Sensitivity of ocean circulation to warming during the Early Eocene greenhouse.

Multiple abrupt warming events ("hyperthermals") punctuated the Early Eocene and were associated with deep-sea temperature increases of 2 to 4 °C, seafloor carbonate dissolution, and negative carbon isotope (δ13C) excursions. Whether hyperthermals were associated with changes in the global ocean overturning circulation is important for understanding their driving mechanisms and feedbacks and for gaining insight into the circulation's sensitivity to climatic warming. Here, we present high-resolution benthic foraminiferal stable isotope records (δ13C and δ18O) throughout the Early Eocene Climate Optimum (~53.26 to 49.14 Ma) from the deep equatorial and North Atlantic. Combined with existing records from the South Atlantic and Pacific, these indicate consistently amplified δ13C excursion sizes during hyperthermals in the deep equatorial Atlantic. We compare these observations with results from an intermediate complexity Earth system model to demonstrate that this spatial pattern of δ13C excursion size is a predictable consequence of global warming-induced changes in ocean overturning circulation. In our model, transient warming drives the weakening of Southern Ocean-sourced overturning circulation, strengthens Atlantic meridional water mass aging gradients, and amplifies the magnitude of negative δ13C excursions in the equatorial to North Atlantic. Based on model-data consistency, we conclude that Eocene hyperthermals coincided with repeated weakening of the global overturning circulation. Not accounting for ocean circulation impacts on δ13C excursions will lead to incorrect estimates of the magnitude of carbon release driving hyperthermals. Our finding of weakening overturning in response to past transient climatic warming is consistent with predictions of declining Atlantic Ocean overturning strength in our warm future.

Arterial stiffness and augmentation index are associated with balance function in young adults.

OBJECTIVE: Arterial stiffness and pulsatile central hemodynamics have been shown to affect various aspects of physical function, such as exercise capacity, gait speed, and motor control. The aim of this study was to examine the potential association between arterial stiffness and balance function in healthy younger men and women. METHODS: 112 participants (age = 21 ± 4 years, n = 78 women) underwent measures of arterial stiffness, pulsatile central hemodynamics, balance function and physical fitness in this cross-sectional study. Postural sway was measured in triplicate while participants stood on a foam surface with their eyes closed for 20 s. The average total center of pressure path length from the three trials was used for analysis. Measures of vascular function were estimated using an oscillometric blood pressure device while at rest and included pulse wave velocity (PWV), augmentation index (AIx), and pulse pressure amplification. Measures of physical fitness used as covariates in statistical models included handgrip strength determined from a handgrip dynamometer, lower-body flexibility assessed using a sit-and-reach test, estimated maximal aerobic capacity (VO2max) using heart rate and a step test, and body fat percentage measured from air displacement plethysmography. RESULTS: The results from linear regression indicated that after considering sex, mean arterial pressure, body fat, estimated VO2max, handgrip strength, and sit-and-reach, PWV (ß = 0.44, p < 0.05) and AIx (ß = - 0.25, p < 0.01) were significant predictors of postural sway, explaining 10.2% of the variance. CONCLUSION: Vascular function is associated with balance function in young adults independent of physical fitness. Increased arterial stiffness may negatively influence balance, while wave reflections may be protective for balance.

The Inverse Association of Muscular Strength with Carotid Intima-media and Extra-media Thickness in Women.

The purpose of this study was to determine the relationship between strength and atherosclerotic cardiovascular disease (CVD) risk in young women. Carotid intima-media thickness (IMT) and extra-media thickness (EMT) were used as measures of subclinical atherosclerosis and CVD risk. Muscular strength, IMT, and EMT were measured in 70 young women (mean age=21±4 years). Strength was determined using a handgrip dynamometer and expressed relative to body mass. IMT and EMT were measured using ultrasonography of the left common carotid artery. Objectively measured moderate-vigorous physical activity (MVPA) was assessed with accelerometry. Higher relative handgrip strength was associated with lower IMT (r=-0.23; p<0.05) and lower EMT (r=-0.27; p<0.05). Associations between relative handgrip strength and IMT (r=-0.24) as well as EMT (r=-0.25) remained significant after adjusting for potential confounders including traditional CVD risk factors and MVPA (p<0.05). These results show that there is an inverse association between handgrip strength with carotid IMT and EMT in young women. Muscular strength may reduce CVD risk in young women via favorable effects on subclinical carotid atherosclerosis independent of physical activity.

