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Abstract The role of rare non-coding variation in complex human phenotypes is still largely unknown. To elucidate the impact of rare variants in regulatory elements, we performed a whole-genome sequencing association analysis for height using 333,100 individuals from three datasets: UK Biobank (N = 200,003), TOPMed (N = 87,652) and All of Us (N = 45,445). We performed rare (

Background Sex differences in obesity and fat distribution may in part explain differences in cardiovascular risk in men versus women. We sought to examine sex differences in the associations of obesity and adiposity measures with cardiovascular disease–related protein biomarkers. Methods and Results In a cross‐sectional observational cohort study, we examined whether the association of obesity (body mass index [BMI] and waist circumference) and adiposity measures (visceral adipose tissue) with biomarkers demonstrates effect modification by sex using multiplicative interaction terms in multivariable linear regression models. Among 3143 participants (mean age, 50 years; 49% women), sex modified the association of BMI, waist circumference, and visceral adipose tissue with cardiovascular disease–related protein biomarkers (7 for BMI, 3 for waist circumference, and 23 for visceral adipose tissue, false discovery rate [FDR]‐qint

Abstract Background Global life expectancy is rising, with the 60 + age group projected to hit 2 billion by 2050. Aging impacts the immune system. A notable marker of immune system aging is the presence of Aging-Related Immune Cell Phenotypes (ARIPs). Despite their importance, links between immune cell phenotypes including ARIPs and mortality are underexplored. We prospectively investigated 16 different immune cell phenotypes using flow cytometry and IL-6 in relation to survival outcome among dementia-free Framingham Heart Study (FHS) offspring cohort participants who attended the seventh exam (1998–2001). Results Among 996 participants (mean age 62 years, range 40 to 88 years, 52% female), the 19-year survival rate was 65%. Adjusting for age, sex, and cytomegalovirus (CMV) serostatus, higher CD4/CD8 and Tc17/CD8 + Treg ratios were significantly associated with lower all-cause mortality (HR: 0.86 [0.76–0.96], 0.84 [0.74–0.94], respectively), while higher CD8 regulatory cell levels (CD8 + CD25 + FoxP3 +) were associated with increased all-cause mortality risk (HR = 1.17, [1.03–1.32]). Elevated IL-6 levels correlated with higher all-cause, cardiovascular, and non-cardiovascular mortality (HR = 1.43 [1.26–1.62], 1.70 [1.31–2.21], and 1.36 [1.18–1.57], respectively). However, after adjusting for cardiovascular risk factors and prevalent cancer alongside age, sex, and CMV, immune cell phenotypes were no longer associated with mortality in our cohort. Nonetheless, IL-6 remained significantly associated with all-cause and cardiovascular mortality (HRs: 1.3 [1.13–1.49], 1.5 [1.12–1.99], respectively). Conclusions In 19-year follow-up, higher Tc17/CD8 + Treg and CD4/CD8 ratios were associated with lower all-cause mortality, while the CD8 + CD25 + FoxP3 + (CD8 + Treg) phenotype showed increased risk. Elevated IL-6 levels consistently correlated with amplified mortality risks. These findings highlight the links between immune phenotypes and mortality, suggesting implications for future research and clinical considerations.

