Allometric Scaling Research Articles

Observed and expected reliability of echocardiographic volumetric methods and critical change values for quantification of mitral regurgitant fraction in dogs.

Reliability of echocardiographic calculations for stroke volume and mitral regurgitant fraction (RFMR) are affected by observer variability and lack of a gold standard. Variability is used to calculate critical change values (CCVs) that are thresholds representing real change in a measure not associated with observer variability. Observed intra- and interobserver accuracy and variability in healthy dogs help model CCV for RFMR. Reliability cohort of 34 healthy dogs; allometric scaling cohort of 99 dogs with heart disease and 25 healthy dogs. Accuracy, variability, and CCV of 2 observers using geometric and flow-based echocardiography were prospectively compared against a standard of RFMR = 0% and extrapolated across a range of expected RFMR values in the reliability cohort partly derived from cardiac dimensions predicted by the allometric cohort. Accuracy of methods to determine RFMR in descending order was 4-chamber bullet (Bullet4CH), mitral inflow, cube formula, and Simpson's method of disks. Intraobserver variability was relatively high. The CCV for RFMR ranged from 28% to 88% and was inversely related to RFMR when extrapolated for use in affected dogs. For both observers, the Bullet4CH method had the lowest intraobserver CCV (Operator 1:28%, Operator 2:41%). Interobserver strength of agreement was low with intraclass correlation coefficients ranging from 0.210 to 0.413. Echocardiographic volumetric methods used to calculate stroke volume and RFMR have low accuracy and high variability in healthy dogs. Extrapolation of observed CCV to a range of expected RFMR suggests observers and methods are not interchangeable and variability might hinder routine clinical usage. Individual observers should be aware of their own variability and CCV.

Age- and size-related changes in hind limb muscles in two baboon species (Papio anubis and P. papio).

Body size has an impact on all biological functions and analyzing how body size impacts functional traits such as locomotion is critical. Body size does not only vary across species but also during ontogeny. Indeed, juvenile animals are often at a competitive disadvantage due to their smaller absolute size. Consequently, understanding size- and age-related changes in the locomotor system is critical for our understanding of adult phenotypes. Here, we address this question by exploring growth of the hind limb muscles in two species of closely related baboons that differ in their ecology, the olive baboon, Papio Anubis, the Guinea baboon, and Papio papio. To do so, we dissected 40 P. anubis and 10 P. papio and measured the mass and physiological cross-sectional area (PCSA) of the hind limb muscles. Our results showed no sexual differences in size- or age-related growth patterns, but did show differences between species. Whereas the scaling of muscle mass and PCSA was largely isometric in P. anubis, allometric scaling was more common in P. papio. Despite these differences between species, the knee extensors and external rotators at the knee scaled with positive allometry in both species highlighting their important role during adult locomotion. Although life-history data for P. papio are scarce, we suggest that differences between species may be associated with differences in adult body size and age of locomotor independence between species.

Pharmacokinetics of once-daily darunavir/ritonavir in second-line treatment in African children with HIV.

Darunavir is a potent HIV protease inhibitor with a high barrier to resistance. We conducted a nested pharmacokinetic sub-study within CHAPAS-4 to evaluate darunavir exposure in African children with HIV, taking once-daily darunavir/ritonavir for second-line treatment. We used data from the CHAPAS-4 pharmacokinetic sub-study treating children with once-daily darunavir/ritonavir (600/100 mg if 14-24.9 kg and 800/100 mg if ≥25 kg) with either tenofovir alafenamide fumarate (TAF)/emtricitabine (FTC), abacavir/lamivudine or zidovudine/lamivudine. Steady-state pharmacokinetic sampling was done at 0, 1, 2, 4, 6, 8, 12 and 24 hours after observed darunavir/ritonavir intake. Non-compartmental and population pharmacokinetic analyses were used to describe the data and identify significant covariates. Reference adult pharmacokinetic data were used for comparison. We simulated the World Health Organization (WHO) recommended 600/100 mg darunavir/ritonavir dose for the 25-34.9 kg weight band. Data from 59 children with median age and weight 10.9 (range 3.8-14.7) years and 26.0 (14.5-47.0) kg, respectively, were available. A two-compartment disposition model with transit absorption compartments and weight-based allometric scaling of clearance and volume best described darunavir data. Our population achieved geometric mean (%CV) darunavir AUC0-24h, 94.3(50) mg·h/L and Cmax, 9.1(35) mg/L, above adult reference values and Ctrough, 1.5(111) mg/L, like adult values. The nucleoside reverse-transcriptase inhibitor backbone was not found to affect darunavir concentrations. Simulated WHO-recommended darunavir/ritonavir doses showed exposures equivalent to adults. Higher alpha-1-acid glycoprotein increased binding to darunavir and decreased apparent clearance of darunavir. Darunavir exposures achieved in our trial are within safe range. Darunavir/ritonavir can safely be co-administered with TAF/FTC. Both WHO-recommended 600/100 mg and CHAPAS-4 800/100 mg darunavir/ritonavir doses for the 25-34.9 kg weight band offer favourable exposures. The choice between them can depend on tablet availability.

