A National Survey of Orthopaedic Residents Identifies Deficiencies in the Understanding of Medical Statistics.

BACKGROUND: Biomedical research is essential for optimizing patient care. Research has suggested inadequacies in nonorthopaedic trainees' understanding of study design and biostatistics. This study assesses orthopaedic residents' knowledge of common biostatistical and study design concepts, as well as their confidence in utilizing the medical literature. METHODS: A validated survey assessing knowledge and the application of study design concepts was administered to residents at 10 U.S. institutions. The survey tested knowledge as well as confidence and attitudes regarding common biostatistics principles. The association of demographic characteristics, work activities, and confidence and attitude ratings with test performance were examined using t tests and analysis of variance. RESULTS: The survey response rate was 64% (178 of 279). The largest group of participants were men (83%, 137 of 165), were between the ages of 26 and 30 years (59%, 105 of 177), and had graduated medical school within the past 4 to 10 years (43%, 76 of 175). Fifty-three percent (93 of 176) had prior biostatistics training, while 44% (77 of 176) had prior epidemiology training. Less than 5% of biostatistics or epidemiology training had taken place after medical school. Forty-seven percent (83 of 176) were unable to determine a study's design. Thirty-eight percent (67 of 178) could not apply the concept of specificity and sensitivity. Eighty-three percent (147 of 178) could not assess the strength of a relationship using odds ratios. Sixty-nine percent (123 of 178) understood the implications of p values. Previous biostatistics training, but not epidemiology or evidence-based medicine training; inclusion of reading research, attending conferences, and data analysis; as well as a self-reported finding of statistics as important for the analysis of one's own research data were significantly associated with better test performance (p < 0.05). CONCLUSIONS: Notable deficits exist in orthopaedic residents' biostatistical knowledge. Greater emphasis is needed to improve biostatistics and research design training. The impact of biostatistics knowledge and/or aptitude on clinical decision-making is an area of suggested research.

Medicaid Managed Care Structures and Care Coordination.

BACKGROUND: Child enrollment in Medicaid managed care (MMC) has expanded dramatically, primarily through state mandates. Care coordination is a key metric in MMC evaluation because it drives much of the proposed cost savings and may be associated with improved health outcomes and utilization. We evaluated the relationships between enrollment in 2 MMC structures, primary care case management (PCCM) and health maintenance organization (HMO) and access to and receipt of care coordination by children. METHODS: Using data from the 2011/2012 National Survey of Children's Health and the Medicaid Statistical Information System state data mart, we conducted a retrospective, cross-sectional analysis of the relationships between fee-for-service, PCCM or HMO enrollment, and access to and receipt of care coordination. State-level univariate analyses and individual and state multilevel multivariable analyses evaluated correlations between MMC enrollment and care coordination, controlling for demographic characteristics and state financing levels. RESULTS: In univariate and multilevel multivariable analyses, the PCCM penetration rate was significantly associated with increased access to care coordination (adjusted odds ratio: 1.23, P = .034) and receipt of care coordination (adjusted odds ratio: 1.37, P = .02). The HMO penetration rate was significantly associated with lower access to care coordination (adjusted odds ratio: 0.85, P = .05) and receipt of care coordination (adjusted odds ratio: 0.71, P < .001). Fee-for-service served as the referent. CONCLUSIONS: State utilization of MMC varied widely. These data suggest that care coordination may be more effective in PCCM than HMO structures. States should consider care coordination outcomes when structuring their Medicaid programs.

Association of Lymph Node Count and Overall Survival in Node-Negative Endometrial Cancers.

