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Importance: Accelerated diagnostic protocols (ADPs) for chest pain using high-sensitivity troponin (hsTn) levels have excellent sensitivity and negative predictive value for rapid risk stratification of patients with chest pain. However, little is known about the outcomes of patients who are discharged despite abnormal ADP results, ie, after "ruling-in" with a modest elevation of hsTn. Objective: To determine outcomes of patients discharged following ADP, including those who were ruled in with modestly elevated levels of hsTnT but discharged nonetheless. Design, Setting, and Participants: This retrospective cohort study included patients with chest pain who presented to the emergency departments (EDs) of a large multisite health system ED between January 2017 to September 2019. Patients were assessed using an ADP, had a peak hsTnT level measured between the limit of quantitation and 52 ng/L, were discharged, and had follow-up in the electronic medical record. Data analysis was conducted from January 2017 to September 2019. Exposures: Application of an hsTnT ADP. Main Outcomes and Measures: Thirty-day major adverse cardiac events (MACE), including myocardial infarction, urgent coronary revascularization, and all-cause death, comparing patients who were discharged following ADP-concordant vs ADP-discordant results. Results: Of 10 342 patients with chest pain (mean [SD] age 51 [17] years; 5902 [57%] women) discharged following ADP, 29 (0.28%) had MACE. Patients with MACE were older (median [IQR] age, 66 [53-75] years vs 50 [38-62] years; P < .001) and more likely to have prior CAD (12 [41.4%] vs 1805 [17.5%]; P = .002) and hyperlipidemia (13 [44.8%] vs 2248 [21.8%]; P = .006). Additionally, patients with MACE were 5-fold more likely to have been discharged despite ADP discordance (16 [55.2%] vs 1145 [11.1%]; P < .001). A multivariable logistic regression analysis revealed only ADP discordance was independently associated with MACE (odds ratio, 6.42 [95% CI, 2.94-14.0]; P < .001). When stratified by peak hsTnT level, there were no differences in MACE between ADP-concordant and -discordant discharges provided the peak hsTnT measured was less than 12 ng/L. In contrast, patients with peak hsTnT level between 12 and 51 ng/L were significantly more likely to have MACE if they were discharged after ADP-discordant vs -concordant hsTnT series (14 of 609 [2.30%] vs 5 of 1047 [0.48%]; P < .002). Notably, a HEART (history, electrocardiogram, age, risk factors, troponin) score of 4 or greater retrospectively identified the most ADP-discordant discharges (13 of 16 [81.3%]) who had MACE. Conclusions and Relevance: In this cohort study, an hsTnT ADP identified patients who could be discharged from the ED with low 30-day risk of MACE, provided the discharge was based on ADP-concordant "rule-out." Conversely, the rate of MACE was significantly higher among patients discharged despite ADP discordance. Most patients with ADP-discordant discharges who experienced MACE had a HEART score of 4 or greater, suggesting that application of this score may augment discharge decisions of patients despite ADP-discordant troponin series.

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Many therapeutic agents are macrocyclic trisubstituted alkenes but preparation of these structures is typically inefficient and non-selective. A possible solution would entail catalytic macrocyclic ring-closing metathesis, but these transformations require high catalyst loading, conformationally rigid precursors and are often low yielding and/or non-stereoselective. Here we introduce a ring-closing metathesis strategy for synthesis of trisubstituted macrocyclic olefins in either stereoisomeric form, regardless of the level of entropic assistance. The goal was achieved by addressing several unexpected difficulties, including complications arising from pre-ring-closing metathesis alkene isomerization. The power of the method is highlighted by two examples. The first is the near-complete reversal of substrate-controlled selectivity in the formation of a macrolactam related to an antifungal natural product. The other is a late-stage stereoselective generation of an E-trisubstituted alkene in a 24-membered ring, en route to the cytotoxic natural product dolabelide C.

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We investigate the connection between the choice of transportation mode used by commuters and the probability of COVID-19 transmission. This interplay might influence the choice of transportation means for years to come. We present data on commuting, socioeconomic factors, and COVID-19 disease incidence for several US metropolitan areas. The data highlights important connections between population density and mobility, public transportation use, race, and increased likelihood of transmission. We use a transportation model to highlight the effect of uncertainty about transmission on the commuters' choice of transportation means. Using multiple estimation techniques, we found strong evidence that public transit ridership in several US metro areas has been considerably impacted by COVID-19 and by the policy responses to the pandemic. Concerns about disease transmission had a negative effect on ridership, which is over and above the adverse effect from the observed reduction in employment. The COVID-19 effect is likely to reduce the demand for public transport in favor of lower density alternatives. This change relative to the status quo will have implications for fuel use, congestion, accident frequency, and air quality. More vulnerable communities might be disproportionally affected as a result. We point to the need for additional studies to further quantify these effects and to assist policy in planning for the post-COVID-19 transportation future.

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Hematopoietic progenitor kinase (HPK1), a negative regulator of TCR-mediated T-cell activation, has been recognized as a novel antitumor immunotherapy target. Structural optimization of kinase inhibitor 4 through a systematic two-dimensional diversity screen of pyrazolopyridines led to the identification of potent and selective compounds. Crystallographic studies with HPK1 revealed a favorable water-mediated interaction with Asp155 and a salt bridge to Asp101 with optimized heterocyclic solvent fronts that were critical for enhanced potency and selectivity. Computational studies of model systems revealed differences in torsional profiles that allowed for these beneficial protein-ligand interactions. Further optimization of molecular properties led to identification of potent and selective reverse indazole inhibitor 36 that inhibited phosphorylation of adaptor protein SLP76 in human PBMC and exhibited low clearance with notable bioavailability in in vivo rat studies.

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Kinetically controlled catalytic cross-metathesis reactions that generate (Z)-α,ß-unsaturated esters selectively are disclosed. A key finding is that the presence of acetonitrile obviates the need for using excess amounts of a more valuable terminal alkene substrates. On the basis of X-ray structure and spectroscopic investigations a rationale for the positive impact of acetonitrile is provided. Transformations leading to various E,Z-dienoates are highly Z-selective as well. Utility is highlighted by application to stereoselective synthesis of the C1-C12 fragment of biologically active natural product (-)-laulimalide.

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The first examples of catalyst-controlled stereoselective macrocyclic ring-closing metathesis reactions that generate Z-enoates as well as (E,Z)- or (Z,E)-dienoates are disclosed. Reactions promoted by 3.0-10 mol % of a Mo-based monoaryloxide pyrrolide complex proceed to completion within 2-6 h at room temperature. The desired macrocycles are formed in 79:21 to >98:2 Z/E selectivity; stereoisomerically pure products can be obtained in 43-75% yield after chromatography. Utility is demonstrated by application to a concise formal synthesis of the natural product (+)-aspicilin.

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The first examples of catalytic cross-metathesis (CM) reactions that furnish Z-(pinacolato)allylboron and Z-(pinacolato)alkenylboron compounds are disclosed. Products are generated with high Z selectivity by the use of a W-based monoaryloxide pyrrolide (MAP) complex (up to 91% yield and >98:2 Z:E). The more sterically demanding Z-alkenylboron species are obtained in the presence of Mo-based MAP complexes in up to 93% yield and 97% Z selectivity. Z-selective CM with 1,3-dienes and aryl olefins are reported for the first time. The utility of the approach, in combination with catalytic cross coupling, is demonstrated by a concise and stereoselective synthesis of anticancer agent combretastatin A-4.

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