Biomarker Qualification for Neurofilament Light Chain in Amyotrophic Lateral Sclerosis: Theory and Practice.

OBJECTIVE: To explore whether the utility of neurofilament light chain (NfL), as a biomarker to aid amyotrophic lateral sclerosis (ALS) therapy development, would be enhanced by obtaining formal qualification from the US Food and Drug Administration for a defined context-of-use. METHODS: Consensus discussion among academic, industry, and patient advocacy group representatives. RESULTS: A wealth of scientific evidence supports the use of NfL as a prognostic, response, and potential safety biomarker in the broad ALS population, and as a risk/susceptibility biomarker among the subset of SOD1 pathogenic variant carriers. Although NfL has not yet been formally qualified for any of these contexts-of-use, the US Food and Drug Administration has provided accelerated approval for an SOD1-lowering antisense oligonucleotide, based partially on the recognition that a reduction in NfL is reasonably likely to predict a clinical benefit. INTERPRETATION: The increasing incorporation of NfL into ALS therapy development plans provides evidence that its utility-as a prognostic, response, risk/susceptibility, and/or safety biomarker-is already widely accepted by the community. The willingness of the US Food and Drug Administration to base regulatory decisions on rigorous peer-reviewed data-absent formal qualification, leads us to conclude that formal qualification, despite some benefits, is not essential for ongoing and future use of NfL as a tool to aid ALS therapy development. Although the balance of considerations for and against seeking NfL biomarker qualification will undoubtedly vary across different diseases and contexts-of-use, the robustness of the published data and careful deliberations of the ALS community may offer valuable insights for other disease communities grappling with the same issues. ANN NEUROL 2024;95:211-216.

Development of the Talent Identification Questionnaire in Soccer for Outfield Players (TIDQ-OP): Coaches' perceptions of the key attributes for player recruitment.

Talent identification in sports is a complex process, whereby the aim is to identify, select and promote players who are considered to have the necessary skills and competencies (e.g., technical, tactical, and physical attributes) to succeed in senior adult competition. To support this process, this study focused on the development of a questionnaire to assist in the identification of talent among South African youth soccer players. This will establish a measure of the attributes coaches consider important when making talent identification decisions for outfield soccer players. The questionnaire was constructed following established instrument development phases. In phase 1, 61 questionnaire items were generated based on a review of the relevant literature. In phase 2, a panel of experts examined the content validity of the preliminary items. In phase 3, the provisional 59-item questionnaire (Talent Identification Questionnaire in Soccer for Outfield Players; TIDQ-OP) was administered to 173 experienced South African soccer coaches (130 males and 43 females) who ranged in age from 18 to 64 years. In phase 3, the factorial structure of the questionnaire was established through principal component analysis. The final questionnaire consisted of 58 items. These preliminary analyses indicate the usefulness of the TIDQ-OP as a tool to assist South African coaches in the identification and selection of talented players.

Gender- and Sport-specific Normative Anthropometric and Physical Values in Talent-Identified High School Athletes.

ABSTRACT: Larkin, P, Sortino, B, Carlon, T, Saunders, T, and Pane, C. Gender- and sport-specific normative anthropometric and physical values in talent-identified high school athletes. J Strength Cond Res 37(3): 606-615, 2023-Youth sport is associated with the identification and promotion of athletes within talent development pathways, with anthropometric and physical performance measures being key assessment and monitoring tools. To adequately evaluate performance within a population, normative reference data are needed; however, currently, there is limited normative values of talent-identified youth athletes. The aim of the current study is to present normative values of talent-identified youth sport academy athletes in relation to gender, age, and sport. Over a 5-year period, a total of 794 talent-identified youth athletes who attended a specialized school sports academy were assessed using anthropometric (i.e., heigh,; body mass) and physical performance (i.e., vertical jump, 20-m sprint, Yo-Yo intermittent recovery test 1) measures. In total, 451 male and 343 female athletes (grade 7: 12-13 years; grade 8: 13-14 years; grade 9: 14-15 years; grade 10: 15-16 years) were tested annually. The result demonstrates that for each gender, as age increases, there is a general increase in anthropometric measures (i.e., height and body mass). Furthermore, with increasing age, athletes generally have a higher vertical jump, faster sprint performance, and improved physical endurance. The results highlight sport-specific differences for each measure. Overall, the results of the study provides age-, gender-, and sport-specific normative data of talent-identified youth athletes. These findings provide representative performance profiles of talent-identified high school athletes, with the values potentially being used by coaching staff (i.e., head coaches, strength and conditioning coaches, rehabilitation staff) for comparison purposes.

