Some health concerns are often not identified until late into clinical development of drugs, which can place participants and patients at significant risk. For example, the United States Food and Drug Administration (FDA) labeled the xanthine oxidase inhibitor febuxostat with a"boxed" warning regarding an increased risk of cardiovascular death, and this safety risk was only identified during Phase 3b clinical trials after its approval. Thus, better preclinical assessment of drug efficacy and safety are needed to accurately evaluate candidate drug risk earlier in discovery and development. This study explored whether an in vitro vascular model incorporating human vascular cells and hemodynamics could be used to differentiate the potential cardiovascular risk associated with molecules that have similar on-target mechanisms of action. We compared the transcriptomic responses induced by febuxostat and other xanthine oxidase inhibitors to a database of 111 different compounds profiled in the human vascular model. Of the 111 compounds in the database, 107 are clinical-stage and 33 are FDA-labelled for increased cardiovascular risk. Febuxostat induces pathway-level regulation that has high similarity to the set of drugs FDA-labelled for increased cardiovascular risk. These results were replicated with a febuxostat analog, but not another structurally distinct xanthine oxidase inhibitor that does not confer cardiovascular risk. Together, these data suggest that the FDA warning for febuxostat stems from the chemical structure of the medication itself, rather than the target, xanthine oxidase. Importantly, these data indicate that cardiovascular risk can be evaluated in this in vitro human vascular model, which may facilitate understanding the drug candidate safety profile earlier in discovery and development.
Olecranon fractures are a known and potentially devastating complication of total elbow arthroplasty (TEA), especially if displaced with an incompetent extensor mechanism. The purpose of this study is to present a case series of olecranon fractures after TEA treated with a tension band construct and compare functional results to uncomplicated TEA patients.Six patients with displaced olecranon fractures in the setting of a prior TEA were identified and included in this retrospective case series. All patients were treated with a tension band construct. Functional scores were collected at a minimum of 1 year postoperatively, including the Mayo Elbow Performance Score (MEPS) and Single Assessment Numeric Evaluation (SANE) elbow score. Radiographs were reviewed at the time of injury and at the latest follow-up for fracture displacement, implant loosening or failure, and osseous union. A matched control group of 10 TEAs without complication was identified for comparison of functional scores.One patient was deceased prior to the final follow-up and was not included in the functional score analysis. The average postoperative MEPS was 74 ± 18.5 and the average postoperative SANE score was 69.4 ± 13.7. Average final range of motion was 134 degrees flexion and 18 degrees extension. Three (50%) patients had radiographic signs of osseous union at an average of 3.4 months. One patient had fixation failure and subsequent triceps insufficiency and required multiple reoperations with poor functional scores at the final follow-up. No significant difference was noted in both postoperative MEPS (P = .503) and SANE (P = .142) when comparing patients with olecranon fracture to matched uncomplicated TEA patients.Tension band fixation of olecranon fractures after prior TEA is able to restore function for a difficult problem despite a 50% radiographic union rate. Patients with this complication can expect similar functional results to uncomplicated TEA patients with proper fixation.
The basis of medical nutrition therapy for patients with LC-FAODs is to provide adequate energy to maintain anabolism and prevent catabolism. In practice, energy needs are estimated based on formulas derived from normal populations but it is unknown if energy expenditure among patients with LC-FAODs is similar to the normal population. We measured resting energy expenditure (REE), total energy expenditure (TEE) and body composition in 31 subjects with LC-FAODs ranging in age from 7 to 64 years. Measured REE was lower than estimated REE by various prediction equations and measured TEE was lower than estimated TEE. It is possible that the lower energy expenditure based on prediction formulas from the normal population is due to differences in body composition; we compared body composition to normal data from the 2017–18 National Health and Nutrition Examination Survey (NHANES). Fat free mass and fat mass was similar between subjects with an LC-FAOD and NHANES normal data suggesting no difference in body composition. We then compared measured REE and TEE to normal published data from the Dietary Reference Intakes (DRI). Measured REE and TEE were significantly lower among subjects with LC-FAODs compared to normal published energy expenditure data. Our results suggests patients with a LC-FAOD exhibit a lower REE and therefore actually have a slightly lower TEE than estimated. Current prediction equations may overestimate energy expenditure of patients with a LC-FAOD.
Liver fibrosis progression in chronic liver disease leads to cirrhosis, liver failure, or hepatocellular carcinoma and often ends in liver transplantation. Even with an increased understanding of liver fibrogenesis and many attempts to generate therapeutics specifically targeting fibrosis, there is no approved treatment for liver fibrosis. To further understand and characterize the driving mechanisms of liver fibrosis, we developed a high-throughput genome-wide CRISPR/Cas9 screening platform to identify hepatic stellate cell (HSC)-derived mediators of transforming growth factor (TGF)-β-induced liver fibrosis. The functional genomics phenotypic screening platform described here revealed the novel biology of TGF-β-induced fibrogenesis and potential drug targets for liver fibrosis.