Background: Prolonged preoperative fasting may worsen postoperative outcomes. Cardiac surgery has higher perioperative risk, and longer fasting periods may be not well-tolerated. We analysed the postoperative metabolic and hemodynamic variables in patients undergoing elective coronary artery bypass grafting (CABG) according to their morning or afternoon schedule. Methods: Single-centre retrospective study at University teaching hospital (1-year data collection from electronic medical records). Using a mixed-effects linear regression model adjusted for several covariates, we compared metabolic (lactatemia, pH, and base deficit [BD]) and haemodynamic values (patients on vasoactive support, and vasoactive inotropic score [VIS]) at 7 prespecified time-points (admission to intensive care, and 1st, 3rd, 6th, 12th, 18th, and 24th postoperative hours). Results: 339 patients (n = 176 morning, n = 163 afternoon) were included. Arterial lactatemia and BD were similar (overall P = 0.11 and P = 0.84, respectively), while pH was significantly lower in the morning group (overall P < 0.05; mean difference −0.01). Postoperative urine output, fluid balance, mean arterial pressure, and central venous pressure were similar (P = 0.59, P = 0.96, P = 0.58 and P = 0.53, respectively). A subgroup analysis of patients with diabetes (n = 54 morning, n = 45 afternoon) confirmed the same findings. The VIS values and the proportion of patients on vasoactive support was higher in the morning cases at the 18th (P = 0.002 and p=0.04, respectively) and 24th postoperative hours (P = 0.003 and P = 0.04, respectively). Mean intensive care length of stay was 1.94 ± 1.36 days versus 2.48 ± 2.72 days for the afternoon and morning cases, respectively (P = 0.02). Conclusions: Patients undergoing elective CABG showed similar or better metabolic and hemodynamic profiles when scheduled for afternoon surgery.

BackgroundResting heart rate (HR) and routine physical activity are associated with cardiorespiratory fitness levels. Commercial smartwatches permit remote HR monitoring and step count recording in real-world settings over long periods of time, but the relationship between smartwatch-measured HR and daily steps to cardiorespiratory fitness remains incompletely characterized in the community. ObjectiveThis study aimed to examine the association of nonactive HR and daily steps measured by a smartwatch with a multidimensional fitness assessment via cardiopulmonary exercise testing (CPET) among participants in the electronic Framingham Heart Study. MethodsElectronic Framingham Heart Study participants were enrolled in a research examination (2016-2019) and provided with a study smartwatch that collected longitudinal HR and physical activity data for up to 3 years. At the same examination, the participants underwent CPET on a cycle ergometer. Multivariable linear models were used to test the association of CPET indices with nonactive HR and daily steps from the smartwatch. ResultsWe included 662 participants (mean age 53, SD 9 years; n=391, 59% women, n=599, 91% White; mean nonactive HR 73, SD 6 beats per minute) with a median of 1836 (IQR 889-3559) HR records and a median of 128 (IQR 65-227) watch-wearing days for each individual. In multivariable-adjusted models, lower nonactive HR and higher daily steps were associated with higher peak oxygen uptake (VO2), % predicted peak VO2, and VO2 at the ventilatory anaerobic threshold, with false discovery rate (FDR)–adjusted P values

Background Life's Essential 8 (LE8) is an enhanced metric for cardiovascular health. The interrelations among LE8, biomarkers of aging, and disease risks are unclear. Methods and Results LE8 score was calculated for 5682 Framingham Heart Study participants. We implemented 4 DNA methylation‐based epigenetic age biomarkers, with older epigenetic age hypothesized to represent faster biological aging, and examined whether these biomarkers mediated the associations between the LE8 score and cardiovascular disease (CVD), CVD‐specific mortality, and all‐cause mortality. We found that a 1 SD increase in the LE8 score was associated with a 35% (95% CI, 27–41; P=1.8E‐15) lower risk of incident CVD, a 36% (95% CI, 24–47; P=7E‐7) lower risk of CVD‐specific mortality, and a 29% (95% CI, 22–35; P=7E‐15) lower risk of all‐cause mortality. These associations were partly mediated by epigenetic age biomarkers, particularly the GrimAge and the DunedinPACE scores. The potential mediation effects by epigenetic age biomarkers tended to be more profound in participants with higher genetic risk for older epigenetic age, compared with those with lower genetic risk. For example, in participants with higher GrimAge polygenic scores (greater than median), the mean proportion of mediation was 39%, 39%, and 78% for the association of the LE8 score with incident CVD, CVD‐specific mortality, and all‐cause mortality, respectively. No significant mediation was observed in participants with lower GrimAge polygenic score. Conclusions DNA methylation‐based epigenetic age scores mediate the associations between the LE8 score and incident CVD, CVD‐specific mortality, and all‐cause mortality, particularly in individuals with higher genetic predisposition for older epigenetic age.

