A Machine Learning Approach for Predicting Clinical Trial Patient Enrollment in Drug Development Portfolio Demand Planning

One of the biggest challenges the clinical research industry currently faces is the accurate forecasting of patient enrollment (namely if and when a clinical trial will achieve full enrollment), as the stochastic behavior of enrollment can significantly contribute to delays in the development of new drugs, increases in duration and costs of clinical trials, and the over- or under- estimation of clinical supply. This study proposes a Machine Learning model using a Fully Convolutional Network (FCN) that is trained on a dataset of 100,000 patient enrollment data points including patient age, patient gender, patient disease, investigational product, study phase, blinded vs. unblinded, sponsor CRO selection, enrollment quarter, and enrollment country values to predict patient enrollment characteristics in clinical trials. The model was tested using a dataset consisting of 5,000 data points and yielded a high level of accuracy. This development in patient enrollment prediction will optimize portfolio demand planning and help avoid costs associated with inaccurate patient enrollment forecasting

In vitro reversal of glutathione-S-transferase mediated resistance in canine osteosarcoma (COS31) cells : implications for patient manag[e]ment

Osteosarcoma is a highly malignant and rapidly fatal disease in dogs and humans. Since osteosarcoma in dogs and humans are virtually indistinguishable clinically and pathologically, the dogs has been used as an animal model. In this research, the long-range goal was to understand the role of the glutathione-S-transferases (GSTs) in clinical anticancer drug resistance. The hypothesis to be tested was that cisplatin resistance is mediated by the GSTs in osteosarcomas. The objectives of this research were to 1) determine if an in vivo relationship exists between the relative tumor concentration of GST π and response to cisplatin treatment in dogs with appendicular osteosarcoma, 2) establish canine osteosarcoma cells in culture and determine if cells retain similar biological and pathological properties in vitro and following implantation in nude mice, and 3) establish a canine osteosarcoma cell line resistant to the cytotoxic effects of cisplatin and determine if resistance is mediated by the GSTs and, if so, reversible upon the addition of ethacrynic acid. In this research, an increased expression of GST π in the primary tumors of a dog with osteosarcoma was related to a shorter remission and survival time. Furthermore, When canine osteosarcoma cells were established in culture, the cell line displayed all of the classical in vitro growth parameters of human osteosarcoma as well as the ability to produce tumors histologically typical of canine osteosarcoma when transplanted in athymic nude mice. Following prolonged exposure to increasing concentrations of cisplatin in vitro, a two-fold increase in and eight-fold increase in cisplatin resistance was observed. Complete reversal of cisplatin resistance occurred when the GST inhibitor; ethacrynic acid, was used. The cell lines created and evaluated in this research may exemplify the proper biologic and therapeutic model for studying cisplatin resistance mechanisms and innovative strategies to circumvent or delay its induction. From these results, it is anticipated that inhibiting the function of GST π with ethacrynic acid pretreatment in humans and dogs with osteosarcoma that more tumor cells than normal cells will be killed in vivo by cisplatin, thus significantly prolonging lifespan without increasing host toxicity

Clinical Evaluation of Denture Retention by Multi-suction Cup and Denture Adhesive

AIM: The aim of the study was to compare the retention of two modalities: Multi-suction cup denture, and denture adhesive and to evaluate the change of retention by different time intervals. PATIENTS AND METHODS: Twelve completely edentulous patients were selected. The patients received two dentures: One conventional denture, and the other with multi-suction cups. The retention was measured by a universal testing machine at insertion, 15 min, 30 min, 1 h, 2 h, and 4 h. All values were recorded in Newtons. Statistical analysis was carried out using two-way analysis of variance with post hoc Tukey’s test. RESULTS: Retention was higher in denture adhesive than multi-suction cup, and the change of retention was not statistically significant by time. CONCLUSION: Denture adhesive showed better retention clinically and simplified laboratory procedures than multi-suction denture

Polydimethylsiloxane (PDMS)/Carbon Nanofiber Nanocomposite with Piezoresistive Sensing Functions

