Group method of data handling to predict scour depth around vertical piles under regular waves

AbstractThis paper presents a new application of the Group Method Of Data Handling (GMDH), to predict pile scour depth exposed to waves. The GMDH network was developed using the Levenberg–Marquardt (LM) method in the training stage for scour prediction. Scour depth due to regular waves was modeled as a function of five dimensionless parameters, including pile Reynolds number, grain Reynolds number, sediment number, Keulegan–Carpenter number, and shields parameter. The testing results of the GMDH-LM were compared with those obtained using the Adaptive Neuro-Fuzzy Inference System (ANFIS), Radial Basis Function-Neural Network (RBF-NN), and empirical equations. In particular, the GMDH-LM provided the most accurate prediction of scour depth compared to other models. Also, the Keulegan–Carpenter number has been determined as the most effective parameter on scour depth through a sensitivity analysis. The GMDH-LM was utilized successfully to investigate the influence of the pile cross section and Keulegan–Carpenter number on scour depth

Expression and response surface optimization of the recovery and purification of recombinant D-galactose dehydrogenase from Pseudomonas fluorescens

The enzyme D-galactose dehydrogenase (GalDH) has been used in diagnostic kits to screen blood serum of neonates for galactosemia. It is also a significant tool for the measurement of β-D-galactose, α-D-galactose and lactose as well. In this study, response surface methodology (RSM) was used to identify the suitable conditions for recovery of recombinant GalDH from Pseudomonas fluorescens in aqueous two-phase systems (ATPS). The identified GalDH gene was amplified by PCR and confirmed by further cloning and sequencing. E. coli BL-21 (DE3) containing the GalDH gene on a plasmid (pET28aGDH) was used to express and purify the recombinant enzyme. The polyethylene glycol (PEG) and ammonium sulfate concentrations and pH value were selected as variables to analyze purification of GalDH. To build mathematical models, RSM with a central composite design was applied based on the conditions for the highest separation. The recombinant GalDH enzyme was expressed after induction with IPTG. It showed NAD+-dependent dehydrogenase activity towards D-Galactose. According to the RSM modeling, an optimal ATPS was composed of PEG-2000 14.0 (w/w) and ammonium sulfate 12.0 (w/w) at pH 7.5. Under these conditions, GalDH preferentially concentrated in the top PEG-rich phase. The enzyme activity, purification factor (PF) and recovery (R) were 1400 U/ml, 60.0 and 270.0, respectively. The PEG and salt concentrations were found to have significant effect on the recovery of enzyme. Briefly, our data showed that RSM could be an appropriate tool to define the best ATPS for recombinant P. fluorescens GalDH recovery. © 2015 National Institute of Science Communication and Information Resources (NISCAIR). All rights reserved

Development and evaluation of nanoemulsion and microsuspension formulations of curcuminoids for lung delivery with a novel approach to understanding the aerosol performance of nanoparticles

YesExtensive research has demonstrated the potential effectiveness of curcumin against various diseases, including asthma and cancers. However, few studies have used liquid-based vehicles in the preparation of curcumin formulations. Therefore, the current study proposed the use of nanoemulsion and microsuspension formulations to prepare nebulised curcuminoid for lung delivery. Furthermore, this work expressed a new approach to understanding the aerosol performance of nanoparticles compared to microsuspension formulations. The genotoxicity of the formulations was also assessed. Curcuminoid nanoemulsion formulations were prepared in three concentrations (100, 250 and 500 µg/ml) using limonene and oleic acid as oil phases, while microsuspension solutions were prepared by suspending curcuminoid particles in isotonic solution (saline solution) of 0.02% Tween 80. The average fine particle fraction (FPF) and mass median aerodynamic diameter (MMAD) of the nebulised microsuspension formulations ranged from 26% and 7.1 µm to 40% and 5.7 µm, for 1000 µg/ml and 100 µg/ml respectively. In a comparison of the low and high drug concentrations of the nebulised nanoemulsion, the average FPF and MMAD of the nebulised nanoemulsion formulations prepared with limonene oil ranged from 50% and 4.6 µm to 45% and 5.6 µm, respectively; whereas the FPF and MMAD of the nebulised nanoemulsion prepared with oleic acid oil ranged from 46% and 4.9 µm to 44% and 5.6 µm, respectively. The aerosol performance of the microsuspension formulations were concentration dependent, while the nanoemulsion formulations did not appear to be dependent on the curcuminoids concentration. The performance and genotoxicity results of the formulations suggest the suitability of these preparations for further inhalation studies in animals

