Bi-exponential modelling of $$W^{^{\prime}}$$ reconstitution kinetics in trained cyclists

Purpose The aim of this study was to investigate the individual $$W^{^{\prime}}$$ W ′ reconstitution kinetics of trained cyclists following repeated bouts of incremental ramp exercise, and to determine an optimal mathematical model to describe $$W^{^{\prime}}$$ W ′ reconstitution. Methods Ten trained cyclists (age 41 ± 10 years; mass 73.4 ± 9.9 kg; $$\dot{V}{\text{O}}_{2\max }$$ V ˙ O 2 max 58.6 ± 7.1 mL kg min−1) completed three incremental ramps (20 W min−1) to the limit of tolerance with varying recovery durations (15–360 s) on 5–9 occasions. $$W^{^{\prime}}$$ W ′ reconstitution was measured following the first and second recovery periods against which mono-exponential and bi-exponential models were compared with adjusted R2 and bias-corrected Akaike information criterion (AICc). Results A bi-exponential model outperformed the mono-exponential model of $$W^{^{\prime}}$$ W ′ reconstitution (AICc 30.2 versus 72.2), fitting group mean data well (adjR2 = 0.999) for the first recovery when optimised with parameters of fast component (FC) amplitude = 50.67%; slow component (SC) amplitude = 49.33%; time constant (τ)FC = 21.5 s; τSC = 388 s. Following the second recovery, W′ reconstitution reduced by 9.1 ± 7.3%, at 180 s and 8.2 ± 9.8% at 240 s resulting in an increase in the modelled τSC to 716 s with τFC unchanged. Individual bi-exponential models also fit well (adjR2 = 0.978 ± 0.017) with large individual parameter variations (FC amplitude 47.7 ± 17.8%; first recovery: (τ)FC = 22.0 ± 11.8 s; (τ)SC = 377 ± 100 s; second recovery: (τ)FC = 16.3.0 ± 6.6 s; (τ)SC = 549 ± 226 s). Conclusions W′ reconstitution kinetics were best described by a bi-exponential model consisting of distinct fast and slow phases. The amplitudes of the FC and SC remained unchanged with repeated bouts, with a slowing of W′ reconstitution confined to an increase in the time constant of the slow component.

Linguistic creativity and discourse profiles of English language children’s novels

Contemporary discourse studies face the necessity to develop the methods of contrastive sub-discourse analysis which apply numeric and comparable data to diversify and describe sub-discourse types. The aim of the research is to propose a method of discourse profiling serving the purpose, and to further test the method in the contrastive study of linguistic creativity in different types of English language childrens novels. The category of linguistic creativity being the leading form of language poesis receives parametric description on all language representation levels (in written form) and provides the discourse values for contrastive analysis. These values are explored in the fragments of non-autobiographic and autobiographic adventure novel sub-discourse types authored by J.C. George, F. Gibson, J.D. Ullman, and G. Durrell (a total amount of 120.000 signs) annotated manually for 52 linguistic creativity parameters on phonological, morphological, word-formation, lexical, syntactic, and graphic levels. The working hypothesis is that the linguistic creativity parametric activity distributions represent the sub-discourse profiles and may serve to contrast sub-discourse types by means of their vectors contingency values. The analysis in individual parameter activity and in parameter groups activity demonstrated significant variance in sub-discourse construal, with autobiographic sub-discourse of G. Durrell manifesting several higher activity values in word-formation (occasional compounding), lexical use (the use of professional language, lexical tropes, allusive names, higher register style) and syntactic use (the use of parallel structures and syntactic intensifiers). In terms of morphological activity, the parameter values tend to be lower (morphological category shifts), the same stands true of some syntactic (the use of elliptical structures) and lexical parameters (the use of lower register types and proper names). The sub-discourse profiles demonstrate several common features, evidently typical of the discourse type itself, and the features differentiating non-autobiographic and autobiographic discourse subtypes. Vector correlation analysis revealed lower correlation values for autobiographic sub-discourse, which proves its specificity and testifies to the discourse profiling method applicability.

