Antidoping 2.0: Is Adding Power-Output Data to the Antidoping Pool the Next Step? Experts' Viewpoint.

BACKGROUND: Efforts are needed to improve antidoping procedures. The widespread use of power meters among cyclists could help in this regard. However, controversy exists on whether performance monitoring through power-output data could be of help for antidoping purposes. PURPOSE: The objective of the present study was to provide insight into the feasibility and utility of implementing power-based performance monitoring in elite cycling. An expert panel of 15 applied sport scientists and professional cycling coaches were asked for their opinions and perspectives on incorporating power data into the antidoping risk-assessment process. RESULTS: Two different viewpoints were identified from the responses provided by the experts. Some believed that power monitoring could be implemented as an antidoping tool, provided that several surmountable challenges are first addressed. These authors provided suggestions related to the potential practical implementation of such measures. Others, on the contrary, believed that power meters lack sufficient reliability and suggest that the professional cycling world presents conflicts of interest that make this intervention impossible to implement nowadays. CONCLUSIONS: The debate around the utility of power-meter data in the antidoping fight has been ongoing for more than a decade. According to the opinions provided by the experts' panel, there is still no consensus on the real utility and practical implementation of this intervention.

Risk stratification of new-onset psychiatric disorders using clinically distinct traumatic brain injury phenotypes.

BACKGROUND: Patients with traumatic brain injury (TBI) constitute a highly heterogeneous population, with varying risks for New-onset Psychiatric Disorders (NPDs). The objectives of this study were to identify TBI phenotypes and determine how NPDs differ among these phenotypes. METHODS: Hospitalized TBI patients from 2003 to 2019 were obtained from the provincial trauma registry. Propensity score matching was conducted to balance covariates among patients with TBI and controls. To uncover heterogeneity in TBI, latent class analysis (LCA)-based clustering was applied. LCA was conducted separately for two TBI cohorts: those with and without pre-injury psychiatric conditions The effect of classes on NPDs was assessed using log binomial regression models. RESULTS: A total of 3,453 patients with TBI and 13,112 controls were included in the analysis. In a conditional regression involving propensity matched patients with TBI and controls, TBI was significantly associated with the development of NPD-A (OR: 2.78; 95% CI: 2.49-3.09), as well as NPD-P (OR: 2.36; 95% CI: 2.07-2.70). Eight distinct latent classes were identified which differed in the incidence of NPDs. Four classes displayed a 53% (RR:1.53; 95% CI: 1.31-1.78), 48% (RR:1.48; 95% CI: 1.26-1.74), 28% (RR:1.28; 95% CI: 1.08-1.54), and 20% (RR: 1.20, 95%CI: 1.03-1.39), increased NPD risk. CONCLUSION: TBI is a significant predictor of NPDs. There are clinically distinguishable phenotypes with different patterns of NPD risk among patients with TBI. Identifying individuals with respect to their phenotype may improve risk stratification of patients with TBI and promote early intervention for psychiatric care in this vulnerable population.

Progress in physiologically based pharmacokinetic-pharmacodynamic models of amino acids in humans.

PURPOSE OF REVIEW: Amino acids are critical to health, serving both as constituents of proteins and in signaling and metabolism. Amino acids are consumed as nutrients, supplements, and nutraceuticals. Much remains to be learned about amino acid function. Physiologically based pharmacokinetic and pharmacodynamic (PBPK-PD) modeling is an emerging tool for studying their complex biology. This review highlights recent PBPK-PD models developed to study amino acid physiology and metabolism and discusses their potential for addressing unresolved questions in the field. RECENT FINDINGS: PBPK-PD models provided several insights. They revealed the interplay between the mechanisms by which leucine governs skeletal muscle protein metabolism in healthy adults. The models also identified optimal dosing regimens of amino acid supplementation to treat sickle-cell disease and recurrent hypoglycemia, and to minimize drug side effects in seizure disorders. Additionally, they characterized the effects of novel anticancer drugs that seek to deprive cancer cells of amino acids. Future models may inform treatment strategies for sarcopenia, characterize distinctions between animal- and plant-based nutrition, and inform nutrient-drug interactions in Parkinson's disease. SUMMARY: PBPK-PD models are powerful tools for studying amino acid physiology and metabolism, with applications to nutrition, pharmacology, and their interplay.