A comparison of the antiepileptogenic efficacy of two rationally chosen multitargeted drug combinations in a rat model of posttraumatic epilepsy

Post-traumatic epilepsy (PTE) is a recurrent and often drug-refractory seizure disorder caused by traumatic brain injury (TBI). No single drug treatment prevents PTE, but preventive drug combinations that may prophylax against PTE have not been studied. Based on a systematic evaluation of rationally chosen drug combinations in the intrahippocampal kainate (IHK) mouse model of acquired epilepsy, we identified two multi-targeted drug cocktails that exert strong antiepileptogenic effects. The first, a combination of levetiracetam (LEV) and topiramate, only partially prevented spontaneous recurrent seizures in the model. We therefore added atorvastatin (ATV) to the therapeutic cocktail (TC) to increase efficacy, forming “TC-001”. The second cocktail – a combination of LEV, ATV, and ceftriaxone, termed “TC-002” – completely prevented epilepsy in the mouse IHK model. In the present proof-of-concept study, we tested whether the two drug cocktails prevent epilepsy in a rat PTE model in which recurrent electrographic seizures develop after severe rostral parasagittal fluid percussion injury (FPI). Following FPI, rats were either treated over 3–4 weeks with vehicle or drug cocktails, starting either 1 or 4–6 h after the injury. Using mouse doses of TC-001 and TC-002, no significant antiepileptogenic effect was obtained in the rat PTE model. However, when using allometric scaling of drug doses to consider the differences in body surface area between mice and rats, PTE was prevented by TC-002. Furthermore, the latter drug cocktail partially prevented the loss of perilesional cortical parvalbumin-positive GABAergic interneurons. Plasma and brain drug analysis showed that these effects of TC-002 occurred at clinically relevant levels of the individual TC-002 drug components. In silico analysis of drug-drug brain protein interactions by the STITCH database indicated that TC-002 impacts a larger functional network of epilepsy-relevant brain proteins than each drug alone, providing a potential network pharmacology explanation for the observed antiepileptogenic and neuroprotective effects observed with this combination.

Sexual dimorphism and functional allometry in scorpions: A comparative study from a neotropical species

Sexual dimorphism (SD), the divergence of secondary sexual traits between males and females within a species, can arise from diverse evolutionary forces, such as natural selection, mate choice, and intrasexual competition. Allometric scaling patterns of dimorphic traits are related to their functional roles and the different selective pressures that affect each sex. Generally, traits that threaten rivals involved in intrasexual competition tend to exhibit the highest allometric slopes. Conversely, non-sexual traits often display isometric scaling, while genitalia and traits in direct contact between the sexes during courtship and copulation typically show hypoallometry. A good approach to study patterns of SD and allometry is to complement interspecific studies with analyzes of case studies, where the functional aspect is known in detail. Here, we review the occurrence of SD and evaluation of allometry in the Order Scorpiones, allowing us to compare general trends in a broader comparative framework within the group. In addition, we examined SD and allometric slopes of multiple traits (including somatic traits used in sexual and non-sexual interactions, as well as genitalia) in adult individuals of the scorpion Timogenes elegans (Scorpiones, Bothriuridae). We found that at an interspecific level there was a variation in SD between species and morphological traits, with most traits showing a male-biased SD, except for the chelicerae, which were found to be wider in females. Regarding SD studies, we found relatively few reports of functional allometry showing differences in allometric patterns between species. The results in T. elegans follow some of the general patterns found in other scorpions. We found hypoallometry in genital traits and hyperallometry in the pedipalps of both sexes, with steeper allometric slopes observed for pedipalp height in males. These results suggest that genital traits are under stabilizing selective pressure, while pedipalps in both sexes may be under natural and sexual selective pressure. Understanding allometric patterns and their relationship to function in scorpions provides significant insights into the evolutionary pressures driving the divergence of morphological traits used in both sexual and non-sexual contexts.

