bluuebunny/crossref_metadata_2025 huggingface dataset:
On the Effectiveness of Graph Statistics of Shareholder Relation Network in Predicting Bond Default Risk
Authors: Huang Zhiguo
Published: November 2022

Starting from the theoretical effectiveness of shareholder relation network information for predicting bond default risk, we propose two efficient schemes for extracting two different graph statistics of shareholder relation networks: graph structure statistics and graph distance statistics. In order to test the effectiveness of the two schemes, seven machine learning methods and three types of prediction tasks are used. The shareholder relation network information’s effectiveness and machine learning methods are also analyzed. Results show that the graph statistics of shareholder relationship networks are insufficient to be used independently as input features for predicting bond default risk but can provide helpful incremental information based on financial features. The shareholder relation information is effective for predicting bond default risk. The structure statistics perform best among all graph statistics overall, and Cascade Forest and LightGBM perform best among all seven machine learning methods.
Improvement of Injera Shelf Life and Staling through Vacuum and Nonvacuum Polyethylene Packaging: Their Synergistic Effect with Chemical Preservative
Authors: Terefe Abinet , Emire Shimelis Admasu , Gemede Habtamu Fekadu , Woldegiorgis Ashagrie Z.
Published: November 2022

The application of vacuum packaging (VP) and nonvacuum packaging (NP) of injera, with or without preservative added (sodium benzoate), has been studied for 15 days with the aim of determining their effect on the shelf-life and staling of injera. Samples were tested for microbial load analysis, moisture content (MC), pH, and color “L” value (lightness) determination, visible mold sign inspection, and sensory quality evaluation. Oxygen exclusion of the packaging methods and antimicrobial activities of preservative used, prolong the storage duration of injera without visible mold growth to more than 15 days; with VP (vacuum packaging), VP+ (vacuum packaging with preservative), and NP+ (nonvacuum packaging with preservative) treatments. Among these, VP+ had the least microbial load (

5.3
∗

10

1

&

9.0
∗

10

1

bacterial & yeast and mold colony forming unit (cfu)/g, respectively). But it was least effective regarding staling as it had the least average scoring of MC, pH, and L value (60.96%, 3.33, and 45.92, respectively) and sensory acceptability, basically due to the crumbling effect of the packaging method used. Besides, NP + had a lower microbial load (

7.5
∗

10

1

bacterial cfu/g and

9.0
∗

10

1

yeast and mold cfu/g). Despite VP and VP+, NP+ was a relatively effective method regarding sensory acceptability and staling as it had 62.73%, 3.32, and 48.70 average MC, pH, and L value, respectively. Generally, packaging methods and preservative used were found to have a significant effect (

P
<
0.05

) on microbial load, physico-chemical properties, and sensory attributes of injera. Moreover, it was proved that NP+ was the most effective method to improve the shelf life and staling of injera.
Extremely Lightweight PUF-based Batch Authentication Protocol for End-Edge-Cloud Hierarchical Smart Grid
Authors: Liu Feifei , Yan Yu , Sun Yu , Liu Jianwei , Li Dawei , Guan Zhenyu
Published: November 2022

Smart grid is gradually replacing traditional grid with two-way communication and improved management. Besides the efficiency and reliability it brings, the smart grid is inevitably fraught with rampant physical and cyber-attack. Although several physical unclonable function (PUF)-based schemes have been proposed, they are unsuited to the end-edge-cloud hierarchical smart grid. This paper proposes a PUF-based batch authentication and key agreement protocol, which protects both meters and gateways and provides end-to-end authentication between meters and the server. By offloading heavy operations from field devices to the server, the computation overhead is reduced substantially. Moreover, we innovatively devolve batch authentication and access control to the gateway, which additionally decreases downlink communication and signaling cost, and is superior to most recent schemes. Our protocol is proved by Tamarin under extended Dolev–Yao adversary and the Real-or-Random model and is evaluated to be secure against various attacks. Using extremely lightweight operations, our protocol is implemented on the MSP430FR5969 microcontroller.
The New Mitogenome of Erpornis zantholeuca (Aves: Passeriformes): Sequence, Structure, and Phylogenetic Analyses
Authors: Yuan Qingmiao , Sha Jianbin , Duan Yubao
Published: November 2022

White-bellied Erpornis (Erpornis zantholeuca) is a group of birds in the order Passeriformes, but its taxonomic status remains controversial. To understand the phylogenetic position of E. zantholeuca and phylogenetic relations within this family, we sequenced the complete mitochondrial genome of E. zantholeuca, which was 16,902 bp in length, containing 13 protein-coding genes (PCGs), 22 transfer RNA (tRNA) genes, 2 ribosomal RNA (rRNA) genes, and a control region. The nucleotide composition of the whole genome was 30.10% A, 30.48% C, 15.14% G, and 24.28% T and showed an elevated AT content (54.38%). All genes were encoded on the H-strand, with the exceptions of 8 tRNAs (trnQ, trnA, trnN, trnC, trnY, trnS2(UCN), trnP, trnE) and 1 PCG (Mt-ND6). Most PCGs used standard ATN as start codons, and TAN as stop codons. All tRNAs were predicted to form the typical cloverleaf secondary structures. The gene order of E. zantholeuca was consistent with that of Gallus gallus, which was considered to be a plesiomorphic or typical avian gene order. Phylogenetic relationships based on bayesian inference and maximum likelihood methods showed that E. zantholeuca was well supported as the sister group of (Vireo altiloquus + Vireo olivaceus). In addition, Pteruthius melanotis was sister to the other members of Vireonidae.
Regulatory Measures to Improve the Safety of CAR-T-Cell Treatment
Authors: Berg Philipp , Schönefeld Sonja , Ruppert-Seipp Gabriele , Funk Markus B.
Published: November 2022