The bacterial microbiome and resistome of house dust mites in Irish homes.

Dust samples were collected from Irish homes. House Dust Mite and storage mites were separated from the dust. The microbiome and resistome of mites and originating dust were assessed using a culture-independent approach. The bacterial microbiome of mites and dust were predominantly populated by Staphylococci. There was a highly significant (P = 0.005; Spearman's rank test) correlation between the bacterial microbiome of mites and the dust. One-hundred and eighteen antimicrobial resistance genes (ARGs) were associated with mites and 176 with dust. Both contained ARGs encoding resistance for multi drug resistances, macrolide-lincosamide-streptogramin B, mobile genetic elements, Beta-lactam, Tetracycline and Aminoglycosides. By contrast, 15 ARGs were found for a laboratory-grown strain of Dermatophagoides pteronyssinus. A significant difference (P = 0.03; t test) was found in means between the resistome of mites and the household dust from which they emanated. No significant correlations (P = 0.23 and P = 0.22; Mantel test) were observed between the microbiome and resistome of mite and dust samples. There was not a significant difference (P = 0.54; t-test) between the means of ARGs for homes with and without a history of antibiotic use.

The Role of Denosumab Treatment in Recurrent Giant Cell Bone Tumor of the Orbit.

Giant cell tumor of the bone (GCTB) is a rare primary bone neoplasm, representing about 5% of all primary bone tumors. Most GCTBs are found in the epiphysis of long bones, with only 2% of GCTBs involving the skull. In recent years, the receptor activator of nuclear factor Kappa ligand monoclonal antibody denosumab has been demonstrated as a promising therapeutic option for GCTB; however, this is an evolving field. We present a case of a 57-year-old female with a rare GCTB in the right orbit and sinuses, originally thought to be an aneurysmal bone cyst. Her symptoms included proptosis, intermittent blurry vision, sinus congestion, and frontal headaches. After excision, the tumor recurred within 18 months. Upon repeat excision, a diagnosis of GCTB was made. The patient started denosumab therapy and had no tumor growth over the ensuing 2 years, with stability of symptoms and clinical signs on follow-up.

Exploring Greater Flexibility for Chronic Toxicity Study Designs to Support Human Safety Assessment While Balancing 3Rs Considerations.

Chronic repeated-dose toxicity studies are required to support long-term dosing in late-stage clinical trials, providing data to adequately characterize adverse effects of potential concern for human safety. Different regulatory guidances for the design and duration of chronic toxicity studies are available, with flexibility in approaches often adopted for specific drug modalities. These guidances may provide opportunities to reduce time, cost, compound requirement and animal use within drug development programs if applied more broadly and considered outside their current scopes of use. This article summarizes presentations from a workshop at the 43rd Annual Meeting of the American College of Toxicology (ACT) in November 2022, discussing different approaches for chronic toxicity studies. A recent industry collaboration between the Netherlands Medicines Evaluation Board (MEB) and UK National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) illustrated current practices and the value of chronic toxicity studies for monoclonal antibodies (mAbs) and evaluated a weight of evidence (WOE) model where a 3-month study rather than a 6-month study might be adequate. Other topics included potential opportunities for single-species chronic toxicity studies for small molecules, peptides and oligonucleotides and whether a 6-month duration non-rodent study can be used more routinely than a 9-month study (similar to ICH S6(R1) for biological products). Also addressed were opportunities to optimize recovery animal use if warranted and whether restriction to one study only (if at all) can be applied more widely within and outside ICH S6(R1).

Identification and expression of MarCE, a marine carboxylesterase with synthetic ester-degrading activity.