Flexible material that can be deployed for sensing a wide range of pressure and strain is an active research area due to potential applications in engineering and biomedical devices. Current load sensing materials such as metals, semiconductor, and piezo ceramics have limitations in certain applications, due to their heavy density and small maximum measurable strain. In order to overcome those issues, this thesis delves into an alternative material class based on polydimethyl siloxane (PDMS) and carbon nanofiber (CNF) nanocomposites. Although silica and carbon nanoparticles have been traditionally used to reinforce mechanical properties in PDMS matrix nanocomposites, this study focuses on novel sensing systems with high sensitivity and wide load ranges. A series of nanocomposites with different CNF and silica concentrations were synthesized and characterized to understand their thermal, electrical, and sensing capabilities. The thermal properties, such as thermal stability and thermal diffusivity, of the developed nanocomposites were studied using thermogravimetirc and laser flash techniques, respectively. The electrical volume conductivity of each type of nanocomposite was measured using the four-probe method to eliminate the effects of contact electrical resistance during measurement. Scanning electron microscopy (SEM) was used at different length scales which showed uniform dispersion. Experimental results showed that both CNFs and silica were able to impact on the overall properties of the synthesized PDMS/CNF nanocomposites. The pressure sensing functions were achieved by correlating the piezoresistance variations of the materials to the applied load on the sensing area. Due to the conductive network formed by carbon nanofibers (CNFs) and the tunneling effect between neighboring CNFs, the experimental results showed a clear correlation between piezoresistance and the loading conditions. The proposed nanocomposite based sensor materials were experimentally characterized under both quasi-static and cyclic tensile and compressive loading conditions. The optimal nanocomposite formulation was identified by choosing materials with the highest sensing gauge factors under the required load ranges. The ideal material were employed to sense strain as high as 30% and pressures up to 50, 100, and 150 psi, which was a significant improvement compared to current off-the-shelf similar sensors. The sensing capability and sensitivity of the identified nanocomposites were further optimized using advanced optimization algorithms and finite element analysis method. Three different shapes including cylinder, conical, and truncated pyramid shaped sensing units were designed, fabricated, and characterized. Cyclic compression tests verified that the optimized sensor units enhanced the sensing capability by obtaining higher gauge factors. Finally, optimized sensing units were assembly in array forms for the continuous monitoring of pressure in a large area. The prototypes of sensor arrays successfully demonstrated their sensing capability under both static and cyclic pressure conditions in the desired pressure range

The Role of Subterminal Hydroxyeicosatetraenoic Acids in the Pathogenesis of Cardiac Hypertrophy

Cardiac hypertrophy is a complex condition which is characterized by increased mass of the heart muscle. If untreated, cardiac hypertrophy can ultimately lead to heart failure (HF), arrhythmia and sudden death. Accumulating evidence suggest that pathological cardiac hypertrophy is strongly correlated with aberrations in cytochrome P450 (CYP)-mediated arachidonic acid (AA) metabolism in the cardiac tissue. In the heart, AA is metabolized by the recently recognized CYP pathway, forming several biologically-active epoxyeicosatrienoic acids (EETs) and hydroxyeicosatetraenoic acids (HETEs). HETEs could be further classified as mid-chain, subterminal and terminal HETEs. Subterminal HETEs are group of lipid mediators that are implicated in a spacious array of physiological and pathophysiological processes. However, their role in the heart has yet to be investigated. Another important group of AA metabolites in the heart are mid-chain HETEs. Several experimental studies have demonstrated a role of CYP1B1 and its associated mid-chain HETEs metabolites in the development of cardiovascular diseases. Characterization of the role of subterminal HETEs in the heart and modulating the CYP1B1/mid-chain HETEs pathway will help to identify novel points of intervention that could help in the development of new therapeutic agents for cardiac hypertrophy and heart failure. Therefore, the objectives of the current work were to test whether R- and S-enantiomers of 19-HETE have differential role in the cardioprotective mechanism against cardiac hypertrophy, examine the inhibitory effect of both enantiomers of 19-HETE on human recombinant CYP1B1 enzyme, test the capability of synthetic analogues of 19-HETE to exert an inhibitory effect on some human recombinant CYP enzymes and test the cardioprotective effects of CYP modulators such as resveratrol and fluconazole on experimental models of cardiac hypertrophy and HF. The results demonstrated that both enantiomers of 19-HETE protected against angiotensin II (Ang II)-induced cardiac hypertrophy via decreasing the level of cardiotoxic mid-chain HETEs, inhibiting the catalytic activity of CYP1B1 and decreasing the protein expression level of LOX and COX-2 enzymes, with the S-enantiomer having more protection than the R-enantiomer. In addition, both enantiomers of 19-HETE noncompetitively inhibited human recombinant CYP1B1 enzymatic activity with higher potency of the S-enantiomer. Also, we have tested the potential inhibitory effect of synthetic 19-HETE analogs on different CYP enzymes. We showed that the synthetic analogues of 19(R)-HETE and 19(S)-HETE noncompetitively inhibited CYP1A1 and CYP1B1 enzymatic activity with preferential selectivity of the S-analogue. Interestingly, we demonstrated that resveratrol attenuated Ang II-induced cardiac hypertrophy and caused a significant decrease of CYP1B1 protein expression and mid-chain HETEs. Furthermore, in vivo studies showed that low dose resveratrol reduces the severity of myocardial infarction (MI)-induced HF, at least in part, through the inhibition of CYP1B1 and cardiotoxic mid-chain HETE metabolites. Lastly, the results showed that the protective role of fluconazole against pressure overload-induced cardiac hypertrophy is associated with a significant inhibition of CYP1B1 at the gene and protein levels and a reduction in the formation rate of mid-chain HETEs. In conclusion, the findings of the current work highlight the role of subterminal HETEs in the development of cardiac hypertrophy and indicate that their synthetic analogues could serve as a novel target for the treatment of heart diseases. Also, the findings of this work point out the potential repurposing of available clinically-approved drugs including resveratrol and fluconazole as a CYP1B1 inhibitors for the treatment of cardiovascular diseases

