Discovery and optimization of a highly efficacious class of 5-aryl-2-aminopyridines as FMS-like tyrosine kinase 3 (FLT3) inhibitors.

Based on a putative binding mode of quizartinib (AC220, 1), a potent FMS-like tyrosine kinase 3 (FLT3) inhibitor in Phase III clinical development, we have designed de novo a simpler aminopyridine-based hinge binding motif. Further optimization focusing on maximizing in vivo efficacy and minimizing CYP3A4 time-dependent inhibition resulted in a highly efficacious compound (6s) in tumor xenograft model for further preclinical development.

Discordance between patient and surgeon satisfaction after total joint arthroplasty.

We surveyed 331 patients undergoing total hip or knee arthroplasty pre-operatively, and patients and surgeons were both surveyed 6 and 12 months post-operatively. We identified variables (demographic factors, operative factors and patient expectations) as possible predictors for discordance in patient-surgeon satisfaction. At 12 months, 94.5% of surgeons and 90.3% of patients recorded satisfaction with the outcome. The discordance between patient and surgeon satisfaction was mainly due to patient dissatisfaction-surgeon satisfaction. In an adjusted analysis, the strongest predictors of discordance in patient-surgeon satisfaction were unmet patient expectations and the presence of complications. Advice to potential joint arthroplasty candidates regarding the decision to proceed with surgery should be informed by patient reported outcomes, rather than the surgeon's opinion of the likelihood of success.

Satisfaction with joint replacement in public versus private hospitals: a cohort study.

INTRODUCTION: In Australia, the majority of total knee and hip replacement surgeries occur in the private sector. Outcome-based research needs to be inclusive of this sector if the findings are intended to reflect the broader picture. This study compares outcomes up to 1 year post knee and hip replacement between patients treated in the public and private sectors. METHODS: A prospective, observational study was performed in four high-volume joint replacement centres: two public, two private. Experienced orthopaedic surgeons contributed via their public and private practices. Knee and hip patients were recruited preoperatively. Self-reported questionnaires were completed preoperatively and at 6 and 12 months post-operatively. The primary outcome was satisfaction with surgery. Secondary outcomes included Oxford score, and SF-36 physical and mental component summary scores. Regression modelling was performed to adjust for potential confounders. RESULTS: Three hundred and thirty-one patients (184 public, 147 private; 215 knees, 116 hips) were recruited, with 6- and 12-month follow-up rates of 95% and 89%, respectively. Satisfaction rates were high in both public and private patients (approximately 90%) at 6 and 12 months, but private patients were less likely to be satisfied after adjusting for the strong effect of patient expectation. For both hip and knee cohorts, no between-sector differences were found in either the magnitude or rate of improvement in Oxford score or quality of life post-operatively. DISCUSSION: Joint replacement outcomes are similar for patients treated in public and private hospitals. Surgeons should manage patient expectation prior to surgery, particularly in private patients.

Pulsed electromagnetic field stimulation for acute tibial shaft fractures: a multicenter, double-blind, randomized trial.

