Apixaban Use in Obese Patients: A Review of the Pharmacokinetic, Interventional, and Observational Study Data.

Relatively little is known about the influence of extreme body weight on the pharmacokinetics (PK), pharmacodynamics (PD), efficacy, and safety of drugs used in many disease states. While direct oral anticoagulants (DOACs) have an advantage over warfarin in that they do not require routine drug monitoring, some may regard this convenience as less compelling in obese patients. Some consensus guidelines discourage using DOACs in patients weighing > 120 kg or with a body mass index > 35-40 kg/m2, given a sparsity of available data in this population and the concern that fixed dosing in obese patients might lead to decreased drug exposure and lower efficacy. Per the prescribing information, apixaban does not require dose adjustment in patients weighing above a certain threshold (e.g., ≥ 120 kg). Data from healthy volunteers and patients with nonvalvular atrial fibrillation (NVAF) or venous thromboembolism (VTE) have shown that increased body weight has a modest effect on apixaban's PK. However, the paucity of exposure data in individuals > 120 kg and the lack of guideline consensus on DOAC use in obese patients continue to raise concerns about potential decreased drug exposure at extreme weight. This article is the first to comprehensively review the available PK data in obese individuals without NVAF or VTE, and PK, PD, efficacy, effectiveness, and safety data for apixaban in obese patients with either NVAF or VTE, including subgroup analyses across randomized controlled trials and observational (real-world) studies. These data suggest that obesity does not substantially influence the efficacy, effectiveness, or safety of apixaban in these patients. Trial Registration ARISTOTLE: NCT00412984; AVERROES: NCT00496769; AMPLIFY: NCT00643201; AMPLIFY-EXT: NCT00633893; ADVANCE-1: NCT00371683; ADVANCE-2: NCT00452530; ADVANCE-3: NCT00423319 Apixaban Use in Obese Patients: A Review of the Pharmacokinetic, Interventional, and Observational Study Data (MP4 161.22 MB).

Follistatin improves skeletal muscle healing after injury and disease through an interaction with muscle regeneration, angiogenesis, and fibrosis.

Recovery from skeletal muscle injury is often incomplete because of the formation of fibrosis and inadequate myofiber regeneration; therefore, injured muscle could benefit significantly from therapies that both stimulate muscle regeneration and inhibit fibrosis. To this end, we focused on blocking myostatin, a member of the transforming growth factor-ß superfamily and a negative regulator of muscle regeneration, with the myostatin antagonist follistatin. In vivo, follistatin-overexpressing transgenic mice underwent significantly greater myofiber regeneration and had less fibrosis formation compared with wild-type mice after skeletal muscle injury. Follistatin's mode of action is likely due to its ability to block myostatin and enhance neovacularization. Furthermore, muscle progenitor cells isolated from follistatin-overexpressing mice were significantly superior to muscle progenitors isolated from wild-type mice at regenerating dystrophin-positive myofibers when transplanted into the skeletal muscle of dystrophic mdx/severe combined immunodeficiency mice. In vitro, follistatin stimulated myoblasts to express MyoD, Myf5, and myogenin, which are myogenic transcription factors that promote myogenic differentiation. Moreover, follistatin's ability to enhance muscle differentiation is at least partially due to its ability to block myostatin, activin A, and transforming growth factor-ß1, all of which are negative regulators of muscle cell differentiation. The findings of this study suggest that follistatin is a promising agent for improving skeletal muscle healing after injury and muscle diseases, such as the muscular dystrophies.

Technical tricks when using the reamer irrigator aspirator technique for autologous bone graft harvesting.

