bluuebunny/crossref_metadata_2025 huggingface dataset:
Electrochemical Measurement of Water Transport Numbers in Anion-Exchange Membranes
Authors: Petrovick John G. , Kushner Douglas I. , Goyal Priyamvada , Kusoglu Ahmet , Radke Clayton J. , Weber Adam Z.
Published: November 2023

Anion-exchange membranes (AEMs) are a possible replacement for perfluorosulfonic-acid membranes in energy-conversion devices, primarily due to the hydroxide mobile ion allowing the devices to operate in alkaline conditions with less expensive electrocatalysts. However, the transport properties of AEMs remain understudied, especially electro-osmosis. In this work, an electrochemical technique, where the open-circuit voltage is measured between two ends of a membrane maintained at different relative humidities, is used to determine the water transport number of various ionomers, including Versogen and Sustainion AEMs and Nafion cation-exchange membrane (CEM), as a function of water content and temperature. In addition, the CEMs and AEMs are examined in differing single-ion forms, specifically proton and sodium (CEM) and hydroxide and carbonate (AEM). Carbonate-form AEMs have the highest transport number (∼11), followed by sodium-form CEMs (∼8), hydroxide-form AEMs (∼6), and proton-form CEMs (∼3). Finally, a multicomponent transport model based on the Stefan-Maxwell-Onsager framework of binary interactions is used to develop a link between water transport number and water-transport properties, extracting a range for the unmeasured membrane water permeability of Versogen as a function of water content.
Impedance and Dielectric Spectroscopy of Functional Materials: A Critical Evaluation of the Two Techniques
Authors: Ramírez-González Julia , Sinclair Derek C. , West Anthony R.
Published: November 2023

Impedance and dielectric spectroscopies are closely related techniques for measuring the electrical properties of materials. The techniques differ in two ways. First, impedance measurements are usually made over several decades of frequency (i.e. broadband) whereas most dielectric measurements are made at fixed frequency. Second, time constants that control semicircles in impedance complex plane plots and peaks in permittivity or tan δ spectroscopic plots are not the same. Differences between the techniques are confined to data analysis procedures and interpretation since they use similar instrumentation for measurements and data collection. In impedance data, time constants represent conducting components and parallel resistance-capacitance (RC) combinations; in permittivity data, they represent dielectric processes and series RC combinations. Using broadband data, it is possible to (i) determine the best equivalent circuit to fit experimental data, (ii) unambiguously evaluate and assign resistance, capacitance, and time constant parameters to regions of the material being measured and (iii) quantify departures from ideality using constant phase elements, CPEs. Using fixed frequency, variable temperature data in either impedance or dielectric methodologies, it is possible to detect the presence of different electrical components that contribute to a data set. However, it is not possible to separate the effects of frequency and temperature in terms of equivalent circuits, nor to deconvolute, parametrise, quantify, and assign the results to different regions of the sample. The advantages of using broadband measurements are highlighted with two examples: calcium copper titanate, CCTO which is often, erroneously, described as a giant or colossal dielectric; lead magnesium niobate, PMN, the classic relaxor ferroelectric whose characteristic properties are controlled entirely by the presence of non-ideality, represented by a CPE, in its equivalent circuit.
Design of Active Integrated GNSS Antenna Based on the Impedance Transforming Quadrature Four-Feed Network
Authors: Wang Yao , Liu Hongmei , Li Shuo , Wang Zhongbao , Fang Shaojun
Published: November 2023

In the paper, a wideband miniaturized impedance-transforming quadrature four-feed network with a flat output phase difference is presented and applied to the design of an active integrated GNSS antenna where no extra impedance matching circuit is needed. The features of impedance transformation and flat output phase difference are achieved by the proposed miniaturized rat-race coupler. When combining the proposed rat-race coupler with two trans-directional (TRD) couplers, a four-feed network with stable sequential quadrature phase shifts is obtained in the whole GNSS band. Since the quadrature four-feed network has the feature of impedance transformation, integration with a low-noise amplifier (LNA) can be realized without extra impedance matching circuits, which reduce the overall size and losses. For validation, a simple rectangular patch is applied as the radiator, and the active prototype is fabricated. Measurement results show that over the entire GNSS band from 1.164 GHz to 1.610 GHz, the miniaturized integrated antenna exhibits a return loss of more than 10 dB, an axial ratio of less than 3 dB axial ratio, and a gain of greater than 16 dBic.
Common Pollen Modulate Immune Responses against Viral-Like Challenges in Airway Coculture Model
Authors: Tossavainen Tarleena , Martikainen Maria-Viola , Loukola Hanna , Roponen Marjut
Published: November 2023

Recent research indicates that exposure to pollen increases the risk and severity of respiratory infections, while studies also suggest that it may possess a protective function. Our aim was to investigate how exposure to common pollen modifies airway cells’ responses to viral- or bacterial-like challenges and vice versa. Cocultured A549 and THP-1 cells were exposed to three doses of four different pollens (Alnus glutinosa, Betula pendula, Phleum pratense, or Ambrosia artemisiifolia) and subsequently to Toll-like receptor (TLR) ligands mimicking bacterial and viral challenges (TLR3, TLR4, TLR7/8). The stimulation experiment was replicated in reverse order. Toxicological and immunological end points were analyzed. When cells were primed with pollen, especially with grass (P. pratense) or weed (A. artemisiifolia), the ability of cells to secrete cytokines in response to bacterial- and viral-like exposure was decreased. In contrast, cells primed with viral ligand TLR7/8 showed greater cytokine responses against pollen than cells exposed to ligands or pollen alone. Our results suggest that pollen exposure potentially weakens immune reactions to bacterial- or viral-like challenges by modulating cytokine production. They also indicate that TLR7/8-mediated viral challenges could elicit exaggerated immune responses against pollen. Both mechanisms could contribute to the acceleration and complication of infections during the pollen season.
Review of the Effect of Grinding Aids and Admixtures on the Performance of Cements
Authors: Nthiga Njiru Eric , Wachira Muthengia Jackson , Mulwa Munyao Onesmus , Karanja Mutitu Daniel , Munyao Musyoki David
Published: November 2023

