Volume Of Distribution Research Articles

Development of a predictive algorithm for the efficacy of half-life extension strategies

A challenge in development of peptide and protein therapeutics is rapid elimination from the body, necessitating frequent dosing that may lead to toxicities and/or poor patient compliance. To solve this issue, there has been great investment into half-life extension of rapidly eliminated drugs using approaches such as albumin binding, fusion to albumin or Fc, or conjugation to polyethylene glycol. Despite clinical successes of half-life extension products, no clear relationship has been drawn between properties of drugs and the pharmacokinetic parameters of their half-life extended analogues. In this study, non-compartmentally derived pharmacokinetic parameters (half-life, clearance, volume of distribution) were collected for 186 half-life extended drugs and their unmodified parent molecules. Statistical testing and regression analysis was performed to evaluate relationships between pharmacokinetic parameters and a matrix of variables. Multivariate linear regression models were developed for each of the three pharmacokinetic parameters and model predictions were in good agreement with observed data with r2 values for each parameter being: half-life: 0.879, clearance: 0.820, volume of distribution: 0.937. Significant predictors for each parameter included the corresponding pharmacokinetic parameter of the parent drug and descriptors related to molecular weight. This model represents a useful tool for prediction of the potential benefits of half-life extension.

Development and validation of individualized tacrolimus dosing software for Chinese pediatric liver transplantation patients: a population pharmacokinetic approach.

We aim to describe the population pharmacokinetics (PPK) of tacrolimus in Chinese pediatric patients under 4years old after liver transplantation and to develop individualized tacrolimus dosing software. A total of 663 blood concentrations from 85 patients aged 4.57months to 3.97years were collected in this study. PPK analysis was performed using a nonlinear mixed effects modeling approach with the software, Phoenix. Using C#, an individualized tacrolimus dosing software was created. The software was then used to predict the concentrations of another ten pediatric liver transplantation patients to verify the accuracy of said software. The predictive error (PE) and the absolute predictive error (APE) for each predicted time point were computed. A one-compartment model with first-order elimination best fitted the data. The apparent volume of distribution (V/F) and apparent clearance (CL/F) were 198.65 L and 2.41 L/h. Postoperative days (POD), total bilirubin (TBIL), and the use of voriconazole significantly influenced tacrolimus apparent clearance. The incorporation of an increasing number of actual blood drug concentrations into the prediction resulted in a decrease in both PE (72%, 17%, 7%) and APE (87%, 53%, 26%). A qualified PPK model of tacrolimus was developed in Chinese pediatric patients. The individualized tacrolimus dosing software could be used as a suitable tool for the personalization of tacrolimus dosing for pediatric patients after liver transplantation.

Population pharmacokinetics of free and liposome-encapsulated mitoxantrone in patients with relapsed/refractory lymphoma or small cell lung cancer.

This study is aimed at investigating the pharmacokinetic (PK) characteristics of pegylated liposomal mitoxantrone (PLM) in patients with relapsed/refractory lymphoma or small cell lung cancer (SCLC) by constructing population pharmacokinetic (popPK) models for both liposome-encapsulated mitoxantrone and free mitoxantrone. A total of 23 patients with relapsed/refractory lymphoma and 42 patients with SCLC were included. A popPK model was simultaneously developed utilizing a non-linear mixed effects model (NONMEM) to explore the PK profiles of liposome-encapsulated mitoxantrone and free mitoxantrone. Clearance (CL) and distribution volume (V) were calculated, and covariate analysis was employed to evaluate the influence of patient disease type, demographic information, and biochemical indicators of liver and kidney function on PK parameters. The concentration-time profiles for both liposome-encapsulated mitoxantrone and free mitoxantrone were described by a one-compartment model. The release (Rel) of liposome-encapsulated mitoxantrone to free mitoxantrone was determined to be 0.0191 L/h, and the V of liposome-encapsulated mitoxantrone was 2.32 L. The apparent CL of free mitoxantrone was estimated at 1.66 L/h. The apparent V of free mitoxantrone was 35.8 L in patients with relapsed/refractory lymphoma and 22.2 L for patients with SCLC. In patients with relapsed/refractory lymphoma, lower maximum concentration (Cmax) and higher apparent V of free mitoxantrone were observed compared with patients with SCLC. The popPK characteristics of both liposome-encapsulated and free mitoxantrone in patients with relapsed/refractory lymphoma or SCLC were effectively described by a one-compartment model.

