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Background Palpitations are a common emergency department (ED) complaint, yet relatively little research exists on this topic from an emergency care perspective. Objectives We sought to describe the perceptions and clinical decision-making processes of emergency physicians (EP) surrounding patients with palpitations. Methods We conducted 21 semistructured interviews with a convenience sample of EPs. We recruited participants from academic and community practice settings from four regions of the United States. The transcribed interviews were analyzed using a combination of structural coding and grounded theory approaches with ATLAS.ti, a qualitative data analysis software program (version 7; Atlas.ti Scientific Software Development GmbH, Berlin, Germany). Results EPs perceive palpitations to be a common but generally benign chief complaint. EPs' clinical approach to palpitations, with regards to testing, treatment, and ED management, can be classified as relating to one or more of the following themes: 1) risk stratification, 2) diagnostic categorization, 3) algorithmic management, and 4) case-specific gestalt. With regard to disposition decisions, four main themes emerged: 1) presence of a serious diagnosis, 2) perceived need for further cardiac testing/monitoring, 3) presence of key associated symptoms, 4) request of other physician or patient desire. The interrater reliability exercise yielded a Fleiss' kappa measure of 0.69, indicating substantial agreement between coders. Conclusion EPs perceive palpitations to be a common but generally benign chief complaint. EPs rely on one or more of four main clinical approaches to manage these patients. These findings could help guide future efforts at developing risk-stratification tools and clinical algorithms for patients with palpitations.

Cancer dependency maps have accelerated the discovery of tumor vulnerabilities that can be exploited as drug targets when translatable to patients. The Cancer Genome Atlas (TCGA) is a compendium of 'maps' detailing the genetic, epigenetic and molecular changes that occur during the pathogenesis of cancer, yet it lacks a dependency map to translate gene essentiality in patient tumors. Here, we used machine learning to build translational dependency maps for patient tumors, which identified tumor vulnerabilities that predict drug responses and disease outcomes. A similar approach was used to map gene tolerability in healthy tissues to prioritize tumor vulnerabilities with the best therapeutic windows. A subset of patient-translatable synthetic lethalities were experimentally tested, including PAPSS1/PAPSS12 and CNOT7/CNOT78, which were validated in vitro and in vivo. Notably, PAPSS1 synthetic lethality was driven by collateral deletion of PAPSS2 with PTEN and was correlated with patient survival. Finally, the translational dependency map is provided as a web-based application for exploring tumor vulnerabilities., (© 2024. The Author(s).)

Background: Our recently developed C oronary A rtery T ree description and L esion E valua T ion (CatLet) angiographic scoring system is unique in its description of the variability in the coronary anatomy, the degree of stenosis of a diseased coronary artery, and its subtended myocardial territory, and can be utilized to predict clinical outcomes for patients with acute myocardial infarction (AMI) presenting ≤12 h after symptom onset. The current study aimed to assess whether the Clinical CatLet score (CCS), as compared with CatLet score (CS), better predicted clinical outcomes for AMI patients presenting >12 h after symptom onset., Methods: CS was calculated in 1018 consecutive AMI patients enrolled in a retrospective registry. CCS was calculated by multiplying CS by the ACEF I score (age, creatinine, and left ventricular ejection fraction). Primary endpoint was major adverse cardiac events (MACEs) at 4-year-follow-up, a composite of cardiac death, myocardial infarction, and ischemia-driven revascularization., Results: Over a 4-year follow-up period, both scores were independent predictors of clinical outcomes after adjustment for a broad spectrum of risk factors. Areas-under-the-curve (AUCs) for CS and CCS were 0.72(0.68-0.75) and 0.75(0.71-0.78) for MACEs; 0.68(0.63-0.73) and 0.78(0.74-0.83) for all-cause death; 0.73(0.68-0.79) and 0.83(0.79-0.88) for cardiac death; and 0.69(0.64-0.73) and 0.75(0.7-0.79) for myocardial infarction; and 0.66(0.61-0.7) and 0.63(0.58-0.68) for revascularization, respectively. CCS performed better than CS in terms of the above-mentioned outcome predictions, as confirmed by the net reclassification and integrated discrimination indices., Conclusions: CCS was better than CS to be able to risk-stratify long-term outcomes in AMI patients presenting >12 h after symptom onset. These findings have indicated that both anatomic and clinical variables should be considered in decision-making on management of patients with AMI presenting later.

Background: XC001 is a novel adenoviral-5 vector designed to express multiple isoforms of VEGF (vascular endothelial growth factor) and more safely and potently induce angiogenesis. The EXACT trial (Epicardial Delivery of XC001 Gene Therapy for Refractory Angina Coronary Treatment) assessed the safety and preliminary efficacy of XC001 in patients with no option refractory angina., Methods: In this single-arm, multicenter, open-label trial, 32 patients with no option refractory angina received a single treatment of XC001 (1×10 11 viral particles) via transepicardial delivery., Results: There were no severe adverse events attributed to the study drug. Twenty expected severe adverse events in 13 patients were related to the surgical procedure. Total exercise duration increased from a mean±SD of 359.9±105.55 seconds at baseline to 448.2±168.45 (3 months), 449.2±175.9 (6 months), and 477.6±174.7 (12 months; +88.3 [95% CI, 37.1-139.5], +84.5 [95% CI, 34.1-134.9], and +115.5 [95% CI, 59.1-171.9]). Total myocardial perfusion deficit on positron emission tomography imaging decreased by 10.2% (95% CI, -3.1% to 23.5%), 14.3% (95% CI, 2.8%-25.7%), and 10.2% (95% CI, -0.8% to -21.2%). Angina frequency decreased from a mean±SD 12.2±12.5 episodes to 5.2±7.2 (3 months), 5.1±7.8 (6 months), and 2.7±4.8 (12 months), with an average decrease of 7.7 (95% CI, 4.1-11.3), 6.6 (95% CI, 3.5-9.7), and 8.8 (4.6-13.0) episodes at 3, 6, and 12 months. Angina class improved in 81% of participants at 6 months., Conclusions: XC001 administered via transepicardial delivery is safe and generally well tolerated. Exploratory improvements in total exercise duration, ischemic burden, and subjective measures support a biologic effect sustained to 12 months, warranting further investigation., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04125732., Competing Interests: Disclosures Dr Nakamura received institutional research support from XyloCor Therapeutics and consulting fees from XyloCor Therapeutics and Sana Biotechnology. Dr Henry received consulting fees (Steering Committee) from XyloCor Therapeutics. Dr Latter received consulting fees from and is a data and safety monitoring board (DSMB) member of XyloCor Therapeutics. Dr Mokadam received consulting fees from Abbott, Medtronic, SynCardia, and XyloCor Therapeutics and is a DSMB member of XyloCor Therapeutics, Medtronic, and Carmat. Dr Williams received consulting fees from XyloCor Therapeutics. Dr Sun received consulting fees from Abbott Vascular and is a DSMB member of 4C Medical and Abbott. Dr DiCarli received institutional research support from XyloCor Therapeutics and Gilead Sciences, consulting fees from Sanofi and MedTrace Pharma, and institutional in-kind research support from Amgen. Dr Chaitman received consulting fees and institutional research support from XyloCor Therapeutics. M.W. Peterson is an employee of XyloCor Therapeutics. D.G. Byrnes is an employee of XyloCor Therapeutics. Dr Ohman is an employee of Amgen. Dr Pepine received institutional research support from XyloCor Therapeutics, BioCardia, Caladrius, Duke Clinical Research Institute, the Gatorade Foundation, the McJunkin Family Foundation Trust, Mesoblast, National Institutes of Health/National Heart, Lung, and Blood Institute, Patient-Centered Outcomes Research Institute/National Patient-Centered Clinical Research Network, Pfizer, Sanofi, University of Florida Clinical and Translational Science Institute, and US Department of Defense and consulting fees from AbbVie, Akros, BioCardia, Bloomer Tech, Caladrius, Imbria Pharmaceuticals, Ironwood Pharmaceuticals, Milestone Pharmaceuticals, and Verily Life Sciences LLC. Dr Crystal received consulting fees from and has equity in XyloCor Therapeutics. Dr Rosengart is an advisor of, is a board of directors member of, and received consulting fees, royalties, and honoraria from XyloCor Therapeutics. Dr Kowalewski received institutional research support from XyloCor Therapeutics. Dr Koch received institutional research support from XyloCor Therapeutics. Dr Dittrich is an employee of XyloCor Therapeutics. Dr Povsic received institutional research support from XyloCor Therapeutics, CSL Behring, Priovant, Bayer, Ionis Pharmaceuticals, UCB Biopharma SRL, BodyPort, and Merck Pharmaceuticals; consulting fees from AstraZeneca, Biocardia, Boehringer Ingelheim, Caladrius Biosciences, Recardio, Veralox Therapeutics, Sana Biotechnology, Inc, Guidepoint Global LLC, and the Gerson Lehrman Group; is a DSMB member of Corvia, Novo Nordisk, and Parexel International; and has leadership or fiduciary role in the American Heart Association and the American College of Cardiology.

