A Bayesian way to solve the pdf selection problem: an application in geotechnical analysis

Single probability density functions (pdf) are often selected based on a best-fit approach or the minimum description length (MDL) theorem that finds its description by the theory of complexity by Kolmogorov. However, it often occurs that random data cannot be accurately described by any of the commonly used pdf's. In this paper a method is presented which solves the problem of selecting single pdf's by predicting the probability of contending pdf's true given the data. These probabilities are combined when drawing inferences. The new method is illustrated on the prediction of the ultimate limit state (bearing capacity) of a single The aim of this paper is demonstrating the application of the Bayesian statistical method in combining statistical properties based of multiple pdf's. Waarts et al The present paper is outlined as follows. First the application of Bayes' theorem will be discussed to solve the problem of single pdf selection, i.e. the probabilities of contending pdf's being true given the data. Then the individual probabilities of the contending pfd's will be combined to one multiple parameter pdf. Thereafter, the new method is illustrated by an example where three contending pdf's have been combined for the model factor of axial pile capacities, i.e. the ratio of measured to calculated values. Subsequently, Level II analyses are carried out using the multiple parameter pdf for the model uncertainty. These analyses yield results that are important for practical use, such as the assessment of the partial safety factors and the establishments of the cumulative distribution function for axial pile capacity. Finally, concluding remarks and directions for further research are given

Experimental Research on the Behaviour of Combined Web Crippling and Bending of Steel Deck Sections

At an interior support, sections of cold-formed steel are subjected to a concentrated load and a bending moment Existing design rules describing the section failure at an interior support are subject to improvement and are not based on the section\u27s physical failure behaviour. In the last decade, several analytical models have been developed that predict the section ultimate concentrated load and directly include the influence of the bending moment, so that an empirical interaction method is not needed. However, the authors believe that these models are correct only for a concentrated load and a small bending moment In practice large bending moments occur. Therefore, the aim of the current research project is to develop an analytical model for trapezoidal hat sections subjected to a concentrated load and a bending moment as occurring in practice. The development of this model will be based on both experimental and numerical research will be carried out. In this article, a part of the experimental research will be presented

Experimental Research on the Behaviour of Combined Web Crippling and Bending of Steel Deck Sections

At an interior support, sections of cold-formed steel are subjected to a concentrated load and a bending moment Existing design rules describing the section failure at an interior support are subject to improvement and are not based on the section\u27s physical failure behaviour. In the last decade, several analytical models have been developed that predict the section ultimate concentrated load and directly include the influence of the bending moment, so that an empirical interaction method is not needed. However, the authors believe that these models are correct only for a concentrated load and a small bending moment In practice large bending moments occur. Therefore, the aim of the current research project is to develop an analytical model for trapezoidal hat sections subjected to a concentrated load and a bending moment as occurring in practice. The development of this model will be based on both experimental and numerical research will be carried out. In this article, a part of the experimental research will be presented

A Vortex Sheet/Point Vortex Dynamical Model For Unsteady Separated Flows

This paper presents a hybrid vortex sheet/point vortex method for modeling unsteady separated flows. We use vortex sheets to capture the dynamics of the shear layers immediately behind a wing in motion. The sheets provide a natural way of capturing vortex shedding, a feature missing from many point vortex models. We overcome the high computational cost traditionally associated with vortex sheet methods by approximating the spiraling cores of the sheets using point vortices with time-varying circulation. Circulation is continuously truncated from the tips of the vortex sheets and fed into their associated point vortices. To compensate for the discontinuous force response that results from this redistribution of vorticity, we adjust the velocity of the variable strength point vortices. We demonstrate the viability of the method by modeling the impulsive translation of a wing at a fixed angle of attack. We show that the proposed model correctly predicts the dynamics of large-scale vortical structures in the flow by comparing the distribution of vorticity from results of high-fidelity simulation, a model using only vortex sheets, and the proposed model. For the test cases attempted, the hybrid model predicts similar force responses to those of the sheet-only model, while being orders of magnitude faster