Predicting 3-month risk for adolescent suicide attempts among pediatric emergency department patients.

BACKGROUND: The incidence of adolescent suicide is rising in the United States, yet we have limited information regarding short-term prediction of suicide attempts. Our aim was to identify predictors of suicide attempts within 3-months of an emergency department (ED) visit. METHODS: Adolescents, ages 12-17, seeking health care at 13 pediatric EDs (Pediatric Emergency Care Applied Research Network) and one Indian Health Service Hospital in the United States were consecutively recruited. Among 10,664 approached patients, 6,448 (60%) were enrolled and completed a suicide risk survey. A subset of participants (n = 2,897) was assigned to a 3-month telephone follow-up, and 2,104 participants completed this follow-up (73% retention). Our primary outcome was a suicide attempt between the ED visit and 3-month follow-up. RESULTS: One hundred four adolescents (4.9%) made a suicide attempt between enrollment and 3-month follow-up. A large number of baseline predictors of suicide attempt were identified in bivariate analyses. The final multivariable model for the full sample included the presence of suicidal ideation during the past week, lifetime severity of suicidal ideation, lifetime history of suicidal behavior, and school connectedness. For the subgroup of adolescents who did not report recent suicidal ideation at baseline, the final model included only lifetime severity of suicidal ideation and social connectedness. Among males, the final model included only lifetime severity of suicidal ideation and past week suicidal ideation. For females, the final model included past week suicidal ideation, lifetime severity of suicidal ideation, number of past-year nonsuicidal self-injury (NSSI) incidents, and social connectedness. CONCLUSIONS: Results indicate that the key risk factors for adolescent suicide attempts differ for subgroups of adolescents defined by sex and whether or not they report recent suicidal thoughts. Results also point to the importance of school and social connectedness as protective factors against suicide attempts.

Prognostic Significance of Lymphovascular Space Invasion in the Absence of Lymph Node Metastases in Early-Stage Endometrial Cancer.

OBJECTIVE: Lymphovascular space invasion (LVSI) has been defined as a significant adverse prognostic factor in early-stage endometrial cancer, primarily because of its high association with nodal metastases. This study aimed to determine if LVSI provides any prognostic significance in pathologic node-negative surgically staged (T1N0) endometrial cancer patients. METHODS/MATERIALS: This retrospective cohort study included all patients with pathologic stage T1N0 endometrial carcinoma treated at The Ottawa Hospital Cancer Centre from 1998 to 2007. Patient demographics, pathologic findings, treatment, and outcome data were collected. Univariate and multivariate cox regression modeling was used to assess significance and adjust for demographic and histopathologic covariates. Kaplan-Meier curves were used to estimate the 5-year overall and recurrence-free survival. RESULTS: Our study included 400 pathologic stage T1N0 patients who received an initial total hysterectomy and bilateral salpingo-oophorectomy with lymphadenectomy. The median age at diagnosis was 62 years, and the median follow-up was 66 months. Fifty-four patients (13.5%) had a positive LVSI status, and 346 (86.5%) had a negative LVSI status. The 5-year overall survival was 97.3% in patients without LVSI and 90.9% in those with LVSI (P < 0.001). The 5-year recurrence-free survival was 95.2% in patients without LVSI and 85.9% in those with LVSI (P = 0.006). Univariate analysis identified grade, stage, and LVSI as the covariates significantly associated with time to recurrence, and identified age, grade, stage, and LVSI to be significantly associated with overall survival. There were no significant covariates for recurrence-free survival by multivariate analysis, and only age and LVSI were significant for overall survival. CONCLUSIONS: Lymphovascular space invasion is an overall poor prognostic factor in T1N0 endometrial cancer. After adjusting for other factors, LVSI remains an independent risk factor for worse overall survival. Therefore, estimation of overall survival in patients with early-stage, node-negative endometrial cancer should take into account LVSI status.