Grinding aids (GAs) are polar chemicals introduced in cement mills in either liquid or powder form to improve on mill grindability efficiency. Studies have shown that some GAs not only help in grinding efficiency but also play vital roles in improving the product particle size distribution, product ability to flow in the mill, grinding energy reduction, and improvement on the separator efficiency. This review investigated the impacts of the GAs on the performance of some properties of cement when used as either mortar and/or concrete. The influence of the GAs incorporation in cement grinding on properties such as workability and setting times of the placed concrete and/or mortar has been covered in this review. The performance of GAs on ordinary portland cement (OPC) and blended cements with other supplementary cementitious materials such as pozzolana, fly ash, and slag has also been discussed. This is in view to tapping the maximum benefits of using GAs in cement production and use. This review work established that GAs have a positive influence on mill performance when properly applied. It further established that blended cements work better when dosed with additives such as GAs and/or quality improvers when compared to OPC. The review work demonstrated that some superplasticizers help in lowering the water demand in highly blended pozzolanic-based cements. The review finally recommended that the future course of action in the production of blended cements should apply GAs. This is in order to help produce highly replaced blended cements that are sustainable.
Retailer‐to‐Individual Customer Product Supply Strategies Under a Semireal Demand Pattern
Authors: Zhuo Zhiyi , Chen Shuhong , Lin Weihua , Yan Hong , He Yue
Published: November 2023

In the consumer goods supply chain, there are three different modes of demand: real, false, and semireal. It is an interesting topic to discuss the optimal profit of enterprises according to these three demand patterns. This paper develops three mathematical models that can be used to investigate the factors that affect retailers with respect to the design of product supply strategies for individual customers under a semireal demand pattern and thereby addresses the problem of retailers’ maximum profitability. The results of the present study show that these models may effectively help retailers develop appropriate supply strategies for individual customers under a semireal demand pattern; in turn, this may help retailers improve operational performance. The main contribution of the current study lies in the construction of mathematical models of product supply strategies for the individual customer in the off‐invoice mode, the scan‐back mode, and the unsold‐item processing mode under the semireal demand pattern. The effectiveness of the models has been verified through numerical calculations. In concrete management practice, the mathematical model given in this paper can be used to effectively adjust the quantity of goods purchased, correct retail prices, and optimize sales discounts to maximize profits.
Alveolar Differentiation Drives Resistance to KRAS Inhibition in Lung Adenocarcinoma
Authors: Li Zhuxuan , Zhuang Xueqian , Pan Chun-Hao , Yan Yan , Thummalapalli Rohit , Hallin Jill , Torborg Stefan , Singhal Anupriya , Chang Jason C. , Manchado Eusebio , Dow Lukas E. , Yaeger Rona , Christensen James G. , Lowe Scott W. , Rudin Charles M. , Joost Simon , Tammela Tuomas
Published: November 2023

Lung adenocarcinoma (LUAD), commonly driven by KRAS mutations, is responsible for 7% of all cancer mortality. The first allele-specific KRAS inhibitors were recently approved in LUAD, but the clinical benefit is limited by intrinsic and acquired resistance. LUAD predominantly arises from alveolar type 2 (AT2) cells, which function as facultative alveolar stem cells by self-renewing and replacing alveolar type 1 (AT1) cells. Using genetically engineered mouse models, patient-derived xenografts, and patient samples, we found inhibition of KRAS promotes transition to a quiescent AT1-like cancer cell state in LUAD tumors. Similarly, suppressing Kras induced AT1 differentiation of wild-type AT2 cells upon lung injury. The AT1-like LUAD cells exhibited high growth and differentiation potential upon treatment cessation, whereas ablation of the AT1-like cells robustly improved treatment response to KRAS inhibitors. Our results uncover an unexpected role for KRAS in promoting intratumoral heterogeneity and suggest that targeting alveolar differentiation may augment KRAS-targeted therapies in LUAD.

Significance:

Treatment resistance limits response to KRAS inhibitors in LUAD patients. We find LUAD residual disease following KRAS targeting is composed of AT1-like cancer cells with the capacity to reignite tumorigenesis. Targeting the AT1-like cells augments responses to KRAS inhibition, elucidating a therapeutic strategy to overcome resistance to KRAS-targeted therapy.

This article is featured in Selected Articles from This Issue, p. 201
First-in-Human Study of the Reversible BTK Inhibitor Nemtabrutinib in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia and B-Cell Non–Hodgkin Lymphoma
Authors: Woyach Jennifer A. , Stephens Deborah M. , Flinn Ian W. , Bhat Seema A. , Savage Ronald E. , Chai Feng , Eathiraj Sudharshan , Reiff Sean D. , Muhowski Elizabeth M. , Granlund Lindsey , Szuszkiewicz Lyndsey , Wang Wayne , Schwartz Brian , Ghori Razi , Farooqui Mohammed Z.H. , Byrd John C.
Published: November 2023

Nemtabrutinib is an orally bioavailable, reversible inhibitor of Bruton tyrosine kinase (BTK) and C481S mutant BTK. We evaluated the safety, pharmacology, and antitumor activity of nemtabrutinib in relapsed/refractory hematologic malignancies. Forty-eight patients with chronic lymphocytic leukemia (CLL), B-cell non–Hodgkin lymphoma (NHL), or Waldenström macroglobulinemia (WM), relapsed/refractory after ≥2 prior therapies were enrolled in the open-label, single-arm, phase I MK-1026-001 study (NCT03162536) to receive nemtabrutinib 5 to 75 mg once daily in 28-day cycles. Dose finding progressed using a 3 + 3 dose escalation design. Primary endpoints were safety and the recommended phase II dose (RP2D). Among 47 treated patients, 29 had CLL, 17 had NHL, and 1 had WM. Grade ≥3 treatment-emergent adverse events occurred in 37 (89%), most commonly neutropenia (11; 23.4%), febrile neutropenia (7; 14.9%), and pneumonia (7; 14.9%). The RP2D was 65 mg daily. An overall response rate of 75% was observed in patients with CLL at 65 mg daily.