PGE2 signaling via the neuronal EP2 receptor increases injury in a model of cerebral ischemia.

The inflammatory prostaglandin E2 (PGE2) EP2 receptor is a master suppressor of beneficial microglial function, and myeloid EP2 signaling ablation reduces pathology in models of inflammatory neurodegeneration. Here, we investigated the role of PGE2 EP2 signaling in a model of stroke in which the initial cerebral ischemic event is followed by an extended poststroke inflammatory response. Myeloid lineage cell-specific EP2 knockdown in Cd11bCre;EP2lox/lox mice attenuated brain infiltration of Cd11b+CD45hi macrophages and CD45+Ly6Ghi neutrophils, indicating that inflammatory EP2 signaling participates in the poststroke immune response. Inducible global deletion of the EP2 receptor in adult ROSA26-CreERT2 (ROSACreER);EP2lox/lox mice also reduced brain myeloid cell trafficking but additionally reduced stroke severity, suggesting that nonimmune EP2 receptor-expressing cell types contribute to cerebral injury. EP2 receptor expression was highly induced in neurons in the ischemic hemisphere, and postnatal deletion of the neuronal EP2 receptor in Thy1Cre;EP2lox/lox mice reduced cerebral ischemic injury. These findings diverge from previous studies of congenitally null EP2 receptor mice where a global deletion increases cerebral ischemic injury. Moreover, ROSACreER;EP2lox/lox mice, unlike EP2-/- mice, exhibited normal learning and memory, suggesting a confounding effect from congenital EP2 receptor deletion. Taken together with a precedent that inhibition of EP2 signaling is protective in inflammatory neurodegeneration, these data lend support to translational approaches targeting the EP2 receptor to reduce inflammation and neuronal injury that occur after stroke.

Ambient-pressure endstation of the Versatile Soft X-ray (VerSoX) beamline at Diamond Light Source.

The ambient-pressure endstation and branchline of the Versatile Soft X-ray (VerSoX) beamline B07 at Diamond Light Source serves a very diverse user community studying heterogeneous catalysts, pharmaceuticals and biomaterials under realistic conditions, liquids and ices, and novel electronic, photonic and battery materials. The instrument facilitates studies of the near-surface chemical composition, electronic and geometric structure of a variety of samples using X-ray photoelectron spectroscopy (XPS) and near-edge X-ray absorption fine-structure (NEXAFS) spectroscopy in the photon energy range from 170 eV to 2800 eV. The beamline provides a resolving power hν/Δ(hν) > 5000 at a photon flux > 1010 photons s-1 over most of its energy range. By operating the optical elements in a low-pressure oxygen atmosphere, carbon contamination can be almost completely eliminated, which makes the beamline particularly suitable for carbon K-edge NEXAFS. The endstation can be operated at pressures up to 100 mbar, whereby XPS can be routinely performed up to 30 mbar. A selection of typical data demonstrates the capability of the instrument to analyse details of the surface composition of solid samples under ambient-pressure conditions using XPS and NEXAFS. In addition, it offers a convenient way of analysing the gas phase through X-ray absorption spectroscopy. Short XPS spectra can be measured at a time scale of tens of seconds. The shortest data acquisition times for NEXAFS are around 0.5 s per data point.

Validity and reliability of an Australian football small-sided game to assess kicking proficiency.

In Australian Football (AF), small sided games have been used extensively as an alternative training method for technical and physical adaptations. Considering their application to AF, it is surprising a valid and reliable small-sided game kicking assessment remains absent. Therefore, the aim of this study was to develop a valid and reliable 5v6 Australian football small-sided game kicking proficiency assessment. Youth male AF players (n = 145) from different stages within the AF talent pathway were recruited. Validity (i.e., logical and construct) and reliability (i.e., test re-test) were assessed. The largest kicking proficiency difference was between U13 and U16 players and between novice and sub-elite players. Between the ages of U16 and U18 kicking proficiency appears to stabilise. The Australian football small-sided kicking assessment was 97% successful in identifying players as either novice or sub-elite. Larger physical performance (i.e., odometer, m/min-1 and %HIR) outputs were noted between U14 and U18 players and novice and sub-elite players. Collectively, these findings suggest the Australian football small-sided kicking assessment is a valid and reliable AF kicking proficiency assessment tool and may provide worthwhile information to coaches regarding kicking performance along the AFL pathway, to profile player strengths whilst identifying specific areas of improvement.