Carboxylic ester hydrolases with the capacity to degrade polyesters are currently highly sought after for their potential use in the biological degradation of PET and other chemically synthesized polymers. Here, we describe MarCE, a carboxylesterase family protein identified via genome mining of a Maribacter sp. isolate from the marine sponge Stelligera stuposa. Based on phylogenetic analysis, MarCE and its closest relatives belong to marine-associated genera from the Cytophaga-Flavobacterium-Bacteroides taxonomic group and appear evolutionarily distinct to any homologous carboxylesterases that have been studied to date in terms of structure or function. Molecular docking revealed putative binding of BHET, a short-chain PET derivative, onto the predicted MarCE three-dimensional structure. The synthetic ester-degrading activity of MarCE was subsequently confirmed by MarCE-mediated hydrolysis of 2 mM BHET substrate, indicated by the release of its breakdown products MHET and TPA, which were measured, respectively, as 1.28 and 0.12 mM following 2-h incubation at 30°C. The findings of this study provide further insight into marine carboxylic ester hydrolases, which have the potential to display unique functional plasticity resulting from their adaptation to complex and fluctuating marine environmentsw.

Alcohol is a risk factor for helmet non-use and fatalities in off-road vehicle and motorcycle crashes.

OBJECTIVES: Off-road vehicle (ORV) and motorcycle use is common in Canada; however, risk of serious injury is heightened when these vehicles are operated without helmets and under the influence of alcohol. This study evaluated the impact of alcohol intoxication on helmet non-use and mortality among ORV and motorcycle crashes. METHODS: Using data collected from the Nova Scotia Trauma Registry, a retrospective analysis (2002-2017) of ORV and motorcycle crashes resulting in major traumatic brain injury was performed. Patients were grouped by blood alcohol concentration (BAC) as negative (< 2 mmol/L), legally intoxicated (2-17.3 mmol/L) or criminally intoxicated (> 17.3 mmol/L). Logistic regression models were constructed to test for helmet non-use and mortality. RESULTS: A total of 424 trauma patients were included in the analysis (220 ORV, 204 motorcycle). Less than half (45%) of patients involved in ORV crashes were wearing helmets and 65% were criminally intoxicated. Most patients involved in motorcycle crashes were helmeted at time of injury (88.7%) and 18% were criminally intoxicated. Those with criminal levels of intoxication had 3.7 times the odds of being unhelmeted and were 3 times more likely to die prehospital compared to BAC negative patients. There were significantly increased odds of in-hospital mortality among those with both legal (OR = 5.63), and criminal intoxication levels (OR = 4.97) compared to patients who were BAC negative. CONCLUSION: Alcohol intoxication is more frequently observed in ORV versus motorcycle crashes. Criminal intoxication is associated with helmet non-use. Any level of intoxication is a predictor of increased in-hospital mortality.

Microbial metabolites as modulators of host physiology.

The gut microbiota is increasingly recognised as a key player in influencing human health and changes in the gut microbiota have been strongly linked with many non-communicable conditions in humans such as type 2 diabetes, obesity and cardiovascular disease. However, characterising the molecular mechanisms that underpin these associations remains an important challenge for researchers. The gut microbiota is a complex microbial community that acts as a metabolic interface to transform ingested food (and other xenobiotics) into metabolites that are detected in the host faeces, urine and blood. Many of these metabolites are only produced by microbes and there is accumulating evidence to suggest that these microbe-specific metabolites do act as effectors to influence human physiology. For example, the gut microbiota can digest dietary complex polysaccharides (such as fibre) into short-chain fatty acids (SCFA) such as acetate, propionate and butyrate that have a pervasive role in host physiology from nutrition to immune function. In this review we will outline our current understanding of the role of some key microbial metabolites, such as SCFA, indole and bile acids, in human health. Whilst many studies linking microbial metabolites with human health are correlative we will try to highlight examples where genetic evidence is available to support a specific role for a microbial metabolite in host health and well-being.

A native mass spectrometry approach to qualitatively elucidate interfacial epitopes of transient protein-protein interactions.

Native mass spectrometric analysis of TPR2A and GrpE with unpurified peptides derived from limited proteolysis of their respective PPI partners (HSP90 C-terminus and DnaK) facilitated efficient, qualitative identification of interfacial epitopes involved in transient PPI formation. Application of this approach can assist in elucidating interfaces of currently uncharacterised transient PPIs.

Engineering supramolecular dynamics of self-assembly and turnover of oncogenic microRNAs to drive their synergistic destruction in tumor models.

