Relationship Between External Training Load and Session Rating of Perceived Exertion Training Impulse in Elite Sprinters.

PURPOSE: To quantify the change in session rating of perceived exertion training impulse (RPE-TRIMP) that may occur in response to increased running distance at 3 running velocity ranges in elite sprinters. METHODS: We monitored training load in elite sprinters (women: n = 7; men: n = 11) using wearable Global Positioning System technology and RPE-TRIMP for a total of 681 individual training sessions during a 22-week competition-preparation period. Internal training load was operationalized by RPE-TRIMP, and external training load was operationalized by distance covered in 3 velocity ranges. A linear mixed-effects model with athlete as a random effect was fit to RPE-TRIMP with total distance covered at ≤69.99% (low-velocity running [LVR]), 70% to 84.99% (high-velocity running [HVR]), and 85% to 100% (very-high-velocity running [VHVR]) of individual maximum velocity. RESULTS: Increased running distance in all 3 velocity ranges (LVR, HVR, and VHVR) resulted in a significant (P < .001) increase in RPE-TRIMP. Coefficients (95% CIs) were .10 (.08-.11) for LVR, .23 (.18-.28) for HVR, and .44 (.35-.53) for VHVR. A 50-m increase in running distance covered in the LVR, HVR, and VHVR velocity ranges was associated with increases in RPE-TRIMP of 5, 11.5, and 22 arbitrary units, respectively. CONCLUSIONS: Internal training load, calculated as RPE-TRIMP, increased with increases in total distance covered in the LVR, HVR, and VHVR velocity ranges (P < .001). RPE-TRIMP can be a practical solution for monitoring global training-session load in elite sprinters.

Validity of Global Positioning System Technology to Measure Maximum Velocity Sprinting in Elite Sprinters.

ABSTRACT: Thome, M, Thorpe, RT, Jordan, MJ, and Nimphius, S. Validity of global positioning system (GPS) technology to measure maximum velocity sprinting in elite sprinters. J Strength Cond Res 37(12): 2438-2442, 2023-The objective of this study was to assess the concurrent validity of 10-Hz wearable Global Positioning System (GPS) technology to measure maximum velocity sprinting (Vmax) relative to Doppler radar in elite sprinters. Data were collected from a single training session performed by elite 100 and 200 m sprinters (males: n = 5; 100 m best times: 10.02 ± 0.07 seconds, range: 9.94-10.10 seconds; 200 m best times: 20.29 ± 0.42 seconds, range: 19.85-20.80 seconds; females: n = 2; age: 28.0 ± 4.2 years; body mass: 65.8 ± 4.6 kg; 100 m best times: 11.18 ± 0.34 seconds; 200 m best times: 22.53 ± 0.04 seconds). Velocity and time data from 16 maximal, 60-m sprint efforts were recorded simultaneously with 10 Hz GPS and 47 Hz radar. Validity was assessed using Bland-Altman 95% limits of agreement (LOA) and intraclass correlation coefficient (ICC), each with respective 95% confidence intervals (CI). Vmax measured with 10 Hz GPS demonstrated a LOA of -0.11 m·s-1 (-0.17, -0.05) and an ICC of 0.99 (0.98, 1.0) relative to the radar device.10 Hz GPS overestimated Vmax by 0.11 m·s-1 relative to the radar but could still be considered a suitable tool for monitoring external load in elite sprinters. However, the much smaller average annual improvement in this population (∼0.1-0.2%) in comparison with the ∼1% overestimation reduces the utility of 10 Hz GPS to detect meaningful performance changes in maximum velocity.

International nonproprietary names for monoclonal antibodies: an evolving nomenclature system.

Appropriate nomenclature for all pharmaceutical substances is important for clinical development, licensing, prescribing, pharmacovigilance, and identification of counterfeits. Nonproprietary names that are unique and globally recognized for all pharmaceutical substances are assigned by the International Nonproprietary Names (INN) Programme of the World Health Organization (WHO). In 1991, the INN Programme implemented the first nomenclature scheme for monoclonal antibodies. To accompany biotechnological development, this nomenclature scheme has evolved over the years; however, since the scheme was introduced, all pharmacological substances that contained an immunoglobulin variable domain were coined with the stem -mab. To date, there are 879 INN with the stem -mab. Owing to this high number of names ending in -mab, devising new and distinguishable INN has become a challenge. The WHO INN Expert Group therefore decided to revise the system to ease this situation. The revised system was approved and adopted by the WHO at the 73rd INN Consultation held in October 2021, and the radical decision was made to discontinue the use of the well-known stem -mab in naming new antibody-based drugs and going forward, to replace it with four new stems: -tug, -bart, -mig, and -ment.

WHO informal consultation on revision of guidelines on evaluation of similar biotherapeutic products, virtual meeting, 30 June - 2 July 2021.