Positive youth development and gender differences in high performance sport.

We examined positive youth development within a high performance sport environment. Youth football players (N = 455; Males = 315; Females = 140) completed a range of questionnaires including: the Youth Experiences Survey for Sport; Self-Confidence subscale of the Competitive State Anxiety Inventory-2 Revised; Sport Competence Inventory; Prosocial and Antisocial Behaviour in Sport Scale; and the modified Coach-Athlete Relationship questionnaire. The players reported a relatively high level of self-confidence, competence and positive youth experiences. They felt a strong coach-athlete relationship and displayed higher levels of prosocial than antisocial behaviour. Males scored significantly higher than females on self-confidence, perceived self-competence, antisocial behaviour to teammates and opponents, relationship with their coach, and cognitive skills. Findings suggest a relationship between high performance sport environments and positive youth development.

Effects of manipulating player numbers on technical and physical performances participating in an Australian football small-sided game.

In Australian Football (AF), small-sided games (SSGs) are used extensively to replicate particular technical, tactical or physiological responses. Whilst research on SSGs has been extensive in soccer, in AF it has been limited to agility demands and exploring the effect of field dimensions on technical skill (i.e., handballing) and physical responses of senior athletes. Therefore, this study investigated the effect of four different SSG player number conditions (5v5, 5v6, 6v6, 7v7) on the technical (e.g., kicking) and physical (i.e., odometer, m-min-1, max velocity and percentage of high intensity running) performance outcomes in 22 sub-elite youth AF players. Particular constraints were applied to the SSG to ensure the focus was on kicking (i.e., after each handball a kick must be performed). The results of this study demonstrate when more technical events are required under more pressured situations (i.e., physical and time) the 5v6 condition appears to be most appropriate. However, when the focus is on kicking to a contested possession (i.e., kicking to leading or covered players) balanced player numbers (e.g., 6v6) would appear optimal. Alternatively, when the SSG focus is on increasing physiological demands (i.e., m.min-1) lower player density conditions (i.e., 5v5) appear more suitable.

Observations of youth football training: How do coaches structure training sessions for player development?

We used systematic observation tools to explore the structure (i.e., activity and inactivity) and sequencing (i.e., the types of activities used) of football coaching sessions in Australia following the implementation of a new National Curriculum. Youth soccer coaches (n = 34), coaching within the Skill Acquisition (U11-U13 n = 19) and Game Training (U14-U17 n = 15) phases of the Football Federation Australia National Curriculum participated. Participants were filmed during a regular coaching session, with systematic observation of the session undertaken to provide a detailed analysis of the practice activities and coach behaviours. Findings indicated a session comprised of Playing Form activities (40.9%), Training Form activities (22.3%), inactivity (31%), and transitions between activities (5.8%). Coaches prescribed more Training Form activities (e.g., individual (5.4%) and drills (15.1%)) early in the session and progressed to Playing Form activities (i.e., small-sided games (15.3%) then larger games (24.8%)) later in the session. Most inactivity reflected the players listening to the coach - either in a team huddle (9.9%) or frozen on the spot during an activity (16.5%). In addition, coaches generally spent over 3 min communicating to players prior to explaining and introducing an activity regardless of when in the session the activity was scheduled.

Video-based training to improve perceptual-cognitive decision-making performance of Australian football umpires.

