Lag Time Research Articles

Rheology of Ti-6Al-4V alloy under non equilibrium conditions during β forging

During the “β-forging” of Ti-6Al-4V structural aircraft components that follows pre-heating above the β-transus, the skin zone of the blank actually cools down to below the β-transus whilst being deformed, as a result of heat losses towards the atmosphere or the dies. The core areas of the bulkiest sections of the blank, however, can be deformed above the β-transus during the whole processing time. This paper focuses on the development of an innovative rheological model to support the numerical modelling of the forging process, suitable for both the equilibrium conditions above the β-transus and the non-equilibrium conditions below. For that purpose, small-scale hot compression tests were performed with the thermomechanical simulator Gleeble 3500, after pre-heating in the β-field of Ti-6Al-4V at 1100 °C and rapid cooling to the compression temperature under the β-transus, which was varied between 750 °C and 950 °C. In some cases, a lag time -or stabilization time- at constant temperature was introduced between the cooling step and the deformation step. Effects of lag time and deformation temperature on microstructural evolutions and rheological properties of Ti-6Al-4V were investigated. Results show that the lack of stabilization time leads to a significant reduction of the flow stress at low strain. Such a behavior is associated with non-equilibrium thermodynamic conditions at the beginning of deformation and the progress of phase transformation during deformation. Based on that observation, an analytical formulation for the targeted rheological model is proposed. It includes a sub-model for the kinetics of phase transformation derived from the literature.

Access to Innovative Medicines: Regulation Change and Factors Associated with Drug Approval Lag in Malaysia.

Drug approval lag is the time difference for new medicine to obtain marketing authorization approval in the study country compared to the first global approval. Drug approval lag delays the availability of innovative medicine to patients. This may lead to delay in treatment and severe public health implications. The study aimed to determine drug approval lag in Malaysia, the factors associated with drug approval lag (drug characteristics, regulatory factors and applicant type) and the association of the submission lag and review time with the regulation change. All new pharmaceutical products approved between January 2015 and March 2021 were examined (n = 136) using publicly available information. Factors associated with drug approval lag were determined using multiple linear regression. The median drug approval lag was 855days. Drug approval lag was associated with drug characteristics and regulatory factors. Median submission lag and median review time for products which fulfilled the requirement for the new regulations (Conditional Registration/ Facilitated Registration Pathway) were shorter compared to products which did not fulfil the requirement. Drug approval lag may delay the access of innovative medicine to patients, and this may lead to an increase in morbidity, mortality and healthcare costs. Good Regulatory Practices ensure efficient and transparent regulatory system which support the public health policy objectives in the most efficient way. The new regulations in Malaysia reduced the median submission lag and review time. The findings may be useful for regulators to consider for future policy development for medication access.

Bacteroides thetaiotaomicron metabolic activity decreases with polysaccharide molecular weight.

Polysaccharides are complex molecules that are commonly found in our diet. While humans lack the ability to degrade many polysaccharides, their intestinal microbiota contain bacterial commensals that are versatile polysaccharide utilizers. The gut commensal Bacteroides thetaiotaomicron dedicates roughly 20% of their genomes to the expression of polysaccharide utilization loci for the broad range utilization of polysaccharides. Although it is known that different polysaccharide utilization loci are dedicated to the degradation of specific polysaccharides with unique glycosidic linkages and monosaccharide compositions, it is often overlooked that specific polysaccharides may also exist in various molecular weights. These different physical attributes may impact their processability by starch utilization system-like systems, leading to differing growth rates and nutrient-sharing properties at the community level. Therefore, understanding how molecular weight impacts utilization by gut microbe may lead to the potential design of novel precision prebiotics.

Diagnostic utility of immunocytochemistry by using liquid-based cytology (LBC) slides.