A systematic review of allometric scaling exponents for IgG mAbs

Increasing complexity of mAbs in development creates challenges in predicting human pharmacokinetic (PK) parameters from preclinical data. The aim of this analysis was to identify optimal allometric scaling exponents. Data were extracted from literature to create a central database (currently the largest available published database) of two-compartment model parameters for mAbs (n = 59) in cynomolgus monkey (CM) and human. Global allometric exponents were calculated and drug-dependent factors were investigated as potential variables in determining the optimal scaling factor. The global exponents for scaling CM mAb PK data were 0.74 (CL), 0.80 (CL with Fc-modified mAbs excluded), 0.44 (CL with Fc-modified mAbs only), 0.71 (Q), 1.12 (V1), and 0.99 (V2). These values are in line with previously published literature values.

Pharmacokinetic and Pharmacodynamic Assessment of Valganciclovir in Infants With Congenital Cytomegalovirus Infection.

Valganciclovir (VGCV) is administered at a dose of 16 mg/kg 2 times daily for 6 months to treat symptomatic congenital cytomegalovirus (CMV) infections. During the treatment period, approximately 20% of the patients developed grade 3 or higher neutropenia. Currently, information on the pharmacokinetics and pharmacodynamics of ganciclovir, an active metabolite of VGCV, in infants is limited. In the current study, the relationship between ganciclovir concentration and neutropenia was investigated, and a population pharmacokinetic (PPK) model of ganciclovir in infants with symptomatic congenital CMV infection was developed. Japanese infants who were prescribed oral VGCV for symptomatic congenital CMV infections between July 2017 and January 2021 were included. The relationship between the observed trough ganciclovir concentrations and neutrophil counts was examined. PPK analysis was performed to evaluate the covariates affecting the pharmacokinetics of ganciclovir. Twenty-seven ganciclovir serum samples from 8 patients were analyzed. A moderate negative correlation was observed between the observed trough ganciclovir concentration and neutrophil count. PPK model analysis showed that postmenstrual age (PMA) affected the total body clearance of ganciclovir after correcting for the empirical allometric scaling of body weight. Based on PMA and body weight, a nomogram to achieve the target area under the concentration-time curve from 0 to 24 hours of 40-60 mcg·h·mL-1 of ganciclovir was calculated. The relationship between neutrophil count and ganciclovir trough concentration in infants was clarified. The PPK model showed that the dose of VGCV should be reduced in patients with a low PMA to achieve target exposure.

Population modeling analyses of crizotinib in pediatric patients with ALK-positive advanced cancers.

Alterations in the ALK (anaplastic lymphoma kinase) gene play a critical role in pathogenesis of anaplastic large cell lymphoma (ALCL). Crizotinib is a small molecule competitive inhibitor of ALK, ROS1, and MET kinases and was approved for pediatric patients with ALK-positive relapsed or refractory, systemic ALCL, and ALK-positive unresectable, recurrent, or refractory inflammatory myofibroblastic tumors (IMT). Crizotinib data from pediatric patients with relapsed or refractory solid tumors, IMT, or ALCL were included in the analyses. All patients received crizotinib orally at doses ranging from 100 to 365mg/m2 twice daily (BID). PopPK analyses were conducted to characterize crizotinib disposition in pediatric patients. Exposure-response (ER) safety and antitumor analyses were conducted to characterize relationships between crizotinib dose or exposure with safety and antitumor activity endpoints of interest. The population pharmacokinetic (popPK), ER safety, and ER antitumor analysis included 98, 110, and 36 pediatric patients, respectively. A one-compartment pharmacokinetic model with allometric scaling, first-order elimination, and first-order absorption with lag time adequately described the data. Natural log-transformed model-predicted crizotinib AUCss (steady-state area under the concentration-time curve) demonstrated a significant, positive relationship with Grade ≥3 NEUTROPENIA and Any Grade VISION DISORDER. Crizotinib dose demonstrated a positive relationship with objective response rate. No significant differences in PK were identified across a wide range of ages or across tumor types, suggesting body surface area (BSA)-based dosing adequately adjusted for differences in patient size to achieve similar systemic crizotinib exposures across young children and adolescent pediatric patients. None of the myelosuppressive events except Grade ≥3 NEUTROPENIA had significant relationships identified with crizotinib dose or exposure, suggesting crizotinib is a tolerable treatment with less hematological toxicity than traditional chemotherapy regimens for pediatric patients with ALK-mutated cancers. Results from the presented analyses support the pediatric dosing recommendations in the product label.

