bluuebunny/crossref_metadata_2025 huggingface dataset:
Discussion on the Mechanism of Gandoufumu Decoction Attenuates Liver Damage of Wilson’s Disease by Inhibiting Autophagy through the PI3K/Akt/mTOR Pathway Based on Network Pharmacology and Experimental Verification
Authors: Tang Lulu , Zhao Chenling , Zhang Jing , Dong Ting , Chen Huaizhen , Wei Taohua , Wang Jiuxiang , Yang Wenming
Published: June 2023

Background. Gandoufumu decoction (GDFMD) is a traditional Chinese medicine that has been widely used to treat Wilson’s disease (WD) liver damage patients. However, its specific molecular mechanism currently remains unclear. Autophagy as a key contributor to WD liver damage has been intensely researched in the recent years. Therefore, the aim of this present study is to explore the effect of GDFMD on autophagy in WD liver damage, and the final purpose is to provide scientific evidence for GDFMD treatment in WD liver damage. Methods. The molecular mechanisms and autophagy-related pathways of GDFMD in the treatment of WD liver damage were predicted using network pharmacology. Copper assay kit was used to determine copper content in serum. Enzyme-linked immunosorbent assay (ELISA) was utilized to quantify serum levels of liver enzymes and oxidative stress-related indicators. Hematoxylin-eosin (HE), Masson, and Sirius red staining were used for the characterization of liver pathological changes. Transmission electron microscopy, immunofluorescence, and Western blot analyses were used to evaluate autophagy activity. The impact of the GDFMD on typical autophagy-related pathway (PI3K/Akt/mTOR pathway) molecules was also assessed via Western blot analysis. Results. GDFMD effectively attenuated serum liver enzymes, oxidative stress, autophagy, and degree of hepatic histopathological impairment and reduced serum copper content. Through network pharmacological approaches, PI3K/Akt/mTOR pathway was identified as the typical autophagy-related pathway of GDFMD in the treatment of WD liver damage. Treatment with GDFMD activated the PI3K/Akt/mTOR pathway, an effect that was able to be counteracted by LY294002, a PI3K antagonist or Rapa (rapamycin), an autophagy inducer. Conclusions. GDFMD imparted therapeutic effects on WD through autophagy suppression by acting through the PI3K/Akt/mTOR pathway.
Maternal and Perinatal Outcomes of Pregnant Patients with Coronavirus Disease 2019: Data from a University Hospital Setting in Tirana, Albania, May 2020 to November 2021
Authors: Prifti Enkeleda , Como Najada , Vrapi Enxhi , Qosja Alketa Hoxha , Kreko Evelina , Kryemadhi Nevila , Petrela Elizana , Mehmeti Irsida , Hyska Genci
Published: June 2023

Scientific evidence suggests an increased risk of maternal and obstetric complications in pregnant patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study is aimed at evaluating perinatal and maternal outcomes among patients with coronavirus disease 2019 (COVID-19) in a university hospital setting. This was a prospective cohort study of 177 pregnant women with confirmed SARS-CoV-2 infection at a tertiary hospital between May 2020 and November 2021. Both symptomatic and asymptomatic women with a positive reverse transcription-polymerase chain reaction test result at any time during pregnancy were included in this study. For the purpose of this study, we classified COVID-19 cases into two groups: mild and severe cases. The two groups were then compared to predict how the clinical presentation of COVID-19 affected adverse maternal and perinatal outcomes. Gestational

age
≥
20

weeks at the time of infection was significantly associated with the occurrence of severe forms of the disease (relative risk (RR) 3.98,

p
=
0.01

). Cesarean section was the preferred mode of delivery, with 95 women (62.1%) undergoing surgery. A total of 149 neonates were delivered to women who had confirmed SARS-CoV-2 infection at any time during the course of pregnancy of which thirty-five (23.5%) were admitted to the neonatal intensive care unit (NICU). Severe forms of COVID-19 increased the risk of premature delivery (RR 6.69,

p
<
0.001

), emergency cesarean delivery (RR 9.4,

p
<
0.001

), intensive care hospitalization (RR 51,

p
<
0.001

), and maternal death (RR 12.3,

p
=
0.02

). However, severe forms of SARS-CoV-2 infection are not directly responsible for low birth weight or the need for neonatal resuscitation. Our findings suggest that pregnant women presenting with severe COVID-19 disease are at an increased risk of adverse maternal and perinatal outcomes, such as premature delivery, cesarean section, admission to the ICU, and maternal death. Infection after the 20th week of gestation increases the risk of developing severe forms of the disease.
Agreement between Parkinson Disease Home Diary and Observer Assessments before and after Structured Patient Training
Authors: Janz Carin , Timpka Jonathan , Löhle Matthias , Bremer Alexander , Gandor Florin , Ebersbach Georg , Storch Alexander , Odin Per
Published: June 2023

Objectives. Recent studies showed only fair agreement between observer and patients’ motor state assessments on the Parkinson’s disease (PD) home diary (HD). This could possibly be explained by the patients’ insufficient knowledge about motor fluctuations. Therefore, the study is aimed at investigating the effect of structured training concerning motor fluctuations on the agreement between observer and HD ratings and daily motor state times. Methods. Participants from a previous validation study of the HD were invited back for a study extension. This interventional study consisted of a screening visit including a structured training concerning motor fluctuations and one day of motor ratings onsite during which observer and patient simultaneously and independently evaluated the patient’s motor state every half hour. Results. Observer and 20 patients completed 316 pairs of motor state assessments. The overall agreement was 68% before training and 76% after training (

P
=
.093

) and Cohen’s κ increased from .438 to .559 (

P
=
.320

). There was no significant improvement in the correlation/reliability of HD-documented daily motor state time when compared with observer ratings. Moreover, before training, the agreement in observed “on with dyskinesias” was 58%, and after training, it was 80% (