BackgroundStudies evaluating the usability of mobile-phone assessments in older adults are limited. ObjectiveThis study aims to identify design-based barriers and facilitators to mobile app survey completion among 2 samples of older adults; those in the Framingham Heart Study and a more diverse sample from a hospital-based setting. MethodsWe used mixed methods to identify challenging and beneficial features of the mobile app in participants from the electronic Framingham Heart Study (n=15; mean age of 72 years; 6/15, 40% women; 15/15, 100% non-Hispanic and White) and among participants recruited from a hospital-based setting (n=15; mean age of 71 years; 7/15, 47% women; 3/15, 20% Hispanic; and 8/15, 53% non-White). A variety of app-based measures with different response formats were tested, including self-reported surveys, pictorial assessments (to indicate body pain sites), and cognitive testing tasks (eg, Trail Making Test and Stroop). Participants completed each measure using a think-aloud protocol, while being audio- and video-recorded with a qualitative interview conducted at the end of the session. Recordings were coded for participant usability errors by 2 pairs of coders. Participants completed the Mobile App Rating Scale to assess the app (response range 1=inadequate to 5=excellent). ResultsIn electronic Framingham Heart Study participants, the average total Mobile App Rating Scale score was 7.6 (SD 1.1), with no significant differences in the hospital-based sample. In general, participants were pleased with the app and found it easy to use. A large minority had at least 1 navigational issue, most committed only once. Most older adults did not have difficulty completing the self-reported multiple-choice measures unless it included lengthy instructions but participants had usability issues with the Stroop and Trail Making Test. ConclusionsOur methods and results help guide app development and app-based survey construction for older adults, while also giving consideration to sociodemographic differences.

BackgroundShort-term blood pressure variability (BPV) is associated with arterial stiffness in patients with hypertension. Few studies have examined associations between arterial stiffness and digital home BPV over a mid- to long-term time span, irrespective of underlying hypertension. ObjectiveThis study aims to investigate if arterial stiffness traits were associated with subsequent mid- to long-term home BPV in the electronic Framingham Heart Study (eFHS). We hypothesized that higher arterial stiffness was associated with higher home BPV over up to 1-year follow-up. MethodsAt a Framingham Heart Study research examination (2016-2019), participants underwent arterial tonometry to acquire measures of arterial stiffness (carotid-femoral pulse wave velocity [CFPWV]; forward pressure wave amplitude [FWA]) and wave reflection (reflection coefficient [RC]). Participants who agreed to enroll in eFHS were provided with a digital blood pressure (BP) cuff to measure home BP weekly over up to 1-year follow-up. Participants with less than 3 weeks of BP readings were excluded. Linear regression models were used to examine associations of arterial measures with average real variability (ARV) of week-to-week home systolic (SBP) and diastolic (DBP) BP adjusting for important covariates. We obtained ARV as an average of the absolute differences of consecutive home BP measurements. ARV considers not only the dispersion of the BP readings around the mean but also the order of BP readings. In addition, ARV is more sensitive to measurement-to-measurement BPV compared with traditional BPV measures. ResultsAmong 857 eFHS participants (mean age 54, SD 9 years; 508/857, 59% women; mean SBP/DBP 119/76 mm Hg; 405/857, 47% hypertension), 1 SD increment in FWA was associated with 0.16 (95% CI 0.09-0.23) SD increments in ARV of home SBP and 0.08 (95% CI 0.01-0.15) SD increments in ARV of home DBP; 1 SD increment in RC was associated with 0.14 (95% CI 0.07-0.22) SD increments in ARV of home SBP and 0.11 (95% CI 0.04-0.19) SD increments in ARV of home DBP. After adjusting for important covariates, there was no significant association between CFPWV and ARV of home SBP, and similarly, no significant association existed between CFPWV and ARV of home DBP (P>.05). ConclusionsIn eFHS, higher FWA and RC were associated with higher mid- to long-term ARV of week-to-week home SBP and DBP over 1-year follow-up in individuals across the BP spectrum. Our findings suggest that higher aortic stiffness and wave reflection are associated with higher week-to-week variation of BP in a home-based setting over a mid- to long-term time span.