Cytological specimens, such as fine needle aspirations (FNAs) and exfoliative cytology samples, are minimally invasive options for diagnostic purposes. Liquid-based cytology (LBC), originally designed for cervical cytology, has gained prominence as an alternative technique for non-gynecological cytology. Immunocytochemistry (ICC) is an ancillary method used when diagnosis becomes challenging due to morphological overlap or the need for cellular origin clarification. This study aims to assess the diagnostic utility of ICC when applied to LBC slides and evaluate its effectiveness in relation to the waiting (lag) time of residual material. A total of 74 cases in which ICC was applied to LBC slides were studied over one year in a reference pathology laboratory (Prof. Dr. Cemil Tascioglu, Pathology Laboratory, City Hospital, Istanbul, Turkey). Cases in which immunohistochemistry (IHC) was performed on formalin-fixed paraffin-embedded cell blocks were excluded. The SurePath PAP method was used for the main LBC cytology slides. For the ICC study, 1-4 PAP-stained LBC slides were obtained from each case's residual material and stained with a primary antibody. The positive immunostaining was obtained in 81% of cases. The samples were categorized into groups based on the waiting time of residual LBC material for ICC analysis: 1-5 days, 6-10 days, 11-20 days, and 21-38 days. Comparative analysis revealed a decline in ICC efficacy as the waiting (lag) time increased. Additionally, a statistically significant difference was observed between the 11-20 days and 21-38 days groups (P < 0.05). An analysis of 142 LBC slides stained by ICC revealed that nuclear markers exhibited higher positivity compared to non-nuclear markers, although no significant difference was detected between the two groups. High positivity rates can be obtained in ICC studies performed on additional slides obtained from residual LBC material within the first 20 days. ICC applied to LBC slides is an important and useful alternative for diagnostic and prognostic markers in cases without a cell block or with a cell block without sufficient number of cells.

Endogenous thrombin potential and time-dependent thrombin generation parameters are independent risk factors for mortality in the general population

BackgroundThrombin generation (TG) is used as a global test of coagulation and is an indicator of thrombosis and bleeding risk. Until now, data on the association of TG and mortality are inconclusive. ObjectivesWe investigated the association between TG and mortality in the prospective Moli-sani cohort (n = 21 920). MethodsTG was measured using calibrated automated thrombinography using PPP-Reagent Low. Lag time (LT), endogenous thrombin potential (ETP), peak height, time-to-peak (TTP), and velocity index were quantified. The association of TG and mortality was studied by Cox regression and adjusted for sex, age, body mass index, smoking, contraceptives, and medical history (cardiovascular diseases, hypertension, hypercholesterolemia, diabetes, and cancer). ResultsLT and TTP were 4.1 ± 1.0 minutes and 6.6 ± 1.5 minutes, on average. The peak height was 364 ± 88 nM, velocity index was 163 ± 63 nM/min, and ETP was 1721 ± 411 nM·min. ETP was negatively associated with all-cause mortality (hazard ratio [HR], 0.86; 95% CI, 0.81-0.92; P < .001). Subjects in the lowest quintile of the ETP (ETPQ1) had a 1.3-fold higher mortality rate. Additionally, a high TTP/LT ratio was negatively associated with mortality (HR, 0.71; 95% CI, 0.57-0.89; P = .003). Individuals in quintile 1 of the TTP/LT ratio had a 1.4-fold higher mortality rate compared with the remainder of the cohort. Subjects that were both in ETPQ1 and TTP/LTQ1 had a 1.8-fold higher mortality rate, regardless of whether they reported history of cardiovascular disease at baseline (HR, 1.61 [CI: 1.07-2.42]) or not (HR, 1.89 [CI: 1.51-2.36]). ConclusionLow ETP and TTP/LT ratios are independent risk factors for all-cause mortality in the general population.

Formulation and Evaluation of Pulsatile drug delivery of Albuterol sulphate and Theophylline drugs using modified Pulsincap technology