Background: Aberrant expressions of desmoglein 2 (Dsg2) and desmocollin 2(Dsc2), the two most widely distributed desmosomal cadherins, have been found to play various roles in cancer in a context-dependent manner. Their specific roles on breast cancer (BC) and the potential mechanisms remain unclear., Methods: The expressions of Dsg2 and Dsc2 in human BC tissues and cell lines were assessed by using bioinformatics analysis, immunohistochemistry and western blotting assays. Wound-healing and Transwell assays were performed to evaluate the cells' migration and invasion abilities. Plate colony-forming and MTT assays were used to examine the cells' capacity of proliferation. Mechanically, Dsg2 and Dsc2 knockdown-induced malignant behaviors were elucidated using western blotting assay as well as three inhibitors including MK2206 for AKT, PD98059 for ERK, and XAV-939 for β-catenin., Results: We found reduced expressions of Dsg2 and Dsc2 in human BC tissues and cell lines compared to normal counterparts. Furthermore, shRNA-mediated downregulation of Dsg2 and Dsc2 could significantly enhance cell proliferation, migration and invasion in triple-negative MDA-MB-231 and luminal MCF-7 BC cells. Mechanistically, EGFR activity was decreased but downstream AKT and ERK pathways were both activated maybe through other activated protein tyrosine kinases in shDsg2 and shDsc2 MDA-MB-231 cells since protein tyrosine kinases are key drivers of triple-negative BC survival. Additionally, AKT inhibitor treatment displayed much stronger capacity to abolish shDsg2 and shDsc2 induced progression compared to ERK inhibition, which was due to feedback activation of AKT pathway induced by ERK inhibition. In contrast, all of EGFR, AKT and ERK activities were attenuated, whereas β-catenin was accumulated in shDsg2 and shDsc2 MCF-7 cells. These results indicate that EGFR-targeted therapy is not a good choice for BC patients with low Dsg2 or Dsc2 expression. Comparatively, AKT inhibitors may be more helpful to triple-negative BC patients with low Dsg2 or Dsc2 expression, while therapies targeting β-catenin can be considered for luminal BC patients with low Dsg2 or Dsc2 expression., Conclusion: Our finding demonstrate that single knockdown of Dsg2 or Dsc2 could promote proliferation, motility and invasion in triple-negative MDA-MB-231 and luminal MCF-7 cells. Nevertheless, the underlying mechanisms were cellular context-specific and distinct., (© 2024. The Author(s).)

BACKGROUND Esophagogastric devascularization and splenectomy (EGDS) is widely used to treat patients with portal hypertension in China. This study aimed to determine risk factors that increase risk of rebleeding after EGDS and evaluate the effect of portal vein thrombosis (PVT) on rebleeding rates after EGDS. MATERIAL AND METHODS Clinical data of patients with cirrhosis (n=138) who underwent EGDS between December 2010 and January 2016 were retrospectively analyzed. Patients were assigned to rebleeding or non-rebleeding groups and followed up. Univariate and multivariate Cox regression analyses identified the independent predictors of 3-year and 5-year rebleeding. RESULTS A total of 138 consecutive patients who underwent EGDS and met the inclusion criteria were enrolled. Total bilirubin (HR: 2.392, 95% CI 1.032-5.545, P=0.042) and PVT (HR: 3.345, 95% CI 1.477-7.573, P=0.004) predicted 3-year rebleeding during univariate analysis. Multivariate analysis revealed that PVT (HR: 3.967, 95% CI 1.742-9.035, P=0.001) was an independent predictor. Hemoglobin >87.5 g/L (HR: 3.104, 95% CI 1.283-7.510, P=0.012) and PVT (HR: 2.349, 95% CI 1.231-4.483, P=0.010) were predictors of 5-year rebleeding during multivariate analysis. Albumin >37.5 g/L was an independent predictor of rebleeding in patients with PVT at 3 and 5 years (HR: 3.964, 95% CI 1.301-9.883, P=0.008; HR: 3.193, 95% CI 1.275-7.997, P=0.013, respectively). CONCLUSIONS PVT is associated with increased 3-year and 5-year rebleeding rates after EGDS but not at 10 years. Also, hemoglobin >87.5 g/L predicted rebleeding at 5 years. Albumin has huge prospects as a predictor of rebleeding at 3 and 5 years in patients with PVT.