An Approach of Lip Synchronization with Facial Expression Rendering for an ECA

E-Tutoring systems have emerged as effective tools for remote learning and personalized education. However, to foster engaging and interactive experiences, there is a need to enhance the communication and expressiveness of virtual tutors within these systems. This research focuses on integrating facial expression animation and lip-syncing capabilities into an e-tutoring system, aiming to improve the realism and effectiveness of virtual tutor interactions. The study presents a novel approach to animating the facial expressions of the virtual tutor’s avatar using computer graphics, 3D animation, and computer vision techniques. Working with 3D files and using them to interpolate each face vertex are employed to track and map the facial movements onto the avatar accurately. This enables the virtual tutor to display various facial expressions, including happiness, surprise, and concern, to convey emotions and engage with the learner effectively. Additionally, the system incorporates lip-syncing techniques to synchronize the avatar’s lip movements with the spoken content. By analyzing the audio input, the system identifies the phonemes and maps them to the corresponding facial movements, ensuring realistic lip-syncing and enhancing the perception of natural speech

Blood Metabolic Profile in Barki Ewes during Transition Period

ΔΕΝ ΔΙΑΤΙΘΕΤΑΙ ΠΕΡΙΛΗΨΗThis technical research article investigated the changes in the hemato-biochemical profile in Barki ewes during the transition period. A total of 15 healthy pregnant Barki ewes (age, 4.9 ± 0.7 years old; weight, 38.5 ± 4.9 Kg) were randomly selected for the current study. Blood samples were collected from the selected ewes via jugular vein puncture during the transition period at five different time points; 4 and 2 weeks prior the estimated date of delivery (EDD), at the parturition time, then at 2 and 4 weeks post-partum. Red blood cells (RBCs) count and packed cell volume (PCV) were significantly (P<0.05) decreased 2 weeks before the EDD and at the parturition time. Mean corpuscular volume (MCV) was significantly (P<0.05) decreased 4 weeks post-partum. The neutrophil count and neutrophil/lymphocyte ratio were significantly (P < 0.05) increased 2 weeks post-partum. The level of β-hydroxy butyric acid (BHBA) and concentration of non-esterified fatty acid (NEFA) in the serum were significantly (P<0.05) increased 2 weeks before EDD, at the parturition time, and 2 weeks post-partum. Both cholesterol and triglyceride levels increased significantly (P<0.05) 2 weeks before EDD and at the parturition time. Leptin level was significantly (P<0.05) decreased at 2 weeks and 4 weeks post-partum. Glucose level increased significantly (P<0.05) at the parturition time then decreased significantly (P<0.05) at 2 weeks post-partum, after which it increased again 4 weeks post-partum. Total protein level was significantly (P<0.05) increased 2 weeks post-partum. The level of both calcium and inorganic phosphorus was significantly (P<0.05) decreased at the parturition time and 2 weeks post-partum. The results revealed that Barki ewes showed profound physiological alterations during the transition period which are not necessarily indicative of a disease, but reflect physiological variations. Therefore, metabolic profile test was needed to determine the nutritional status of Barki ewes, and to take the possible preventive measures that increase ewes’ productivity and predict health disorders