Decision-making is a central component of the in-game performance of Australian football umpires; however, current umpire training focuses largely on physiological development with decision-making skills development conducted via explicit lecture-style meetings with limited practice devoted to making actual decisions. Therefore, this study investigated the efficacy of a video-based training programme, aimed to provide a greater amount of contextualised visual experiences without explicit instruction, to improve decision-making skills of umpires. Australian football umpires (n = 52) were recruited from metropolitan and regional Division 1 competitions. Participants were randomly assigned to an intervention or control group and classified according to previous umpire game experience (i.e., experienced; less experienced). The intervention group completed a 12-week video-based decision-making training programme, with decision-making performance assessed at pre-training, and 1-week retention and 3-week retention periods. The control group did not complete any video-based training. Results indicated a significant Group (intervention; Control) × Test interaction (F(1, 100) = 3.98; P = 0.02, partial ῆ2 = 0.074), with follow-up pairwise comparisons indicating significant within-group differences over time for the intervention group. In addition, decision-making performance of the less experienced umpires in the intervention group significantly improved (F(2, 40) = 5.03, P = 0.01, partial ῆ2 = 0.201). Thus, video-based training programmes may be a viable adjunct to current training programmes to hasten decision-making development, especially for less experienced umpires.

Tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase 1 make separate, tissue-specific contributions to basal and inflammation-induced kynurenine pathway metabolism in mice.

BACKGROUND: In mammals, the majority of the essential amino acid tryptophan is degraded via the kynurenine pathway (KP). Several KP metabolites play distinct physiological roles, often linked to immune system functions, and may also be causally involved in human diseases including neurodegenerative disorders, schizophrenia and cancer. Pharmacological manipulation of the KP has therefore become an active area of drug development. To target the pathway effectively, it is important to understand how specific KP enzymes control levels of the bioactive metabolites in vivo. METHODS: Here, we conducted a comprehensive biochemical characterization of mice with a targeted deletion of either tryptophan 2,3-dioxygenase (TDO) or indoleamine 2,3-dioxygenase (IDO), the two initial rate-limiting enzymes of the KP. These enzymes catalyze the same reaction, but differ in biochemical characteristics and expression patterns. We measured KP metabolite levels and enzyme activities and expression in several tissues in basal and immune-stimulated conditions. RESULTS AND CONCLUSIONS: Although our study revealed several unexpected downstream effects on KP metabolism in both knockout mice, the results were essentially consistent with TDO-mediated control of basal KP metabolism and a role of IDO in phenomena involving stimulation of the immune system.

The effects of physical exertion on decision-making performance of Australian football umpires.

Decision-making is a key component of an umpire's in-game performance, with each decision potentially having a direct impact on the result of the game. Additionally, umpires have to be physically fit to ensure they keep up with the gameplay. While research has identified the decision-making demands and running demands of umpires separately, few have explored the relationship between them. The aim of this investigation was to examine the relationship between physical exertion and decision-making performance of Australian football umpires at the sub-elite and junior levels. A total of 18 Australian football umpires (sub-elite, n = 10; junior n = 8) performed 10 × 300 m runs, with each repetition immediately followed by a video-based decision-making test, then 1 min of recovery. A Mann-Whitney U assessment indicated a significant difference between the sub-elite and junior level umpires for decision-making accuracy (U = 13.00, z = -2.43, P = 0.016, r = -0.5). However, there was no significant difference in response time (U = 28.00, z = -1.07, P = 0.315, r = -0.25). The sub-elite umpires completed the running efforts in significantly less time than the junior umpires (P < 0.05). Further, there was no significant correlation between decision-making performance and running times for either skill level (P > 0.05). This suggests decision-making performance may not be affected by physical exertion. Therefore, it may be suggested coaches of football umpires allocate more time to the decision-making development of their umpires instead of focusing largely on the physical fitness side, as is currently the trend.

Perfectionism and sport-specific engagement in elite youth soccer players.

