bluuebunny/crossref_metadata_2025 huggingface dataset:
FDA Approval Summary: Tucatinib with Trastuzumab for Advanced Unresectable or Metastatic, Chemotherapy Refractory, HER2-Positive RAS Wild-Type Colorectal Cancer
Authors: Casak Sandra J. , Horiba M. Naomi , Yuan Mengdie , Cheng Joyce , Lemery Steven J. , Shen Yuan Li , Fu Wentao , Moore Jason N. , Li Yangbing , Bi Youwei , Auth Doris , Fesenko Nataliya , Kluetz Paul G. , Pazdur Richard , Fashoyin-Aje Lola A.
Published: June 2023

On January 19, 2023, the FDA granted accelerated approval to tucatinib in combination with trastuzumab for the treatment of patients with unresectable or metastatic RAS wild-type, HER2-positive colorectal cancer who have received prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan. Approval was based on the pooled analysis of patients receiving tucatinib in combination with trastuzumab in MOUNTAINEER (NCT03043313), an open-label, multicenter trial. The primary endpoint was overall response rate (ORR) by RECIST 1.1 as per blinded central review committee (BIRC) assessment. The main secondary endpoint was duration of response (DOR) per BIRC assessment. Eighty-four eligible patients received the combination tucatinib and trastuzumab. With a median follow-up of 16 months, the ORR was 38% [95% confidence interval (CI): 28–49] and median DOR was 12.4 months (95% CI: 8.5–20.5); 81% of responders had a response lasting more than 6 months. The most common adverse reactions observed in at least 20% of patients receiving tucatinib in combination with trastuzumab were diarrhea, fatigue, rash, nausea, abdominal pain, infusion-related reactions, and fever. FDA concluded that the magnitude of ORR and durable responses observed in patients treated with tucatinib in combination with trastuzumab in the MOUNTAINEER trial are clinically meaningful, particularly in the context of a disease with estimated survival of 6–7 months with available therapy. This is the first approval for the subset of patients with HER2-positive colorectal cancer. This article summarizes the FDA's thought process and review of the data supporting this accelerated approval.
Supplementary Table 6 from Phase 1b/2 Study of a Liposomal Formulation of Eribulin (E7389-LF) Plus Nivolumab in Patients with Advanced Solid Tumors: Results from Phase 1b
Authors: Ida Hanae , Shimizu Toshio , Nishino Makoto , Nakamura Yoshiaki , Yazaki Shu , Katsuya Yuki , Sato Jun , Koyama Takafumi , Iwasa Satoru , Sudo Kazuki , Kondo Shunsuke , Yonemori Kan , Shitara Kohei , Shiono Satoshi , Matsuoka Daiko , Yasuda Keisuke , Otake Yohei , Suzuki Takuya , Takase Takao , Takashima Shuya , Yamaguchi Kohei , Semba Taro , Yamamoto Noboru
Published: June 2023

Supplementary Table 6. Analyses of Median Changes in Plasma Protein Expression of Biomarker Analytes From Baseline to C1D8 and C1D15 in All Dosing Cohorts
Supplementary Table 4 from Phase 1b/2 Study of a Liposomal Formulation of Eribulin (E7389-LF) Plus Nivolumab in Patients with Advanced Solid Tumors: Results from Phase 1b
Authors: Ida Hanae , Shimizu Toshio , Nishino Makoto , Nakamura Yoshiaki , Yazaki Shu , Katsuya Yuki , Sato Jun , Koyama Takafumi , Iwasa Satoru , Sudo Kazuki , Kondo Shunsuke , Yonemori Kan , Shitara Kohei , Shiono Satoshi , Matsuoka Daiko , Yasuda Keisuke , Otake Yohei , Suzuki Takuya , Takase Takao , Takashima Shuya , Yamaguchi Kohei , Semba Taro , Yamamoto Noboru
Published: June 2023

Supplementary Table 4. Pharmacokinetic Parameters After Administration of E7389-LF
Supplementary Table S9 from Desmoplastic Reaction Associates with Prognosis and Adjuvant Chemotherapy Response in Colorectal Cancer: A Multicenter Retrospective Study
Authors: Hu Qingru , Wang Yiting , Yao Su , Mao Yun , Liu Liu , Li Zhenhui , Chen Yonghe , Zhang Shenyan , Li Qian , Zhao Yingnan , Fan Xinjuan , Cui Yanfen , Zhao Ke , Liu Zaiyi
Published: June 2023

The discrimination performance in the two cohorts
Supplementary Table S8 from Desmoplastic Reaction Associates with Prognosis and Adjuvant Chemotherapy Response in Colorectal Cancer: A Multicenter Retrospective Study
Authors: Hu Qingru , Wang Yiting , Yao Su , Mao Yun , Liu Liu , Li Zhenhui , Chen Yonghe , Zhang Shenyan , Li Qian , Zhao Yingnan , Fan Xinjuan , Cui Yanfen , Zhao Ke , Liu Zaiyi
Published: June 2023

Correlation between DR and Stroma AReactive Invasion Front Areas
Supplementary Table S7 from Desmoplastic Reaction Associates with Prognosis and Adjuvant Chemotherapy Response in Colorectal Cancer: A Multicenter Retrospective Study
Authors: Hu Qingru , Wang Yiting , Yao Su , Mao Yun , Liu Liu , Li Zhenhui , Chen Yonghe , Zhang Shenyan , Li Qian , Zhao Yingnan , Fan Xinjuan , Cui Yanfen , Zhao Ke , Liu Zaiyi
Published: June 2023

Multivariate analyses in stage II CRC patients
Supplementary Figure 3 from Phase 1b/2 Study of a Liposomal Formulation of Eribulin (E7389-LF) Plus Nivolumab in Patients with Advanced Solid Tumors: Results from Phase 1b
Authors: Ida Hanae , Shimizu Toshio , Nishino Makoto , Nakamura Yoshiaki , Yazaki Shu , Katsuya Yuki , Sato Jun , Koyama Takafumi , Iwasa Satoru , Sudo Kazuki , Kondo Shunsuke , Yonemori Kan , Shitara Kohei , Shiono Satoshi , Matsuoka Daiko , Yasuda Keisuke , Otake Yohei , Suzuki Takuya , Takase Takao , Takashima Shuya , Yamaguchi Kohei , Semba Taro , Yamamoto Noboru
Published: June 2023