Optimization of Facile Synthesized ZnO/CuO Nanophotocatalyst for Organic Dye Degradation by Visible Light Irradiation Using Response Surface Methodology

In this study, we aimed to observe how different operating parameters influenced the photocatalytic degradation of rhodamine B (RhB, cationic dye) and bromophenol Blue (BPB, anionic dye) over ZnO/CuO under visible light irradiation. This further corroborated the optimization study employing the response surface methodology (RSM) based on central composite design (CCD). The synthesis of the ZnO/CuO nanocomposite was carried out using the co-precipitation method. The synthesized samples were characterized via the XRD, FT-IR, FE-SEM, Raman, and BET techniques. The characterization revealed that the nanostructured ZnO/CuO formulation showed the highest surface area (83.13 m2·g−1). Its surface area was much higher than that of pure ZnO and CuO, thereby inheriting the highest photocatalytic activity. To substantiate this photocatalytic action, the investigative analysis was carried out at room temperature, associating first-order kinetics at a rate constant of 0.0464 min−1 for BPB and 0.07091 min−1 for RhB. We examined and assessed the binary interactions of the catalyst dosage, concentration of dye, and irradiation time. The suggested equation, with a high regression R2 value of 0.99701 for BPB and 0.9977 for RhB, accurately matched the experimental results. Through ANOVA we found that the most relevant individual parameter was the irradiation time, followed by catalyst dose and dye concentration. In a validation experiment, RSM based on CCD was found to be suitable for the optimization of the photocatalytic degradation of BPB and RhB over ZnO/CuO photocatalysts, with 98% degradation efficiency.

Estimating the Public Health Impact from Introducing Tobacco-Free Nicotine Pouches Into the US

BackgroundFor smokers not intending to quit, switching to a reduced-risk nicotine product should be healthier than continuing smoking. We estimate the health impact, over the period 2000-2050, of introducing into the US the nicotine pouch ZYN. ZYN’s toxicant profile and method of use is like that for Swedish snus, a product with known health effects much less than smoking. MethodsOur modelling approach is similar to others developed for estimating potential effects of new tobacco products. It starts with a simulated cohort of 100,000 individuals in the year 2000 subdivided by age, sex, and smoking status (including years since quitting). They are followed annually accounting for births, net immigrations, deaths and product use changes, with follow-up carried out in the Base Case (ZYN not introduced) and Modified Case (ZYN introduced). Using informed assumptions about initiation, quitting and switching rates, distributions of the population over time are then constructed for each Case, which are used to estimate product-related mortality based on assumptions about the relative risk according to product use. ResultsWhereas in both Base and Modified Cases, the prevalence of any current product use is predicted to decline from about 22% to 10% during follow-up, in the Modified Case about 25% of current users use ZYN by 2050, about a quarter being dual users and the rest ZYN-only users. Over the 50 years, deaths at ages 35-84 from product use among the 100,000 are estimated as 249 less in the Modified than the Base Case, equivalent to about 700,000 less deaths in the whole US. Sensitivity analyses varying individual parameter values confirm the benefits of switching to ZYN, which increase as either the switching rate to ZYN increases or the initiation rate of ZYN relative to smoking increases. Even assuming the reduction in excess mortality risk using ZYN use is 20% of that from smoking rather than the 3.5% assumed in the main analyses, the reduction in product-related deaths would still be 213, or about 600,000 in the US. ConclusionsAlthough such model-based estimates are subject to uncertainties, the results suggest that introducing ZYN could substantially reduce smoking-attributable deaths.