Purpose: To estimate whether the number of lymph nodes removed during surgery is associated with overall survival among women with endometrial cancer. Methods: We performed a retrospective cohort study of women with node-negative, stage I to IIIB endometrial cancer (n = 152,702) identified from the 1998-2011 National Cancer Database. Multivariable Cox proportional hazards regression tested for an association of lymph node count with survival. Restricted mean survival and relative hazard curves were plotted for survival as a function of number of removed lymph nodes. Results: Among women with node-negative endometrioid endometrial cancer, for each additional five lymph nodes removed, the hazard for death decreased: stage I, the hazard ratio (HR) was 0.95 (95% CI, 0.93 to 0.97; P < .001), stage II, HR was 0.90 (95% CI, 0.87 to 0.94; P < .001); and stage IIIA-B, HR was 0.92 (95% CI, 0.88 to 0.96; P < .001). When grouped by grade, each additional five lymph nodes removed was also associated with decreased hazard for death: grade 1, HR was 0.96 (95% CI, 0.93 to 0.99; P = .009); grade 2,HR was0.91 (95%CI, 0.89 to0.94; P <.001);and grade 3,HR was 0.95 (95%CI, 0.92 to 0.97; P <.001). Increased lymph node dissection was also associated with increased survival among women with node-negative stage II (HR, 0.92; 95% CI, 0.86 to 0.98; P = .01) or stage IIIA-B (HR, 0.94; 95% CI, 0.89 to 0.99; P = .025) uterine serous carcinoma, but not among women with carcinosarcoma or clear cell adeno-carcinoma. Five-year survival for women with one to four nodes removed and endometrioid or serous histology was 85% (95% CI, 84% to 85%) and 54% (95% CI, 50% to 59%), respectively. Five-year survival was significantly higher for women with ≥ 20 removed nodes and endometrioid (91%; 95% CI, 90% to 91%) or serous (72%; 95% CI, 68% to 76%) histology (P < .001). Conclusion: Increased lymph node count is associated with a 1% to 14% decreased hazard of death per each additional five lymph nodes removed and a 5% to 20% increased 5-year survival among women with pathologically node-negative endometrioid and serous endometrial cancers.

Evolvix BEST Names for semantic reproducibility across code2brain interfaces.

Names in programming are vital for understanding the meaning of code and big data. We define code2brain (C2B) interfaces as maps in compilers and brains between meaning and naming syntax, which help to understand executable code. While working toward an Evolvix syntax for general-purpose programming that makes accurate modeling easy for biologists, we observed how names affect C2B quality. To protect learning and coding investments, C2B interfaces require long-term backward compatibility and semantic reproducibility (accurate reproduction of computational meaning from coder-brains to reader-brains by code alone). Semantic reproducibility is often assumed until confusing synonyms degrade modeling in biology to deciphering exercises. We highlight empirical naming priorities from diverse individuals and roles of names in different modes of computing to show how naming easily becomes impossibly difficult. We present the Evolvix BEST (Brief, Explicit, Summarizing, Technical) Names concept for reducing naming priority conflicts, test it on a real challenge by naming subfolders for the Project Organization Stabilizing Tool system, and provide naming questionnaires designed to facilitate C2B debugging by improving names used as keywords in a stabilizing programming language. Our experiences inspired us to develop Evolvix using a flipped programming language design approach with some unexpected features and BEST Names at its core.

Simulation Training for Forceps-Assisted Vaginal Delivery and Rates of Maternal Perineal Trauma.

OBJECTIVE: To evaluate the association of a forceps simulation training curriculum for obstetrics residents on rates of severe perineal lacerations after forceps deliveries. METHODS: This was a retrospective cohort study. We created a novel simulation curriculum for forceps-assisted vaginal delivery based on the best practices of local experts, and trained all residents beginning in 2013. We then retrospectively reviewed all forceps deliveries performed in the 2.5 years after initiation of the training and the 7.5 years before the training program. We identified patients who experienced a severe perineal laceration (third- or fourth-degree) and examined the relationship of resident training status and perineal laceration. Known risk factors for lacerations were identified and a multilevel multivariable model was created including these factors as well as resident training. RESULTS: During the study period, we identified 6,058 forceps-assisted vaginal deliveries. We examined temporal trends in rates of forceps of severe perineal laceration. We identified a decrease in severe lacerations between 2005 and 2008, ending 5 years before the initiation of the training curriculum. These years were censored from the data, yielding a baseline observational period of 4,279 deliveries with no significant trend in laceration rate. Univariate analysis reveals a 22% reduction in severe perineal laceration (odds ratio [OR] 0.78; P=.005) among women delivered by residents who had completed forceps simulation training compared with women delivered by residents who had not. After adjusting for known maternal and delivery risk factors for perineal laceration, the magnitude of the reduction increased to 26% in the full data set model (OR 0.74; P=.002). CONCLUSION: A forceps simulation curriculum for obstetrics residents was associated with a significant reduction in severe perineal lacerations.

