bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence and Risk Factors of Constipation Symptoms among Patients Undergoing Colonoscopy: A Single-Center Cross-Sectional Study
Authors: Komori Shiori , Akiyama Junichi , Tatsuno Naoko , Yamada Erika , Izumi Atsuko , Hamada Mariko , Seto Kana , Nishiie Yuriko , Suzuki Keigo , Hisada Yuya , Otake Yuki , Yanai Yuka , Okubo Hidetaka , Watanabe Kazuhiro , Akazawa Naoki , Yamamoto Natsuyo , Tanaka Yasuo , Yanase Mikio , Saito Akiko , Yamada Kazuhiko , Yokoi Chizu , Nagahara Akihito
Published: May 2024

Introduction: Constipation is one of the most common gastrointestinal symptoms. It may compromise quality of life and social functioning and result in increased healthcare use and costs. We aimed to evaluate the prevalence and risk factors of constipation symptoms, as well as those of refractory constipation symptoms among patients who underwent colonoscopy. Methods: Over 4.5 years, patients who underwent colonoscopy and completed questionnaires were analyzed. Patients’ symptoms were evaluated using the Gastrointestinal Symptoms Rating Scale. Results: Among 8,621 eligible patients, the prevalence of constipation symptoms was 33.3%. Multivariate analysis revealed female sex (odds ratio [OR] 1.7, p < 0.001), older age (OR 1.3, p < 0.001), cerebral stroke with paralysis (OR 1.7, p = 0.009), chronic renal failure (OR 2.6, p < 0.001), ischemic heart disease (OR 1.3, p = 0.008), diabetes (OR 1.4, p < 0.001), chronic obstructive pulmonary disease (OR 1.5, p = 0.002), benzodiazepine use (OR 1.7, p < 0.001), antiparkinsonian medications use (OR 1.9, p = 0.030), and opioid use (OR 2.1, p = 0.002) as independent risk factors for constipation symptoms. The number of patients taking any medication for constipation was 1,134 (13.2%); however, refractory symptoms of constipation were still present in 61.4% of these patients. Diabetes (OR 1.5, p = 0.028) and irritable bowel syndrome (OR 3.1, p < 0.001) were identified as predictors for refractory constipation symptoms. Conclusions: Constipation occurred in one-third of patients, and more than half of patients still exhibited refractory symptoms of constipation despite taking laxatives. Multiple medications and concurrent diseases seem to be associated with constipation symptoms.
Abstract 30: Early-Life Tobacco Exposure, Genetic Risk, and Incident Type 2 Diabetes
Authors: Jiang Xuanwei , Zhong Victor W
Published: May 2024

Introduction:
Tobacco exposure in adulthood is a well-established risk factor for type 2 diabetes (T2D), but how early-life tobacco exposure implicates in the development of T2D as well as whether this association varies by different genetic predisposition to T2D are unclear. Addressing these gaps may provide novel insights into early interventions of T2D.

Hypothesis
We hypothesized that tobacco exposure in utero and childhood/adolescence stages was significantly associated with incident T2D in adulthood and there were significant interactions and joint effects between early-life tobacco exposure and genetic risk for T2D in relation to risk of T2D.

Methods:
This prospective cohort study used data from the UK Biobank. In utero tobacco exposure and age of smoking initiation [never smoking, childhood (5-14 years), adolescence (15-17 years), and adulthood (≥18 years)] were assessed through self-reported questionnaires. Multivariable Cox proportional hazard models, adjusted for demographics and early-life factors, were used to estimate the associations of tobacco exposure in utero and childhood/adolescence stages with incident T2D. A polygenic risk score (PRS) for T2D divided into tertiles was used to assess the interactions and joint effects between early-life tobacco exposure and genetic susceptibility on the development of T2D.

Results:
A total of 475,957 participants without T2D at baseline were included. During a median follow-up time of 14.6 years (IQR, 13.7-15.3), 23,480 incident T2D events occurred. Tobacco exposure in utero vs no exposure was significantly associated with incident T2D (hazard ratio [HR], 1.22 [95% CI, 1.18-1.26]). Compared with never smoking, smoking initiation in childhood (HR, 2.19 [95% CI, 2.08-2.29]), adolescence (HR, 1.57 [95% CI, 1.51-1.62]), and adulthood (HR, 1.33 [95% CI, 1.28-1.38]) were significantly associated with incident T2D (
P
for trend <0.001). Additive interactions were observed between tobacco exposure in utero or childhood/adolescence stages and PRS for T2D (relative excess risk due to interaction >0,
P
interaction
<0.001). Compared with participants having no early-life tobacco exposure and a low PRS, those with a high PRS had a 330% higher risk of developing T2D when exposed to tobacco in utero (HR, 4.30 [95% CI, 4.07-4.54]), a 639% higher risk of developing T2D when starting smoking in childhood (HR, 7.39 [95% CI, 6.84-7.99]), and a 427% higher risk when starting smoking in adolescence (HR, 5.27 [95% CI, 4.95-5.62]).

Conclusions:
In utero tobacco exposure was significantly associated with incident T2D. Earlier smoking initiation was more strongly associated with incident T2D than later initiation. Early-life tobacco exposure and genetic predisposition to T2D interacted and jointly determined risk of T2D.
Abstract 43: Development and Internal Validation of Risk Scores to Predict Survival to Discharge Following Pediatric In-Hospital Cardiac Arrest
Authors: Mawani Minaz , Knight Jessica , McNally Bryan , Shen Ye , Brown Linda , Ebell Mark
Published: May 2024

Introduction:
In-hospital cardiac arrest (IHCA) in the pediatric population is associated with poor survival and neurological outcomes. We aimed to develop and internally validate a risk score to predict survival to discharge in pediatric IHCA patients.

