Background: Tibial shaft fractures are the most common long-bone injury, with a reported annual incidence of more than 75 000 in the United States. This study aimed to determine whether patients with ...tibial fractures managed with intramedullary nails experience a lower rate of reoperation if treated at higher-volume hospitals, or by higher-volume or more experienced surgeons. Methods: The Study to Prospectively Evaluate Reamed Intramedullary Nails in Patients with Tibial Fractures (SPRINT) was a multicentre randomized clinical trial comparing reamed and nonreamed intramedullary nailing on rates of reoperation to promote fracture union, treat infection or preserve the limb in patients with open and closed fractures of the tibial shaft. Using data from SPRINT, we quantified centre and surgeon volumes into quintiles. We performed analyses adjusted for type of fracture (open v. closed), type of injury (isolated v. multitrauma), gender and age for the primary outcome of reoperation using multivariable logistic regression. Results: There were no significant differences in the odds of reoperation between high-and low-volume centres (p = 0.9). Overall, surgeon volume significantly affected the odds of reoperation (p = 0.03). The odds of reoperation among patients treated by moderate-volume surgeons were 50% less than those among patients treated by very-low-volume surgeons (odds ratio OR 0.50, 95% confidence interval CI 0.28-0.88), and the odds of reoperation among patients treated by high-volume surgeons were 47% less than those among patients treated by very-low-volume surgeons (OR 0.53, 95% CI 0.30-0.93). Conclusion: There appears to be no significant additional patient benefit in treatment by a higher-volume centre for intramedullary fixation of tibial shaft fractures. Additional research on the effects of surgical and clinical site volume in tibial shaft fracture management is needed to confirm this finding. The odds of reoperation were higher in patients treated by very-low-volume surgeons; this finding may be used to optimize the results of tibial shaft fracture management. Clinical trial registration: ClinicalTrials.gov, NCT00038129 Contexte: La fracture de la diaphyse tibiale est la plus commune des fractures des os longs, avec une incidence annuelle declaree de plus 75 000 cas aux Etats-Unis. Cette etude visait a determiner si les patients traites par enclouage intra-medullaire pour une fracture du tibia sont moins souvent reoperes quand l'intervention est effectuee dans des etablissements qui traitent de plus forts volumes de cas ou par des chirurgiens operant un plus fort volume de cas ou plus experimentes. Methodes: L'etude SPRINT (Study to Prospectively Evaluate Reamed Intramedullary Nails in Patients with Tibial Fractures) est un essai clinique multicentrique randomise qui a compare l'effet de l'enclouage alese c. non alese sur le taux des reinterventions visant a promouvoir la consolidation osseuse de la fracture, a traiter une infection ou a preserver le membre chez des patients victimes de fractures fermees ou ouvertes de la diaphyse tibiale. A partir des donnees de l'etude SPRINT, nous avons classe les etablissements et les chirurgiens en quintiles selon les volumes de cas traites. Nous avons effectue des analyses ajustees en fonction du type de fracture (ouverte c. fermee), du type de blessure (isolee c. polytraumatisme), du sexe et de l'age, pour etablir le taux de reintervention (parametre principal), en utilisant la regression logistique multivariee. Resultats: On n'a note aucune difference significative quant au risque de reinter-vention entre les centres qui traitaient des volumes eleves c. bas (p = 0,9). Dans l'ensemble le volume d'operations des chirurgiens a significativement influe sur le risque de reintervention (p = 0,03). Le risque de reintervention chez les patients traites par des chirurgiens dont le volume d'interventions etait moyen etait de 50 % de moins que chez les patients traites par des chirurgiens dont le volume etait tres bas (risque relatif RR 0,50, intervalle de confiance IC a 95 % 0,28-0,88) et le risque de reinter-vention chez les patients traites par des chirurgiens dont le volume etait tres eleve etait de 47 % de moins que chez les patients traites par des chirurgiens dont le volume etait tres bas (RR 0,53, IC a 95 % 0,30-0,93). Conclusion: Il ne semble y avoir aucun bienfait additionnel significatif au fait d'etre opere dans un centre ou le volume d'interventions pour enclouage intra-medullaire des fractures de la diaphyse tibiale est eleve. Il faudra approfondir la recherche sur les effets du volume chirurgical et de l'experience clinique des etablissements pour confirmer cette observation. Le risque de reintervention a ete plus eleve chez les patients traites par des chirurgiens dont le volume d'interventions etait tres bas; cette observation pourrait etre utilisee pour optimiser l'issue du traite-ment des fractures de la diaphyse tibiale. Enregistrement de l'essai clinique: ClinicalTrials.gov, NCT00038129.