P
=
.074

). Conclusion. Our structured patient training in motor fluctuations did not significantly improve the agreement between observer and HD or the reliability of daily times spent in the different motor states as an aggregate measure of HD in this PD patient group. However, there are indications of an improvement in the participants’ ability to detect dyskinesias.
Data from ZDHHC2-Mediated AGK Palmitoylation Activates AKT–mTOR Signaling to Reduce Sunitinib Sensitivity in Renal Cell Carcinoma
Authors: Sun Yan , Zhu Liang , Liu Pian , Zhang Huan , Guo Feng , Jin Xin
Published: June 2023

Abstract
Tyrosine kinase inhibitors (TKI) that can suppress the VEGF signaling pathway and angiogenesis have been developed to impede the progression of malignant tumors and have been approved as first-line targeted agents for clear cell renal cell carcinoma (ccRCC). Dysregulation of lipid metabolism is a major driver of TKI resistance in renal cancer. In this study, we showed that the palmitoyl acyltransferase ZDHHC2 is abnormally upregulated in tissues and cell lines resistant to TKIs, such as sunitinib. Upregulation of ZDHHC2 contributed to sunitinib resistance in cells and mice, and ZDHHC2 regulated angiogenesis and cell proliferation in ccRCC. Mechanistically, ZDHHC2 mediated AGK S-palmitoylation to promote translocation of AGK into the plasma membrane and activation of the PI3K–AKT–mTOR signaling pathway in ccRCC, which modulated sunitinib sensitivity. In conclusion, these results identify a ZDHHC2–AGK signaling axis and suggest that ZDHHC2 is a targetable candidate for improving the antitumor efficacy of sunitinib in ccRCC.
Significance:
ZDHHC2 confers sunitinib resistance to clear cell renal cell carcinoma by catalyzing AGK palmitoylation to activate the AKT–mTOR pathway.
Data from Distinct Nrf2 Signaling Thresholds Mediate Lung Tumor Initiation and Progression
Authors: DeBlasi Janine M. , Falzone Aimee , Caldwell Samantha , Prieto-Farigua Nicolas , Prigge Justin R. , Schmidt Edward E. , Chio Iok In Christine , Karreth Florian A. , DeNicola Gina M.
Published: June 2023

Abstract
Mutations in the KEAP1–NRF2 (Kelch-like ECH-associated protein 1–nuclear factor-erythroid 2 p45-related factor 2) pathway occur in up to a third of non–small cell lung cancer (NSCLC) cases and often confer resistance to therapy and poor outcomes. Here, we developed murine alleles of the KEAP1 and NRF2 mutations found in human NSCLC and comprehensively interrogated their impact on tumor initiation and progression. Chronic NRF2 stabilization by Keap1 or Nrf2 mutation was not sufficient to induce tumorigenesis, even in the absence of tumor suppressors, p53 or LKB1. When combined with KrasG12D/+, constitutive NRF2 activation promoted lung tumor initiation and early progression of hyperplasia to low-grade tumors but impaired their progression to advanced-grade tumors, which was reversed by NRF2 deletion. Finally, NRF2 overexpression in KEAP1 mutant human NSCLC cell lines was detrimental to cell proliferation, viability, and anchorage-independent colony formation. Collectively, these results establish the context-dependence and activity threshold for NRF2 during the lung tumorigenic process.
Significance:
Stabilization of the transcription factor NRF2 promotes oncogene-driven tumor initiation but blocks tumor progression, indicating distinct, threshold-dependent effects of the KEAP1/NRF2 pathway in different stages of lung tumorigenesis.
A Giant Urachal Accessory Spleen: Case Report
Authors: Ma Wenmin , Ma Xuejin , Jiang Lin , Yang Wei , Zhang Jiaren , Mu Fangfang , Li Shiguang
Published: June 2023

Accessory spleen (AS) refers to single or multiple splenic tissues which appear outside the relative normal spleen position results from embryonic dysplasia similar in structure and function to the spleen. AS is frequently observed in the splenic hilus and or adjacent to the tail of pancreas, and only a few cases occurred in the pelvic cavity. We present an extremely rare AS case in urachus, which was initially considered as an urachal neoplasm revealed on CT images with big mass. However, the postoperative pathology confirmed it was an AS that had not been reported at urachal before. Urachal AS can be misdiagnosed as a tumor, so it is vital to make an accurate imaging preoperative diagnosis to avoid unnecessary biopsy and surgery.
“Sonhei que morri” Guerra e morte nos sonhos de jovens que cumprem medida socioeducativa de privação de liberdade
Authors: Bayer Bruna , Gurski Rose
Published: June 2023

Este artigo apresenta reflexões acerca da experiência com as Rodas de Sonhos, um dispositivo clínico-político construído em meio aos trabalhos de pesquisa-intervenção do NUPPEC junto aos adolescentes que cumpriam medida socioeducativa de privação de liberdade. Destacamos a temática da guerra e da morte presente nos relatos dos sonhos dos meninos em enlace com o desejo de morte que a sociedade brasileira dirige a esses jovens. Explicitamos o contexto violento da juventude brasileira em situação de vulnerabilidade social, sustentado pela lógica dos discursos capitalistas e neoliberais. Compartilhamos algumas narrativas oníricas, nas quais problematizamos os efeitos das políticas de morte e da violência dirigidas aos jovens negros e pobres do país. Entendemos que as Rodas de Sonhos oferecem um modo de resistência frente aos discursos mortíferos dirigidos a esses jovens.
Clusterização de precedentes de IRPJ no CARF
Authors: Costa Fabiano de Castro Liberato , Martinez Antonio Lopo , Klann Roberto Carlos
Published: June 2023