Methods:
For model development and validation, we included pediatric IHCA patients captured in the Get With The Guidelines® registry (provided by the American Heart Association) between 2005 and 2021. We used logistic regression (LR), classification and regression trees (CART), and artificial neural networks (ANN) to develop models using 70% of the data and validate them using the remaining 30% of the data. The discrimination of the models was compared based on the area under the receiver operating characteristic curve (AUC), calibration based on the ratio of observed to expected (O: E), and predictive accuracy based on percent survival in each risk group.

Results:
We included 6141 pediatric patients (mean age 4.82 years, 41.3% infants, 54.7% male). Most patients survived to hospital discharge (60.9%). We developed separate models for infants vs. older children using LR, CART, and ANN. The least absolute shrinkage and selection operator (LASSO) identified age, illness category, acyanotic cardiac malformation, hepatic insufficiency, hypotension/hypoperfusion, metabolic/electrolyte abnormality, metastatic/hematologic malignancy, renal insufficiency, septicemia, and pediatric cerebral performance score on admission as important predictor variables for analysis. Table 1 shows a comparison of model parameters. Logistic regression models were found to be better at classifying survivors into risk categories with higher specificity and discrimination.

Conclusion:
Pediatric patients experiencing IHCA can be classified into low, moderate, and high-risk categories using a simple risk score and easily identified pre-arrest variables. These risk scores can support clinical decisions, facilitate research, and help monitor the quality of medical services.
Abstract P117: Trial Recruitment Advertisement Modalities and Demographics of Participants: Implications for Equitable Representation in Clinical Trials
Authors: Cha Jaeyoon , Cao Jingyi , Col Hannah , Feng Yuanyuan , Choppa Nikhilsai , Harry Tamunotonye , Plante Timothy , Hermosilla Manuel , Elborki Marwa , Aidoo Emily , Turkson-Ocran Ruth-Alma N , Juraschek Stephen P
Published: May 2024

Background:
Convenience and cost are major determinants of which strategies are used to recruit clinical trial participants. However, little is known about the impacts of recruitment strategy on representation of people from diverse backgrounds.

Objective:
Using the high-throughput recruitment drives of two trials, we assessed whether referral source was associated with demographic and social characteristics of people who inquired about the trials or participated in screening.

Methods:
The GoFresh studies (NCT05121337 & NCT05393232) are two randomized trials testing the impact of a home-delivered DASH-patterned grocery intervention on blood pressures of Black adults residing in urban food deserts, with or without treated hypertension (HTN). Both share a common recruitment drive, incentive plan, and study design. Principal recruitment strategies were: mailed brochure to patients, advertising on public transit (bus or subway), or word-of-mouth referral. In prescreening, participants provide their age, HTN treatment status, and how they heard about the trial. Those eligible proceed to in-person screening, where they are asked about biologic sex, ethnicity, birthplace, car ownership, insurance status, education, employment, marital status, home ownership, income, and number of dependents.

Results:
Of 1,601 people who submitted a prescreening inquiry, 602 (38%) completed screening. At prescreening, people responding via public transit were younger (mean [SD] 36 [13]; overall 46 [16]) and fewer had treated HTN (18%; overall 35%). At screening, there were significant differences by referral source in sex, car ownership, employment, marital status, and home ownership (
Table
). Other factors did not differ (ethnicity, birthplace, insurance status, education, income, and dependents).

Conclusion:
Demographics and social characteristics of clinical trial participants differed by advertising modality. Trials intending to recruit diverse populations would benefit from multimodal forms of outreach.
Abstract P135: Effect of Cardiovascular Health Improvement at Midlife on Cardiovascular Event and Mortality Risk in Diabetes
Authors: Sattler Elisabeth L , Lassale Camille , Lloyd-Jones Donald M , PERIER Marie-Cécile , Joseph Joshua J , Jouven Xavier , Gaye Bamba
Published: May 2024

Objective:
This prospective cohort study examined the relationships between changes in CVH during midlife, as assessed by the Life's Simple 7, and risks of CVD events and all-cause mortality among individuals with diabetes and compared to individuals without diabetes.

Methods:
The study utilized data from the Atherosclerosis Risk in Communities Study, collected during visits 1 (1987-1989) and visit 3 (1993-1995) with a median follow-up of 23 years.

Results:
Among the final sample (N=8,741), 806 had diabetes (9.2%). Among participants with diabetes at baseline, 62.3% had consistently low CVH at both visits, 12.0% maintained moderate CVH, and 0.4% maintained favorable CVH. Meanwhile, 15.0% showed improvement, and 10.3% experienced a decline in CVH. Those who improved their CVH status had lower CVD event risks (HR=0.69; 95% CI: 0.50 to 0.93), as did those who maintained moderate CVH (HR=0.68; 95% CI: 0.50 to 0.94) or shifted from moderate to low CVH (HR=0.60; 95% CI: 0.41 to 0.88). These results were largely influenced by positive changes in blood pressure, cholesterol levels, physical activity, and smoking. Similar patterns were observed for all-cause mortality. In comparison to participants without diabetes who maintained a favorable CVH trajectory at midlife, those with diabetes consistently displayed higher risks of CVD events and mortality, regardless of their CVH trajectory (Figure 1). However, individuals with diabetes who maintained a favorable CVH trajectory at midlife had CVD event and mortality risks similar to those without diabetes who had consistently low CVH.

