastolic blood pressure, carotid intima-media thickness and glycated hemoglobin. The habitual diet was not different between the groups in terms of macronutrient, cholesterol, egg and dairy food intake, with the exception of the weekly number of portions of milk (higher in the low LDL-C group vs. the high LDL-C group) and ricotta cheese (higher in the high LDL-C group vs. the LDL-C group). No significant correlation was found between LDL-C blood levels and the habitual intake of dairy products or the dietary intake of cholesterol and fats. The multivariate regression analyses (R2 = 0.94) showed that LDL-C blood levels were significantly associated with the habitual intake of milk (p &lt, 0.005) and ricotta cheese (p &lt, 0.001) and with BMI (p &lt, 0.001). Conclusion: Our study reported that total dairy food consumption was not correlated with LDL-C blood levels. However, multivariate analyses showed an inverse association between serum LDL-C and milk intake as well as a positive association between ricotta cheese intake and LDL-C concentrations. More studies are needed to better characterize the relationship between dairy products and circulating LDL-C.

Background: One of the mechanisms suggested to link physical activity (PA) to favorable brain health is through stimulation of neural growth factors such as brain-derived neurotrophic factor (BDNF). Acute bouts of PA stimulate circulating BDNF levels. Objective: In this investigation, we assessed whether habitual, accelerometer-measured PA levels were related to circulating BDNF levels in a middle-aged cohort. Methods: In the Framingham Heart Study Third Generation cohort, 1,769 participants provided reliable accelerometry data and were not missing BDNF measurement or platelet counts. In a cross-sectional analysis, using multivariable regression, we related PA measures to serum BDNF levels, adjusting for age, sex, smoking status, platelet count, depression status, and accelerometer wear time. Results: Our study participants (mean age 47±9 years, 50.8% women) spent an average of 22.3 mins/day in moderate-to-vigorous (MV)PA. Most PA variables (steps, MVPA, light activity, and sedentary time) were not related to BDNF levels (p > 0.05). We observed a non-linear trend, where 15–50 mins/week vigorous activity was associated with lower BDNF compared to those with 0 min vigorous activity (β= –0.049±0.024, p = 0.05), but with no significant associations at lower or higher vigorous activity levels. In smokers, MVPA was also associated with lower BDNF levels (β= –0.216±0.079, p = 0.01). Conclusion: Our study reveals that circulating BDNF is not chronically elevated in individuals with higher levels of habitual PA in middle-aged adults from the community and may even be chronically suppressed with higher PA in subgroups, including current smokers. These results do not contradict previous studies demonstrating that circulating BDNF rises acutely after PA.

COVID-19 is a complex syndrome caused by SARS-Cov-2. It mainly affects the respiratory system, but it could cause serious harm during pregnancy. An increase in stillbirths and preterm births has been highlighted by many authors. Although WHO and Royal College of Obstetrics and Gynecology don't recommend elective cesarean section in women with confirmed infection, cesarean sections were performed by many clinicians. This short narrative review aims to analyze pieces of evidence found in literature about the effectiveness of cesarean section in preventing stillbirths in COVID-19 positive mothers.Studies included in the present review were retrieved searching MEDLINE (last access August 5th, 2021) with the following keywords: "pregnant woman with covid-19", "Caesarean section", "Ab-dominal Delivery" and "Stillbirth". Studies regarding the mode of delive-ry in pregnant women infected with COVID-19 and neonatal outcomes were included. Studies about biology, anesthesiology and necroscopy were excluded. Filters for "human" and "English" were applied.Searching MEDLINE, 24 references were found. Other 103 articles were found searching bibliography. Two references were excluded after duplicate removal, 77 references after the title screen and 27 after the abstract screen. The final number of references included was 23. Most of the included studies were case reports. Most of them were from China.Many authors highlighted the increased risk of fetal death in pregnancies complicated with SARS-Cov-2 infection, but it is not clear if Caesarean Section could reduce this risk. Pieces of evidence show that most clinicians choose to perform an elective cesarean section mostly because of maternal conditions or the fear of possible vertical transmission. Data show that mode of delivery doesn't affect the neonatal outcome and Caesarean Section doesn't reduce the positivity rate among neonates. Different opinions were found about the possible infection of amniotic fluid, cord blood and placenta. The risk of vertical transmission is considered moderate or low by most of the authors. Positivity to SARS-Cov-2 isn't an indication of elective cesarean section by itself, but this mode of delivery should be optioned in patients with other obstetrical indications or with severe conditions due to COVID. The recent increase in stillbirths could be related to the overall deterioration of maternal conditions.

Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease. Hundreds of genetic loci associated with age at menopause, combined with experimental evidence in mice, highlight mechanisms of reproductive ageing across the lifespan.

BACKGROUND: Older adults may have difficulty meeting the Physical Activity (PA) Guidelines. A favorable balance between PA and sedentary time (SED) is an important determinant of physical performance in older adults. Our objective was to explore associations of PA/SED with physical performance across mid-older age in adults without overt mobility disability. METHODS: Framingham Offspring Study participants free of mobility disability with accelerometry and physical performance data (gait speed, chair stand time, and handgrip strength), were studied in cross-sectional analysis (n = 1352). We regressed physical performance on PA level, measured using steps, moderate to vigorous (MV) PA and SED. We stratified by age groups, adjusted for covariates, and modelled MVPA and SED separately and together as predictors. RESULTS: Only 38% of adults 50–64 years and 15% of adults ≥75 years met the PA Guidelines (i.e., 150 min MVPA per week). Individuals achieving at least 5 min/day of MVPA had 0.062 ± 0.013 m/s greater gait speed and better chair stands and handgrip strength (in women) than those with < 5 min/day of MVPA (p < 0.01) across mid-older age. SED was associated with poorer performance on gait speed and chair stand tests, but results were not significant after adjusting for MVPA (p > 0.05). For adults ≥75 years, every 5000 more steps/day related to ~0.045 m/s greater gait speed (p = 0.006). CONCLUSION: Our cross-sectional study demonstrated that, across mid-older adulthood, MVPA related to better physical performance, but in adults ≥75 years, total steps walked associated with better gait speed. These data warrant future research on the impact of PA on physical performance and health outcomes in older age.

Aims. Circulating insulin-like growth factor- (IGF-) 1, vascular endothelial growth factor (VEGF), and brain-derived neurotrophic factor (BDNF) levels are often lower in individuals with diabetes mellitus (DM) and are important for repairing vascular and neuronal dysfunction. The purpose of this investigation was to determine the cross-sectional relations of physical activity to circulating concentrations of IGF-1, VEGF, and BDNF in individuals with and without DM.Methods. In 1730 participants from the Framingham Offspring Study examination cycle 7, including those with DM (n=179, mean age 64 years, 39% women) and without DM (n=1551, mean age 60 years, 46% women), we related self-reported physical activity variables to circulating concentrations of IGF-1, VEGF, and BDNF using linear multivariable regression models. We also tested for interactions by age. Participants with prevalent cardiovascular disease, stroke, and dementia or taking hormone replacement therapy were excluded.Results. In participants with DM, more ambulatory physical activity was associated with higher IGF-1 levels (β±standarderrorSE=0.22±0.08,p=0.009), and more total physical activity was related to higher BDNF levels (β±SE=0.18±0.08,p=0.035), but physical activity was not significantly related to circulating VEGF. In participants without DM, no associations were observed. Moreover, in the examination of interactions by age, the association of ambulatory physical activity with IGF-1 levels was only observed in older adults with DM (age≥60years,β±SE=0.23±0.11,p=0.042) but not in middle-aged adults with DM (age<60years,β±SE=0.06±0.13,p=0.645).Conclusion. Our results suggest that more physical activity is associated with higher circulating IGF-1 and BDNF in participants with DM. These results, dissecting interactions by both age and DM status, may also help to explain some of the inconsistent results in studies relating physical activity to growth and neurotrophic factors.