Development of a gas chromatography-mass spectrometric technique for the biological control of volatile industrial pollutants

Introduction. General industrial pollutants, which includes volatile industrial pollutants (VIP) allyl chloride, butyl chloride, chloroacetonitrile, pentachloroethane, hexachloroethane, trans-1,4-dichloro-2-butene, acrylonitrile, methacrylonitrile, methyl methacrylate, ethyl methacrylate, methyl acrylate, 2-nitropropane, nitrobenzene , diethyl ether, tetrahydrofuran and carbon disulfide are widely used in the domestic chemical industry, but effective methods for the quantitative determination of their biomarkers in the biological media of chemical production workers have not yet been developed. The purpose of the study is to develop a highly sensitive gas chromatographic technique for the determination of compounds of the VIP group in whole blood and urine for their biological control, and its testing using modeling of intoxication in laboratory animals. Material and methods. Experimental modeling of intoxication was carried out with subcutaneous (s/c) injection of toxicants to male chinchilla rabbits. Determination of biomarkers of toxicants was performed using a gas chromatograph with a single quadrupole mass analyzer (GC-MS) with preliminary extraction of components from the vapor phase above the sample by solid-phase microextraction. Results. A method for the determination of allyl chloride, butyl chloride, chloroacetonitrile, pentachloroethane, hexachloroethane, trans-1,4-dichloro-2-butene, acrylonitrile, methacrylonitrile, methyl methacrylate, ethyl methacrylate, methyl acrylate, 2-nitropropane, nitrobenzene, diethyl ether, tetrahydrofuran, and carbon disulfide in blood and urine was developed and metrologically certified. The achieved limits of quantification are no more than 1 ng/ml with a detection limit of 0.2 ng/ml in blood and urine. Limitations. Toxicokinetic parameters were experimentally determined on one animal species; allometric scaling was used for extrapolation to humans. Conclusion. Analysis of the results of the assessment of the expected concentrations of VIP in blood and urine shows that biological control in the working area at the level of 0.5 MPC can be carried out for carbon disulfide, diethyl ether, butyl chloride, 1,4-dichlorobutene-2 and tetrahydrofuran in the study of blood and urine; methacrylonitrile and hexachloroethane (the lower value of the determination limit) – in the study of urine only. The developed approaches to substantiate methods of biological control of harmful substances are a scientific and methodological platform for the introduction of biological MPC and ensuring the chemical safety of the Russian Federation.

Bimodal pattern of allometric scaling along grapevine shoots.

Each branch internode, and the organs growing on it, can be seen as a single morphological phytomer subunit, made of structurally and functionally interrelated components. However, allometric relationships between anatomy and morphology of these subunits remain unclear, particularly in the axial context. This study aims to address this knowledge gap, by measuring morpho-anatomical parameters and their allometric relationships along grapevine shoots. To facilitate comparison, shoot length was normalized and a relative position index was calculated for each internode, ranging from 0 at the base to 1 at the apex. Scaling relationships between morpho-anatomical parameters along the axis were developed and validated by statistical modeling. Most morpho-anatomical parameters displayed an axial behaviour of increasing then decreasing in size from base to apex, with the exception of shoot diameter and shoot vessel density. Relative position index of 0.2 acted as the data turning point for most variables analysed. During the first phase (relative position index below 0.2), the phytomer organs traits are uncoupled and show weak allometric correlation, and during the second phase the traits are strongly allometrically related. Our findings suggest that allometric relationships along grapevine shoots are not constant- they exhibit a bimodal pattern, possibly influenced by seasonal temperatures. This work could aid managing productivity shifts in agricultural and natural systems under global climate change and add to basic knowledge of differentiation and development of growth units in plants.