Conclusions:
For individuals with diabetes at midlife, achieving or maintaining ideal CVH levels through lifestyle factors may help reduce excess CVD events and mortality risk. Nonetheless, CVD risk in diabetes is not completely mitigated by favorable cardiovascular risk factor trajectories.
Abstract P171: Patient and Interdisciplinary HIV Care Experts Illness Representations on HIV Comorbidities and Usability of a Virtual Environment as Heart Disease Prevention Education in Ethnic and Racial Sexual Minority Men With HIV
Authors: Ramos S. Raquel , Vorderstrasse Allison , Johnson Constance , Melkus Gail , Kershaw Trace , Reynolds Harmony
Published: May 2024

Background:
Black and Latinx sexual minority men with HIV are at increased risk of CVD and have been underrepresented in clinical trials. The American Heart Association has called for an increase in interventions that focus on enhancing cardiovascular health in underserved communities by addressing social determinants and modifiable risk factors of CVD.

Objective:
To explore patient and HIV care experts’ perceptions about HIV comorbidities and assess usability of a virtual environment as CVD prevention education in Black and Latinx sexual minority men with HIV.

Methods:
This two-phase study is part of a pilot behavioral clinical trial informed by the American Heart Association’s metrics for cardiovascular health. Qualitative Phase 1 data were collected June 2021 to May 2022. Phase 2 data were collected August 2022 to October 2022. Using convenience sampling, we recruited a) Black and Latinx sexual minority men with HIV, and b) interdisciplinary HIV care experts. Eligibility criteria for non-HIV care experts were: 1) self-identify as gay or bisexual; 2) HIV serostatus positive; 3) ages 30 to 65; 4) access to a laptop or desktop. We explored HIV comorbidities of concern and conducted usability testing of the virtual environment. Eighty-four pages of interview data were analyzed using NVivo 12.

Results:
Phase 1 themes included: Mixed Perceptions about Health, High Risk for Comorbidities, and Virtual Environment Features. CVD risk factors were consistently expressed in relation to HIV, including hypertension, heart attack, stroke, and diabetes. Additionally, kidney, and liver disease were identified as important. Cancer was a common concern and so were the development of mental health conditions. All participants in Phase 2 completed the usability checklist with favorable feedback.

Conclusions:
We identified hypertension, diabetes, asthma, and cancer were comorbidities of concern. These findings carry significant implications for mitigating barriers to preventative health screenings in Black and Latinx sexual minority men with HIV, given shared risk factors between HIV, CVD, and cancer. We also found that usability of a virtual environment as CVD prevention education was promising as it offered anonymity and access to reliable health information that traverses geography. A virtual environment may serve as a novel modality for extending the reach of prevention education and clinical trials into the hands of ethnic and racial, sexual minoritized individuals that have been underrepresented in advancements in health equity.
Abstract P179: Association Between Serum Metabolites and Carotid Atherosclerosis Among Japanese Men
Authors: Ganbaatar Gantsetseg , Kadota Aya , Okami Yukiko , Whiley Luke , Chan Queenie , Barinas-Mitchell Emma , Torii Sayuki , Kondo Keiko , Morino Katsutaro , Hisamatsu Takashi , Fujiyoshi Akira , Sekikawa Akira M , Ueshima Hirotsugu , Miura Katsuyuki ,   The SESSA Rsch Group
Published: May 2024

Background:
Complex metabolic pathways may exist for atherosclerosis. We examined metabolomic signatures that reflect mechanistic pathways associated with carotid atherosclerosis in apparently healthy men.

Methods:
A cross-sectional study was conducted in 675 Japanese men (46-83 years) from the SESSA Study (2010-2014). A total of 468 serum metabolites were quantified by liquid chromatography mass spectrometry. The mean intima-media thickness (IMT) and total number of plaques from carotid arteries were measured using B-mode ultrasound. All metabolites were standardized prior to the analysis. We used partial least square regression and variable importance projection (VIP) method to extract the principal metabolites most associated with the mean IMT and total number of plaques. We used a multivariable linear model for the log-mean IMT and a multivariable Poisson model for the total number of plaques to assess the association between individual extracted serum metabolites and carotid measures. Each metabolite multivariable model adjusted for age, body mass index, smoking and drinking status, medications for hypertension, diabetes and dyslipidemia, and systolic blood pressure, high- and low-density lipoprotein cholesterols and hemoglobin A1c. We used false discovery rate adjusted p-values to control for multiple testing.

Results:
The average mean IMT and total number of plaques were 0.80 mm (SD: 0.16) and 2.06 (range: 0-14), respectively. There were 191 metabolites with a VIP value of one or higher for mean IMT. None of these metabolites was significantly associated with the log-mean IMT. On the other hand, there were 209 metabolites with a VIP value of one or higher for the total number of plaques. Among them, SulfoHexCer(d18:2/24:0(OH)) and SulfoHexCer(d18:2/16:0(OH)) had an inverse association with the total number of plaques (Figure 1).

Conclusion:
We identified distinct metabolites associated with the total number of plaques. The results suggest an important role of sphingolipids in carotid plaque formation.
Abstract P190: Association of Meal Timing With Measures of Obesity: The Hispanic Community Health Study/Study of Latinos
Authors: Alver Sarah , Peters-Samuelson Brandilyn , Mossavar-Rahmani Yasmin , Qi Qibin , McClain Amanda C , Thyagarajan Bharat , Daviglus Martha L , Van Horn Linda , Kaplan Robert
Published: May 2024

Introduction:
Time-restricted feeding has been associated with healthier weight, and as a weight-control intervention, can reduce caloric intake without calorie counting. Previous research showed that individuals with overweight who shortened their eating duration (time between first and last food intake of the day) experienced beneficial weight reduction. We explored this association in understudied US Hispanic/Latino individuals, as they experience a high prevalence of overweight and obesity.

Hypothesis:
We assessed the hypothesis that shorter eating duration is associated with healthier body mass index (BMI), percent body fat, or waist to hip ratio.