Inflammatory cytokines and chemokines related to the innate and adaptive immune system have been linked to neuroinflammation in Alzheimer’s Disease, dementia, and cognitive disorders. We examined the association of 11 plasma proteins (CD14, CD163, CD5L, CD56, CD40L, CXCL16, SDF1, DPP4, SGP130, sRAGE, and MPO) related to immune and inflammatory responses with measures of cognitive function, brain MRI and dementia risk. We identified Framingham Heart Study Offspring participants who underwent neuropsychological testing (n = 2358) or brain MRI (n = 2100) within five years of the seventh examination where a blood sample for quantifying the protein biomarkers was obtained; and who were followed for 10 years for incident all-cause dementia (n = 1616). We investigated the association of inflammatory biomarkers with neuropsychological test performance and brain MRI volumes using linear mixed effect models accounting for family relationships. We further used Cox proportional hazards models to examine the association with incident dementia. False discovery rate p-values were used to account for multiple testing. Participants included in the neuropsychological test and MRI samples were on average 61 years old and 54% female. Participants from the incident dementia sample (average 68 years old at baseline) included 124 participants with incident dementia. In addition to CD14, which has an established association, we found significant associations between higher levels of CD40L and myeloperoxidase (MPO) with executive dysfunction. Higher CD5L levels were significantly associated with smaller total brain volumes (TCBV), whereas higher levels of sRAGE were associated with larger TCBV. Associations persisted after adjustment for APOE ε4 carrier status and additional cardiovascular risk factors. None of the studied inflammatory biomarkers were significantly associated with risk of incident all-cause dementia. Higher circulating levels of soluble CD40L and MPO, markers of immune cell activation, were associated with poorer performance on neuropsychological tests, while higher CD5L, a key regulator of inflammation, was associated with smaller total brain volumes. Higher circulating soluble RAGE, a decoy receptor for the proinflammatory RAGE/AGE pathway, was associated with larger total brain volume. If confirmed in other studies, this data indicates the involvement of an activated immune system in abnormal brain aging.

Background When studied in community-based samples, the association of physical activity with blood pressure (BP) remains controversial and is perhaps dependent on the intensity of physical activity. Prior studies have not explored the association of smartwatch-measured physical activity with home BP. Objective We aimed to study the association of habitual physical activity with home BP. Methods Consenting electronic Framingham Heart Study (eFHS) participants were provided with a study smartwatch (Apple Watch Series 0) and Bluetooth-enabled home BP cuff. Participants were instructed to wear the watch daily and transmit BP values weekly. We measured habitual physical activity as the average daily step count determined by the smartwatch. We estimated the cross-sectional association between physical activity and average home BP using linear mixed effects models adjusting for age, sex, wear time, antihypertensive drug use, and familial structure. Results We studied 660 eFHS participants (mean age 53 years, SD 9 years; 387 [58.6%] women; 602 [91.2%] White) who wore the smartwatch 5 or more hours per day for 30 or more days and transmitted three or more BP readings. The mean daily step count was 7595 (SD 2718). The mean home systolic and diastolic BP (mmHg) were 122 (SD 12) and 76 (SD 8). Every 1000 increase in the step count was associated with a 0.49 mmHg lower home systolic BP (P=.004) and 0.36 mmHg lower home diastolic BP (P=.003). The association, however, was attenuated and became statistically nonsignificant with further adjustment for BMI. Conclusions In this community-based sample of adults, higher daily habitual physical activity measured by a smartwatch was associated with a moderate, but statistically significant, reduction in home BP. Differences in BMI among study participants accounted for the majority of the observed association.

Background Frailty occurs in 10-15% of community-living older adults and inflammation is a key determinant of frailty. Though diet is a modulator of inflammation, there are few prospective studies elucidating the role of diet-associated inflammation on frailty. Objective To determine whether a pro-inflammatory diet was associated with increased odds of frailty in adults from the Framingham Heart Study (FHS). Design and methods This study is nested in a prospective cohort that included individuals without frailty. Diet was assessed in 1998-2001 using a valid food frequency questionnaire (FFQ) and frailty was measured in 2011-2014. FFQ-derived energy-adjusted dietary inflammatory index (E-DII®) scores were computed, with higher E-DII scores indicating a more pro-inflammatory diet. Frailty was defined as fulfilling ≥3 of 5 Fried Phenotype criteria. Information on potential mediators, serum interleukin-6 and C-reactive protein was obtained in 1998-2001. Logistic regression estimated odds ratios (OR) and 95% confidence intervals (95% CI) for E-DII (as continuous and in quartiles) and frailty onset adjusting for relevant confounders. Results Of 1,701 individuals without frailty at baseline (mean age = 58 years, SD = 8, range: 33-81; 55% female), 224 developed frailty (13% incidence) over ∼12 years. Mean E-DII score was -1.95 (SD = 2.20; range: -6.71 to +5.40). After adjusting for relevant confounders, a one-unit higher E-DII score was associated with 16% increased odds of developing frailty (95% CI = 1.07, 1.25). In categorical analyses, participants in the highest (pro-inflammatory) vs. lowest quartile of E-DII had >2-fold increased odds of frailty (ORquartile4vs.1 = 2.22, 95% CI = 1.37, 3.60, Ptrend Conclusions In this cohort of middle-aged and older adults, a pro-inflammatory diet was associated with increased odds of frailty over ∼12 years of follow-up. Trials designed to increase consumption of anti-inflammatory foods for frailty prevention are warranted.Clinical registry number and website: Not applicable.

Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p = 4 × 10−17), arthritis (GDF5 p = 4 × 10−13), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing., Muscle weakness has been associated with morbidity and mortality in older people. Here, the authors have investigated this trait further by performing a genome-wide meta-analysis of grip strength and Mendelian randomization to discover causal relationships between muscle weakness and other diseases.

BackgroundeCohort studies offer an efficient approach for data collection. However, eCohort studies are challenged by volunteer bias and low adherence. We designed an eCohort embedded in the Framingham Heart Study (eFHS) to address these challenges and to compare the digital data to traditional data collection.ObjectiveThe aim of this study was to evaluate adherence of the eFHS app-based surveys deployed at baseline (time of enrollment in the eCohort) and every 3 months up to 1 year, and to compare baseline digital surveys with surveys collected at the research center.MethodsWe defined adherence rates as the proportion of participants who completed at least one survey at a given 3-month period and computed adherence rates for each 3-month period. To evaluate agreement, we compared several baseline measures obtained in the eFHS app survey to those obtained at the in-person research center exam using the concordance correlation coefficient (CCC).ResultsAmong the 1948 eFHS participants (mean age 53, SD 9 years; 57% women), we found high adherence to baseline surveys (89%) and a decrease in adherence over time (58% at 3 months, 52% at 6 months, 41% at 9 months, and 40% at 12 months). eFHS participants who returned surveys were more likely to be women (adjusted odds ratio [aOR] 1.58, 95% CI 1.18-2.11) and less likely to be smokers (aOR 0.53, 95% CI 0.32-0.90). Compared to in-person exam data, we observed moderate agreement for baseline app-based surveys of the Physical Activity Index (mean difference 2.27, CCC=0.56), and high agreement for average drinks per week (mean difference 0.54, CCC=0.82) and depressive symptoms scores (mean difference 0.03, CCC=0.77).ConclusionsWe observed that eFHS participants had a high survey return at baseline and each 3-month survey period over the 12 months of follow up. We observed moderate to high agreement between digital and research center measures for several types of surveys, including physical activity, depressive symptoms, and alcohol use. Thus, this digital data collection mechanism is a promising tool to collect data related to cardiovascular disease and its risk factors.

Handgrip strength is a widely used measure of muscle strength and a predictor of a range of morbidities including cardiovascular diseases and all-cause mortality. Previous genome-wide association studies of handgrip strength have focused on common variants primarily in persons of European descent. We aimed to identify rare and ancestry-specific genetic variants associated with handgrip strength by conducting whole-genome sequence association analyses using 13,552 participants from six studies representing diverse population groups from the Trans-Omics in Precision Medicine (TOPMed) Program. By leveraging multiple handgrip strength measures performed in study participants over time, we increased our effective sample size by 7–12%. Single-variant analyses identified ten handgrip strength loci among African-Americans: four rare variants, five low-frequency variants, and one common variant. One significant and four suggestive genes were identified associated with handgrip strength when aggregating rare and functional variants; all associations were ancestry-specific. We additionally leveraged the different ancestries available in the UK Biobank to further explore the ancestry-specific association signals from the single-variant association analyses. In conclusion, our study identified 11 new loci associated with handgrip strength with rare and/or ancestry-specific genetic variations, highlighting the added value of whole-genome sequencing in diverse samples. Several of the associations identified using single-variant or aggregate analyses lie in genes with a function relevant to the brain or muscle or were reported to be associated with muscle or age-related traits. Further studies in samples with sequence data and diverse ancestries are needed to confirm these findings.