Two atypical cases of infectious mononucleosis in two teenagers with initially negative serology and non-evocative blood examinations are reported. The first patient had recently traveled to Africa, and Epstein-Barr virus negative serology led us to make many extensive investigations. The second patient complained of asthenia for a month, and PET/CT was performed to suspicion of lymphoma. PET scan revealed hypermetabolic lymph nodes in the supradiaphragmatic and subdiaphragmatic stations, along with18F-FDG uptake in the spleen and pharynx, raising more suspicion of lymphoma. Fortunately, Epstein-Barr virus DNA testing was performed and turned positive in both cases, and Epstein-Barr virus serology subsequently became positive. Diagnosing EBV infection can be challenging in rare cases, as EBV-specific serology may be negative in the early stages and confounding factors may be present. Therefore, Epstein-Barr virus DNA testing should be considered early in the diagnostic algorithm to prevent unnecessary investigations in similar cases.

Within the coronae of stars, abundances of those elements with low first ionization potential (FIP) often differ from their photospheric values. The coronae of the Sun and solar-type stars mostly show enhancements of low-FIP elements (the FIP effect) while more active stars such as M dwarfs have coronae generally characterized by the inverse-FIP (I-FIP) effect. Highly localized regions of I-FIP effect solar plasma have been observed by Hinode's EUV Imaging Spectrometer in a number of highly complex active regions (ARs), usually around strong light bridges of the umbrae of coalescing/merging sunspots. These observations can be interpreted in the context of the ponderomotive force fractionation model, which predicts that plasma with I-FIP effect composition is created by the refraction of waves coming from below the plasma fractionation region in the chromosphere. A plausible source of these waves is thought to be reconnection in the (high-plasma -β ) subchromospheric magnetic field. In this study, we use the 3D visualization technique of Chintzoglou & Zhang combined with observations of localized I-FIP effect in the corona of AR 11504 to identify potential sites of such reconnection and its possible consequences in the solar atmosphere. We found subtle signatures of episodic heating and reconnection outflows in the expected places, in between magnetic flux tubes forming a light bridge, within the photosphere of the AR. Furthermore, on either side of the light bridge, we observed small antiparallel horizontal magnetic field components, supporting the possibility of reconnection occurring where we observe I-FIP plasma. When taken together with the I-FIP effect observations, these subtle signatures provide a compelling case for indirect observational evidence of reconnection below the fractionation layer of the chromosphere, however direct evidence remains elusive.

The composition of the solar corona differs from that of the photosphere, with the plasma thought to fractionate in the solar chromosphere according to the first ionization potential (FIP) of the different elements. This produces a FIP bias, wherein elements with a low FIP are preferentially enhanced in the corona compared to their photospheric abundance, but direct observations of this process remain elusive. Here, we use a series of spectroscopic observations of active region AR 12759 as it transited the solar disk over a period of 6 days from 2020 April 2–7 taken using the Hinode Extreme ultraviolet Imaging Spectrometer and Interface Region Imaging Spectrograph (IRIS) instruments to look for signatures of plasma fractionation in the solar chromosphere. Using the Si x /S x and Ca xiv /Ar xiv diagnostics, we find distinct differences between the FIP bias of the leading and following polarities of the active region. The widths of the IRIS Si iv lines exhibited clear differences between the leading and following polarity regions, indicating increased unresolved wave activity in the following polarity region compared to the leading polarity region, with the chromospheric velocities derived using the Mg ii lines exhibiting comparable, albeit much weaker, behavior. These results are consistent with plasma fractionation via resonant/nonresonant waves at different locations in the solar chromosphere following the ponderomotive force model, and indicate that IRIS could be used to further study this fundamental physical process.