Significance:

This first-in-human phase I study demonstrates the safety and preliminary efficacy of nemtabrutinib in patients with relapsed/refractory B-cell malignancies. These data support further exploration of nemtabrutinib in larger clinical studies.

This article is featured in Selected Articles from This Issue, p. 5
Patient Benefits of Radical Prostatectomy in Certified Prostate Cancer Centers: Comparative Results from the Multicenter IMPROVE Study
Authors: Sikic Danijel , Fiebig Christian , Wullich Bernd , Wolff Ingmar , Hoschke Bernd , Manseck Andreas , Gillitzer Rolf , Burger Maximilian , Steinestel Julie , Harke Nina , Löbig Niklas , Distler Florian A. , May Matthias , Peter Julia , Gilfrich Christian
Published: November 2023

Introduction: We investigated differences in treatment outcomes following radical prostatectomy (RP) between certified centers (CCs) and noncertified centers (nCCs) within the IMPROVE study group. Methods: A validated survey assessing various factors, including stress urinary incontinence (SUI) and decision regret (DR), was administered to 950 patients who underwent RP across 19 hospitals (12 CCs and 7 nCCs) at a median follow-up of 15 months after RP (interquartile range: 11–20). The response rate was 74%, with 703 patients participating, including 480 (68%) from CCs. Multivariate binary regression models were used to analyze differences between CCs and nCCs regarding the following binary endpoints: nerve-sparing (NS), positive surgical margins (PSM), SUI (defined as >1 safety pad), complications based on the Clavien-Dindo classification (grade ≥1, grade ≥3) and DR (>15 points indicating critical DR). Results: Considering the multivariate analysis, the rate of NS surgery was lower in CCs than in nCCs (OR = 0.52; p = 0.004). No significant differences were observed in the PSM rate (OR = 1.67; p = 0.051), SUI (OR = 1.03; p = 0.919), and DR (OR = 1.00; p = 0.990). SUI (OR 0.39; p < 0.001) and DR (OR 0.62; p = 0.026) were reported significantly less frequently by patients treated with robotic-assisted RP, which was significantly more often performed in CCs than in nCCs (68.3% vs. 18%; p < 0.001). The total complication rate was 45% lower in CCs (OR = 0.55; p = 0.004), although the number of complications requiring intervention (Clavien-Dindo classification ≥3) did not differ significantly between CCs and nCCs (OR = 2.52; p = 0.051). Conclusion: Within the IMPROVE study group, similarly favorable outcomes after RP were found in both CCs and nCCs, which, however, cannot be transferred to the general treatment landscape of PCA in Germany. Of note, robotic-assisted RP was more often performed in CCs and associated with less SUI and DR, while open prostatectomy was the treatment of choice in low-volume nCCs. Future prospective and region wide studies should also investigate the surgeon caseload and experience as well as a spillover effect of the certification process on nCCs.
Inverted Internal Limiting Membrane Flap versus Internal Limiting Membrane Peeling for <400 μm Macular Hole: A Meta-Analysis and Systematic Review
Authors: Li Pingping , Li Lu , Wu Jianhua
Published: November 2023

Introduction: The inverted internal limiting membrane (ILM) flap technique was initially developed for the closure of large macular holes (MHs). However, its efficacy in treating small holes has been a matter of debate. This study aimed to compare the anatomical and visual outcomes of vitrectomy (PPV) combined with the inverted ILM flap and ILM peeling in cases of small and medium-sized MHs. Methods: A meta-analysis was conducted by searching the relevant literature in databases, including PubMed, Web of Science, Embase, and Cochrane Library. The search included articles published from the inception of the databases up until January 2023. The inclusion criteria limited the studies to only experimental-based research. The heterogeneity, publication bias, and sensitivity analysis were performed to ensure the statistical power and reliability of the analysis. Results: Five studies, including two non-randomized concurrent control trials and three non-randomized concurrent control trials, comprising a total of 269 eyes, were analysed. The results showed no significant difference in the MH closure rate between the two groups (odds ratio (OR) = 0.29, 95% confidence interval: 0.04–1.96, p = 0.33). Furthermore, there were no significant differences observed in visual acuity, external limiting membrane (ELM), and ellipsoid zone (EZ) integrity at 3 months (ELM OR = 0.88, EZ OR = 0.85) or 12 months (ELM OR = 0.96, EZ OR = 1.39) post-operation between the two groups. Conclusion: The surgical repair of MHs smaller than 400 μm with ILM flap seems to be similar in visual acuity improvement and anatomical recovery compared to the traditional technique.
Abstract 16902: Molecular Basis of the Vascular Cell Phenotypic Switch and Wall Remodeling in Abdominal Aortic Aneurysm: NOX4 NADPH Oxidase-Derived Mitochondrial Oxidative Stress and DNA Damage
Authors: Vendrov Aleksandr E , Silveira Fernandes Chamon Jamille , Levin Julia , Hayami Takayuki , Runge Marschall S , Madamanchi Nageswara R
Published: November 2023

