Stepwise Increase Research Articles

Combined western diet and bisphenol A exposure induces an oxidative stress-based paraoxonase 1 response in larval zebrafish

Paraoxonase 1 (PON1) is an antioxidant enzyme linked to metabolic disorders by genome-wide association studies in humans. Exposure to metabolic disrupting chemicals (MDCs) such as bisphenol A (BPA), together with genetic and dietary factors, can increase the risk of metabolic disorders. The objective of this study was to investigate how PON1 responds to the metabolic changes and oxidative stress caused by a western diet, and whether exposure to BPA alters the metabolic and PON1 responses. Zebrafish larvae at 14 days post fertilization were fed a custom-made western diet with and without aquatic exposure to two concentrations of BPA for 5 days. A combination of western diet and 150 μg/L BPA exposure resulted in a stepwise increase in weight, length and oxidative stress, suggesting that BPA amplifies the western diet-induced metabolic shift. PON1 arylesterase activity was increased in all western diet and BPA exposure groups and PON1 lactonase activity was increased when western diet was combined with exposure to 1800 μg/L BPA. Both PON1 activities were positively correlated to oxidative stress. Based on our observations we hypothesize that a western diet caused a shift towards fatty acid-based metabolism, which was increased by BPA exposure. This shift resulted in increased oxidative stress, which in turn was associated with a PON1 activity increase as an antioxidant response. This is the first exploration of PON1 responses to metabolic challenges in zebrafish, and the first study of PON1 in the context of MDC exposure in vertebrates.

A Process Improvement Project to Increase Compliance With Cephalosporin-based Surgical Antimicrobial Prophylaxis in Children With Non-severe Penicillin Allergies

Background/purposeCephalosporins are considered safe and first-line prophylaxis in children with non-severe penicillin allergies. However, use of second-line agents is common and is primarily driven by poor allergic response documentation and misunderstanding of cross-reactivity risk. The goal of this project was to improve compliance with cephalosporin prophylaxis through improved documentation and targeted educational efforts. MethodsA multidisciplinary working group including representatives from allergy, surgery, infectious disease, and pharmacy developed staged interventions to facilitate compliance with cephalosporin prophylaxis. These included: (1) caregiver outreach to clarify incomplete allergy documentation, (2) a decision-support algorithm for prophylaxis use in penicillin-allergic patients, (3) standardized educational resources for surgical faculty and rotating trainees, (4) email reminders with prophylaxis recommendations sent out prior to scheduled cases, and (5) EMR-based decision support during antibiotic ordering. Rates of complete allergy documentation and cephalosporin utilization were compared for general surgery procedures between a 12-month pre-intervention and 14-month post-intervention period. Results578 patients with penicillin allergies recorded in the EMR were included (301 pre-intervention and 277 post-intervention), 54.0% of which received prophylaxis. Compared to the pre-intervention period, complete documentation of allergic reactions increased from 57.1% to 84.2% (p < 0.001) following implementation of all interventions. Appropriate prophylaxis utilization increased from 34.5% to 88.5% following implementation of all interventions (p < 0.001), and evidence of a stepwise increase in appropriate utilization was evident with each intervention stage. Persistent compliance failures during the post-implementation period were most commonly associated with urgent and emergent add-on cases. No adverse events or allergic responses were reported before or after project implementation. ConclusionsCompliance with cephalosporin prophylaxis significantly improved following a multidisciplinary effort targeting education, allergy documentation, and clinical support at the point of care. Ongoing efforts include postoperative audits within 24 h for noncompliant cases in order to identify barriers and improve compliance for urgent and emergent add-on cases. Level of EvidenceIII. Type of StudyProspective.

Existing Nongated CT Coronary Calcium Predicts Operative Risk in Patients Undergoing Noncardiac Surgeries (ENCORES).