The IGF2 methylation score for adrenocortical cancer:an ENSAT validation study

Adrenocortical carcinoma (ACC) is diagnosed using the histopathological Weiss score (WS), but remains clinically elusive unless it has metastasized or grows locally invasive. Previously, we proposed the objective IGF2 methylation score as diagnostic tool for ACC. This multicenter European cohort study validates these findings. Patient and tumor characteristics were obtained from adrenocortical tumor patients. DNA was isolated from frozen specimens, where after DMR2, CTCF3, and H19 were py rosequenced. The predictive value of the methylation score for malignancy, defined by the WS or metastasis development, was assessed using receiver operating characteristic curves and logistic and Cox regression analyses. Seventy-six ACC patients and 118 patients with adrenocortical adenomas were included from seven centers. The methylation score and tumor size were independently associated with the pathological ACC diagnosis (OR 3.756 95% CI 2.224-6.343; OR 1.467 95% CI 1.202-1.792, respectively; Hosmer-Lemeshow test P = 0.903), with an area under the curve (AUC) of 0.957 (95% CI 0. 930-0.984). The methylation score alone resulted in an AUC of 0.910 (95% CI 0.8 66-0.952). Cox regression analysis revealed that the methylation score, WS and tumor size predicted development of metastases in univariate analysis. In multivariate analysis, only the WS predicted development of metastasis (OR 1.682 95% CI 1.285-2.202; P <0.001). In conclusion, we validated the high diagnostic accuracy of the IGF2 methylation score for diagnosing ACC in a multicenter European cohort study. Considering the known limitations of the WS, the objective IGF2 methylation score could potentially provide extra guidance on decisions on postoperative strategies in adrenocortical tumor patients

Generation of human motor units with functional neuromuscular junctions in microfluidic devices

Neuromuscular junctions (NMJs) are specialized synapses between the axon of the lower motor neuron and the muscle facilitating the engagement of muscle contraction. In motor neuron disorders, such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), NMJs degenerate, resulting in muscle atrophy and progressive paralysis. The underlying mechanism of NMJ degeneration is unknown, largely due to the lack of translatable research models. This study aimed to create a versatile and reproducible in vitro model of a human motor unit with functional NMJs. Therefore, human induced pluripotent stem cell (hiPSC)-derived motor neurons and human primary mesoangioblast (MAB)-derived myotubes were co-cultured in commercially available microfluidic devices. The use of fluidically isolated micro-compartments allows for the maintenance of cell-specific microenvironments while permitting cell-to-cell contact through microgrooves. By applying a chemotactic and volumetric gradient, the growth of motor neuron-neurites through the microgrooves promoting myotube interaction and the formation of NMJs were stimulated. These NMJs were identified immunocytochemically through co-localization of motor neuron presynaptic marker synaptophysin (SYP) and postsynaptic acetylcholine receptor (AChR) marker α-bungarotoxin (Btx) on myotubes and characterized morphologically using scanning electron microscopy (SEM). The functionality of the NMJs was confirmed by measuring calcium responses in myotubes upon depolarization of the motor neurons. The motor unit generated using standard microfluidic devices and stem cell technology can aid future research focusing on NMJs in health and disease

Efficacy of alpha-Blockers on Hemodynamic Control during Pheochromocytoma Resection:A Randomized Controlled Trial

CONTEXT: Pretreatment with α-adrenergic receptor blockers is recommended to prevent hemodynamic instability during resection of a pheochromocytoma or sympathetic paraganglioma (PPGL). OBJECTIVE: To determine which type of α-adrenergic receptor blocker provides the best efficacy. DESIGN: Randomized controlled open-label trial (PRESCRIPT; ClinicalTrials.gov NCT01379898). SETTING: Multicenter study including 9 centers in The Netherlands. PATIENTS: 134 patients with non-metastatic PPGL. INTERVENTION: phenoxybenzamine or doxazosin starting 2-3 weeks before surgery using a blood pressure targeted titration schedule. Intraoperative hemodynamic management was standardized. MAIN OUTCOME MEASURES: Primary efficacy endpoint was the cumulative intraoperative time outside the blood pressure target range (i.e., SBP >160 mmHg or MAP <60 mmHg) expressed as a percentage of total surgical procedure time. Secondary efficacy endpoint was the value on a hemodynamic instability score. RESULTS: Median cumulative time outside blood pressure targets was 11.1% [IQR: 4.3-20.6] in the phenoxybenzamine group compared to 12.2% [5.3-20.2] in the doxazosin group (P=0.75, r=0.03). The hemodynamic instability score was 38.0 [28.8-58.0] and 50.0 [35.3-63.8] in the phenoxybenzamine and doxazosin group, respectively (P=0.02, r=0.20). The 30-day cardiovascular complication rate was 8.8% and 6.9% in the phenoxybenzamine and doxazosin group, respectively (P=0.68). There was no mortality after 30 days. CONCLUSIONS: The duration of blood pressure outside the target range during resection of a PPGL was not different after preoperative treatment with either phenoxybenzamine or doxazosin. Phenoxybenzamine was more effective in preventing intraoperative hemodynamic instability, but it could not be established whether this was associated with a better clinical outcome

Efficacy of α-Blockers on Hemodynamic Control during Pheochromocytoma Resection: A Randomized Controlled Trial