Introduction: Regulatory activities aim to facilitate the safe use of novel therapeutics such as genetically engineered chimeric antigen receptor (CAR)-T cells. Toxicities associated with CAR-T-cell therapies have led to modified safety management guidance in clinical trials and the implementation of post-marketing requirements. The aim of this study was to estimate the effect of individual risk-minimizing measures to evaluate the appropriateness of regulatory activities. Methods: We re-examined clinical trial data prior to and after the introduction of revised treatment guidelines; we analysed spontaneous adverse drug reaction (ADR) reports submitted to the EudraVigilance database in 2019/2020 regarding their completeness; and we performed a survey of treatment centres in Germany that have been qualified for the use of commercial CAR-T cells. Results: Lower combined incidences of severe cytokine release syndrome (CRS) as well as neurotoxicity occurred following CAR-T-cell treatment after a revision of management guidelines, suggesting earlier intervention compared to before (12.6% vs. 20.5%). Numerous post-marketing ADR reports lacked information important for case assessment. Full details on treatment indication, CRS onset, outcome, and grading were available for just 38.3% of CRS cases. Survey responses support the majority of regulatory requirements for centre qualification. Time investment was highest for training of healthcare professionals, which required an average of 6.5 staff members (range 2–20) and lasted more than 2 days per person in half of the facilities. The need to harmonize the regulatory requirements for the different CAR-T-cell therapeutics was emphasized. Conclusion: Defined regulatory measures can support the safe and effective use of new therapies and are indicated for structured recording of post-marketing data, and the evaluation of such measures appears to be necessary for the continuous improvement.
Groove Pancreatitis: Clinical Cases and Review of the Literature
Authors: Neto do Nascimento Catarina , Palmela Carolina , Soares António Sampaio , Antunes Maria Lobo , Fidalgo Catarina Andrade , Glória Luísa
Published: November 2022

Introduction: Groove pancreatitis (GP) is a type of chronic segmental pancreatitis that affects the pancreatoduodenal groove area, and it is often misdiagnosed. Outflow obstruction of the minor papilla associated with alcohol consumption seems to be the main pathophysiological mechanism, and it affects mainly middle-aged males. Symptoms include nausea and postprandial vomiting from gastric outlet obstruction, weight loss, and abdominal pain. Despite modern advances, such as radiological and endoscopic methods, distinction between GP and pancreatic cancer remains a challenge, and histological examination is sometimes necessary. When a diagnosis can be obtained without a surgical specimen, management can be conservative in the absence of acute or chronic complications. Case Presentation: The authors present 2 clinical cases which portray the diagnostic workup and management decisions of this entity. Discussion/Conclusion: GP is a clinical entity, offering diagnostic and therapeutic challenges. Imaging exams are crucial in the diagnosis and follow-up, but surgery may be necessary in a significant number of cases due to the incapacity to rule out malignancy.
Association of Sleep Duration with Physical Performance in Hemodialysis Patients: A Multicenter Cross-Sectional Study
Authors: Zhan Qiunan , Zhao Junli , Guo Qi , Niu Jianying , Yu Chen , Ding Wei , Zhang Liming , Qi Hualin , Shao Xiang
Published: November 2022

Background: Hemodialysis (HD) patients have decreased physical function. Getting enough sleep is important for maintaining physical function. However, the relationship between sleep duration and physical performance in HD patients is unclear. Methods: We conducted a multicenter cross-sectional study at seven HD centers in Shanghai and Suzhou, China. 880 HD patients were enrolled between July 2020 and April 2021. Clinical Characteristics, laboratory indicator, sleep assessment data were collected. Physical performance included balance function, muscle strength, and mobility, which were measured by timed up and go test (TUGT), handgrip, and 4-m walk test, respectively. We divided sleep duration into four groups <7 h, 7–8 h, >8–9 h, ≥9 h. Results: A total of 840 patients had completed data (men 525, women 315, mean age 61.24 years). TUGT in group <7 h and ≥9 h was higher than mid-range sleep duration. Handgrip strength in group ≥9 h was lower than group <7 h and 7–8 h. Gait speed in group <7 h and ≥9 h was lower than group 7–8 h. Adjusting for the covariates, short and long sleep duration were associated with slower gait speed. Conclusion: HD patients with abnormal sleep duration had poorer physical performance. Short and long sleep duration were significantly associated with gait speed.
Catastrophic Fibromuscular Dysplasia Presenting with Concomitant Bilateral Renal Infarction, Vertebral Artery Dissection, and Mesenteric Ischaemia
Authors: Gourd Nicholas Martin , Jenkins Hannah Elizabeth , Miles Richard , Lee Adrienne , Mason Justin , Connor Andrew
Published: November 2022

Fibromuscular dysplasia (FMD) is a non-atherosclerotic, non-inflammatory disorder of the arterial wall muscular layer which can lead to arterial stenosis, occlusion, and dissection. Clinical presentations of FMD vary depending on the arterial territories involved, often leading to diagnostic challenges. This case report describes an exceptionally unusual presentation of FMD, not previously described, affecting a previously fit and well 37-year-old female presenting with bilateral renal infarction, sequential vertebral artery dissections, mesenteric ischaemia, and the requirement for continued renal replacement. This report highlights how unusual presentations of FMD can mask the underlying diagnosis. Early consideration of FMD in a differential diagnosis can guide an effective management strategy, including appropriate imaging and multi-speciality involvement.
Role of Hemodialysis in Acute Severe Alcohol Intoxication: A Meta-Analysis
Authors: Zeng Siyao , Ma Lei , Yang Lishan , Hu Xiaodong , Wang Cheng , Guo Xinxin , Li Yi , Gou Yi
Published: November 2022