Preoperative cardiovascular risk stratification before noncardiac surgery is a common clinical challenge. Coronary artery calcium scores from ECG-gated chest computed tomography (CT) imaging are associated with perioperative events. At the time of preoperative evaluation, many patients will not have had ECG-gated CT imaging, but will have had nongated chest CT studies performed for a variety of noncardiac indications. We evaluated relationships between coronary calcium severity estimated from previous nongated chest CT imaging and perioperative major clinical events (MCE) after noncardiac surgery. We retrospectively identified consecutive adults age ≥45 years who underwent in-hospital, major noncardiac surgery from 2016 to 2020 at a large academic health system composed of 4 acute care centers. All patients had nongated (contrast or noncontrast) chest CT imaging performed within 1 year before surgery. Coronary calcium in each vessel was retrospectively graded from absent to severe using a 0 to 3 scale (absent, mild, moderate, severe) by physicians blinded to clinical data. The estimated coronary calcium burden (ECCB) was computed as the sum of scores for each coronary artery (0 to 9 scale). A Revised Cardiac Risk Index was calculated for each patient. Perioperative MCE was defined as all-cause death or myocardial infarction within 30 days of surgery. A total of 2554 patients (median age, 68 years; 49.7% women; median Revised Cardiac Risk Index, 1) were included. The median time interval from nongated chest CT imaging to noncardiac surgery was 15 days (interquartile range, 3-106 days). The median ECCB was 1 (interquartile range, 0-3). Perioperative MCE occurred in 136 (5.2%) patients. Higher ECCB values were associated with stepwise increases in perioperative MCE (0: 2.9%, 1-2: 3.7%, 3-5: 8.0%; 6-9: 12.6%, P<0.001). Addition of ECCB to a model with the Revised Cardiac Risk Index improved the C-statistic for MCE (from 0.675 to 0.712, P=0.018), with a net reclassification improvement of 0.428 (95% CI, 0.254-0.601, P<0.0001). An ECCB ≥3 was associated with 2-fold higher adjusted odds of MCE versus an ECCB <3 (adjusted odds ratio, 2.11 [95% CI, 1.42-3.12]). Prevalence and severity of coronary calcium obtained from existing nongated chest CT imaging improve preoperative clinical risk stratification before noncardiac surgery.

Phenotyping left ventricular systolic dysfunction in asymptomatic individuals for improved risk stratification.

Left ventricular systolic dysfunction (LSVD) is a heterogeneous condition with several factors influencing prognosis. Better phenotyping of asymptomatic individuals can inform preventative strategies. This study aims to explore the clinical phenotypes of LVSD in initially asymptomatic subjects and their association with clinical outcomes and cardiovascular abnormalities through multi-dimensional data clustering. Clustering analysis was performed on 60 clinically available variables from 1563 UK Biobank participants without pre-existing heart failure (HF) and with left ventricular ejection fraction (LVEF) < 50% on cardiovascular magnetic resonance (CMR) assessment. Risks of developing HF, other cardiovascular events, death, and a composite of major adverse cardiovascular events (MACE) associated with clusters were investigated. Cardiovascular imaging characteristics, not included in the clustering analysis, were also evaluated. Three distinct clusters were identified, differing considerably in lifestyle habits, cardiovascular risk factors, electrocardiographic parameters, and cardiometabolic profiles. A stepwise increase in risk profile was observed from Cluster 1 to Cluster 3, independent of traditional risk factors and LVEF. Compared with Cluster 1, the lowest risk subset, the risk of MACE ranged from 1.42 [95% confidence interval (CI): 1.03-1.96; P < 0.05] for Cluster 2 to 1.72 (95% CI: 1.36-2.35; P < 0.001) for Cluster 3. Cluster 3, the highest risk profile, had features of adverse cardiovascular imaging with the greatest LV re-modelling, myocardial dysfunction, and decrease in arterial compliance. Clustering of clinical variables identified three distinct risk profiles and clinical trajectories of LVSD amongst initially asymptomatic subjects. Improved characterization may facilitate tailored interventions based on the LVSD sub-type and improve clinical outcomes.

Association between diastolic blood pressure during the first 24 h and 28-day mortality in patients with septic shock: a retrospective observational study

BackgroundAlthough the mean arterial pressure (MAP) target of 65 mmHg was achieved, diastolic blood pressure (DBP) was still low in some septic shock patients. The effects of DBP on the prognosis and optimal target for patients with septic shock are unclear. We sought to investigate the relationship between DBP and 28-day mortality in septic shock patients.MethodsIn this retrospective observational study, we obtained data from the Chinese Database in Intensive Care (CDIC). We included patients with an admission diagnosis of septic shock and shock was controlled. DBP was measured every 1 h, and the mean DBP during the first 24 h (mDBP24h) was recorded. The primary outcome was 28-day mortality. Multivariable logistic regression determined the relationship between mDBP24h and 28-day mortality.ResultsIn total, 1251 patients were finally included. The 28-day mortality of included septic shock patients was 28.3%. The mDBP24h, not mSBP24h, was higher among 28-day survivors compared with non-survivors. 28-day mortality was inversely associated with mDBP24h (unadjusted OR 0.814 per 10 mmHg higher mDBP24h, P = 0.003), with a stepwise increase in 28-day mortality at lower mDBP24h. The 28-day mortality of patients with mDBP24h < 59 mmHg had an absolute risk reduction of 9.4% (P = 0.001). And mDBP24h < 59 mmHg was the remaining high risk factor inversely associated with 28-day mortality after multivariable adjustment (adjusted OR 1.915, 95% CI 1.037–3.536, P = 0.038), while mMAP24h and mSBP24h were not.ConclusionIn patients with septic shock after initial resuscitation, we observed an inverse association between mDBP24h and 28-day mortality. The poor outcomes in patients with mDBP24h < 59 mmHg provide indirect evidence supporting a further DBP goal of 59 mmHg for patients with septic shock after MAP of 65 mmHg was achieved.