Vascular cells phenotypic changes and wall remodeling are the hallmarks of abdominal aortic aneurysm (AAA) pathology. Mitochondrial oxidative stress (mtOS) is associated with the vascular smooth muscle cells (SMC) and macrophage phenotypic switch. We previously reported that NOX4 NADPH oxidase expression is increased in cardiovascular cells in response to pathological insult inducing mtOS and dysfunction and vascular disease progression. We tested the hypothesis that NOX4-dependent mtOS and DNA damage induce vascular phenotypic changes and remodeling resulting in AAA progression. In angiotensin II (Ang II)-induced AAA model
Apoe
-/-
/
Nox4
Tg mice with mitochondria-targeted overexpression of NOX4 had the highest, whereas
Apoe
-/-
/
Nox4
-/-
displayed the lowest incidence of AAA, abdominal aorta area and diameter as compared with
Apoe
-/-
mice. The aortic wall ROS levels, oxidative DNA damage and DNA damage response markers, elastin degradation index, MMP2 expression, and macrophage infiltration were significantly higher in AngII-treated
Apoe
-/-
/
Nox4
TG mice compared with
Apoe
-/-
or
Apoe
-/-
/
Nox4
-/-
mice. Spectral flow cytometry analysis of AAA cell suspension from Ang II-infused mice revealed a decrease in contractile SMCs but an increase in macrophage-like SMC populations, as well as increased number of infiltrating pro-inflammatory macrophages in
Apoe
-/-
/
Nox4
TG mice. As compared with wild-type or

Nox4
-/-

mice, Ang II-treated SMC from
Nox4
TG mice showed significantly elevated mtOS, DNA damage, dysfunction, as well as activation of cGAS-STING pathway and NLRP3/AIM2 inflammasome expression. Flow cytometry analysis of Ang II-treated
Nox4
TG mice SMC contained a lower proportion of cells with contractile markers (ACTA2
+
, MYH11
+
, TAGLN
+
) and a higher proportion of cells with macrophage-like markers (CD68
+
, CD11b
+
, LGALS3
+
). These data suggest that NOX4-dependent mitochondrial DNA damage and activation of DNA-sensing pathways have a causal role in AAA development, leading to macrophage-like SMCs, increased inflammation, and vessel wall remodeling. NOX4 inhibition and mitochondrial function augmentation may be beneficial in preserving aortic wall integrity in AAA-susceptible patients.
Abstract 16908: CTX310: An Investigational
in vivo
CRISPR-Based Therapy Efficiently and Durably Reduces ANGPTL3 Protein and Triglyceride Levels in Non-Human Primates After a Single Dose
Authors: Morrow Phuong Khanh , Chen Yi-Shan , Serwer Laura , Detwiler Zachary , Flanagan Nicole , Koch Elizabeth , Lei Zhang Maria , Mu Michelle , Nguyen Thao , Sula Erisa , Thorstensen Erin , Tomp Samuel , Urbaez Kayla , Usadi Jacob , Wang Li , Watrud Kaitlin , Wood Tess , Zhang Xuezhi
Published: November 2023

Background:
Angiopoietin-like 3 (ANGPTL3) is a key regulator of lipid metabolism. In humans, naturally occurring loss-of-function variants in ANGPTL3 are associated with reduced levels of serum lipids and reduced risk of atherosclerotic cardiovascular disease. CTX310™ is an investigational
in vivo
CRISPR/Cas9 gene editing therapy designed to knock out hepatic expression of ANGPTL3. CTX310 consists of Cas9 mRNA and guide RNA (gRNA) targeting
ANGPTL3
encapsulated into lipid nanoparticles (LNPs). Here we assessed the efficacy, safety, and durability of CTX310 in primary human cells, mice, and non-human primates (NHPs).

Methods:
CTX310 was evaluated
in vitro
in primary human hepatocytes (PHHs),
in vivo
in wildtype C57BL/6J and LDLR-/- mice using a mouse surrogate gRNA, and
in vivo
in NHPs where the human target sequence is conserved. For the NHP studies, cynomolgus monkeys were infused with a single dose of CTX310 at doses ranging from 0.5 to 3.0 mg/kg to evaluate efficacy (N=32) and durability (N=8).

Results:
In PHHs, >90% on-target editing was achieved with CTX310, leading to a >90% reduction in ANGPTL3 production. Comprehensive genomic assessment indicated no sign of unintended genomic changes introduced by CTX310. In wildtype mice administered LNPs containing a mouse surrogate gRNA along with the same Cas9 mRNA and lipid components as CTX310, ~50% liver editing yielded a >95% reduction in plasma ANGPTL3 protein and ~40% reduction in triglyceride levels, sustained up to nine months post-dosing. Similar levels of editing and efficacy were observed in LDLR-/- mice, suggesting an LDLR-independent uptake mechanism.In NHPs, dose-dependent editing of
ANGPTL3
in the liver of up to 71% was observed, resulting in reduced levels of plasma ANGPTL3 protein (up to 86%) and triglycerides (up to 64%). Reductions in ANGPTL3 protein and triglycerides were durable past 32 weeks. As is commonly observed with LNP delivery, transient elevation of liver enzymes was observed and resolved within 14 days without intervention.