Background: Hemodialysis therapy has been used in the treatment of acute alcohol intoxication for many years, especially acute severe alcohol intoxication. Objectives: This study aimed to evaluate whether the combination of conventional treatment and naloxone with hemodialysis has advantages over conventional treatment and naloxone alone in patients with acute severe alcohol intoxication. Methods: After searching 12 databases and 2 clinical trial centers. According to the established inclusion and exclusion criteria, the qualified literatures were screened. The outcome indicators were length of hospital stay, coma time, time of symptom disappearance, the overall complication rate, the incidence of pancreatitis, the incidence of aspiration pneumonia, the incidence of hepatic and renal dysfunction. Analysis was performed using Revman 5.3. Results: This meta-analysis included 13 studies, including 932 subjects. In the treatment of acute severe alcohol intoxication, the use of hemodialysis on the basis of conventional treatment and naloxone could reduce the length of hospital stay (WMD = −15.16, 95% CI: −17.45 to −12.86, p < 0.001) in hours and (WMD = −4.89, 95% CI: −5.53 to −4.25, p < 0.001) in days; coma time (WMD = −5.43, 95% CI: −6.43 to −4.43, p < 0.001); time of symptom disappearance (WMD = −3.92, 95% CI: −5.37 to −2.47, p < 0.001); the overall complication rate (RR = 0.39, 95% CI: 0.28–0.55, p < 0.001); the incidence of pancreatitis (RR = 0.14, 95% CI: 0.05–0.43, p = 0.0006); the incidence of aspiration pneumonia (RR = 0.15, 95% CI: 0.04–0.66, p = 0.01), and the incidence of hepatic and renal dysfunction (RR = 0.21, 95% CI: 0.06–0.72, p = 0.01). Conclusions: It can be concluded that compared with the use of conventional treatment and naloxone alone, the use of hemodialysis on the basis of conventional treatment and naloxone for acute severe alcohol intoxication can reduce the length of hospital stay, coma time, time of symptom disappearance, and the incidence of some complications rate. Large scale, multicenter, and well-designed RCTs are needed in the future to prove our conclusions.
The Olfactomedin-4-Defined Human Neutrophil Subsets Differ in Proteomic Profile in Healthy Individuals and Patients with Septic Shock
Authors: Lundquist Hans , Andersson Henrik , Chew Michelle S. , Das Jyotirmoy , Turkina Maria V. , Welin Amanda
Published: November 2022

The specific granule glycoprotein olfactomedin-4 (Olfm4) marks a subset (1–70%) of human neutrophils and the Olfm4-high (Olfm4-H) proportion has been found to correlate with septic shock severity. The aim of this study was to decipher proteomic differences between the subsets in healthy individuals, hypothesizing that Olfm4-H neutrophils have a proteomic profile distinct from that of Olfm4 low (Olfm4-L) neutrophils. We then extended the investigation to septic shock. A novel protocol for the preparation of fixed, antibody-stained, and sorted neutrophils for LC-MS/MS was developed. In healthy individuals, 39 proteins showed increased abundance in Olfm4-H, including the small GTPases Rab3d and Rab11a. In Olfm4-L, 52 proteins including neutrophil defensin alpha 4, CXCR1, Rab3a, and S100-A7 were more abundant. The data suggest differences in important neutrophil proteins that might impact immunological processes. However, in vitro experiments revealed no apparent difference in the ability to control bacteria nor produce oxygen radicals. In subsets isolated from patients with septic shock, 24 proteins including cytochrome b-245 chaperone 1 had significantly higher abundance in Olfm4-H and 30 in Olfm4-L, including Fc receptor proteins. There was no correlation between Olfm4-H proportion and septic shock severity, but plasma Olfm4 concentration was elevated in septic shock. Thus, the Olfm4-H and Olfm4-L neutrophils have different proteomic profiles, but there was no evident functional significance of the differences in septic shock.
Evidence-Based Approach to the Discontinuation of Immunomodulators or Biologics in Inflammatory Bowel Disease
Authors: Miyatani Yusuke , Kobayashi Taku
Published: November 2022

Background: Biologics and immunomodulators are key drugs in the long-term treatment of inflammatory bowel diseases, while they may negatively impact patients’ quality of life due to concerns of adverse events, need for frequent hospital visits, and medical expenses. The basic concept of drug withdrawal should be based on the risk of relapse and the efficacy of re-treatment. Considering a number of patients may relapse even if treatment is continued, the disadvantage of discontinuation should be recognized not by all relapse after discontinuation, but by the increase in relapse. Summary: Discontinuation of immunomodulator monotherapy is associated with an increased risk of relapse. However, prolonged remission might be an indication of withdrawal, concerning the long-term adverse effect including lymphoma and nonmelanoma skin cancers. When considering discontinuation from combination therapy of anti-tumor necrosis factor (TNF) agents with immunomodulators, therapeutic drug monitoring may be useful to understand the pharmacokinetic effect. However, recent randomized controlled trials, as well as large-scale observational studies, demonstrated that discontinuation of anti-TNF agents, but not of immunomodulators, resulted in a significantly higher risk of relapse even in deep remission. Therefore, discontinuation of anti-TNF agents should be considered with caution and close monitoring combined with fecal calprotectin may be necessary. On the other hand, evidence of not only short-term relapse rate but of the true long-term influence on the patient’s quality of life should be clarified by a multidimensional approach. Key Messages: Discontinuation of treatment should be implemented based on shared decision-making with careful interpretation of evidence and the condition.
A Co-Management Model for Myeloid Malignancies That Evolved during the COVID-19 Pandemic
Authors: Goradia Niyati , Shastri Aditi , Verma Amit , Feldman Eric , Cooper Dennis , Konopleva Marina , Fox Susan , Gritsman Kira , Shah Nishi , Mantzaris Ioannis , Braunschweig Ira , Kornblum Noah , Sica Alejandro , Levitz David , Comas Monica , Goldfinger Mendel
Published: November 2022