The Effects of Interpersonal Violence on Sleep Following the COVID-19 Stay-at-Home Order.

PURPOSE: Lack of sleep is a harm that can lead to chronic diseases ranging from diabetes to heart disease. We examined the exposure to interpersonal violence and its association with sleep, following the COVID-19 stay-at-home order. DESIGN: Cross-sectional. SETTING: Surveys were completed online and via paper-and-pencil in English and Spanish (N = 2049; RR = 68.4%). SUBJECTS: Respondents were 18+ and residing in Chicago. MEASURES: The Chicago Department of Public Health's "2022 Healthy Chicago Survey COVID-19 Social Impact Survey". ANALYSIS: We developed two weighted models. Model 1 examined the effects of neighborhood violence on meeting the national sleep recommendation. Model 2 examined the effects of violence in the home among friends or family on meeting the sleep recommendation, incorporating additional predictors: victimization, stress, gender, race/ethnicity, household income, and general health. Odds ratios were estimated using multivariate logistic regression. RESULTS: Exposure to neighborhood violence and sleep was not significant, but knowing a friend or family member who experienced violence or mistreatment in their home affected the odds of meeting the sleep recommendation (OR = .61, 95% CI = .44-.84). Non-Hispanic Blacks had 52% lower odds of meeting sleep recommendations (OR = .48, 95% CI = .37-.63). CONCLUSION: Addressing the harms to sleep that followed COVID-19 should engage diverse stakeholders in implementing culturally responsive interventions to promote adequate sleep and prevent chronic disease.

Monitoring Changes to Alkenone Biosynthesis in Commercial Tisochrysis lutea Microalgae.

Alkenones are unique lipids produced by certain species of microalgae, well-known for use in paleoclimatology, and more recently pursued to advance sustainability across multiple industries. Beginning in 2018, the biosynthesis of alkenones by commercially grown Tisochrysis lutea (T-Iso) microalgae from one of the world's most established producers, Necton S.A., changed dramatically from structures containing 37 and 38 carbons, to unusual shorter-chain C35 and C36 diunsaturated alkenones (C35:2 and C36:2 alkenones). While the exact reasons for this change remain unknown, analysis of alkenones isolated from T-Iso grown in 2021 and 2023 revealed that this change has persisted. The structure of these rare shorter-chain alkenones, including double bond position, produced by Necton T-Iso remained the same over the last five years, which was determined using a new and optimized cross-metathesis derivatization approach with analysis by comprehensive two-dimensional gas chromatography and NMR. However, noticeable differences in the alkenone profiles among the different batches were observed. Combined with fatty acid compositional analysis, the data suggest a connection between these lipid classes (e.g., increased DHA corresponds to lower amounts of shorter-chain alkenones) and the ability to manipulate their biosynthesis in T-Iso with changes to cultivation conditions.

Decreased fucosylation impacts epithelial integrity and increases risk for COPD.