The aim of the present study was to analyze the association among systemic sclerosis (SSc), periodontitis (PT), we also evaluated the impact of PT and SSc on vitamin D levels. Moreover, we tested the association with potential confounders. A total of 38 patients with SSc, 40 subjects with PT, 41 subjects with both PT and SSc, and 41 healthy controls were included in the study. The median vitamin D levels in PT subject were 19.1 (17.6–26.8) ng/mL, while SSc + PT group had vitamin d levels of 15.9 (14.7–16.9) ng/mL, significantly lower with respect to SSc patients (21.1 (15.4–22.9) ng/mL) and to healthy subjects (30.5 (28.8–32.3) ng/mL) (p &lt, 0.001). In all subjects, vitamin D was negatively associated with c-reactive protein (CRP) (p &lt, 0.001) and with probing depth (PD), clinical attachment level (CAL), bleeding on probing (BOP), and plaque score (PI) (p &lt, 0.001 for all parameters) and positively related to the number of teeth (p &lt, 0.001). Moreover, univariate regression analysis demonstrated an association among high low-density lipoproteins (LDL) cholesterol (p = 0.021), CRP (p = 0.014), and PT (p &lt, 0.001) and reduced levels of vitamin D. The multivariate regression analysis showed that PT (p = 0.011) and CRP (p = 0.031) were both predictors of vitamin D levels. Subjects with PT and SSc plus PT had significant lower vitamin D values with respect to SSc and to healthy subjects. In addition, PT seems negatively associated with levels of vitamin D in all analyzed patients.

STUDY QUESTIONDoes the expansion of genome-wide association studies (GWAS) to a broader range of ancestries improve the ability to identify and generalise variants associated with age at menarche (AAM) in European populations to a wider range of world populations?SUMMARY ANSWERBy including women with diverse and predominantly non-European ancestry in a large-scale meta-analysis of AAM with half of the women being of African ancestry, we identified a new locus associated with AAM in African-ancestry participants, and generalised loci from GWAS of European ancestry individuals.WHAT IS KNOWN ALREADYAAM is a highly polygenic puberty trait associated with various diseases later in life. Both AAM and diseases associated with puberty timing vary by race or ethnicity. The majority of GWAS of AAM have been performed in European ancestry women.STUDY DESIGN, SIZE, DURATIONWe analysed a total of 38 546 women who did not have predominantly European ancestry backgrounds: 25 149 women from seven studies from the ReproGen Consortium and 13 397 women from the UK Biobank. In addition, we used an independent sample of 5148 African-ancestry women from the Southern Community Cohort Study (SCCS) for replication.PARTICIPANTS/MATERIALS, SETTING, METHODSEach AAM GWAS was performed by study and ancestry or ethnic group using linear regression models adjusted for birth year and study-specific covariates. ReproGen and UK Biobank results were meta-analysed using an inverse variance-weighted average method. A trans-ethnic meta-analysis was also carried out to assess heterogeneity due to different ancestry.MAIN RESULTS AND THE ROLE OF CHANCEWe observed consistent direction and effect sizes between our meta-analysis and the largest GWAS conducted in European or Asian ancestry women. We validated four AAM loci (1p31, 6q16, 6q22 and 9q31) with common genetic variants at P LARGE SCALE DATAN/ALIMITATIONS, REASONS FOR CAUTIONExtreme AAM (18 years) were excluded from analysis. Women may not fully recall their AAM as most of the studies were conducted many years later. Further studies in women with diverse and predominantly non-European ancestry are needed to confirm and extend these findings, but the availability of such replication samples is limited.WIDER IMPLICATIONS OF THE FINDINGSExpanding association studies to a broader range of ancestries or ethnicities may improve the identification of new genetic variants associated with complex diseases or traits and the generalisation of variants from European-ancestry studies to a wider range of world populations.STUDY FUNDING/COMPETING INTEREST(S)Funding was provided by CHARGE Consortium grant R01HL105756-07: Gene Discovery For CVD and Aging Phenotypes and by the NIH grant U24AG051129 awarded by the National Institute on Aging (NIA). The authors have no conflict of interest to declare.