Albuterol Sulphate and Theophylline are used as anti-asthma agents. The objective of the present investigation was to design develop and evaluate a modified pulsincap drug delivery system of Albuterol Sulphate and Theophylline for the treatment of Asthma. The body of capsule was made insoluble with water by cross linking with formaldehyde. This modified capsule was completely filled with drug with polymer such as HPMCK15M, HPMC K 100M, PVPK-30 to expel the drug after predetermined lag time. A hydrogel plug was inserted in the body of a capsule to obtain desired drug release after a lag time for chronotherapy of asthma. Untreated capsule was attached to the treated body and was released. The drug was exerted to precompression parameter such as Angle of repose, Bulk density, Tapped density, Car’s index Hassner’s ratio. These capsules were subjected to further post formulation studies such as weight variation, drug content, invitro dissolution studies separately. The pre and post formulation parameters were found to be within permissible limit. The mere compatibility of drug, polymer and excipients were determined by Fourier transform infrared analysis (FTIR) and UV-Visible spectroscopy (UV). The results showed that drug was completely compatible with polymer and excipients. In vitro dissolution were carried out by using pH 6 .8 and pH 7.4 buffers. Based on the result obtained F5 Formulation shows good dissolution profile. Higuchi, Hixson crowell. Koresmeyer peppas to evaluate the kinetics and drug release. The drug release follows first order kinetics and the mechanism was found to be NON FICKS DIFFUSION.&#x0D; Keywords: Albuterol Sulphate, Theophylline, modified pulsincap drug delivery system, FTIR, Dissolution

Influence of surface mining on seasonal hydrology response to storms across eastern Kentucky, USA

ABSTRACT Mountain Top Removal and Valley Fill (MTR/VF) practices have drastically altered the surface cover, topography and hydrology of many watersheds across the Appalachian region of the US. These practices strip the bedrock from the ridges and peaks of watersheds, before removing the coal seams and depositing the waste fill into adjacent valleys. Existing research has generated conflicting outcomes as to the resulting hydrological impacts in response to storms. This creates potential issues for subsequent mitigation projects seeking to recreate prior hydrological conditions and riparian ecosystems. Our study focused on the potential influence of MTR/VF practices for a series of mined and unmined watersheds across the Eastern Coalfield of Kentucky. We analyzed rainfall-runoff response, focusing on how quickly rainfall was converted to quickflow and how much water left the catchment during storms for the 2022 water year. Lag times were shortened for the mined watersheds while quickflow coefficients reduced when vegetation cover increased. Valley fill-in mined watersheds also appears to create a delayed secondary release of quickflow from headwater locations during more extreme storms. These findings may assist future reclamation/mitigation practices for mined watersheds across Eastern Kentucky aiming to correctly recreate the hydrologic conditions that resemble those of unmined landscapes.

Dashing Growth Curves: a web application for rapid and interactive analysis of microbial growth curves

BackgroundRecording and analyzing microbial growth is a routine task in the life sciences. Microplate readers that record dozens to hundreds of growth curves simultaneously are increasingly used for this task raising the demand for their rapid and reliable analysis.ResultsHere, we present Dashing Growth Curves, an interactive web application (http://dashing-growth-curves.ethz.ch/) that enables researchers to quickly visualize and analyze growth curves without the requirement for coding knowledge and independent of operating system. Growth curves can be fitted with parametric and non-parametric models or manually. The application extracts maximum growth rates as well as other features such as lag time, length of exponential growth phase and maximum population size among others. Furthermore, Dashing Growth Curves automatically groups replicate samples and generates downloadable summary plots for of all growth parameters.ConclusionsDashing Growth Curves is an open-source web application that reduces the time required to analyze microbial growth curves from hours to minutes.

Atmospheric pollen concentrations and chronic obstructive pulmonary disease (COPD) patients visits in Beijing: time series analysis using a generalized additive model

To investigate the correlation between the daily visits of chronic obstructive pulmonary disease (COPD) patients in hospital clinic and pollen concentrations in Beijing. We collected daily visits of COPD patients of Beijing Shijitan Hospital from April 1st, 2019 to September 30th, 2019. The relationship between pollen concentrations and COPD patient number was analyzed with meteorological factors, time trend, day of the week effect and holiday effect being controlled by the generalized additive model of time series analysis. R4.1.2 software was applied to generate Spearman correlation coefficient, specific and incremental cumulative effect curves of relative risks as well as the response and three-dimensional diagrams for the exposure lag effect prediction. The fitting models were used to predict the lag relative risk and 95% confidence intervals for specific and incremental cumulative effects of specific pollen concentrations. The number of COPD patients was positively correlated with pollen concentration. When pollen concentration increased by 10 grains/1000 mm2, the peak value of the specific cumulative effect appeared on day0, with the effect gone on day4 and a lag time of 4 days observed, whereas the incremental cumulative effect’s peak value was shown on day17, and the effect disappeared on day18, with a lag time of 18 days. The results showed that pollen concentration was not only positively correlated with the number of COPD patients, but also had a bimodal lag effect on COPD visits in the hospital at Beijing.