P07.02.B A FATTY-ACID BASED PROBE FOR NEAR INFRARED FLUORESCENCE GUIDED SURGERY OF GLIOBLASTOMA

Abstract BACKGROUND Glioblastoma (GBM) is the most aggressive primary tumor of the brain with a median survival of 15 months. Maximal safe resection is the initial standard-of-care, but resection is limited by the diffuse invasiveness of the tumor. Fluorescence imaging has been shown to aid intra-operative tumor identification, but the current options fail to do so consistently. Recent literature has shown fatty acid (FA) metabolism and uptake to be altered in glioblastoma. For this reason, we introduce a novel, near-infrared fluorescent dye, fatty-acid indocyanine green (FA-ICG), that aims to target the enhanced fatty acid uptake of glioblastoma. We evaluate this dye in in vitro and in vivo models. MATERIAL AND METHODS FA-ICG consists of palmitic acid, a long-chain, saturated fatty acid, that has been covalently linked to indocyanine green (ICG), as described previously. We validated FA-ICG in vitro in one animal cell line and four (two primary and two recurrent) patient-derived neurosphere glioblastoma cell lines. We performed in vitro temporal uptake dynamics and oleic acid based inhibition assays for FA-ICG and ICG on all cell lines. Time uptake was investigated by starving and then incubating cells with either dye for an increasing length of time. Similarly, inhibition was tested by incubating cells with increasing concentrations of oleic acid (in addition to either FA-ICG or ICG). Subsequently, the dye was tested in an NRMI mouse model without tumor for pharmacokinetic properties. Mice were injected with the dye and blood was collected at multiple time points post-injection. Quantification of fluorescence signals in serum was performed using a fluorescent standard curve. RESULTS FA-ICG was taken up by all glioblastoma cells lines. Across all cell cultures, uptake of FA-ICG showed a stepwise increase of up to 5-30 times higher uptake (compared to uptake at baseline) when cells were starved longer, while ICG uptake showed the same trend in only three out of five cell lines (and only up to 5 times higher uptake than at baseline). Oleic acid was found to inhibit FA-ICG uptake by 40% at low concentrations and up to 80-90% at higher concentrations across all cell lines, while ICG was unaffected. In vivo pharmacokinetics showed FA-ICG to have a mean half-life of 65 minutes in blood. CONCLUSION Our findings indicate that the uptake of FA-ICG is affected by starvation and oleic acid competition across all cell lines while ICG uptake is only partially affected by starvation. In vivo pharmacokinetic shows the half-life of FA-ICG to be significantly longer than that of ICG in literature. Taken together, these findings might point to an enhanced targeting and retention mechanism of FA-ICG in glioblastoma. Therefore, these results support the further translation of FA-ICG for fluorescence guided surgery in GBM.

Risk of Cause-Specific Mortality across Glucose Spectrum in Elderly People: A Nationwide Population-Based Cohort Study.

This study investigated the risk of cause-specific mortality according to glucose tolerance status in elderly South Koreans. A total of 1,292,264 individuals aged ≥65 years who received health examinations in 2009 were identified from the National Health Information Database. Participants were classified as normal glucose tolerance, impaired fasting glucose, newly-diagnosed diabetes, early diabetes (oral hypoglycemic agents ≤2), or advanced diabetes (oral hypoglycemic agents ≥3 or insulin). The risk of system-specific and disease-specific deaths was estimated using multivariate Cox proportional hazards analysis. During a median follow-up of 8.41 years, 257,356 deaths were recorded. Diabetes was associated with significantly higher risk of all-cause mortality (hazard ratio [HR], 1.58; 95% confidence interval [CI], 1.57 to 1.60); death due to circulatory (HR, 1.49; 95% CI, 1.46 to 1.52), respiratory (HR, 1.51; 95% CI, 1.47 to 1.55), and genitourinary systems (HR, 2.22; 95% CI, 2.10 to 2.35); and neoplasms (HR, 1.30; 95% CI, 1.28 to 1.32). Diabetes was also associated with a significantly higher risk of death due to ischemic heart disease (HR, 1.70; 95% CI, 1.63 to 1.76), cerebrovascular disease (HR, 1.46; 95% CI, 1.41 to 1.50), pneumonia (HR, 1.69; 95% CI, 1.63 to 1.76), and acute or chronic kidney disease (HR, 2.23; 95% CI, 2.09 to 2.38). There was a stepwise increase in the risk of death across the glucose spectrum (P for trend <0.0001). Stroke, heart failure, or chronic kidney disease increased the risk of all-cause mortality at every stage of glucose intolerance. A dose-dependent association between the risk of mortality from various causes and severity of glucose tolerance was noted in the elderly population.