Conclusion:
CTX310 was well-tolerated in NHPs and led to significant and durable reductions in circulating ANGPTL3 and triglycerides. This data suggests that CTX310 could be used to treat dyslipidemias in humans.
Abstract 16917: Ross Procedure versus Biological Aortic Valve Replacement in Adults in a Single Center Setting: A Propensity Score Matched Comparison
Authors: Penov Kiril , Merz Tobias , Radakovic Dejan , Madrahimov Nodir , Hamouda Khaled , Gorski Armin , Leyh Rainer , Bening Constanze
Published: November 2023

Background:
Guidelines suggested alternative for middle-aged adults undergoing aortic valve replacement is mechanical prosthesis, followed by the Ross procedure (Ross). However, increasingly more patients receive a biological prosthesis (bio AVR) even in young adult age. Is this practice justified?

Objectives:
To compare long-term outcomes in a single center after Ross vs bio AVR.

Methods:
For this retrospective study, we screened 2624 patients 04/2007 - 03/2020. Out of these, 231 received Ross, and 2393 received bio AVR ± CABG or aortic surgery. Exclusion criteria: emergency surgery and concomitant mitral or tricuspid valve surgery. Using 1:1 propensity score 99 matches were paired. Primary end-point was all-cause mortality. Secondary end-point was composite of death, need for repeat intervention, and stroke (MACCE). Median follow-up was 7.5 years (IQR: 4.4 - 10.6 years).

Results:
Mean age for Ross was 56.2±6.1, and for bio AVR was 56.2±5.9. Actuarial 10-year survival for Ross was 89.3%, but significantly lower for the bio AVR 57.9%. All-cause mortality was significantly lower after the Ross procedure compared to the bio AVR (log rank p<0.001). The MACCE-free survival was significantly better after the Ross procedure (log rank p<0.001).

Conclusion:
In middle-aged adults undergoing AVR, the Ross procedure was superior over the conventional bio AVR after 10 years F/U. Bio AVR should therefore be avoided in this patient population every time possible.

Overall long-term survival after Ross vs bio AVR:

MACCE free survival after Ross vs bio AVR:
Abstract 16926: Associations of Preeclampsia and Preterm Delivery With Lifetime Posttraumatic Stress
Authors: Stuart Jennifer J , Rich-Edwards Janet W , Koenen Karestan C , Rexrode Kathryn M
Published: November 2023

Introduction:
Adverse pregnancy outcomes (APOs) are female-specific CVD risk factors while posttraumatic stress disorder (PTSD) is a female-predominant CVD risk factor. Preeclampsia and preterm delivery are acute APOs with negative maternal and fetal consequences that, for some, results in trauma.

Hypothesis:
We hypothesized that individuals with a history of preeclampsia or preterm delivery would be more likely to screen positive for lifetime PTSD.

Methods:
Parous Nurses’ Health Study II participants who responded to a 2008 questionnaire ascertaining trauma (Brief Trauma Questionnaire, with targeted query of 16 event types) and PTSD (Short Screening Scale for DSM-IV PTSD) comprised the analytic sample (n=40,256). Trauma and PTSD were categorized using four categories: no trauma, trauma with no PTSD symptoms, 1-3 symptoms, or ≥4 symptoms (probable PTSD). Ordered logistic regression, using a cumulative logit link and multinomial distribution, estimated odds ratios (OR) and 95% confidence intervals (CI), adjusting for age at enrollment, race/ethnicity, and parental education.

Results:
Seven percent of participants had a history of preeclampsia (n=3,012) while 13.5% (n=5,418) ever delivered preterm. Twenty-one percent of participants screened positive for PTSD (n=8,336), endorsing ≥4 symptoms from their worst trauma. Among participants with PTSD, 66% of those with preterm preeclampsia in their first pregnancy endorsed having a traumatic pregnancy complication or labor/birth, compared to 23% among those who delivered normotensive first pregnancies at term. Odds of PTSD were higher with history of ever preeclampsia (OR=1.36, CI: 1.27-1.45) or preterm delivery (OR=1.41, CI: 1.34-1.48), compared to only normotensive pregnancies and term deliveries, respectively. Further adjustment for physical or sexual abuse in childhood/adolescence did not change conclusions but did attenuate the odds ratio for preeclampsia (OR=1.26, CI: 1.18-1.35).

Conclusions:
History of preeclampsia or preterm delivery identifies a population at higher risk for lifetime posttraumatic stress. Further studies are needed to disentangle temporality and examine to what extent subsequent mental health conditions may mediate the relationship between APOs and CVD.
Abstract 16934: Eicosapentaenoic Acid Inhibits Lipoprotein(a) With Higher Rates of Oxidation Compared to Non-Modified Low-Density Lipoprotein in vitro
Authors: Sherratt Samuel C , Libby Peter , Bhatt Deepak L , Mason Preston
Published: November 2023

Background:
Lp(a) synthesis is the result of covalent binding of apolipoprotein a to apolipoprotein B on LDL particles. Elevated Lp(a) levels are an independent and causal risk factor for cardiovascular (CV) disease. Atherogenic mechanisms for Lp(a) include increased inflammation due to its associated oxidized lipids. The omega-3 fatty acid (n3-FA) EPA administered as icosapent ethyl reduced CV events in REDUCE-IT. As a potential mechanism, EPA inhibits oxidation of different sized ApoB-containing lipoproteins compared to other n3-FAs. We tested EPA effects on oxidation of lipoprotein samples enriched with Lp(a) compared to control LDL samples.

Methods:
Lp(a) was enriched to 40% of total ApoB-containing particles from patients with elevated levels by isopycnic centrifugation. Samples of Lp(a) (100 μg/mL) and non-modified LDL were incubated at 37°C for 30 min with EPA (50 μM). Samples were then subjected to copper sulfate-induced oxidation (20 μM) monitored by formation of malondialdehyde (MDA).