The objective of this study was to cluster judgments of the Administrative Council of Tax Appeals (CARF) related to corporate income tax (IRPJ) rendered between 2016 and 2020, employing machine learning (ML) techniques for the clustering of textual documents. The analysis resulted in 13 unique clusters, an unprecedented finding in the tax accounting literature in Brazil. This identification is relevant for the CARF, taxpayers, tax administration, and accounting and tax professionals involved in accounting and tax issues related to the IRPJ. The ML algorithms used proved efficient in solving complex natural language processing (NLP) problems, such as creating vector representations of terms and identifying themes in unstructured data, providing valuable contributions to understanding controversial IRPJ issues in light of administrative case law. The clustering of precedents translates into greater accessibility and analysis of patterns in judgments, facilitating decision-making in tax accounting.
Endothelial TIE1 Restricts Angiogenic Sprouting to Coordinate Vein Assembly in Synergy With Its Homologue TIE2
Authors: Cao Xudong , Li Taotao , Xu Beibei , Ding Kai , Li Weimin , Shen Bin , Chu Man , Zhu Dengwen , Rui Li , Shang Zhi , Li Xiao , Wang Yinyin , Zheng Shuyu , Alitalo Kari , Liu Ganqiang , Tang Jing , Kubota Yoshiaki , He Yulong
Published: June 2023

BACKGROUND:

Vascular growth followed by vessel specification is crucial for the establishment of a hierarchical blood vascular network. We have shown that TIE2 is required for vein development while little is known about its homologue TIE1 (tyrosine kinase with immunoglobulin-like and EGF [epithelial growth factor]-like domains 1) in this process.

METHODS:

We analyzed functions of TIE1 as well as its synergy with TIE2 in the regulation of vein formation by employing genetic mouse models targeting
Tie1
,
Tek
, and
Nr2f2
, together with in vitro cultured endothelial cells to decipher the underlying mechanism.

RESULTS:

Cardinal vein growth appeared normal in TIE1-deficient mice, whereas TIE2 deficiency altered the identity of cardinal vein endothelial cells with the aberrant expression of DLL4 (delta-like canonical Notch ligand 4). Interestingly, the growth of cutaneous veins, which was initiated at approximately embryonic day 13.5, was retarded in mice lack of TIE1. TIE1 deficiency disrupted the venous integrity, displaying increased sprouting angiogenesis and vascular bleeding. Abnormal venous sprouts with defective arteriovenous alignment were also observed in the mesenteries of
Tie1
-deleted mice. Mechanistically, TIE1 deficiency resulted in the decreased expression of venous regulators including TIE2 and COUP-TFII (chicken ovalbumin upstream promoter transcription factor, encoded by
Nr2f2
, nuclear receptor subfamily 2 group F member 2) while angiogenic regulators were upregulated. The alteration of TIE2 level by TIE1 insufficiency was further confirmed by the siRNA-mediated knockdown of
Tie1
in cultured endothelial cells. Interestingly, TIE2 insufficiency also reduced the expression of TIE1. Combining the endothelial deletion of
Tie1
with 1 null allele of
Tek
resulted in a progressive increase of vein-associated angiogenesis leading to the formation of vascular tufts in retinas, whereas the loss of
Tie1
alone produced a relatively mild venous defect. Furthermore, the induced deletion of endothelial
Nr2f2
decreased both TIE1 and TIE2.

CONCLUSIONS:

Findings from this study imply that TIE1 and TIE2, together with COUP-TFII, act in a synergistic manner to restrict sprouting angiogenesis during the development of venous system.
Apo CIII Proteoforms, Plasma Lipids, and Cardiovascular Risk in MESA
Authors: Sinari Shripad , Koska Juraj , Hu Yueming , Furtado Jeremy , Jensen Majken K. , Budoff Matthew J. , Nedelkov Dobrin , McClelland Robyn L. , Billheimer Dean , Reaven Peter
Published: June 2023

Background:

Apo CIII (apolipoprotein CIII) is an important regulator of triglyceride metabolism and was associated with cardiovascular risk in several cohorts. It is present in 4 major proteoforms, a native peptide (CIII
0a
), and glycosylated proteoforms with zero (CIII
0b
), 1 (CIII
1
, most abundant), or 2 (CIII
2
) sialic acids, which may differentially modify lipoprotein metabolism. We studied the relationships of these proteoforms with plasma lipids and cardiovascular risk.

Methods:

Apo CIII proteoforms were measured by mass spectrometry immunoassay in baseline plasma samples of 5791 participants of Multi-Ethnic Study of Atherosclerosis, an observational community-based cohort. Standard plasma lipids were collected for up to 16 years and cardiovascular events (myocardial infarction, resuscitated cardiac arrest, or stroke) were adjudicated for up to 17 years.

Results:

Apo CIII proteoform composition differed by age, sex, race and ethnicity, body mass index, and fasting glucose. Notably, CIII
1
was lower in older participants, men and Black and Chinese (versus White) participants, and higher in obesity and diabetes. In contrast, CIII
2
was higher in older participants, men, Black, and Chinese persons, and lower in Hispanic individuals and obesity. Higher CIII
2
to CIII
1
ratio (CIII
2
/III
1
) was associated with lower triglycerides and higher HDL (high-density lipoprotein) in cross-sectional and longitudinal models, independently of clinical and demographic risk factors and total apo CIII. The associations of CIII
0a
/III
1
and CIII
0b
/III
1
with plasma lipids were weaker and varied through cross-sectional and longitudinal analyses. Total apo CIII and CIII
2
/III
1
were positively associated with cardiovascular disease risk (n=669 events, hazard ratios, 1.14 [95% CI, 1.04–1.25] and 1.21 [1.11–1.31], respectively); however, the associations were attenuated after adjustment for clinical and demographic characteristics (1.07 [0.98–1.16]; 1.07 [0.97–1.17]). In contrast, CIII
0b
/III
1
was inversely associated with cardiovascular disease risk even after full adjustment including plasma lipids (0.86 [0.79–0.93]).