Methods:
We analyzed cross-sectional data from n=12079 Hispanic/Latino participants from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) who were not pregnant, not underweight, had reliable 24-hour dietary recall data, and had at least 3 accelerometer wear days. For each participant, we calculated eating duration, defined as the time between the first and last food intake of the day averaged over two 24-hour dietary recalls. We modeled eating duration in hours as the primary exposure in linear regression models with baseline measured BMI, percent body fat, or waist to hip ratio as outcomes of interest. We adjusted for age, sex, Hispanic background, field center, socioeconomic factors, sleep duration, glycemic status, diet quality, measured physical activity, and energy balance (ratio of energy intake to estimated energy needs). BMI was log transformed to help meet assumptions. Analyses accounted for complex survey design, missing accelerometer data, and accelerometer wear time.

Results:
Mean (SE) eating duration was 11.9 (0.04) hours. Those with longer eating duration tended to have higher energy intake (though less apparent for those with BMI at least 30), spend more time in moderate or vigorous physical activity, and were more likely to be employed full-time and perform shift work. After adjusting for energy balance and socioeconomic, medical and lifestyle factors, we found a significant positive association between eating duration and log-transformed BMI (regression coefficient 0.003 for eating duration in hours, SE 0.001, p=0.02). This significant association emerged only after adjusting for energy balance, demonstrating the importance of controlling for confounding between eating duration and intake. In sensitivity analysis, we excluded those with prevalent heart disease or diabetes, and obtained similar results. No statistically significant associations were noted between eating duration and the other obesity measures.

Conclusions:
Longer eating duration was associated with higher BMI in Hispanic/Latino persons after adjusting for covariates and energy balance from self-reported intake.
Abstract P196: The Effects of Initiating a 24-hour Fast With a Low versus a High Carbohydrate Protein Shake on Heart Rate Variability in the Elderly
Authors: Deru Landon , Gipson Elizabeth , Hales Katelynn , Bailey Bruce
Published: May 2024

Introduction:
While multiple studies demonstrate the potential cardiovascular benefits of fasting, the effects of the fast-initiating meal have not been evaluated. The aim of this secondary analysis was to examine the effects of the macronutrient composition of a fast-initiating meal on the autonomic nervous system through measurements of heart rate variability (HRV) in older, sedentary adults with abdominal obesity.

Methods:
Using a crossover design, each of the 24 participants (13 male, 11 female) completed two 24-hour fasts (8:00 am to 8:00 am) separated by 6-10 days. Participants were 59.54 ± 6.67 years old and had a body mass index of 31.59 ± 5.59 kg/m
2
. Each fast was initiated with either a low carbohydrate protein shake or an isocaloric and isovolumetric high carbohydrate protein shake (592.13 ± 104.57 kcal). Heart rate variability was measured for 10 minutes immediately prior to, one hour after, and then 24 hours after shake consumption.

Results:
A mixed effects model with repeated measures was used to assess the effects of the fasting conditions on various HRV outcomes. The sympathetic (SNS) index increased significantly over the time of each fast (p = 0.0033), but was not different between conditions (p = 0.7229). The parasympathetic PNS index experienced no change over time (p = 0.1521) and no change between conditions (p = 0.8961). The stress index increased over time (p = 0.0021), but was not different between conditions (p = 0.7308). There was no difference in standard deviation of the normal-to-normal interval (SDNN) or root mean square of successive difference (RMSSD) over time (p = 0.2022 and p = 0.2770, respectively) or between condition (p = 0.9054 and p = 0.9857, respectively). The High Frequency (HF) reading was elevated in the high-carbohydrate condition compared to the low-carbohydrate condition (p < 0.0001), and the low frequency to high frequency (LF/HF) ratio showed no difference between conditions (p = 0.3460), but increased over time (p = 0.0044) and demonstrated a time by condition interaction (p = 0.0089).

Conclusions:
Acute fasting places strain on the cardiometabolic systems as evident by the increased SNS index and stress index as well as the increase in LF/HF ratio over the course of both fasts. A low carbohydrate shake reduced HF readings, indicating more anxiety or panic in this condition. These results agree with previous works and are unique in demonstrating that most HRV parameters are neither strengthened nor weakened by the composition of the pre-fast meal.
Abstract P348: Weight Loss of Machine Learning Identified Metabolic Subtypes in Response to Dietary Interventions
Authors: Li Xiang , Feng Han , Qian Qian , Bray George , Sacks Frank M , Qi Lu
Published: May 2024

Introduction:
Metabolic syndrome is a constellation of metabolic risk factors. However, various combinations of metabolic disorders may exhibit distinct responses to weight loss interventions.

Objective:
To identify metabolic subtypes using the machine learning method and assess their associations with weight loss response to dietary interventions.

Methods:
The study includes 645 participants from the POUNDS Lost trial. Five criteria for metabolic syndrome were used as the grouping factors. Hierarchical clustering was performed with an 8:2 train/test ratio.

Results:
Three metabolic subtypes were identified and validated among the POUNDS Lost participants. Cluster 1 was characterized by high proportions of central obesity and high blood pressure but low triglycerides; Cluster 2 showed central obesity with relatively low blood pressure; Cluster 3 had the lowest level of central obesity and blood pressure but the highest triglycerides level. Changes in body weight varied significantly across clusters (p=0.003 at 6 months and p< 0.001 at 2 years). At 6 months, adjusted least-square mean (SE) weights were: -6.5 (0.8) kg in cluster 1, -5.4 (0.6) kg in cluster 2, and -4.2 (0.7) kg in cluster 3. Participants regained weight after 6 months, but the difference across the clusters persisted: -5.5 (1.0) kg in Cluster 1, -3.1 (0.8) kg in Cluster 2, and -1.7 (0.8) kg in Cluster 3.

