Allometric exponents for scaling running economy in human samples: A systematic review and meta-analysis.

Ratio-scaled VO2 is the widely used method for quantifying running economy (RE). However, this method should be criticized due to its theoretical defect and curvilinear relationship indicated by the allometric scaling, although no consensus has been achieved on the generally accepted exponent b value of body weight. Therefore, this study aimed to provide a quantitative synthesis of the reported exponents used to scale VO2 to body weight. Six electronic databases were searched based on related terms. Inclusion criteria involved human cardiopulmonary testing data, derived exponents, and reported precision statistics. The random-effects model was applied to statistically analyze exponent b. Subgroup and meta-regression analyses were conducted to explore the potential factors contributing to variation in b values. The probability of the true exponent being below 1 in future studies was calculated. The estimated b values were all below 1 and aligned with the 3/4 power law, except for the 95 % prediction interval of the estimated fat-free body weight exponent b. A publication bias and a slightly greater I2 and τ statistic were also observed in the fat-free body weight study cohort. The estimated probabilities of the true body weight exponent, full body weight exponent, and fat-free body weight exponent being lower than 1 were 93.8 % (likely), 95.1 % (very likely), and 94.5 % (likely) respectively. 'Sex difference', 'age category', 'sporting background', and 'testing modality' were four potential but critical variables that impacted exponent b. Overall, allometric-scaled RE should be measured by full body weight with exponent b raised to 3/4.

Interspecies Scaling of Transgene Products for Viral Vector Gene Therapies: Method Assessment Using Data from Eleven Viral Vectors.

The prediction of transgene product expression in human is important to guide first-in-human (FIH) dose selection for viral vector-based gene replacement therapies. Recently, allometric scaling from preclinical data and interspecies normalization of dose-response (D-R) relationship have been used to predict human transgene product expression of adeno-associated virus (AAV) vectors. In this study, we assessed two interspecies allometric scaling methods and two dose-response methods in predicting human transgene product expression of nine intravenously administered AAV vectors, one intramuscularly administered AAV vector, and one intravesical administered adenoviral vector. Among the four methods, normalized D-R method generated the highest prediction accuracy, with geometric mean fold error (GMFE) of 2.9 folds and 75% predictions within fivefold deviations of observed human transgene product levels. The vg/kg-based D-R method worked well for locally delivered vectors but substantially overpredicted human transgene product levels of some hemophilia A and B vectors. For both intravenously and locally administered vectors, the prediction accuracy of allometric scaling using body weight^-0.25 (AS by W^-0.25) was superior to allometric scaling using log(body weight) (AS by logW). This study successfully extended the use of allometric scaling and interspecies D-R normalization methods for human transgene product prediction from intravenous viral vectors to locally delivered viral vectors.

Energetic costs of feeding in 12 species of small-bodied primates.

There are no comparative, empirical studies of the energetic costs of feeding in mammals. As a result, we lack physiological data to better understand the selection pressures on the mammalian feeding apparatus and the influence of variables such as food geometric and material properties. This study investigates interspecific scaling of the net energetic costs of feeding in relation to body size, jaw-adductor muscle mass and food properties in a sample of 12 non-human primate species ranging in size from 0.08 to 4.2 kg. Net energetic costs during feeding were measured by indirect calorimetry for a variety of pre-cut and whole raw foods varying in geometric and material properties. Net feeding costs were determined in two ways: by subtracting either the initial metabolic rate prior to feeding or subtracting the postprandial metabolic rate. Interspecific scaling relationships were evaluated using pGLS and OLS regression. Net feeding costs scale negatively relative to both body mass and jaw-adductor mass. Large animals incur relatively lower feeding costs indicating that small and large animals experience and solve mechanical challenges in relation to energetics in different ways. This article is part of the theme issue 'Food processing and nutritional assimilation in animals'.

Meta-Assessment of Metformin Absorption and Disposition Pharmacokinetics in Nine Species.