Results:
Lp(a) enriched ApoB particles underwent increased oxidation by 18% after 2 h which was significantly higher than non-modified LDL (13.24 ± 0.47 vs 11.23 ± 0.44 μM, p<0.001). EPA significantly inhibited Lp(a) and non-modified LDL oxidation; after 2 h, EPA inhibited MDA levels by 56% and 76%, respectively (p<0.001). The inhibition of oxidation in both particles with EPA was time dependent.

Conclusions:
Lp(a) enriched plasma underwent oxidation to a greater extent than non-modified LDL and this process was inhibited in a dose-dependent fashion by EPA. The antioxidant actions of EPA may contribute to reduced events in outcome trials, including in subjects with elevated Lp(a).
Abstract 16947: Sotagliflozin, a Dual SGLT 1 and 2 Inhibitor, Has High Membrane Affinity and Hydrocarbon Core Location Compared With Empagliflozin
Authors: Sherratt Samuel C , Weindorf Alexa V , Libby Peter , Bhatt Deepak L , Mason Preston
Published: November 2023

Background:
The dual SGLT-1 and 2 inhibitor sotagliflozin (sota) reduced atherothrombotic events and hospitalization for worsening heart failure in patients with diabetes in clinical trials (SCORED, SOLOIST). Unlike selective SGLT2 inhibitors such as empagliflozin (empa), sota binds with higher affinity to SGLT1, which is located in the intestine, kidney, heart, brain, and vascular endothelial cells. To elucidate the physico-chemical basis for differences in tissue distribution and receptor affinity, we compared the effects of these drugs on membrane binding and molecular location.

Methods:
Membranes reconstituted from cardiac phospholipid and cholesterol were used to measure drug partitioning across a range of cholesterol concentrations. Multilamellar vesicles were prepared as mixtures of cardiac phospholipid (CPL), cholesterol, and each agent at 30 μM or vehicle. Drug-membrane partitioning was determined by rapid centrifugation and UV/Vis spectrophotometry. In parallel experiments, we used small angle x-ray scattering (SAXS) to identify drug location in model membranes containing phosphatidylcholine and cholesterol.

Results:
Sota had a membrane partition coefficient (8590 ± 2078) that was 16-fold higher than empa (519 ± 195, p<0.001) in CPL membranes. This high membrane affinity was preserved over a range of cholesterol levels compared to empa (p<0.001). Consistent with high membrane affinity, SAXS analysis showed that sota had a location evidenced by a broad increase in electron density in the hydrocarbon core extending to approximately 20 Å from the membrane center. By contrast, empa had a location limited to the polar headgroup region, consistent with its lower lipophilicity and tissue penetration.

Conclusions:
Sota had high membrane affinity and distinct location in the hydrocarbon core compared to empa. This may contribute to the effect of its dual SGLT-1 and 2 inhibition in vivo across various tissues including the heart. These distinct membrane interactions may also partially explain the reduced atherothrombotic risk as demonstrated in outcome trials with sota but not selective SGLT-2 inhibitors.
Abstract 19135: Deep Learning Model for Detection of Conduction Disorders and Arrhythmias From PDF Outputs of Commercially Available Wearable Devices
Authors: Sangha Veer , Khunte Akshay , Dhingra Lovedeep S , Oikonomou Evangelos K , Khera Rohan
Published: November 2023

Background:
Wearable and portable devices with ECG capabilities have the potential to enable broad AI-based screening for clinical disorders, but models trained on single-lead signals are limited by challenges accessing the raw signal data from proprietary systems. Additionally, wearable ECGs have traditionally been limited to diagnosing only a few rhythm disorders.

Methods:
From 385,601 clinical ECGs performed at Yale during 2015-2021, we extracted lead I data, and simulated wearable PDF outputs from commercial wearable devices. Gold-standard diagnosis statements from cardiologists accompanying these ECGs were processed and used to generate 41 clinical labels. We developed a multilabel model to predict these labels from wearable-adapted PDF outputs using an EfficientNet-B3 convolutional neural network with self-supervised pretraining. The model deployment pipeline was optimized to segment and process PDF outputs across all commercially available devices as inputs to the model (Fig A & B).

Results:
In a held-out test set of 11,611 ECGs, the model accurately detected a diverse set of disorders. For the rhythm disorders sinus tachycardia, sinus bradycardia, atrial fibrillation, atrial flutter, premature atrial contraction, and premature ventricular contraction, the model had AUROCs of 0.99, 0.98, 0.98, 0.93, 0.96 and 0.95 respectively. For the conduction disorders left bundle branch blocks, right bundle branch blocks, 1
st
and 2
nd
degree AV blocks, the model had AUROCs of 0.98, 0.97, 0.96 and 0.95, respectively. Finally, for key disorders such as STEMI, LVH, and low limb-lead voltage, the model had AUROCs of 0.81, 0.86, and 0.77, respectively (Fig C).

Conclusions:
We developed and validated a deep learning model to identify conduction disorders and arrhythmias from PDF image outputs of wearable and handheld single-lead devices. This approach allows for automated and easily accessible insights into wearable and portable ECGs at the point of care.
Abstract 19153: In-Hospital Outcomes and Complications of Atrial Fibrillation Ablation: A Comparison Between Geriatric and Non-Geriatric Population
Authors: Adabale Olanrewaju , Bolaji Olayiwola , Ouedraogo Faizal , Bandaru Revanth Reddy , Anand Reddy Maligireddy , Antia Akanimo , Yanogo Arnaud , Oghoghorie Stanley O , Kamanu Chukwuemezie , Graham Saeed , Chyn Eric
Published: November 2023

Introduction:
Atrial fibrillation (AF) is the most common arrhythmia associated with significant morbidity and mortality. The availability of different types of ablation for the treatment of AF is improved patient mortality and mitigate the disease burden. However, there is limited data on comparing post ablation results for AF in the geriatric population on geriatric population.