Targeting the Wnt/ß-catenin pathway in primary ovarian cancer with the porcupine inhibitor WNT974.

Preclinical studies in ovarian cancer have demonstrated upregulation of the Wnt/ß-catenin pathway promoting tumor proliferation and chemoresistance. Our objective was to evaluate the effect of the Wnt/ß-catenin pathway inhibitor, WNT974, in primary ovarian cancer ascites cells. Ascites cells from patients with papillary serous ovarian cancer were isolated and treated with 1 µM WNT974±100 µM carboplatin. Viability was evaluated with the ATPlite assay. The IC50 was calculated using a dose-response analysis. Immunohistochemistry (IHC) was performed on ascites cells and tumor. Expression of R-spondin 2 (RSPO2), RSPO3, PORCN, WLS, AXIN2, and three previously characterized RSPO fusion transcripts were assessed using Taqman assays. Sixty ascites samples were analyzed for response to WNT974. The ascites samples that showed a decrease in ATP concentration after treatment demonstrated no difference from the untreated cells in percent viability with trypan blue staining. Flow cytometry demonstrated fewer cells in the G2 phase and more in the G1 and S phases after treatment with WNT974. Combination therapy with WNT974 and carboplatin resulted in a higher percentage of samples that showed ≥30% reduction in ATP concentration than either single drug treatment. IHC analysis of Wnt pathway proteins suggests cell cycle arrest rather than cytotoxicity after WNT974 treatment. QPCR indicated that RSPO fusions are not prevalent in ovarian cancer tissues or ascites. However, higher PORCN expression correlated to sensitivity to WNT974 (P=0.0073). In conclusion, WNT974 produces cytostatic effects in patient ascites cells with primary ovarian cancer through inhibition of the Wnt/ß-catenin pathway. The combination of WNT974 and carboplatin induces cytotoxicity plus cell cycle arrest in a higher percentage of ascites samples than with single drug treatment. RSPO fusions do not contribute to WNT974 sensitivity; however, higher PORCN expression indicates increased WNT974 sensitivity.

Accelerated approval of cancer drugs: improved access to therapeutic breakthroughs or early release of unsafe and ineffective drugs?

PURPOSE: Accelerated approval (AA) was initiated by the US Food and Drug Administration (FDA) to shorten development times of drugs for serious medical illnesses. Sponsors must confirm efficacy in postapproval trials. Confronted with several drugs that received AA on the basis of phase II trials and for which confirmatory trials were incomplete, FDA officials have encouraged sponsors to design AA applications on the basis of interim analyses of phase III trials. METHODS: We reviewed data on orphan drug status, development time, safety, and status of confirmatory trials of AAs and regular FDA approvals of new molecular entities (NMEs) for oncology indications since 1995. RESULTS: Median development times for AA NMEs (n = 19 drugs) and regular-approval oncology NMEs (n = 32 drugs) were 7.3 and 7.2 years, respectively. Phase III trials supported efficacy for 75% of regular-approval versus 26% of AA NMEs and for 73% of non-orphan versus 45% of orphan drug approvals. AA accounted for 78% of approvals for oncology NMEs between 2001 and 2003 but accounted for 32% in more recent years. Among AA NMEs, confirmatory trials were nine-fold less likely to be completed for orphan drug versus non-orphan drug indications. Postapproval, black box warnings were added to labels for four oncology NMEs (17%) that had received AA and for two oncology NMEs (9%) that had received regular approval. CONCLUSION: AA oncology NMEs are safe and effective, although development times are not accelerated. A return to endorsing phase II trial designs for AA for oncology NMEs, particularly for orphan drug indications, may facilitate timely FDA approval of novel cancer drugs.