BACKGROUND: Tibial shaft fractures are sometimes complicated by delayed union and nonunion, necessitating further surgical interventions. Pulsed electromagnetic field stimulation is an effective treatment for delayed unions and nonunions, but its efficacy in preventing healing complications in patients with acute fractures is largely untested. The purpose of this pragmatic trial was to determine whether adjuvant pulsed electromagnetic field therapy for acute tibial shaft fractures reduces the rate of surgical revision because of delayed union or nonunion. METHODS: In a double-blind randomized trial involving six metropolitan trauma hospitals, 259 participants with acute tibial shaft fractures (AO/OTA type 42) were randomized by means of external allocation to externally identical active and inactive pulsed electromagnetic field devices. Participants were instructed to wear the device for ten hours daily for twelve weeks. Management was otherwise unaltered. The primary outcome was the proportion of participants requiring a secondary surgical intervention because of delayed union or nonunion within twelve months after the injury. Secondary outcomes included surgical intervention for any reason, radiographic union at six months, and the Short Form-36 Physical Component Summary and Lower Extremity Functional Scales at twelve months. Main analyses were by intention to treat. RESULTS: Two hundred and eighteen participants (84%) completed the twelve-month follow-up. One hundred and six patients were allocated to the active device group, and 112 were allocated to the placebo group. Compliance was moderate, with 6.2 hours of average daily use. Overall, sixteen patients in the active group and fifteen in the inactive group experienced a primary outcome event (risk ratio, 1.02; 95% confidence interval, 0.95 to 1.14; p = 0.72). According to per-protocol analysis, there were six primary events (12.2%) in the active, compliant group and twenty-six primary events (15.1%) in the combined placebo and active, noncompliant group (risk ratio, 0.97; 95% confidence interval, 0.86 to 1.10; p = 0.61). No between-group differences were found with regard to surgical intervention for any reason, radiographic union, or functional measures. CONCLUSIONS: Adjuvant pulsed electromagnetic field stimulation does not prevent secondary surgical interventions for delayed union or nonunion and does not improve radiographic union or patient-reported functional outcomes in patients with acute tibial shaft fractures.

Novel series of pyrrolotriazine analogs as highly potent pan-Aurora kinase inhibitors.

The synthesis and SAR for a novel series of pyrrolotriazines as pan-Aurora kinase inhibitors are described. Optimization of the cyclopropane carboxamide terminus of lead compound 1 resulted in analogs with high cellular activity and improved rat PK profiles. Notably, compound 17l demonstrated tumor growth inhibition in a mouse xenograft model.

Trends of spinal fusion surgery in Australia: 1997 to 2006.

BACKGROUND: This study aims to explore the trend in spine fusion surgery in Australia over the past 10 years, and to explore the possible influence of health insurance status (private versus public) on the rate of surgery. METHODS: Data pertaining to the rate of lumbar spine fusion from 1997 to 2006 were collected from Inpatient Statistics Collection of NSW Health, Medicare Australia Statistics and the Australian Bureau of Statistics. Data on total hip and total knee arthroplasties were collected to provide a comparator. RESULTS: The number of publicly performed spinal fusion procedures increased by 2% from 1997 to 2006. In comparison, privately performed spinal fusion procedures increased by 167% over the same 10-year period. In 2006, spine fusion surgery was 10.8 times more likely to be done in the private sector than in the public sector, compared with corresponding figures of 4.2 times and 3.0 times for knee replacement and hip replacement, respectively. Waiting list data showed no increase in demand for spine fusion surgery in the public sector. CONCLUSION: There is a disproportionately high rate of lumbar spine fusion surgery performed in the private sector, given the rate of private insurance. The rate of increase was found to be higher than that for hip or knee arthroplasty procedures. Possible explanations for this difference include: over-servicing in the private sector, under-servicing in the public sector, differences in medical referral patterns, surgeon and patient preferences and financial incentives.

Predictors of patient and surgeon satisfaction after orthopaedic trauma.