Comparison of Benefit-Risk Assessment Methods for Prospective Monitoring of Newly Marketed Drugs: A Simulation Study

AbstractObjectivesTo compare benefit-risk assessment (BRA) methods for determining whether and when sufficient evidence exists to indicate that one drug is favorable over another in prospective monitoring.MethodsWe simulated prospective monitoring of a new drug (A) versus an alternative drug (B) with respect to two beneficial and three harmful outcomes. We generated data for 1000 iterations of six scenarios and applied four BRA metrics: number needed to treat and number needed to harm (NNT|NNH), incremental net benefit (INB) with maximum acceptable risk, INB with relative-value–adjusted life-years, and INB with quality-adjusted life-years. We determined the proportion of iterations in which the 99% confidence interval for each metric included and excluded the null and we calculated mean time to alerting.ResultsWith no true difference in any outcome between drugs A and B, the proportion of iterations including the null was lowest for INB with relative-value–adjusted life-years (64%) and highest for INB with quality-adjusted life-years (76%). When drug A was more effective and the drugs were equally safe, all metrics indicated net favorability of A in more than 70% of the iterations. When drug A was safer than drug B, NNT|NNH had the highest proportion of iterations indicating net favorability of drug A (65%). Mean time to alerting was similar among methods across the six scenarios.ConclusionsBRA metrics can be useful for identifying net favorability when applied to prospective monitoring of a new drug versus an alternative drug. INB-based approaches similarly outperform unweighted NNT|NNH approaches. Time to alerting was similar across approaches

Using the Incremental Net Benefit Framework for Quantitative Benefit–Risk Analysis in Regulatory Decision-Making—A Case Study of Alosetron in Irritable Bowel Syndrome

AbstractObjectiveThere is consensus that a more transparent, explicit, and rigorous approach to benefit–risk evaluation is required. The objective of this study is to evaluate the incremental net benefit (INB) framework for undertaking quantitative benefit–risk assessment by performing a quantitative benefit–risk analysis of alosetron for the treatment of irritable bowel syndrome from the patients’ perspective.MethodsA discrete event simulation model was developed to determine the INB of alosetron relative to placebo, calculated as “relative value-adjusted life-years (RVALYs).”ResultsIn the base case analysis, alosetron resulted in a mean INB of 34.1 RVALYs per 1000 patients treated relative to placebo over 52 weeks of treatment. Incorporating parameter uncertainty into the model, probabilistic sensitivity analysis revealed a mean INB of 30.4 (95% confidence interval 15.9–45.4) RVALYs per 1000 patients treated relative to placebo over 52 weeks of treatment. Overall, there was >99% chance that both the incremental benefit and incremental risk associated with alosetron are greater than placebo. As hypothesized, the INB of alosetron was greatest in patients with the worst quality of life experienced at baseline. The mean INB associated with alosetron in patients with mild, moderate, and severe symptoms at baseline was 17.97 (−0.55 to 36.23), 29.98 (17.05–43.37), and 35.98 (23.49–48.77) RVALYs per 1000 patients treated, respectively.ConclusionsThis study demonstrates the potential utility of applying the INB framework to real-life decision-making, and the ability to use simulation modeling incorporating outcomes data from different sources as a benefit–risk decision aid

Ogre and Pythia: An Invariance Proof Method for Weak Consistency Models

We design an invariance proof method for concurrent programs parameterised by a weak consistency model. The calculational design of the invariance proof method is by abstract interpretation of a truly parallel analytic semantics. This generalises the methods by Lamport and Owicki-Gries for sequential consistency. We use cat as an example of language to write consistency specifications of both concurrent programs and machine architectures

Antifungal susceptibility testing of <i>Candida </i>species isolated from the immunocompromised patients admitted to ten university hospitals in Iran

Abstract Background Antifungal susceptibility testing is a subject of interest in the field of medical mycology. The aim of the present study were the distributions and antifungal susceptibility patterns of various Candida species isolated from colonized and infected immunocompromised patients admitted to ten university hospitals in Iran. Methods In totally, 846 Candida species were isolated from more than 4000 clinical samples and identified by the API 20 C AUX system. Antifungal susceptibility testing was performed by broth microdilution method according to CLSI. Results The most frequent Candida species isolated from all patients was Candida albicans (510/846). The epidemiological cutoff value and percentage of wild-type species for amphotericin B and fluconazole in Candida albicans, Candida tropicalis, Candida glabrata and Candida krusei were 0.5 μg/ml (95%) and 4 μg/ml (96%); 1 μg/ml (95%) and 8 μg/ml (95%); 0.5 μg/ml (99%) and 19 μg/ml (98%); and 4 μg/ml (95%) and 64 μg/ml (95%), respectively. The MIC90 and epidemiological cutoff values to posaconazole in Candida krusei were 0.5 μg/ml. There were significant differences between infecting and colonizing isolates of Candida tropicalis in MIC 90 values of amphotericin B, and isolates of Candida glabrata in values of amphotericin B, caspofungin, and voriconazole (P < 0.05). Conclusions Our findings suggest that the susceptibility patterns of Candida species (colonizing and infecting isolates) in immunocompromised patients are not the same and acquired resistance was seen in some species