Treatment plan quality on a new slip ring-mounted radiotherapy system for cervical and breast cancer: Dosimetry and plan complexity analysis

PurposeThis study focuses on evaluating the performance of ring-mounted LINAC TAICHI, a novel radiotherapy system, with treatment plans obtained from Raystation TPS (TAICHI-RS), by comparing its plans with those on the C-arm LINAC TrueBeam with Eclipse TPS (TrueBeam-E) in the context of cervical cancer and breast cancer treatments. The study aims to assess the dosimetric results and plan complexity metrics of this new system. Method and materialsThe research randomly selected 13 cervical cancer and 11 breast cancer patients treated with VMAT on the TAICHI LINAC. The plans were reproduced in Eclipse TPS for the TrueBeam LINAC using the same CT and structure sets. Dosimetric metrics, including dose distribution in the target volume and the dose received by OARs, were analyzed. Complexity metrics were also assessed to evaluate plan complexity. In addition, patient-specific quality assurance (PSQA) was measured for both TAICHI-RS and TrueBeam-E systems. ResultsResults have shown that in cervical cancer plans, both systems performed similarly in terms of OARs. In breast cancer plans, TAICHI-RS system demonstrated significant advantages, achieving better dose homogeneity, lower irradiated doses in OARs, and more uniform dose distributions in the target volume compared to TrueBeam-E system (P values < 0.05). Complexity metrics indicated that for cervival cancer, TAICHI-RS plans were generally more complex than TrueBeam-E plans, while they were similar for breast cancer. The average PSQA passing rates of TAICHI-RS versus TrueBeam-E systems were 98.5% versus 98.7% (2%/2 mm criteria) and 99.9% versus 99.9% (3%/3 mm criteria) for cervival cancer plans, and 95.7% versus 97.4% (2%/2 mm criteria) and 99.3% versus 99.5% (3%/3 mm criteria) for breast cancer plans respectively. ConclusionIn conclusion, the new TAICHI-RS system was demonstrated to be clinically useful and accurate in delivering treatment plans for cervical and breast cancer. The study suggests that TAICHI-RS system could offer advantages in breast cancer treatments particularly. Further multi-center research is recommended for comprehensive validation.

A systematic review and meta-analysis of neuroimaging studies examining synaptic density in individuals with psychotic spectrum disorders

BackgroundPsychotic disorders have long been considered neurodevelopmental disorders where excessive synaptic pruning and cortical volume loss are central to disease pathology. We conducted a systematic review of the literature to identify neuroimaging studies specifically examining synaptic density across the psychosis spectrum.MethodsPRISMA guidelines on reporting were followed. We systematically searched MEDLINE, Embase, APA PsycINFO, Web of Science and The Cochrane Library from inception to December 8, 2023, and included all original peer-reviewed articles or completed clinical neuroimaging studies of any modality measuring synaptic density in participants with a diagnosis of psychosis spectrum disorder as well as individuals with psychosis-risk states. The NIH quality assessment tool for observational cohort and cross-sectional studies was used for the risk of bias assessment.ResultsFive studies (k = 5) met inclusion criteria, comprising n = 128 adults (psychotic disorder; n = 61 and healthy volunteers; n = 67 and specifically measuring synaptic density via positron emission tomography (PET) imaging of the synaptic vesicle glycoprotein 2 A (SV2A). Three studies were included in our primary meta-analysis sharing the same outcome measure of SV2A binding, volume of distribution (VT). Regional SV2A VT was reduced in psychotic disorder participants in comparison to healthy volunteers, including the occipital lobe (Mean Difference (MD)= -2.17; 95% CI: -3.36 to -0.98; P < 0.001 ), temporal lobe (MD: -2.03; 95% CI: -3.19 to -0.88; P < 0.001 ), parietal lobe (MD:-1.61; 95% CI: -2.85 to -0.37; P = 0.01), anterior cingulate cortex (MD= -1.47; 95% CI: -2.45 to -0.49; P = 0.003), frontal cortex (MD: -1.16; 95% CI: -2.18 to -0.15; P = 0.02), amygdala (MD: -1.36; 95% CI: -2.20 to -0.52, p = 0.002), thalamus (MD:-1.46; 95% CI:-2.46 to -0.46, p = 0.004) and hippocampus (MD= -0.96; 95% CI: -1.59 to -0.33; P = 0.003).ConclusionsPreliminary studies provide in vivo evidence for reduced synaptic density in psychotic disorders. However, replication of findings in larger samples is required prior to definitive conclusions being drawn.PROSPEROCRD42022359018.

