Identification of muscle weakness in older adults from normalized upper and lower limbs strength: a cross-sectional study

Background To propose cut-off points for older adults’ weakness for upper and lower limbs muscle strength normalized by body size with the ratio standard/muscle quality and allometric scaling. Methods Ninety-four community-dwelling older adults (69.1% women) were assessed for 49 body-size variables (anthropometry, body composition and body indexes), handgrip strength (HGS), one maximum repetition measurement for knee extensors (1RM), isokinetic knee extension peak torque at 60°/s (PT), and six-minute walk test (6MWT). Ratio standard or muscle quality (muscle strength/body size) and allometric scaling (muscle strength/body sizeb; when b is the allometric exponent) were applied for body-size variables significantly correlated with HGS, 1RM and PT. Cut-off points were computed according to sex based on mobility limitation (6MWT < 400 m) with ROC curve and Youden index. Results Absolute HGS, 1RM and PT cut-off points were not adequate because they were associated with body size (r > 0.30). But it was corrected with muscle strength normalization according to body size-variables: HGS (n = 1); 1RM (n = 24) and PT (n = 24). The best cut-off points, with the highest area under the curve (AUC), were found after normalization for men: HGS/forearm circumference (1.33 kg/cm, AUC = 0.74), 1RM/triceps skinfold (4.22 kg/mm, AUC = 0.81), and PT/body mass*height0.43 (13.0 Nm/kg*m0.43, AUC = 0.94); and for women: HGS/forearm circumference (1.04 kg/cm, AUC = 0.70), 1RM/body mass (0.54 kg/kg, AUC = 0.76); and PT/body mass0.72 (3.14 Nm/kg0.72; AUC = 0.82). Conclusions Upper and lower limbs muscle weakness cut-off points standardized according to body size were proposed for older adults of both sexes. Normalization removes the effect of extreme body size on muscle strength (both sexes) and improves the accuracy to identify weakness at population level (for women, but not in men), reducing the risk of false-negative/positive cases.

Subcutaneous Marzeptacog Alfa (Activated) Versus Intravenous rFVIIa for Treatment of Episodic Bleeding in FVIII Deficient Hemophilia a Rats

Background: FVIII deficient knock-out (F8 -/-) rats mimic the bleeding incidents seen in severe human hemophilia A (HA). Subcutaneous (SQ) marzeptacog alfa activated (MarzAA), a novel, engineered recombinant activated coagulation Factor VII (rFVIIa) has been shown to effectively treat episodic bleeding in a pilot experiment in HA rats. This study evaluated the effect of single SQ doses of MarzAA and a single intravenous (IV) dose of rFVIIa on episodic bleeding in F8 -/- rats. Moreover, it compared the effect of SQ MarzAA and IV rFVIIa directly. Methods: Animals were allocated to treatment with either SQ vehicle, SQ MarzAA (60, 180 or 385 µg/kg) or IV rFVIIa (NovoSeven ®) (580 µg/kg) immediately after the bleeding was diagnosed. Doses were based on allometric scaling from humans (Nair AB and Jacob S. J Basic Clin Pharm 2016; 7: 27-31). The primary endpoint of the study was clinical efficacy as rated by a well-defined 4-point scale (Excellent, Good, Fair or Poor), and the efficacy assessment was either treatment success (Excellent or Good) or treatment failure (Fair or Poor) at the 24-hour timepoint. All personnel handling or assessing animals were blinded to the treatment status of each animal except those dosing animals who knew the route of administration. Results: A total of 86 F8 -/- rats was enrolled in the study. Of these, 61 rats presented treatment eligible bleeds between 3 and 10 weeks of age. No statistically significant difference in bleeding severity score were found across groups on diagnosis. As assessed by the clinical outcome at 24 hours, all three SQ MarzAA dose groups exhibited a statistically significant effect on treatment response when compared to SQ vehicle treatment (Figure 1). Conversely, no statistically significant effect could be identified when the single IV rFVIIa 580 µg/kg dose group was compared to vehicle. The overall treatment success rates at 24 hours were: SQ vehicle: 8%, SQ MarzAA 60 µg/kg: 58%, SQ MarzAA 180 µg/kg: 67%, SQ MarzAA 385 µg/kg: 85%, and IV rFVIIa 580 µg/kg: 33%. When compared directly using allometric scaling of clinical doses, SQ MarzAA at 385 µg/kg exhibited a statistically superior effect compared to IV rFVIIa at 580 µg/kg (p=0.0154, Fischer's exact test). Conclusion: Single doses of SQ MarzAA were effective in treating episodic bleeding in HA rats and statistically distinguishable from vehicle at all dose levels tested. When clinically relevant doses were compared directly to rFVIIa, SQ MarzAA compared favorably to IV rFVIIa. Taken together, these data provide robust nonclinical evidence that a single dose of SQ MarzAA may be successful in treating episodic bleeding when administered after bleeding has started. Figure 1 Figure 1. Disclosures Knudsen: Catalyst Biosciences: Current Employment, Current holder of individual stocks in a privately-held company. Blouse: Catalyst Biosciences: Current Employment.