Artifact reduction of coaxial needles in magnetic resonance imaging-guided abdominal interventions at 1.5 T: a phantom study

Needle artifacts pose a major limitation for MRI-guided interventions, as they impact the visually perceived needle size and needle-to-target-distance. The objective of this agar liver phantom study was to establish an experimental basis to understand and reduce needle artifact formation during MRI-guided abdominal interventions. Using a vendor-specific prototype fluoroscopic T1-weighted gradient echo sequence with real-time multiplanar acquisition at 1.5 T, the influence of 6 parameters (flip angle, bandwidth, matrix, slice thickness, read-out direction, intervention angle relative to B0) on artifact formation of 4 different coaxial MR-compatible coaxial needles (Nitinol, 16G–22G) was investigated. As one parameter was modified, the others remained constant. For each individual parameter variation, 2 independent and blinded readers rated artifact diameters at 2 predefined positions (15 mm distance from the perceived needle tip and at 50% of the needle length). Differences between the experimental subgroups were assessed by Bonferroni-corrected non-parametric tests. Correlations between continuous variables were expressed by the Bravais–Pearson coefficient and interrater reliability was quantified using the intraclass classification coefficient. Needle artifact size increased gradually with increasing flip angles (p = 0.002) as well as increasing intervention angles (p < 0.001). Artifact diameters differed significantly between the chosen matrix sizes (p = 0.002) while modifying bandwidth, readout direction, and slice thickness showed no significant differences. Interrater reliability was high (intraclass correlation coefficient 0.776–0.910). To minimize needle artifacts in MRI-guided abdominal interventions while maintaining optimal visibility of the coaxial needle, we suggest medium-range flip angles and low intervention angles relative to B0.

Fibrinolytic Dysregulation Contributes to the Hypercoagulable State in Pulmonary Embolism Patients

Introduction: The multifactorial and complex pathophysiology of pulmonary embolism (PE) involves dysregulation of hemostatic system including fibrinolytic imbalance, endothelial compromise and generation of thrombotic mediators, along with cellular defects and hemodynamic derangement. It is estimated that 6000 cases of pulmonary embolism and DVT are reported yearly of which 1000 result in death. PE evolves from a pre-existing venous thrombus, obstructing pulmonary artery leading to pulmonary failure. The progression of clot formation results in increase in right ventricular pressure, systemic hypoperfusion, hypoxemia ischemia and eventually multi organ failure. Fibrinolytic dysregulation and generation of procoagulant mediators result in increased clot burden and lead to adverse outcomes. Profiling of the component of the fibrinolytic system for such mediators as the activators and inhibitors of fibrinolysis, vWF and cellular microparticles may provide additional insights into the pathogenesis of PE. The purpose of this study is to profile plasma samples from PE patients for various mediators of hemostatic dysregulation which contribute to the fibrinolytic dysregulation in PE patients. Material & Method: Seventy-eight patients of 18 years or older age, were included in this study through enrolment conducted in conjunction with an ongoing IRB approved project by the pulmonary embolism response team (PERT) registry. Diagnosis of PE was confirmed by computed tomography (CT), angiography or ventilation perfusion imaging. Blood samples were drawn with in 24 hours of confirmed diagnosis of acute PE in 3.2% sodium citrate tubes at the time of diagnosis, processed for platelet poor plasma and frozen. Control plasma samples were obtained from 50 healthy individuals. Both the patient and control plasma samples were analyzed for D-Dimer, PAI-1 antigen, tPA, TAFI-a, protein C, alpha-2 antiplasmin, microparticles and vWF using ELISA methods (Hypen Biomedical, Franklin, Ohio). A functional PAI-1 chromogenic substrate method and an ELISA based uPA antigen method was used (Biomedica, Halifax, Nova Scotia, Canada). Circulating levels of each of the individual biomarkers were compared to normal plasma, descriptive statistics including non-parametric Mann-Whitney t-test and spearman correlation coefficient analysis was carried out by using GraphPad Prism software. Percent Increase from the normal mean was calculated for each individual parameter. p value &lt;0.05 was considered statistically significant. Result: In comparison to normal group, the PE patients exhibited varying levels of increase in the D-Dimer, tPA, uPA, PAI-1 antigen, PAI-1 functional, TAFI antigen, microparticles and vWF, whereas decreased levels were noted for protein C and alpha-2 antiplasmin as shown on Figure 1. D-Dimer showed the most pronounced increase (368.2-fold) followed by tPA (165.9-fold), PAI-1 antigen (3.91-fold), microparticles (2.14-fold), vWF (1.83-fold), uPA (0.5-fold), TAFI antigen (0.40-fold) and PAI-1 functional (0.34-fold). In correlation analysis, D-Dimer negatively correlated with TAFI antigen (r= -0.3106) and alpha-2 antiplasmin (r= -0.3056), functional PAI-1 levels positively correlated with tPA (r= 0.3117) and protein C (r= 0.4059), tPA negatively correlated with TAFI antigen (r= -0.4601), alpha-2 antiplasmin (r= -0.2460) and positively correlated with microparticles (r= 0.2456) , TAFI antigen positively correlated with protein C (r= 0.3612), alpha-2 antiplasmin (r= 0.3899) and negatively correlated with microparticles (r= -0.2470) whereas protein C showed a negative correlation with vWF (r= -0.2838). Conclusion: The markedly increased D-Dimer levels suggest increase clot burden in PE patients. tPA antigen is also markedly increased, whereas the uPA showed modest increase which may suggest compensatory upregulation, PAI-1 antigen levels were much higher in comparison to PAI-1 functional activity, suggesting consumption of this inhibitor. Decreased alpha-2 antiplasmin and protein C levels also suggest consumption. Increased TAFI antigen contribute to the clot resistant to fibrinolysis. Cellular consumption and endothelial dysfunction results in increased in vWF and microparticles promoting thrombogenesis. Measurement of these biomarkers may be useful in the understanding of the pathogenesis, risk stratification and clinical management of PE patients. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Mechanistic Computational Models of Epithelial Cell Transporters-the Adorned Heroes of Pharmacokinetics