DNA-dependent protein kinase (DNA-PK), a driver of the non-homologous end-joining (NHEJ) DNA damage response pathway, plays an instrumental role in repairing double-strand breaks (DSB) induced by DNA-damaging poisons. We evaluate ZL-2201, an orally bioavailable, highly potent, and selective pharmacologic inhibitor of DNA-PK activity, for the treatment of human cancerous malignancies. ZL-2201 demonstrated greater selectivity for DNA-PK and effectively inhibited DNA-PK autophosphorylation in a concentration- and time-dependent manner. Initial data suggested a potential correlation between ataxia-telangiectasia mutated (ATM) deficiency and ZL-2201 sensitivity. More so, ZL-2201 showed strong synergy with topoisomerase II inhibitors independent of ATM status in vitro . In vivo oral administration of ZL-2201 demonstrated dose-dependent antitumor activity in the NCI-H1703 xenograft model and significantly enhanced the activity of approved DNA-damaging agents in A549 and FaDu models. From a phosphoproteomic mass spectrometry screen, we identified and validated that ZL-2201 and PRKDC siRNA decreased Ser108 phosphorylation of MCM2, a key DNA replication factor. Collectively, we have characterized a potent and selective DNA-PK inhibitor with promising monotherapy and combinatory therapeutic potential with approved DNA-damaging agents. More importantly, we identified phospho-MCM2 (Ser108) as a potential proximal biomarker of DNA-PK inhibition that warrants further preclinical and clinical evaluation., Significance: ZL-2201, a potent and selective DNA-PK inhibitor, can target tumor models in combination with DNA DSB-inducing agents such as radiation or doxorubicin, with potential to improve recurrent therapies in the clinic., (© 2023 The Authors; Published by the American Association for Cancer Research.)

Enhancing the generation of active groups is of great significance for alleviating the catalyst deactivation of formaldehyde (HCHO) by accelerating the decomposition of intermediate products. Herein, an electric-field-enhanced catalytic effect was proposed for the efficient capture and degradation of HCHO base on carbon cloth loaded manganese oxide catalyst (MnO x -CC). Under the action of electric field, MnO x can generate more hydroxyl radicals (•OH) and superoxide radicals (•O 2 - ), thus accelerating the degradation of HCHO and intermediates at room temperature. After the introduction electric field (∼1 ×10 4 V/m), •O 2 - and •OH radical on the surface of MnO x -CC catalyst can be increased by 8 times and 23 times, respectively. At weight hourly space velocity of 300,000 mL/(g cat h) for ∼15 ppm HCHO, MnO x -CC-Electric Field catalyst reached the removal efficiency of 99.4%, and the CO 2 conversion efficiency of 81.2%, without decrease significantly within 80 h. Theoretical calculation shows that the electric field can increase the electron state density of Mn atom at the Fermi level and reduce the adsorption energy of HCHO, O 2 and H 2 O, thus promoting the generation of active groups and degradation of intermediate products. The electric-field-enhancement catalytic effect provides a new approach for the degradation of Volatile Organic Compounds., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: New therapies are needed for patients with refractory angina. Encoberminogene rezmadenovec (XC001), a novel adenoviral-5 vector coding for all 3 major isoforms of VEGF (vascular endothelial growth factor), demonstrated enhanced local angiogenesis in preclinical models; however, the maximal tolerated dose and safety of direct epicardial administration remain unknown., Methods: In the phase 1 portion of this multicenter, open-label, single-arm, dose-escalation study, patients with refractory angina received increasing doses of encoberminogene rezmadenovec (1×10 9 , 1×10 10 , 4×10 10 , and 1×10 11 viral particles) to evaluate its safety, tolerability, and preliminary efficacy. Patients had class II to IV angina on maximally tolerated medical therapy, demonstrable ischemia on stress testing, and were angina-limited on exercise treadmill testing. Patients underwent minithoracotomy with epicardial delivery of 15 0.1-mL injections of encoberminogene rezmadenovec. The primary outcome was safety via adverse event monitoring over 6 months. Efficacy assessments included difference from baseline to months 3, 6 (primary), and 12 in total exercise duration, myocardial perfusion deficit using positron emission tomography, angina class, angina frequency, and quality of life., Results: From June 2, 2020 to June 25, 2021, 12 patients were enrolled into 4 dosing cohorts with 1×10 11 viral particle as the highest planned dose. Seventeen serious adverse events were reported in 7 patients; none were related to study drug. Six serious adverse events in 4 patients were related to the thoracotomy, 3 non-serious adverse events were possibly related to study drug. The 2 lowest doses did not demonstrate improvements in total exercise duration, myocardial perfusion deficit, or angina frequency; however, there appeared to be improvements in all parameters with the 2 higher doses., Conclusions: Epicardial delivery of encoberminogene rezmadenovec via minithoracotomy is feasible, and up to 1×10 11 viral particle appears well tolerated. A dose response was observed across 4 dosing cohorts in total exercise duration, myocardial perfusion deficit, and angina class. The highest dose (1×10 11 viral particle) was carried forward into phase 2., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT04125732., Competing Interests: Disclosures Dr Povsic receives research support from XyloCor Therapeutics, CSL Behring. Dr Henry is a consultant for XyloCor Therapeutics. Dr Answini is consultant for for XyloCor Therapeutics. Dr Sun is consultant for Abbott, Xylocor Therapeutics. Dr Arnaoutakis is a consultant for Terumo Aortic. Dr Williams is a consultant for Xylocor Inc and Stryker Inc, and received research funding from Humacyte Inc and Artivion Inc. Dr Dittrich is an employee of XyloCor Therapeutics. Dr Tarka is a former employee of XyloCor Therapeutics. Dr Latter performs consulting for XyloCor Therapeutics. Dr Magnus Ohman is a former consultant to XyloCor Therapeutics, employee, Amgen Inc. M.W. Peterson is an employee of XyloCor Therapeutics. D. Byrnes is an employee of XyloCor Therapeutics. Dr Crystal provides equity in and consulting for XyloCor Therapeutics. Dr Rosengart performs consulting for XyloCor Therapeutics. Dr Mokadam is a consultant for Abbott, Medtronic, SynCardia, Carmat, and Xylocor.