The objective of this study was to systematically assess literature datasets and quantitatively analyze metformin PK in plasma and some tissues of nine species. The pharmacokinetic (PK) parameters and profiles of metformin in nine species were collected from the literature. Based on a simple allometric scaling, the systemic clearances (CL) of metformin in these species highly correlate with body weight (BW) (R2 = 0.85) and are comparable to renal plasma flow in most species except for rabbit and cat. Reported volumes of distribution (VSS) varied appreciably (0.32 to 10.1 L/kg) among species. Using the physiological and anatomical variables for each species, a minimal physiologically based pharmacokinetic (mPBPK) model consisting of blood and two tissue compartments (Tissues 1 and 2) was used for modeling metformin PK in the nine species. Permeability-limited distribution (low fd1 and fd2) and a single tissue-to-plasma partition coefficient (Kp) value for Tissues 1 and 2 were applied in the joint mPBPK fitting. Nonlinear regression analysis for common tissue distribution parameters along with species-specific CL values reasonably captured the plasma PK profiles of metformin across most species, except for rat and horse with later time deviations. In separate fittings of the mPBPK model to each species, Tissue 2 was considered as slowly-equilibrating compartment consisting of muscle and skin based on in silico calculations of the mean transit times through tissues. The well-fitted mPBPK model parameters for absorption and disposition PK of metformin for each species were compared with in vitro/in vivo results found in the literature with regard to the physiological details and physicochemical properties of metformin. Bioavailability and absorption rates decreased with the increased BW among the species. Tissues such as muscle dominate metformin distribution with low permeability and partitioning while actual tissue concentrations found in rats and mice show likely transporter-mediated uptake in liver, kidney, and gastrointestinal tissues. Metformin has diverse pharmacologic actions, and this assessment revealed allometric relationships in its absorption and renal clearance but considerable variability in actual and modeled tissue distribution probably caused by transporter differences.

Local adaptation reduces the metabolic cost of environmental warming.

Metabolism shapes the ecosystem role of organisms by dictating their energy demand and nutrient recycling potential. Metabolic theory (MTE) predicts consumer metabolic and recycling rates will rise with warming, especially if body size declines, but it ignores potential for adaptation. We measured metabolic and nutrient excretion rates of individuals from populations of a globally invasive fish that colonized sites spanning a wide temperature range (19-37°C) on two continents within the last 100 yr. Fish body size declined across our temperature gradient and MTE predicted large rises in population energy demand and nutrient recycling. However, we found that the allometry and temperature dependency of metabolism varied in a countergradient pattern with local temperature in a way that offset predictions of MTE. Scaling of nutrient excretion was more variable and did not track temperature. Our results suggest that adaptation can reduce the metabolic cost of warming, increasing the prospects for population persistence under extreme warming scenarios.

Utility of a human FcRn transgenic mouse model in drug discovery for early assessment and prediction of human pharmacokinetics of monoclonal antibodies.

Therapeutic antibodies continue to develop as an emerging drug class, with a need for preclinical tools to better predict in vivo characteristics. Transgenic mice expressing human neonatal Fc receptor (hFcRn) have potential as a preclinical pharmacokinetic (PK) model to project human PK of monoclonal antibodies (mAbs). Using a panel of 27 mAbs with a broad PK range, we sought to characterize and establish utility of this preclinical animal model and provide guidance for its application in drug development of mAbs. This set of mAbs was administered to both hemizygous and homozygous hFcRn transgenic mice (Tg32) at a single intravenous dose, and PK parameters were derived. Higher hFcRn protein tissue expression was confirmed by liquid chromatography-high resolution tandem mass spectrometry in Tg32 homozygous versus hemizygous mice. Clearance (CL) was calculated using non-compartmental analysis and correlations were assessed to historical data in wild-type mouse, non-human primate (NHP), and human. Results show that mAb CL in hFcRn Tg32 homozygous mouse correlate with human (r(2) = 0.83, r = 0.91, p < 0.01) better than NHP (r(2) = 0.67, r = 0.82, p < 0.01) for this dataset. Applying simple allometric scaling using an empirically derived best-fit exponent of 0.93 enabled the prediction of human CL from the Tg32 homozygous mouse within 2-fold error for 100% of mAbs tested. Implementing the Tg32 homozygous mouse model in discovery and preclinical drug development to predict human CL may result in an overall decreased usage of monkeys for PK studies, enhancement of the early selection of lead molecules, and ultimately a decrease in the time for a drug candidate to reach the clinic.

Model-based approaches for ivabradine development in paediatric population, part I: study preparation assessment.