Epithelial membrane transporter kinetics portray an irrefutable role in solute transport in and out of cells. Mechanistic models are used to investigate the transport of solutes at the organ, tissue, cell or membrane scale. Here, we review the recent advancements in using computational models to investigate epithelial transport kinetics on the cell membrane. Various methods have been employed to develop transport phenomena models of solute flux across the epithelial cell membrane. Interestingly, we noted that many models used lumped parameters, such as the Michaelis-Menten kinetics, to simplify the transporter-mediated reaction term. Unfortunately, this assumption neglects transporter numbers or the fact that transport across the membrane may be affected by external cues. In contrast, more recent mechanistic transporter kinetics models account for the transporter number. By creating models closer to reality researchers can investigate the downstream effects of physical or chemical disturbances on the system. Evidently, there is a need to increase the complexity of mechanistic models investigating the solute flux across a membrane to gain more knowledge of transporter-solute interactions by assigning individual parameter values to the transporter kinetics and capturing their dependence on each other. This change results in better pharmacokinetic predictions in larger scale platforms. More reliable and efficient model predictions can be made by creating mechanistic computational models coupled with dedicated in vitro experiments. It is also vital to foster collaborative efforts among transporter kinetics researchers in the modeling, material science and biological fields.

Mapping and situation analysis of basic WASH facilities at households in Bangladesh: Evidence from a nationally representative survey