Background Aims: Therapeutic disruption of immune checkpoints has significantly advanced the armamentarium of approaches for treating cancer. The prominent role of the programmed death-1 (PD-1)/programmed death ligand-1 axis for downregulating T cell function offers a tractable strategy for enhancing the disease-modifying impact of CAR-T cell therapy., Methods: To address checkpoint interference, primary human T cells were genome edited with a next-generation CRISPR-based platform (Cas9 chRDNA) by knockout of the PDCD1 gene encoding the PD-1 receptor. Site-specific insertion of a chimeric antigen receptor specific for CD19 into the T cell receptor alpha constant locus was implemented to drive cytotoxic activity., Results: These allogeneic CAR-T cells (CB-010) promoted longer survival of mice in a well-established orthotopic tumor xenograft model of a B cell malignancy compared with identically engineered CAR-T cells without a PDCD1 knockout. The persistence kinetics of CB-010 cells in hematologic tissues versus CAR-T cells without PDCD1 disruption were similar, suggesting the robust initial debulking of established tumor xenografts was due to enhanced functional fitness. By single-cell RNA-Seq analyses, CB-010 cells, when compared with identically engineered CAR-T cells without a PDCD1 knockout, exhibited fewer T reg cells, lower exhaustion phenotypes and reduced dysfunction signatures and had higher activation, glycolytic and oxidative phosphorylation signatures. Further, an enhancement of mitochondrial metabolic fitness was observed, including increased respiratory capacity, a hallmark of less differentiated T cells., Conclusions: Genomic PD-1 checkpoint disruption in the context of allogeneic CAR-T cell therapy may provide a compelling option for treating B lymphoid malignancies., Competing Interests: Declaration of Competing Interest All authors are current or former employees of Caribou Biosciences, Inc., (Copyright © 2023 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Data showing the efficacy and safety of the transplantation of hearts obtained from donors after circulatory death as compared with hearts obtained from donors after brain death are limited., Methods: We conducted a randomized, noninferiority trial in which adult candidates for heart transplantation were assigned in a 3:1 ratio to receive a heart after the circulatory death of the donor or a heart from a donor after brain death if that heart was available first (circulatory-death group) or to receive only a heart that had been preserved with the use of traditional cold storage after the brain death of the donor (brain-death group). The primary end point was the risk-adjusted survival at 6 months in the as-treated circulatory-death group as compared with the brain-death group. The primary safety end point was serious adverse events associated with the heart graft at 30 days after transplantation., Results: A total of 180 patients underwent transplantation; 90 (assigned to the circulatory-death group) received a heart donated after circulatory death and 90 (regardless of group assignment) received a heart donated after brain death. A total of 166 transplant recipients were included in the as-treated primary analysis (80 who received a heart from a circulatory-death donor and 86 who received a heart from a brain-death donor). The risk-adjusted 6-month survival in the as-treated population was 94% (95% confidence interval [CI], 88 to 99) among recipients of a heart from a circulatory-death donor, as compared with 90% (95% CI, 84 to 97) among recipients of a heart from a brain-death donor (least-squares mean difference, -3 percentage points; 90% CI, -10 to 3; P<0.001 for noninferiority [margin, 20 percentage points]). There were no substantial between-group differences in the mean per-patient number of serious adverse events associated with the heart graft at 30 days after transplantation., Conclusions: In this trial, risk-adjusted survival at 6 months after transplantation with a donor heart that had been reanimated and assessed with the use of extracorporeal nonischemic perfusion after circulatory death was not inferior to that after standard-care transplantation with a donor heart that had been preserved with the use of cold storage after brain death. (Funded by TransMedics; ClinicalTrials.gov number, NCT03831048.)., (Copyright © 2023 Massachusetts Medical Society.)

Improving the adsorption kinetics of metal-oxide catalysts is critical for the enhancement of catalytic performance in heterogeneous catalytic oxidation reactions. Herein, based on the biopolymer pomelo peels (PP) and metal-oxide catalyst manganese oxide (MnO x ), an adsorption-enhanced catalyst (MnO x -PP) was constructed for catalytic organic dyes oxidative-degradation. MnO x -PP shows excellent methylene blue (MB) and total carbon content (TOC) removal efficiency of 99.5 % and 66.31 % respectively, and keeps the long-lasting stable dynamic degradation efficiency during 72 h based on the self-built continuous single-pass MB purification device. The chemical structure similarity and negative-charge polarity sites of the biopolymer PP improve the adsorption kinetics of organic macromolecule MB, and construct the adsorption-enhanced catalytic oxidation microenvironment. Meanwhile, the adsorption-enhanced catalyst MnO x -PP obtains lower ionization potential and O 2 adsorption energy to promote the continuous generation of active substance (O 2 *, OH*) for the further catalytic oxidation of adsorbed MB molecules. This work explored the adsorption-enhanced catalytic oxidation mechanism for the degradation of organic pollutants, and provided a feasible technical idea for designing adsorption-enhanced catalysts for the long-lasting efficient removal of organic dyes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

This work presents a screening method of physical solvents for methyl mercaptan (MeSH) absorption using quantum chemical calculations. The absorption solubility and thermodynamic behaviors of dimethyl sulfoxide (DMSO), sulfolane (SUL), propylene carbonate (PC), N , N -dimethylformamide (DMF), and 1-methyl-2-pyrrolidinone (NMP) for MeSH were calculated and analyzed using the COSMO-RS model, and the absorption mechanism was probed combining the quantum theory of atoms in molecules (QTAIM) and reduced density gradient (RDG). Results show that the absorption solubility of the five solvents for MeSH by COSMO-RS model calculations follow the order of NMP > PC > DMSO > SUL > DMF, and the van der Waals forces and hydrogen bond forces determine the absorption solubility of physical solvents for MeSH. In addition, the experimental results of MeSH Henry coefficients in the above five solvents follow the same order as the calculated results. However, the calculated Henry coefficients' value largely deviates from the experimental value; therefore, we believe that this calculation method is only available for qualitative screening. This work provided a feasible approach to screening high-performance physical solvents for MeSH removal., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Background: Current American College of Cardiology/American Heart Association/Heart Rhythm Society (ACC/AHA/HRS) and European Society of Cardiology (ESC) guidelines recommend different strategies to avoid low-yield admissions in patients with syncope., Objective: The purpose of this study was to directly compare the safety and efficacy of applying admission criteria of both guidelines to patients presenting with syncope to the emergency department in 2 multicenter studies., Methods: The international BASEL IX (BAsel Syncope EvaLuation) study (median age 71 years) and the U.S. SRS (Improving Syncope Risk Stratification in Older Adults) study (median age 72 years) were investigated. Primary endpoints were sensitivity/specificity for the adjudicated diagnosis of cardiac syncope (BASEL IX only) and 30-day major adverse cardiovascular events (30d-MACE)., Results: Among 2560 patients in the BASEL IX and 2085 in SRS studies, ACC/AHA/HRS and ESC criteria recommended admission for a comparable number of patients in BASEL IX (27% vs 28%), but ACC/AHA/HRS criteria less often in SRS (19% vs 32%; P <.01). Recommendations were discordant in ∼25% of patients. In BASEL IX, sensitivity for cardiac syncope and 30d-MACE among patients without admission criteria was comparable for ACC/AHA/HRS and ESC criteria (64% vs 65%, P = .86; and 67% vs 71%, P = .15, respectively). In SRS, sensitivity for 30d-MACE was lower with ACC/AHA/HRS (54%) vs ESC criteria (88%; P <.001). Similarly, specificity for cardiac syncope and 30d-MACE in BASEL IX was comparable for both guidelines, but in SRS the ACC/AHA/HRS guidelines showed a higher specificity for 30d-MACE than the ESC guidelines., Conclusion: ACC/AHA/HRS and ESC guidelines showed disagreement regarding admission for 1 in 4 patients and had only modest sensitivity, all indicating possible opportunities for improvements., (Copyright © 2022 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