COPD causes significant morbidity and mortality worldwide. Epithelial damage is fundamental to disease pathogenesis, although the mechanisms driving disease remain undefined. Published evidence from a COPD cohort (SPIROMICS) and confirmed in a second cohort (COPDgene) demonstrate a polymorphism in Fucosyltransferese-2 (FUT2) is a trans-pQTL for E-cadherin, which is critical in COPD pathogenesis. We found by MALDI-TOF analysis that FUT2 increased terminal fucosylation of E-cadherin. Using atomic force microscopy, we found that FUT2-dependent fucosylation enhanced E-cadherin-E-cadherin bond strength, mediating the improvement in monolayer integrity. Tracheal epithelial cells from Fut2-/- mice have reduced epithelial integrity, which is recovered with reconstitution of Fut2. Overexpression of FUT2 in COPD derived epithelia rescues barrier function. Fut2-/- mice show increased susceptibility in an elastase model of disease developing both emphysema and fibrosis. We propose this is due to the role of FUT2 in proliferation and cell differentiation. Overexpression of FUT2 significantly increased proliferation. Loss of Fut2 results in accumulation of Spc+ cells suggesting a failure of alveolar type 2 cells to undergo transdifferentiation to alveolar type 1. Using a combination of population data, genetically manipulated mouse models, and patient-derived cells, we present a novel mechanism by which post-translational modifications modulate tissue pathology and serve as a proof of concept for the development of a disease-modifying target in COPD.

Prediction of Suicide Attempts and Suicide-Related Events Among Adolescents Seen in Emergency Departments.

Importance: Screening adolescents in emergency departments (EDs) for suicidal risk is a recommended strategy for suicide prevention. Comparing screening measures on predictive validity could guide ED clinicians in choosing a screening tool. Objective: To compare the Ask Suicide-Screening Questions (ASQ) instrument with the Computerized Adaptive Screen for Suicidal Youth (CASSY) instrument for the prediction of suicidal behavior among adolescents seen in EDs, across demographic and clinical strata. Design, Setting, and Participants: The Emergency Department Study for Teens at Risk for Suicide is a prospective, random-series, multicenter cohort study that recruited adolescents, oversampled for those with psychiatric symptoms, who presented to the ED from July 24, 2017, through October 29, 2018, with a 3-month follow-up to assess the occurrence of suicidal behavior. The study included 14 pediatric ED members of the Pediatric Emergency Care Applied Research Network and 1 Indian Health Service ED. Statistical analysis was performed from May 2021 through January 2023. Main Outcomes and Measures: This study used a prediction model to assess outcomes. The primary outcome was suicide attempt (SA), and the secondary outcome was suicide-related visits to the ED or hospital within 3 months of baseline; both were assessed by an interviewer blinded to baseline information. The ASQ is a 4-item questionnaire that surveys suicidal ideation and lifetime SAs. A positive response or nonresponse on any item indicates suicidal risk. The CASSY is a computerized adaptive screening tool that always includes 3 ASQ items and a mean of 8 additional items. The CASSY's continuous outcome is the predicted probability of an SA. Results: Of 6513 adolescents available, 4050 were enrolled, 3965 completed baseline assessments, and 2740 (1705 girls [62.2%]; mean [SD] age at enrollment, 15.0 [1.7] years; 469 Black participants [17.1%], 678 Hispanic participants [24.7%], and 1618 White participants [59.1%]) completed both screenings and follow-ups. The ASQ and the CASSY showed a similar sensitivity (0.951 [95% CI, 0.918-0.984] vs 0.945 [95% CI, 0.910-0.980]), specificity (0.588 [95% CI, 0.569-0.607] vs 0.643 [95% CI, 0.625-0.662]), positive predictive value (0.127 [95% CI, 0.109-0.146] vs 0.144 [95% CI, 0.123-0.165]), and negative predictive value (both 0.995 [95% CI, 0.991-0.998], respectively). Area under the receiver operating characteristic curve findings were similar among patients with physical symptoms (ASQ, 0.88 [95% CI, 0.81-0.95] vs CASSY, 0.94 [95% CI, 0.91-0.96]). Among patients with psychiatric symptoms, the CASSY performed better than the ASQ (0.72 [95% CI, 0.68-0.77] vs 0.57 [95% CI, 0.55-0.59], respectively). Conclusions and Relevance: This study suggests that both the ASQ and the CASSY are appropriate for universal screening of patients in pediatric EDs. For the small subset of patients with psychiatric symptoms, the CASSY shows greater predictive validity.

Exploration of cerebral hemodynamic pathways through which large artery function affects neurovascular coupling in young women.