Conclusions:

Our data indicate differences in clinical and demographic relationships of apo CIII proteoforms, and highlight the importance of apo CIII proteoform composition in predicting future lipid patterns and cardiovascular disease risk.
Abstract 02: Intravenous Oxygen Microparticles as Resuscitative Fluid Improves Outcomes in a Swine Model of Asphyxial Cardiac Arrest
Authors: Garcia Mancebo Julia , Sack Kristen , Hartford Jay , Dominguez Saffron , Nedder Arthur , Barcarcel-Monzon Michelle , Kheir John , Peng Yifeng
Published: June 2023

Introduction:
Asphyxia-induced cardiac arrest (ACA) can lead to organ damage and death within minutes, with a reported survival rate of 25-38%. It is the leading cause of in-hospital cardiac arrest in children and elderly and the second in adults. The direct injection of oxygen as a rescue therapy for ACA is not yet possible.

Methods:
We manufactured immediate-release intravenous oxygen (IVO
2
) microparticles with a shell composed of biocompatible dextran polymers formed by nanoprecipitation. Following intravenous injection, the hydrophobic shell transitions from a crystalline state to a rapidly dissolving, fluid shell based on pH (A). IVO
2
was manufactured following Good Manufacturing Practice control over particle size, chemical purity, and sterility. Following instrumentation, Yorkshire swine (n=10 control, n=6 IVO
2
) underwent complete asphyxia by endotracheal tube occlusion for 12 minutes (B). ACLS was performed whenever SBP<40 mmHg. At minute 6, 8 and 10 of asphyxia, IVO
2
or placebo (20 mL/kg fluid phase) was administered. Animals were then survived for 4 days in an ICU environment, followed by brain MRI and neurohistology.

Results:
Animals receiving IVO
2
exhibited increased arterial oxygen saturation during asphyxia (p<0.05, C), with less CPR time (p<0.001, D) and higher ROSC (p=0.011, E). Three out of 6 IVO
2
animals vs 0/3 surviving controls were successfully extubated (p=0.035). IVO
2
treatment was associated with increased survival (p=0.037, F) with improved swine neurologic deficit scores (p<0.05, G). MRI (H) and pathology (I) demonstrated devastating hypoxic-ischemic injury in all surviving controls, endpoints that were significantly improved with IVO
2
. No significant adverse effects were noted in hematologic, coagulation, hepatic, or renal function due to IVO
2
.

Conclusion:
Treatment of ACA with IVO
2
may diminish critical oxygen deficit, resulting in improved survival and neurological outcomes.
Abstract 10035: COVID-19 and Cardiac Transplant Rejection - Coincidence or Not?
Authors: Yan Crystal L , Thakkar Rivera Nina
Published: June 2023

Overlap between the histopathologic changes of acute rejection and viral myocarditis presents a diagnostic dilemma. A 34 year-old female with a past medical history of postpartum cardiomyopathy and subsequent orthotopic heart transplant in December 2019, presented for routine surveillance heart biopsy seven months post-transplant. Her AlloMap was elevated and AlloSure was uptrending, concerning for rejection. Ten days prior to presentation, she tested positive for COVID-19 via polymerase chain reaction (PCR) testing. Her symptoms were fatigue and mild headache for two weeks prior to diagnosis. She did not seek medical attention for her symptoms and received no COVID-19 specific treatment. Endomyocardial biopsy showed grade 2R acute cellular rejection. Her echocardiogram was unchanged with normal left ventricular ejection fraction and right ventricular function. SARS-CoV-2 levels were measured by PCR of ribonucleic acid (RNA) isolated from the biopsy specimen and were undetectable. The patient was treated with two short courses of high dose prednisone which eventually abated her transplant rejection. The patient remained positive on PCR testing for COVID-19 for the next six months. Chest x-ray and computed tomography for follow up after COVID-19 infection showed no evidence of pulmonary fibrosis or superinfection considering ongoing immunosuppression for rejection. Our patient illustrates a case of concomitant COVID-19 infection and presumed transplant rejection, raising the question of whether the findings seen on immunohistochemistry were truly rejection or instead an elevated immune response due to COVID-19 infection. Given that our patient had a predominance of CD3+ T cells and less CD68+ macrophages (the former being more prominent in acute cellular rejection and the latter being more prominent in COVID-19 myocarditis), we are inclined to believe the former.
Abstract 10044: An Analysis of Thrombectomy Usage Among Different Hospital Types
Authors: Patel Karan , Taneja Kamil , Oak Solomon , Wolfe Jared , Patel Pratit , Mullen Michael T , Siegler James E
Published: June 2023

Introduction:
Introduction: Prior studies have shown an increase in utilization of thrombectomy in acute stroke over the past few years. However, the likelihood of a thrombectomy being performed may be different among different hospital types.

Methods:
Using the National Emergency Department Sample (NEDS) database, we retrospectively queried patients with acute cerebral infarction from 2006 to 2019. Patients were compared based on treatment with or without thrombectomy. Multivariable logistic regression was performed to estimate the odds of thrombectomy based on hospital characteristics to identify disparities in treatment utilization.

Results:
Of the 2,998,192 patients with an acute stroke, 44,548 (1.49%) had a thrombectomy. Patients treated after 2006 had significantly higher odds of having a thrombectomy, with a stepwise increase in the odds of thrombectomy for each subsequent year. After adjustment for factors such as income status, insurance type, gender, and comorbidities, we found that patients from trauma centers were more likely to undergo thrombectomy than patients admitted to non-trauma centers (Level 1 vs. non-trauma OR 3.06, 95%CI 2.37- 3.95; Level 2 vs. non-trauma OR 1.97, 95%CI 1.42-2.73). Also, patients admitted to metropolitan teaching centers were more likely to have a thrombectomy than patients admitted to non-metropolitan teaching centers (OR 2.77 95%CI 1.80-4.25).