The Association of Rheumatologist Supply and Multidisciplinary Care With Timely Patient Access to Rheumatologists: Evidence From British Columbia, Canada.

The objective was to understand how the expansion of rheumatology supply and the introduction of multidisciplinary care was associated with access to rheumatology services. We accessed Population Data BC, a longitudinal database with de-identified individual-level health data on all residents of British Columbia, Canada, to analyze physician visits and prescribing from 2010-2011 to 2019-2020. We calculated access as the time from referral to first rheumatologist visit and, for people with rheumatoid arthritis (RA), time to first disease-modifying antirheumatic drug (DMARD). Associations between lag time, patient characteristics, and system variables were explored using quantile regression. Over the study period, there were 149,902 new rheumatologist visits, with 31% more visits in 2019-2020 than in 2010-2011. The proportion of first visits for patients with inflammatory arthritis increased from 28% to 51%. The median time from referral to first visit decreased by 22 days (35%) from 63 days (interquartile range 21-120 days) in 2010-2011. For people with RA, time from referral to DMARD decreased by 4 days (6%) to 62 days. Male sex, living in metropolitan areas, and having a rheumatologist who used a multidisciplinary care assessment code were associated with shorter times from referral to first DMARD. Access to rheumatology care improved, and the increased proportion of patients with IA in the first visits case-mix indicates that rheumatologist supply and incentives for multidisciplinary care may have improved referral patterns. However, time to DMARDs for people with RA remained long, and we found signals of unequal access for female patients and people living outside of metropolitan areas.

Comparative evaluation of the dynamics of terrestrial water storage and drought incidences using multiple data sources: Tana sub-basin, Ethiopia

Abstract Evaluating water storage changes and addressing drought challenges in areas like the Tana sub-basin in Ethiopia is difficult due to limited data availability. The aim of this study was to evaluate the dynamics of terrestrial water anomaly and drought incidences by employing multiple data source. The Gravity Recovery and Climate Experiment (GRACE) and Global Land Data Assimilation System (GLDAS) datasets were used to assess the long-term water storage dynamics and drought incidences using the weighted water storage deficit index (WWSDI). WWSDI was used to identify drought periods, which ranged from severe to extreme drought. Despite the overall increase in average annual total water storage anomaly (TWSA) by 0.43 cm/year and a net gain of 50.68 cm equivalent water height from 2003 to 2022, there were instances of terrestrial water storage deficits, particularly in 2005, 2006, and 2009, during historical drought periods. The TWSA exhibited a strong correlation with Lake Tana water storage and precipitation anomalies after adjusting lag times. WWSDI displayed a high correlation with WSDI but a weak correlation with SPI and SPEI. Therefore, utilization of GRACE and GLDAS data is promising for evaluating terrestrial water storage and monitoring drought in data-deficient regions like the Tana sub-basin in Ethiopia.

Population pharmacokinetics of the dual endothelin receptor antagonist aprocitentan in subjects with or without essential or resistant hypertension.

Aprocitentan is a novel, potent, dual endothelin receptor antagonist that recently demonstrated efficacy in the treatment of difficult-to-treat (resistant) hypertension. The aim of this study was to develop a population pharmacokinetic (PK) model describing aprocitentan plasma concentration over time, to investigate relationships between subject-specific factors (covariates) and model parameters, and to quantify the influence of the identified covariates on the exposure to aprocitentan via model-based simulations, enabling judgment about the clinical relevance of the covariates.PK data from 902 subjects in ten Phase 1, one Phase 2, and one Phase 3 study were pooled to develop a joint population PK model. The concentration-time course of aprocitentan was described by a two-compartment model with absorption lag time, first-order absorption and elimination, and reduced relative bioavailability following very high doses of 300 and 600mg.The population PK model described the observed data well. Volume and clearance parameters were associated with body weight. Renal function as reflected by estimated glomerular filtration rate (eGFR), hepatic impairment, and sex were identified as relevant covariates on clearance.The subject-specific characteristics of body weight, eGFR, hepatic impairment, and sex were shown to influence exposure parameters area under the concentration-time curve and maximum concentration in steady state to a limited extent, i.e., not more than 25% different from a reference subject, and therefore do not warrant dose adjustments.

