Development of a quantitative systems pharmacology model of chronic kidney disease: metabolic bone disorder.

Chronic kidney disease mineral bone disorder (CKD-MBD) is a virtually universal complication of kidney diseases, starting early in the course of disease and resulting in devastating clinical consequences ranging from bone fragility to accelerated atherosclerosis and early cardiovascular death. Guidelines for therapeutic goals for CKD-MBD have been published, and achievement of these guidelines is associated with improved survival. However, the incomplete understanding of CKD-MBD and the individual variability in the manifestations of CKD-MBD have made it difficult to achieve these guidelines. We hypothesized that the progression of MBD through all stages of CKD, including end-stage kidney disease, could be represented by a quantitative systems pharmacology/systems biology (QSP) model. To address this hypothesis, we constructed a QSP model of CKD-MBD, building on an open-source model of calcium and phosphorus metabolism. Specifically, we estimated and validated the model using data from 5,496 patients with CKD enrolled in the Chronic Renal Insufficiency Cohort study. Our model accurately predicted changes in markers of mineral metabolism related to progressing CKD. We demonstrated that the incorporation of fibroblast growth factor 23 and the soft tissue compartment is essential for accurate modeling of the changes in calcium, phosphorus, intact parathyroid hormone, and calcitriol in CKD-MBD. We conclude that our systems biology model accurately represents CKD-MBD disease progression and can be used as a test bench for improving therapeutic interventions.

Reverse shoulder arthroplasty glenoid fixation: is there a benefit in using four instead of two screws?

BACKGROUND: To allow osseous integration to occur and thus provide long-term stability, initial glenoid baseplate fixation must be sufficiently rigid. A major contributing factor to initial rigid fixation is baseplate screw fixation. Current baseplate designs use a 4-screw fixation construct. However, recent literature suggests adequate fixation can be achieved with fewer than 4 screws. The purpose of the present study was to determine whether a 4-screw construct provides more baseplate stability than a 2-screw construct. METHODS: A flat-backed glenoid baseplate with 4 screw hole options was implanted into 6 matched pairs of cadaver scapulas using standard surgical technique. Within each pair, 2 screws or 4 screws were implanted in a randomized fashion. A glenosphere was attached allowing cyclic loading in an inferior-to-superior direction and in an anterior-to-posterior direction. Baseplate motion was measured using 4 linear voltage displacement transducers evenly spaced around the glenosphere. RESULTS: There was no statistical difference in the average peak central displacements between fixation with 2 or 4 screws (P = .338). Statistical increases in average peak central displacement with increasing load (P < .001) and with repetitive loading (P < .002) were found. CONCLUSION: This study demonstrates no statistical difference in baseplate motion between 2-screw and 4-screw constructs. Therefore, using fewer screws could potentially lead to a reduction in operative time, cost, and risk, with no significant negative effect on overall implant baseplate motion.