Short-Term Changes in Peak VO2 After Initiation of Dapagliflozin in Heart Failure Across Iron Status

BackgroundSome studies have indicated that sodium-glucose cotransporter-2 (SGLT2) inhibitors promote an increase in cell iron use. ObjectivesThe aim of this study was to examine, in patients with stable heart failure with reduced left ventricular ejection fraction (HFrEF), the effect of dapagliflozin on ferrokinetic parameters and whether short-term changes in peak oxygen consumption (Vo2) after dapagliflozin treatment are influenced by baseline and serial ferrokinetic status. MethodsThis was an exploratory analysis of a randomized, double-blind clinical trial that evaluated the effect of dapagliflozin vs placebo on peak Vo2 in patients with HFrEF (NCT04197635) and included 76 of the 90 patients initially enrolled in the trial. Changes in peak Vo2 at 1 and 3 months were explored according to baseline and longitudinal ferrokinetic parameters (natural logarithm [ln] ferritin, transferrin saturation index [TSAT], soluble transferrin receptor, and hepcidin). Linear mixed-effect regression was used for the analyses. ResultsCompared with placebo, dapagliflozin led to a significant decrease in 3-month ln ferritin (P = 0.040) and an increase in 1-month ln soluble transferrin receptor (P = 0.023). Between-treatment comparisons revealed a stepwise increase in peak Vo2 in the dapagliflozin group at 1 and 3 months, which was especially apparent at lower baseline values of TSAT and ferritin (P < 0.05). Lower time-varying values of TSAT (1 and 3 months) also identified patients with greater improvements in peak Vo2. ConclusionsIn patients with stable HFrEF, treatment with dapagliflozin resulted in short-term increases in peak Vo2, which were most marked in patients with surrogates of greater iron deficiency at baseline and during treatment. (Short-Term Effects of Dapagliflozin on Peak Vo2 in HFrEF [DAPA-VO2]; NCT04197635)

Abstract P362: Length Of Stay Discrepancies Between Rural And Urban Hospitals - A Cross Sectional Analysis Of Cardiovascular Disease Health Inequity

Introduction: Rural communities have historically been shown to have greater obstacles to healthcare compared to their urban counterparts. These barriers manifest through multiple factors such as a reduced access to healthcare and public health services, lower availability of specialty care, and a larger number of uninsured. Compounded with a greater poverty rate, these disparities in minority populations have been shown to parallel their worse health outcomes and higher death rates. Our study aims to highlight cardiovascular disease health inequity between rural and urban populations through a cross-sectional analysis of the Length of Stay (LOS) with respect to cardiovascular disease admissions, specifically for unstable angina (UA), NSTEMI, and STEMI. Methods: This is a cross-sectional review for the LOS estimates in patients with cardiovascular disease in the state of New York, stratified by the type of community hospital. This review utilizes the 2020 National Inpatient Sample (NIS) for the state of New York. Cardiovascular disease was categorized using ICD-10 codes for STEMI (I21), NSTEMI (I21.4), and Unstable Angina (I20.0). Community hospital setting was categorized as either rural or urban, determined by the zip code of the primary inpatient hospital. Results: LOS was unique across both classification of cardiovascular disease ( p &lt;0.001) and community hospital setting ( p &lt;0.001). Overall, the LOS was less in urban-level community hospitals compared to their rural counterparts, 3.5 days vs 5.1 days ( p &lt;0.001), as shown in Figure 1. Stratified by the cardiovascular disease classifications, admissions in rural hospitals had an overall increased LOS, 0.8 days for UA ( p &lt;0.001), 1.4 days for NSTEMI ( p &lt;0.001), and 2.7 days for STEMI ( p &lt;0.001). Conclusion: The LOS of patients admitted for ACS was significantly higher across the board for rural hospitals. Furthermore, there was a stepwise increase in the comparative LOS between these two communities as the severity of their cardiovascular disease increased. Factors such as socioeconomic status, general access to healthcare and preventative services, insurance status, and availability of specialty care services are just some of the factors that contribute to rural health disparities.