Universal Ontogenetic Growth without Fitting Parameters: Implications for Life History Invariants & Population Growth

Since the work of Von Bertalanffy (1957), several models have been proposed that relate the ontogenetic scaling of energy assimilation and metabolism to growth, being able to describe ontogenetic growth trajectories for living organisms and collapse them onto a single universal curve (West et al. 2001; Barnavar et al. 2002). Nevertheless, all these ontogenetic growth models critically depends on fitting parameters and on the allometric scaling of the metabolic rate. Using a new metabolic rate relation (Escala 2019) applied to a Bertalanffy-type ontogenetic growth equation, we find that ontogenetic growth can also be described by an universal growth curve for all studied species, but without the aid of any fitting parameters. We find that the inverse of the heart frequency fH, rescaled by the ratio of the specific energies for biomass creation and metabolism, defines the characteristic timescale for ontogenetic growth. Moreover, our model also predicts a generation time and lifespan that explains the origin of several 'Life History Invariants' (Charnov 1993) and predicts that the Mathusian Parameter should be inversely proportional to both the generation time and lifespan, in agreement with the data in the literature (Duncan et al. 1997; Dillingham et. al 2016; Hatton et al 2019). In our formalism, several critical timescales and rates (lifespan, generation time & intrinsic population growth rate) are all proportional to the heart frequency fH, thus their allometric scaling relations comes directly from the allometry of the heart frequency, which is typically fH ∝ M-0.25 under basal conditions.

Allometric scaling of RNA abundance from genes to communities

The metabolic theory of ecology (MTE) and growth rate hypothesis (GRH) help explain the mechanistic basis of size (allometry) and temperature dependence on growth rate and whole-body-RNA content in organisms. However, testing RNA allometric scaling with next-generation sequencing is yet to be done. Here, we validated the assumptions of GRH and MTE on messenger RNA and ribosome abundance using mock community metatranscriptome analysis. Our findings highlight that fast-growing smaller species harbor greater RNA abundance per mass of tissue compared with species having larger body sizes and slower growth rates, where allometric slopes for genomic and gene-level RNA abundance range from –⅓ to −1. We found that genome size and body size impose significant constraints in interspecific RNA abundance scaling, while the assumed temperature dependence appeared to be weak. Lastly, allometric scaling integration in community-level models may extend the use of metatranscriptomics as a reliable tool for estimating ecosystem processes.

Toxicokinetics of U-47700, tramadol, and their main metabolites in pigs following intravenous administration: is a multiple species allometric scaling approach useful for the extrapolation of toxicokinetic parameters to humans?

New synthetic opioids (NSOs) pose a public health concern since their emergence on the illicit drug market and are gaining increasing importance in forensic toxicology. Like many other new psychoactive substances, NSOs are consumed without any preclinical safety data or any knowledge on toxicokinetic (TK) data. Due to ethical reasons, controlled human TK studies cannot be performed for the assessment of these relevant data. As an alternative animal experimental approach, six pigs per drug received a single intravenous dose of 100 µg/kg body weight (BW) of U-47700 or 1000 µg/kg BW of tramadol to evaluate whether this species is suitable to assess the TK of NSOs. The drugs were determined in serum and whole blood using a fully validated method based on solid-phase extraction and LC–MS/MS. The concentration–time profiles and a population (pop) TK analysis revealed that a three-compartment model best described the TK data of both opioids. Central volumes of distribution were 0.94 L/kg for U-47700 and 1.25 L/kg for tramadol and central (metabolic) clearances were estimated at 1.57 L/h/kg and 1.85 L/h/kg for U-47700 and tramadol, respectively. The final popTK model parameters for pigs were upscaled via allometric scaling techniques. In comparison to published human data, concentration–time profiles for tramadol could successfully be predicted with single species allometric scaling. Furthermore, possible profiles for U-47700 in humans were simulated. The findings of this study indicate that unlike a multiple species scaling approach, pigs in conjunction with TK modeling are a suitable tool for the assessment of TK data of NSOs and the prediction of human TK data.