Rationally-engineered functional biomaterials offer the opportunity to interface with complex biology in a predictive, precise, yet dynamic way to reprogram their behaviour and correct shortcomings. Success here may lead to a desired therapeutic effect against life-threatening diseases, such as cancer. Here, we engineered "Crab"-like artificial ribonucleases through coupling of peptide and nucleic acid building blocks, capable of operating alongside and synergistically with intracellular enzymes (RNase H and AGO2) for potent destruction of oncogenic microRNAs. "Crab"-like configuration of two catalytic peptides ("pincers") flanking the recognition oligonucleotide was instrumental here in providing increased catalytic turnover, leading to ≈30-fold decrease in miRNA half-life as compared with that for "single-pincer" conjugates. Dynamic modeling of miRNA cleavage illustrated how such design enabled "Crabs" to drive catalytic turnover through simultaneous attacks at different locations of the RNA-DNA heteroduplex, presumably by producing smaller cleavage products and by providing toeholds for competitive displacement by intact miRNA strands. miRNA cleavage at the 5'-site, spreading further into double-stranded region, likely provided a synergy for RNase H1 through demolition of its loading region, thus facilitating enzyme turnover. Such synergy was critical for sustaining persistent disposal of continually-emerging oncogenic miRNAs. A single exposure to the best structural variant (Crab-p-21) prior to transplantation into mice suppressed their malignant properties and reduced primary tumor volume (by 85 %) in MCF-7 murine xenograft models.

What influences provision of information about recovery on stroke units? A focused ethnographic case study.

OBJECTIVE: Patients and carers frequently report dissatisfaction with post-stroke information provision. This study aimed to develop an in-depth understanding of the factors influencing provision of information about recovery in stroke units. METHODS: Focused ethnographic case-studies in two UK stroke units, including non-participant observations and semi-structured interviews with professionals, patients and carers, and documentary analysis. A Framework approach to analysis was undertaken. RESULTS: Twenty patients, 17 carers and 47 professionals participated. The unpredictable recovery trajectory led professionals to present prognostic estimates as uncertain possibilities. The need to maintain patients' motivation limited sharing of negative predictions, and generic information over-emphasised the importance of therapy in recovery. A structured multidisciplinary team approach to delivering information improved consistency. Complex clinical reasoning was required to identify and meet patients' needs. Hospital environments and routines restricted opportunities for dialogue, particularly with carers. CONCLUSIONS: The process of providing information about post-stroke recovery is complex, requiring enhanced clinical reasoning and communication. The challenges faced by professionals are numerous and if not addressed can result in suboptimal provision. PRACTICE IMPLICATIONS: Professionals should develop a co-ordinated multidisciplinary approach to information provision; and engage in dialogue to ensure a tailored approach to identifying and meeting patients' and carers' information needs.

Fidelity, pragmatism and the "grey line" in between-exploring the delivery of a pragmatic physical activity randomised controlled trial-a secondary analysis.

BACKGROUND: Intervention fidelity in health services research has been poor with a reported lack of understanding about what constitutes pragmatic adaptation of interventions and what constitutes failure to maintain intervention fidelity. However, the challenges facing those delivering such interventions have not been thoroughly explored. The aims of this study were to critically explore the challenges in maintaining fidelity experienced by physiotherapy staff and support workers when delivering a complex intervention for older people living with frailty. METHODS: This study is a secondary analysis of data from a process evaluation of a large randomised controlled trial (RCT). The process evaluation employed qualitative methodologies with mixed methods including a variety of data collection methods, including participant observation, semi-structured interviews and documentary analysis. Thematic analysis was used to make sense of the data. RESULTS: Many therapy staff felt ongoing confusion about what was acceptable to adapt and what needed to follow the protocol exactly. We found that some therapy staff were able to embrace the challenges of pragmatically adapting interventions while maintaining intervention fidelity, others stuck rigidly to the protocol and failed to adapt interventions where it was necessary. CONCLUSION: It was clear that the understanding of fidelity and pragmatism was poor. While pragmatic trials are vital to replicate real world clinical practice, further guidance may need to be developed in order to guide the level of adaptation that is acceptable before fidelity is undermined.

Global indicators of the environmental impacts of invasive alien species and their information adequacy.