Impaired Renal Function and Major Cardiovascular Events in Young Adults

BackgroundCardiovascular (CV) disease in young adults (aged 18-39 years) is on the rise. Whether subclinical reductions in kidney function (ie, estimated glomerular filtration rate [eGFR] above the current threshold for chronic kidney disease but below age-expected values) are associated with elevated CV risk is unknown. ObjectivesThe goal of this study was to examine age-specific associations of subclinical eGFR reductions in young adults with major adverse cardiovascular events (MACEs) and MACE plus heart failure (MACE+). MethodsA retrospective cohort study of 8.7 million individuals (3.6 million aged 18-39 years) was constructed using linked provincial health care data sets from Ontario, Canada (January 2008-March 2021). Cox models were used to examine the association of categorized eGFR (50-120 mL/min/1.73 m2) with MACE (first of CV mortality, acute coronary syndrome, and ischemic stroke) and MACE+, stratified according to age (18-39, 40-49, and 50-65 years). ResultsIn the study cohort (mean age 41.3 years; mean eGFR 104.2 mL/min/1.73 m2; median follow-up 9.2 years), a stepwise increase in the relative risk of MACE and MACE+ was observed as early as eGFR <80 mL/min/1.73 m2 in young adults (eg, for MACE, at eGFR 70-79 mL/min/1.73 m2, ages 18-30 years: 2.37 events per 1,000 person years [HR: 1.31; 95% CI: 1.27-1.40]; ages 40-49 years: 6.26 events per 1,000 person years [HR: 1.09; 95% CI: 1.06-1.12]; ages 50-65 years: 14.9 events per 1,000 person years [HR: 1.07; 95% CI: 1.05-1.08]). Results persisted for each MACE component and in additional analyses (stratifying according to past CV disease, accounting for albuminuria at index, and using repeated eGFR measures). ConclusionsIn young adults, eGFR below age-expected values were associated with an elevated risk for MACE and MACE+, warranting age-appropriate risk stratification, proactive monitoring, and timely intervention.

Validation of a Heart Failure Risk Score in a Cohort of Cardiac Resynchronization Therapy Patients Under Remote Monitoring: Results from the TriageHF™ Algorithm.

The heart failure risk status (HFRS) is a validated dynamic tool for risk score prediction, based on the TriageHF™ algorithm (Medtronic, Minneapolis, MN, USA), for the occurrence of a heart failure (HF) event in the 30 days following a remote monitoring (RM) transmission. The aim of this study was to evaluate the accuracy of the HFRS in predicting an unplanned hospital admission due to HF decompensation in a real-world cohort of patients submitted to cardiac resynchronization therapy (CRT). We conducted a single-center review of a cohort of 40 consecutive HF patients, under RM, with CRT devices using the HFRS of the TriageHF™ algorithm. The correlation of the HFRS with hospital admissions was analyzed. During a mean follow-up of 36 months, a stepwise increase in the HFRS was significantly associated with a higher risk of HF admission (odds ratio, 12.7; 95% confidence interval, 3.2-51.5; P < .001), and the HFRS was demonstrated to have good discrimination for HF hospitalization, with an area under the receiver-operating characteristic curve of 0.812. The TriageHF™ algorithm effectively predicted HF-related hospitalization in a cohort of CRT patients during long-term RM follow-up, providing a novel clinical pathway to optimize the clinical management of this complex population.

Genetic Risk Score Analysis Supports a Joint View of TwoClassification Systems for Age-Related Macular Degeneration.

The purpose of this study was to evaluate the utility of combining the Clinical Classification (CC) and the Three Continent age-related macular degeneration (AMD) Consortium Severity Scale (3CACSS) for classification of AMD. In two independent cross-sectional datasets of our population-based AugUR study (Altersbezogene Untersuchungen zur Gesundheit der Universität Regensburg), we graded AMD via color fundus images applying two established classification systems (CC and 3CACSS). We calculated the genetic risk score (GRS) across 50 previously identified variants for late AMD, its association via logistic regression, and area under the curve (AUC) for each AMD stage. We analyzed 2188 persons aged 70 to 95 years. When comparing the two classification systems, we found a distinct pattern: CC "age-related changes" and CC "early AMD" distinguished individuals with 3CACSS "no AMD"; 3CACSS "mild/moderate/severe early AMD" stages, and distinguished CC "intermediate AMD". This suggested a 7-step scale combining the 2 systems: (i) "no AMD", (ii) "age-related changes", (iii) "very early AMD", (i.e. CC "early"), (iv) "mild early AMD", (v) "moderate early AMD", (vi) "severe early AMD", and (vii) "late AMD". GRS association and diagnostic accuracy increased stepwise by increased AMD severity in the 7-step scale and by increased restriction of controls (e.g. for CC "no AMD without age-related changes": AUC = 55.1%, 95% confidence interval [CI] = 51.6, 58.6, AUC = 62.3%, 95% CI=59.1, 65.6, AUC = 63.8%, 95% CI=59.3, 68.3, AUC=78.1%, 95% CI=73.6, 82.5, AUC = 82.2%, 95% CI = 78.4, 86.0, and AUC = 79.2%, 95% CI = 75.4, 83.0). A stepwise increase was also observed by increased drusen size and area. The utility of a 7-step scale is supported by our clinical and GRS data. This harmonization and full data integration provides an immediate simplification over using either CC or 3CACSS and helps to sharpen the control group.

Visual guidance of honeybees approaching a vertical landing surface.

