The Pharmacogenomics Research Network Translational Pharmacogenetics Program: Outcomes and Metrics of Pharmacogenetic Implementations Across Diverse Healthcare Systems.

Numerous pharmacogenetic clinical guidelines and recommendations have been published, but barriers have hindered the clinical implementation of pharmacogenetics. The Translational Pharmacogenetics Program (TPP) of the National Institutes of Health (NIH) Pharmacogenomics Research Network was established in 2011 to catalog and contribute to the development of pharmacogenetic implementations at eight US healthcare systems, with the goal to disseminate real-world solutions for the barriers to clinical pharmacogenetic implementation. The TPP collected and normalized pharmacogenetic implementation metrics through June 2015, including gene-drug pairs implemented, interpretations of alleles and diplotypes, numbers of tests performed and actionable results, and workflow diagrams. TPP participant institutions developed diverse solutions to overcome many barriers, but the use of Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines provided some consistency among the institutions. The TPP also collected some pharmacogenetic implementation outcomes (scientific, educational, financial, and informatics), which may inform healthcare systems seeking to implement their own pharmacogenetic testing programs.

The rate of wear of second-generation highly crosslinked polyethylene liners five years post-operatively does not increase if large femoral heads are used.

AIMS: The increased in vivo resistance to wear of highly crosslinked polyethylene (HXLPE) in total hip arthroplasty (THA) has led to an increased use of larger articulations which have been shown to reduce the incidence of early dislocation. To date, there are few reports of the wear of larger articulations using second generation HXLPE liners. Our prospective cohort study measured the bedding-in and early wear of large (36 mm and 40 mm diameter) articulations involving a second generation X3 HXLPE liner and compared our findings with previous clinical and in vitro studies of the same material. PATIENTS AND METHODS: The proximal penetration of the femoral head five years post-operatively was measured for 15 patients using radiostereometric analysis (RSA). RESULTS: The median proximal bedding-in within the first post-operative year was 0.022 mm (interquartile range (IQR) -0.050 to 0.091). The median proximal rate of wear between one and five years was -0.004 mm/year (IQR -0.021 to 0.022). The rates of proximal, medial, 2D or 3D wear between one and five years post-operatively of the X3 HXLPE liner did not increase with larger articulations compared with our previous study of 32 mm articulations. CONCLUSION: Although reassuring, the use of larger articulations requires continued monitoring to determine whether the low wear observed in the short-term continues to the mid- to long-term. Cite this article: Bone Joint J 2016;98-B:1604-10.

Attitudes of clinicians following large-scale pharmacogenomics implementation.

Clinician attitudes toward multiplexed genomic testing may be vital to the success of translational programs. We surveyed clinicians at an academic medical center about their views on a large pharmacogenomics implementation, the PREDICT (Pharmacogenomic Resource for Enhanced Decisions in Care and Treatment) program. Participants were asked about test ordering, major factors influencing use of results, expectations of efficacy and responsibility for applying results to patient care. Virtually all respondents (99%) agreed that pharmacogenomics variants influence patients' response to drug therapy. The majority (92%) favored immediate, active notification when a clinically significant drug-genome interaction was present. However, clinicians were divided on which providers were responsible for acting on a result when a prescription change was indicated and whether patients should be directly notified of a significant result. We concluded genotype results were valued for tailoring prescriptions, but clinicians do not agree on how to appropriately assign clinical responsibility for actionable results from a multiplexed panel.The Pharmacogenomics Journal advance online publication, 11 August 2015; doi:10.1038/tpj.2015.57.

Physician response to implementation of genotype-tailored antiplatelet therapy.

Physician responses to genomic information are vital to the success of precision medicine initiatives. We prospectively studied a pharmacogenomics implementation program for the propensity of clinicians to select antiplatelet therapy based on CYP2C19 loss-of-function variants in stented patients. Among 2,676 patients, 514 (19.2%) were found to have a CYP2C19 variant affecting clopidogrel metabolism. For the majority (93.6%) of the cohort, cardiologists received active and direct notification of CYP2C19 status. Over 12 months, 57.6% of poor metabolizers and 33.2% of intermediate metabolizers received alternatives to clopidogrel. CYP2C19 variant status was the most influential factor impacting the prescribing decision (hazard ratio [HR] in poor metabolizers 8.1, 95% confidence interval [CI] [5.4, 12.2] and HR 5.0, 95% CI [4.0, 6.3] in intermediate metabolizers), followed by patient age and type of stent implanted. We conclude that cardiologists tailored antiplatelet therapy for a minority of patients with a CYP2C19 variant and considered both genomic and nongenomic risks in their clinical decision-making.