INTRODUCTION: Patient satisfaction has only recently gained attention as an outcome measure in orthopaedics, where it has been reported for joint replacement surgery. Little has been published regarding predictors of patient satisfaction in orthopaedic trauma. This study aims to explore the predictors of patient satisfaction, and of surgeon satisfaction, after orthopaedic trauma. MATERIALS AND METHODS: Adult patients admitted to hospital with fractures after motor vehicle trauma were surveyed on admission, and at six months. Demographic, injury, socio-economic and compensation-related factors were measured. The two outcomes were satisfaction with progress of the injury, and satisfaction with recovery. The treating surgeons were also surveyed at six months to determine surgeon satisfaction with progress, and recovery (using the same questions), and the presence or absence of fracture union and any complications. Multivariate analysis was used to determine significant predictors of satisfaction for both groups, and satisfaction rates were compared between surgeons and patients. RESULTS: Of 306 patients recruited, 232 (75.8%) returned completed questionnaires, but only 141 (46.1%) surgeons responded. Patients rated their satisfaction with progress and recovery as 74.6% and 44.4%, respectively, whereas surgeon-rated satisfaction with progress and recovery was significantly higher, at 88.0% and 66.7%, respectively (p<0.0001). Significant predictors of patient dissatisfaction were: blaming others for the injury, being female, and using a lawyer. Patient-rated satisfaction was not significantly associated with objective injury or treatment factors. The only significant predictor of surgeon dissatisfaction was fracture non-union. CONCLUSIONS: Orthopaedic surgeons overestimated the progress of the injury and the level of recovery compared to patients' own ratings. Surgeons' ratings were influenced by objective, treatment-related factors, whereas patients' ratings were not. Measures of outcome commonly used by orthopaedic surgeons, such as fracture union, do not predict patient satisfaction.

Factors predicting patient satisfaction following major trauma.

INTRODUCTION: Patient satisfaction is an intuitively important outcome measure and has been previously linked to general health status. Previous research on patient satisfaction after injury has concentrated on satisfaction with medical care. This study aims to explore possible predictors of patient satisfaction with outcome following major trauma. METHODS: A cross-sectional survey involving consecutive adult patients involved in major accidental trauma from a major metropolitan trauma centre, over a 5-year period, was performed between 1 and 6 years post-injury. The outcome used was patient satisfaction with progress since the injury. Multiple logistic regression was used to develop a model of significant predictors of patient satisfaction. RESULTS: The survey was mailed to 728 eligible patients, 56 were excluded due to death or inability to complete the survey, 93 refused to participate and 90 were not contactable. One hundred and thirty-four patients did not respond and 355 completed surveys were returned. Patient dissatisfaction was found to be significantly associated with unemployment at the time of follow up (OR, 2.38; 95% CI, 1.38-4.08; p=0.004), having one or more chronic illnesses at the time of injury (OR, 2.57; 95% CI, 1.45-4.55; p=0.001), being involved in a motor vehicle accident (OR, 1.83; 95% CI, 1.02-3.30; p=0.04) and having an unsettled compensation claim (OR, 5.19; 95% CI, 2.80-9.65; p<0.0001). Patient satisfaction was not significantly associated with any measure of injury severity. CONCLUSIONS: Having an unsettled compensation claim after major trauma is the strongest predictor of patient dissatisfaction following major trauma, allowing for other factors.

Targeted disruption of RC3 reveals a calmodulin-based mechanism for regulating metaplasticity in the hippocampus.

We used homologous recombination in the mouse to knock-out RC3, a postsynaptic, calmodulin-binding PKC substrate. Mutant brains exhibited lower immunoreactivity to phospho-Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) but had the same synaptic density as wild type and did not exhibit a gross neuroanatomical phenotype. Basal excitatory synaptic transmission in CA1 was depressed, long-term potentiation (LTP) was enhanced, and the depressant effects of the metabotropic glutamate receptor (mGluR) agonist (RS)-3,5-dihydroxyphenylglycine was occluded compared with littermate controls. The frequency-response curve was displaced to the left, and long-term depression (LTD) could not be induced unless low-frequency stimuli were preceded by high-frequency tetani. Depotentiation was much more robust in the mutant, and only one stimulus was required to saturate LTD in primed mutant hippocampi, whereas multiple low-frequency stimuli were required in wild-type slices. Thus, ablation of RC3 appears to render the postsynaptic neuron hypersensitive to Ca(2+), decreasing its LTD and LTP thresholds and accentuating the effects of priming stimuli. We propose an mGluR-dependent CaM-based sliding threshold mechanism for metaplasticity that is governed by the phosphorylation states of RC3 and CaMKII.