It is acknowledged that the time invested in sport-specific activities contributes to higher levels of performance. However, there is limited understanding of the potential impact of personality traits, such as perfectionism, on engagement in sport-specific activities. In the current study, we examine whether elite youth soccer players who demonstrate higher and lower levels of perfectionistic strivings tendencies can be differentiated based on their sport-specific engagement. The Sport Multidimensional Perfectionism Scale 2 and an adapted Player History Questionnaire were completed by 419 elite youth male soccer players competing at the Australian age-related national youth championships (under 13, n = 133; under 14, n = 166; under 15, n = 120). A quartile split approach was used to separate higher (n = 100) and lower (n = 107) perfectionistic strivings groups. Findings revealed the higher perfectionistic strivings group accumulated more time in sport-specific activities, including coach-led practice, individual practice, peer-led play and indirect involvement in soccer when compared to individuals with lower perfectionistic strivings tendencies. Descriptive analysis indicates this equates to approximately 159 h a year (i.e. 17 h coach-led practice, 22 h individual practice, 60 h of peer-led play and 60 h of indirect involvement) more than the lower perfectionistic strivings group. In summary, the results suggest players with varying levels of perfectionistic strivings may be differentiated based on their engagement in soccer-specific activity in a sample of elite youth players in Australia, and suggests that perfectionistic strivings may have an adaptive influence on sport-specific engagement.

Suppression of Alzheimer-associated inflammation by microglial prostaglandin-E2 EP4 receptor signaling.

A persistent and nonresolving inflammatory response to accumulating Aß peptide species is a cardinal feature in the development of Alzheimer's disease (AD). In response to accumulating Aß peptide species, microglia, the innate immune cells of the brain, generate a toxic inflammatory response that accelerates synaptic and neuronal injury. Many proinflammatory signaling pathways are linked to progression of neurodegeneration. However, endogenous anti-inflammatory pathways capable of suppressing Aß-induced inflammation represent a relatively unexplored area. Here we report that signaling through the prostaglandin-E2 (PGE2) EP4 receptor potently suppresses microglial inflammatory responses to Aß42 peptides. In cultured microglial cells, EP4 stimulation attenuated levels of Aß42-induced inflammatory factors and potentiated phagocytosis of Aß42. Microarray analysis demonstrated that EP4 stimulation broadly opposed Aß42-driven gene expression changes in microglia, with enrichment for targets of IRF1, IRF7, and NF-κB transcription factors. In vivo, conditional deletion of microglial EP4 in APPSwe-PS1ΔE9 (APP-PS1) mice conversely increased inflammatory gene expression, oxidative protein modification, and Aß deposition in brain at early stages of pathology, but not at later stages, suggesting an early anti-inflammatory function of microglial EP4 signaling in the APP-PS1 model. Finally, EP4 receptor levels decreased significantly in human cortex with progression from normal to AD states, suggesting that early loss of this beneficial signaling system in preclinical AD development may contribute to subsequent progression of pathology.

Assessment of decision-making performance and in-game physical exertion of Australian football umpires.

The aim of this study is to investigate the effects of in-game physical exertion on decision-making performance of Australian football umpires. Fifteen Australian football umpires (Mage = 36, s = 13.5 years; Mgames umpired = 235.2, s = 151.3) volunteered to participate in the study. During five competitive Australian football pre-season games, measures of in-game physical exertion (blood lactate levels, global positioning system [GPS]) and decision-making performance (video-based test) were obtained. There were no significant correlations between physical exertion in a particular quarter and decision-making performance in either the same quarter or any other quarter. Video-based decision-making performance was effected by time in game χ(2)(3) = 24.24, P = 0.001, with Quarter 4 performance significantly better than both Quarter 2 and Quarter 3. In-game physical exertion (blood lactate) significantly decreased over the course of the game χ(2)(3) = 11.58, P = 0.009. Results indicate no definable link between in-game physical exertion and decision-making performance. It is, however, presumed that decision-making performance may be affected by the time or context of the game. Future research is warranted to explore the relationship between physical exertion and decision-making performance to potentially inform Australian football umpire training programmes that replicate in-game physical and decision-making demands.

Lessons for cannabinoid regulation from electronic nicotine delivery system product regulation.

Cannabis legalization continues to spread, with 38 states permitting the use of medical marijuana, 22 states permitting recreational use, and growing political momentum for federal legalization. The last time the Food and Drug Administration (FDA) was tasked with regulating a new product occurred with 2009's Family Smoking Prevention and Tobacco Control Act, which created the Center for Tobacco Products (CTP). Thus, the time is ripe to review the history of CTP with particular attention to difficulties the nascent center faced in regulating novel products such as e-cigarettes or electronic nicotine delivery systems (ENDS). Specifically, FDA has struggled with defining its scope of authority, determining which review pathway(s) to utilize, and promulgating timely and transparent product standards for marketing authorization-all of which offer lessons for improving cannabis product oversight and enforcement.