CLDN18.2 (Claudin18.2)-targeting therapeutic antibodies have shown promising clinical efficacy in approximately 30% of gastric cancers expressing high levels of CLDN18.2 and less pronounced activity in low expressing malignancies. Here, we report that ZL-1211 is a mAb targeting CLDN18.2 engineered to promote enhanced antibody-dependent cellular cytotoxicity (ADCC) with the goal of achieving more potent activity in a wider spectrum of high- and low-CLDN18.2 expressing tumors. ZL-1211 demonstrated more robust in vitro ADCC activity than clinical benchmark not only in CLDN18.2-high but also CLDN18.2-low expressing gastric tumor cell lines. Greater antitumor efficacy was also observed in mouse xenograft models. Natural killer (NK) cell played critical roles in ZL-1211 efficacy and NK-cell depletion abrogated ZL-1211-mediated ADCC activity in vitro . ZL-1211 efficacy in vivo was also dependent on the presence of an NK compartment. Strikingly, NK cells strongly induced an inflammatory response in response to ZL-1211 treatment, including increased IFNγ, TNFα, and IL6 production, and were recruited into tumor microenvironment in patient-derived gastric tumors expressing CLDN18.2 upon ZL-1211 treatment to lyse the tumor cells. Taken together, our data suggest that ZL-1211 more effectively targets CLDN18.2-high gastric cancers as well as -low expressing malignancies that may not be eligible for treatment with the leading clinical benchmark by inducing enhanced ADCC response and activating NK cells with robust inflammation to enhance antitumor efficacy. Clinical activity of ZL-1211 is currently under evaluation in a phase I clinical trial (NCT05065710)., Significance: ZL-1211, anti-CLDN18.2 therapeutic antibody can target CLDN18.2-high as well as -low gastric cancers that may not be eligible for treatment with clinical benchmark. ZL-1211 treatment induces NK-cell activation with robust inflammation to further activate antitumor immunity in tumor microenvironment., Competing Interests: C. Szeto reports other from Zai Lab (US) during the conduct of the study; other from Zai Lab (US) outside the submitted work. O. Kabbarah reports a patent to Zai Lab US LLC pending. No disclosures were reported by the other authors., (© 2022 The Authors; Published by the American Association for Cancer Research.)

Aims: Stress echocardiography (SE) findings and interpretations are commonly documented in free-text reports. Reusing SE results requires laborious manual reviews. This study aimed to develop and validate an automated method for abstracting SE reports in a large cohort., Methods and Results: This study included adult patients who had SE within 30 days of their emergency department visit for suspected acute coronary syndrome in a large integrated healthcare system. An automated natural language processing (NLP) algorithm was developed to abstract SE reports and classify overall SE results into normal, non-diagnostic, infarction, and ischaemia categories. Randomly selected reports ( n = 140) were double-blindly reviewed by cardiologists to perform criterion validity of the NLP algorithm. Construct validity was tested on the entire cohort using abstracted SE data and additional clinical variables. The NLP algorithm abstracted 6346 consecutive SE reports. Cardiologists had good agreements on the overall SE results on the 140 reports: Kappa (0.83) and intraclass correlation coefficient (0.89). The NLP algorithm achieved 98.6% specificity and negative predictive value, 95.7% sensitivity, positive predictive value, and F -score on the overall SE results and near-perfect scores on ischaemia findings. The 30-day acute myocardial infarction or death outcomes were highest among patients with ischaemia (5.0%), followed by infarction (1.4%), non-diagnostic (0.8%), and normal (0.3%) results. We found substantial variations in the format and quality of SE reports, even within the same institution., Conclusions: Natural language processing is an accurate and efficient method for abstracting unstructured SE reports. This approach creates new opportunities for research, public health measures, and care improvement., Competing Interests: Conflict of interest: Author, B.C.S., was a consultant for Medtronic. The remaining authors have no conflicts of interest to report., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Overcoming drug resistance in cancer therapies remains challenging, and the tumor microenvironment plays an important part in it. Microvesicles (MVs) are functional natural carriers of cellular information, participate in intercellular communication, and dynamically regulate the tumor microenvironment. They contribute to drug resistance by transferring functional molecules between cells. Conversely, due to their specific cell or tissue targeting ability, MVs are considered as carriers for therapeutic molecules to reverse drug resistance. Thus, in this mini-review, we aim to highlight the crucial role of MVs in cell-to-cell communication and therefore their diverse impact mainly on liver cancer progression and treatment. In addition, we summarize the possible mechanisms for sorafenib resistance (one of the main hurdles in hepatocellular carcinoma treatments) and recent advances in using MVs to reverse sorafenib resistance in liver cancer therapies. Identifying the functional role of MVs in cancer therapy might provide a new aspect for developing precise novel therapeutics in the future., Competing Interests: All authors declared that there are no conflicts of interest., (© The Author(s) 2022.)

Background: Findings and interpretations of myocardial perfusion imaging (MPI) studies are documented in free-text MPI reports. MPI results are essential for research, but manual review is prohibitively time consuming. This study aimed to develop and validate an automated method to abstract MPI reports., Methods: We developed a natural language processing (NLP) algorithm to abstract MPI reports. Randomly selected reports were double-blindly reviewed by two cardiologists to validate the NLP algorithm. Secondary analyses were performed to describe patient outcomes based on abstracted-MPI results on 16,957 MPI tests from adult patients evaluated for suspected ACS., Results: The NLP algorithm achieved high sensitivity (96.7%) and specificity (98.9%) on the MPI categorical results and had a similar degree of agreement compared to the physician reviewers. Patients with abnormal MPI results had higher rates of 30-day acute myocardial infarction or death compared to patients with normal results. We identified issues related to the quality of the reports that not only affect communication with referring physicians but also challenges for automated abstraction., Conclusion: NLP is an accurate and efficient strategy to abstract results from the free-text MPI reports. Our findings will facilitate future research to understand the benefits of MPI studies but requires validation in other settings., (© 2020. American Society of Nuclear Cardiology.)