Abstract Secondary endpoints (SEPs) provide crucial information in the interpretation of clinical trials, but their features are not yet well understood. Thus, we sought to empirically characterize ...the scope and publication rate of SEPs among late-phase oncology trials. We assessed SEPs for each randomized, published phase III oncology trial across all publications and ClinicalTrials.gov, performing logistic regressions to evaluate associations between trial characteristics and SEP publication rates. After screening, a total of 280 trials enrolling 244,576 patients and containing 2,562 SEPs met inclusion criteria. Only 22% of trials (62/280) listed all SEPs consistently between ClinicalTrials.gov and the trial protocol. The absolute number of SEPs per trial increased over time, and trials sponsored by industry had a greater number of SEPs (median 9 vs 5 SEPs per trial, P < 0.0001). In total, 69% of SEPs (1770/2562) were published. The publication rate significantly varied by SEP category Χ2(5, N = 2562) = 245.86, p < 0.001. SEPs that place the greatest burden on patients, patient-reported outcomes and translational correlatives, were published at 63% (246/393) and 44% (39/88) respectively. Trials with more SEPs were associated with lower publication rates. Overall, our findings are that SEP publication rates in late-phase oncology trials are highly variable based on type of SEP. To avoid undue burden on patients and promote transparency of findings, trialists should weigh the biologic and clinical relevance of each SEP with its feasibility at the time of trial design.
Primary end point (PEP) changes to an active clinical trial raise questions regarding trial quality and the risk of outcome reporting bias. It is unknown how the frequency and transparency of the ...reported changes depend on reporting method and whether the PEP changes are associated with trial positivity (ie, the trial met the prespecified statistical threshold for PEP positivity).
To assess the frequency of reported PEP changes in oncology randomized clinical trials (RCTs) and whether these changes are associated with trial positivity.
This cross-sectional study used publicly available data for complete oncology phase 3 RCTs registered in ClinicalTrials.gov from inception through February 2020.
The main outcome was change between the initial PEP and the final reported PEP, assessed using 3 methods: (1) history of tracked changes on ClinicalTrials.gov, (2) self-reported changes noted in the article, and (3) changes reported within the protocol, including all available protocol documents. Logistic regression analyses were performed to evaluate whether PEP changes were associated with US Food and Drug Administration approval or trial positivity.
Of 755 included trials, 145 (19.2%) had PEP changes found by at least 1 of the 3 detection methods. Of the 145 trials with PEP changes, 102 (70.3%) did not have PEP changes disclosed within the manuscript. There was significant variability in rates of PEP detection by each method (χ2 = 72.1; P < .001). Across all methods, PEP changes were detected at higher rates when multiple versions of the protocol (47 of 148 31.8%) were available compared with 1 version (22 of 134 16.4%) or no protocol (76 of 473 16.1%) (χ2 = 18.7; P < .001). Multivariable analysis demonstrated that PEP changes were associated with trial positivity (odds ratio, 1.86; 95% CI, 1.25-2.82; P = .003).
This cross-sectional study revealed substantial rates of PEP changes among active RCTs; PEP changes were markedly underreported in published articles and mostly occurred after reported study completion dates. Significant discrepancies in the rate of detected PEP changes call into question the role of increased protocol transparency and completeness in identifying key changes occurring in active trials.
As high-throughput sequencing continues to increase in speed and throughput, routine clinical and industrial application draws closer. These 'production' settings will require enhanced quality ...monitoring and quality control to optimize output and reduce costs. We developed SeqControl, a framework for predicting sequencing quality and coverage using a set of 15 metrics describing overall coverage, coverage distribution, basewise coverage and basewise quality. Using whole-genome sequences of 27 prostate cancers and 26 normal references, we derived multivariate models that predict sequencing quality and depth. SeqControl robustly predicted how much sequencing was required to reach a given coverage depth (area under the curve (AUC) = 0.993), accurately classified clinically relevant formalin-fixed, paraffin-embedded samples, and made predictions from as little as one-eighth of a sequencing lane (AUC = 0.967). These techniques can be immediately incorporated into existing sequencing pipelines to monitor data quality in real time. SeqControl is available at http://labs.oicr.on.ca/Boutros-lab/software/SeqControl/.