Conclusion:
We identified 3 metabolic subtypes that predict different responses to dietary weight loss interventions, which may contribute to subtype-specific precision medicine for obesity prevention and management.
Abstract P485: Exercise Influences Metabolic Parameters and Expression of Markers of Endoplasmic Reticulum Stress in a Diet-Dependent Manner
Authors: Vail McClain , Le Vey Austin , Nguyen Thuy-Linh , Rodriguez Aaron , Spears Nathaniel , Jasperse Jeffrey L , Houghton Jeffrey , Gigliotti Joseph
Published: May 2024

The relationship between diet, exercise, and metabolic dysfunction is widely established; however the mechanisms responsible remain unclear. Endoplasmic reticulum stress (ERS) has been shown to play a significant role in metabolic homeostasis and disease processes; however it is unclear how diet and exercise interact to influence ERS. Therefore, the objective of this project was to determine how diet and exercise influence metabolic markers and mRNA expression of ERS-related genes. Weanling C57Bl/6 mice were randomly assigned to receive
ad libitum
access to standard laboratory chow, AIN93 diet, and our novel “Americanized” diet (AD) for 4-weeks. After 2-weeks, mice from each diet group were randomly assigned to exercise (n=7) or sedentary control groups (n=3). The exercise condition consisted of access to an exercise wheel, three times per week, for 16 hours per day. Wheel utilization was recorded using a bicycle computer/sensor. Insulin sensitivity was determined using standardized insulin-tolerance test. Mice were fasted, euthanized, and blood and liver tissues were collected. Circulating glucose and lipid levels were quantified and hepatic mRNA expression of genes related to ERS (
Ddit3
,
Hspa5
, and
Erdj4
) were determined. Data were analyzed using GLM procedures in SPSS. Despite having no influence on body weight, diet (P=0.04) significantly influenced liver weight, with mice fed AD having greater (P = 0.01) liver weight compared to mice fed chow. Exercise tended to increase liver weight compared to the control (P=0.095), while reducing liver lipid content in mice fed chow and AD. AD fed mice had the highest circulating glucose values compared to mice fed chow (P=0.013) and also tended to be greater than mice fed AIN (P=0.056). Exercise significantly increased circulating triglycerides (P=0.03) and tended to reduce circulating glucose levels (P=0.07). Diet significantly influenced insulin sensitivity (P = 0.003), with mice fed AD having less insulin sensitivity as compared to mice fed chow (P<0.001) and also tended to be lower than mice fed AIN (P=0.06). While non-significant (P=0.15), exercising mice tended to have less insulin sensitivity than controls. Exercise caused an increase in Erdj4 mRNA expression (P=0.02), most notably in mice fed AD, which had a greater ER-stress response with exercise than other diet groups (P=0.04). Our data suggests that the physiological responses to acute exercise is dependent upon the quality of diet consumed, and these effects are associated with changes of markers of ERS. Additional studies are needed to further elucidate the mechanisms by which diet, exercise, and ERS interact to influence metabolic health.
Abstract P490: The Oral Microbiome and Prospective Risks of All-Cause and Cardiometabolic Mortality: The National Health and Nutrition Examination Survey
Authors: Adam Hamdi S , Demmer Ryan , Pankow Jim S
Published: May 2024

Background:
Dysbiosis of the oral microbiome and periodontitis (an inflammatory disease induced by dysbiosis) are plausible risk factors for cardiometabolic (CM) diseases. The relationship between the oral microbiome and CM mortality is less known.

Hypothesis:
Greater oral microbial diversity is associated with lower risks of all-cause and CM mortality, while poorer periodontal health is associated with greater mortality risk.

Methods:
We included n=5,255 adults aged 30+ from the National Health and Nutrition Examination Survey (NHANES) who had periodontal examinations and provided saliva samples at baseline. Baseline enrollment occurred in the 2009-2010 (n=2,681) and 2011-2012 (n=2,574) study cycles. Salivary microbiome data were generated in NHANES via 16s gene sequencing. Shannon and Inverse Simpson alpha diversity metrics were used to quantify oral microbial diversity for each participant. Clinical attachment loss (CAL) and probing depths from periodontal exams were included as historic and active measures of periodontitis, respectively. All-cause (non-accident deaths) and CM mortality (due to cardiovascular disease, cerebrovascular disease, diabetes, nephritis) through 2019 were ascertained via National Death Index linkages. We used multivariable Cox regression to compute hazard ratios and 95% confidence intervals (HR [95%CI]) of all-cause and CM mortality among 2
nd
and 3
rd
tertiles (vs 1
st
tertile) of alpha diversity, CAL, and probing depth. We adjusted for study cycle, demographics, CM risk factors.

Results:
Mean age (SE) of participants was 48.1(0.2) years and 50% were men. Across 8.8 years of median follow-up, 193 all-cause deaths and 85 CM deaths occurred. Higher alpha diversity were associated with lower risks of all-cause and CM mortality, although non-significant. Relative risk of CM mortality in CAL Tertiles 3 vs. 1 is 1.81 (1.05, 3.09) (see
Table
).

Conclusion:
Lower oral microbiome diversity and poorer indicators of periodontitis were not associated with all-cause and CM mortality.
Abstract P513: Coronary Artery Calcium Burden in Rural Alabama: Initial Findings From the Risk Underlying Rural Areas Longitudinal Cohort Study
Authors: Razavi Alexander C , Vasan Ramachandran S , van den Heuvel Edwin , Whelton Seamus P , Dzaye Omar , Mujahid Mahasin S , Lewis Tene T , Judd Suzanne E , Rotter Jerome I , van Assen Marly , De Cecco Carlo N , Quyyumi Arshed A , Blaha Michael J , Sperling Laurence , Budoff Matthew J , Vaccarino Viola
Published: May 2024

Introduction:
Individuals living in rural areas have a disproportionately high rate of cardiovascular disease (CVD) mortality. Coronary artery calcium (CAC) scanning may inform CVD risk stratification. However, the prevalence of CAC in rural areas is unknown.
Research Question:
What is the prevalence of CAC according to age, sex, and self-reported race (Black, White) in two rural counties in Alabama?