Antimicrobial Pharmacokinetic Considerations in Extracorporeal Membrane Oxygenation.

Critical illness creates challenges for healthcare providers in determining the optimal treatment of severe disease, particularly in determining the most appropriate selection and dosing of medications. Critically ill patients experience endogenous physiologic changes that alter the pharmacokinetics (PKs) of medications. These alterations can be further compounded by mechanical support modalities such as extracorporeal membrane oxygenation (ECMO). Specific components of the ECMO circuit have the potential to affect drug PKs through drug sequestration and an increase in the volume of distribution. Factors related to the medications themselves also play a role. These PK alterations create problems when trying to properly utilize antimicrobials in this patient population. The literature seeking to identify appropriate antimicrobial dosing regimens is both limited and difficult to evaluate due to patient variability and an inability to determine the exact role of the ECMO circuit in reduced drug concentrations. Lipophilic and highly protein bound medications are considered more likely to undergo significant drug sequestration in an ECMO circuit, and this general trend represents a logical starting point in antimicrobial selection and dosing in patients on ECMO support. This should not be the only consideration, however, as identifying infection and evaluating the efficacy of treatments in this population is challenging. Due to these challenges, therapeutic drug monitoring should be utilized whenever possible, particularly in cases with severe infection or high concern for drug toxicity.

Population Pharmacokinetic of the Diterpenes ent-Polyalthic Acid and Dihydro-ent-Agathic Acid from Copaifera Duckei Oil Resin in Rats.

Copaifera duckei oleoresin is a plant product extensively used by the Brazilian population for multiple purposes, such as medicinal and cosmetic. Despite its ethnopharmacological relevance, there is no pharmacokinetic data on this important medicinal plant. Due to this, we determined the pharmacokinetic profile of the major nonvolatile compounds of C. duckei oleoresin. The diterpenes ent-polyalthic acid and dihydro-ent-agathic acid correspond to approximately 40% of the total oleoresin. Quantification was performed using LC-MS/MS, and the validated analytical method showed to be precise, accurate, robust, reliable, and linear between 0.57 and 114.74 µg/mL plasma and 0.09 to 18.85 µg/mL plasma, respectively, for ent-polyalthic acid and dihydro-ent-agathic acid, making it suitable for application in preclinical pharmacokinetic studies. Wistar rats received a single 200 mg/kg oral dose (gavage) of C. duckei oleoresin, and blood was collected from their caudal vein through 48 h. Population pharmacokinetics analysis of ent-polyalthic and dihydro-ent-agathic acids in rats was evaluated using nonlinear mixed-effects modeling conducted in NONMEN software. The pharmacokinetic parameters of ent-polyalthic acid were absorption constant rate = 0.47 h-1, central and peripheral apparent volume of distribution = 0.04 L and 2.48 L, respectively, apparent clearance = 0.15 L/h, and elimination half-life = 11.60 h. For dihydro-ent-agathic acid, absorption constant rate = 0.28 h-1, central and peripheral apparent volume of distribution = 0.01 L and 0.18 L, respectively, apparent clearance = 0.04 L/h, and elimination half-life = 3.49 h. The apparent clearance, central apparent volume of distribution, and peripheral apparent volume of distribution of ent-polyalthic acid were approximately 3.75, 4.00-, and 13.78-folds higher than those of dihydro-ent-agathic.

The Relationship Between Static Characteristics of Physicians and Patient Consultation Volume in Internet Hospitals: Quantitative Analysis.