The main objective was to help design a paediatric study for ivabradine, a compound already marketed in adults, focusing on: the paediatric formulation evaluation, the doses to be administered, the sampling design and the sampling technique. A secondary objective was to perform a comparison of the prediction of ivabradine pharmacokinetics (PK) in children using a physiologically-based pharmacokinetic (PBPK) approach and allometric scaling of a population pharmacokinetic (PPK) model. A study was conducted in order to assess the relative bioavailability (Frel) of the paediatric formulation and a similar Frel was observed between the paediatric formulation and the adult marketed tablet. PBPK modelling was used to predict initial doses to be administered in the paediatric study and to select the most appropriate sample time collections. The dried blood spot technique was recommended in the clinical trial in children. Simulations obtained by both the PBPK approach and allometric scaling of a PPK model were compared a posteriori to the paediatric study observations. Both PPK and PBPK approaches allowed an adequate prediction of the PK of ivabradine and its metabolite in children.

Model-based approaches for ivabradine development in paediatric population, part II: PK and PK/PD assessment.

The objectives of this work were first to describe the pharmacokinetic (PK) of ivabradine and its active metabolite in a paediatric patient population after repeated oral administration of ivabradine using a population PK approach, and secondly to assess whether the blood/plasma ratio and the pharmacokinetic/pharmacodynamic (PK/PD) relationship are preserved in the paediatric population in comparison to adult. PK data for 70 patients were obtained after blood sampling using dried blood spot and one plasma sample in order to assess the relationship between blood and plasma concentration. In order to describe ivabradine and its metabolite blood concentrations in children, a joint population PK model was developed taking into account weight & age effects on PK parameters. Plasma PK exposure parameters were calculated in children using plasma PK profiles. In order to assess the PK/PD relationship in children, an adult PK/PD model was used. The relationship between blood and plasma concentrations was described using linear mixed effect models. Two and one-compartment models best described parent and metabolite dispositions. Weight effects were fixed to the allometric values of ¾ on clearance (CL) and 1 on volume. A maturation function was added on metabolite formation clearance (CL PM ) reflecting enzyme maturation. Plasma exposure comparison indicated that higher dose/kg were necessary to achieve a similar exposure between younger and older children. No differences between age classes were observed in terms of range of exposure at the maintenance dose. The PK/PD relationship in adult patients is conserved in children.

Influência do modelo alométrico na relação entre consumo máximo de oxigênio e desempenho de corredores fundistas / Influence of the allometric model on relationship between running economy and performance in long-distance runners / Influencia del modelo alométrico en la relación entre consumo máximo de oxígeno y rendimiento en corredores fondistas

Resumo Investigou-se o efeito do modelo alométrico na relação entre o consumo máximo de oxigênio (VO2máx) e o desempenho em corrida de longa distância. Doze corredores fundistas do sexo masculino (idade: 28,6 ± 7,4 anos; massa corporal: 67,9 ± 9,4 kg; estatura: 1,71 ± 0,7 m) foram submetidos a um teste de esforço máximo em esteira rolante para a determinação do VO2máx e a uma corrida máxima de 10.000 m. Apesar das diferenças significativas verificadas entre as formas de relativização do VO2máx (pela massa corporal total, pelo expoente alométrico amostral e pela massa corporal magra), as fortes correlações verificadas entre VO2máx e desempenho demonstram que a predição desse independe da forma de relativização da potência metabólica máxima.

Abstract The aim was investigated the effect of allometric model in relationship between maximal Oxygen uptake (VO2max ) and long-distance running performance. Twelve runners (age: 28.6 ± 7.4 years, body mass: 67.9 ± 9.4 kg, height: 1.71 ± 0.7 m) were submitted to an incremental treadmill running protocol for determination of VO 2max and participated in a trail of 10.000 m. despite the significant differences found between the forms of relativization of VO2max (by total body mass, allometric exponent for sampling and lean body mass), the strong correlations verified between VO2max and performance show that this prediction is independent of how the VO2max is relativized.