Monitoring the extent to which invasive alien species (IAS) negatively impact the environment is crucial for understanding and mitigating biological invasions. Indeed, such information is vital for achieving Target 6 of the Kunming-Montreal Global Biodiversity Framework. However, to-date indicators for tracking the environmental impacts of IAS have been either lacking or insufficient. Capitalizing on advances in data availability and impact assessment protocols, we developed environmental impact indicators to track realized and potential impacts of IAS. We also developed an information status indicator to assess the adequacy of the data underlying the impact indicators. We used data on 75 naturalized amphibians from 82 countries to demonstrate the indicators at a global scale. The information status indicator shows variation in the reliability of the data and highlights areas where absence of impact should be interpreted with caution. Impact indicators show that growth in potential impacts are dominated by predatory species, while potential impacts from both predation and disease transmission are distributed worldwide. Using open access data, the indicators are reproducible and adaptable across scales and taxa and can be used to assess global trends and distributions of IAS, assisting authorities in prioritizing control efforts and identifying areas at risk of future invasions. This article is part of the theme issue 'Ecological novelty and planetary stewardship: biodiversity dynamics in a transforming biosphere'.

A nature-positive future with biological invasions: theory, decision support and research needs.

In 2050, most areas of biodiversity significance will be heavily influenced by multiple drivers of environmental change. This includes overlap with the introduced ranges of many alien species that negatively impact biodiversity. With the decline in biodiversity and increase in all forms of global change, the need to envision the desired qualities of natural systems in the Anthropocene is growing, as is the need to actively maintain their natural values. Here, we draw on community ecology and invasion biology to (i) better understand trajectories of change in communities with a mix of native and alien populations, and (ii) to frame approaches to the stewardship of these mixed-species communities. We provide a set of premises and actions upon which a nature-positive future with biological invasions (NPF-BI) could be based, and a decision framework for dealing with uncertain species movements under climate change. A series of alternative management approaches become apparent when framed by scale-sensitive, spatially explicit, context relevant and risk-consequence considerations. Evidence of the properties of mixed-species communities together with predictive frameworks for the relative importance of the ecological processes at play provide actionable pathways to a NPF in which the reality of mixed-species communities are accommodated and managed. This article is part of the theme issue 'Ecological novelty and planetary stewardship: biodiversity dynamics in a transforming biosphere'.

FIVE YEARS OF PARTULA SNAIL PRE-EXPORT HEALTH SCREENING.

Between 2015 and 2019, a health screening was carried out annually on captive-bred Partula snails prior to export for reintroduction as part of an international effort to repopulate areas of French Polynesia, where the snails were extinct or critically endangered. In total, 129 separate tank populations of 12 different species were screened at ZSL London Zoo. Wet mounts and smears stained with modified Ziehl-Neelsen (MZN) of 535 fecal samples were examined, and 45% contained flagellated protozoa, and 35.5% had MZN-positive oocysts, measuring 3-5 µm in diameter. Smaller (2 µm) presumptive spores, MZN-positive bacilli, ciliated protozoa and nematodes were recorded less frequently. Fecal bacterial culture yielded mixed species, with a clear predominance of Myroides species (88.9% of samples). The MZN-positive oocysts (3-5 µm) were present in 6.5% of impression smears from the apices of 432 snails examined postmortem, plus acid-fast bacilli in a few cases, but no 2 µm spores. Mixed bacteria were cultured from coelomic swabs, with Myroides species again the most common (63.5%). Histologic examination was carried out on 292 snails. Autolysis affected almost 90% of those found dead but only 3.4% of euthanized snails. Histology commonly identified microsporidial sporocysts in the digestive gland and midgut epithelium of all but two species. Intracellular, extracytoplasmic Cryptosporidium-like organisms were also common in the midgut but were only observed when snails were fixed in 10% formalin (2017-2019), not ethanol. There were no clear pathologic changes associated with either organism. Pigmented hemocytic nodules were commonly observed, most frequently in the foot process; these were either age related or evidence of prior chronic inflammatory reaction and of low clinical significance. With no evidence of poor health and no significant organisms found, a total of 4,978 individuals representing 12 species were exported for reintroduction.