Rationale: A sedentary lifestyle is associated with increased risk for cardiovascular disease (CVD). Smartwatches enable accurate daily activity monitoring for physical activity measurement and intervention. Few studies, however, have examined physical activity measures from smartwatches in relation to traditional risk factors associated with future risk for CVD. Objective: To investigate the association of habitual physical activity measured by smartwatch with predicted CVD risk in adults. Methods and Results: We enrolled consenting FHS (Framingham Heart Study) participants in an ongoing eFHS (electronic Framingham Heart Study) at the time of their FHS research center examination. We provided participants with a smartwatch (Apple Watch Series 0) and instructed them to wear it daily, which measured their habitual physical activity as the average daily step count. We estimated the 10-year predicted risk of CVD using the American College of Cardiology/American Heart Association 2013 pooled cohort risk equation. We estimated the association between physical activity and predicted risk of CVD using linear mixed effects models adjusting for age, sex, wear time, and familial structure. Our study included 903 eFHS participants (mean age 53±9 years, 61% women, 9% non-White) who wore the smartwatch ≥5 hours per day for ≥30 days. Median daily step count was similar among men (7202 with interquartile range 3619) and women (7260 with interquartile range 3068; P =0.52). Average 10-year predicted CVD risk was 4.5% (interquartile range, 6.1%) for men and 1.2% (interquartile range, 2.2%) for women ( P =1.3×10 −26 ). Every 1000 steps higher habitual physical activity was associated with 0.18% lower predicted CVD risk ( P =3.2×10 −4 ). The association was attenuated but remained significant after further adjustment for body mass index ( P =0.01). Conclusions: In this community-based sample of adults, higher daily physical activity measured by a study smartwatch was associated with lower predicted risk of CVD. Future research should examine the longitudinal association of prospectively measured daily activity and incident CVD.

Summary MicroRNAs (miRNAs) regulate gene expression with emerging data suggesting miRNAs play a role in skeletal muscle biology. We sought to examine the association of miRNAs with grip strength in a community‐based sample. Framingham Heart Study Offspring and Generation 3 participants (n = 5668 54% women, mean age 55 years, range 24, 90 years) underwent grip strength measurement and miRNA profiling using whole blood from fasting morning samples. Linear mixed‐effects regression modeling of grip strength (kg) versus continuous miRNA ‘Cq’ values and versus binary miRNA expression was performed. We conducted an integrative miRNA–mRNA coexpression analysis and examined the enrichment of biologic pathways for the top miRNAs associated with grip strength. Grip strength was lower in women than in men and declined with age with a mean 44.7 (10.0) kg in men and 26.5 (6.3) kg in women. Among 299 miRNAs interrogated for association with grip strength, 93 (31%) had FDR q value

DNA methylation (DNAm) has a well-established association with age in many tissues, including peripheral blood mononuclear cells (PBMCs). Compared to DNAm, the closely related epigenetic modification known as DNA hydroxymethylation (DNAhm) was much more recently discovered in mammals. Preliminary investigations have observed a positive correlation between gene body DNAhm and cis-gene expression. While some of these studies have observed an association between age and global DNAhm, none have investigated region-specific age-related DNAhm in human blood samples. In this study, we investigated DNAhm and gene expression in PBMCs of 10 young and 10 old, healthy female volunteers. Thousands of regions were differentially hydroxymethylated in the old vs. young individuals in gene bodies, exonic regions, enhancers, and promoters. Consistent with previous work, we observed directional consistency between age-related differences in DNAhm and gene expression. Further, age-related DNAhm and genes with high levels of DNAhm were enriched for immune system processes which may support a role of age-related DNAhm in immunosenescence.

We hypothesize that mechanisms associated with extended reproductive age may overlap with mechanisms for the selection of genetic variants that slow aging and decrease risk for age-related diseases. Therefore, the goal of this analysis is to search for genetic variants associated with delayed age of menopause (AOM) among women in a study of familial longevity.We performed a meta-analysis of genome-wide association studies for AOM in 1,286 women in the Long Life Family Study (LLFS) and 3,151 women in the Health and Retirement Study, and then sought replication in the Framingham Heart Study (FHS). We used Cox proportional hazard regression of AOM to account for censoring, with a robust variance estimator to adjust for within familial relations.In the meta-analysis, a single nucleotide polymorphism (SNP) previously associated with AOM reached genome-wide significance (rs16991615; HR = 0.74, P = 6.99 × 10). A total of 35 variants reached10 level of significance and replicated in the FHS and in a 2015 large meta-analysis (ReproGen Consortium). We also identified several novel SNPs associated with AOM including rs3094005: MICB, rs13196892: TXNDC5 | MUTED, rs72774935: SSBP2 | ATG10, rs9447453: COL12A1, rs114298934: FHL2 | NCK2, rs6467223: TNPO3, rs9666274 and rs10766593: NAV2, and rs7281846: HSPA13.This work indicates novel associations and replicates known associations between genetic variants and AOM. A number of these associations make sense for their roles in aging.Supplemental Digital Content 1, http://links.lww.com/MENO/A420.