A high-throughput screen (HTS) with the National Institute of Health–Molecular Libraries Small Molecule Repository (NIH–MLSMR) compound collection identified a class of acyl hydrazones to be ...selectively lethal to breast cancer stem cell (CSC) enriched populations. Medicinal chemistry efforts were undertaken to optimize potency and selectivity of this class of compounds. The optimized compound was declared as a probe (ML239) with the NIH Molecular Libraries Program and displayed greater than 20-fold selective inhibition of the breast CSC-like cell line (HMLE_sh_Ecad) over the isogenic control line (HMLE_sh_GFP).
We performed a single-institution retrospective analysis of 137 patients with muscle-invasive urothelial carcinoma who underwent neoadjuvant chemotherapy and radical cystectomy to assess the ...prognostic significance of carcinoma in situ (CIS). The pathologic complete response rates were significantly decreased for patients with CIS identified on transurethral resection of the bladder tumor before treatment. The long-term follow-up data from patients with isolated CIS at cystectomy revealed prolonged progression-free and overall survival.
Carcinoma in situ (CIS) is a poor prognostic finding in urothelial carcinoma. However, its significance in muscle-invasive urothelial carcinoma (MIUC) treated with neoadjuvant chemotherapy (NAC) is uncertain. We assessed the effect of CIS found in pretreatment transurethral resection of bladder tumor (TURBT) biopsies on the pathologic and clinical outcomes.
Subjects with MIUC treated with NAC before cystectomy were identified. The pathologic complete response (pCR) rates stratified by TURBT CIS status were compared. The secondary analyses included tumor response, progression-free survival (PFS), overall survival (OS), and an exploratory post hoc analysis of patients with pathologic CIS only (pTisN0) at cystectomy.
A total of 137 patients with MIUC were identified. TURBT CIS was noted in 30.7% of the patients. The absence of TURBT CIS was associated with a significantly increased pCR rate (23.2% vs. 9.5%; odds ratio, 4.08; 95% confidence interval, 1.19-13.98; P = .025). Stage pTisN0 disease was observed in 19.0% of the TURBT CIS patients. TURBT CIS status did not significantly affect the PFS or OS outcomes. Post hoc analysis of the pTisN0 patients revealed prolonged median PFS (104.5 vs. 139.9 months; P = .055) and OS (104.5 vs. 152.3 months; P = .091) outcomes similar to those for the pCR patients.
The absence of CIS on pretreatment TURBT in patients with MIUC undergoing NAC was associated with increased pCR rates, with no observed differences in PFS or OS. Isolated CIS at cystectomy was frequently observed, with lengthy PFS and OS durations similar to those for pCR patients. Further studies aimed at understanding the biology and clinical effect of CIS in MIUC are warranted.
Study Type – Therapy (case series) Level of Evidence 4
OBJECTIVE
To report the long‐term outcome of high‐grade prostate cancer treated with radical prostatectomy (RP) as initial monotherapy, analyse ...the effect of clinical and pathological variables on survival, and report cancer‐related symptoms.
PATIENTS AND METHODS
A retrospective chart review was conducted to identify patients with Gleason 8–10 prostate cancer found on pathological review in men undergoing RP as initial therapy for clinically localized disease between 1988 and 2005. Kaplan‐Meier analysis was used to calculate event‐free survival. Univariable and multivariable analyses were used to assess the effects of clinical and pathological variables on prostate‐specific antigen (PSA) recurrence.
RESULTS
After excluding 20 patients, 119 were identified with pathologically confirmed high‐grade cancers at the time of RP. The overall median (interquartile range) follow‐up was 73 (41–113) months. Twenty‐four (20%) patients had organ‐confined cancer, 60 (50%) had specimen‐confined cancer, and 14 (12%) had nodal metastasis. Kaplan‐Meier analysis showed overall survival rates at 5 and 10 years, respectively, of 90% and 75%, cancer‐specific survival of 92% and 82%, and a PSA recurrence‐free follow‐up at 5 years of 31%. Using univariable analysis, preoperative PSA level, pathological Gleason score, pathological stage, surgical margin status and tumour volume were found to significantly affect the PSA recurrence‐free follow‐up. No variables were significant on multivariable analysis. Cancer‐related symptoms were reported by only 14 patients, with a median time from surgery to first symptom of 43 months.