S3. Imaging of 2 Patients with Cholangiocarcinoma During Treatment.
Table S6 from Systemic Treatments and Molecular Biomarkers for Perivascular Epithelioid Cell Tumors: A Single-Institution Retrospective Analysis
Authors: Testa Stefano , Bui Nam Q. , Ganjoo Kristen N.
Published: June 2023

Table S6 shows median Overall Survival in months, as well as 5-year Overall Survival rate for the whole cohort.
Table S2 from Systemic Treatments and Molecular Biomarkers for Perivascular Epithelioid Cell Tumors: A Single-Institution Retrospective Analysis
Authors: Testa Stefano , Bui Nam Q. , Ganjoo Kristen N.
Published: June 2023

Table S2 shows the results of molecular testing available for each patient in the study.
Figure S8 from Systemic Treatments and Molecular Biomarkers for Perivascular Epithelioid Cell Tumors: A Single-Institution Retrospective Analysis
Authors: Testa Stefano , Bui Nam Q. , Ganjoo Kristen N.
Published: June 2023

Figure S8 shows combined clinical progression-free survival (cPFS) in the whole cohort comparing each mTOR inhibitors to other treatments.
Figure S7 from Systemic Treatments and Molecular Biomarkers for Perivascular Epithelioid Cell Tumors: A Single-Institution Retrospective Analysis
Authors: Testa Stefano , Bui Nam Q. , Ganjoo Kristen N.
Published: June 2023

Figure S7 shows Kaplan-Meier curves for combined PFS in patients with PEComas, specifically showing effect of TP53 and TSC1/TSC2 mutational status, as well as uterine vs extra-uterine location on combined PFS.
Figure S3 from Systemic Treatments and Molecular Biomarkers for Perivascular Epithelioid Cell Tumors: A Single-Institution Retrospective Analysis
Authors: Testa Stefano , Bui Nam Q. , Ganjoo Kristen N.
Published: June 2023

Figure S3 shows a bar graph with the number of treatment episodes in each disease group classified based on type and line of treatment.
Figure S10 from Systemic Treatments and Molecular Biomarkers for Perivascular Epithelioid Cell Tumors: A Single-Institution Retrospective Analysis
Authors: Testa Stefano , Bui Nam Q. , Ganjoo Kristen N.
Published: June 2023

Figure S10 shows a Kaplan-Meier curve that represents effects of different treatments on combined clinical PFS only in patients with malignant PEComa.
Data from Phase Ib/II Study of a Liposomal Formulation of Eribulin (E7389-LF) plus Nivolumab in Patients with Advanced Solid Tumors: Results from Phase Ib
Authors: Ida Hanae , Shimizu Toshio , Nishino Makoto , Nakamura Yoshiaki , Yazaki Shu , Katsuya Yuki , Sato Jun , Koyama Takafumi , Iwasa Satoru , Sudo Kazuki , Kondo Shunsuke , Yonemori Kan , Shitara Kohei , Shiono Satoshi , Matsuoka Daiko , Yasuda Keisuke , Otake Yohei , Suzuki Takuya , Takase Takao , Takashima Shuya , Yamaguchi Kohei , Semba Taro , Yamamoto Noboru
Published: June 2023

Purpose:
To determine a recommended dose of liposomal eribulin (E7389-LF) in combination with nivolumab in patients with advanced solid tumors, and to evaluate the safety, efficacy, pharmacokinetics, and biomarker impact of this regimen.
Experimental Design:
 Japanese patients with advanced, nonresectable, or recurrent solid tumors and no existing alternative standard/effective therapy (except nivolumab monotherapy) were assigned to either E7389-LF 1.7 mg/m2 plus nivolumab 360 mg every 3 weeks, E7389-LF 2.1 mg/m2 plus nivolumab 360 mg every 3 weeks, E7389-LF 1.1 mg/m2 plus nivolumab 240 mg every 2 weeks, or E7389-LF 1.4 mg/m2 plus nivolumab 240 mg every 2 weeks. Primary objectives were to evaluate the safety/tolerability of each dose cohort and to determine the recommended phase II dose (RP2D). Secondary/exploratory objectives, including safety [dose-limiting toxicities (DLT) and adverse events (AE)], pharmacokinetics, efficacy [including objective response rate (ORR)], and biomarker results were used in determining the RP2D.
Results:
 Twenty-five patients were enrolled to treatment [E7389-LF 1.7 mg/mg2 every 3 weeks (n = 6), E7389-LF 2.1 mg/m2 every 3 weeks (n = 6), E7389-LF 1.1 mg/m2 every 2 weeks (n = 7), E7389-LF 1.4 mg/m2 every 2 weeks (n = 6)]. Twenty-four patients were evaluated for DLTs, of whom 3 had DLTs (1 at E7389-LF 1.7 mg/m2 every 3 weeks, 1 at 1.1 mg/m2 every 2 weeks, and 1 at 1.4 mg/m2 every 2 weeks). All patients had ≥1 treatment-related treatment-emergent AE (TEAE); 68.0% had ≥1 grade 3–4 treatment-related TEAE. Changes in vasculature and IFN-related biomarkers were seen in each cohort. The overall ORR was 16%.
Conclusions:
E7389-LF plus nivolumab was tolerable overall; the recommended dose for future study was 2.1 mg/m2 plus nivolumab 360 mg every 3 weeks.
Significance:
This phase Ib part of a phase Ib/II study assessed the tolerability and activity of a liposomal formulation of eribulin (E7389-LF) plus nivolumab in 25 patients with advanced solid tumors. The combination was tolerable overall; 4 patients had a partial response. Vasculature and immune-related biomarker levels increased, suggesting vascular remodeling.
Melatonin Alters Innate Immune Function in Infants with Neonatal Encephalopathy
Authors: Aslam Saima , O'Dea Mary , Kelly Lynne A. , O'Neill Amanda , McKenna Ellen , Hurley Tim , Branagan Aoife , O'Driscoll David , Normile Caoimhe , Saleemi Shahid , Sweetman Deirdre , Vavasseur Claudine , Murphy John , Donoghue Veronica , Watson William , Molloy Eleanor J.
Published: June 2023