Wave attenuation by intertidal vegetation is mediated by trade‐offs between shoot‐ and canopy‐scale plant traits

Abstract Nature‐based solutions, through conservation or (re)creation of vegetated shorelines, are recognized to mitigate the impact of waves and erosion risks on shorelines. Wave attenuation is known to be dependent on plant traits, resulting in increasing wave attenuation rates with increasing shoot density, shoot thickness, height, and stiffness. However, following the allometric scaling theory, we hypothesize that increasing shoot density (a canopy‐scale trait) may be associated with decreasing shoot thickness and stiffness (a shoot‐scale trait), with potential opposing effects on overall wave attenuation. This study investigates (1) the presence of such allometric relations across intertidal shore plant species via existing literature and (2) the trade‐off effects on the overall wave attenuation capacity of shore vegetation through a flume experiment. Our results reveal for the first time the presence of allometric relationships between shoot‐scale and canopy‐scale plant properties in perennial intertidal plant species. Across different species, increasing shoot densities are indeed associated with decreasing shoot thickness and shoot stiffness. Next, we performed a wave flume experiment with plant mimics, showing that wave attenuation rate follows a logarithmic increase with increasing shoot density, even though the increasing shoot density was associated with thinner and more flexible individual shoots. Synthesis and applications. We conclude that wave attenuation is predominantly governed by canopy‐scale properties, but a trade‐off with shoot‐scale properties mediates the overall wave attenuation capacity of the vegetated shore. Our findings imply that nature‐based projects (re‐)creating vegetated shorelines should account for potential trade‐off effects of species‐specific plant traits at the canopy scale and individual shoot scale.

Allometric Scaling of Maximal Strength Performance in Physically Active College-Aged Males: Removing the Effects of Body Weight

Allometric Scaling of Maximal Strength Performance in Physically Active College-Aged Males: Removing the Effects of Body Weight

Advancing ecotoxicological studies: Utilizing new approach methodologies to enable cross-species extrapolation and reduce avian testing

Ecological risk assessments of agrochemicals have traditionally depended on in vivo guideline tests using northern bobwhite and mallard to provide relevant endpoints for avian species. However, these studies have limitations, including animal welfare concerns, the time and cost involved, limited potential for extrapolation to more realistic exposure conditions, and the lack of mechanistic understanding. The proof-of-concept work presented a case study for thiamethoxam in three avian species, demonstrating the potential of physiologically based kinetic (PBK) modeling to enable dosimetry extrapolations that inform hazard characterization in risk assessment, and reduce the use of avian testing. The model structure for northern bobwhite and mallard contained ten compartments, while an additional ovulation model was included for chicken in the physiological state of egg-laying. The model was first parameterized and evaluated for chicken and northern bobwhite using in vitro kinetic measurements and in vivo toxicokinetic (TK) data. The chicken model was then extrapolated to mallard based on allometric scaling. The models were then used to map the TK profiles across species by simulating internal dose metrics in different avian toxicology studies. These metrics, including peak blood concentrations (Cmax) and area under the curve (AUC) for blood concentration, were determined for acute, subacute, or chronic toxicity endpoints for mallard and northern bobwhite, enabling a quantitative cross-species and cross-route comparison of dosimetry. The results suggested that the chronic toxicological response of birds exposed to thiamethoxam is highly dependent on internal exposure, while mallard appeared to be more dynamically sensitive to thiamethoxam on an acute oral exposure basis. The case study increases the confidence in using new approach methodologies (NAMs) for interpreting avian toxicity studies and facilitating in vitro-in silico-based ecological risk assessments of agrochemicals.

Predicting Tumor Volume Doubling Time and Progression-Free Survival in Untreated Patients from Patient-Derived-Xenograft (PDX) Models: A Translational Model-Based Approach

Tumor volume doubling time (TVDT) has been shown to be a potential surrogate marker of biological tumor activity. However, its availability in clinics is strongly limited due to ethical and practical reasons, as its assessment requires at least two subsequent tumor volume measurements in untreated patients. Here, a translational modeling framework to predict TVDT distributions in untreated cancer patient populations from tumor growth data in patient-derived xenograft (PDX) mice is proposed. Eleven solid cancer types were considered. For each of them, a set of tumor growth studies in PDX mice was selected and analyzed through a mathematical model to characterize the distribution of the exponential tumor growth rate in mice. Then, assuming an exponential growth of the tumor mass in humans, the growth rates were scaled from PDX mice to humans through an allometric scaling approach and used to predict TVDTs in untreated patients. A very good agreement was found between model predicted and clinically observed TVDTs, with 91% of the predicted TVDT medians fell within 1.5-fold of observations. Further, exploiting the intrinsic relationship between tumor growth dynamics and progression free survival (PFS), the exponential growth rates in humans were used to generate the expected PFS curves in absence of anticancer treatment. Predicted curves were extremely close to published PFS data from studies involving patient cohorts treated with supportive care or low effective therapies. The proposed approach shows promise as a potential tool to increase knowledge about TVDT in humans without the need of directly measuring tumor dimensions in untreated patients, and to predict PFS curves in untreated patients, that could fill the absence of placebo-controlled arms against which to compare treaded arms during clinical trials. However, further validation and refinement are needed to fully assess its effectiveness in this regard.