Effect of vitamin d3 on mitochondrial biogenesis in granulosa cells derived from polycystic ovary syndrome

Background: Polycystic ovary syndrome (PCOS) is an endocrine disorder diagnosed by anovulation hyperandro-genism. Hyperandrogenism increases apoptosis, which will eventually disturb follicular growth in PCOS patients. Since mitochondria regulate apoptosis, they might be affected by high incidence of follicular atresia. This may cause infertility. Since vitamin D3 has been shown to improve the PCOS symptoms, the aim of study was to investigate the effects vitamin D3 on mtDNA copy number, mitochondrial biogenesis, and membrane integrity of granulosa cells in a PCOS-induced mouse model. Materials and Methods: In this experimental study, the PCOS mouse model was induced by dehydroepiandrosterone (DHEA). Granulosa cells after identification by follicle-stimulating hormone receptor (FSHR) were cultured in three groups: 1. granulosa cells treated with vitamin D3 (100 nM for 24 hours), 2. granulosa cells without any treatments, 3. Non-PCOS granulosa cells (control group). Mitochondrial biogenesis gene (TFAM) expression was compared between different groups using real-time PCR. mtDNA copy number was also investigated by qPCR. The mitochon-drial structure was evaluated by transmission electron microscopy (TEM). Hormonal levels were measured by an enzymelinked immunosorbent assay (ELISA) kit. Results: The numbers of pre-antral and antral follicles increased in PCOS group in comparison with the non-PCOS group. Mitochondrial biogenesis genes were downregulated in granulosa cells of PCOS mice when compared to the non-PCOS granulosa cells. However, treatment with vitamin D3 increased mtDNA expression levels of these genes compared to PCOS granulosa cells with no treatments. Most of the mitochondria in the PCOS group were spherical with almost no cristae. Our results showed that in the PCOS group treated with vitamin D3, the mtDNA copy number increased significantly in comparison to PCOS granulosa cells with no treatments. Conclusion: According to this study, we can conclude, vitamin D3 improves mitochondrial biogenesis and membrane integrity, mtDNA copy number in granulosa cells of PCOS mice which might improve follicular development and subsequently oocyte quality. © 2020, Royan Institute (ACECR). All rights reserved

Elevated Brain Cannabinoid CB1 Receptor Availability in Posttraumatic Stress Disorder: A Positron Emission Tomography Study

Endocannabinoids and their attending cannabinoid type 1 receptor (CB1) have been implicated in animal models of posttraumatic stress disorder (PTSD). However, their specific role has not been studied in people with PTSD. Herein, we present an in vivo imaging study using positron emission tomography (PET) and the CB1-selective radioligand [11C]OMAR in individuals with PTSD, and healthy controls with lifetime histories of trauma (trauma controls [TC]) and those without such histories (healthy controls [HC]). Untreated individuals with PTSD (N=25) with non-combat trauma histories, and TC (N=12) and HC (N=23) participated in a magnetic resonance (MR) imaging scan and a resting PET scan with the CB1 receptor antagonist radiotracer [11C]OMAR, which measures volume of distribution (VT) linearly related to CB1 receptor availability. Peripheral levels of anandamide, 2-arachidonoylglycerol (2-AG), oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and cortisol were also assessed. In the PTSD group, relative to the HC and TC groups, we found elevated brain-wide [11C]OMAR VT values (F(2,53)=7.96, p=.001; 19.5% and 14.5% higher, respectively) which were most pronounced in women (F(1,53)=5.52, p=.023). Anandamide concentrations were reduced in the PTSD relative to the TC (53.1% lower) and HC (58.2% lower) groups. Cortisol levels were lower in the PTSD and TC groups relative to the HC group. Three biomarkers examined collectively—OMAR VT, anandamide, and cortisol—correctly classified nearly 85% of PTSD cases. These results suggest that abnormal CB1 receptor-mediated anandamide signaling is implicated in the etiology of PTSD, and provide a promising neurobiological model to develop novel, evidence-based pharmacotherapies for this disorder