Introduction: Melatonin has been suggested an adjunctive therapy in neonatal encephalopathy (NE). Melatonin reduces oxidative stress and neutrophil activation; however, the immunological effects in NE have not been studied. Methods: Infants with NE and neonatal controls were prospectively recruited. Whole blood was sampled in the first week of life. Following endotoxin and or melatonin treatment, diurnal variation was measured by RT PCR for circadian rhythm genes (brain and Muscle Arnt-Like protein [BMAL1], circadian locomotor output cycles kaput [CLOCK], Nuclear Receptor Subfamily 1 Group D Member 2 [REV Erβ], and cryptochrome circadian clock [CRY]). Neutrophil and monocyte cell surface markers of activation CD11b, reactive oxygen intermediates (ROIs), and Toll-like receptor (TLR)-4 were also examined by flow cytometry in matching samples. Results: Serum and RNA samples from forty infants were included (controls n = 20; NE n = 20) over the first week of life. Melatonin reduced neutrophil CD11b and TLR-4 expression in response to LPS in infants with NE compared to controls. There were no differences in ROIs. BMAL1 and CLOCK baseline gene expression levels were similar. BMAL1 was significantly decreased with LPS stimulation in NE. There was no significant diurnal variation in melatonin, neutrophil, and monocyte function or circadian genes. Conclusions: Melatonin alters immune function ex vivo in infants with NE. Infants with NE have altered immune circadian responses following LPS stimulation, which have potential for modulation.
Dental Caries a Risk Factor for Intracerebral Hemorrhage
Authors: LaValley Elizabeth A. , Sen Souvik , Mason Emma , Logue Makenzie , Trivedi Tushar , Moss Kevin , Beck James , Rosamond Wayne D , Gottesman Rebecca F.
Published: June 2023

Introduction: Streptococcus mutans is a known cause of dental caries that contains a collagen-binding protein, Cnm, and exhibits inhibition of platelet aggregation and matrix metalloproteinase-9 activation. This strain has been linked to aggravation of experimental intracerebral hemorrhage (ICH) and may be a risk factor for ICH. The purpose of this study was to test the association between dental caries and incident ICH. Methods: The presence of dental caries and periodontal disease was assessed in subjects from the Dental Atherosclerosis Risk in Communities (DARIC) study without prior stroke or ICH. This cohort was followed for incident ICH over a period of 10 years. Cox regression was used to compute crude and adjusted hazards ratio from the dental assessment. Results: Among 6,315 subjects, dental surface caries and/or root caries were recorded in 1,338 (27%) subjects. Of those, 7 (0.5%) had incident ICH over a period of 10 years following the visit 4 assessment. Of the remaining 4,977 subjects, 10 (0.2%) had incident ICH. Those with dental caries versus those without dental caries were slightly younger (mean age 62.0 ± 5.7 vs. 62.4 ± 5.6, p = 0.012), had a greater proportion of males (51 vs. 44%, p < 0.001), African Americans (44 vs. 10%, p < 0.001), and were hypertensive (42 vs. 31%, p < 0.001). The association between caries and ICH was significant (crude HR 2.69, 95% CI 1.02–7.06) and strengthened after adjustment for age, gender, race, education level, hypertension, and periodontal disease (adjusted HR 3.88, 95% CI 1.34–11.24). Conclusion: Dental caries is a potential risk for incident ICH after caries detection. Future studies are needed to determine if treatment of dental caries can reduce the risk of ICH.
Migraine Attacks Triggered by Ingestion of Watermelon
Authors: Silva-Néto Raimundo Pereira , Bezerra Gabriela Leal , Araújo Natália Rebeca Alves , Silva Sângela Fernandes , Pereira Suyanne Kássia Soares , Lima Layana Karine Farias , Soares Adriana Almeida , Lopes Luciano Silva
Published: June 2023

Introduction: Ingesting some foods can trigger headache attacks in migraine patients. Diet-sourced citrulline activates the l-arginine-nitric oxide pathway, acting on the pathophysiology of migraine. Methods: The study was a clinical trial, interventional, controlled, and with group comparison. The sample was non-random, composed of 38 volunteers with migraine and 38 without headache (control). Both groups ingested a portion of watermelon to determine the onset of headache attacks. Before and after ingesting watermelon, they underwent blood collections to determine serum nitrite levels. Results: There were 38 volunteers diagnosed with migraine without aura and 38 controls, whose mean age was, respectively, 22.4 ± 1.5 and 22.9 ± 3.1 years (p = 0.791). Headache was triggered by watermelon ingestion after 124.3 ± 20.5 min of ingestion in 23.7% (9/38) of the migraine volunteers and in none of the controls (p = 0.002). There was an increase in serum nitrite levels, both in migraine volunteers (23.4%) and in the control group (24.3%), after watermelon ingestion. This difference was significant (p < 0.001). Discussion: Watermelon ingestion triggered headache attacks in migraine patients and increased serum nitrite levels, attesting to a possible activation of the l-arginine-nitric oxide pathway.
Real-World Effectiveness and Risk Factors for Discontinuation of Ustekinumab in Ulcerative Colitis
Authors: Uchida Genta , Nakamura Masanao , Yamamura Takeshi , Maeda Keiko , Sawada Tsunaki , Ishikawa Eri , Furukawa Kazuhiro , Iida Tadashi , Mizutani Yasuyuki , Yamao Kentaro , Ishikawa Takuya , Ishizu Yoji , Honda Takashi , Ishigami Masatoshi , Kawashima Hiroki
Published: June 2023