Conclusions:
The varying degrees of thrombectomy usage may be due to centralized resources and multi-disciplinary care available at larger, urban centers. It could also be explained by the lack of neurointerventionalists who perform thrombectomies in community centers.
Abstract 10066: Clonal Hematopoiesis of Indeterminate Potential is Not Associated With Incident Atrial Fibrillation
Authors: Nafissi Navid A , Regan Jessica A , Kwee Lydia C , Kraus William E , Bick Alexander G , Natarajan Pradeep , Jaiswal Siddhartha , Shah Svati H
Published: June 2023

Introduction:
Inflammation is involved in the initiation and maintenance of atrial fibrillation (AF). Clonal hematopoiesis of indeterminate potential (CHIP) increases cardiovascular risk through pro-inflammatory mechanisms.

Hypothesis:
The presence of CHIP is associated with increased risk of incident AF.

Methods:
Individuals with AF were identified from the CATHGEN cohort, a study of 9,334 sequential individuals undergoing cardiac catheterization at Duke University Hospital, using ICD-9/10 codes and ECG interpretations. Incident AF was defined as AF diagnosed after blood sample collection. Individuals with predisposing or provoking conditions leading to AF (i.e., cardiomyopathy, valve disease, congenital heart disease, thyroid disease, and recent STEMI or cardiac surgery) were excluded. The remaining individuals with incident AF were matched 1:1 to controls without an AF diagnosis based on age, sex, ancestry-defined race, BMI, diabetes, hypertension, and smoking status. Whole exome sequencing was performed in DNA extracted from whole blood, and CHIP carriers in 68 genes of interest were identified.

Results:
Among 1,716 individuals with incident AF, 335 had no predisposing or provoking conditions leading to AF. Among these individuals, 17 (5.1%) were CHIP carriers, compared to 18 (5.4%) matched controls (odds ratio, 0.94; 95% confidence interval [CI], 0.48-1.86;
p
=0.9). Ten individuals (3.0%) with incident AF were carriers of a CHIP clone with variant allele fraction >10%, compared to 11 (3.3%) matched controls (odds ratio 0.90; 95% CI, 0.37-2.22;
p
=0.8). Restriction to the two most common genes (
DNMT3A
or
TET2
) also did not show an association between CHIP and AF (
Table 1
).

Conclusions:
There is no association between CHIP carrier status, high burden of CHIP, or CHIP in
DNMT3A
or
TET2
and incident AF in the CATHGEN cohort.
Abstract 10094: Perception of Cardiovascular Disease in Female Health Care Workers and Urgent Opportunity Gaps for Health Promotion
Authors: Bargehr Johannes , Cao Jenny Jia Ling , Mehmood Zia , Evans Jonathan , Aglan Omar , Lwin May , Schofield Rebecca
Published: June 2023

Introduction:
Cardiovascular disease (CVD) is the largest killer in women worldwide, yet minority of GPs and less than 50% of Cardiologists feel well prepared for risk assessment in women. Women have historically been under-represented in many major CV clinical trials. The percentage of women identifying CVD as leading cause of death (LCOD) has declined from 64% in 2009 to 43% in 2019, according to surveys in the United States. In 2020, we conducted the largest single-centre survey in the United Kingdom to explore the perceptions of CVD in female healthcare workforce in North-West Anglia NHS Foundation Trust.

Methods:
In September 2020, a total of 620 female healthcare workers in our institute completed an online questionnaire on health concerns, LCOD in women, screening/risk factors for CVD, and perceived personal risk status. There were 21 questions containing binary, ranked and best single choice answers which took approximately 15-minutes to complete.

Results:
Only 51% respondents were aware of CVD as the LCOD in women and 37% correctly identified lifetime incidence of CVD as one-in-three. Sixty-five percent believed to be at risk of CVD but only 18% had CVD as their biggest health concern. Three-quarters correctly identified CVD risk factors, but 74%, 59% and 40% were not aware of their cholesterol, diabetic status and BP, respectively. CVD screening was deemed necessary aged more than 40 by 31%, and aged more than 50 by 40%. Ninety-percent had never been screened for CVD. One-in-two believed a woman was more likely to survive a heart attack at the age of 60 compared to a man of similar age. Only 12% correctly indicated that BP below 120/80mmHg was normal and 57% were not aware of effects of HRT on CVD. Lastly, 82% did not feel well informed about their CV health.

Conclusions:
The survey did not include baseline demographics to associate age and social/ethnical background with the responses, nevertheless, there are significant gaps in knowledge and misconception about CVD in women among female healthcare workers. This study highlights opportunities for urgent education to bring more screening programmes into practice through major stakeholders i.e. local councils, GPs and Cardiologists.
Abstract 10114: A Systematic Review, Meta-Analysis of Sham and Placebo Controlled Trials Testing Spironolactone and Renal Denervation as Treatments for Resistant Hypertension
Authors: Ahmed Mohammad , Nudy Matthew , Bussa Rahul , Foy Andrew
Published: June 2023

Introduction:
The most common 4
th
-line treatment for resistant hypertension (RHTN) is the addition of a mineralocorticoid receptor antagonist (MRA). Renal denervation (RD) has also been investigated as a treatment option for RHTN. A lack of data on the comparative effectiveness of these two therapies poses challenges in choosing optimal treatment strategies for patients with RHTN.

Methods:
Placebo-controlled and sham-controlled randomized clinical trials testing spironolactone or RD as treatments for RHTN were included in this analysis. Prespecified subgroup analyses comparing the efficacy of MRA and RD were conducted for the outcomes of 24-hour blood pressure (BP) and office BP.