Resumen Se investigó el efecto del modelo alométrico en la relación entre el consumo máximo de oxígeno (VO2máx ) y el rendimiento en carreras de larga distancia. Doce corredores fondistas de sexo masculino (edad: 28,6 ± 7,4 años; masa corporal: 67,9 ± 9,4 kg; estatura: 1,71 ± 0,7 m) pasaron un test de esfuerzo máximo en una cinta de correr para la determinación del VO2máx y participaron en una carrera de 10.000 m. A pesar de las diferencias entre las formas de relativización del VO2máx (por la masa corporal total, por el exponente alométrico general de la muestra y por la masa corporal magra), las fuertes correlaciones encontradas entre VO2máx y rendimiento demuestran que la predicción de éste es independiente de la forma de relativización del consumo máximo de oxígeno.

Impact of methodology and the use of allometric scaling on the echocardiographic assessment of the aortic root and arch: a study by the Research and Audit Sub-Committee of the British Society of Echocardiography.

The aim of the study is to establish the impact of 2D echocardiographic methods on absolute values for aortic root dimensions and to describe any allometric relationship to body size. We adopted a nationwide cross-sectional prospective multicentre design using images obtained from studies utilising control groups or where specific normality was being assessed. A total of 248 participants were enrolled with no history of cardiovascular disease, diabetes, hypertension or abnormal findings on echocardiography. Aortic root dimensions were measured at the annulus, the sinus of Valsalva, the sinotubular junction, the proximal ascending aorta and the aortic arch using the inner edge and leading edge methods in both diastole and systole by 2D echocardiography. All dimensions were scaled allometrically to body surface area (BSA), height and pulmonary artery diameter. For all parameters with the exception of the aortic annulus, dimensions were significantly larger in systole (P<0.05). All aortic root and arch measurements were significantly larger when measured using the leading edge method compared with the inner edge method (P<0.05). Allometric scaling provided a b exponent of BSA(0.6) in order to achieve size independence. Similarly, ratio scaling to height in subjects under the age of 40 years also produced size independence. In conclusion, the largest aortic dimensions occur in systole while using the leading edge method. Reproducibility of measurement, however, is better when assessing aortic dimensions in diastole. There is an allometric relationship to BSA and, therefore, allometric scaling in the order of BSA(0.6) provides a size-independent index that is not influenced by the age or gender.

Energetic cost of brain functional connectivity.

The brain's functional connectivity is complex, has high energetic cost, and requires efficient use of glucose, the brain's main energy source. It has been proposed that regions with a high degree of functional connectivity are energy efficient and can minimize consumption of glucose. However, the relationship between functional connectivity and energy consumption in the brain is poorly understood. To address this neglect, here we propose a simple model for the energy demands of brain functional connectivity, which we tested with positron emission tomography and MRI in 54 healthy volunteers at rest. Higher glucose metabolism was associated with proportionally larger MRI signal amplitudes, and a higher degree of connectivity was associated with nonlinear increases in metabolism, supporting our hypothesis for the energy efficiency of the connectivity hubs. Basal metabolism (in the absence of connectivity) accounted for 30% of brain glucose utilization, which suggests that the spontaneous brain activity accounts for 70% of the energy consumed by the brain. The energy efficiency of the connectivity hubs was higher for ventral precuneus, cerebellum, and subcortical hubs than for cortical hubs. The higher energy demands of brain communication that hinges upon higher connectivity could render brain hubs more vulnerable to deficits in energy delivery or utilization and help explain their sensitivity to neurodegenerative conditions, such as Alzheimer's disease.

Energy cost of running and Achilles tendon stiffness in man and woman trained runners.

The energy cost of running (E run), a key determinant of distance running performance, is influenced by several factors. Although it is important to express E run as energy cost, no study has used this approach to compare similarly trained men and women. Furthermore, the relationship between Achilles tendon (AT) stiffness and E run has not been compared between men and women. Therefore, our purpose was to determine if sex-specific differences in E run and/or AT stiffness existed. E run (kcal kg(-1) km(-1)) was determined by indirect calorimetry at 75%, 85%, and 95% of the speed at lactate threshold (sLT) on 11 man (mean ± SEM, 35 ± 1 years, 177 ± 1 cm, 78 ± 1 kg, [Formula: see text]1 = 56 ± 1 mL kg(-1) min(-1)) and 18 woman (33 ± 1 years, 165 ± 1 cm, 58 ± 1 kg, [Formula: see text]2 = 50 ± 0.3 mL kg(-1) min(-1)) runners. AT stiffness was measured using ultrasound with dynamometry. Man E run was 1.01 ± 0.06, 1.04 ± 0.07, and 1.07 ± 0.07 kcal kg(-1) km(-1). Woman E run was 1.05 ± 0.10, 1.07 ± 0.09, and 1.09 ± 0.10 kcal kg(-1) km(-1). There was no significant sex effect for E run or RER, but both increased with speed (P < 0.01) expressed relative to sLT. High-range AT stiffness was 191 ± 5.1 N mm(-1) for men and 125 ± 5.5 N mm(-1), for women (P < 0.001). The relationship between low-range AT stiffness and E run was significant at all measured speeds for women (r (2) = 0.198, P < 0.05), but not for the men. These results indicate that when E run is measured at the same relative intensity, there are no sex-specific differences in E run or substrate use. Furthermore, differences in E run cannot be explained solely by differences in AT stiffness.