CONCLUSION
High‐grade prostate cancer can be treated with RP as initial monotherapy with an acceptable 10‐year cancer‐specific survival (82%). The PSA recurrence‐free follow‐up is poor (31% at 5 years). However, few patients progress to symptomatic recurrence after PSA relapse within the first 5 years.
Water flow and P dynamics in a low-relief landscape manipulated by extensive canal and ditch drainage systems were modeled utilizing an ontology-based simulation model. In the model, soil water flux ...and processes between three soil inorganic P pools (labile, active, and stable) and organic P are represented as database objects. And user-defined relationships among objects are used to automatically generate computer code (Java) for running the simulation of discharge and P loads. Our objectives were to develop ontology-based descriptions of soil P dynamics within sugarcane- (Saccharum officinarum L.) grown farm basins of the Everglades Agricultural Area (EAA) and to calibrate and validate such processes with water quality monitoring data collected at one farm basin (1244 ha). In the calibration phase (water year WY 99–00), observed discharge totaled 11,114 m3 ha−1 and dissolved P 0.23 kg P ha−1; and in the validation phase (WY 02–03), discharge was 10,397 m3 ha−1 and dissolved P 0.11 kg P ha−1. During WY 99–00 the root mean square error (RMSE) for monthly discharge was 188 m3 ha−1 and for monthly dissolved P 0.0077 kg P ha−1; whereas during WY 02–03 the RMSE for monthly discharge was 195 m3 ha−1 and monthly dissolved P 0.0022 kg P ha−1. These results were confirmed by Nash–Sutcliffe Coefficient of 0.69 (calibration) and 0.81 (validation) comparing measured and simulated P loads. The good model performance suggests that our model has promise to simulate P dynamics, which may be useful as a management tool to reduce P loads in other similar low-relief areas.
An ontology-based simulation (OntoSim) is a unique data modeling environment where soil–plant-nutrient processes are represented as database objects and the user-defined relationships among objects ...are used to generate computer code (Java) for running the simulation. The aim of this study was to model hydrologic processes of sugarcane-grown organic soils utilizing OntoSim in the Everglades Agricultural Area (EAA) of South Florida. This OntoSim-Sugarcane model describes the complex hydrology of sub-irrigation and open ditch drainage commonly used on Florida farms.
Model calibration was conducted by (i) selecting rectangular farm water management units (<12
ha), which are encompassed with farm ditches, from two farms in the EAA, (ii) assembling all relevant input data including water tables (WT) recorded at the monitoring farm well of each unit, and (iii) optimizing the fits between the simulated and observed daily WT during two consecutive water years (WY). By calibrating two site-specific parameters – lateral saturated hydraulic conductivities of soil profiles and vertical saturated hydraulic conductivity of the underlying limestone bedrock – good agreement between simulated and observed daily WT was obtained (Nash–Sutcliffe efficiency coefficient >0.65; coefficient of residual mass <1%) within the units during WY96–97 (May 1995–April 1997). The validation of the model during subsequent WY98–99 at both units also showed Nash–Sutcliffe efficiency >0.55 and coefficient of residual mass <3%. It indicated that OntoSim-Sugarcane is able to simulate daily fluctuations of WT within the farm units and estimate lateral drainage/sub-irrigation and deep seepage that significantly contribute to the water balance at farms in the EAA. Thus, it can be a promising management tool to provide farmers with accurate assessment of water movement in this agricultural area.
Soldiers undergo regular physical testing to assess their functional capacity. However, current physical tests, such as push-ups, sit-ups, and pull-ups, do not necessarily assess job-specific ...physical capability. This article assesses the utility of generic predictive tests and a task-related predictive test in predicting performance against four job-critical military manual handling tasks. The box lift and place test was found to be the superior predictor in performance of four job tasks; a pack lift and place (R(2) = 0.76), artillery gunner loading simulation (R(2) = 0.36), bombing up an M1 tank simulation, (R(2) = 0.47) and a bridge building simulation (R(2) = 0.63). Pull-ups and push-ups were poor predictors of performance in the majority of job tasks. Although the box lift and place had a larger correlation with the artillery gunner loading task than the generic assessment, it only accounted for 36% of the variance, indicating that a task simulation may be more appropriate to assess soldiers' capacity to perform this job task. These results support the use of a box lift and place rather than generic fitness tests for the evaluation of military manual handling tasks.
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