Results:
Fourteen studies (8 MRA and 6 RD) were identified that included 2,306 participants (1,414 MRA and 892 RD). Cochran risk of bias assessment showed 84% of the domains to be low risk of bias for the MRA studies and 88% of the domains to be low risk of bias for the RD studies. The raw mean difference (RMD) between MRA and placebo control was statistically significant for 24-hour systolic (SBP) (-10.59 mmHg; 95% confidence interval (CI) -12.88 to -8.31), 24-hour diastolic (DBP) (-5.03 mmHg; 95% CI -6.75 to -3.32), office SBP (-10.43 mmHg; 95% CI -12.23 to -8.63), and office DBP (-4.10 mmHg; 95% CI -5.18 to -3.02). The RMD between RD and sham control was not statistically significant for 24-hour SBP (-1.85 mmHg; 95% CI -3.88 to 0.18), 24-hour DBP (-0.67 mmHg; 95% CI -1.84 to 0.51), office SBP (-1.93 mmHg; 95% CI -5.17 to 1.31), and office DBP (-1.55 mmHg; 95% CI -3.43 to 0.33). The interaction between the subgroups was statistically significant for all analyses.

Discussion:
MRAs had a greater reduction in 24-hour ambulatory and office BP compared to RD among patients with RHTN. This data may help physicians s counsel their patients regarding optimal treatment options for RHTN.
Abstract 10138: Exercise Inhibits Doxorubicin-Induced Cardiotoxicity by Preventing Cardiomyocyte Cellular Senescence
Authors: Jeyabal Prince , Peng Zhanglong , kleinerman eugenie
Published: June 2023

Introduction:
Doxorubicin (Dox) induces cardiomyocyte cellular senescence thru proinflammatory mechanisms and by damaging DNA, resulting in Dox-induced cardiotoxicity. Inhibiting cardiomyocyte cellular senescence inhibits Dox-induced cardiac damage. We showed that exercise inhibits both acute and late Dox-induced cardiotoxicity using our juvenile cardiotoxicity mouse model. Here we used p16-3MR transgenic mice to track the induction of senescent cardiomyocytes to determine whether exercise prevents Dox-induced cardiotoxicity by inhibiting senescence.

Hypothesis:
Cellular senescence plays a key role in Dox-induced cardiotoxicity in the heart following therapy. Exercise prevents Dox-induced cardiotoxicity by inhibiting myocardial cell senescence.

Methods:
To confirm induction of senescence by Dox
in vitro
,
mouse cardiomyocytes were isolated and treated with 250 nmol/L Dox for 24 h for 24h cells, washed and then analyzed 7 days later for senescent markers. Mice were treated with PBS, Dox (2.5mg/kg 2x/wk for 2 wks), or Dox + exercise (walking 45 min/day at 12 meter/min). Cardiac function was evaluated by echocardiography 24 h after therapy to confirm Dox-induced cardiotoxicity. Heart tissue was collected 14 days after therapy. Tissue sections were analyzed by immunohistochemical and Western immunoblot.

Results:
Dox-induced senescence was confirmed by a significant increase in β-galactosidase in cardiomyocytes from the
in vitro
study. Decreased ejection fraction, fractional shortening and F-actin distribution was seen in Dox but not Dox + exercise-treated mice confirming Dox-induced cardiotoxicity and prevention of heart damage by exercise. There was an increase in p16
INK4a
expression (signifying senescent cells) in cardiac tissue from Dox-treated but not Dox + exercise-treated mice compared with PBS controls.

Conclusion:
Taken together our data demonstrated that exercise inhibited Dox-induced cardiotoxicity by inhibiting the induction of cardiomyocyte senescence.
Abstract 10144: New Cardiovascular Events After Covid 19 Infection
Authors: Russo Pierantonio , Nathan Ramaa , Sicilia Michael , Gosh Anirvan
Published: June 2023

Introduction:
The incidence and persistence of cardiovascular events (CVES) occurring for the first time following COVID-19 is not completely established.

Hypothesis:
After COVID-19 there is an increased risk of new CVES that may persist several months after the acute infection.

Methods:
A retrospective claims analysis using the Symphony Health IDV, healthcare database of administrative medical and pharmacy claims for ~ 280 million lives in the USA. Patients with a claim for COVID-19 between April and June 2020 were identified and a sub cohort with new claims for CVES up to 12 months post COVID-19 was analyzed. Patients with prior history of CVES were excluded

Results:
17,360 patients without prior history of CVES, age range 18-80 year (average: 55; SD: 16), 46% males and 54% females, experienced various CVES for the first-time post COVID-19. Specifically, a sub-cohort of 6,545 (38%) hospitalized patients experienced congestive heart failure (CHF) (18% ); myocardial infarction (MI) (36% ); stroke (54%);Arrythmias (54%); pulmonary embolism (15%) and peripheral arterial thrombosis (1%). Cardiomyopathy/myocarditis was reported in 253 patients. Of the new events, 25% of acute CHF, 46% of acute MI and 31% of acute stroke occurred within 28 days of hospitalization for COVID-19. The hazard of CVES peaked within 1 month from the onset of the infection and persisted up to 12 months after hospitalization. Highest residual risk factors were CHF, pericarditis, and myocarditis. Machine Learning analysis identified hypertension and COPD as strong predictors of new CVES post Covid-19.

Conclusions:
The occurrence of new CVES in survivors of COVID-19 is substantial. A deeper understanding of the biologic mechanisms triggering new cardiovascular disease after COVID-19 infection is needed to design interventions directed at preventing the incidence and persistence of new CVES post COVID-19 infection.
Abstract 10158: Initial Bilateral Pulmonary Artery Banding for Infants With Critical Left Heart Obstruction: A Multi-Institutional Analysis of Outcomes
Authors: Argo Madison B , Barron David J , Eghtesady Pirooz , Alsoufi Bahaaldin , Carrillo Sergio A , Honjo Osami , Husain Adil , Jacobs Jeffrey P , Jegatheeswaran Anusha , Kirklin James K , Lambert Linda M , Paramananthan Tharini , Rahman Maha , Ramakrishnan Karthik , Yerebakan Can , Galantowicz Mark E , Caldarone Christopher A , Decampli William M , Karamlou Tara , Nelson Jennifer , Romano Jennifer C , Turek Joseph W , McCrindle Brian W
Published: June 2023

Introduction:
The hybrid procedure (bilateral PA bands [PAB] ± ductal stent) is a contemporary management option for infants with critical left heart obstruction. We sought to determine patient/procedural characteristics, subsequent outcomes and associated factors after PAB in a multi-institutional study.