The WHO informal consultation was held to promote the revision of WHO guidelines on evaluation of similar biotherapeutic products (SBPs) adopted by the Expert Committee on Biological Standardization (ECBS) in 2009. It was agreed in the past consultations that the evaluation principles in the guidelines are still valid, but a review was recommended to provide more clarity and case-by-case flexibility. The opportunity was therefore taken to review the experience and identify areas where the current guidance could be more permissive without compromising its basic principles, and where additional explanation could be provided regarding the possibility of reducing the amount of data needed for regulatory approval. The meeting participants applauded the leading role taken by the WHO in providing a much-needed streamlined approach for development and evaluation of SBPs which will provide efficient and cost-effective product development and increase patient access to treatments. It was recognized that the principles as currently described in the draft WHO guidelines are based on sound science and experience gained over the last fifteen years of biosimilar approvals. However, since these guidelines when finalised will constitute the global standard for biosimilar evaluation and assist national regulatory authorities in establishing revised guidance and regulatory practice in this complex area, it was felt that further revision and clarity on certain perspectives in specific areas was necessary to dispel uncertainties arising in the current revised version. This report describes the principles in the draft guidelines, including topics discussed and consensus reached.

Regulatory challenges with biosimilars: an update from 20 countries.

The World Health Organization (WHO) issued guidelines for the regulatory evaluation of biosimilars in 2009 and has provided considerable effort toward helping member states implement the evaluation principles in the guidelines into their regulatory practices. Despite this effort, a recent WHO survey (conducted in 2019-2020) has revealed four main remaining challenges: unavailable/insufficient reference products in the country; lack of resources; problems with the quality of some biosimilars (and even more with noninnovator products); and difficulties with the practice of interchangeability and naming of biosimilars. The following have been identified as opportunities/solutions for regulatory authorities to deal with the existing challenges: (1) exchange of information on products with other regulatory authorities and accepting foreign licensed and sourced reference products, hence avoiding conducting unnecessary (duplicate) bridging studies; (2) use of a "reliance" concept and/or joint review for the assessment and approval of biosimilars; (3) review and reassessment of the products already approved before the establishment of a regulatory framework for biosimilar approval; and (4) setting appropriate regulatory oversight for good pharmacovigilance, which is essential for the identification of problems with products and establishing the safety and efficacy of interchangeability of biosimilars.

The regulatory landscape of biosimilars: WHO efforts and progress made from 2009 to 2019.

The World Health Assembly in 2014 adopted a resolution that mandates both Member States and the WHO Secretariat to facilitate access to biotherapeutic products in a way that ensures their quality, safety and efficacy. The availability of biosimilars is expected to increase access to biotherapeutic products by providing more treatment options triggering competition which would lead to a consistent reduction in the average price of treatment. Since the WHO guidelines for regulatory evaluation of biosimilars were issued in 2009, WHO has provided immense effort towards harmonizing the terminology and the regulatory framework for biosimilars globally. This article describes the progress made and the regulatory landscape changes for biosimilars in 21 countries during the past ten years. Based on the information from regulators and from publicly available data, the following has been identified: 1) WHO guidelines have contributed to setting the regulatory framework for biosimilars in countries and increasing regulatory convergence at global level; 2) terminology used for biosimilars is more consistent than in the past; 3) biosimilars are now approved in all participating countries; and 4) the dominant product class for candidate biosimilars under development is monoclonal antibodies.

Harmonization and standardization of immunogenicity assessment of biotherapeutic products.

Understanding of the determinants of immunogenicity, the testing paradigm, the impact of antibody attributes on clinical outcomes and regulatory guidance is leading to harmonized practices for immunogenicity assessment of biotherapeutics. However, generation of robust immunogenicity data for inclusion in product labels to support clinical practice continues to be a challenge. Assays, protocols and antibody positive controls/standards need to be developed in sufficient time to allow assessment of clinical immunogenicity using validated methods and optimized protocols. Standardization and harmonization play a significant role in achieving acceptable results. Harmonization in the postapproval setting is crucial for a valid interpretation of the product's immunogenicity and its clinical effects. Efforts are ongoing to standardize assays where possible for antibody measurement and for measuring product/drug levels by producing reference standards. Provision of such standards will help toward personalized treatment strategies with better patient outcomes.

Quality assessment and its impact on clinical performance of a biosimilar erythropoietin: A simulated case study.

The case study described in this paper was developed for the purpose of training for a better understanding of principles relating especially to a comprehensive evaluation of multiple quality attributes as outlined in the WHO guidelines on evaluation of similar biotherapeutic products. It is also to emphasize the importance of an understanding of the critical quality attributes and a risk assessment of the impact on clinical performance. It was prepared to mimic a real situation in which regulators need to evaluate the differences in quality attributes known to have potential impact on clinical activity. Erythropoietin has been identified as one of the important glycosylated therapeutic proteins and a good example to illustrate how structural characteristics would affect product efficacy and safety. The case study illustrates biosimilarity assessment of a candidate of erythropoietin biosimilar and the important quality attributes that need to be considered in order to understand the importance of structure-function relationships as they contribute to the stepwise evaluation of biosimilarity. This paper reflects the outcomes of the case study exercise and discussion from two WHO implementation workshops held in Ghana (September 2015) and Denmark (July 2017).

