Building a vertically integrated genomic learning health system: The biobank at the Colorado Center for Personalized Medicine.

Precision medicine initiatives across the globe have led to a revolution of repositories linking large-scale genomic data with electronic health records, enabling genomic analyses across the entire phenome. Many of these initiatives focus solely on research insights, leading to limited direct benefit to patients. We describe the biobank at the Colorado Center for Personalized Medicine (CCPM Biobank) that was jointly developed by the University of Colorado Anschutz Medical Campus and UCHealth to serve as a unique, dual-purpose research and clinical resource accelerating personalized medicine. This living resource currently has more than 200,000 participants with ongoing recruitment. We highlight the clinical, laboratory, regulatory, and HIPAA-compliant informatics infrastructure along with our stakeholder engagement, consent, recontact, and participant engagement strategies. We characterize aspects of genetic and geographic diversity unique to the Rocky Mountain region, the primary catchment area for CCPM Biobank participants. We leverage linked health and demographic information of the CCPM Biobank participant population to demonstrate the utility of the CCPM Biobank to replicate complex trait associations in the first 33,674 genotyped individuals across multiple disease domains. Finally, we describe our current efforts toward return of clinical genetic test results, including high-impact pathogenic variants and pharmacogenetic information, and our broader goals as the CCPM Biobank continues to grow. Bringing clinical and research interests together fosters unique clinical and translational questions that can be addressed from the large EHR-linked CCPM Biobank resource within a HIPAA- and CLIA-certified environment.

Thermodynamic examination of pH and magnesium effect on U6 RNA internal loop.

U6 RNA contains a 1 × 2-nt internal loop that folds and unfold during spliceosomal assembly and activation. The 1 × 2 loop consists of a C67•A79 base pair that forms an additional hydrogen bond upon protonation, C67•A+79, and uracil (U80) that coordinates the catalytically essential magnesium ions. We designed a series of RNA and DNA constructs with a 1 × 2 loop sequence contained in the ISL, and its modifications, to measure the thermodynamic effects of protonation and magnesium binding using UV-visible thermal denaturation experiments. We show that the wild-type RNA construct gains 0.43 kcal/mol in 1 M KCl upon lowering the pH from 7.5 to 5.5; the presence of magnesium ions increases its stability by 2.17 kcal/mol at pH 7.5 over 1 M KCl. Modifications of the helix closing base pairs from C-G to U•G causes a loss in protonation-dependent stability and a decrease in stability in the presence of magnesium ions, especially in the C68U construct. A79G single-nucleotide bulge loop construct showed the largest gain in stability in the presence of magnesium ions. The DNA wild-type construct shows a smaller effect on stability upon lowering the pH and in the presence of magnesium ions, highlighting differences in RNA and DNA structures. A U6 RNA 1 × 2 loop sequence is rare in the databases examined.

Association of Virtual Surgical Planning With External Incisions in Complex Maxillectomy Reconstruction.

Importance: Maxillectomy can commonly be performed through a transoral approach, but maxillectomy defect reconstruction can be difficult to precisely design, contour, and inset through this approach. Objective: To evaluate whether the use of virtual surgical planning (VSP) and 3-dimensional (3-D) modeling is associated with a decrease in the requirement of lateral rhinotomy (LR) for patients undergoing total and partial maxillectomy reconstruction. Design, Setting, and Participants: This retrospective cohort study was conducted among patients undergoing subtotal or total maxillectomy with microvascular free flap reconstruction with or without VSP and 3-D modeling at a single tertiary care academic medical center between January 1, 2008, and October 3, 2019. Interventions: Maxillectomy and free flap reconstruction with or without VSP. Main Outcomes and Measures: Necessity of LR or other external incision for contouring, placement, and fixation of reconstruction as well as surgical complications. Results: Fifteen patients (12 men [80%]; mean age, 64 years) underwent maxillectomy with free flap reconstruction without VSP. Eight patients (53%) in this group underwent total maxillectomy, and 4 patients in this group (27%) underwent partial maxillectomy. Twenty-three patients (18 men [78%]; mean age, 58 years) underwent maxillectomy with free flap reconstruction and VSP and 3-D modeling. Twelve of these patients (52%) underwent total maxillectomy, and 11 (48%) underwent partial maxillectomy. Lateral rhinotomy was necessary for 1 patient (4%) in the VSP group vs 12 patients (80%; 95% CI, 54%-98%) in the pre-VSP group. There were no LR complications in the VSP group vs 6 in the pre-VSP group. Among both groups, 14 patients underwent fibula free flap, 22 patients underwent subscapular system free flap, and 2 patients underwent cutaneous or osteocutaneous radial forearm free flap. There were no flap failures in the LR group and 1 flap failure in the group without LR. Conclusions and Relevance: This cohort study suggests that the use of VSP and 3-D modeling for maxillectomy reconstruction is associated the a decrease in the need for external incisions without compromising reconstructive flap utility.