Aims:
To determine the prevalence of a CAC score >0, a CAC score ≥100, and premature CAC among rural persons without clinical CVD and the extent to which they differ by demographic group.

Methods:
We studied 789 participants between the age of 25 and 64 years in the Risk Underlying Rural Areas Longitudinal (RURAL) Cohort Study sample in Alabama who underwent CAC scoring on non-contrast cardiac computed tomography. Premature CAC was defined as CAC >0 for men <45 years old, and women <55 years old. Multivariable logistic regression (including age, sex, race) estimated adjusted odds ratios (aOR) for CAC >0 and CAC ≥100.

Results:
The median age was 51 years, 70% were women, and 80% were Black. Among the were 37% with CAC >0 the median CAC score was 64, while 14% had CAC ≥100 and 12% had premature CAC. Significant differences in all three CAC categories were consistently observed across age and sex, but not race (
Figure
). After adjusting for age and race, women had an approximate 70% lower odds of CAC >0 (aOR=0.29, 95% CI: 0.19-0.44) and CAC ≥100 (aOR=0.28, 95% CI: 0.18-0.43) compared to men. There were no significant differences in CAC >0 (aOR=0.70, 95% CI: 0.43-1.12) or CAC ≥100 (aOR=0.76, 95% CI: 0.46-1.25) for Black versus White persons independent of age and sex.

Conclusion(s):
In a Southern rural cohort of young and middle-aged persons, approximately one in three had prevalent CAC and one in eight had premature CAC. In contrast to previously published urban cohorts, rural Black adults had a similar CAC burden to their White counterparts. There is a need to explore the factors implicated in the high CAC burden within Southern rural communities.
Abstract P524: Prolonged Mild Sleep Restriction Results in Specific Alterations in Genome-Wide DNA Methylation: A Randomized Crossover Trial
Authors: Barragan Rocio , Coltell Oscar , Dye Christian , Cheng Bin , Honig Lawrence , Corella Dolores , St-Onge Marie-Pierre
Published: May 2024

Introduction:
Short sleep duration is associated with increased cardiometabolic risk. DNA methylation plays a critical role in the regulation of gene expression and studies suggest that sleep deprivation may alter DNA-methylation patterns. However, most findings are from acute sleep deprivation or short duration studies.

Hypothesis:
Prolonged sleep restriction study that mimics real-life situations is associated with differentially methylated CpG loci (DML) in the core clock candidate genes and across the epigenome in an epigenome-wide association study (EWAS)

Methods:
Sixty participants (65% women) aged 21-73 y were included in randomized crossover studies with 2 phases of 6 weeks each. Phases differed in sleep duration: either adequate sleep (AS; sleep ≥7h/night) or sleep restriction (SR; -1.5h/night relative to AS). DNA was isolated from whole blood at wk 0 and wk 6 of each phase. DNA methylation (DNAm) was quantified the Illumina Infinium MethylationEPIC BeadChip array v.2.0 (>900K methylation sites) and Partek Genomic Suite v.720.0831. After quality control and normalization, several global and stratified EWASs were performed to test the impact of sleep condition on DNAm. Analyses were adjusted for week, phase, sex, age, BMI and cell type composition. We also focused on methylation changes of the selected core-clock candidate genes (
RORA, CRY1, NR1D2, TIMELESS, NPAS2, NFIL3, RORB, PER3, CSNK1E, ARNTL2, CRY2, CLOCK, ARNTL, RORC, PER2, BHLHE40, NR1D1, CSNK1D, BHLHE41 and PER1
).

Results:
In the candidate gene approach, we detected several significant DML. Top-ranked DML in selected core clock genes with significant interactions between condition and time were: cg02394126 at
ARNTL
(p<0.001), cg23506964 at
CLOCK
(p=0.001), cg03701037 at
NPAS2
(p=0.009), cg06606972 at
NPAS2
(p=0.009), and cg13576304 at
RORA
(p=0.008). Hypermethylation was primarily observed after 6 wk of SR vs AS for cg02394126, cg23506964, cg03701037, and cg06606972, while hypomethylation was observed cg13576304 (
RORA
). In our EWAS, we detected some suggestive significant condition x time interactions in cg23738833 at
SNHG3-RCC1
(p=1,34E-06), cg13280380 in the
FAF1
gene (p=2,25E-05), cg03179866 in the
MMP12
gene (p=2,78E-05), and cg13063696 (p=3,21E-05). All but cg23738833 (
SNHG3-RCC1
) showed hypermethylation after 6 wk of SR vs AS.

Conclusion:
Six weeks of mild SR was associated with changes in DNAm in core-clock candidate genes and in other genes in the EWAS. However, further studies are needed to confirm these findings and determine the functional pathways.
Abstract P535: Correlates of Cardiac Structure and Function in African-Ancestry Adults in the Caribbean: The Tobago Heart Study
Authors: Katz Rain , Gupta Deepak K , Mallugari Ravinder R , Thomas Clifford , Gonzalez Iovank , Cvejkus Ryan , Wheeler Victor , Miljkovic Iva , Kuipers Allison L
Published: May 2024

Introduction:
The population of Tobago is a unique African-ancestry population with a high prevalence of chronic disease, including hypertension and obesity. These conditions are associated with abnormalities in cardiac structure and function that confer an increased risk of heart failure. However, the distribution and correlates of these abnormalities have not been described in Tobagonian women, or any Afro-Caribbean population.

Hypothesis:
Abnormalities in cardiac structure and function will correlate with BMI and blood pressure.