Introduction: Myeloid malignancies are a heterogeneous group of clonal bone marrow disorders that are complex to manage in the community and therefore often referred to subspecialists at tertiary oncology referral centers. Many patients do not live in close proximity to tertiary referral centers and are unable to commute long distances due to age, comorbidities, and frailty. Interventions that minimize the travel time burden without compromising quality of care are an area of unmet need. We describe a cancer care delivery model for patients with myeloid malignancies that is built around telehealth and enables this vulnerable population access to care at an NCI-designated cancer center while receiving majority of their care close to home. Methods and Materials: We report on a cohort of patients with myeloid malignancies who were co-managed by a general community oncologist and an academic leukemia subspecialist at Montefiore Einstein Cancer Center in New York. Patients were initially referred to our institute for a second opinion by community practices that are in partnership with Montefiore Health System, and initial visits were in-person or via telehealth. Treatment plans were made after discussion with patient’s local community oncologist. Patients then continued to receive majority of their treatment and supportive care including transfusion support with their local oncologist, and follow-up visits were mainly via telehealth with the academic leukemia subspecialist. Results: Our cohort of 12 patients had a median age of 81 years (range, 59–88 years). Patients remained on active treatment for a median time of 357 days (range, 154–557 days). Most of our patients had a performance status of ECOG 2 or higher. Three patients had myelodysplastic syndromes, 7 patients had acute myeloid leukemia, and 2 patients had myelofibrosis. The median number of hospitalizations over the total treatment time period was one. Conclusion: We demonstrate a shared academic and community care co-management model for the treatment of myeloid malignancies in elderly, frail patients using telehealth as a backbone with a very low hospitalization rate.
Drug Interactions Causing Warfarin Overdose in a Patient with Pancreatic Cancer: A Case Report
Authors: Moussouni Marie , Graff Véronique , Couturier Franck , Herrscher Hugo
Published: November 2022

Mistletoe, Viscum album, is a medicinal plant used in complementary medicine in oncology. Patients do not necessarily mention to their oncologist this phytotherapeutic treatment which may be responsible for unsuspected drug interactions. Some patients are adept at taking medicinal plants, a practice often unknown to health professionals who take care of them. This case reports drug interactions leading to bleeding secondary to warfarin overdose. A patient over 75 years of age was treated with nab-paclitaxel and gemcitabine as a first course for metastatic pancreatic adenocarcinoma (day 0). He was also treated with warfarin for atrial fibrillation. At day 3, he reported faintness and melena. At day 5, the biological assessment revealed anemia with hemoglobinemia of 5.1 g/dL and an international normalized ratio of 7.3, indicating vitamin K antagonist (VKA) overdose. Warfarin was discontinued and the patient received vitamin K supplementation and transfusions. The final diagnosis was an anemic syndrome due to gastrointestinal bleeding secondary to VKA overdose. Based on the chronology, a drug interaction between chemotherapy and warfarin was first suspected. Then, the patient interview found out that he self-medicated with subcutaneous injections of mistletoe extracts: 10 mg on day 0 and on day 2. Nab-paclitaxel can displace warfarin from its albumin binding sites and increase the free and active concentration of warfarin. Mistletoe extracts (V. album) are used as complementary medicine in oncology. Warfarin is predominantly metabolized in the liver by 1A2, 2C9, and 3A4 cytochrome P450 (CYP) isoforms. An inhibitor of these cytochromes prevents the degradation of warfarin into inactive metabolites, leading to accumulation or even overdose of this narrow therapeutic index VKA. Nab-paclitaxel and gemcitabine do not act on these cytochromes. V. album is a cytochrome P450 3A4 inhibitor which therefore probably led to an increase in exposure to warfarin. Thus, there are two pharmacokinetic hypotheses that may explain warfarin overdose: the displacement of warfarin from its albumin binding sites or the inhibition of CYP3A4 by mistletoe. This adverse drug event was reported to the Regional Pharmacovigilance Center of Strasbourg on June 30, 2021, and registered under the number ST20212767.
Renal Mechanisms for Hypercalciuria Induced by Metabolic Acidosis
Authors: Kim Gheun-Ho
Published: November 2022

Background: In metabolic acidosis, a negative calcium balance is induced by decreased renal tubular calcium reabsorption. This occurs independently of the action of parathyroid hormone or vitamin D and was attributed to a direct action of metabolic acidosis on the renal tubular cells. The latter has been verified by recent studies on the molecular levels in the kidney. Summary: Whereas the regulatory role of urinary calcium excretion was traditionally assigned to the transcellular calcium transport in the distal convoluted tubule (DCT) and connecting tubule (CNT), most of the calcium reabsorption from the glomerular filtrate paracellularly occurs through the tight junctions in the proximal tubule (PT) and the thick ascending limb (TAL) of Henle’s loop. Interestingly, all these nephron segments participate in producing hypercalciuria caused by metabolic acidosis. Claudin-2 is the major route of paracellular calcium transport in the PT and was downregulated in rats with 5 days’ NH4Cl loading. In the TAL, the lumen-positive voltage produced by apical K+ recycling drives paracellular reabsorption of Ca2+ and Mg2+ via the claudin-16/19 complex. Activation of calcium-sensing receptor (CaSR) by extracellular calcium upregulates claudin-14, which in turn interacts with the claudin-16/19 complex and inhibits its cation permeability. This TAL CaSR-claudins axis was activated by chronic NH4Cl loading in rats. Finally, the major transcellular calcium transporters TRPV5 and 28K calcium-binding protein in the DCT-CNT were also downregulated by NH4Cl or acetazolamide administration in mice. Key Messages: Both paracellular and transcellular calcium transport pathways in the kidney are regulated by metabolic acidosis and lead to renal calcium wasting. In the PT, claudin-2 is downregulated by acidic pH. In the TAL of Henle’s loop, CaSR is stimulated by the ionized calcium released from bone and upregulates claudin-14, which in turn inhibits the claudin-16/19 complex and leads to calcium and magnesium wasting. Finally, the transcellular calcium transporters, TRPV5 and calbindin-D28K, are downregulated by metabolic acidosis in the DCT and CNT.
Clinical Outcomes of Persistent Severe Acute Kidney Injury among Patients with Kidney Disease Improving Global Outcomes Stage 2 or 3 Acute Kidney Injury
Authors: Koyner Jay L. , Mackey Rachel H. , Rosenthal Ning A. , Carabuena Leslie Ann , Kampf J. Patrick , Rodriguez Toni , Sanghani Aarti , Echeverri Jorge , McPherson Paul , Blackowicz Michael J. , Textoris Julien
Published: November 2022