PANDAS are known as the spectrum of autoimmune pathologies related to a previous or current infection by group A beta-hemolytic streptococcus (SBEGA), dealing with several neuropsychiatric manifestations that mainly affect pediatric age. The main features consist of behavioral disease or movement disease characterized by acute-onset, presenting especially through infant period or adolescence. Specific manifestations, occurring during the progression of the disease, are the presence of otorhinolaryngologic symptoms (ENT) and orofacial movement disorders associated with temporomandibular joint pain.We enrolled 130 children (5-15 years) with a clinical diagnosis of PANDAS between 2012 and 2018. Participants were assessed using ENT specific parameters, PSG to examine respiratory disorders and conventional audiological evaluation. Descriptive and comparative statistical analyses were performed with a control group of 51 healthy patients.The prevalence of ENT symptoms associated was significantly detected in 88 patients of 130 in Group A (relative frequency (%) 67.6; p=0.041) and in 51 patients of 130 in the control Group B (relative frequency (%) 39.2; p=0.063). In relation to prevalence of SDB, 54 subjects have presented nocturnal respiratory obstructive symptoms from mild to severe (relative frequency (%) 61.3; p=0.033) vs. 20 patients of Group B (relative frequency (%) 39.2; p=0.055). The obstructive severity average type was correlated to the consensual adenotonsillar development (size 3-4), (relative frequency (%) 45.4; p=0.047). The audiological deficits found were mostly of transmissive type with OME correlated and linked to the presence of occasional episodes of AOM. The four PANDAS patients who presented orobuccal dystonia (relative frequency (%) 4.54; p=0.091) achieved an improvement of the algic symptoms through the exercises of self-rehabilitation.Findings from our study show that respiratory diseases, characterizing a group of patients with pandas, are the direct consequences of the malformed or hypertrophic condition and suggesting in these conditions surgical therapy as an approaching tool.

Birth weight (BW) variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. These associations have been proposed to reflect the lifelong consequences of an adverse intrauterine environment. In earlier work, we demonstrated that much of the negative correlation between BW and adult cardio-metabolic traits could instead be attributable to shared genetic effects. However, that work and other previous studies did not systematically distinguish the direct effects of an individual’s own genotype on BW and subsequent disease risk from indirect effects of their mother’s correlated genotype, mediated by the intrauterine environment. Here, we describe expanded genome-wide association analyses of own BW (n=321,223) and offspring BW (n=230,069 mothers), which identified 278 independent association signals influencing BW (214 novel). We used structural equation modelling to decompose the contributions of direct fetal and indirect maternal genetic influences on BW, implicating fetal- and maternal-specific mechanisms. We used Mendelian randomization to explore the causal relationships between factors influencing BW through fetal or maternal routes, for example, glycemic traits and blood pressure. Direct fetal genotype effects dominate the shared genetic contribution to the association between lower BW and higher type 2 diabetes risk, whereas the relationship between lower BW and higher later blood pressure (BP) is driven by a combination of indirect maternal and direct fetal genetic effects: indirect effects of maternal BP-raising genotypes act to reduce offspring BW, but only direct fetal genotype effects (once inherited) increase the offspring’s later BP. Instrumental variable analysis using maternal BW-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring BP. In successfully separating fetal from maternal genetic effects, this work represents an important advance in genetic studies of perinatal outcomes, and shows that the association between lower BW and higher adult BP is attributable to genetic effects, and not to intrauterine programming.

Radium 223 dichloride (Ra223) is the only targeted alpha therapy able to extend survival in patients with bone metastases from prostate cancer. Mechanism of action and data currently available focused mainly on osteoblastic metastases from prostate cancer. Phase 1 and 2 trials documented a clinical efficacy also in breast cancer patients with predominately bone disease, highlighting a reduction in alkaline phosphatase and other bone biomarkers. In our institution, a patient with breast cancer affected by osteolytic metastases was treated with off-label use of Ra223. Our patient had a good treatment compliance and up to now she has not been revealed the presence of SSE or hematological complications. Our preliminary experience shows that Ra223 may play a critical role to bone metastates in patients with breast cancer.

Genome-wide association studies of birth weight have focused on fetal genetics, whereas relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86 577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother–child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P < 5 Â 10 À8 . In SEM analyses, at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration. The identified associations indicate that genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth. Further characterization of these associations in mechanistic and causal analyses will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights., Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe, 628