Introduction: Ustekinumab (UST) has been approved for the treatment of moderate-to-severe ulcerative colitis (UC). Real-world data showing the effectiveness and safety of UST are necessary to confirm the results of clinical trials for applicability in daily clinical practice. Although some studies have reported real-world evidence of UST, only few studies have confirmed its effectiveness in the real world. The aim of this study was to assess the short- and long-term effectiveness, durability, safety, and risk factors for discontinuation of UST in UC in clinical practice. Methods: This was a retrospective, single-center, observational study. From March 2020 to January 2023, all consecutive patients with active UC who were treated with UST at Nagoya University Hospital were included. The primary outcome was the clinical remission rate at weeks 2–8 and weeks 24–48. The secondary outcomes included clinical response, persistence of UST therapy, endoscopic changes during follow-up, risk factors for UST discontinuation, and occurrence of any adverse events. The clinical effectiveness was evaluated using the Lichtiger score. Results: A total of 31 patients were included in this study. The clinical remission rates were 9.7%, 29.0%, 54.8%, and 64.5% at weeks 2, 8, 24, and 48, respectively. Twelve (38.7%) patients discontinued UST during the follow-up period. The probability of continuing UST was 93.5%, 80.6%, 77%, and 70% at weeks 2, 8, 24, and 48, respectively. The major reason for discontinuation of UST was primary failure (75.0%). A high baseline C-reactive protein (CRP) level was a significant risk factor for the discontinuation of UST. No adverse events were observed in this study. Conclusion: UST is effective for patients with UC. High CRP levels were identified as a risk factor for UST discontinuation. The findings of this study would help clinicians to select appropriate treatment options for patients with UC by identifying the risk factors for treatment discontinuation.
O amor pedagógico e o romance escolar: outras reflexões sobre a psicologia do colegial
Authors: Rocha Lorenna Pinheiro , Santos Patrícia Lavinas , Lima Maria Celina Peixoto
Published: June 2023

O presente artigo aborda a questão da educação de jovens frente aos impasses relativos à transmissão no encontro entre gerações. Apontamos a necessidade de considerarmos a relação transferencial que se estebelece entre professores e alunoscomo vetor necessário para a construção de uma certa relação com o saber, somente possível pelo amor que o professor dirige ao conhecimento e aos próprios alunos – o amor pedagógico. Seguindo nessa mesma direção, propomos aconstrução de um Romance Escolar como saída possível frente ao fracasso do projeto educacional contemporâneo,uma vez que possiblita ao jovem uma construção ficcional de si e do mundo, permitindo-lhe conferir novos sentidos à vida, ao saber e à própria experiência escolar, na esteira do que lhe foi deixado como legado pela tradição transmitida pelas gerações que o precederam.
Cytokine-Mediated Degradation of the Transcription Factor ERG Impacts the Pulmonary Vascular Response to Systemic Inflammatory Challenge
Authors: Schafer Christopher M. , Martin-Almedina Silvia , Kurylowicz Katarzyna , Dufton Neil , Osuna-Almagro Lourdes , Wu Meng-Ling , Johnson Charmain F. , Shah Aarti V. , Haskard Dorian O. , Buxton Andrianna , Willis Erika , Wheeler Kate , Turner Sean , Chlebicz Magdalena , Scott Rizaldy P. , Kovats Susan , Cleuren Audrey , Birdsey Graeme M. , Randi Anna M. , Griffin Courtney T.
Published: June 2023

BACKGROUND:

During infectious diseases, proinflammatory cytokines transiently destabilize interactions between adjacent vascular endothelial cells (ECs) to facilitate the passage of immune molecules and cells into tissues. However, in the lung, the resulting vascular hyperpermeability can lead to organ dysfunction. Previous work identified the transcription factor ERG (erythroblast transformation-specific–related gene) as a master regulator of endothelial homeostasis. Here we investigate whether the sensitivity of pulmonary blood vessels to cytokine-induced destabilization is due to organotypic mechanisms affecting the ability of endothelial ERG to protect lung ECs from inflammatory injury.

METHODS:

Cytokine-dependent ubiquitination and proteasomal degradation of ERG were analyzed in cultured HUVECs (human umbilical vein ECs). Systemic administration of TNFα (tumor necrosis factor alpha) or the bacterial cell wall component lipopolysaccharide was used to cause a widespread inflammatory challenge in mice; ERG protein levels were assessed by immunoprecipitation, immunoblot, and immunofluorescence. Murine
Erg
deletion was genetically induced in ECs (

Erg
fl/fl
;Cdh5[PAC]-Cre
ERT2

), and multiple organs were analyzed by histology, immunostaining, and electron microscopy.

RESULTS:

In vitro, TNFα promoted the ubiquitination and degradation of ERG in HUVECs, which was blocked by the proteasomal inhibitor MG132. In vivo, systemic administration of TNFα or lipopolysaccharide resulted in a rapid and substantial degradation of ERG within lung ECs but not ECs of the retina, heart, liver, or kidney. Pulmonary ERG was also downregulated in a murine model of influenza infection.

Erg
fl/fl
;Cdh5(PAC)-Cre
ERT2

mice spontaneously recapitulated aspects of inflammatory challenges, including lung-predominant vascular hyperpermeability, immune cell recruitment, and fibrosis. These phenotypes were associated with a lung-specific decrease in the expression of
Tek
—a gene target of ERG previously implicated in maintaining pulmonary vascular stability during inflammation.

CONCLUSIONS:

Collectively, our data highlight a unique role for ERG in pulmonary vascular function. We propose that cytokine-induced ERG degradation and subsequent transcriptional changes in lung ECs play critical roles in the destabilization of pulmonary blood vessels during infectious diseases.
Health Disparities in Peripheral Artery Disease: A Scientific Statement From the American Heart Association
Authors: Allison Matthew A. , Armstrong David G. , Goodney Philip P. , Hamburg Naomi M. , Kirksey Lee , Lancaster Kristie J. , Mena-Hurtado Carlos I. , Misra Sanjay , Treat-Jacobson Diane J. , White Solaru Khendi T. ,   on behalf of the American Heart Association Council on Peripheral Vascular Disease; Council on Hypertension; and Council on Lifestyle and Cardiometabolic Health
Published: June 2023

Peripheral artery disease (PAD) affects 200 million individuals worldwide. In the United States, certain demographic groups experience a disproportionately higher prevalence and clinical effect of PAD. The social and clinical effect of PAD includes higher rates of individual disability, depression, minor and major limb amputation along with cardiovascular and cerebrovascular events. The reasons behind the inequitable burden of PAD and inequitable delivery of care are both multifactorial and complex in nature, including systemic and structural inequity that exists within our society. Herein, we present an overview statement of the myriad variables that contribute to PAD disparities and conclude with a summary of potential novel solutions.
Abstract 08: Computed Tomography Perfusion Of Cerebral Blood Flow During Open Cardiac Massage For Hypovolemic And Normovolemic Cardiac Arrest In Swine
Authors: Treffalls Rebecca N , Stonko David P , Patel Neerav , Edwards Joseph , Abdou Hossam , Elansary Noha , Walker Patrick , Morrison Jonathan J
Published: June 2023

Introduction:
Adequate cerebral blood flow (CBF) during open cardiac massage (OCM) in cardiac arrest is critical for survivors to be neurologically intact. Cerebral perfusion is known to be poor during OCM but has not been quantified using a brain perfusion technique. The aim of this study is to measure CBF in swine undergoing OCM in hypovolemia and normovolemia using computed tomography perfusion (CTP) scanning.