Internet medical treatment, also known as telemedicine, represents a paradigm shift in health care delivery. This contactless model allows patients to seek medical advice remotely, often before they physically visit a doctor's clinic. Herein, physicians are in a relatively passive position, as patients browse and choose their health care providers. Although a wealth of experience is undoubtedly a draw for many patients, it remains unclear which specific facets of a doctor's credentials and accomplishments patients prioritize during their selection process. Our primary aim is to delve deeper into the correlation between physicians' static characteristics-such as their qualifications, experiences, and profiles on the internet-and the number of patient visits they receive. We seek to achieve this by analyzing comprehensive internet hospital data from public hospitals. Furthermore, we aim to offer insights into how doctors can present themselves more effectively on web-based platforms, thereby attracting more patients and improving overall patient satisfaction. We retrospectively gathered web-based diagnosis and treatment data from the First Affiliated Hospital of Guangxi Medical University in 2023. These data underwent rigorous analysis, encompassing basic descriptive statistics, correlation analyses between key factors in doctors' internet-based introductions, and the number of patient consultation visits. Additionally, we conducted subgroup analyses to ascertain the independence of these vital factors. To further distill the essence from these data, we used nonnegative matrix factorization to identify crucial demographic characteristics that significantly impact patient choice. The statistical results suggested that there were significant differences in the distribution of consultation volume (P<.001), and the correlation analysis results suggested that there was a strong correlation between the two groups of data (ρ=0.93; P<.001). There was a correlation between the richness of a profile and popularity (P<.001). Patients were more interested in physicians with advanced titles, doctoral degrees, social activities, and scientific achievements (P<.001) as well as other institutional visit experiences (P=.003). More prosperous social activities, scientific achievements, experiences of other institutional visits, and awards were more common among people with advanced professional titles. Doctoral degrees remained attractive to patients when data were limited to senior physicians (P<.001). Patients trusted the medical staff with advanced titles, social activities, scientific achievements, and doctoral degrees (P<.001). Patient preferences for choosing a health care provider differed significantly between free and paid consultations. Notably, patients tended to trust doctors with advanced professional titles more and were more likely to seek out those with doctoral qualifications over other professional ranks. Additionally, physicians who actively participated in social events and scientific endeavors often had an advantage in attracting new patients. Given these insights, doctors who invest in enhancing their personal and professional experiences within these domains are likely to see increased popularity and patient satisfaction.

Ultrafast Interfacial Self-Assembly toward Bioderived Polyester COF Membranes with Microstructure Optimization.

The precise manipulation of the microstructure (pore size, free volume distribution, and connectivity of the free-volume elements), thickness, and mechanical characteristics of membranes holds paramount significance in facilitating the effective utilization of self-standing membranes. In this contribution, the synthesis of two innovative ester-linked covalent-organic framework (COF) membranes is first reported, which are generated through the selection of plant-derived ellagic acid and quercetin phenolic monomers in conjunction with terephthaloyl chloride as a building block. The optimization of the microstructure of these two COF membranes is systematically achieved through the application of three different interfacial electric field systems: electric neutrality, positive electricity, and negative electricity. It is observed that the positively charged system facilitates a record increase in the rate of membrane formation, resulting in a denser membrane with a uniform pore size and enhanced flexibility. In addition, a correlation is identified wherein an increase in the alkyl chain length of the surfactants leads to a more uniform pore size and a decrease in the molecular weight cutoff of the COF membrane. The resulting COF membrane exhibits an unprecedented combination of high water permeance, superior sieving capability, robust mechanical strength, chemical robustness for promising membrane-based separation science and technology.

Population pharmacokinetics of TLD-1, a novel liposomal doxorubicin, in a phase I trial.

TLD-1 is a novel pegylated liposomal doxorubicin (PLD) formulation aiming to optimise the PLD efficacy-toxicity ratio. We aimed to characterise TLD-1's population pharmacokinetics using non-compartmental analysis and nonlinear mixed-effects modelling. The PK of TLD-1 was analysed by performing a non-compartmental analysis of longitudinal doxorubicin plasma concentration measurements obtained from a clinical trial in 30 patients with advanced solid tumours across a 4.5-fold dose range. Furthermore, a joint parent-metabolite PK model of doxorubicinentrapped, doxorubicinfree, and metabolite doxorubicinol was developed. Interindividual and interoccasion variability around the typical PK parameters and potential covariates to explain parts of this variability were explored. Medians standard deviations of dose-normalised doxorubicinentrapped+free Cmax and AUC0-∞ were 0.342 0.134mg/L and 40.1 18.9mg·h/L, respectively. The median half-life (95h) was 23.5h longer than the half-life of currently marketed PLD. The novel joint parent-metabolite model comprised a one-compartment model with linear release (doxorubicinentrapped), a two-compartment model with linear elimination (doxorubicinfree), and a one-compartment model with linear elimination for doxorubicinol. Body surface area on the volumes of distribution for free doxorubicin was the only significant covariate. The population PK of TLD-1, including its release and main metabolite, were successfully characterised using non-compartmental and compartmental analyses. Based on its long half-life, TLD-1 presents a promising candidate for further clinical development. The PK characteristics form the basis to investigate TLD-1 exposure-response (i.e., clinical efficacy) and exposure-toxicity relationships in the future. Once such relationships have been established, the developed population PK model can be further used in model-informed precision dosing strategies. ClinicalTrials.gov-NCT03387917-January 2, 2018.