Landing is a critical phase for flying animals, whereby many rely on visual cues to perform controlled touchdown. Foraging honeybees rely on regular landings on flowers to collect food crucial for colony survival and reproduction. Here, we explored how honeybees utilize optical expansion cues to regulate approach flight speed when landing on vertical surfaces. Three sensory-motor control models have been proposed for landings of natural flyers. Landing honeybees maintain a constant optical expansion rate set-point, resulting in a gradual decrease in approach velocity and gentile touchdown. Bumblebees exhibit a similar strategy, but they regularly switch to a new constant optical expansion rate set-point. In contrast, landing birds fly at a constant time to contact to achieve faster landings. Here, we re-examined the landing strategy of honeybees by fitting the three models to individual approach flights of honeybees landing on platforms with varying optical expansion cues. Surprisingly, the landing model identified in bumblebees proved to be the most suitable for these honeybees. This reveals that honeybees adjust their optical expansion rate in a stepwise manner. Bees flying at low optical expansion rates tend to increase their set-point stepwise, while those flying at high optical expansion rates tend to decrease it stepwise. This modular landing control system enables honeybees to land rapidly and reliably under a wide range of initial flight conditions and visual landing platform patterns. The remarkable similarity between the landing strategies of honeybees and bumblebees suggests that this may also be prevalent among other flying insects. Furthermore, these findings hold promising potential for bioinspired guidance systems in flying robots.

Association of gender with cardiovascular and autonomic responses to central hypovolemia.

Lower body negative pressure (LBNP) eliminates the impact of weight-bearing muscles on venous return, as well as the vestibular component of cardiovascular and autonomic responses. We evaluated the hemodynamic and autonomic responses to central hypovolemia, induced by LBNP in both males and females. A total of 44 participants recruited in the study. However, 9 participants did not complete the study protocol. Data from the remaining 35 participants were analysed, 18 males (25.28 ± 3.61 years, 181.50 ± 7.43 cm height, 74.22 ± 9.16 kg weight) and 17 females (22.41 ± 2.73 years, 167.41 ± 6.29 cm height, 59.06 ± 6.91 kg weight). During the experimental protocol, participants underwent three phases, which included 30 min of supine rest, four 4 min intervals of stepwise increases in LBNP from -10 mmHg to -40 mmHg, and 5 min of supine recovery. Throughout the protocol, hemodynamic variables such as blood pressure, heart rate, stroke index, cardiac index, and total peripheral resistance index were continuously monitored. Autonomic variables were calculated from heart rate variability measures, using low and high-frequency spectra, as indicators of sympathetic and parasympathetic activity, respectively. At rest, males exhibited higher systolic (118.56 ± 9.59 mmHg and 110.03 ± 10.88 mmHg, p < 0.05) and mean arterial (89.70 ± 6.86 and 82.65 ± 9.78, p < 0.05) blood pressure as compared to females. Different levels of LBNP altered hemodynamic variables in both males and females: heart rate [F(1,16) = 677.46, p < 0.001], [F(1,16) = 550.87, p < 0.001]; systolic blood pressures [F(1,14) = 3,186.77, p < 0.001], [F(1,17) = 1,345.61, p < 0.001]; diastolic blood pressure [F(1,16) = 1,669.458, p < 0.001], [F(1,16) = 1,127.656, p < 0.001]; mean arterial pressures [F(1,16) = 2,330.44, p < 0.001], [F(1,16) = 1,815.68, p < 0.001], respectively. The increment in heart rates during LBNP was significantly different between both males and females (p = 0.025). The low and high-frequency powers were significantly different for males and females (p = 0.002 and p = 0.001, respectively), with the females having a higher increase in low-frequency spectral power. Cardiovascular activity and autonomic function at rest are influenced by gender. During LBNP application, hemodynamic and autonomic responses differed between genders. These gender-based differences in responses during central hypovolemia could potentially be attributed to the lower sympathetic activity in females. With an increasing number of female crew members in space missions, it is important to understand the role sex-steroid hormones play in the regulation of cardiovascular and autonomic activity, at rest and during LBNP.

Experimental study on mass transfer behavior and mechanism in nuclide-containing sandy soil under temperature gradient