Background: The interactions between large artery function and neurovascular coupling (NVC) are emerging as important contributors to cognitive health. Women are disproportionally affected by Alzheimer's disease and related dementia later in life. Understanding large artery correlates of NVC in young women may help with preservation of cognitive health with advancing age. Purpose: To explore the association between large artery function, NVC and cognitive performance in young women. Methods: Vascular measurements were made in 61 women (21 ± 4 yrs) at rest and during a cognitive challenge (Stroop task). Transcranial Doppler was used to measure left middle cerebral artery (MCA) maximum velocity (Vmax), mean velocity (Vmean), and pulsatility index (PI). NVC was determined as MCA blood velocity reactivity to the Stroop task. Large artery function was determined using carotid-femoral pulse wave velocity (cfPWV) as a proxy measure of aortic stiffness and carotid ultrasound-derived measures of compliance and reactivity (diameter change to the Stroop task). Cognitive function was assessed separately using a computerized neurocognitive battery that included appraisal of response speed, executive function, information processing efficiency, memory, attention/concentration, and impulsivity. Results: MCA Vmax reactivity was positively associated with executive function (ß = 0.26, 95% CI 0.01-0.10); MCA Vmean reactivity was negatively associated with response speed (ß = -0.33, 95% CI -0.19 to -0.02) and positively with memory score (ß = 0.28, 95% CI 0.01-0.19). MCA PI reactivity was negatively associated with attention performance (ß = -0.29, 95% CI -14.9 to -1.0). Path analyses identified significant paths (p < 0.05) between carotid compliance and carotid diameter reactivity to select domains of cognitive function through MCA reactivity. Conclusions: NVC was associated with cognitive function in young women. Carotid artery function assessed as carotid compliance and carotid reactivity may contribute to optimal NVC in young women through increased blood flow delivery and reduced blood flow pulsatility.

Resistant Starch Combined with Whey Protein Increases Postprandial Metabolism and Lowers Glucose and Insulin Responses in Healthy Adult Men.

Resistant starch (RS) and/or protein consumption favorably influence energy metabolism, substrate utilization, and weight management. The current study administered four different versions of a pancake breakfast containing waxy maize or RS with and without whey protein (WP) and measured postprandial thermogenesis (TEM), fuel utilization, and circulating satiation and appetite factors for 180 min in a group of healthy, adult men. On four separate visits to the laboratory, eight participants were administered four different pancake breakfast meal challenges using a single-blind, randomized crossover design: (1) waxy maize starch (WMS) control; (2) WMS and WP (WMS + WP); (3) RS; or (4) RS and WP (RS + WP). TEM (kcals/180 min) was significantly greater (p < 0.05) in RS + WP (45.11; confidence interval (CI), 33.81-56.41) compared to WMS (25.61; CI, 14.31-36.91), RS (29.44; CI, 18.14-40.74), and WMS + WP (24.64; CI, 13.34-35.94), respectively. Fat oxidation was enhanced (p < 0.05) after RS + WP compared to RS at 60 min (+23.10%), WMS at 120 min (+27.49%), and WMS and WMS + WP at 180 min (+35.76%; +17.31%, respectively), and RER was decreased with RS + WP versus the other three meals (mean differences: ≥-0.021). Insulin concentrations were decreased (p < 0.05) following RS + WP compared to WMS, whereas both RS (-46.19%) and RS + WP (-53.05%) insulin area under the curve (AUC) were greatly reduced (p < 0.01) compared to WMS. While limited by sample size, meals containing both RS and WP increased postprandial thermogenesis and fat oxidation, and lowered insulin response compared to isocaloric meals without this combination. Therefore, RS + WP may favorably impact energy metabolism and thus weight control and body composition under chronic feeding conditions.

Prospective Development and Validation of the Computerized Adaptive Screen for Suicidal Youth.