Prediction of human serum concentration–time profiles of therapeutic monoclonal antibodies using common marmosets (Callithrix jacchus): initial assessment with canakinumab, adalimumab, and bevacizumab

Cynomolgus monkeys and human FcRn transgenic mice are generally used for pharmacokinetic predictions of therapeutic monoclonal antibodies (mAbs). In the present study, the application of the common marmoset, a small nonhuman primate, as a potential animal model for prediction was evaluated for the first time. Canakinumab, adalimumab, and bevacizumab, which exhibited linear pharmacokinetics in humans, were selected as the model compounds. Marmoset pharmacokinetic data were reportedly available only for canakinumab, and those for adalimumab and bevacizumab were acquired in-house. Four pharmacokinetic parameters for a two-compartment model (i.e. clearance and volume of distribution in the central and peripheral compartments) in marmosets were extrapolated to the values in humans with allometric scaling using the average exponents of the three mAbs. As a result, the observed human serum concentration–time curves of the three mAbs following intravenous administration and those of canakinumab and adalimumab following subcutaneous injections (with an assumed absorption rate constant and bioavailability) were reasonably predicted. Although further prediction studies using a sufficient number of other mAbs are necessary to evaluate the versatility of this model, the findings indicate that marmosets can be an alternative to preceding animals for human pharmacokinetic predictions of therapeutic mAbs.

Sex difference in mitral valve prolapse regurgitant volume is resolved by normalization of regurgitant volume to left ventricular end-diastolic volume

Women with primary mitral insufficiency have a smaller regurgitant volume at the same regurgitant fraction than men. We hypothesized that normalizing regurgitant volume with left ventricular end-diastolic volume or allometric scaling would eliminate the difference in regurgitant volume between women and men. The study cohort consisted of 101 patients with mitral valve prolapse undergoing cardiac MRI. Descriptive statistics and linear regression were performed to assess differences between sexes. Of the 101 patients, 46 (46%) were women. Women had a significantly smaller left and right ventricular end-diastolic volume, end-systolic volume, and stroke volume. While there was no difference in regurgitant fraction between women and men (34 ± 13% vs. 35 ± 14%; p = 0.71), women had a significantly smaller regurgitant volume (36 ± 18 ml vs. 49 ± 26 ml; p = 0.005). The slope-intercept relationship between regurgitant fraction and regurgitant volume revealed unique slopes and y-intercept values for men and women (p-value < 0.0001). Normalizing regurgitant volume to left ventricular end-diastolic volume (RVol/LVEDV), body surface area1.5 (RVol/BSA1.5) and height2.7 (RVol/height2.7) all had essentially identical slope-intercept relationships with regurgitant fraction for men and women, but RVol/LVEDV had the smallest effect size. In mitral insufficiency secondary to mitral valve prolapse women have a significantly smaller regurgitant volume than men despite no difference in regurgitant fraction. The significant difference in regurgitant volume between women and men is secondary to women having a smaller left ventricular end-diastolic volume.

Young dove trees tend to invest more biomass in vegetative and reproductive organs than old trees at the twig level

Research on the functional traits of twigs is of great significance to clarify the plant life-history strategies, especially for endangered plants. However, little attention has been given to the environmental adaptation strategy of different age twigs. The dove tree (Davidia involucrata Baill.), a relict and critically endangered Chinese species, was employed as a model species. Total lamina mass and area, stem mass and length, total bract mass and area, and total petiole mass were measured for 100 current-year terminal twigs (50 per age group) from old and young dove trees in Pingwu County, Sichuan, southwest China. Then, the scaling relationships within the twig were determined using the standardized major axis (SMA) regression method. Our results showed that the significantly positive correlations among traits of D. involucrata twigs, and scaling relationships between these traits are different between the two age groups. At the twig level, isometric scaling relationships exist between stem mass and lamina size (or bract size) and between total lamina mass and total lamina area (or total petiole mass). In contrast, allometric scaling relationships exist between lamina size (total mass and area) and stem length (with a common slope > 1), and between total lamina mass and total petiole mass (with a common slope < 1). For a given stem mass, stem length and bract area, young trees have larger total lamina mass and total bract mass, larger total lamina mass and area, and larger total bract mass than old trees, respectively. The results suggest that young trees tend to have more vegetative and reproductive organ mass per unit of supporting organ mass than old trees to meet their rapid growth needs.