The level of nuclear waste emergency disposal is an important factor restricting the rapid development of the nuclear energy industry under the trend of global energy revolution. To promote the effective application of artificial ground freezing (AGF) for the treatment of nuclear wastewater leakage, the mass transfer and migration mechanism of key nuclides (137Cs, 90Sr, and 129I) during unidirectional freezing of saturated silty sand were elucidated in this study. Temperature sensors and a nuclear magnetic resonance (NMR) were used to explore the internal temperature and moisture variation characteristics of nuclide-containing sandy soil during the freezing. Furthermore, using the designed device, a unidirectional freezing of different nuclide-containing sandy soils was performed to establish a relationship between the development characteristics of the freezing front and the mass transfer of nuclide. The results show that the T2 spectrum of nuclide-containing sandy soils has the most significant change from 0 °C to -1 °C, and the bound water content of I-containing sandy soil remains evident change when the temperature decreases below -1 °C. During unidirectional freezing, owing to the influence of the freezing front on nuclide migration, the resistivity curve exhibits a V-shaped jump, and the concentration peaks appear in turn along the freezing direction and show a stepwise increase. Nuclide mobility is closely related to the freezing rate of the corresponding location. With an increase in freezing thickness, the freezing rate decreases and the nuclide mobility increases. Owing to the combined influence of water-ice phase transition, concentration gradient and matrix suction in sandy soil, the concentration only increases within a small area at the face of the freezing front. The differences in migration behavior of nuclides in sandy soil driven by temperature gradient is mainly due to the different degrees of compression of nuclide ion on the diffusion double electric layer of soil particles, which results in different forms of unfrozen water within the sandy soils. The overall mobility of the three nuclides shows the following sequence: Cs>I>Sr. In the practical application of AGF, attention should be paid to the effects caused by the rapid migration of low-valence cationic nuclides and the retention of high valence cationic nuclides in the frozen wall.

Electrochemical Li+ Insertion/Extraction Reactions at LiPON/Epitaxial Graphene Interfaces.

Redox reactions of the Li+ insertion/extraction from one to two interlayers of graphene (Gr) on area-defined single-crystalline SiC substrates are investigated using lithium phosphorus oxynitride glass (LiPON) as the solid-state electrolyte. Unlike an organic liquid electrolyte, this glassy electrolyte does not induce a reduction current and excludes the desolvation reaction of Li+. Gr electrodes with less than two Gr layers show a single reduction peak and one or two oxidation peaks below +0.21 V (vs Li+/Li), differing distinctly from those of graphite and multilayer Gr, which display multiple peaks (multiple stage transitions). However, this finding aligns with the conventional understanding that graphite stage structure transitions proceed with stepwise increases or decreases in the number of Gr layers between adjacent Li-inserted interlayers. Cyclic voltammetry measurements indicate the presence of surface capacity due to Li+ adsorption/desorption at the LiPON/Gr interface. Moreover, Li+ insertion and extraction induce different charge transfer resistances at the level of a single interlayer. These sensitive measurements are achieved using high-quality epitaxial Gr and LiPON electrolyte, which prevent the formation of a solid electrolyte interphase and the desolvation reaction of Li+. Similar measurements using bilayer Gr produced by chemical vapor deposition coupled with a Gr transfer method and an ethylene carbonate/dimethyl carbonate liquid electrolyte are not reliable. Thus, the proposed method is effective for electrochemical measurement of Gr electrodes with a controlled number of layers.

Understanding the swap Monte Carlo algorithm in a size-polydisperse model glassformer.

The dynamics of a polydisperse model glassformer are investigated by augmenting molecular dynamics (MD) simulation with swap Monte Carlo (SMC). Three variants of the SMC algorithm are analyzed with regard to convergence and performance. We elucidate the microscopic mechanism responsible for the drastic speed-up of structural relaxation at low temperature. It manifests in a stepwise increase of the mean-squared displacement when the timescale between the application of swap sweeps is significantly larger than a characteristic microscopic timescale. Compared to Newtonian dynamics, with the hybrid MD-SMC dynamics the glass transition shifts to a lower temperature and a different temperature dependence of the localization length is found.

Abstract P3134: Impaired Calcium Homeostasis Underlies Lamin A/C Mutation R331Q Associated Atrial Fibrillation

Background: Atrial fibrillation (AF) is one of the first cardiac manifestations in patients harboring mutations in nucleoskeletal protein lamin A/C (LMNA). However, the underlying arrhythmogenic mechanisms are unclear. Objective: We hypothesize that impaired intracellular Ca 2+ -homeostasis contribute to LMNA mutation-associated atrial arrhythmogenesis. Methods: LMNA mutation R331Q was introduced in a healthy control induced pluripotent stem cell (iPSC) line using CRISPR/Cas9 and cells were differentiated into atrial iPSC-derived cardiomyocytes (iPSC-CMs). L-type Ca 2+ current and intracellular Ca 2+ concentration were measured using patch-clamp technique and epifluorescence microscopy (Fluo-3), respectively. Results: R331Q iPSC-CMs demonstrated increased L-type Ca 2+ current density followed by increased amplitude of systolic Ca 2+ transient (CaT) compared to isogenic control (Fig. A). Sarcoplasmic reticulum (SR) Ca 2+ content was evaluated from caffeine-induced CaT amplitude and integrated Na + -Ca 2+ exchange current, and found to be greater in R331Q iPSC-CMs (Fig. B). Confocal line scan analysis revealed an increased Ca 2+ spark frequency in R331Q iPSC-CMs (Fig. C). In addition, by applying a stepwise increase in stimulation frequency (1-5 Hz), R331Q iPSC-CMs developed Ca 2+ alternans at lower threshold frequency (Fig. D). Conclusions: LMNA mutation R331Q is associated with disturbed intracellular Ca 2+ cycling, promoting occurrence of diastolic Ca 2+ sparks and arrhythmogenic Ca 2+ alternans. Collectively, our findings suggest that impaired Ca 2+ homeostasis may contribute to atrial arrhythmogenesis in patients harboring LMNA mutations.