Methods:
Participants from the Tobago Women’s Study aged 45+ were recruited for the Tobago Heart Study without regard to health status. Participants underwent transthoracic echocardiography, a health history, clinical examination, and blood draw. Hypertension was defined by blood pressure measures or prescription of relevant medication. The eventual recruitment goal is 900 men and women; the current analysis is a preliminary assessment of 376 women with data currently available. Statistical analyses included descriptive statistics and Spearman correlations.

Results:
The mean age of the study sample was 60.8 years (range 46-79). The prevalence of hypertension and obesity were 76.2% and 60.1%, respectively. Abnormalities in cardiac structure were detected in 77.5% of participants (of these, 87.9% concentric remodeling, 9.4% concentric hypertrophy, 2.7% eccentric hypertrophy). Diastolic dysfunction was present in 13.6% of participants (of these, 83.7% grade I, 14.3% grade II, and 2.0% grade III dysfunction); cardiomyopathy was found in 1.9%. Results of Spearman correlations are shown in Table 1.

Conclusion:
In a population of Tobagonian women, a low prevalence of diastolic dysfunction was observed despite highly prevalent abnormal left ventricle geometry. Blood pressure and BMI are important correlates of cardiac structure and function in this understudied population. In future analyses these results will be updated with greater sample size and compared to findings in men.
Genome-Wide CRISPR Screen Identifies an NF2-Adherens Junction Mechanistic Dependency for Cardiac Lineage
Authors: Lee Chang Jie Mick , Autio Matias I. , Zheng Wenhao , Song Yoohyun , Wang Shyi Chyi , Wong Darren Chen Pei , Xiao Jingwei , Zhu Yike , Yusoff Permeen , Yei Xi , Chock Wan Kee , Low Boon Chuan , Sudol Marius , Foo Roger S.-Y.
Published: May 2024

BACKGROUND:

Cardiomyocyte differentiation involves a stepwise clearance of repressors and fate-restricting regulators through the modulation of BMP (bone morphogenic protein)/Wnt-signaling pathways. However, the mechanisms and how regulatory roadblocks are removed with specific developmental signaling pathways remain unclear.

METHODS:

We conducted a genome-wide CRISPR screen to uncover essential regulators of cardiomyocyte specification in human embryonic stem cells using a myosin heavy chain 6 (
MYH6
)-GFP (green fluorescence protein) reporter system. After an independent secondary single guide ribonucleic acid validation of 25 candidates, we identified NF2 (neurofibromin 2), a moesin-ezrin-radixin like (MERLIN) tumor suppressor, as an upstream driver of early cardiomyocyte lineage specification. Independent monoclonal
NF2
knockouts were generated using CRISPR-Cas9, and cell states were inferred through bulk RNA sequencing and protein expression analysis across differentiation time points. Terminal lineage differentiation was assessed by using an in vitro 2-dimensional-micropatterned gastruloid model, trilineage differentiation, and cardiomyocyte differentiation. Protein interaction and post-translation modification of NF2 with its interacting partners were assessed using site-directed mutagenesis, coimmunoprecipitation, and proximity ligation assays.

RESULTS:

Transcriptional regulation and trajectory inference from
NF2
-null cells reveal the loss of cardiomyocyte identity and the acquisition of nonmesodermal identity. Sustained elevation of early mesoderm lineage repressor
SOX2
and upregulation of late anticardiac regulators
CDX2
and
MSX1
in
NF2
knockout cells reflect a necessary role for
NF2
in removing regulatory roadblocks. Furthermore, we found that NF2 and AMOT (angiomotin) cooperatively bind to YAP (yes-associated protein) during mesendoderm formation, thereby preventing YAP activation, independent of canonical MST (mammalian sterile 20-like serine-threonine protein kinase)–LATS (large tumor suppressor serine-threonine protein kinase) signaling. Mechanistically, cardiomyocyte lineage identity was rescued by wild-type and NF2 serine-518 phosphomutants, but not NF2 FERM (ezrin-radixin-meosin homology protein) domain blue-box mutants, demonstrating that the critical FERM domain–dependent formation of the AMOT-NF2-YAP scaffold complex at the adherens junction is required for early cardiomyocyte lineage differentiation.

CONCLUSIONS:

These results provide mechanistic insight into the essential role of NF2 during early epithelial-mesenchymal transition by sequestering the repressive effect of YAP and relieving regulatory roadblocks en route to cardiomyocytes.
Allele-Specific Suppression of Variant MHC With High-Precision RNA Nuclease CRISPR-Cas13d Prevents Hypertrophic Cardiomyopathy
Authors: Yang Ping , Lou Yingmei , Geng Zilong , Guo Zhizhao , Wu Shuo , Li Yige , Song Kaiyuan , Shi Ting , Zhang Shasha , Xiong Junhao , Chen Alex F. , Li Dali , Pu William T. , Da Lintai , Zhang Yan , Sun Kun , Zhang Bing
Published: May 2024

BACKGROUND:

Familial hypertrophic cardiomyopathy has severe clinical complications of heart failure, arrhythmia, and sudden cardiac death. Heterozygous single nucleotide variants (SNVs) of sarcomere genes such as
MYH7
are the leading cause of this type of disease. CRISPR-Cas13 (clustered regularly interspaced short palindromic repeats and their associated protein 13) is an emerging gene therapy approach for treating genetic disorders, but its therapeutic potential in genetic cardiomyopathy remains unexplored.