Avaliação dos níveis séricos de lactato em cães submetidos a anestesia dissociativa / Evaluación de los niveles séricos de lactato en perros sometidos a anestesia dissociativa / Seric level assessment of lactate in dogs submitted to dissociative anesthesia

A mensuração da lactatemia como indicador indireto da oxigenação dos tecidos e, por conseguinte, de estresse e acidemia, tem potencial para se tornar uma ferramenta muito útil em medicina veterinária. Neste estudo, 10 cães domésticos adultos clinicamente saudáveis foram anestesiados pela associação de tiletamina, zolazepam, xilazina e atropina, em doses calculadas por meio de extrapolação alométrica intraespecífica. A lactatemia foi mensurada por meio de reação enzimática, com leitura por fotometria de reflectância, 1.140 minutos e um minuto antes da administração da associação anestésica por via intramuscular, aos 10, 20, 40, 60, 80, 180, 360, 720, 1.140, 2.880 e 14.440 minutos após a injeção. O comportamento das concentrações de lactato frente aos eventos experimentais evidenciou normalidade antes e depois da anestesia, e queda significativa durante a mesma. Concluiu-se que a anestesia dissociativa pela associação de tiletamina, zolazepam, xilazina e atropina, em doses calculadas por meio de extrapolação alométrica intraespecífica, não eleva a lactatemia. De fato, durante a anestesia ocorreu queda significativa das concentrações de lactato em relação aos níveis considerados basais.

Lactate level measuring as an indirect indicator of tissue oxygenation, and consequently stress and acidemia, isa potentially useful tool for Veterinary Medicine. In this study 10 adult healthy dogs were anesthetized with the combination of tiletamine, zolazepam, xylazine and atropine, with dosages calculated by intraespecific allometric scaling. Blood lactate was measured by enzymatic reaction with reflectancy photometry 1.140 and one minute before intramuscular administration of the anesthetic combination, and at 10, 20, 40, 60, 80, 180, 360, 720, 1,140, 2.880 and 14.440 minutes after the injection. Serum lactate concentrations were normal prior and after anesthesia, and presented significant decrease throughout it. It was concluded that the combination of tiletamina, zolazepam, xylazine and atropine in allometrically scaled dosages do not increase lactatemia. In fact, significant decrease of lactate serum concentrations in comparison with basal levels was observed during anesthesia.

La mensuración de la lactatemia como indicador indirecto de la oxigenación de los tejidos, así como de estrés y acidemia, tiene potencial para tornarse una herramienta muy útil en medicina veterinaria. En este estudio fueron anestesiados 10 perros adultos saludables con la asociación de tiletamina, zolazepam, xilacina y atropina, en dosis calculadas por medio de extrapolación alométrica intraespecífica. La lactatemia fue mensurada por medio de reacción enzimática, con evaluación porfotometría de reflectancia, 1.140 minutos y un minuto antes de la suministración de la combinación anestésica por vía intramuscular,y a los 10, 20, 40, 60, 80, 180, 360, 720, 1.140, 2.880 y 14.440 minutos después de la inyección. El comportamiento de las concentraciones de lactato delante de los eventos experimentales evidenció normalidad antes y después de la anestesia, y caída significativa durante la misma. Se concluyó que la anestesia disociativa por la combinación de tiletamina, zolazepam, xilacina y atropina, en dosis calculadas por medio de extrapolación alométrica intraespecífica, no eleva la lactatemia. De facto, durante la anestesia ocurrió caída significativa de las concentraciones de lactato en relación a los niveles considerados basales.