In-silico mechanistic analysis of adsorption of Iodinated Contrast Media agents on graphene surface

The study aims at assessing the potential of graphene-based adsorbents to reduce environmental impacts of Iodinated Contrast Media Agents (ICMs). We analyze an extensive collection of ICMs. A modeling approach resting on molecular docking and Density Functional Theory simulations is employed to examine the adsorption process at the molecular level. The study also relies on a Quantitative Structure-Activity Relationship (QSAR) modeling framework to correlate molecular properties with the adsorption energy (Ead) of ICMs, thus enabling identification of the key mechanisms underpinning adsorption and of the key factors contributing to it. A collection of distinct QSAR-based models is developed upon relying on Multiple Linear Regression and a standard genetic algorithm method. Having at our disposal multiple models enables us to take into account the uncertainty associated with model formulation. Maximum Likelihood and formal model identification/discrimination criteria (such as Bayesian and/or information theoretic criteria) are then employed to complement the traditional QSAR modeling phase. This has the advantage of (a) providing a rigorous ranking of the alternative models included in the selected set and (b) quantifying the relative degree of likelihood of each of these models through a weight or posterior probability. The resulting workflow of analysis enables one to seamlessly embed DFT and QSAR studies within a theoretical framework of analysis that explicitly takes into account model and parameter uncertainty. Our results suggest that graphene-based surfaces constitute a promising adsorbent for ICMs removal, π-π stacking being the primary mechanism behind ICM adsorption. Furthermore, our findings offer valuable insights into the potential of graphene-based adsorbent materials for effectively removing ICMs from water systems. They contribute to ascertain the significance of various factors (such as, e.g., the distribution of atomic van der Waals volumes, overall molecular complexity, the presence and arrangement of Iodine atoms, and the presence of polar functional groups) on the adsorption process.

Population pharmacokinetics and dose optimization of magnesium sulfate in Chinese preeclampsia population

ObjectiveTo establish the population pharmacokinetics (PPK) of magnesium sulfate (MgSO4)in women with preeclampsia (PE), and to determine the key covariates having an effect in magnesium pharmacokinetics in Chinese PE.MethodsPregnant women with PE prescribed MgSO4 were enrolled in this prospective study from April 2021 to April 2023. On the initial day of administration, the patients were administered a loading dose of 5 g in conjunction with 10 g of magnesium sulfate as a maintenance dose. On the second day, only the maintenance dose was administration, and maternal blood samples were taken at 0, 4, 5, and 12 h after the second day’s 10 g maintenance dose. The software Phoenix was used to estimate PPK parameters of MgSO4, such as clearance (CL) and volume of distribution (V), and to model PPK models with patient demographic, clinical, and laboratory covariates.ResultsA total of 199 blood samples were collected from 51 women with PE and PPK profiles were analyzed. The PPK of MgSO4 is consistent with to a one-compartment model. The base model adequately described the maternal serum magnesium concentrations after magnesium administration. The population parameter estimates were as follows: CL was 2.98 L/h, V was 25.07 L. The model predictions changed significantly with covariates (BMI, creatinine clearance, and furosemide). Furosemide statistically influences V. The creatinine clearance, BMI and furosemide jointly affects CL. Monte Carlo simulation results showed that a loading dose combined with a maintenance dose would need to be administered daily to achieve the therapeutic blood magnesium concentrations. For the non-furosemide group, the optimal dosing regimen was a 5 g loading dose combined with a 10 g maintenance dose of MgSO4. For the furosemide group, the optimal dosing regimen was a 2.5 g loading dose combined with a 10 g maintenance dose of MgSO4.ConclusionsThe magnesium PPK model was successfully developed and evaluated in Chinese preeclampsia population, and the dose optimization of MgSO4 was completed through Monte Carlo simulation.

Pharmacokinetics and pharmacodynamics of intravenously and subcutaneously administered pantoprazole in sheep (Ovis aries).