Compounding endowment effects when trading draft picks in the Australian Football League.

Endowment effect relates to a situation when decision makers are more likely to retain an object they own, than acquire the same object when they do not own it. Studies have often concluded that players recruited early on through drafts are more likely to be held in team rosters irrespective of their marginal utility. We tested the hypothesis wherein this effect would compound when the pick used to select a player is traded between teams. Using a sample of draftees selected between 2003 and 2016 in the Australian Football League, we created a proportional hazard model to predict the career longevity of a player with their drafting team and overall career. The results suggest each subsequent trade marginally reduced the exit of a player by a log normal rate of 0.269 in their career with the team that initially drafted them. The findings were attributed to the premium requested by the original team that is compounded with every exchange as the reference points used to determine value have also shifted with the trade.

Deferring draft picks: Empirical analysis of the AFL draft.

Trading picks is a common transaction observed in sporting leagues that employ player drafts. However, many current and revised draft formats employed by professional leagues allow for the trading of picks in the current year for those in the future. This in turn raises a question of an appropriate rate of discount which can be used to account for the delay in relinquishing current picks for those in the future. This study proposes a discount rate function in the Australian Football League based on the difference between a player's contribution to his team in his first season to that of his career. The findings reveal a varying discount rate that decreases with the progression of the draft ranging between 42% and 51%, given the increasing deviation of post draft outcomes in the same range. Furthermore, after discounting said picks for four years, the variance in pick reduced considerably as poor performers are delisted after their initial contract period. Upon adopting the model to evaluate previous trades, it is evident that almost all parties infer a higher value on current year selections than future selections (discounting future picks by up to 120%), seeking instant returns over deferred options. Hence, a decision maker trying to capitalise on pick value only would be better off deferring the right to choose in the current year.

The Determinants of Maximal Speed Adaptation During Preseason in Subelite Female Australian Rules Footballers.

PURPOSE: Maximal speed is an important physical-fitness attribute for female Australian footballers. The effects of sprint training, maximal strength, and technical training have been reported in laboratory studies. However, no study has determined the combined effect and relative contribution of these training modalities on maximal speed adaptation in situ. Therefore, the aim of this study was to determine the training factors affecting maximal speed adaptation during a preseason in subelite female Australian Rules footballers. METHODS: Maximal speed during field training, predicted 1-repetition maximum (1RM) for box squat and hip thrust, and sprint biomechanics were assessed during early and late preseason (∼9 wk apart) in 15 female subelite Australian Rules Football players (age 20 [3] y). On-field training volume and intensity (total distance, high-speed running, very-high-speed running, and maximal speed) were determined using a Global Positioning System. A multivariate regression model was used to determine the factors associated with changes in maximal speed across the preseason. RESULTS: The preseason training program had a small effect on maximal speed and large to very large effects on strength and sprint biomechanics. The multivariate regression with the greatest fit (P < .001, R2 = .939) included change in estimated 1RM box squat (ß = -0.63), total distance per week (ß = -0.55), and change in hip projection (ß = 0.16) as factors. Multivariate regression of biomechanical factors (P = .044, R2 = .717) and maximal strength factors (P = .003, R2 = .676) were also significant. CONCLUSION: The development of maximal speed across a preseason is dependent on (1) total distance per week, (2) maximal strength adaptation, and (3) sprint technique adaptation in female subelite Australian rules football players.

Optionality in Australian Football League draftee contracts.

Though player drafts have commonly been utilised to equitably disperse amateur talent and avoid bidding wars, often they have also been accused of creating a monopsony labour market which restricts player movement. Within the Australian Football League (AFL) some have called for the increase of the initial draftee contract from two to three seasons, which further pushes the envelope on monopsony power. Instead of increasing the contract length, this paper suggests a call option to be purchased by the teams allowing them to add a further season to the draftee contract at a predetermined compensation package should they choose to do so at the end of the initial contract. The call prices per pick were calculated using the Black-Scholes model and were valued between 1% and 1.5% of the pick value. However, it failed to follow a monotonic function similar to pick value, owing to managerial overconfidence and sunk investment plays. Overall, the findings allow teams to procure the option of increasing initial draftee contracts and not impede further on a player's ability to move.