Methods:
From 2005-2019, 214 of 1236 infants from 24 Congenital Heart Surgeons’ Society participating institutions underwent PAB. Median follow-up was 7 years. Parametric hazard modeling with competing risk methodology was performed to determine risk and associated factors for end-states of biventricular repair (BVR), Fontan, transplantation (Tx) or death without an end-state.

Results:
PAB was performed at a median age of 7 days & median weight of 3.1 kg. Intention of PAB varied - institutional preference (21%), non-cardiac comorbidities (20%), BVR consideration (12%), etc. Ductal stent was placed in 69% of patients (74% same day as PAB) and atrial septal interventions occurred in 61% (24% same day as PAB). Preoperative comorbidities (e.g. prematurity, genetic syndromes, neurological diagnoses, etc.) were present in 70%. At 5 years, 9% had reached BVR, 36% Fontan and 12% Tx (21/26 Tx immediately after PAB), with 35% having died and 8% alive without an end-state (Figure). Significant factors associated with BVR were presence of VSD and ductal stent; with Tx: earlier era, underlying aortic atresia, older age and greater weight at PAB, and absence of ductal stent; with death: low birth weight, ≥ moderate tricuspid valve regurgitation before PAB, & older age at PAB.

Conclusions:
Heterogeneity is prevalent in patient/procedural characteristics and subsequent procedures and outcomes after PAB, possibly influenced by institutional preference and different intended management pathways. There is important mortality and <50% of patients achieve a Fontan or BVR. Preoperative factors influence the use of this approach and thus are an important influence on outcomes.
Abstract 10172: Q Neurons-Induced Hypometabolism Ameliorates Acute Kidney Injury Associated With Renal Ischemia in a Mouse Model Mimicking Cardiovascular Surgery Requiring Circulatory Arrest
Authors: Kyo Shoichi , Murata Kozue , Kawatou Masahide , Minatoya Kenji , Sunagawa Genshiro A , Masumoto Hidetoshi
Published: June 2023

Introduction:
Acute kidney injury (AKI) is a serious complication after cardiovascular surgery requiring circulatory arrest and hypothermia has been used for organ protection. We recently reported that mice can be induced into a hibernation-like hypometabolic state by the stimulation of a specific neuron producing pyroglutamylated RFamide peptide (QRFP) located at hypothalamus (Q neurons-induced hypometabolism; QIH). Here, we investigated the efficacy of QIH for the amelioration of AKI in an experimental circulatory arrest under normal and reduced body temperature using a transgenic mouse model in which QIH can be induced.

Methods:
We genetically prepared mice in which Q neurons specifically express iCre, a Cre recombinase (Qrfp
iCre
mice), from male C57/B6J mice. To prepare QIH-ready mice, we intracranially injected AAV8-hSyn-DIO-hM3-mCherry targeting hypothalamus for specific expression of hM3Dq in which QIH can be induced by intraperitoneal injection (i.p.) of clozapine-N-oxide (CNO), an agonist of hM3Dq. For the control, we injected AAV8-hSyn-DIO-mCherry. Mice were divided into 4 groups (n=6 for each): QIH-ready; normothermia (QN), QIH-ready; hypothermia (QH), control; normothermia (CN), and control; hypothermia (CH). At 3 hours after CNO i.p., left thoracotomy and 15-minutes descending aorta cross-clamping were conducted. After re-perfusion, we collected kidneys and evaluated histological changes and serum biochemical markers, neutrophil gelatinase-associated lipocalin (NGAL) and Cystatin C indicating early kidney injury.

Results:
Normothermia showed higher tubular injury scores than those in hypothermia (QN vs QH: p=0.0021, CN vs CH: p<0.001). QN showed a lower tendency than CN (CN vs QN: 3.0±1.1 vs 2.5±0.55, p=0.51). QN exhibited lower NGAL and Cystatin C levels than those in CN (NGAL: CN vs QN:1.51±0.71 vs 0.82±0.32, p=0.0414 / Cystatin C: 1.48±0.39 vs 0.71±0.26, p=0.0015). There was no significant difference between QN and QH (NGAL: 0.82±0.32 vs 0.44±0.13, p=0.411 / Cystatin C: 0.71±0.26 vs 0.65±0.22, p=0.987).

Conclusions:
QIH partly ameliorated AKI in a mouse ischemia model even in normothermia. QIH might be a promising approach to achieving sufficient kidney protection without hypothermic circulatory arrest in the future.
Abstract 10184: The Risk Factors for Ischemic Sudden Cardiac Death in Women
Authors: Hookana Ida , Holmstrom Lauri , Kiviniemi Antti , Kentta Tuomas , Haukilahti Anette , Vahatalo Juha , Tulppo Mikko , Ukkola Olavi , Lepojarvi Samuli , Tikkanen Jani , Piira Olli-Pekka , Pakanen Lasse , Perkiomaki Juha , Huikuri Heikki , Junttila Juhani
Published: June 2023

Background:
Sudden cardiac death (SCD) is a significant cause of death accounting for 15-20 % of all deaths in Western countries. Coronary artery disease (CAD) is the most common cause of SCD. Even though women are at a lower risk for SCD & CAD, the decline in mortality of these conditions has been slower in women than in men. Previous studies have shown that CAD is more challenging to detect in women, hence SCD is often the first manifestation of underlying CAD among women. The aim of this case-control study was to determine factors associated to SCD due to CAD in women.

