Pain, Nausea, and Hospital Admission after Uterine Fibroid Embolization: A Comparison of 2 Protocols.

Uterine fibroid embolization (UFE) procedures performed from 2013 to 2019 were reviewed. Seventy-two patients were treated with a standard protocol consisting of sedation, ketorolac, ondansetron, and overnight parenteral analgesics and antiemetics. Ninety-six patients were treated with a new protocol, which added transdermal scopolamine, lorazepam, and intravenous acetaminophen. Outpatient uterine fibroid embolization (OP-UFE) not requiring hospitalization was successful in 81.4% and 2.7% of patients treated with the new and old protocols, respectively (odds ratio [OR], 141.4; P < .0001). Procedural fentanyl doses were lower with the new protocol than with the old one (mean, 148 vs 186 mcg; P = .0016). In the new protocol subset, patients were 1.01 times more likely to fail OP-UFE for every microgram increase in procedural fentanyl (OR, 0.99, P = .009), and those presenting with pain were less likely to succeed with OP-UFE than those with bleeding or bulk symptoms (OR, 0.31, P = .04). In conclusion, decreasing the opioid dose while increasing the antiemetic and nonopioid analgesic medications improves the chances of same day discharge after UFE.

MRI hemodynamic markers of progressive bicuspid aortic valve-related aortic disease.

PURPOSE: To determine the reproducibility of MRI aortic hemodynamic markers and to assess their relationship to aortic growth in a cohort of patients with bicuspid aortic valves (BAV). MATERIALS AND METHODS: Twenty-five patients previously studied with four-dimensional (4D) Flow imaging who had at least two separate cross-sectional imaging studies to assess for aortic growth were included: tricuspid aortic valve (TAV) controls without valvular disease (n = 12) and patients with BAV (n = 13). Flow data from the ascending aorta was used for calculation of peak velocity, normalized flow displacement, maximum wall shear stress (WSS), mean WSS, and minimal WSS. Pearson's correlation was used to evaluate interobserver agreement, and linear regression to evaluate the correlation between the different hemodynamic markers and growth. Patient informed consent was waived by the institutional review board that approved the study. RESULTS: Peak velocity and flow displacement were very reproducible (r = 0.90-1.0 and r = 0.91-0.98, respectively). The range of WSS parameters was largely reproducible (0.47 < r < 0.96) with the greatest variability at the data extraction stage of analysis (0.47 < r < 0.85). Flow displacement best correlated with interval aortic growth (r = 0.65), peak velocity was moderately correlated (r = 0.35), but the WSS parameters did not correlate well with growth (r < 0.17). CONCLUSION: Flow displacement is a simple and reproducible hemodynamic marker that shows good correlation with aortic growth in patients with bicuspid aortic valves.

Highly parallel translation of DNA sequences into small molecules.

A large body of in vitro evolution work establishes the utility of biopolymer libraries comprising 10(10) to 10(15) distinct molecules for the discovery of nanomolar-affinity ligands to proteins. Small-molecule libraries of comparable complexity will likely provide nanomolar-affinity small-molecule ligands. Unlike biopolymers, small molecules can offer the advantages of cell permeability, low immunogenicity, metabolic stability, rapid diffusion and inexpensive mass production. It is thought that such desirable in vivo behavior is correlated with the physical properties of small molecules, specifically a limited number of hydrogen bond donors and acceptors, a defined range of hydrophobicity, and most importantly, molecular weights less than 500 Daltons. Creating a collection of 10(10) to 10(15) small molecules that meet these criteria requires the use of hundreds to thousands of diversity elements per step in a combinatorial synthesis of three to five steps. With this goal in mind, we have reported a set of mesofluidic devices that enable DNA-programmed combinatorial chemistry in a highly parallel 384-well plate format. Here, we demonstrate that these devices can translate DNA genes encoding 384 diversity elements per coding position into corresponding small-molecule gene products. This robust and efficient procedure yields small molecule-DNA conjugates suitable for in vitro evolution experiments.

Mesofluidic devices for DNA-programmed combinatorial chemistry.

Hybrid combinatorial chemistry strategies that use DNA as an information-carrying medium are proving to be powerful tools for molecular discovery. In order to extend these efforts, we present a highly parallel format for DNA-programmed chemical library synthesis. The new format uses a standard microwell plate footprint and is compatible with commercially available automation technology. It can accommodate a wide variety of combinatorial synthetic schemes with up to 384 different building blocks per chemical step. We demonstrate that fluidic routing of DNA populations in the highly parallel format occurs with excellent specificity, and that chemistry on DNA arrayed into 384 well plates proceeds robustly, two requirements for the high-fidelity translation and efficient in vitro evolution of small molecules.

Synthetic ligands discovered by in vitro selection.

The recognition and catalytic properties of biopolymers derive from an elegant evolutionary mechanism, whereby the genetic material encoding molecules with superior functional attributes survives a selective pressure and is propagated to subsequent generations. This process is routinely mimicked in vitro to generate nucleic-acid or peptide ligands and catalysts. Recent advances in DNA-programmed organic synthesis have raised the possibility that evolutionary strategies could also be used for small-molecule discovery, but the idea remains unproven. Here, using DNA-programmed combinatorial chemistry, a collection of 100 million distinct compounds is synthesized and subjected to selection for binding to the N-terminal SH3 domain of the proto-oncogene Crk. Over six generations, the molecular population converges to a small number of novel SH3 domain ligands. Remarkably, the hits bind with affinities similar to those of peptide SH3 ligands isolated from phage libraries of comparable complexity. The evolutionary approach has the potential to drastically simplify and accelerate small-molecule discovery.

Chemical evolution as a tool for molecular discovery.

In modern academic and industrial laboratories, evolutionary strategies are used routinely to identify biopolymers with novel activities. Large libraries of nucleic acids (approximately 10(15)) or peptides and proteins (approximately 10(13)) can be subjected to multiple rounds of selective pressure, amplification, and diversification, yielding individual sequences with desirable properties. Although the evolutionary approach is a powerful search tool, the chemical nature of biopolymers is not suited for all purposes. Application of evolutionary strategies to libraries of arbitrary chemical composition would overcome this problem, and radically change traditional small-molecule discovery. The chemical make-up of in vitro evolution libraries has necessarily been limited, because library synthesis relies on enzymes. A great deal of current research focuses on expanding the chemical repertoire of in vitro evolution by (a) broadening enzyme substrate specificities to include unnatural building blocks, or (b) developing methods to translate DNA sequences into multistep organic syntheses. We discuss the strengths and weaknesses of the approaches, review the successes, and consider the future of chemical evolution as a tool.

DNA display III. Solid-phase organic synthesis on unprotected DNA.

DNA-directed synthesis represents a powerful new tool for molecular discovery. Its ultimate utility, however, hinges upon the diversity of chemical reactions that can be executed in the presence of unprotected DNA. We present a solid-phase reaction format that makes possible the use of standard organic reaction conditions and common reagents to facilitate chemical transformations on unprotected DNA supports. We demonstrate the feasibility of this strategy by comprehensively adapting solid-phase 9-fluorenylmethyoxycarbonyl-based peptide synthesis to be DNA-compatible, and we describe a set of tools for the adaptation of other chemistries. Efficient peptide coupling to DNA was observed for all 33 amino acids tested, and polypeptides as long as 12 amino acids were synthesized on DNA supports. Beyond the direct implications for synthesis of peptide-DNA conjugates, the methods described offer a general strategy for organic synthesis on unprotected DNA. Their employment can facilitate the generation of chemically diverse DNA-encoded molecular populations amenable to in vitro evolution and genetic manipulation.