Population pharmacokinetic modeling of oral brepocitinib in healthy volunteers and patients with immuno-inflammatory diseases.

The objective of this population pharmacokinetic (PK) analysis was to characterize the concentration-time profile of brepocitinib plasma concentration after single- and multiple-oral administration in healthy volunteers (HVs) and patients with immuno-inflammatory diseases. Blood samples from phase I HV and phase II clinical studies of patients with alopecia areata, psoriasis, psoriatic arthritis, ulcerative colitis (UC), vitiligo, and hidradenitis suppurativa were analyzed using a nonlinear mixed-effects modeling approach. Effects of patients' characteristics on brepocitinib exposure were investigated. Overall, 8552 brepocitinib plasma concentrations from 775 individuals were included in the analysis. The PKs of brepocitinib were adequately described by a two-compartment model with first-order absorption and a lag time for tablet formulation, dose-dependent bioavailability, and Box-Cox transformed interindividual variabilities on apparent clearance (CL/F) and apparent central volume of distribution (Vc/F). For a typical 70-kg non-Asian female patient with baseline aspartate aminotransferase of 22 unit/liter, CL/F and Vc/F estimates were 17.5 L/h and 88.5 L, respectively. Asians had a higher exposure (independent of body weight), caused by a 10% lower CL/F when compared to other individuals. Independent of baseline body weight, the male population showed 13% higher Vc/F compared to the female population. Patients with UC were predicted to have 46% slower absorption rate compared to other individuals. The PKs of brepocitinib were well-characterized by a two-compartment model with first-order absorption and dose-dependent bioavailability. Several covariates, such as race and sex, were identified to have statistically significant, but not clinically meaningful, effects on the estimated PK parameters.

Analysis of Factors Driving Subtropical Forest Phenology Differentiation, Considering Temperature and Precipitation Time-Lag Effects: A Case Study of Fujian Province

Subtropical forest phenology differentiation is affected by temperature, precipitation, and topography. Understanding the primary contributing elements and their interactions with forest phenology can help people better comprehend the subtropical forest growth process and its response to climate. Meanwhile, the temporal and spatial variations of phenological rhythms are important indicators of climatic impacts on forests. Therefore, this study aimed to analyze both a total area and different forest growth environments within the whole (i.e., coastal site areas (II, IV) and inland site areas (I, III)) as to spatiotemporal patterns associated with subtropical forests in Fujian Province, which is located at the boundary between the middle and south subtropical zones. Considering the asymmetric effects of climate and forest growth, this study chose pre-seasonal and cumulative temperature and precipitation factors and utilized the GeoDetector model to analyze the dominant drivers and interactions within phenology differentiation in Fujian Province. The results show the following: (1) All of the phenological parameters were advanced or shortened over the 19-year observation period; those of shrubland and deciduous broadleaf forests fluctuated greatly, and their stability was poor. (2) The phenological parameters were more distinct at the borders of the site areas. Additionally, the dates associated with the end of the growth season (EOS) and the date-position of peak value (POP) in coastal areas (i.e., II and IV) were later than those in inland areas (i.e., I and III). Among the parameters, the length of the growth season (LOS) was most sensitive to altitude. (3) Precipitation was the main driving factor affecting the spatial heterogeneity of the start of the growth season (SOS) and the EOS. The relatively strong effects of preseason and current-month temperatures on the SOS may be influenced by the temperature threshold required to break bud dormancy, and the relationship between the SOS and temperature was related to the lag time and the length of accumulation. The EOS was susceptible to the hydrothermal conditions of the preseason accumulation, and the variation trend was negatively correlated with temperature and precipitation. Spatial attribution was used to analyze the attribution of phenology differentiation from the perspectives of different regions, thus revealing the relationships between forest phenology and meteorological time-lag effects, the result which can contribute to targeted guidance and support for scientific forest management.