Methods:
Anesthetized swine underwent instrumentation with right atrial and aortic pressure catheters. A pigtail catheter placed in the ascending aorta was used to administer iodinated contrast and CTP imaging acquired. Brain parenchymal attenuation was measured over time from which CBF (mL/100g of brain) and time to peak (TTP; secs) were derived. Animals were then euthanized exsanguination (hypovolemic group) or potassium chloride injection (normovolemic group). Animals were subject to a clamshell thoracotomy, OCM and repeated CTP. Data pertaining to peak coronary perfusion pressure (pCPP; mmHg) was collected and % CPP >15mmHg (% CPP; secs) calculated post hoc.

Results:
Normovolemic animals achieved superior pCPP compared to the hypovolemic animals (pCPP: 39.3 vs 12.3, p<0.001; % CPP: 14.5 ± 1.9 vs 30.9 ± 6.5, p<0.001). CTP was successfully performed during OCM generating an attenuation curve (figure). The TTP elongated from spontaneous circulation, normovolemia to hypovolemia (5.7 vs 10.8 vs 14.8, p=0.01). CBF during OCM was similar between hypovolemic and normovolemic groups (7.5 ± 8.1 vs 4.9 ± 6.0, p =0.73) which was lower than baseline values (51.9 ± 12.1, p<0.001).

Conclusions:
OCM in normovolemia generates superior coronary hemodynamics compared to hypovolemia. Despite this, neither generates adequate CBF as measured by CTP, compared to baseline. To improve the rate of neurologically intact survivors, novel resuscitative techniques need to be investigated that specifically target cerebral perfusion as existing techniques are inadequate.
Abstract 10038: Combined Low Endothelial Shear Stress and High Plaque Structural Stress Heterogeneity Predicts Non-Culprit Major Adverse Cardiovascular Events; Insights From the PROSPECT Study
Authors: Gu Sophie Z , Ahmed Mona E , Huang Yuan , Hakim Diaa , Maynard Chuck , Cefalo Nicholas , Coskun Ahmed U , Costopoulos Charis , Maehara Akiko , Stone Gregg , Stone Peter H , Bennett Martin R
Published: June 2023

Introduction:
Low endothelial shear stress (ESS) is a pro-atherogenic stimulus associated with coronary plaque development, while high plaque structural stress (PSS) and its heterogeneity is associated with plaque destabilization. Previous studies showed that combining ESS and PSS additively predicts plaque progression, but no studies have determined their ability to predict major adverse cardiovascular events (MACE). We examined whether combining ESS and PSS improves MACE prediction in patients with acute coronary syndrome.

Methods:
We examined baseline ESS, ESS gradient, PSS, and PSS heterogeneity index (HI) in 22 non-culprit lesions (NCL) leading to future MACE, and 64 randomly selected control NCLs without MACE from the PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) study. ESS was calculated by computational fluid dynamics and PSS by finite element analysis on co-registered lesions.

Results:
86 lesions (55 thin-cap and 31 thick-cap fibroatheromas) were analyzed from 67 patients. Lesions that caused future MACE showed baseline higher PSS HI (0.32 vs. 0.24, p<0.001), lower ESS (0.56 vs. 0.91 Pa, p=0.007), higher ESS gradient (3.82 vs. 1.96 Pa/mm, p=0.007), smaller minimum lumen area (MLA, 3.83 vs. 5.05 mm
2
, p=0.002), and larger plaque burden (PB, 70% vs. 59.4%, p<0.001). Independent predictors of MACE in multivariate analysis included high PSS HI (hazard ratio [HR] 3.9, 95% confidence interval [CI] 1.5-10.4, p=0.006), high ESS gradient (HR 3.4, 95% CI 1.4-8.1, p=0.007), and high PB at the MLA (HR 2.6, 95% CI 1.1-6.3, p=0.035). Combining low ESS and high PSS HI improved test specificity to 0.83 and positive predictive value (PPV) to 59.3%, while maintaining high sensitivity at 0.73 and high negative predictive value (NPV) at 89.8%. Combining low ESS, high ESS gradient, and high PSS HI further improved prognostication, predicting 80% of MACE over 3-year follow-up (p<0.001).

Conclusions:
Combining baseline low ESS, high ESS gradient and high PSS heterogeneity significantly improves risk stratification of NCLs over each parameter alone. Combining parameters exceeds PPV and NPV achieved by imaging alone, and may identify lesions suitable for preemptive intervention strategies to avert future MACE.
Abstract 10054: Super Resolution Deep Learning Reconstruction for Detection of In-Stent Restenosis
Authors: Kawai Hideki , Motoyama Sadako , Sarai Masayoshi , Sato Yoshihiro , Takahashi Hiroshi , Muramatsu Takashi , Narula Jagat , Izawa Hideo
Published: June 2023

Introduction:
Evaluation of in-stent-restenosis (ISR), especially of small stents, remains a challenge for computed tomography (CT) angiography.

Hypothesis:
To quantitatively define stent strut thickness and lumen vessel diameter at the stent site by deep learning reconstruction and compare this with conventional reconstruction strategies.

Methods:
We employed ultra-high-resolution CT (URCT) data to train a super resolution neural network (Precise IQ engine, or PIQE) and apply the network to current standard resolution CT (Forward projected model-based Iterative Reconstruction SoluTion, FIRST). We examined 166 stents in 85 consecutive patients who underwent CT and invasive coronary angiography (ICA) within three months of each other from 2019-2021 after percutaneous coronary intervention with coronary stent placement. The diagnostic accuracy for the presence of ISR was defined as percent diameter stenosis > 50% on ICA. All images were reconstructed with PIQE and FIRST and assessed by two blinded cardiovascular imagers.