Abomasal ulcers are recognized in sheep of all ages, but research regarding therapeutic interventions is limited. Proton Pump Inhibitors (PPIs) such as pantoprazole, are clinically used with a paucity of evidence regarding efficacy in mature sheep. Intravenous and subcutaneously administered pantoprazole dosed at 1.0 mg/kg in adult sheep will increase the pH of abomasal fluid compared to pre-administration baseline. The objectives were to assess the effect of pantoprazole, after single and multiple administration, on abomasal fluid pH in adult sheep. A third objective was to describe the pharmacokinetic parameters of IV and SC pantoprazole. Four clinically healthy adult Southdown ewes previously fitted with a gastrostomy tube in the abomasum were utilized in this randomized, 2-way cross-over trial. Ewes received pantoprazole (1.0 mg/kg) as a single and 3-dose regimen (every 24 hours). After a 10 day washout period the reverse treatment was applied. Blood for analysis of pantoprazole concentration was collected intermittently for 24 hours, and abomasal fluid pH was measured at intervals for a 96-hour period. The pH of the abomasal fluid was higher in pantoprazole treatments for up to 24 hours after dosing. Following intravenous administration of pantoprazole to study ewes, elimination half-life, volume of distribution, and clearance of pantoprazole was estimated as 3.29 hours, 0.35 L/kg, and 65.26 mL/hr/kg respectively. After subcutaneous dosing, maximum concentration, time to maximum concentration, half-life of elimination, and volume of distribution, were estimated as 2604 ng/mL, 0.55 hours, 2.48 hours, and 0.37 L/kg. Additionally, the bioavailability was estimated as 83.33%. Pantoprazole administered IV or SC may be useful for treatment or prevention of abomasal ulcers in adult sheep.

Mechanical and surface characteristics in laser-assisted machining of NiFeCr alloy: An atomic-scale understanding

This investigation explores mechanical characteristics and subsurface damage of NiFeCr alloy in laser-assisted machining through molecular dynamics simulation. The results of machining force, friction coefficient, local strain/stress, temperature distribution, subsurface damage, surface morphology, and worn volume are comprehensively explored, thereby revealing the mechanism of laser-assisted machining under different working conditions. Compared to conventional processing, average machining force, shear strain, subsurface damage, and dislocated length are all reduced in laser-assisted machining, which improves surface finish quality. Amorphization of removed chips in laser-assisted machining enhances the material removal efficiency. Analysis of various laser powers shows a decreased machining force with increasing laser power. However, residual stress and temperature rise, potentially impacting surface integrity. The subsurface damage depth exhibits nonlinearity with increasing laser energy, highlighting the competition between mechanical stress and thermal effect. The surface morphology and atomic flow demonstrate effective material removal with increasing laser power. The average machining force, friction coefficient, and subsurface damage depth show nonlinear relationships with cutting speed. The number of worn atoms is proportional to machining length and cutting speed, indicating enhanced material removal during high-speed machining.

Amyloid and tau burden relate to longitudinal changes in the performance of complex everyday activities among cognitively unimpaired older adults: results from the performance-based Harvard Automated Phone Task.

Changes in everyday functioning constitute a clinically meaningful outcome, even in the early stages of Alzheimer's disease. Performance-based assessments of everyday functioning might help uncover these early changes. We aimed to investigate how changes over time in everyday functioning relate to tau and amyloid in cognitively unimpaired older adults. Seventy-six cognitively unimpaired participants (72 ± 6 years old, 61% female) completed multiple Harvard Automated Phone Task (APT) assessments over 2.0 ± 0.9 years. The Harvard APT consists of three tasks, performed through an automated phone system, in which participants refill a prescription (APT-Script), select a new primary care physician (APT-PCP), and transfer money to pay a bill (APT-Bank). Participants underwent Pittsburgh compound-B and flortaucipir positron emission tomography scans at baseline. We computed distribution volume ratios for a cortical amyloid aggregate and standardized uptake volume ratios for medial temporal and neocortical tau regions. In separate linear mixed models, baseline amyloid by time and tau by time interactions were used to predict longitudinal changes in performance on the Harvard APT tasks. Three-way amyloid by tau by time interactions were also investigated. Lastly, we examined associations between tau and change in Harvard APT scores in exploratory voxel-wise whole-brain analyses. All models were adjusted for age, sex, and education. Amyloid [unstandardized partial regression coefficient estimate (β) = -0.007, 95% confidence interval (95% CI) = (-0.013, -0.001)], and medial temporal tau [β = -0.013, 95% CI = (-0.022, -0.004)] were associated with change over time in years on APT-PCP only, i.e., higher baseline amyloid and higher baseline tau were associated with steeper rate of decline of APT-PCP. Voxel-wise analyses showed widespread associations between tau and change in APT-PCP scores over time. Even among cognitively unimpaired older adults, changes over time in the performance of cognitively complex everyday activities relate to cortical amyloid and widespread cerebral tau burden at baseline. These findings support the link between Alzheimer's disease pathology and function and highlight the importance of measuring everyday functioning in preclinical disease stages.