INTRODUCTION: Brain magnetic resonance imaging (MRI) and inflammatory biomarkers are crucial for investigating preclinical neurocognitive disorders. Current investigations focus on a few inflammatory markers. The study aims to investigate the associations between inflammatory biomarkers and MRI measures and to examine sex differences among the associations in the Framingham Heart Study. METHODS: Dementia and stroke‐free participants underwent OLINK Proteomics profiling and MRI measurements within 5 years. Pairwise cross‐sectional analysis assessed 68 biomarkers with 13 brain MRI volumes, adjusting for covariates and familial correlations. RESULTS: Elevated CDCP1, IL6, OPG, and 4E.BP1 were related to smaller total cerebral brain volume (TCBV), whereas higher HGF, IL8, and MMP10 were associated with smaller TCBV, total and frontal white matter volumes. Higher SCF and TWEAK were associated with larger TCBV. In sex‐stratified analyses, associations were observed exclusively among males. DISCUSSION: We report several associations between inflammatory biomarkers and brain volumes, highlighting different associations within sex subgroups. Highlights: Higher CDCP1, IL6, OPG, and 4E.BP1 levels were associated with smaller TCBV.Higher levels of HGF, IL8 and MMP10 were associated with smaller TCBV, CWV and FWV.Higher levels of SCF and TWEAK, were associated with larger TCBV.Significance diminished in models adjusting for CVD risk factors.Associations were observed exclusively in males. [ABSTRACT FROM AUTHOR]

Background: Complexity and change in health care environments, the rapid pace of knowledge generation, and changing education policy have led to national calls for change in nursing education. Many nursing programs have adopted a concept-based curriculum (CBC) to address these challenges. Yet, much is still uncertain about the outcomes and effectiveness of CBC, which requires large scale, time-consuming, and resource-intensive change. Method: This integrative review assesses the outcomes of CBC in nursing higher education with a focus on the comparison of CBC to traditional curricula. Results: The four relevant themes that emerged after an extensive literature review were critical thinking/clinical judgment, NCLEX-RN© (National Council Licensure Examination for Registered Nurses) pass rates, graduation rates, and student satisfaction scores. Overall, the evidence base is not robust. A valid and reliable tool to measure clinical judgment is needed. The review specifically addresses CBC effects on student critical thinking and clinical judgment, traditional outcome metrics, (NCLEX-RN success, graduation rates, and student satisfaction), and other perceived benefits. Conclusion: The authors found promising results on the effect CBC may have on critical thinking and clinical judgment and other perceived benefits. Findings were inconclusive on traditional outcome metrics. [J Nurs Educ. 2024;63(11):725–729.] [ABSTRACT FROM AUTHOR]

Context. Solar active regions (ARs) are often surrounded by dark large areas of reduced emission compared to the quiet Sun, observed at various wavelengths corresponding to the chromosphere, transition region (TR), and corona, known as dark halos (DHs). The mechanisms behind the darker emission of DHs remain unclear and merit a wider scope of study. Aims. This study aims to investigate for the first time the fine structure of a DH observed by the EUV High Resolution Imager (HRIEUV) on board the ESA's Solar Orbiter (SO) mission and its appearance in the TR. Aims. We utilized the extensive 1 hour dataset from SO on 19 March 2022, which includes high-resolution observations of NOAA 12967 and part of the surrounding DH. We analyzed the dynamics of the HRIEUV DH fine structure and its appearance in the HRILyα image. We also analyzed the Spectral Imaging of the Coronal Environment (SPICE) Lyβ, C III, N VI, O VI, and Ne VIII lines, which sample the TR in the log T(K) ∼ 4.0–5.8 range. This analysis was complemented with a simultaneous BLOS magnetogram taken by the High Resolution Telescope (HRT). Methods. We report the presence of a peculiar fine structure that has not been observed for the quiet Sun. It is characterized by combined bright EUV bundles and dark regions, arranged and interconnected in such a way that they cannot be clearly separated. They form a spatial continuum extending approximately radially from the AR core, suggesting a deep connection between the DH and the AR. Additionally, we find that the bright EUV bundles are observed in all the SPICE TR lines and the HRILyα band and present photospheric BLOS footprints in the HRT magnetogram. This spatial correlation indicates that the origin of the 174 Å DH may lie in the low atmosphere: the photosphere and chromosphere. [ABSTRACT FROM AUTHOR]