This report describes technical tricks for using the reamer irrigator aspirator to harvest autologous bone graft from the femur. This device is a focus of interest in orthopaedics because it can be used to harvest bone graft from the femoral canal and medial condyle in voluminous quantities. Moreover, according to some authors, the osteogenic potential of this graft is at least as effective as that of autogenous bone obtained from the iliac crest. The reamer irrigator aspirator device has substantially different design characteristics and technicalities compared with those of a standard reamer. First, a guidewire must be redirected into multiple areas, including the center of the distal femur and into both condyles, to harvest ample bone graft. This is accomplished by prebending the guidewire in a stronger fashion than required for regular reaming in the case of femoral nailing procedures. This bend can increase the risk for eccentric reaming as well as lodging of the suctioning device within the femoral canal. Second, the front and lateral drilling surfaces of this device are very sharp and further cleaned and maintained sharp by the irrigation process to permit the surgeon to obtain significant volumes of graft with a single passage of this device. At the same time, however, this sharp front-end cutting design can increase the risk of iatrogenic fracture if reaming is performed without caution. Third, a powerful suctioning device is connected to the reamer such that the blood loss that can occur during continuous reaming, irrigation, and aspiration must be considered with this technique. We hereby discuss these potential dangers and describe the correct use of this device with technical tricks to minimize the risk of unexpected intraoperative events.

The personal interview: assessing the potential for personality similarity to bias the selection of orthopaedic residents.

PURPOSE: The selection of medical students for training in orthopaedic surgery consists of an objective screening of cognitive skills to secure interviews for the brightest candidates, followed by subjective measures of candidates to confirm whether applicants are worthy of further consideration. The personal interview and its potential biased impact on the orthopaedic workforce were evaluated. METHOD: During 2004-2006 at the Penn State College of Medicine, the authors performed a prospective cohort study in which 30 consenting interviewers and 135 interviewees completed the Myers-Briggs Type Indicator before the interviews. Completed surveys were evaluated after submitting the resident selection list to the National Residency Matching Program, and candidate rankings based solely on the personal interview were analyzed. RESULTS: Clinicians ranked candidates more favorably when they shared certain personality preferences (P = .044) and when they shared the preference groupings of the quadrant extrovert-sensing and either the function pair sensing-thinking (P = .007) or the temperament sensing-judging (P = .003), or the function pair sensing-feeling and the temperament sensing-judging (P = .029). No associations existed between personality preferences and interviewee rankings performed by basic scientists and resident interviewers. CONCLUSIONS: The results support the hypothesis that, within the department studied, there was a significant association between similarities in personality type and the rankings that individual faculty interviewers assigned to applicants at the completion of each interview session. The authors believe that it is important for the faculty member to recognize that this tendency exists. Finally, promoting diversity within the admission committee may foster a diverse resident body and orthopaedic workforce.

Stem cells for the treatment of skeletal muscle injury.

Skeletal muscle injuries are extremely common, accounting for up to 35%-55% of all sports injuries and quite possibly affecting all musculoskeletal traumas. These injuries result in the formation of fibrosis, which may lead to the development of painful contractures, increases patients' risk for repeat injuries, and limits their ability to return to a baseline or pre-injury level of function. The development of successful therapies for these injuries must consider the pathophysiology of these musculoskeletal conditions. We discuss the direct use of muscle-derived stem cells and some key cell population dynamics as well as the use of clinically applicable modalities that may enhance the local supply of stem cells to the zone of injury by promoting angiogenesis.

Dominant negative Bmp5 mutation reveals key role of BMPs in skeletal response to mechanical stimulation.

BACKGROUND: Over a hundred years ago, Wolff originally observed that bone growth and remodeling are exquisitely sensitive to mechanical forces acting on the skeleton. Clinical studies have noted that the size and the strength of bone increase with weight bearing and muscular activity and decrease with bed rest and disuse. Although the processes of mechanotransduction and functional response of bone to mechanical strain have been extensively studied, the molecular signaling mechanisms that mediate the response of bone cells to mechanical stimulation remain unclear. RESULTS: Here, we identify a novel germline mutation at the mouse Bone morphogenetic protein 5 (Bmp5) locus. Genetic analysis shows that the mutation occurs at a site encoding the proteolytic processing sequence of the BMP5 protein and blocks proper processing of BMP5. Anatomic studies reveal that this mutation affects the formation of multiple skeletal features including several muscle-induced skeletal sites in vivo. Biomechanical studies of osteoblasts from these anatomic sites show that the mutation inhibits the proper response of bone cells to mechanical stimulation. CONCLUSION: The results from these genetic, biochemical, and biomechanical studies suggest that BMPs are required not only for skeletal patterning during embryonic development, but also for bone response and remodeling to mechanical stimulation at specific anatomic sites in the skeleton.