Hypothesis:
To study the in-hospital outcomes and complication of AF ablation among the geriatric and non-geriatric population groups.

Methods:
The National Inpatient Sampling from October 2016 to December 2019, a nationally representative sample of US hospitalizations. Adult (>18 years) inpatient admissions with AF and ablation were identified based on International Classification of Diseases-Tenth Revision. The patient population is divided into three groups based on age i.e., group A (18-64 years), group B (65-74 years), group C (>75 years).

Results:
A total of 15,800 AF patients over the age of 18 undergoing ABLA were identified. Among them, Group A accounted for 36.8%, Group B for 34.2%, and Group C for 28.9% of the patients. The female population in Group A was 28.7%, in Group B it was 40%, and in Group C it was 54.3% (p=0.03). Group C had higher prevalence rates of CHF (53.5%), COPD (22%), and CKD (30%) compared to the other groups (p<0.000). When comparing Group C with Group A and B, patients in Group C experienced higher in-hospital mortality (0.8% vs 0.3% vs 0.4%; p<0.000), cardiac complications (13.4% vs 5.9% vs 7.5%; p<0.000), AKI (17% vs 11% vs 11.8%; p<0.000), and major adverse events (MI or non-fatal stroke or CV death) (28.5% vs 16.9% vs 19.2%; p<0.000). The rates of ICD/pacemaker implantation differed among Group A, B, and C (5.9% vs 10% vs 20.5%; p=0.000).

Conclusions:
Among AF patients undergoing ablation, those aged over 75 demonstrated higher rates of CHF, COPD, and CKD compared to other age groups. This population also experienced increased in-hospital mortality, cardiac complications, AKI, major adverse events (MI or non-fatal stroke or CV death), and had a significantly higher rate of ICD/pacemaker implantation. These findings emphasize the need for tailored interventions and closer monitoring for AF patients aged over 75 to improve outcomes.
Abstract 19154: Impact of Personal ECG Monitoring on Health Care Resource Utilization
Authors: GREEN BENJAMIN , Zema Carla L , Albert David E , Althoff Amanda , Rasouliyan Lawrence , Johnson Drew , Frisch Daniel
Published: November 2023

Introduction:
Atrial fibrillation (AF) monitoring is essential to optimize AF control, reducing the risk of adverse outcomes such as stroke. Traditional noninvasive monitoring options are limited to 30 days. KardiaMobile (KM) are medical-grade, personal ECG devices that record and detect common heart rhythm abnormalities over months to years. This study examined the use of KM to monitor AF and determine its impact on health care resource utilization (HCRU).

Methods:
This retrospective, observational study used anonymized administrative claims from 2017-2022 and linked to KM users with AF to compare their HCRU to AF patients that did not use KM. The index date for the KM group was the first device use after the first AF claim. The index date of the non-KM group was randomly matched. All-cause HCRU was identified within 1 year after index date.

Results:
A total of 243,450 AF patients were included with 121,725 in each group. The KM user group was similar to the comparison group in age (mean age 68.1 [SD=10.7] vs 69.1 [10.4]) and gender (62% males in both groups). The percentage of patients that had at least 1 outpatient visit was higher for the KM group (80% vs 64%, p<0.0001), but lower for ER/urgent care visits (28% vs 30%, p<0.0001) and lower for hospitalizations (16% vs 20%, p<0.0001). Among patients with at least 1 hospitalization, KM users had nearly half as many hospitalizations as the comparison group (Figure, p<0.0001). For those that had an ER/urgent care visit, KM users also had significantly less visits (Figure, p<0.0001).

Conclusions:
AF patients that use a KM personal ECG are more likely to have outpatient visits but have fewer ER/urgent care visits and fewer hospitalizations than those who do not use KM. These results suggest that ER/urgent care and hospitalizations are reduced in AF patients who use KM.

Figure. Comparison of utilization in the year following the index date for those with at least one visit in the category
Cardiovascular Disease and Alzheimer's Disease: The Heart–Brain Axis
Authors: Saeed Anum , Lopez Oscar , Cohen Ann , Reis Steven E.
Published: November 2023

Cardiovascular disease (CVD) remains one of the leading causes of morbidity and mortality in aging adults across the United States. Prior studies indicate that the presence of atherosclerosis, the pathogenic basis of CVD, is linked with dementias. Alzheimer's disease (AD) and AD‐related dementias are a major public health challenge in the United States. Recent studies indicate that ≈3.7 million Americans ≥65 years of age had clinical AD in 2017, with projected increases to 9.3 million by 2060. Treatment options for AD remain limited. Development of disease‐modifying therapies are challenging due, in part, to the long preclinical window of AD. The preclinical incubation period of AD starts in midlife, providing a critical window for identification and optimization of AD risk factors. Studies link AD with CVD risk factors such as hypertension, inflammation, and dyslipidemia. Both AD and CVD are progressive diseases with decades‐long development periods. CVD can clinically manifest several years earlier than AD, making CVD and its risk factors a potential predictor of future AD. The current review focuses on the state of literature on molecular and metabolic pathways modulating the heart–brain axis underlying the potential association of midlife CVD risk factors and their effect on AD and related dementias. Further, we explore potential CVD/dementia preventive strategies during the window of opportunity in midlife and the future of research in the field in the multiomics and novel biomarker use era.
Temporal Trends in Heart Failure Management and Outcomes: Insights From a Japanese Multicenter Registry of Tertiary Care Centers
Authors: Nakamaru Ryo , Kohsaka Shun , Shiraishi Yasuyuki , Kohno Takashi , Goda Ayumi , Nagatomo Yuji , Kitamura Mitsunobu , Nakano Shintaro , Takei Makoto , Mizuno Atsushi , Yoshikawa Tsutomu
Published: November 2023

Background

The management of heart failure (HF) has markedly changed, due to changes in demographics and the emergence of novel pharmacotherapies. However, detailed analyses on the temporal trends in characteristics and outcomes among patients with HF are scarcely available. This study aimed to assess the temporal trends over 11 years in clinical management and outcomes in patients with HF.