Results:
Compared to FIRST, the full width at half maximum of the lumen was larger, and that of the strut was smaller in PIQE. Image quality score was significantly better in PIQE than in FIRST (4.2±1.1 vs. 2.7±1.2, P <0.01). The sensitivity, specificity, PPV, NPV, and accuracy for detection of ISR in PIQE were better than the FIRST (86.1, 89.5, 50.0, 98.1, and 89.2 vs. 80.6, 77.4, 30.2, 97.0, and 77.7, respectively); the differences were particularly pronounced in a group with < 3.0 mm stent diameter.

Conclusions:
PIQE provides superior image quality and diagnostic accuracy for ISR, even in stents with < 3.0 mm diameter.
Abstract 10062: Statin Utilization in a Real-World Primary Prevention Cohort of Older Adults
Authors: Walker Aaron J , Zhu Jianhui , Thoma Floyd W , MARROQUIN Oscar C , Makani Amber , Aiyer Aryan , Gulati Martha , Virani Salim S , Reis Steven , Ballantyne Christie M , Mulukutla Suresh R , Saeed Anum
Published: June 2023

Introduction:
Statins are a cost-effective therapy for prevention of atherosclerotic cardiovascular disease (ASCVD). Although the ACC/AHA guidelines recommend statins for primary prevention among various groups aged 40-75, the guidelines are less clear for older adults (>75y). We investigated statin use in older adults without ASCVD events, stratified by risk category, in a large healthcare network.

Methods:
Inclusion criteria were adults aged 75-79, without CAD, PVD or ischemic stroke. Statin utilization, based on the ACC/AHA 10-year ASCVD risk calculation, was evaluated in intermediate (7.5%-19.9%) and high-risk patients (≥ 20%). Patients were categorized into using low and ‘moderate or high’ intensity statins. Cox regression models were used to assess hazard ratios for ASCVD events and mortality over ≈6 years.

Results:
Among 8114 patients aged 75-79, 86.8% were high risk and 46% of these patients were on any statin. Compared with those on moderate or high intensity statins, older high-risk patients not on any statin had a significantly increased risk of MI
[HR 1.53 (1.25-1.87); p<0.001]
, stroke
[HR 1.52 (1.17-1.96); p<0.01]
and mortality
[HR 1.43 (1.24-1.64); p<0.001]
(Table 1).
High risk older adults on no statin had a higher risk of MI compared to those high risk <75y on no statin
[HR 1.15 (1.02-1.29);
p value for age interaction <0.05].
Statin initiation probability for those without any statin at first healthcare interaction was ≈36% at 5 years.

Conclusion:
In a large healthcare network, 54% of high-risk primary prevention older adults were not on any statin and initiation remained low at 5 years. Lack of statin use was associated with increased ASCVD events and mortality in high-risk older adults. Given the benefits appreciated with statin use in this older population in contemporary practices, statin use may need to be more strongly considered for primary ASCVD prevention among high-risk older adults. Further studies are needed to assess the risk-benefit ratio.
Abstract 10068: High Pericoronary Adipose Tissue Attenuation on Coronary Computed Tomography Angiography Predicts Cardiovascular Events in Patients Without Obstructive Coronary Artery Disease
Authors: Nishihara Takahiro , Miyoshi Toru , Ichikawa Keishi , Nakashima Mitsutaka , Miki Takashi , Yoshida Masatoki , Toda Hironobu , Yoshida Masashi , Nakamura Kazufumi , Morita Hiroshi , Ito Hiroshi
Published: June 2023

Introduction:
Patients without obstructive coronary artery disease (CAD) have an increased risk of major adverse coronary events compared to patients with no coronary artery stenosis. However, risk stratification among patients without obstructive CAD has not been established.

Hypothesis:
This study was aimed to investigate whether pericoronary adipose tissue attenuation (PCATA) on coronary computed tomography angiography (CCTA), a novel imaging biomarker of pericoronary inflammation, is a useful predictor for cardiovascular events in patients without obstructive CAD.

Methods:
A total of 1183 patients without obstructive CAD undergoing clinically indicated CCTA in our institute from August 2011 and December 2016 were enrolled. Obstructive CAD was defined as luminal narrowing of ≧50% in any coronary artery. We also examined PCATA and high-risk plaque features on CCTA as well as coronary artery calcium score and pericardial fat volume. PCATA in Hounsfield units (HU) was assessed at proximal 40-mm segments of all 3 major coronary arteries. The outcome was composite cardiovascular events including cardiovascular death, acute coronary syndrome, and late coronary revascularization.

Results:
During a median follow-up of 23.0 months, 32 cardiovascular events were observed. Left anterior descending artery (LAD)-PCATA in patients with cardiovascular events was significantly higher than that in patients without (-64.0 ± 6.0 HU vs -66.9 ± 7.3 HU, p=0.012), whereas right coronary artery- and left circumflex artery-PCATA were not. High LAD-PCATA was significantly associated with cardiovascular events in a model that included traditional risk factors, coronary artery calcium score and adverse CTA findings, such as degree of stenosis and high-risk plaque (HR; 1.467, 95%CI; 1.03-2.09, p = 0.033). Finally, incremental prognostic value of PCATA was evaluated. After adding LAD-PCATA to a model including traditional risk factors and the adverse CTA findings, global chi-square values increased significantly from 33.0 to 37.5 (p = 0.032).

Conclusions:
High LAD-PCATA has incremental prognostic value over conventional risk factors and CTA findings in patients without obstructive CAD.
Abstract 10083: Cardiovascular Outcomes of Non-ST-Elevation Myocardial Infarction (NSTEMI) Patients Without Standard Modifiable Risk Factors (SMuRF-less): The Intermountain Healthcare Experience
Authors: Anderson Jeffrey L , Knight Stacey , May Heidi T , Le Viet T , Bair Tami L , Knowlton Kirk U , Muhlestein Joseph B
Published: June 2023

Introduction:
Recent interest has focused on STEMI patients (pts) without standard modifiable risk factors (SMuRF-less), noting that they are surprisingly common (14-27%). These studies have reported them to have a worse, or at best similar, in-hospital/short-term prognosis. However, relatively little attention has been paid to the prevalence and prognosis of SMuRF-less patients with non-ST elevation myocardial infarction (NSTEMI). The aim of our study was to identify the proportion and outcomes of SMuRF-less NSTEMI pts in a large US healthcare population.