Background Ensuring water, sanitation, and hygiene (WASH) facilities for households remains a major public health concern in low- and middle-income countries (LMICs). This study investigated the current situation of basic WASH facilities for households in Bangladesh and drew a national coverage map. Methods We analyzed the publicly available nationally representative 2019 Multiple Indicator Cluster Survey (MICS) dataset that was carried out by the Bangladesh Bureau of Statistics (BBS) with support from the United Nations Children’s Emergency Fund (UNICEF). A total of 61,209 households (weighted) were included in the analysis. Both bivariate and multivariate analyses were employed to examine the relationships between independent variables (socio-demographic and economic status) and their distributions over outcome variables (basic water, sanitation, and hygiene). Further, the spatial distribution of WASH facilities at the household level was depicted. Results Coverage of access to basic water facilities at the household level was 99.5% (95% CI 99.4% to 99.6%), sanitation 60.7% (95% CI 60.0% to 61.5%), and hygiene 56.3% (95% CI 55.6% to 57.0%). However, coverage of combined access to all three components was 40.2% (95% CI 39.4% to 40.9%). Among all 64 administrative districts of Bangladesh, we found comparatively lower coverage of WASH facilities in the South and South-East regions and relatively higher in the households of the North and North-Western regions. An adjusted regression model revealed that richest households [AOR = 29.64, 95% CI 26.31 to 33.39], households in the rural areas [AOR = 1.64, 95% CI 1.50 to 1.79], household heads with higher educational attainment [AOR = 2.28, 95% CI 2.09 to 2.49], and households with 5+ family members [AOR = 1.64, 95% CI 1.56 to 1.71] had the higher likelihood to have basic WASH facilities. Conclusion Less than half of the Bangladeshi households had access to all three major WASH components (basic water, sanitation, and hygiene facilities); however, variation exists at the individual parameter of basic water, sanitation, and hygiene facilities. A comprehensive WASH approach may reduce the gap and improve the quality of WASH facilities in Bangladesh.

Estimation of The Main Effect and Total Effect of a PBPK Model Based on The Uncertainty of Individual Parameter for Treatment Planning in PSMA Therapy

The purpose of this study was to identify the most important physiologically-based pharmacokinetic (PBPK) model parameters determining the absorbed dose (AD) in prostate-specific membrane antigen (PSMA) therapy. The extended-Sobol’ global sensitivity analysis method was used to analyze the sensitivity of the PBPK model parameters obtained from 3 patients. The investigated PBPK model parameters were the blood flow to the organs, PSMA binding rate, biological release rates, and density of organs receptor. The outputs of extended Sobol method were the main effect Si and the total effect STi of the parameter of interests for each ADs. The sampling strategy of extended Sobol has been implemented based on the mean and covariance matrix of the parameters. From the simulations, the most important parameters which determine the ADs to the kidney was the kidney receptor density (Si=0,4, STi=0,8). For tumors, it was shown that tumor receptor density was the most essential parameter (Si=0,7, STi=0,8). In conclusion, measurement of the blood flow and organ receptor densities might be of interest to improve individualized treatment of PSMA therapy.

An Eight Year Experience of Autologous Oocyte Vitrification for Infertile Patients Owing to Unavailability of Sperm on Oocyte Retrieval Day

Objective: The objective of this study was to provide a descriptive analysis of the clinical outcomes achieved in oocyte vitrification in cases where sperm was unavailable on oocyte retrieval day, and to identify predictors of oocyte survival.Methods: This retrospective cohort study used data from a university-affiliated reproductive medical center. There were 321 cycles in which some of, or all oocytes were vitrified owing to the unavailability of sperm between March 2009 and October 2017. A descriptive analysis of the clinical outcomes including both fresh embryo transfers and cryopreserved embryo transfers was provided. The ability of an individual parameter to forecast oocyte survival per thawing cycle was assessed by binary logistic regression analysis. The cumulative probability of live birth (CPLB) was estimated by using the Kaplan-Meier method according to the total number of oocytes thawed in consecutive procedures.Results: The average survival rate was 83.13%. High-quality embryo rate and blastocyst rate decreased significantly decreased significantly in vitrification oocyte group compared to fresh control oocytes. The comparison of sibling oocytes in part-oocyte-vitrified cycles shows fewer high-quality embryos developed in the vitrified group. The live birth rate per warmed-oocyte was 4.3%. Reasons for lack of sperm availability on oocyte retrieval day and serum cholesterol levels were found to be associated with oocyte survival rate in the present study. Kaplan-Meier analysis showed no significant difference in CPLB between patients ≤35 vs. &gt;35 years.Conclusions: Oocyte vitrification is an indispensable and effective alternative when sperm are not available on oocyte retrieval day. The present study provided evidence that oocytes from infertile couples were more likely to suffer oocyte/embryo vitrification injury. Clinicians need to take this into account when advising patients in similar situations. Further studies will be necessary to clarify the correlation between serum metabolism parameters and human oocyte survival after vitrification.