Methods and Results

We analyzed data from a multicenter registry of hospitalized patients with acute HF, including 6877 patients registered from 2011 to 2021. Age‐adjusted mortality was calculated using standardized mortality ratios. During the study period, mean age increased from 75.2 years in 2011 to 2012 to 76.4 years in 2020 to 2021 (
P
for trend <0.001). The proportion of HF with reduced ejection fraction (HFrEF, left ventricular ejection fraction <40%) remained constant (from 43.4% to 42.7%,
P
for trend=0.38). The median duration of hospital stays (from 15 to 17 days,
P
for trend<0.001) had increased. As for the implementation of guideline‐directed medical therapy, the use of mineralocorticoid receptor antagonist at discharge increased in patients with HFrEF (from 44.3% to 60.2%,
P
for trend<0.001). There was also an increase in the use of sodium‐glucose cotransporter‐2 inhibitors following their approval for use. The age‐adjusted 1‐year mortality decreased in patients with HFrEF (from 18.0% to 9.3%,
P
for trend<0.001) but not in patients with non‐HFrEF (left ventricular ejection fraction ≥40%; from 9.2% to 9.5%,
P
for trend=0.79).

Conclusions

Hospitalized patients with HF have been aging over the past decade. Their long‐term outcomes after discharge have improved predominantly because of decreased mortality in patients with HFrEF.
Surface-to-Interior Transport Timescales and Ventilation Patterns in a Time-Dependent Circulation Driven by Sustained Climate Warming
Authors: Liu Y. , Primeau F.
Published: November 2023

The effect of climate warming in response to rising atmospheric CO2 on the ventilation of the ocean remains uncertain. Here we make theoretical advances in elucidating the relationship between ideal age and transit time distribution (TTD) in a time-dependent flow. Subsequently, we develop an offline tracer-transport model to characterize the ventilation patterns and time scales in the time-evolving circulation for the 1850–2300 period as simulated with the Community Earth System Model version 1 (CESMv1) under a business-as-usual warming scenario. We found that by 2300 2.1% less water originates from the high-latitude deep water formation regions (both hemispheres) compared to 1850. In compensation, there is an increase in the water originating from the subantarctic. We also found that slowing meridional overturning circulation causes a gradual increase in mean age during the 1850–2300 period, with a globally averaged mean-age increase of ∼110 years in 2300. Where and when the water will be re-exposed to the atmosphere depends on the post-2300 circulation. For example, if we assume that the circulation persists in its year-2300 state (scenario 1), the mean interior-to-surface transit time in year 1850 is ∼1140 years. In contrast, if we assume that the circulation abruptly recovers to its year-1850 state (scenario 2), the mean interior-to-surface transit time in 1850 is only ∼740 years. By 2300, these differences become even larger; in scenario 1, the mean interior-to-surface transit time increases by ∼200 years, whereas scenario 2 decreases by ∼80 years. The dependence of interior-to-surface transit time on the future ocean circulation produces an additional unavoidable uncertainty in the long-term durability of marine carbon dioxide removal strategies.

Significance Statement

The ocean’s circulation, when altered by climate warming, can affect its capacity to absorb heat and CO2, which are crucial for the global climate. In our study, we investigated how global warming, caused by rising CO2 levels, might impact the ocean circulation—the way water moves from deep ocean to the surface and vice versa. We discovered that by 2300, if we continue on our current warming trajectory, the origins of water within the ocean will shift, with less coming from deep, cold zones near the poles and more from subantarctic regions. As a result, deep water will take longer time before it resurfaces than shallow water. How quickly this water travels from deep regions to the surface could change, depending on the state of future ocean circulation. If the circulation remains as predicted in 2300, this journey will take longer. Conversely, if it reverts to the pattern in 1850, the process will be quicker. This variability introduces added uncertainty to strategies aimed at mitigating climate change by storing CO2 in the ocean. Our work highlights the intricate ways in which climate change can influence our oceans, potentially affecting our plans to mitigate global warming.
Born Again French: Explaining Inconsistency in Citizenship Declarations in French Longitudinal Data
Authors: Caron Louise , McAvay Haley , Safi Mirna
Published: November 2023

Citizenship is a fundamental boundary in contemporary societies that entails rights, a sense of belonging, and social status. Drawing on longitudinal census data, this article tracks individual changes in self-reported citizenship over 30 years in France. Respondents choose one of three categories: “French by birth,” “became French,” or “foreigner.” The first category should be stable over the life course: one is born, but cannot become, “French by birth.” Yet, our findings indicate that about 19 percent of foreign-origin respondents in a given census switch to “French by birth” declarations at the next census, in a process we call reclassification. Immigrant assimilation variables, such as nativity and length of stay, and events such as intermarriage, naturalization, and residential mobility, trigger reclassification. Yet reclassification is also higher among individuals with lower socioeconomic status and respondents of African and Southeast Asian origin, as well as those with origins in former French colonies. These findings suggest reclassification is a byproduct of immigrant assimilation, which triggers feelings of national identity, as well as status upgrading, whereby disadvantaged and discriminated groups change their citizenship declaration to compensate for low social status. Empirically novel, reclassification offers original theoretical insights into the meanings of citizenship, civic stratification, and boundary-crossing.