The efficacy of allogeneic mesenchymal precursor cells for the repair of an ovine tibial segmental defect.

INTRODUCTION: Synthetic void-fillers offer an alternative to autograft or allograft bone in the repair of segmental defects. However, the reparative process is delayed as only osteoconductive elements are present. The inclusion of pluripotential cells may resolve this limitation, and the use of allogeneic tissue provides the opportunity for an off-the-shelf remedy. The current study evaluated the utilisation of mesenchymal precursor cells (MPC) for the repair of an ovine critical-size tibial segmental defect. METHODS: Twenty-four, mature female sheep underwent surgery for the creation of a 3 cm tibial diaphyseal defect. In one group of 12 sheep the scaffold was used alone, and in the second group the scaffold was seeded with MPC. The defect was stabilised using a locking intramedullary nail and allowed to heal over a nine-month-period. Outcome assessments of healing included radiology of callus formation, computed tomography, assessment of new-bone volume, mechanical attributes, and histological evaluation of linear bone apposition rate and tissue response. RESULTS: The MPC-treated group displayed a significantly greater level of callus formation and rate of bone apposition in the defect. DISCUSSION: The incorporation of allogeneic MPC to a synthetic void filler stimulated early repair of critical-size diaphyseal segmental defects and holds potential as an off-the-shelf therapy for augmenting bone regeneration.

The utilization of a synthetic bone void filler (JAX) in the repair of a femoral segmental defect.

OBJECTIVES: Currently available synthetic void fillers are indicated for bony voids or gaps that are not intrinsic to the stability of the structure. Jax TCP (tricalcium phosphate) is an osteoconductive bioceramic fabricated into 4 mm granules with a unique interlocking form, promoting structural integrity while allowing bone ingrowth. The objective of this study was to assess bone ingrowth using a large, critically sized, femoral defect. METHODS: A 5 cm segmental ostectomy was created in the mid-diaphysis of 16 adult ovine femora. A stainless steel intramedullary nail was introduced and locked with two proximal and two distal fully-threaded locking screws. Each defect was surrounded with a resorbable macroporous poly (L-lactide-co-D,L) lactide mesh acting as graft containment. Treatment groups (n = 4) were as follows: 1) Empty defect; 2) Morselized cortical bone; 3) Cortical strut; 4) Jax TCP. Serial radiographs were taken postoperatively and at two, four and six months. Femora retrieved at necropsy (six months) underwent computed tomography for volumetric analysis followed by histological assessment of the biological response. RESULTS: Little bone was apparent in the empty defect group, whereas significant bone was evident in both autograft groups and the Jax TCP group. Three-dimensional CT reconstructions and volumetric analysis were in close agreement with the radiographic findings. CLINICAL SIGNIFICANCE: Jax TCP bone graft substitute has been proven to be effective in the healing of a large, critically sized, contained segmental defect. The healing observed was superior to that of cortical struts and the new bone laid down had similar radio-opacity to autograft.

An evaluation of prosthetic femoral head impact on acetabular articular cartilage in a hemiarthroplasty model.

OBJECTIVES: The quantitation of the impact of hemiarthroplasty currently involves clinical outcome measures and radiographic evaluation. This study used in vivo and in vitro means in order to evaluate articular cartilage changes following hemiarthroplasty in the sheep. METHODS: Radiostereometric analysis (RSA) was utilized in order to quantitate migration (penetration) in vivo of the femoral head into the articular cartilage of the acetabulum. Dynamic stiffness of retrieved specimens was quantitated in vitro using a handheld device. Chondrocyte viability was assessed using live/dead cell staining and quantitated using image analysis techniques. Saffranin-O staining provided histological assessment of the cellular response to hemiarthroplasty. RESULTS: RSA showed rapid penetration of the femoral head into the acetabular cartilage over six months. Significantly higher levels of dynamic stiffness were observed in the acetabula following hemiarthroplasty. Confocal imagery highlighted changes in chondrocyte distribution and morphology. A loss of metachromasia, fibrovascular tissue invasion and apoptosis were observed histologically. CONCLUSIONS: RSA and measurement of the dynamic mechanical characteristics of cartilage provide a means of evaluating the development of degenerative articular cartilage changes in response to hemiarthroplasty.