Introduction: The burden of persistent (≥3 days) severe AKI (PS-AKI) is poorly described among inpatients with stage 2–3 AKI in the ward or ICU. Quantification could motivate targeted interventions to decrease duration of AKI in these high-risk patients. Methods: This retrospective cohort study included adult patients discharged from January 1, 2017, to December 31, 2019, from US hospitals in the PINC AI Healthcare Database. Patients with KDIGO stage 2 or 3 AKI, length of stay ≥3 days, ≥3 serum creatinine measures, and no history of renal transplant, dialysis, or stage 5 chronic kidney disease were included. Patients were classified as PS-AKI (stage 3 AKI lasting ≥3 days or with death in ≤3 days, or stage 2 or 3 AKI with dialysis in ≤3 days) or not PS-AKI (NPS-AKI) (stage 3 AKI for ≤2 days, or stage 2 AKI without dialysis in ≤3 days). Outcomes during index (initial) hospitalization were PS-AKI incidence, ICU use, and in-hospital mortality, and during 30 days post-discharge were readmissions, in-hospital mortality, dialysis, and “new” dialysis (dialysis among patients without dialysis during index hospitalization). For index outcomes, we used a sensitivity definition, PS-AKISens, that excluded patients who met PS-AKI criteria by dialysis/death in ≤3 days of AKI onset. Multivariable-adjusted logistic regression quantified differences between PS-AKI and NPS-AKI, overall, and separately for ICU and non-ICU patients. Results: Among 126,528 inpatients with stage 2 or 3 AKI, PS-AKI developed in 24.4% (30,916), with 39% of PS-AKI occurring in non-ICU patients. With NPS-AKI as the reference group, adjusted odds ratios (aORs) (95% CI) for PS-AKI and for PS-AKISens were 2.15 (2.09–2.21) and 1.28 (1.24–1.32) for ICU use and 4.58 (4.41–4.75) and 1.79 (1.70–1.89) for in-hospital mortality during index hospitalization. For outcomes during 30 days post-discharge, aORs for PS-AKI versus NPS-AKI were 1.07 (1.02–1.11) for readmissions, 1.33 (1.18–1.49) for in-hospital mortality, 15.66 (13.87–17.67) for dialysis, and 6.80 (5.84–7.93) for new dialysis. Despite higher mortality among ICU patients, aORs for outcomes during index and 30 days post-discharge were similar for ICU and non-ICU patients. Conclusion: In and out of the ICU, PS-AKI frequently affected inpatients with stage 2 or 3 AKI and was independently associated with worse clinical outcomes during index hospitalization and during 30 days post-discharge. These results suggest that interventions to prevent persistence of severe AKI may reduce adverse clinical outcomes among patients with stage 2 or 3 AKI in or out of the ICU.
The SCN5A Gene Is a Predictor of Phenotype Severity in Brugada Syndrome: A Comprehensive Literature Review
Authors: Deica Andreea Valentina , Paduraru Livia Florentina , Paduraru Dan Nicolae , Andronic Octavian
Published: November 2022

Objective: The purpose of this review was to ascertain whether patients with Brugada syndrome (BrS) having SCN5A mutations have a more severe clinical phenotype and prognosis than do patients without SCN5A mutations. Methods: A comprehensive Scopus database search was conducted; studies were selected by using Brugada syndrome and SCN5A as keywords for the main query. Results: The available literature consistently shows greater electrophysiological abnormalities in patients with BrS having SCN5A-related etiology. These include conduction disorder evidenced by longer QRS, PQ, and His-ventricular interval duration. Novel lines of evidence suggest that SCN5A mutations are predictors of malignant arrhythmic events. In addition, SCN5A-positive patients and their carrier relatives frequently suffer from various abnormal cardiac phenotypes such as sick sinus syndrome and progressive conduction disorder. Rare variants have also been shown to play a role in cases of epilepsy, hyperthyroidism, irritable bowel syndrome, and malignancy. Conclusion: In this review, we show how the SCN5A mutation status predicts phenotypic characteristics and prognosis in patients with BrS. We conclude that SCN5A mutations weakly predict greater malignant arrhythmic event risk in BrS patients. However, SCN5A mutations do not show robust enough associations with severity indicators to be an independent part of current risk stratification strategies. With advancing knowledge of BrS genetics, the integration of data on rare variants of SCN5A and polygenic risk scores could make an impact on clinical decision-making.
Abstract 117: A Genome-wide CRISPR/Cas9 Knockout Screen Reveals New Targets To Increase Cellular LDL Uptake.
Authors: Lucero Diego , Aligabi Zahra , Das Maumita , Tang Jingrong , Vaisman Boris , Remaley Alan T
Published: November 2022

Identifying new genetic factors involved in lipoprotein metabolism will provide new targets to lower plasma lipids and prevent cardiovascular disease; however, genetic epidemiological studies failed to recognize all the contributors to plasma lipids levels. Recently, using a CRISPR-Cas9 knockout screen in HepG2 cells, we found that knocking out transgelin, an actin-binding protein, reduces LDL uptake in hepatoma cells by interfering with the actin-dependent phase of the clathrin-mediated endocytosis (CME). An ideal therapeutic target to reduce plasma LDL would be one like PCSK9 in which, once knocked out or inhibited, cellular LDL uptake would increase.