Physiological response of Symbiodiniaceae to thermal stress: Reactive oxygen species, photosynthesis, and relative cell size.

This study investigates the physiological response to heat stress of three genetically different Symbiodiniaceae strains isolated from the scleractinian coral Mussismilia braziliensis, endemic of the Abrolhos Bank, Brazil. Cultures of two Symbiodinium sp. and one Cladocopium sp. were exposed to a stepwise increase in temperature (2°C every second day) ranging from 26°C (modal temperature in Abrolhos) to 32°C (just above the maximum temperature registered in Abrolhos during the third global bleaching event-TGBE). After the cultures reached their final testing temperature, reactive oxygen species (ROS) production, single cell attributes (relative cell size and chlorophyll fluorescence), and photosynthetic efficiency (effective (Y(II)) and maximum (Fv/Fm) quantum yields) were measured within 4 h and 72 h. Non-photochemical coefficient (NPQ) was estimated based on fluorescence values. Population average ROS production was variable across strains and exposure times, reaching up a 2-fold increase at 32°C in one of the Symbiodinium sp. strains. A marked intrapopulation difference was observed in ROS production, with 5 to 25% of the cells producing up to 10 times more than the population average, highlighting the importance of single cell approaches to assess population physiology. Average cell size increases at higher temperatures, likely resulting from cell cycle arrest, whereas chlorophyll fluorescence decreased, especially in 4 h, indicating a photoacclimation response. The conditions tested do not seem to have elicited loss of photosynthetic efficiency nor the activation of non-photochemical mechanisms in the cells. Our results unveiled a generalized thermotolerance in three Symbiodiniaceae strains originated from Abrolhos' corals. Inter and intra-specific variability could be detected, likely reflecting the genetic differences among the strains.

Factors Associated with Presentation of Severe Adolescent Idiopathic Scoliosis

Background: Adolescent idiopathic scoliosis (AIS) is a common referral to pediatric orthopaedic surgeons. Timely treatment with appropriate bracing decreases the risk of curve progression and need for surgical intervention. Despite pediatrician screening, patients still present to orthopaedic surgeons with curve magnitudes too large for nonoperative bracing to prevent progression to surgical curve magnitude. The aim of this study was to identify the sociodemographic differences between patients who are initially diagnosed with mild versus moderate/severe AIS.Methods: This retrospective cross-sectional study included patients aged 10 to 18 years diagnosed with AIS between 2011-2021 at a major metropolitan tertiary care center. Scoliosis severity was classified based on initial radiographs. Sociodemographic factors were recorded including patient addresses, which were cross-referenced with the diversitydatakids.org Child Opportunity Index (COI) database, which analyzes the quality of resources in a geographic area.Results: Gender, health insurance provider, race/ethnicity, and COI were all found to have a statistically significant relationship with Cobb angle (CA) and age at initial presentation. The odds of presenting with severe (versus mild and moderate) scoliosis were 2.3 times higher for patients who identified as Black/African American compared to those who identified as White. Additionally, the odds of initially presenting with severe scoliosis were almost 40% higher in females compared to males. Furthermore, each stepwise increase in COI was associated with a 17%-19% decrease in odds of presenting with severe scoliosis, depending on standardization.Conclusions: There are sociodemographic disparities in the identification and initiation of treatment for AIS. Specifically, the odds of presenting with severe scoliosis are increased in patients who identify as Black/African American or female and/or come from areas with lower access to resources (as defined by COI). Appropriate and timely referral to a pediatric orthopaedic surgeon for AIS treatment thus requires 1) educating primary care providers, pediatricians, and scoliosis screeners on how to appropriately identify scoliosis and the risks associated with late identification/referral and 2) public health initiatives, such as universal school screenings or outreach mobile clinics, to address access to care for patients at risk for late scoliosis identification.Level of Evidence: Level III (Retrospective cohort study) Key Concepts•At the time of diagnosis, a patient's curve magnitude (calculated via Cobb angle) and future growth potential have significant implications in both curve progression and treatment planning.•Avoiding spinal fusion by early curve identification and appropriate nonoperative (i.e., brace) treatment reduces patient risk and healthcare spending.•There are sociodemographic disparities in the identification and initiation of treatment for adolescent idiopathic scoliosis.•The odds of presenting with severe scoliosis are increased in patients who identify as Black/African American or female and/or come from areas with a lower access to resources (as defined by the Child Opportunity Index).