Methods:
Pts with NSTEMI between 2001-2021 presenting to Intermountain Healthcare catheterization laboratories were included. SMuRF included a clinical diagnosis of, or treatment for, hypertension, hyperlipidemia, diabetes, and/or smoking. 60-day and long-term major adverse cardiovascular event (MACE) outcomes were defined as death, myocardial infarction, and heart failure hospitalization and were tested using Cox proportional hazard regression.

Results:
NSTEMI pts totaled 8196, of which1458 (17.8%) were SMuRF-less. SMuRF-less pts were younger, more frequently male, had fewer comorbidities, and were slightly less likely to have PCI/CABG than NSTEMI pts with SMuRF (Table 1). 60-day MACE for SMuRF-less pts were lower (adj HR 0.55, p<0.0001), and this persisted for long-term MACE outcomes (adj HR 0.64, p<0.0001) and for each of its components (Table 2).

Conclusions:
In this large US healthcare population, SMuRF-less NSTEMI presentation, as with STEMI presentation, was found to be common (17.8%). However, unlike STEMI reports, short- and long-term outcomes were generally more favorable for SMuRF-less status. Further studies to increase understanding of risk factors and preventive measures for NSTEMI in SMuRF-less pts are indicated.
Abstract 10145: Cardiovascular Disease Risk and Outcomes Among Veterans by Sexual Orientation
Authors: Streed Carl G , Duncan Meredith S , Heier Kory R , O'Leary John , Skanderson Melissa , Goulet Joseph L
Published: June 2023

Introduction:
Lesbian, gay, and bisexual (LGB) adults have CVD risk and outcome inequities compared to heterosexual peers. With upwards of 7 million sexual minority adults aged >50 by 2030, assessing and addressing their cardiovascular health is critical for clinicians and public health practitioners. However, few electronic health record (EHR) cohorts have been used to study this association.

Methods and Results:
In this analysis, we used the Veterans Healthcare Administration Lesbian, Gay, Bisexual, Transgender EHR cohort, excluding transgender individuals to avoid conflating sexual orientation with gender identity. The baseline date was the first primary care appointment on or after October 1, 2009. Sexual orientation of 1,108,990 veterans was identified via a natural language processing tool with 88.2% sensitivity, 91.5% specificity, and 85.9% PPV; 185,788 veterans were classified as LGB. Prevalent CVD (history of AMI, ischemic stroke, or revascularization in the year preceding the baseline date) was present among 19,887 veterans (4,684 LGB). We calculated sample statistics stratified by sex and sexual minority status; results are displayed in the
Table
. We used logistic regression analyses to assess the association between sexual minority status and prevalent CVD. Adjusting for age, sex, race, and Hispanic ethnicity, LGB veterans had 1.12 [1.16, 1.24] times the odds of prevalent CVD compared to non-sexual minority veterans. Upon additional adjustment for BMI, diabetes, hypertension, lipids, substance use, anxiety, and depression, this association remained significant (OR [95% CI]: 1.08 [1.04, 1.12]).

Conclusion:
This is one of the first studies to examine cardiovascular health within a veteran population stratified by sexual orientation. Addressing the cardiovascular health of marginalized populations requires further exploring the mechanisms by which stress results in CVD risk and outcomes and the inequitable distribution of both.
Abstract 10209: The Effect of the Dual SGLT1 and 2 Inhibitor Sotagliflozin on Cardiovascular Mortality and Hospital Readmission Rates for Heart Failure at 30 and 90 Days Post Discharge in Patients With Type 2 Diabetes Hospitalized for Worsening Heart Failure in the SOLOIST-WHF Trial
Authors: Pitt Bertram , Bhatt Deepak L , Szarek Michael , Sun Franklin , Davies Michael J , Steg Philippe G
Published: June 2023

Introduction:
SGLT inhibitors demonstrate reductions in CV mortality and HHF in patients with diabetes and chronic HF. Despite therapy, patients hospitalized for worsening HF (WHF) are at high risk of death or readmission.

Hypothesis:
The SOLOIST-WHF trial admitted patients for their index WHF event and initiated randomized therapy during hospitalization. This study evaluated the effect of the SGLT1 and 2 inhibitor sotagliflozin on 30- and 90-day CV death and HF readmission rates after discharge.

Methods:
Of 1222 randomized patients with T2D, 86% were admitted for their index WHF event. Of them, 46% (n = 563) started study drug prior to or at discharge. In post hoc exploratory analyses, CV death and HF readmission (HHF or urgent visits for HF) rates were determined 30- or 90-days post discharge. Comparisons were done by Cochran-Mantel-Haenszel test stratified by region and baseline LVEF (<50%, ≥50%).

Results:
Treatment with sotagliflozin showed significant relative risk reduction of >50% for readmission for non-fatal HF-related events or the composite of CV death and readmission for HF-related events within 30 or 90 days of discharge vs placebo (Table 1). The sotagliflozin safety profile in those windows was generally consistent with the overall study duration. Incidence of adverse events (AEs) and serious AEs was similar between groups. Increased incidence of diarrhea and volume-related AEs was noted with sotagliflozin. No appreciable eGFR change from baseline occurred at 30 days, but there was lower incidence of AEs linked to acute kidney injury with sotagliflozin.

Conclusions:
Sotagliflozin, given to patients with T2D prior to or at hospital discharge after an episode of WHF, was well tolerated and resulted in a significant >50% reduction in CV mortality or readmission for a HF event at 30 and 90 days post-discharge.
Abstract 10211: Cardiac MR Overlay Guides Endomyocardial Biopsy in Pediatric Transplant Patients Towards Regions of Interest
Authors: Udine Michelle , Richmann Devika P , Hamann Karin , Downing Tacy E , Kanter Joshua , Rossi Christopher , Staffa Steven , Zurakowski David , Cross Russell , Olivieri Laura
Published: June 2023

Introduction:
Endomyocardial biopsy (EMB) drives rejection diagnosis in pediatric heart transplant patients but is subject to false negatives. Cardiac magnetic resonance imaging (CMR) can detect and quantify fibrosis and edema with T1 and T2 mapping. Overlaying CMR data onto X-ray images may be used for EMB procedural guidance.

Hypothesis:
Overlaying segmented T1 and T2 map images onto X-ray for EMB guidance may improve diagnosis of rejection in pediatric transplant patients.

