Influence of the Door-to-ECG Time on the Prognosis of Patients with Acute Coronary Syndrome.

Background: The rapid acquisition of an electrocardiogram (ECG) plays a crucial role in the diagnosis and management decisions in patients with acute coronary syndrome (ACS). Objectives: We determined the time-to-ECG acquisition, identified factors associated with timely acquisition, and evaluated the influence of time-to-ECG on in-hospital mortality. Methods: We measured the door-to-ECG time for 903 of 2140 patients in the emergency department of Far Eastern Memorial Hospital with a diagnosis of ACS from January 1, 2016 to December 31, 2018, via a retrospective chart review. The primary outcome was in-hospital mortality. Outcome analysis of mortality was conducted using multivariable logistic regression. The secondary outcome was to determine which factors influenced whether or not a patient received an ECG within 10 min. The analysis was conducted using multiple logistic regression. Results: The median time-to-ECG was 5 min (interquartile range: 4-11 min) in all patients. In multivariable logistic regression analysis, we found that older age and more severe heart-broken index were significantly related to timely ECG acquisition. In-hospital mortality was higher in those in whom ECG was performed after more than 10 min. However, in the multivariable logistic regression analysis, it did not have a significant positive correlation with ECG acquisition time. Conclusions: Timely ECG acquisition owing to the triage protocol at our institution, the heart-broken index, led to early PCI and thus better outcomes for the ACS patients in this study. The implementation of a protocol-driven timely evaluation of patients with ACS and prompt PCI are important.

Multiple Synthetic Routes to the Mini-Protein Omomyc and Coiled-Coil Domain Truncations.

The Myc transcription factor represents an "undruggable" target of high biological interest due to its central role in various cancers. An abbreviated form of the c-Myc protein, called Omomyc, consists of the Myc DNA-binding domain and a coiled-coil region to facilitate dimerization of the 90 amino acid polypeptide. Here we present our results to evaluate the synthesis of Omomyc using three complementary strategies: linear Fmoc solid-phase peptide synthesis (SPPS) using several advancements for difficult sequences, native chemical ligation from smaller peptide fragments, and a high-throughput bacterial expression and assay platform for rapid mutagenesis. This multifaceted approach allowed access to up to gram quantities of the mini-protein and permitted in vitro and in vivo SAR exploration of this modality. DNA-binding results and cellular activity confirm that Omomyc and analogues presented here, are potent binders of the E-box DNA engaged by Myc for transcriptional activation and that this 90-amino acid mini-protein is cell permeable and can inhibit proliferation of Myc-dependent cell lines. We also present additional results on covalent homodimerization through disulfide formation of the full-length mini-protein and show the coiled-coil region can be truncated while preserving both DNA binding and cellular activity. Altogether, our results highlight the ability of advanced peptide synthesis to achieve SAR tractability in a challenging synthetic modality.

High-throughput purification platform in support of drug discovery.

The application of parallel synthesis is an efficient approach to explore the chemical space and to rapidly develop meaningful structure activity relationship (SAR) data for drug discovery programs. However, the effectiveness of the parallel synthesis requires a high throughput purification workflow that can process a large number of crude samples within a meaningful time frame. This paper describes a high throughput purification platform that has been adopted at Merck's Rahway research site. The platform includes the evaluation of crude samples, mass-directed HPLC purification, fraction analysis, compound registration, final compound purity assessment and assay distribution. Assisting with the sample tracking and the data management is the internally designed laboratory information management system, Light Automation Framework (LAF). Using this process and the tools described herein, the group has successfully achieved purities of 95% or greater for 90% of samples.