Aim:
To identify genetic factors that, by knocking them out, increase LDL uptake in hepatoma cells.

Methods and Results:
We performed a whole-genome CRISPR-Cas9 knockout screen (targeting 19,144 genes) on HepG2 cells, sorting for cells with increased LDL uptake. Gene enrichment was analyzed with MAGeCK software. As expected,
MYLIP
, a mediator of LDL receptor ubiquitination and degradation, was among the most enriched genes (
ranked #9, log fold change: 4.82
). The 200 top-enriched genes (1%) were analyzed for associations with plasma lipid traits using the NHLBI-GRASP (v2.0.0.0). 35 out of 200 genes had associations with p<2.5x10-4 (0.05/200) and were considered for further
in vitro
analysis. Stable knockout HepG2 cells were generated for a subset of these candidate genes and were tested for LDL uptake. Increased in LDL uptake was observed for:
MYLIP
, +66%;
HUNK
, +38%;
PACSIN1
, +41%;
PACSIN3
, +55%;
RAI14
, +75%;
PSPH
, +134% (% to control, p<0.01 for all). Interestingly, these genes showed interactions with CME-related genes in a protein-protein interactome analysis, revealing interactions with genes related to clathrin-coated pit and actin filament dynamics.

Conclusion:
We found novel genetic factors associated with LDL internalization by applying a validated whole-genome gene editing tool. Our data suggest that these factors may be involved in different steps of LDL endocytosis and may function as possible therapeutic targets to increase hepatic LDL clearance. Further studies will be needed to elucidate the mechanisms underlying these associations.
Abstract 134: Atorvastatin As Opposed To Ezetimibe Reduces Biomarkers Of Thrombosis In The Setting Of Aggressive Lipid Lowering Therapy: Findings From The American Heart Association Strategically Focused Cardiometabolic Health And Type 2 Diabetes Mellitus Research Network
Authors: Garshick Michael , Jindal Manila , Myndzar Khrystyna , Barrett Tessa , Newman Jonathan , Fadzn Maja , Xia Yuhe , Giannarelli Chiara , Fisher Edward , Goldberg Ira J , Berger Jeffrey S
Published: November 2022

Introduction:
CHORD (CHOlesterol lowering and Residual Risk in Diabetes) is an ongoing, prospective, multicenter study designed to evaluate the effect of maximal cholesterol-lowering on cardiovascular (CV) risk. Aggressive lipid-lowering with HMG CoA-reductase inhibitors (e.g. statins), ezetimibe, and PCSK9 inhibitors (such as evolocumab) reduce atherothrombotic events. Statins reduce cholesterol dramatically and are also felt to have pleiotropic, anti-inflammatory properties. We compared the impact of statins and ezetimibe on thrombotic biomarkers after maximal lipid lowering with PCSK9 inhibition.

Methods:
CHORD enrolled subjects (n=57, mean age 52 ± 15 years, 44% male, 58% diabetes) with LDL-cholesterol >100mg/dl and treated with evolocumab (140mg every 2 weeks) plus either atorvastatin (80mg/day, n=27), or ezetimibe (10mg/day, n=30) for 30-days. High-sensitivity C-reactive protein (hs-CRP) and biomarkers of thrombosis (LEGENDplex Human Thrombosis Panel) were measured at baseline and follow-up.

Results:
Significant LDL-C reductions were observed in both the evolocumab + atorvastatin (130 mg/dl [123 - 145] to 31 mg/dl [27 - 39], p<0.001) and evolocumab + ezetimibe (127 mg/dl [106 - 138] to 38 mg/dl [27 - 56], p<0.001) groups. Hs-CRP was reduced after evolocumab + atorvastatin (18% reduction, p<0.01), but not evolocumab + ezetimibe. When compared to evolocumab + ezetimibe, greater reductions in P-selectin, D-Dimer, Factor IX, and a trend towards reduction in sCD40L, and PAI-1 were noted after evolocumab + atorvastatin (
Figure 1).

Conclusion:
Despite similar levels of LDL-C reduction, statins plus evolocumab cause greater reductions in biomarkers of thrombosis and inflammation than ezetimibe and evolocumab. These data suggest that statins provide benefits over and above LDL-C reduction.
Abstract 141: African American Women With Cyp3a4/5 Polymorphisms Have Increased Statin Intolerance.
Authors: Mohammad Somayya J , Schwendeman Ethan , Dib Patrick S , Milks Michael W , McDougle Leon , Binkley Philip F , Smith Sakima
Published: November 2022

Background:
Approximately 3 million Americans have ill managed lipidemia due to statin intolerance (SI) or statin-associated myopathy (SAM). Atorvastatin and simvastatin are the most prescribed statins which are transported into the liver by SLCO1B1 and metabolized by cytochrome P450 (CYP) 3A4 and 3A5. CYP3A4*22 and CYP3A5*3 are two polymorphisms known to decrease their activity; thus, increasing the systemic daily exposure (AUC) and serum concentration (C
max
) of unmetabolized statin. In Caucasian (CAU) populations the prevalence [5-7% CYP3A4*22 and 90% CYP3A5*3] and effect of these polymorphisms is well characterized but not in African American (AA) populations. We hypothesize that the prevalence of SI and SAM are correlated with CYP3A4/5 polymorphisms in AA populations.