Use of biodegradable urethane-based adhesives to appose meniscal defect edges in an ovine model: a preliminary study.

OBJECTIVE: To evaluate the biological response to two urethane-based adhesives used to repair full thickness meniscal wounds created in the partially vascularised (red-white) zone. DESIGN: An ovine bilateral meniscal defect model was used to evaluate the initial biological response of the meniscal cartilage and synovium over a 1-month period. A 10-mm full-thickness defect was created in the medial meniscus of each femorotibial joint. The defects were either left untreated or repaired using the urethane-based adhesives. Synovial fluid, synovial membrane and the meniscal cartilages were retrieved at necropsy for cytological and histological assessment. RESULTS: The ovine model proved to be a suitable system for examining meniscal repair. Untreated defects showed no tissue apposition or cellular healing response, whereas all eight defects repaired with the two urethane-based adhesive formulations showed signs of repair and tissue regeneration with indications of cell infiltration and new collagen deposition in and around the polymer. No adverse cellular response to the adhesives was observed in the meniscal defect or in the synovial membrane and fluid. CONCLUSION: Trauma to the knee commonly results in tears to the meniscal cartilage, with the majority of these occurring in the partially vascularised (red-white) or non-vascularised (white) zones of the meniscus. Repair, and subsequent healing, of these tears is poor because of the reduced vascularity and limited surgical access. The present data indicate that an ovine model is a suitable system for examining meniscal repair, and that development of urethane-based adhesives offers a strategy that may be clinically effective for the treatment of these injuries.

The influence of screw omission on construction stiffness and bone surface strain in the application of bone plates to cadaveric bone.

Biological fracture repair is becoming an increasingly popular means of fracture fixation. This technique involves a reduction in the amount of surgical trauma thereby preserving vascular supply and soft-tissue integrity combined with the implantation of less hardware. The aim is the stimulation of callus formation as the means by which fracture union occurs. This paper describes the mechanical effect of the symmetrical omission of screws on construction stiffness and bone surface strain following the application of bone plates to cadaveric bone. The influence of the pattern of screw omission was evaluated in both intact and osteotomized bone specimens. The application of bone plates using certain patterns of screw omission did not significantly effect the stiffness of the final construction whilst inherent bone surface strain was increased. It was concluded that the omission of screws in certain defined patterns for a given plate-bone construction may meet the criteria for 'biological fixation'. There was no apparent deleterious effect on structural stiffness following the omission of 40% of the total screw complement from a plate-bone construction.

Semi-quantitative assessment of tibial blood flow and distribution in response to surgical intervention using first pass radionuclide angiography and intravascular vital dye.

The acute vascular response in bone to surgical trauma was investigated utilizing a sheep model. Blood flow and distribution were determined using two methods; perfusion of the vasculature with an intravascular vital dye (Disulphine blue) prior to euthanasia and by radionuclide angiography (RNA) before and after each surgical intervention. The pattern of Disulphine blue distribution provided a good indication of local perfusion and response to surgical trauma (drilling holes). Radionuclide angiography provided a dynamic image of the vascular response to surgical trauma. The generation of time activity curves of the first pass of radionuclide bolus enabled calculation of the relative blood flow through selected regions. For both techniques areas of ischaemia were apparent which were directly related to the location of screw holes. We conclude that factors other than bone plate contact influence the ischaemia that develops in bone subsequent to the application of bone plates.

The influence of screw torque, object radius of curvature, mode of bone plate application and bone plate design on bone-plate interface mechanics.