Methods:
The study group consists of women with ischemic SCD (N=888) derived from the Fingesture study conducted in Northern Finland from 1998 to 2017 and all SCDs were autopsy verified. The control group consisted of women with angiographically verified CAD without SCD occurring during the 5-year-follow-up (N=610) from Artemis study. To perform comparison between these groups, we utilized medical records, autopsy findings, echocardiograms and ECGs.

Results:
Subjects with SCD were older (73.2±11.3 vs. 68.8±8.0 p < 0.001) and were more likely to be smokers or ex-smokers (37.1% vs. 27.6 %, p = 0.045). The proportion of subjects with prior myocardial infarction (MI) was higher in controls (46.9 % vs. 41.4 % in SCD subjects, p = 0.037), but in contrast, SCD subjects were more likely to have underlying silent MI (25.6 % vs. 2.4 % in CAD controls, p < 0.001). Decreased left ventricular ejection fraction (LVEF 35-55 %) was more common finding in SCD subjects than in CAD controls (33.1% vs. 8.7 %, p < 0.001, respectively) as well as LV hypertrophy (70.9 % vs. 55.1 %, p < 0.001, respectively). Various ECG-abnormalities were more common in SCD subjects including higher heart rate, prolonged QTc- and JTc-intervals, wide or fragmented QRS-complex, short PR-interval and early repolarization. The prevalence of Q-waves and T-inversions did not differ between these groups.

Conclusions:
Underlying CAD and MI are often underdiagnosed in women with ischemic SCD considering the high proportion of silent myocardial infarctions and the number of subjects without prior CAD diagnosis. LV hypertrophy as well as decreased LVEF were more frequent findings in SCD subjects. Several ECG abnormalities were more common among subjects with SCD.
Abstract 10188: Does Myocardial Contraction Fraction Predict Mortality in the Oldest Old
Authors: Leibowitz David , Bishara Yara , Jacobs Jeremy , Gilon Dan , Stessman-Lande Irit , stessman jochanan
Published: June 2023

Background:
People over the age of 85 are the world's most rapidly growing age group and have a high incidence of cardiovascular mortality. Ejection fraction (EF), the most commonly used index of systolic function, may be limited prognostically in this population given the high incidence of left ventricular hypertrophy and myocardial contraction fraction (MCF) may be more accurate. The objective of this longitudinal study was to assess the prognosis of MCF in an age-homogenous, community-dwelling population of subjects.

Methods:
Subjects were recruited from the Jerusalem Longitudinal Cohort Study. Echocardiography was performed with a portable echocardiograph at the subjects place of residence. Standard echocardiographic assessment of cardiac structure and function including MCF was performed. 5-year mortality was assessed via a centralized government database.

Results:
418 subjects (197 males, 218 females) were enrolled in the study of whom 113 (27%) died at the time of 5-year follow-up. Subjects who died had significantly lower MCF (32 ± 14% vs. 36 ± 12%; p < 0.004) and EF (51.6 ± 11.6% vs 56.3 ± 9.4%; p< 0.0001) than survivors. On Kaplan-Meier analysis MCF was more significantly associated with mortality than EF (p< 0.0005 vs p < 0.04). The association between MCF and mortality remained significant on multivariate analysis as both a categorical and continuous variable while EF was only significant as a continous variable.

Conclusions:
MCF assessed by home echocardiography provides additional prognostic information to EF and may be a superior predictor of 5-year mortality in a community-dwelling population of the oldest old.
Abstract 10204: Single Cell Transcriptomics of Multiple Organ Sources to Develop Better Cell Grafts for Therapeutic Angiogenesis
Authors: Inoue Oto , Usui Soichiro , Goten Chiaki , Nomura Ayano , Hashimuko Daiki , Yamaguchi Kosei , Takeda Yusuke , Ootsuji Hiroshi , Takashima Shinichiro , Sanchez-Gurmaches Juan , Takamura Masayuki
Published: June 2023

Introduction:
To develop better cell therapy to combat cardiovascular disease (CVD), a greater number of cell markers or populations should be tested for their regenerative potentials. We applied single cell RNA-sequencing (scRNA-seq) analysis of multiple organs to identify attractive cell subsets for therapeutic angiogenesis.

Methods:
We revisited scRNA-seq datasets of various human organs. Transcriptomic data were normalized and analyzed for dimension reduction, cell clustering, and gene ontology. The screened cell population was sorted, cultured, and transplanted into a nude mice model of limb ischemia. Furthermore, AT of CVD patients (

n

=40) was evaluated for the cell subset by flowcytometry.

Results:
We analyzed three well-known sources of cell therapy including bone marrow, adipose tissue (AT), and umbilical-cord blood. After clustering, lineage negative mesenchymal cell clusters were compared their expression of pro/anti-angiogenic factors. Interestingly, AT showed the most prominent expression of both pro- and anti-angiogenic factors (
Fig.A
). Then, we divided AT stromal cells into pro- and anti-angiogenic clusters. From this clustering, 17 markers were screened as specific for pro-angiogenic cluster (
Fig.B
). Subsequently, we identified a receptor CD271 as top candidate for angiogenic cell isolation. CD271
+
cells showed enhanced angiogenic capacity in cell therapy experiments when compared to CD271
-
cells. Furthermore, we detected long-term engraftment (PKH26) and increased number of proliferating host tissue cells using EdU labeling (
Fig.C
). Finally, we found CD271
+
cells were significantly reduced and deteriorated in CVD patients with insulin resistance or higher Lp(a) (
Fig.D
).

Conclusions:
CD271
+
cells from AT of metabolically healthy donors appears as an attractive for therapeutic angiogenesis. ScRNA-seq analysis is a potent tool to accelerate cell therapy field to find better cell populations and appropriate resources.