Research of time lag characteristics of Pilot-operated Solenoid Valve Damper based on multi-physics field

The development of semi-active suspensions has introduced Pilot-operated Solenoid Valve Dampers (PSVD) that can adjust damping characteristics for different road conditions while considering stability and comfort. However, the PSVD’s additional control system and valve-controlled components make it challenging to avoid time lag in the response of the damping force when the control current signal is switched. This time lag characteristic significantly impacts the performance of the control system, making it difficult to achieve optimal dynamic performance and potentially compromising the safety of drivers and passengers. As a result, understanding and representing the PSVD time lag characteristics and investigating their influence have become important research areas in the field of semi-active suspension. This article begins by explaining the mechanism behind the generation of PSVD time lag characteristics. It analyzes the structure and operating principle of the PSVD, identifying two main types of time lag: electromagnetic time lag and inertial time lag. To address the limitations of existing simulation models, the study combines parameterization and finite element simulation to create a multi-physics field time lag characteristics kinetic representation model of the PSVD, incorporating the electric, magnetic, mechanical, and fluid aspects. To validate the accuracy of the time lag characteristics simulation model, tests on the velocity and time lag characteristics of the PSVD are conducted. The simulation results are compared to the test results, demonstrating that the maximum error of the lag time meets the engineering confidence requirement. This confirms the feasibility of establishing a simulation model for the PSVD time lag characteristics. Finally, we analyze the PSVD total lag time under different working conditions using the simulation model. It explores the relationship between the PSVD total lag time and the lag time of each component, proposes a lag time decomposition relationship, and investigates the crucial influencing factors on the lag time.

Depression is associated with discoordination between heart rate variability and physical acceleration in older women.

It is well known that depression is closely associated with the autonomic nervous system and physical acceleration (PA), which may cause functional time-deviance between these two parameters. Exploring this relationship is important in sustaining the mental and physical health of older adults in daily life. However, few studies have assessed the relationship between depression and the coordination of parasympathetic nervous activity (PSNA) and PA. The present study was designed to investigate whether the coordination between PSNA and PA is associated with the mental state of healthy volunteers in normal daily lives and the underlying mechanism. In total, 95 adult women were divided into non-older and older groups comprising 50 (aged 20-59 years) and 45 (aged 60-85 years) women, respectively. PSNA and PA data were simultaneously obtained every minute for 24 h during the free-moving day using the ActiveTracer accelerometer. Lag time was determined as the time difference between PSNA and PA, and it was introduced as a parameter of %lag0, which is the percent ratio of the lag = 0 min between PSNA and PA in 1 h. The General Health Questionnaire 28 (GHQ28) was used to evaluate the effects of psychological distress, including depression. In the hour before sleep, %lag0 was significantly lower in older women (38.7 ± 6.4) who had higher GHQ28 values (subscale D = 0, n = 12) compared with that in older women (19.4 ± 10.5) with lower values (subscale D ≧ 1, n = 33) (p < 0.05). Impairments in coordination between PSNA and PA are significantly associated with depression in older women, particularly in the hour before sleep on free-moving days.

Research on unmanned navigation and PID control method for aircraft tractor

Unmanned navigation and control systems are gaining traction in various industries, including aviation. The related issues of control systems are also hot topics in research. This paper comprehensively studies the application of unmanned navigation and the implementation of proportional integral differential (PID) control methods for aircraft tractors. Aiming at the characteristics of large deviation of turning trajectory angle error and long lag time in the process of an unmanned tractor, the dynamic characteristics and state equation of the unmanned tractor are established by the PID method, and the motion equation is established by the Cartesian coordinate system. Finally, the simulation results show that the proposed method has good dynamic stability and rapidity. Compared with proportional control or integral control alone, the PID control system has better stability and a faster frequency response, which can be obtained that the PID control algorithm can effectively improve the work efficiency of the unmanned tractor and reduce its instability and slow response.