Importance: The rate of suicide among adolescents is rising in the US, yet many adolescents at risk are unidentified and receive no mental health services. Objective: To develop and independently validate a novel computerized adaptive screen for suicidal youth (CASSY) for use as a universal screen for suicide risk in medical emergency departments (EDs). Design, Setting, and Participants: Study 1 of this prognostic study prospectively enrolled adolescent patients at 13 geographically diverse US EDs in the Pediatric Emergency Care Applied Research Network. They completed a baseline suicide risk survey and participated in 3-month telephone follow-ups. Using 3 fixed Ask Suicide-Screening Questions items as anchors and additional items that varied in number and content across individuals, we derived algorithms for the CASSY. In study 2, data were collected from patients at 14 Pediatric Emergency Care Applied Research Network EDs and 1 Indian Health Service hospital. Algorithms were independently validated in a prospective cohort of adolescent patients who also participated in 3-month telephone follow-ups. Adolescents aged 12 to 17 years were consecutively approached during randomly assigned shifts. Exposures: Presentation at an ED. Main Outcome and Measure: A suicide attempt between ED visit and 3-month follow-up, measured via patient and/or parent report. Results: The study 1 CASSY derivation sample included 2075 adolescents (1307 female adolescents [63.0%]; mean [SD] age, 15.1 [1.61] years) with 3-month follow-ups (72.9% retention [2075 adolescents]). The study 2 validation sample included 2754 adolescents (1711 female adolescents [62.1%]; mean [SD] age, 15.0 [1.65] years), with 3-month follow-ups (69.5% retention [2754 adolescents]). The CASSY algorithms had excellent predictive accuracy for suicide attempt (area under the curve, 0.89 [95% CI, 0.85-0.91]) in study 1. The mean number of adaptively administered items was 11 (range, 5-21). At a specificity of 80%, the CASSY had a sensitivity of 83%. It also demonstrated excellent accuracy in the study 2 validation sample (area under the curve, 0.87 [95% CI, 0.85-0.89]). In this study, the CASSY had a sensitivity of 82.4% for prediction of a suicide attempt at the 80% specificity cutoff established in study 1. Conclusions and Relevance: In this study, the adaptive and personalized CASSY demonstrated excellent suicide attempt risk recognition, which has the potential to facilitate linkage to services.

Age, sex, and the vascular contributors to cerebral pulsatility and pulsatile damping.

Cerebral pulsatility reflects a balance between the transmission and damping of pulsatility in the cerebrovasculature. Females experience greater cerebral pulsatility with aging, which may have implications for sex differences in stroke risk and cognitive decline. This study sought to explore vascular contributors to cerebral pulsatility and pulsatile damping in men and women. Adults (n = 282, 53% female) underwent measurements of cerebral (middle cerebral artery) pulsatility, pulsatile damping (ratio of cerebral to carotid pulsatility), large artery stiffening (ratio of aortic to carotid pulse wave velocity), and carotid wave transmission/reflection dynamics using wave intensity analysis. Multiple regression revealed that older age, female sex, greater large artery stiffening, higher carotid pulse pressure, and greater forward wave energy was associated with increased cerebral pulsatility (adjusted R2 = 0.44, P < 0.05). Contributors to decreased cerebral pulsatile damping included older age, female sex, and lower wave reflection index (adjusted R2 = 0.51, P < 0.05). Our data link greater large artery stiffening, carotid pulse pressure, and forward wave energy to greater cerebral pulsatility, while greater carotid wave reflection may enhance cerebral pulsatile damping. Lower cerebral pulsatile damping among females may contribute to greater age-associated cerebral pulsatile burden compared with males.NEW & NOTEWORTHY Cerebral pulsatility contributes to brain health and depends on a balance between transmission and damping of pulsatile hemodynamics into the cerebrovasculature. Our data indicate that cerebral pulsatility increases with age, female sex, extracranial artery stiffening, forward wave energy, and pulse pressure, whereas pulsatile damping decreases with age and female sex and increases with greater carotid wave reflections. These novel data identify pulsatile damping as a potential contributor to sex differences in cerebral pulsatile burden.