The impact of thioredoxin reduction of allosteric disulfide bonds on the therapeutic potential of monoclonal antibodies.

Therapeutic mAbs are used to manage a wide range of cancers and autoimmune disorders. However, mAb-based treatments are not always successful, highlighting the need for a better understanding of the factors influencing mAb efficacy. Increased levels of oxidative stress associated with several diseases are counteracted by the activities of various oxidoreductase enzymes, such as thioredoxin (Trx), which also reduces allosteric disulfide bonds in proteins, including mAbs. Here, using an array of in vitro assays, we explored the functional effects of Trx-mediated reduction on the mechanisms of action of six therapeutic mAbs. We found that Trx reduces the interchain disulfide bonds of the mAbs, after which they remain intact but have altered function. In general, this reduction increased antigen-binding capacity, resulting in, for example, enhanced tumor necrosis factor (TNF) neutralization by two anti-TNF mAbs. Conversely, Trx reduction decreased the antiproliferative activity of an anti-tyrosine kinase-type cell-surface receptor HER2 mAb. In all of the mAbs, Fc receptor binding was abrogated by Trx activity, with significant loss in both complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC) activity of the mAbs tested. We also confirmed that without alkylation, Trx-reduced interchain disulfide bonds reoxidize, and ADCC activity is restored. In summary, Trx-mediated reduction has a substantial impact on the functional effects of an mAb, including variable effects on antigen binding and Fc function, with the potential to significantly impact mAb efficacy in vivo.

Cold water immersion settings for reducing muscle tissue temperature: a linear dose-response relationship.

BACKGROUND: Although cold water immersion (CWI) is widely accepted and integrated as a recovery modality in sports practice, questions regarding its proposed working mechanisms remain. This study systematically reviews the existing literature on one the proposed mechanisms of CWI, its effect on muscle tissue temperature, and subsequently tries to identify a dose-response relationship in order to describe an optimal dose. EVIDENCE ACQUISITION: A systematic literature search (PubMed and Sport Discus) was conducted in October 2017. Dose-response relationships were analyzed using linear regression while controlling for possible confounders (muscle measurement depth and immersion position). EVIDENCE SYNTHESIS: A total of 10 studies, with a total of 104 participants, were included utilizing 26 different CWI protocols. Muscle tissue temperatures were reduced significantly by 24 CWI protocols. A significant, relationship with a medium effect size (r=0.51) was identified between muscle tissue temperature and CWI. The most optimal dose-response relationship, with a large effect size, (r=0.87) was described for CWI protocols using full-body immersion at a measurement depth of 30 mm (y = 4.051 x + 0.535). CONCLUSIONS: CWI can decrease muscle tissue temperature significantly if a minimum CWI dose of 1.1 is applied, corresponding with an immersion of 11 minutes with a water temperature of 10 °C.

The INN global nomenclature of biological medicines: A continuous challenge.

Medicines are assigned International Nonproprietary Names (INN) by the World Health Organization (WHO), pursuing the aim to increase patient safety. Following scientific developments in drug discovery and biotechnology, the number of biological medicines is constantly growing and a surge in INN applications for them has been observed. Pharmacologically active biological substances have a complex structure and mechanism of action posing new challenges in selecting names that appropriately reflect such properties. As a consequence, existing nomenclature naming schemes may need to be revised and new ones developed. This review reports on the recently implemented policies for naming fusion proteins, monoclonal antibodies, advanced therapy substances that cover gene and cell therapy, virus-based therapies as well as vaccines and vaccine-like substances. Different approaches, based on the use of a one-word versus a two-word naming scheme, have been developed for different categories of biological substances highlighting a major and still not completely resolved issue, i.e. how to assign a name that is both informative, short and euphonic.

Mass spectrometry analysis reveals differences in the host cell protein species found in pseudotyped lentiviral vectors.

Lentiviral vectors (LVs) have been successfully used in clinical trials showing long term therapeutic benefits. Studying the role of cellular proteins in lentivirus HIV-1 life cycle can help understand virus assembly and budding, leading to improvement of LV production for gene therapy. Lentiviral vectors were purified using size exclusion chromatography (SEC). The cellular protein composition of LVs produced by two different methods was compared: the transient transfection system pseudotyped with the VSV-G envelope, currently used in clinical trials, and a stable producer cell system using a non-toxic envelope derived from cat endogenous retrovirus RD114, RDpro. Proteins of LVs purified by size exclusion chromatography were identified by tandem mass spectrometry (MS/MS). A smaller number of cellular protein species were detected in stably produced vectors compared to transiently produced vector samples. This may be due to the presence of co-purified VSV-G vesicles in transiently produced vectors. AHNAK (Desmoyokin) was unique to RDpro-Env vectors. The potential role in LV particle production of selected proteins identified by MS analysis including AHNAK was assessed using shRNA gene knockdown technique. Down-regulation of the selected host proteins AHNAK, ALIX, and TSG101 in vector producer cells did not result in a significant difference in vector production.