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Introduction: Transcatheter aortic valve replacement (TAVR) has surpassed surgical valve replacement for the management of severe aortic stenosis. High grade AV block is a well-described complication following TAVR. Prior models for predicting risk of pacemaker (PPM) with TAVR lack sensitivity, clinical applicability or cannot be applied pre-procedurally. Hypothesis: To aid planning and patient discussion, we sought to produce a simple tool that can be applied at pre-TAVR clinical visits to stratify risk of PPM associated with TAVR implantation. Methods: We performed an analysis of all patients undergoing TAVR at the University of Colorado. Clinical, valvular, and electrocardiographic data were recorded. Patients were split into a training cohort for development of a predictive model and a testing cohort for model validation. Multivariable stepwise regression was performed on the training cohort to determine patient characteristics most predictive of pacemaker. Results from the initial regression were then applied to the testing cohort for model validation. Results: Of 483 patients analyzed from 2013-2019 in the training cohort, 78 required pacemaker. The need for pacemaker was influenced by 5 pre-procedure variables: RBBB, self-expandable valve, PR interval > 200 ms, ejection fraction > 50%, and albumin > 4.0 g/dL. The regression model produced in our training cohort was highly predictive of need for pacemaker in the validation cohort (Figure). Conclusions: Five pre-procedural characteristics primarily influence risk of PPM after TAVR. These can be used to produce a simple but highly predictive risk model for determining which patients will need pacemaker after TAVR.

The hepatitis C virus (HCV) NS5B replicase is a prime target for the development of direct-acting antiviral drugs for the treatment of chronic HCV infection. Inspired by the overlay of bound structures of three structurally distinct NS5B palm site allosteric inhibitors, the high-throughput screening hit anthranilic acid 4, the known benzofuran analogue 5, and the benzothiadiazine derivative 6, an optimization process utilizing the simple benzofuran template 7 as a starting point for a fragment growing approach was pursued. A delicate balance of molecular properties achieved via disciplined lipophilicity changes was essential to achieve both high affinity binding and a stringent targeted absorption, distribution, metabolism, and excretion profile. These efforts led to the discovery of BMS-929075 (37), which maintained ligand efficiency relative to early leads, demonstrated efficacy in a triple combination regimen in HCV replicon cells, and exhibited consistently high oral bioavailability and pharmacokinetic parameters across preclinical animal species. The human PK properties from the Phase I clinical studies of 37 were better than anticipated and suggest promising potential for QD administration.

Background The incidence of cancer treatment–induced arrhythmia ( CTIA ) associated with novel, targeted chemotherapeutic agents ( TCA s) has not been well described. Methods and Results We identified all patients treated at our institution from January 2010 to December 2015 with selected TCA s. We defined CTIA as any new arrhythmia diagnosis code within 6 months after treatment initiation. As a comparison, we also identified patients treated with anthracycline chemotherapy during the same period. We identified 5026 patients, of whom 2951 (58.7%) received TCA s and 2075 (41.3%) received anthracycline chemotherapy. In the overall cohort, 601 patients (12.0%) developed CTIA . Patients with CTIA were significantly older and more likely to have hypertension, diabetes mellitus, congestive heart failure, coronary disease, and sleep apnea. The incidence of CTIA at 6 months was significantly lower in the TCA group (9.3% versus 15.8%; P CTIA , whereas treatment with TCA s, compared with anthracycline chemotherapy, was associated with a significantly lower risk (hazard ratio, 0.60; 95% confidence interval, 0.51–0.71). Conclusions Compared with anthracyclines, treatment with TCAs was associated with an ≈40% reduced risk of new‐onset arrhythmia diagnoses during the first 6 months of treatment.

Described herein are structure-activity relationship studies that resulted in the optimization of the activity of members of a class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors. Subsequent iterations of analogue design and syntheses successfully addressed off-target activities, most notably human pregnane X receptor (hPXR) transactivation, and led to significant improvements in the physicochemical properties of lead compounds. Those analogues exhibiting improved solubility and membrane permeability were shown to have notably enhanced pharmacokinetic profiles. Additionally, a series of alkyl bridged piperazine carboxamides was identified as being of particular interest, and from which the compound BMS-791325 (2) was found to have distinguishing antiviral, safety, and pharmacokinetic properties that resulted in its selection for clinical evaluation.

Alkoxyanthranilic acid derivatives have been identified to inhibit HCV NS5B polymerase, binding in an allosteric site located at the convergence of the palm and thumb regions. Information from co-crystal structures guided the structural design strategy. Ultimately, two independent structural modifications led to a similar shift in binding mode that when combined led to a synergistic improvement in potency and the identification of inhibitors with sub-micromolar HCV NS5B binding potency.

Recently, considerable attention has been focused on the use of olefin metathesis to convert oleochemicals into value-added products such as the bifunctional molecule methyl 9-decenoate, but the implementation of this process has been hampered by low ethenolysis efficiencies. We report herein the use of alpha olefins as ethylene surrogates in cross metathesis reactions with methyl oleate and soybean oil fatty acid methyl esters (soy FAME) resulting in considerable increases in catalyst efficiencies in the production of this promising chemical product. Additional gains in efficiency were realized by using a peroxide-scavenging feedstock pretreatment.

The incidence of cancer treatment-induced arrhythmia (CTIA) associated with novel, targeted chemotherapeutic agents (TCAs) has not been well described. We retrospectively identified all patients treated at our institution from January 2010 to December 2015 with TCAs (tyrosine kinase inhibitors

Three strategies for the trackball control of an end effector on a laparoscopic graspers tool were tested to see which strategy was most intuitive to the user. The three strategies (UURR, UDRL, UDRR) were tested on four different orientations of the hand: horizontal holding the tool as an extension of the arm while rolling the trackball with the thumb, horizontal holding the tool as an extension of the arm and forearm pronated 90 degrees while rolling with the thumb, horizontal with tool 90° to arm using the thumb, and horizontal with tool 90° to arm using the index finger to roll the ball. Twenty-four subjects, each randomly chosen to test one of the three movement strategies, performed two trials sets per hand orientation, the first to test for intuition and the second to test for the effect of training. The outcome of the trials was a number of correct and incorrect movements of the trackball to control the end effector which was simulated on a computer screen. The results were analyzed using a general linear model test on repeated measures to determine the effects of strategy and hand orientation. Analyses showed that intuitively, subjects were significantly better when the end effector moved as the trackball did (UURR). The analyses of the learned trials showed that subjects did equally well with all three strategies. From these results, it was determined that the trackball control of the forceps will be manipulated using the UURR strategy.

The synthesis of the biologically useful synthon 2-chloro-5-hydroxypyridine from 3-iodo-6-chloropyridine is described.

A series of ruthenium catalysts have been screened under ring-closing metathesis (RCM) conditions to produce five-, six-, and seven-membered carbamate-protected cyclic amines. Many of these catalysts demonstrated excellent RCM activity and yields with as low as 500 ppm catalyst loadings. RCM of the five-membered carbamate series could be run neat, the six-membered carbamate series could be run at 1.0 M, and the seven-membered carbamate series worked best at 0.2−0.05 M.

A total synthesis of the biologically important diterpene ingenol has been completed. Ring-closing olefin metathesis was used to construct the strained "inside-outside" tetracyclic skeleton, and a series of diastereoselective reactions were employed to complete the synthesis. Another naturally occurring ingenane, 20-deoxyingenol, has also been prepared.