CONTEXT: Pretreatment with α-adrenergic receptor blockers is recommended to prevent hemodynamic instability during resection of a pheochromocytoma or sympathetic paraganglioma (PPGL). OBJECTIVE: To determine which type of α-adrenergic receptor blocker provides the best efficacy. DESIGN: Randomized controlled open-label trial (PRESCRIPT; ClinicalTrials.gov NCT01379898). SETTING: Multicenter study including 9 centers in The Netherlands. PATIENTS: 134 patients with nonmetastatic PPGL. INTERVENTION: Phenoxybenzamine or doxazosin starting 2 to 3 weeks before surgery using a blood pressure targeted titration schedule. Intraoperative hemodynamic management was standardized. MAIN OUTCOME MEASURES: Primary efficacy endpoint was the cumulative intraoperative time outside the blood pressure target range (ie, SBP >160 mmHg or MAP <60 mmHg) expressed as a percentage of total surgical procedure time. Secondary efficacy endpoint was the value on a hemodynamic instability score. RESULTS: Median cumulative time outside blood pressure targets was 11.1% (interquartile range [IQR]: 4.3-20.6] in the phenoxybenzamine group compared to 12.2% (5.3-20.2)] in the doxazosin group (P = .75, r = 0.03). The hemodynamic instability score was 38.0 (28.8-58.0) and 50.0 (35.3-63.8) in the phenoxybenzamine and doxazosin group, respectively (P = .02, r = 0.20). The 30-day cardiovascular complication rate was 8.8% and 6.9% in the phenoxybenzamine and doxazosin group, respectively (P = .68). There was no mortality after 30 days. CONCLUSIONS: The duration of blood pressure outside the target range during resection of a PPGL was not different after preoperative treatment with either phenoxybenzamine or doxazosin. Phenoxybenzamine was more effective in preventing intraoperative hemodynamic instability, but it could not be established whether this was associated with a better clinical outcome

Analysis of differential gene expression in human melanocytic tumour lesions by custom made oligonucleotide arrays

Melanoma is one of the most aggressive types of cancer and resection of the tumour prior to dissemination of tumour cells is still the most effective treatment. Therefore, early diagnosis of melanocytic lesions is important and identification of novel (molecular) markers would be helpful to improve diagnosis. Moreover, better understanding of molecular targets involved in melanocytic tumorigenesis could possibly lead to development of novel interventions. In this study, we used a custom made oligonucleotide array containing 298 genes that were previously found to be differentially expressed in human melanoma cell lines 1F6 (rarely metastasising) and Mel57 (frequently metastasising). We determined differential gene expression in human common nevocellular nevus and melanoma metastasis lesions. By performing nine dye-swap array experiments, using individual as well as pooled melanocytic lesions, a constant differential expression could be detected for 25 genes in eight out of nine or nine out of nine array analyses. For at least nine of these genes, namely THBD, FABP7, H2AFJ, RRAGD, MYADM, HR, CKS2, NCK2 and GDF15, the differential expression found by array analyses could be verified by semiquantitative and/or real-time quantitative RT–PCR. The genes that we identified to be differentially expressed during melanoma progression could be potent targets for diagnostic, prognostic and/or therapeutic interventions

Efficacy and Safety of Prucalopride in Patients with Chronic Noncancer Pain Suffering from Opioid-Induced Constipation

Opioid-induced constipation (OIC) has negative effects on quality of life (QOL). Prucalopride is a new, selective 5-HT4 agonist and enterokinetic with strong clinical data in chronic constipation. This study investigated the efficacy, safety, and tolerability of prucalopride in patients with noncancer pain and OIC. A phase II, double-blind, placebo-controlled study of 196 patients randomized to placebo (n = 66), prucalopride 2 mg (n = 66) or 4 mg (n = 64), for 4 weeks, was carried out. The primary endpoint was the proportion of patients with increase from baseline of a parts per thousand yen1 spontaneous complete bowel movement (SCBM)/week. Secondary endpoints [proportion of patients with a parts per thousand yen3 SCBM/week, weekly frequency of (SC)BM, severity of constipation, and efficacy of treatment], adverse events (AEs), and safety parameters were also monitored. More patients had an increase from baseline of a parts per thousand yen1 SCBM per week (weeks 1-4) in the prucalopride groups [35.9% (2 mg) and 40.3% (4 mg)] versus placebo (23.4%), reaching statistical significance in week 1. Over weeks 1-4, more patients in the prucalopride groups achieved an average of a parts per thousand yen3 SBM per week versus placebo (60.7% and 69.0% versus 43.3%), reaching significance at week 1. Prucalopride 4 mg significantly improved patient-rated severity of constipation and effectiveness of treatment versus placebo. Patient Assessment of Constipation-Symptom (PAC-SYM) total scores and Patient Assessment of Constipation-Quality of Life (PAC-QOL) total and satisfaction subscale scores were improved. The most common AEs were abdominal pain and nausea. There were no clinically relevant differences between groups in vital signs, laboratory measures or electrocardiogram parameters. In this population with OIC, prucalopride improved bowel function and was safe and well tolerated