Abstract TP294: Sex Differences in Thrombin Generation in Patients With Acute Ischemic Stroke

Background and Purpose: Sex differences in stroke exist, including variation in stroke risk and outcome. Differences in thrombin generation may contribute to this variation between females and males. To examine this, we assessed sex differences in thrombin generation between females and males with acute ischemic stroke and the relationship to blood cell gene expression. Methods: In 97 patients with acute ischemic stroke thrombin generation was measured by thrombin generation assay. Blood cell gene expression was measured by microarray. Differences in thrombin generation between sexes were identified and the relationship to blood cell gene expression examined. Genes associated with sex differences in thrombin generation were analysed by functional pathway analysis. Results: Females and males had similar overall capacity to generate thrombin. The peak thrombin generated in females was 468.8nM (SD 91.6), comparable to males 479.3 (SD 90.8; p=0.58). Lag time, time to peak thrombin, and endogenous thrombin potential were also similar between females and males. While overall thrombin generation was comparable between females and males with stroke, differences in genes that promote this thrombin generation exist. Females with high peak thrombin had an increase in genes that promote thrombosis, and platelet activation. In contrast, males with high peak thrombin had a decrease in genes involved in thrombus degradation. Conclusion: Females and males with acute ischemic stroke have similar capacity to generate thrombin. However, differences may exist in how this thrombin generation is achieved, with females having increased thrombin signaling, and platelet activation, and males having decreased thrombus degradation. This suggests regulatory differences in thrombosis may exist between females and males that may contribute to sex differences in stroke.

Association between venous thromboembolism-associated genetic variants, coagulation factor levels, and thrombin generation potential.

Recently three large meta-analyses of genome-wide association studies for venous thromboembolism (VTE) identified over 130 genetic variants. However, mechanisms by which newly identified and therefore underexplored VTE-associated genetic variants influence VTE remain unclear. To elucidate the mechanism, we investigated the association between 61 newly identified VTE-associated genetic variants and the levels of coagulation factor (F) VIII, FIX, FXI, and fibrinogen as well as thrombin generation parameters (lag time, peak, endogenous thrombin potential, time-to-peak, and velocity), which are well-known biological traits associated with VTE. This study was conducted on 5341 participants of the Netherlands Epidemiology of Obesity study. The associations between VTE-associated genetic variants and coagulation factor levels and thrombin generation parameters were examined using linear regression analyses, adjusted for age, sex, body mass index, oral contraceptive use, hormone replacement therapy, and menopausal status. Of 61 genetic variants, 33 were associated with one or more of the coagulation factor levels and thrombin generation parameters. Following multiple testing corrections, five genetic variants remained significant, of which MAP1A rs55707100 exhibited the most robust association with thrombin generation parameters and FXI levels (β=-5.33%, 95% confidence interval: -8.44, -2.22). Our findings shed light on the underlying mechanisms by which these genetic variants influence the risk of VTE.

Empirical Dynamic Modeling Reveals Complexity of Methane Fluxes in a Temperate Salt Marsh

AbstractMethane dynamics within salt marshes are complex because vegetation types, temperature, oscillating water levels, and changes in salinity and redox conditions influence CH4 production, consumption, oxidation, and emissions. These non‐linear and complex interactions among variables affect the traditionally expected functional relationships and present challenges for interpreting and developing process‐based models. We employed empirical dynamic modeling (EDM) and convergent cross mapping (CCM) as a novel approach for characterizing seasonal/multiday and diurnal CH4 dynamics by inferring causal variables, lags, and interconnections among multiple biophysical variables within a temperate salt marsh using 5 years of eddy covariance data. EDM/CCM is a nonparametric approach capable of quantifying the coupling between variables while determining time scales where variable interactions are the most relevant. We found that gross primary productivity, tidal creek dissolved oxygen, and temperature were important for seasonal/multiday dynamics (rho = 0.73–0.80), while water level was most important for diurnal dynamics during both the growing and dormancy phenoperiods (rho = 0.72 and 0.56, respectively). Lags for the top‐ranked variables (i.e., gross primary productivity, dissolved oxygen, temperature, water level) occurred between 1 and 5 weeks at the seasonal scale and 1–24 hr at the diurnal scale. The EDM had high prediction capabilities for intra‐/inter‐seasonal patterns and annual CH4 sums but had limitations in representing large, infrequent fluxes. Results highlight the importance of non‐linearity, drivers, lag times, and interconnections among multiple biophysical variables that regulate CH4 fluxes in tidal wetlands. This research introduces a novel approach to examining CH4 fluxes, which will aid in evaluating current paradigms in wetlands and other ecosystems.