Disproportional fraction of inactive components leads to the variation in metabolic scaling

In biological systems, solitary organisms or eusocial groups, the metabolic rate often scales allometrically with systems’ size, when they are inactive, and the scaling becomes nearly isometric when the systems are active. Here I propose a hypothesis attempting to offer a departing point for a general joint understanding of the difference in the scaling powers between inactive and active states. When the system is inactive, there exist inactive components, which consume less energy than the active ones, and the larger the system is, the larger the fraction of the inactive components, which leads to sublinear scaling. When the system is active, most inactive components are activated, which leads to nearly isometric scaling. I hypothesize that the disproportional fraction of the inactive components is caused by the diffusants screening in the complex transportation network. I.e., when metabolites or information diffuses in the system, due to the physical limitation of the network structure and the diffusant’s physical feature, not all the components can equally receive the diffusants so that these components are inactive. Using the mammalian pulmonary system, ant colonies, and other few systems as examples, I discuss how the screening leads to the allometric and isometric metabolic scaling powers in inactive and active states respectively. It is noteworthy that there are a few exceptions, in which the metabolic rate of the system has an isometric scaling relationship with size at rest. I show that these exceptions not only do not disapprove the hypothesis, but actually support it.

Identifying optimal dosing strategies for meropenem in the paediatric intensive care unit through modelling and simulation.

Meropenem, a β-lactam antibiotic commonly prescribed for severe infections, poses dosing challenges in critically ill patients due to highly variable pharmacokinetics. We sought to develop a population pharmacokinetic model of meropenem for critically ill paediatric and young adult patients. Paediatric intensive care unit patients receiving meropenem 20-40 mg/kg every 8 h as a 30 min infusion were prospectively followed for clinical data collection and scavenged opportunistic plasma sampling. Nonlinear mixed effects modelling was conducted using Monolix®. Monte Carlo simulations were performed to provide dosing recommendations against susceptible pathogens (MIC ≤ 2 mg/L). Data from 48 patients, aged 1 month to 30 years, with 296 samples, were described using a two-compartment model with first-order elimination. Allometric body weight scaling accounted for body size differences. Creatinine clearance and percentage of fluid balance were identified as covariates on clearance and central volume of distribution, respectively. A maturation function for renal clearance was included. Monte Carlo simulations suggested that for a target of 40% fT > MIC, the most effective dosing regimen is 20 mg/kg every 8 h with a 3 h infusion. If higher PD targets are considered, only continuous infusion regimens ensure target attainment against susceptible pathogens, ranging from 60 mg/kg/day to 120 mg/kg/day. We successfully developed a population pharmacokinetic model of meropenem using real-world data from critically ill paediatric and young adult patients with an opportunistic sampling strategy and provided dosing recommendations based on the patients' renal function and fluid status.

Predicting the Intravenous Pharmacokinetics of Covalent Drugs in Animals and Humans.

30 covalent drugs were used to assess clearance (CL) prediction reliability in animals and humans. In animals, marked CL underprediction was observed using cryopreserved hepatocytes or liver microsomes (LMs) supplemented for cytochrome P450 activity. Improved quantitative performance was observed by combining metabolic stability data from LMs and liver S9 fractions, the latter supplemented with reduced glutathione for glutathione transferase activity. While human LMs provided reliable human CL predictions, prediction statistics were improved further by incorporating S9 stability data. CL predictions with allometric scaling were less robust compared to in vitro drug metabolism methods; the best results were obtained using the fu-corrected intercept model. Human volume of distribution (Vd) was well predicted using allometric scaling of animal pharmacokinetic data; the most reliable results were achieved using simple allometric scaling of unbound Vd values. These results provide a quantitative framework to guide appropriate method selection for human PK prediction with covalent drugs.