Methods:
After IRB approval, saliva samples were collected from patients currently prescribed atorvastatin or simvastatin at The Ohio State University Medical for genotyping. SLCO1B1 status was assessed to control for its confounding effect. Participants with polymorphic results were contacted to complete 8 blood draws over 13hrs for pharmacokinetic analysis. Electronic medical records were utilized to collect demographic information, medical histories, risk factors, and concomitant medications.

Results:
Preliminary analysis of 502 participants (395 AA, 104 CAU, and 3 others) shows racially different polymorphic prevalence. Reduced activity of CYP3A4 was present in 5.8% CAU vs 0.51% AA. Notably, CYP3A5*3 is inactive in 73% and reduced in 20.3% of CAU compared to 41.7% and 40.7% respectively in AA. A statistically significant increase in SI in AA women vs CAU women (p=0.0032) was observed. In combined analysis, atorvastatin has reduced odds of intolerance compared to simvastatin (OR=0.463; p <0.05). However, the odds of SAM is higher in patients with no history of cardiovascular disease (OR=6.137; p <0.01) and those with chronic kidney disease (OR=1.269; p <0.05).

Clinical significance:
Considering, the CYP3A5 is fully active in 18.5% of the AA population compared to 6.8% CAU, the characterization of this metabolic enzyme is of clinical significance in minority populations to better manage lipidemia, assess the safety profile of current therapeutic doses, and reduce SAM.
Abstract 145: Glycine Metabolism Links Atherosclerosis And NASH: Studies In Humans, Nonhuman Primates And Mice
Authors: Rom Oren , Zhang Jifeng , Chen Eugene
Published: November 2022

A major cause of death in patients with nonalcoholic steatohepatitis (NASH) is cardiovascular disease driven by accelerated atherosclerosis. The mechanisms linking NASH and atherosclerosis remain unclear and there is an urgent need to identify new pathways as targets for NASH without increasing, and preferably while decreasing, atherosclerosis. Lower circulating glycine is emerging as a common feature in both atherosclerosis and NASH, but the mechanisms behind reduced glycine, its potential as a causative factor and a therapeutic target are unclear. Applying unbiased transcriptomics and metabolomics, we uncovered impaired glycine biosynthesis in humans and mice with atherosclerosis and NASH. Hepatic glycine biosynthetic genes were downregulated with a most significant suppression of alanine-glyoxylate aminotransferase (
AGXT
). Functional deficiencies of AGXT lead to oxalate accumulation and we found decreased glycine/oxalate ratio in both NASH and atherosclerosis. In mice, dietary and genetic (
Agxt
–/–
and
Agxt
-/-
/
Apoe
-/-
) approaches to limit glycine availability exacerbated NASH and atherosclerosis with suppressed hepatic fatty acid β-oxidation (FAO) and enhanced inflammation as the underlying pathways. These effects were reversed by glycine supplementation and AAV8-mediated AGXT overexpression. We explored glycine-based compounds as potential therapies for atherosclerosis and NASH and identified a tripeptide (Gly-Gly-L-Leu, DT-109) that protected mice from NASH and atherosclerosis by modulating FAO, glutathione synthesis and the gut microbiome. We further developed a dietary model in cynomolgus monkeys that closely mimics human NASH. DT-109 ameliorated NASH and showed anti-atherogenic properties in monkeys by modulating similar pathways observed in the mice. Altogether, impaired glycine metabolism links atherosclerosis and NASH and can be targeted for the simultaneous treatment of these diseases.
Abstract 159: Effect Of Antiplatelet Agents And Tyrosine Kinase Inhibitors On OxLDL-mediated Platelet Procoagulant Activity
Authors: Zheng Tony J , pang Jiaqing , Kohs Tia , Reitsma Stephanie , Parra-Izquierdo Iván , Melrose Alexander , Larson Mark , Williams Craig D , Hinds Monica T , McCarty Owen JT , Aslan Joseph E
Published: November 2022

Background & Objective:
Oxidized low density lipoprotein (oxLDL) contributes to atherogenesis and cardiovascular disease through interactions with peripheral blood cells, especially platelets. However, the mechanisms by which oxLDL affects platelet activation, and how to best therapeutically target and safely prevent such responses remains unclear. Here, we investigate how oxLDL upregulates glycoprotein VI (GPVI) mediated platelet hemostatic and procoagulant responses, and how traditional and emerging antiplatelet therapies affect oxLDL-enhanced platelet activity
ex vivo
.

Methods:
Human platelets were treated with oxLDL and GPVI specific agonist, crosslinked collage-related peptide (CRP-XL) and assayed for hemostatic and procoagulant responses in the presence of inhibitors of purinergic receptors (P2Y; ticagrelor, AR-C 66096, MRS2179), cyclooxygenase (COX; aspirin, indomethacin), Bruton’s tyrosine kinase (BTK; ibrutinib), and spleen tyrosine kinase (Syk; fostamatinib/R406).

Results:
Ex vivo
, oxLDL enhanced GPVI-mediated platelet dense granule secretion, alpha granule secretion, integrin activation, thromboxane generation, and platelet aggregation, as well as phosphatidylserine exposure and fibrin generation. Our study further demonstrated that CD36 signaling from oxLDL activation overlaps with the GPVI signaling pathway, in such that the phosphorylation of proteins along the Syk-BTK-PI3K/Akt axis was increased. P2Y antagonists (e.g., ticagrelor), BTK inhibitors (e.g., ibrutinib), and Syk inhibitors (e.g. fostamatinib) reduced oxLDL-mediated platelet responses and procoagulant activity, whereas COX inhibitors (e.g., aspirin) had no significant effect.