Using Fuji Prescale Pressure Sensitive Film we evaluated the influence of screw torque, object radius of curvature, mode of bone plate application (compression or neutral loading) and bone plate design on bone-plate interface mechanics. Testing was performed using 4.5 mm and 3.5 mm dynamic compression (DC) (stainless steel) and limited contact-dynamic compression (LC-DC) plates (titanium). Plexiglass tubing, having different radii of curvature, was used to simulate bone but having more uniform geometric and structural properties. With the film interposed between the bone plate and the plexiglass, bone plates were applied at predetermined levels of screw torque. The resultant image was digitized and then underwent computer-assisted analysis to yield the interface contact area (%) and the average force (in Newtons N) between the bone plate and the object to which it was applied. In any given object, screw torque had the most significant influence on both interface contact area (P = 0.0001) and average force (P = 0.0001) at the interface. The bone plates responded differently to dynamization. The DC plate, when applied in compression loading mode, was lifted off the object between the two central screws when compared to the same plate applied in neutral loading mode (P = 0.0001). Conversely, in the LC-DC plate, an increase in the overall interface contact area was observed when applied in compression loading mode (P = 0.0002). At a given level of applied screw torque, the object radius of curvature appeared to be a major determining factor for interface contact area and average force (P = 0.0001, P = 0.0001). We conclude that variables other than bone plate design also influence the interface contact area and average force between a bone plate and object to which it is applied.

Bone plate fixation: an evaluation of interface contact area and force of the dynamic compression plate (DCP) and the limited contact-dynamic compression plate (LC-DCP) applied to cadaveric bone.

OBJECTIVES: To determine the effects of bone morphology on the interfacial mechanics of bone plate fixation. DESIGN: A comparison of two bone plate designs using measures of contact area and force in three conditions of bone type. INTERVENTION: The influence of bone plate design, bone type, and implant location on interfacial characteristics of contact area and average force were evaluated using pressure-sensitive film in cadaveric bone. Data were quantitated using computer-assisted image analysis. MAIN OUTCOME MEASUREMENTS: Means of the two dependent variables in each of the three conditions were compared using analysis of variance. RESULTS: In human femora and equine third metacarpi, there were no apparent differences in interface contact area attributed to bone plate design, although there were significant differences for interface contact force. In humeri, significant differences in both interface contact area and force were found between bone plate designs. CONCLUSIONS: Results show that bone surface topography and implant location are major determinants of the interfacial elements of contact area and average force between a plate and the bone to which it is applied.

Equine laminitis--another hypothesis for pathogenesis.

Laminitis is an important condition in horses and ponies, not just because of the seriousness of the clinical signs and systemic changes involved, but because of the potentially poor prognosis and likelihood of recurrence. Laminitis is particularly prevalent in ponies and involves a multiplicity of aetiological factors. Fat ponies and those having previously suffered laminitis were found to be far more intolerant to oral glucose loading (1 g/kg bwt) than normal ponies or Standardbred horses. These ponies also exhibited a far greater response in plasma insulin levels after glucose loading. Insulin response tests (0.4 iu/kg bwt insulin intravenously) showed only a minimal and very protracted response in both the fat and laminitic ponies establishing the existence of an apparently innate insulin insensitivity in these animals. These findings are important in regulation of carbohydrate and lipid metabolism and play a role in the pathogenesis of laminitis. The reduction of insulin effectiveness leads to elevation in thromboxane A2 activity, predisposing the animal to peripheral vasoconstriction, compromisation of blood flow to the foot and the development of laminitis.

Glucose tolerance and insulin sensitivity in ponies and Standardbred horses.

The existence of an innate insulin insensitivity in ponies was investigated and compared with the situation in larger breeds of horse. Ponies that were fat or had previously suffered laminitis were found to be far more intolerant to oral glucose loading (1 g/kg bodyweight [bwt]) than normal ponies or Standardbreds. These ponies also exhibited a far greater response in plasma insulin levels after glucose loading. Insulin response tests (0.4 iu/kg bwt insulin intravenously) showed only a minimal and very protracted response in both the fat and laminitic groups. The relevance of these findings in regulation of carbohydrate and lipid metabolism, and their role in the pathogenesis of hyperlipaemia, are discussed.