Clinical trials seen shifting overseas.

A Tufts University study released in mid-2003 indicates that increasing numbers of clinical trials for U.S.-produced pharmaceutical are being conducted outside the United States, mainly by contract research organizations. This process speeds up clinical trials, but raises ethical issues of the possible coercion or exploitation of more vulnerable and naive patient populations.     

Postoperative nomogram predicting the 10-year probability of prostate cancer recurrence after radical prostatectomy.

PURPOSE: A postoperative nomogram for prostate cancer recurrence after radical prostatectomy (RP) has been independently validated as accurate and discriminating. We have updated the nomogram by extending the predictions to 10 years after RP and have enabled the nomogram predictions to be adjusted for the disease-free interval that a patient has maintained after RP. METHODS: Cox regression analysis was used to model the clinical information for 1,881 patients who underwent RP for clinically-localized prostate cancer by two high-volume surgeons. The model was externally validated separately on two independent cohorts of 1,782 patients and 1,357 patients, respectively. Disease progression was defined as a rising prostate-specific antigen (PSA) level, clinical progression, radiotherapy more than 12 months postoperatively, or initiation of systemic therapy. RESULTS: The 10-year progression-free probability for the modeling set was 79% (95% CI, 75% to 82%). Significant variables in the multivariable model included PSA (P = .002), primary (P < .0001) and secondary Gleason grade (P = .0006), extracapsular extension (P < .0001), positive surgical margins (P = .028), seminal vesicle invasion (P < .0001), lymph node involvement (P = .030), treatment year (P = .008), and adjuvant radiotherapy (P = .046). The concordance index of the nomogram when applied to the independent validation sets was 0.81 and 0.79. CONCLUSION: We have developed and validated as a robust predictive model an enhanced postoperative nomogram for prostate cancer recurrence after RP. Unique to predictive models, the nomogram predictions can be adjusted for the disease-free interval that a patient has achieved after RP.     

18 Graduate Medical Education and Knowledge Translation: One Problem-Specific Approach in Residency

Traditional graduate medical education approaches to improving clinical performance based upon the latest research have included Journal Club and didactic lectures. Unfortunately, these educational interventions have rarely been demonstrated to change practice behavior or improve patient-important outcomes. Using a structured approach to identifying a gap between best-evidence knowledge and clinical practice, an illustrative one-year residency-wide translational research project was developed in a four year emergency medicine training program. Step one (assigned to the second year residents): identify and quantitatively justify a Knowledge Translation (KT) deficit within our institution. They identified steroids in adult bacterial meningitis as an unequivocal therapeutic option. Based upon a structured one-year chart review, they next demonstrated that only 7% of meningitis patients received pre-antimicrobial steroids. The next step (assigned to the first year residents): identify and quantify the physician "leaks" within the pipeline of information from publication to bedside utilization via an online survey. The third year residents hypothesized plugs for these information leaks, including examples of other specialties or institutions which have successfully navigated this specific clinical scenario. Finally, at an end-of-year Journal Club, the fourth year residents formulated a protocol for the appropriate use of steroids in suspected adult meningitis and brought together individuals from within the institution contributing to the best-practice leak. Knowledge Translation involves multiple stages beyond simple evidence awareness and usually involves continuation beyond the emergency department. The Washington University KT project offers a structured, multidisciplinary example of moving beyond contemplation to implementation of an unequivocal therapy.     

Selective dorsal rhizotomy: long-term experience from Cape Town

Introduction Given the large number of cerebral palsy patients who have undergone selective dorsal rhizotomy in the past two decades, it is clearly imperative that the clinical community be provided with objective and compelling evidence of the long-term sequelae of the procedure. Materials and methods In the early 1980s, Peacock in Cape Town shifted the site of the rhizotomy from the conus medullaris to the cauda equina, and in the past 25 years, more than 200 children have been operated on. We have studied the incidence of spinal deformities after multiple-level laminectomy and recorded a 20% incidence of isthmic spondylolysis or grade-I spondylolisthesis. We have also conducted a long-term prospective gait analysis study on a cohort of 14 ambulatory patients who were operated on in 1985. Results Ten years after surgery, our patients had increased ranges of motion that were within normal limits. Step length was significantly improved, although cadence was unchanged postoperatively and was significantly less than normal age-matched control subjects. Discussion We have recently tracked down all 14 patients from the original cohort and are currently completing a 20-year prospective follow-up analysis of their neuromuscular function and gait. Our preliminary data suggest that selective dorsal rhizotomy is not only an effective method for alleviating spasticity but it also leads to long-term functional benefits.     

Linear and angular measurements of computer-generated models: are they accurate, valid, and reliable?

INTRODUCTION: Traditional advanced imaging modalities such as CT and MRI are limited in their ability to perform accurate linear distance and angular measurements regardless of anatomical orientation. The construction of 3D models has been used to perform anthropometric analyses as well as in the reconstruction of rapid prototypes. We hypothesized that such measurements would be precise to within 2 mm or 2 degrees of measurements performed with a coordinate measurement machine (CMM). We also hypothesized that there would be a high degree of interobserver reliability with these measurements. MATERIALS AND METHODS: Multiple aluminum screws were implanted in various positions in three foam pelvises which were subsequently scanned by CT and rendered as 3D models using a commercially available software package (Mimics). Linear and angular measurements were performed using a CMM machine, the software package, and a dial caliper or goniometer. The deviation of the measurements from the CMM data was compared using ANOVA. The interobserver reliability of both the manual and computer-generated measurements was calculated. RESULTS: The mean difference between the CMM distances and those measured manually and with the software was 2.12 +/- 1.20 mm and 1.57 +/- 1.05 mm, respectively. The mean difference between the CMM angular measurements and the angular measurements performed manually and with the software was 4.07 +/- 4.70 degrees and 1.62 +/- 1.32 degrees, respectively. In all cases, the manual measurements were significantly less accurate (p < 0.0001) and there was a high degree of interobserver reliability. CONCLUSIONS: Computer-generated measurements taken from three-dimensionally reconstructed models are more accurate than manual measurements and are within 2 mm and 2 degrees of measurements performed with a CMM. These measurements have high interobserver reliability.     

Association between the HOXA1 A218G polymorphism and increased head circumference in patients with autism.

BACKGROUND: The HOXA1 gene plays a major role in brainstem and cranial morphogenesis. The G allele of the HOXA1 A218G polymorphism has been previously found associated with autism. METHODS: We performed case-control and family-based association analyses, contrasting 127 autistic patients with 174 ethnically matched controls, and assessing for allelic transmission disequilibrium in 189 complete trios. RESULTS: A, and not G, alleles were associated with autism using both case-control (chi(2) = 8.96 and 5.71, 1 df, p <.005 and <.025 for genotypes and alleles, respectively), and family-based (transmission/disequilibrium test chi(2) = 8.80, 1 df, p <.005) association analyses. The head circumference of 31 patients carrying one or two copies of the G allele displayed significantly larger median values (95.0th vs. 82.5th percentile, p <.05) and dramatically reduced interindividual variability (p <.0001), compared with 166 patients carrying the A/A genotype. CONCLUSIONS: The HOXA1 A218G polymorphism explains approximately 5% of the variance in the head circumference of autistic patients and represents to our knowledge the first known gene variant providing sizable contributions to cranial morphology. The disease specificity of this finding is currently being investigated. Nonreplications in genetic linkage/association studies could partly stem from the dyshomogeneous distribution of an endophenotype morphologically defined by cranial circumference.