Long-term outcomes of ADEM-like and tumefactive presentations of CNS demyelination: a case-comparison analysis

A minority of initial multiple sclerosis (MS) presentations clinically or radiologically resemble other central nervous system (CNS) pathologies, acute disseminated encephalomyelitis (ADEM) or tumefactive demyelination (atypical demyelination presentations). With the aim of better defining the long-term outcomes of this group we have performed a retrospective cohort comparison of atypical demyelination versus ‘typical’ MS presentations. Twenty-seven cases with atypical presentations (both first and subsequent demyelinating events) were identified and compared with typical MS cases. Disease features analysed included relapse rates, disability severity, whole brain and lesion volumes, lesion number and distribution. Atypical cases represented 3.9% of all MS cases. There was considerable overlap in the magnetic resonance imaging (MRI) features of ADEM-like and tumefactive demyelination cases. ADEM-like cases tended to be younger but not significantly so. Atypical cases showed a trend towards higher peak expanded disability severity score (EDSS) score at the time of their atypical presentation. Motor, cranial nerve, cerebellar, cerebral and multifocal presentations were all more common in atypical cases, and less likely to present with optic neuritis. Cerebrospinal fluid (CSF) white cell counts were higher in atypical cases (p = 0.002). One atypical case was associated with peripheral blood myelin oligodendrocyte glycoprotein (MOG) antibodies, but subsequent clinical and radiological course was in keeping with MS. There was no difference in long-term clinical outcomes including annualised relapse rates (ARR), brain volume, lesion numbers or lesion distributions. Atypical demyelination cases were more likely to receive high potency disease modifying therapy early in the course of their illness. Despite the severity of initial illness, our cohort analysis suggests that atypical demyelination presentations do not confer a higher risk of long-term adverse outcomes.

The Intoxication Equivalency of 11-Hydroxy-Δ9-Tetrahydrocannabinol Relative to Δ9-Tetrahydrocannabinol.

Δ9-Tetrahydrocannabinol (THC) is a psychoactive phytocannabinoid found in the Cannabis sativa plant. THC is primarily metabolized into 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC) and 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (COOH-THC), which may themselves be psychoactive. There is very little research-based evidence concerning the pharmacokinetics and pharmacodynamics of 11-OH-THC as an individual compound. Male C57BL/6 mice were treated with THC or 11-OH-THC via intraperitoneal injection, tail vein intravenous injection, or oral gavage, and whole-blood compound levels were measured to determine pharmacokinetic parameters [Cmax, time to Cmax (Tmax), elimination half-life, area under the curve, apparent volume of distribution, systemic clearance, terminal rate constant, and absolute bioavailability] while also monitoring changes in catalepsy, body temperature, and nociception. 11-OH-THC achieved a Tmax at 30 minutes for all routes of administration. The maximum concentration at 30 minutes was not different between intravenous and intraperitoneal routes, but the oral gavage Cmax was significantly lower. THC had a 10-minute time to the maximum concentration, which was the first blood collection time point, for intravenous and intraperitoneal and 60 minutes for oral gavage, with a lower Cmax for intraperitoneal and oral gavage compared with intravenous. When accounting for circulating compound levels and ED50 responses, these data suggest that 11-OH-THC was 153% as active as THC in the tail-flick test of nociception and 78% as active as THC for catalepsy. Therefore, 11-OH-THC displayed equal or greater activity than the parent compound THC, even when accounting for pharmacokinetic differences. Thus, the THC metabolite 11-OH-THC likely plays a critical role in the bioactivity of cannabis; understanding its activity when administered directly will aid in the interpretation of future animal and human studies. SIGNIFICANCE STATEMENT: This study establishes that the primary metabolite of THC, 11-OH-THC, displays equal or greater activity than THC in a mouse model of cannabinoid activity when directly administered and even when accounting for route of administration, sex, pharmacokinetic, and pharmacodynamic differences. These data provide critical insight into the bioactivity of THC metabolites that will inform the interpretation of future in vivo cannabinoid research and represent a model for how THC consumption and metabolism may affect cannabis use in humans.