In this work, a desulfurization method using natural amino acid salts (AAS), which can be green prepared by biological fermentation, is proposed to remove H 2 S from raw biogas. Biogas purification and fertilizer production can be simultaneously achieved to close sulfur recycle. The reaction kinetic characteristics of H 2 S absorption with three kinds of AAS, including potassium β-alaninate (PA), potassium sarcosinate (PS) and potassium l-prolinate (PP) are first studied. Kinetic parameters including orders of reaction, rate constants, pre-exponential factors and activation energies are given. AAS absorbent exhibits good potential for biogas desulfurization. Higee (high gravity) technology is utilized to intensify H 2 S removal. The effects of operating conditions on H 2 S removal efficiency are investigated and PP shows the best desulfurization performance. The phytotoxicity of AAS and amino acid salt sulfide (AASS) is assessed by the germination index of mungbean seeds. PP and its salt sulfide (PPS) show relatively low phytotoxicity and their allowable agricultural feeding concentrations are below 0.08 M and 0.04 M, respectively. The desulfurization method demonstrates a green route for biogas purification to achieve sulfur recycle., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: To construct a novel prognostic nomogram model based on more comprehensive variables for patients with small-cell lung cancer (SCLC). Methods: The data of 722 patients with SCLC confirmed by pathology in Affiliated Cancer Hospital of Shanxi Medical University from January 2015 to December 2018 were retrospectively analyzed [including 592 males and 130 females, aged from 23 to 82(61±9) years]. A random seed count of 133 was used to divide those patients into training set ( n =422) and validation set ( n =300). Kaplan-Meier was used for survival curves analysis and univariate Log-rank test was used for evaluating the influence of clinical variables on the prognosis of sclc, variables with P <0.05 in univariate analysis were included in a multivariate Cox regression model. The nomogram was constructed based on the variables which P <0.05 in multivariate analysis. Receiver operating characteristic (ROC) curve, calibration by Integrated Brier score (IBS) and clinical net benefit by decision curve analysis (DCA) were used to evaluate model discriminative power, prediction error value, and clinical net benefit, and compared with the American Joint Committee on Cancer 8 th TNM. Results: Male, abnormal monocyte (MON) counts, abnormal neuron specific enolase (NSE), abnormal cytokeratin 19 fragment (Cyfra211), M1a stage, M1b stage, M1c stage, radiotherapy (RT), chemotherapy ≥4 cycles and prophylactic cranial irradiation (PCI) were prognostic factors for SCLC[ HR (95% CI )=1.39(1.00-1.92), 1.29(1.02-1.63), 1.41(1.11-1.80), 2.02(1.48-2.76), 1.09(0.77-1.55), 1.44(0.94-2.22), 2.01(1.49-2.71), 0.75(0.57-0.98), 0.40(0.31-0.51)and 0.42(0.26-0.68), respectively, all P <0.05]. The area under ROC curve (AUC) of the nomogram in training set and validation set were 0.814(95% CI : 0.765-0.862)and 0.787 (95% CI : 0.725-0.849), which were higher than TNM [0.616(95% CI : 0.558-0.674) and 0.648(95% CI : 0.581-0.715)].The calibration curve showed a good correlation between the nomogram prediction and actual observation for the 2-year overall survival (OS). IBS indicted a lower prediction error rate (training set: 0.132 vs 0.169; validation set: 0.138 vs 0.169). DCA showed a wider threshold range than TNM (training set: 0.01-0.96 vs 0.01-0.85, validation set: 0.01-0.94 vs 0.01-0.86) and a greater improvement of the clinical net benefit (in training set the nomogram had a greater clinical benefit than TNM in the range of 0.19-0.96, and remained in validation set in the range of 0.19-0.94). Conclusion: The established nomogram model for predicting 2-year OS in patients with SCLC based on 8 variables, including gender, MON, NSE, Cyfra211, M stage, RT, CT cycles and PCI can be used for an more accurately prognosis prediction and reference for therapeutic regimen selection.

Background: Chest pain is the top reason for hospitalization/observation in the USA, but it is unclear if this strategy improves patient outcomes., Objective: The objective of this study was to compare 30-day outcomes for patients admitted versus discharged after a negative emergency department (ED) evaluation for suspected acute coronary syndrome., Design: A retrospective, multi-site, cohort study of adult encounters with chest pain presenting to one of 13 Kaiser Permanente Southern California EDs between January 1, 2015, and December 1, 2017. Instrumental variable analysis was used to mitigate potential confounding by unobserved factors., Patients: All adult patients presenting to an ED with chest pain, in whom an acute myocardial infarction was not diagnosed in the ED, were included., Main Measures: The primary outcome was 30-day acute myocardial infarction or all-cause mortality, and secondary outcomes included 30-day revascularization and major adverse cardiac events., Key Results: In total, 77,652 patient encounters were included in the study (n=11,026 admitted, 14.2%). Three hundred twenty-two (0.4%) had an acute myocardial infarction (n=193, 0.2%) or death (n=137, 0.2%) within 30 days of ED visit (1.5% hospitalized versus 0.2% discharged). Very few (0.3%) patients underwent coronary revascularization within 30 days (0.7% hospitalized versus 0.2% discharged). Instrumental variable analysis found no adjusted differences in 30-day patient outcomes between the hospitalized cohort and those discharged (risk reduction 0.002, 95% CI -0.002 to 0.007). Similarly, there were no differences in coronary revascularization (risk reduction 0.003, 95% CI -0.002 to 0.007)., Conclusion: Among ED patients with chest pain not diagnosed with an acute myocardial infarction, risk of major adverse cardiac events is quite low, and there does not appear to be any benefit in 30-day outcomes for those admitted or observed in the hospital compared to those discharged with outpatient follow-up., (© 2021. Society of General Internal Medicine.)

Aims: Explore the impact of deploying high-sensitivity (hs) cardiac troponin T (cTnT) assay across a state-wide health service., Methods and Results: Presentations to emergency departments of six tertiary hospitals between January 2008 and August 2019 were included; standard cTnT assay was superseded by hs-cTnT in June 2011 without changing the reference range (≥30 ng/L reported as elevated), despite cTnT level of 30 ng/L being equivalent to ∼44 ng/L with hs-cTnT. Clinical outcomes were captured using state-wide linked health records. Interrupted time series analyses were used adjusted for seasonality and multiple co-morbidities using propensity score matching allowing for correlation within hospitals. In total, 614,847 presentations had ≥1 troponin measurement. Clinical ordering of troponin decreased throughout the study with no increase in elevated measurements amongst those tested with hs-cTnT. Small but statistically significant changes in index myocardial infarction (MI) diagnosis (-0.36%/year, 95%CI [confidence interval]:-0.48, -0.24,p < 0.001) and invasive coronary angiography (0.12%/year,95%CI:0, 0.24,p = 0.02) were seen, with no impact on death/MI at 30 days or 3-year survival in episodes of care (EOCs) with elevated cTnT after hs-cTnT implementation. Length of stay (LOS) was shorter among those with an elevated hs-cTnT (-4.44 h/year, 95%CI:-5.27, -3.60, p < 0.001). Non-elevated cTnT EOCs demonstrated shorter total LOS and improved 3-year survival (adjusted hazard ratio:0.90, 95%CI:0.83, 0.97,p = 0.008) although death/MI at 30 days was unchanged using hs-cTnT., Conclusion: Widespread implementation of hs-cTnT without altering clinical thresholds reported to clinicians provided significantly shorter LOS without a clinically significant impact on clinical outcomes. A safer cohort with non-elevated cTnT was identified by hs-cTnT compared to the standard cTnT assay., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background and Objectives : Knowledge of the incidence and time frames of the adverse events of patients presenting syncope at the ED is essential for developing effective management strategies. The aim of the present study was to perform a meta-analysis of the incidence and time frames of adverse events of syncope patients. Materials and Methods : We combined individual patients' data from prospective observational studies including adult patients who presented syncope at the ED. We assessed the pooled rate of adverse events at 24 h, 72 h, 7-10 days, 1 month and 1 year after ED evaluation. Results : We included nine studies that enrolled 12,269 patients. The mean age varied between 53 and 73 years, with 42% to 57% females. The pooled rate of adverse events was 5.1% (95% CI 3.4% to 7.7%) at 24 h, 7.0% (95% CI 4.9% to 9.9%) at 72 h, 8.4% (95% CI 6.2% to 11.3%) at 7-10 days, 10.3% (95% CI 7.8% to 13.3%) at 1 month and 21.3% (95% CI 15.8% to 28.0%) at 1 year. The pooled death rate was 0.2% (95% CI 0.1% to 0.5%) at 24 h, 0.3% (95% CI 0.1% to 0.7%) at 72 h, 0.5% (95% CI 0.3% to 0.9%) at 7-10 days, 1% (95% CI 0.6% to 1.7%) at 1 month and 5.9% (95% CI 4.5% to 7.7%) at 1 year. The most common adverse event was arrhythmia, for which its rate was 3.1% (95% CI 2.0% to 4.9%) at 24 h, 4.8% (95% CI 3.5% to 6.7%) at 72 h, 5.8% (95% CI 4.2% to 7.9%) at 7-10 days, 6.9% (95% CI 5.3% to 9.1%) at 1 month and 9.9% (95% CI 5.5% to 17) at 1 year. Ventricular arrhythmia was rare. Conclusions : The risk of death or life-threatening adverse event is rare in patients presenting syncope at the ED. The most common adverse events are brady and supraventricular arrhythmias, which occur during the first 3 days. Prolonged ECG monitoring in the ED in a short stay unit with ECG monitoring facilities may, therefore, be beneficial.