METHODS:

We developed a sensitive allelic point mutation reporter system to screen the mutagenic variants of Cas13d. On the basis of Cas13d homology structure, we rationally designed a series of Cas13d variants and obtained a high-precision Cas13d variant (hpCas13d) that specifically cleaves the
MYH7
variant RNAs containing 1 allelic SNV. We validated the high precision and low collateral cleavage activity of hpCas13d through various in vitro assays. We generated 2 HCM mouse models bearing distinct
MYH7
SNVs and used adenovirus-associated virus serotype 9 to deliver hpCas13d specifically to the cardiomyocytes. We performed a large-scale library screening to assess the potency of hpCas13d in resolving 45 human
MYH7
allelic pathogenic SNVs.

RESULTS:

Wild-type Cas13d cannot distinguish and specifically cleave the heterozygous
MYH7
allele with SNV. hpCas13d, with 3 amino acid substitutions, had minimized collateral RNase activity and was able to resolve various human
MYH7
pathological sequence variations that cause hypertrophic cardiomyopathy. In vivo application of hpCas13d to 2 hypertrophic cardiomyopathy models caused by distinct human
MYH7
analogous sequence variations specifically suppressed the altered allele and prevented cardiac hypertrophy.

CONCLUSIONS:

Our study unveils the great potential of CRISPR-Cas nucleases with high precision in treating inheritable cardiomyopathy and opens a new avenue for therapeutic management of inherited cardiac diseases.
Stroke Mimics in Children With Moyamoya Arteriopathy
Authors: Andere Ariana J. , Dao Jasmin , Gelfand Amy A. , Morshed Ramin A. , Ross Alexandra C. , Wagstaff Amanda E. , Fullerton Heather J. , Fox Christine K.
Published: May 2024

Background

Comorbid conditions may result in symptoms that mimic stroke in children with moyamoya arteriopathy. Health care usage for stroke mimics is not well characterized.

Methods

Consecutive children (aged <18 years) with moyamoya syndrome or disease treated at a single center (2007–2021) were identified from a registry. Data including documentation of headache, anxiety, and functional neurologic disorders were retrospectively abstracted using standardized forms. Encounters were attributed to the comorbid condition when (1) related symptoms led to the visit; (2) the condition was documented as the visit diagnosis; and (3) in the absence of stroke, transient ischemic attack, or seizure.

Results

We identified 32 children (63% female) with symptomatic moyamoya arteriopathy diagnosed via imaging at a median age of 7.5 years (range, 0.7–17) years, all treated with revascularization surgery. During follow‐up (median, 6.7 years after diagnosis [interquartile range, 4.0–8.3]), 81% of patients reported headache, 53% reported anxiety, 19% reported panic attacks, and 6% developed a functional neurologic disorder. Both patients with functional neurologic disorder also had migraines and anxiety. In 10 patients (31% of the cohort), a stroke mimic led to 33 emergency department encounters and 9 hospital admissions; 9 received head imaging (magnetic resonance imaging, computed tomography, or computed tomographic angiography) as part of the workup.

Conclusion

Headaches, anxiety, and functional neurologic disorders may mimic stroke symptoms in children with moyamoya arteriopathy, leading to significant health care usage. While providers should remain vigilant for stroke, early recognition of stroke mimics should promote interventions to address comorbid conditions.
First‐Line Treatment of Symptomatic Subocclusive Large‐Vessel Stroke: Results of a Nationwide StrokeNet Survey
Authors: Aziz Yasmin N. , Harker Pablo , Ayala Felipe , Ades Laura M.C. , Vagal Vaibhav , Khatri Pooja
Published: May 2024

Background

Limited evidence is available for the treatment of acute symptomatic subocclusive lesions in ischemic stroke. We sought to identify current treatment patterns of stroke teams at academic health centers.

Methods

We conducted an email survey of the National Institutes of Health StrokeNet regional coordinating centers (RCCs). Each RCC principal investigator was asked to nominate a local stroke interventionalist, or a neurologist if the RCC principal investigator was an interventionalist, most aligned with the typical practice pattern of the RCC's lead hospital, to receive a survey. The survey consisted of a clinical vignette and displayed a subocclusive lesion in the left middle cerebral artery on computed tomography angiogram followed by subsequent scenarios, revising only 1 historical, clinical, or radiographic variable at a time. Participants were asked to select initial management for each scenario. Results were reviewed and analyzed by stroke‐trained physicians.

Results

Responses were received from 42 (77.8%) of 54 surveyed individuals, representing 25 (92.6%) of 27 RCCs nationwide, including 25 (59.5%) interventionalists. The majority (76.2%) of respondents treated the patient in the primary clinical vignette with mechanical thrombectomy. Among all 6 clinical scenarios, respondents chose mechanical thrombectomy with or without medical management as first‐line treatment for 4 (67%) vignettes. Exceptions were low National Institutes of Health Stroke Scale score and known ipsilateral stenosis, where respondents chose medical management as first‐line treatment.

Conclusion

Despite limited evidence to support mechanical thrombectomy versus other treatment strategies, the majority of StrokeNet RCC respondents would use mechanical thrombectomy with or without medical therapy to treat acute ischemic stroke due to intracranial subocclusive lesions.
Pinpointing Linguistic Emphasis in Classical Greek
Authors: Vatri Alessandro
Published: May 2024

Emphasis is a ubiquitous notion in classical scholarship, but its vagueness has repeatedly been criticized (and its usefulness, consequently, questioned) by Greek linguists. This brief study seeks to identify (and secure) a place for this notion in the analytical toolbox for the description of Classical Greek by applying the strict but nuanced definition of emphasis in Functional Discourse Grammar (Hengeveld and Mackenzie 2008) to the identification and classification of linguistic devices in the ancient language. In particular, this study argues for a distinction between emphasis as a rhetorical effect and emphasis as a communicative intention. In the former understanding, emphasis may be produced secondarily by a number of linguistic and rhetorical devices. Conversely, linguistic emphasis stricto sensu would only be conveyed by linguistic devices used primarily to intensify linguistic entities of any level (discourse acts, propositional contents, subacts).