Conclusion:
Together, our results demonstrate that oxLDL enhances
ex vivo
platelet responses and procoagulant activity downstream of GPVI signaling in a manner that may be reduced by P2Y antagonists and tyrosine kinase inhibitors, but not significantly affected by COX inhibitors.
Abstract 204: Sex-specific Differences In The Role Of TSP1 On Metabolic Syndrome-induced Atherosclerosis
Authors: Gupta Shreya , Khanal Saugat , Mathias Amy , Lallo Jason , Raman Priya
Published: November 2022

Metabolic syndrome (MetS) amplifies risks of atherosclerotic complications. MetS induces abnormal vascular smooth muscle cell (VSMC) migration and proliferation, hallmark of SMC de-differentiation, crucial in the pathogenesis of atherosclerosis. Despite multiple studies revealing sexual dimorphism in atherosclerosis, underlying sex-specific mechanisms are poorly understood. We previously reported a protective role of a potent proatherogenic protein, thrombospondin-1 (TSP1), in hyperglycemia- or hyperleptinemia-induced atherosclerosis. The goal of the present study was to interrogate sex-specific differences in the role of TSP1 on MetS-induced atherosclerosis. We generated a mouse model of combined MetS and atherosclerosis (KKAy
+/-
ApoE
-/-
) by crossing obese hyperglycemic agouti KKAy
+/-
mice with atherosclerotic ApoE
-/-
. Male and female age-matched MetS KKAy
+/-
ApoE
-/-
and non-MetS KKAy
-/-
ApoE
-/-
mice were placed on standard lab diet from 4-24 wks age. After overnight fasting, mice were harvested; plasma, aorta and heart were collected for various studies. In male MetS KKAy
+/-
ApoE
-/-
, increased aortic root ORO-positive lipid burden, reduced LMOD (SM contractile marker) and SRF (transcriptional activator of SM differentiation) expression in aortic vessels associated with augmented TSP1 expression vs. non-MetS KKAy
-/-
ApoE
-/-
mice. In contrast, no significant differences in lesion lipid burden, TSP1, LMOD and SRF expression were detected between the female genotypes. To delineate whether TSP1 plays a direct role in SMC de-differentiation in MetS, we next crossed KKAy
+/-
with TSP1
-/-
to generate MetS mice with and without global TSP1 deletion. Male and female KKAy
+/-
TSP1
+/+
(with intact TSP1) and KKAy
+/-
TSP1
-/-
(lacking TSP1) on standard lab diet from 4-18 wks age were harvested at endpoint for aortic tissue collection. In male KKAy
+/-
TSP1
-/-
aortic vessels, SM contractile marker expression (LMOD, calponin) was markedly increased vs. KKAy
+/-
TSP1
+/+
, suggesting reduced SMC de-differentiation. In contrast, TSP1 deletion had no effect on SM contractile marker expression in female MetS KKAy
+/-
. Together, these data suggest a sex-specific role of TSP1 on SMC de-differentiation and atherosclerotic lesion formation in MetS.
Abstract 207: Autophagy Is Differentially Regulated In Leukocyte And Nonleukocyte Foam Cells During Atherosclerosis
Authors: Robichaud Sabrina , Rasheed Adil , Pietrangelo Antonietta , Kim Anne , Boucher Dominique , Emerton Chrissy , Vijithakumar Viyashini , Gharibeh Lara , Fairman Garrett , Mak Esther , Nguyen My-anh , Geoffrion Michele , Wirka Robert , Rayner Katey J , Ouimet Mireille I
Published: November 2022

Atherosclerosis is characterized by a build-up of foam cells in the arterial wall, resulting from excess cholesterol uptake and accumulation of cytosolic lipid droplets (LDs). Autophagy has been shown to be atheroprotective in part by promoting the catabolism of LDs which liberates free cholesterol for efflux out of foam cells to cholesterol acceptors (ApoA-I or HDL) for removal from the body. Apart from macrophages (MΦ), vascular smooth muscle cells (VSMCs) comprise 50-70% of foam cells in the plaques. Unlike MΦ, the capacity of VSMC foam cells to metabolize cholesterol via autophagy is unknown. Here, we performed a comparative analysis of the autophagic capacity and cholesterol efflux of arterial foam cell subtypes of the atherosclerotic plaque.

Atherosclerosis was induced in hypercholesterolemic autophagy reporter mice (GFP-LC3 mice receiving PCSK9-AAV and fed a Western diet). Autophagic flux in aortic digests was assessed by quantifying GFP-LC3 fluorescence after
ex vivo
treatment with the autophagy inhibitor Bafilomycin A1 or vehicle. MΦ foam cells displayed functional autophagy as shown by an accumulation of GFP-LC3 upon autophagy inhibition. In contrast, VSMC foam cells did not similarly accumulate GFP-LC3 upon bafilomycin treatment, suggesting dysfunction autophagy in these cells. Additionally, immunostaining of late-stage aortic roots showed MΦ, but not VSMC, foam cells induction of the active autophagy marker pATG16L1. Cell culture studies of lipid loaded MΦ and VSMC corroborated this inability for VSMCs to initiate autophagy
in vivo
.

In vitro
, MΦ foam cells effluxed cholesterol to ApoA-I (14%) and HDL (50%), whereas VSMC foam cells minimally effluxed cholesterol to HDL (7%) but not apoA-I. However, unlike MΦ foam cells, VSMC efflux was pharmacologically induced by treatment with metformin.

Our data therefore demonstrates a lack of functional autophagy in VSMC, as compared to MΦ foam cells, which impairs their ability to perform cholesterol efflux. This autophagy defect in VSMC foam cells can be increased by autophagy activation using metformin, highlighting both the importance of understanding cholesterol metabolism in all foam cell populations and a new avenue to treat atherosclerosis.