Objective: To understand the prevalence of soil-transmitted nematode infections in Yancheng City from 2016 to 2020, so as to provide insights into the development of the scheme for further soil-transmitted nematodiasis surveillance., Methods: Soil-borne nematode infections were detected using the modified Kato-Katz method (two slides for one sample) among the permanent residents living in Yancheng City from 2016 to 2020, and Enterobius vermicularis infection was additionally detected among children at ages of 12 years and lower using the adhesive cellophane-tape perianal swab method. The prevalence and intensity of human soil-borne nematode and E. vermicularis infections were descriptively analyzed., Results: A total of 51 259 person-time residents were detected for soil-borne nematode infections in Yancheng City from 2016 to 2020, and 48 egg-positives were identified, with a 0.09% prevalence. The soil-borne nematodes infecting residents included Ascaris lumbricoides , hookworm and Trichuris trichiura , with 0.04%, 0.05% and 0.002% prevalence rates of infections, and all infections were mild. There was a region-specific prevalence of soil-borne nematode infections in Yancheng City (χ 2 = 18.21, P = 0.02), with the highest prevalence seen in Funing County (0.21%), while no infections were detected in Dafeng District for five successive years. The overall prevalence of E. vermicularis infections was 0.22% among children at ages of 12 years and lower in Yancheng City., Conclusions: The prevalence of soil-borne nematode infections appears a gradual decline in residents living in Yancheng City from 2016 to 2020, and is at an extremely low level. Further surveillance of soil-transmitted nematodiasis requires to be intensified targeting key regions and populations to consolidate the control achievements.

Objective: To analyze the expression of mismatch repair (MMR) proteins in colorectal cancers (CRC) and to evaluate the feasibility and potential pitfalls of immunohistochemistry (IHC) analysis for MMR. Methods: The IHC sections for MMR proteins were reviewed in 3 428 cases of resected CRC without neoadjuvant therapy at Tianjin Medical University Cancer Institute and Hospital from July 2014 to October 2018. For the cases with unclear MMR IHC results during the initial review, IHC staining was repeated and microsatellite instability (MSI) analysis was performed. Relationships between the expression of MMR proteins and MSI status as well as the clinicopathological parameters were analyzed. Results: IHC staining for MMR was repeated in 28 (0.8%) cases due to poor quality of original IHC sections. Inconsistent results between the original diagnosis and re-diagnosis were found in 119 (3.5%) cases, mainly resulting from PMS2 and MLH1. Finally, 261 (7.6%) cases of CRC showed mismatch repair deficiency (dMMR), mainly from the deficiency of both MLH1 and PMS2 (43.3%,113/261). In the 14 cases with MSI results, the concordant of MSI and MMR was 13 cases. In the 29 dMMR cases with next generation sequencing (NGS) results, the concordant of MSI-high and dMMR was 93.1%(27/29). The cases with inconsistent results between MSI and MMR showed negative expression of MSH6 or PMS2. Twenty-one CRC showed negative expression of MLH1 and partially positive (or weak positive) expression of PMS2, or negative expression of MSH2 and partially positive (or weak positive) expression of MSH6. Among the 19 cases with MSI results, 16 cases were MSI-high, two cases were MSI-low, and one case was microsatellite stable. Compared with mismatch repair proficiency (pMMR), dMMR was more frequently detected in female patients younger than 50 years old, with family history, at early stage (Ⅰ-Ⅱ) CRC, and in the tumors from right colon,with poor differentiation, or mucinous adenocarcinoma/signet ring cell carcinoma (all P <0.05). Conclusions: At present, IHC staining is a clinically effective and convenient method to detect MMR expression, but the operating process and result assessment remain variable and need to be standardized. MSI analysis can be performed in the difficult-to-evaluate cases for MMR to enhance prognostic evaluation and treatment option.