Methods:
30 pediatric heart transplant patients referred for clinically indicated EMB underwent noncontrast CMR with T1 and T2 mapping prior to EMB. If present, regions of T1 and T2 elevation were segmented and exported as an overlay image. Biopsies were obtained without (
unguided
) and then with (
guided
) CMR overlay with T1 and T2 “hotspots”. Each biopsy specimen received a rejection grade, blinded to guided vs. unguided. As a surrogate for clinical rejection, treatment decisions were made without knowledge of CMR results, and logged as no change, oral therapy augmentation, or IV therapy initiation. Treatment category and pathologic grade were compared among biopsies with Fisher’s exact test and logistic regression.

Results:
30 patients (median age 13 years (interquartile range (IQR) 8.8, 16.2), BSA 1.36 m2 (IQR 1.09, 1.86), 50% male) underwent 64 encounters for a total of 199 biopsied specimens (58 guided, 141 unguided). Hotspots were identified in 75% (48/64) of encounters, with 69% (33/48) in biopsied regions of the right ventricle allowing for guidance (25 T1 and 8 T2). Patients with T1 or T2 hotspots providing guided EMB were twice as likely to require any augmentation of therapy compared to those with unguided EMB (38% guided vs 17% unguided, p=0.001). Incidence of pathologic biopsy results (grade > 0) was not significantly different between guided and unguided biopsies from the same patients (41% vs 40%, p =0.99).

Conclusions:
Patients with T1/T2 hotspots on CMR and guided EMB require rejection treatment more frequently than patients with only unguided biopsies, although biopsy grade did not significantly differ within the same patient. Future work will evaluate relationship of CMR T1 and T2 hotspots to treatment, which may establish CMR as a superior screening tool for rejection.
Abstract 10262: High Output Cardiac Failure Due to Kratom
Authors: Gareeb Mohammad , Bhardwaj Chetan , Duvvuri Padmaraj D
Published: June 2023

Introduction:
Kratom use has been known to the natives of Malaysia to increase energy and to treat pain. Over the recent past there has been an increase in Kratom usage in the U.S. with the ease of access.

Case Summary:
A 24-year-old male presented to the emergency department due to progressive shortness of breath and pedal edema over one month. The patient reported a history of daily Kratom use for the past 2 years. His vitals upon presentation were BP: 90/50 mmHg, HR 101 bpm, O2 saturation 100% and was afebrile. Relevant abnormal labs were: sodium 114 mEq, and a BNP of 2,747 pg/mL. Other labs including TSH and urine drug screen were unremarkable. Initial ECG showed normal sinus rhythm, right axis deviation and QTc of 552 ms. Chest X ray revealed a prominent pulmonary conus.

After being admitted to the ICU, he had an appropriate gradual increase in sodium level over the next 4 days. The transthoracic echocardiogram showed an LVEF of 70-75% and multiple findings suggestive of severe pulmonary hypertension and severe tricuspid regurgitation (Fig. 1 parts A and B). His estimated PASP was 95 mm Hg. Right heart catheterization demonstrated the following pressures (in mmHg): RA 5/6, PA 52/26 (37), mean PCWP 7. Cardiac output and index were 8.9 L/min and 5 L/min/m2 by Fick, 7.7 L/min and 4.3 L/min/m2 by thermodilution.

Four weeks after cessation of Kratom use he underwent a transthoracic echocardiogram which showed complete normalization of abnormal findings shown in Fig. 1 parts C and D. His RVSP normalized to 26 mm Hg.

Conclusion:
Previously reported adverse cardiovascular events from Kratom use include tachycardia, hypertension, chest pain, conduction defects, QTc prolongation as well as cardiac arrest. We present previously unknown complications of Kratom use, namely combined pre and post capillary pulmonary hypertension and high output heart failure.
Abstract 10342: Sarm1 Deficiency Ameliorates Diabetic Cardiomyopathy by Reversing Lipid Metabolism and Fibrosis
Authors: Lee Chi Fung
Published: June 2023

Introduction and hypothesis:
Diabetes is a risk factor for heart disease and decline in NAD levels is associated with cardiometabolic disease. We aimed to test a hypothesis and identify mechanisms by which deletion of SARM1 NAD hydrolase ameliorates diabetic cardiomyopathy.

Methods and Results:
Metabolomic analysis found that 67 out of 243 plasma metabolites showed changes in unstressed SARM1-KO mice (KO), including elevated levels in markers of metabolic disorder, e.g. phosphatidylcholine or ceramide. Baseline blood glucose levels was slightly elevated in KO. RNA-seq analyses of WT and KO hearts did not find changes in genes of lipid metabolism, suggesting confounding impacts of SARM1 deficiency in other tissues on the altered plasma metabolism. Despite the changes in metabolite levels, KO had no change in cardiac structure and function. WT and KO were challenged with 16-week type 1 diabetic stress. Diabetic WT showed progressive systolic (FS: 50% vs 34%; P<0.01) and diastolic dysfunction (E’/A’: 1.5 vs 1.0, P<0.01), both of which were attenuated by SARM1 deficiency (FS to 48%; E’/A’ to 1.4, P<0.01). Despite differences in baseline metabolite levels, fasting glucose levels were similarly elevated in diabetic WT and KO. Metabolomic analysis showed little changes in diabetic KO plasma, suggesting that the cardioprotection in KO is due to the reversal of cardiac pathogenic mechanisms. SARM1 deficiency normalized the decline in cardiac NAD levels of diabetic hearts, with similar expressions of other NAD hydrolases, Bst1 and Cd38. Diabetic WT hearts up-regulated cardiomyopathy markers such as nppb, Nox4 mRNAs, and myh7/myh6 ratio, which were normalized by SARM1 deficiency. Chronic diabetes promoted cardiac fibrosis and induced profibrotic gene expressions, which were suppressed by SARM1 deficiency. RNA-seq analysis showed that chronic metabolic stress induced gene expressions of lipid metabolism in diabetic WT hearts. SARM1 deficiency reversed some of these upregulation, suggesting that cardiac SARM1 may regulate lipid metabolism in diabetic hearts via maintaining NAD homeostasis.

Conclusion:
Our data suggest that SARM1 regulates metabolism and fibrosis in the progression of diabetic cardiomyopathy but underlying mechanisms are to be dissected.