The relationship between SV2A levels, neural activity, and cognitive function in healthy humans: A [11C]UCB-J PET and fMRI study

Abstract Synaptic terminal density is thought to influence cognitive function and neural activity, yet its role in cognition has not been explored in healthy humans. We examined these relationships using [11C]UCB-J positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) in 25 healthy adults performing cognitive function tasks in the scanner. We found a significant positive association between synaptic terminal density, indicated by [11C]UCB-J PET distribution volume ratio (DVRcs), and neural activity during task switching (PLS-CA, second canonical component, r = 0.63, p = 0.043) with the thalamus-putamen data positively contributing to this relationship (PLS-CA loading 0.679, exploratory Pearson’s correlation r = 0.42, p = 0.044, uncorrected). Furthermore, synaptic terminal density predicted switch cost (PLS-R, R2 = 0.45, RMSE = 0.06, p = 0.022), with DVRcs negatively correlating with switch cost in key brain regions including the dorsolateral prefrontal cortex and posterior frontal cortex. Conversely, no significant relationships were observed between [11C]UCB-J DVRcs and neural activity or performance measures in the N-back working memory task, suggesting interindividual differences in synaptic terminal density may be more closely related to some cognitive functions and not others.

Simulation on the Dispersion of Natural Gas and its Volume Cloud Distribution on an Offshore Fixed Platform

The formation, migration and volume distribution of gas clouds, which are dominated by natural gas after oil and gas leakage, are the material basis of fire and explosion accidents on offshore platforms. Based on an offshore platform as the background, this paper conducts research on the gas cloud using numerical simulation method, the selection of different wind speeds, leak leakage rate of quality, wind direction and the direction angle, the leakage of gas diffusion behaviour simulation studies and its size distribution. There is a “coupling” effect on the volume value of 5% CH4 cloud between different wind speeds, leakage mass rates, and wind direction and leakage direction. When the wind speed is 13 m/s, the leakage mass velocity is 8 kg/s, and the included angle between wind direction and leakage direction is 180°, the “coupling” effect on the volume value of 5% CH4 cloud increases significantly. The above research results can provide a reference for the reasonable division of process risk area, firewall design and quantitative risk assessment of fire and explosion of an offshore platform.

Source Apportionment and Health Risk Assessment of Heavy Metals in Dust Around Bus Stops in Kaifeng City Based on APCS-MLR Model

In order to reveal the influence of urban transportation systems on the quality of urban ecological environment, this study selected surface dust from bus stops, which is strongly disturbed by transportation, as the research object. The contents of eight heavy metals (V, Cr, Co, Ni, Cu, Zn, Cd, and Pb) in the dust were determined through inductively coupled plasma mass spectrometry (ICP-MS) and inductively coupled plasma atomic emission spectroscopy (ICP-ASE). The spatial distribution characteristics and pollution levels of the eight heavy metals in the dust were analyzed using the geo-accumulation index method. A combined qualitative (correlation analysis and principal component analysis) and quantitative (absolute principal component scores-multiple linear regression model (APCS-MLR)) method was used to explore the sources of heavy metals in surface dust near bus stops. The spatial distribution characteristics of heavy metals from different sources were elucidated using the Kriging interpolation method. The health risk assessment model proposed by the United States Environmental Protection Agency was used to evaluate the human health risks. The results showed that the average values of ω(V), ω(Cr), ω(Co), ω(Ni), ω(Cu), ω(Zn), ω(Cd), ω(Pb), and ω(As) in the bus stop surface dust were 68.36, 59.73, 5.81, 19.34, 40.10, 208.32, 1.01, and 49.46 mg·kg-1, respectively. The concentrations of heavy metals (Cd, Zn, Pb, Cu, and Cr) in the dust were all higher than the background values in the surrounding dust, exceeding them by 3.37, 2.70, 2.01, 1.95, and 1.28 times, respectively. The order of the geo-accumulation index for the eight heavy metals was Cd &gt; Zn &gt; Pb &gt; Cu &gt; Cr &gt; V &gt; Ni &gt; Co, with Cd, Zn, Cu, and Pb in the dust indicating mild pollution levels and the others showing no pollution. The source analysis results showed that Cr, Co, and Ni were natural sources, whereas Cu, Zn, Pb, and Cd were traffic sources, and V was derived from a combination of industrial and natural sources. The APCS-MLR results indicated that the average contribution rates of the four sources were as follows:natural source (34.17 %), traffic source (29.84 %), industrial-natural mixed source (14.64 %), and unknown source (21.35 %). The spatial distribution map of the contribution rate of the traffic source was consistent with the trends of traffic volume and bus route density distribution. According to the health risk assessment, the cancer risk and non-cancer risk for children were both higher than those for adults. Cr was the main non-cancer factor, and Cd was the main cancer-causing factor. Natural and traffic sources contributed the most to non-cancer risk and cancer risk, respectively.