Incomplete revascularization following coronary artery bypass grafting (CABG) is associated with increased repeat revascularization, myocardial infarction and death. Whether the rate of incomplete revascularization is increasing over time has not been previously described. All patients with multivessel coronary artery disease who underwent isolated and elective CABG at our Institution in 2007 (n = 291) were compared to patients who underwent CABG in 2017 (n = 290). A Revascularization Index Score was created to compare rates of incomplete revascularization between the 2 years based on the coronary anatomy and degree of stenosis. Comparison of the 2 years disclose that the rate of incomplete revascularization increased from 17.9% in 2007 to 28.3% in 2017 (p = 0.003) and was accompanied by a decline in the Revascularization Index Score from 0.73 to 0.67 (p = 0.005). Left ventricular function improved in both groups following CABG. Two-year cardiovascular mortality was significantly higher in the 2017 cohort compared to the 2007 cohort. These differences may be attributable to patient factors including more severe coronary artery disease associated with older age, greater incidence of smoking and previous percutaneous coronary intervention. In conclusion, the rate of incomplete revascularization following CABG significantly increased in 2017 compared to 2007 and was associated with higher cardiovascular mortality., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Current guidelines for patients with suspected acute myocardial infarction are mainly based on troponin testing, commonly requiring an emergency department visit. HEAR score (History, Electrocardiogram, Age, and Risk factors) is a risk stratification tool validated in Europe, deduced from the HEART score (History, Electrocardiogram, Age, Risk factors, and Troponin), already implemented in clinical practice. We aimed to validate the HEAR score to rule out an acute myocardial infarction without needing biomarker testing., Methods: Retrospective cohort study at 15 emergency departments between May 2016 and December 2017. All adult encounters evaluated for possible acute myocardial infarction with a physician-documented HEART score for health plan members of Kaiser Permanente Southern California were included. Patients with an ST-segment elevation myocardial infarction, those under hospice care, or with a "do not resuscitate" status were excluded. HEAR scores from 0-8 were calculated for each encounter and used to report 30-day acute myocardial infarction or all-cause mortality for each score., Results: There were 22,109 patient encounters included in the study. Overall, 30-day acute myocardial infarction or death occurred in 1.1% of patients. Among the 4106 patients (19%) with a HEAR score <2, 3 died and 2 experienced an acute myocardial infarction within 30 days (0.1%; 95% confidence interval, 0.1-0.3). Sensitivity and specificity were 97.9% and 18.8%, respectively., Conclusions: A low HEAR score may accurately identify patients with a very low risk of 30-day acute myocardial infarction or death, representing a cohort of patients who might appropriately forego biomarker testing. Future research is warranted to assess the impact of implementing the HEAR score into routine clinical practice., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Study Objective: We compare clinical management and outcomes of emergency department (ED) encounters by sex after implementation of a clinical care pathway in 15 community EDs that standardized recommendations based on patient risk, using the History, ECG, Age, Risk Factors, and Troponin (HEART) score., Methods: This was a retrospective analysis of adult ED encounters evaluated for suspected acute coronary syndrome with a documented HEART score from May 20, 2016, to December 1, 2017. The primary outcomes were hospitalization or 30-day stress testing. Secondary outcomes included 30-day acute myocardial infarction or all-cause death (major adverse cardiac event). A generalized estimating equation regression model was used to compare the odds of hospitalization or stress testing by sex; we report HEART scores (0 to 10) stratified by sex and describing major adverse cardiac events., Results: A total of 34,715 adult ED encounters met the inclusion criteria (56.0% women). A higher proportion of women were classified as low risk (60.5% versus 52.4%; odds ratio [OR] 1.39; 95% confidence interval [CI] 1.33 to 1.45). Women were hospitalized or received stress testing less frequently than men for low HEART scores (18.8% versus 22.8%; OR 0.79; 95% CI 0.73 to 0.84) and intermediate ones (46.7% versus 49.7%; OR 0.88; 95% CI 0.83 to 0.95), but similarly for high-risk ones (74.1% versus 74.4%; OR 0.99; 95% CI 0.77 to 1.28). Women had 18% lower odds of hospitalization or noninvasive cardiac testing (OR 0.82; 95% CI 0.78 to 0.86), even after adjusting for HEART score and comorbidities. Men had higher risks of major adverse cardiac events than women for all HEART score categories but the risk for men was significantly higher among low-risk HEART scores (0.4% versus 0.1%)., Conclusion: Women with low-risk HEART scores are hospitalized or stress tested less than men, which is likely appropriate, and women have better outcomes than men. Use of the HEART score has the potential to reduce sex disparities in acute coronary syndrome care., (Copyright © 2020 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

The final phase of the total synthesis of (-)-spirochensilide A is described. A tungsten-mediated cyclopropene-based Pauson-Khand reaction was developed to form the spiral CD ring system with desired stereochemistry at the C13 quaternary center. Other important steps enabling completion of this synthesis included an intermolecular aldol condensation to link the ABCD core with the EF fragment and a Cu-mediated 1,4-addition to stereoselectively install the C21 stereogenic center. The chemistry developed for this total synthesis of (-)-spirochensilide A ( 1 ) will aid the synthesis of polycyclic natural products bearing this unique spiral ring system.

A concise and diastereoselective construction of the ABCD ring system of spirochensilide A is described. The key steps of this synthesis are a semipinacol rearrangement reaction to stereoselectively construct the AB ring system bearing two vicinal quaternary chiral centers and a Co-mediated Pauson-Khand reaction to form the spiro-based bicyclic CD ring system. This chemistry leads to the stereoselective synthesis of 13( R )-demethyl spirochensilide A, paving the way for the first asymmetric total synthesis of (-)-spirochensilide A.

Importance: Chest pain is among the most common reasons for emergency department (ED) presentations. However, most patients are at low risk for acute coronary syndrome (ACS), with low cardiac adverse outcomes rates. Biomarker testing with troponin levels is key in the initial assessment for ACS. Although serial troponin testing can improve the diagnosis of ACS in clinical practice, some patients deemed to be low risk are discharged after a single negative troponin test result., Objective: To report the clinical outcomes of patients discharged after a single negative troponin test result compared with patients discharged after serial troponin measurements., Design, Setting, and Participants: This is a retrospective cohort study of ED encounters from May 5, 2016, to December 1, 2017, across 15 community EDs within an integrated health care system in southern California. The study cohort includes 27 918 adult ED encounters in which patients were evaluated for suspected ACS with a HEART (history, electrocardiogram, age, risk factors, and troponin) score and an initial conventional troponin-I measurement below the level of detection (<0.02 ng/mL). Statistical analysis was performed from December 1, 2019, to December 1, 2020., Exposure: Single troponin test vs multiple troponin tests., Main Outcomes and Measures: The primary outcome was acute myocardial infarction or cardiac mortality; secondary outcomes included coronary artery bypass graft, percutaneous coronary intervention, invasive coronary angiography, and unstable angina within 30 days of discharge. A multivariable logistic regression model was performed to evaluate the association between testing strategies and clinical outcomes., Results: A total of 27 918 patient encounters (16 212 women [58.1%]; mean [SD] age, 58.7 [15.2] years) were included in the study. Of patients with an initial troponin measurement below the level of detection, 14 459 (51.8%) were discharged after a single troponin measurement, and 13 459 (48.2%) underwent serial troponin tests. After adjustment for cardiac risk factors and comorbidities, there was no statistically significant difference in the primary outcome of acute myocardial infarction or cardiac mortality within 30 days between the 2 groups (single troponin, 56 [0.4%] vs serial troponin, 52 [0.4%]; adjusted odds ratio, 1.41 [95% CI, 0.96-2.07]). Patients discharged after a single troponin test had lower rates of coronary artery bypass graft (adjusted odds ratio, 0.24 [95% CI, 0.11-0.48]) and invasive coronary angiography (adjusted odds ratio, 0.46 [95% CI, 0.38-0.56])., Conclusions and Relevance: This study suggests that patients are routinely discharged from the ED after a single negative troponin test result, and when compared with serial troponin testing, a single troponin test appears safe based on current physician decision-making, with no difference in rates of 30-day cardiac mortality and acute myocardial infarction, which are low in both groups.