Efficient α and ß- radionuclide therapy targeting fibroblast activation protein-α in an aggressive preclinical mouse tumour model.

PURPOSE: Targeted radionuclide therapy (TRT) is a cancer treatment with relative therapeutic efficacy across various cancer types. We studied the therapeutic potential of TRT using fibroblast activation protein-α (FAP) targeting sdAbs (4AH29) labelled with 225Ac or 131I in immunocompetent mice in a human FAP (hFAP) expressing lung cancer mouse model. We further explored the combination of TRT with programmed cell death ligand 1 (PD-L1) immune checkpoint blockade (ICB). METHODS: We studied the biodistribution and tumour uptake of [131I]I-GMIB-4AH29 and [225Ac]Ac-DOTA-4AH29 by ex vivo γ-counting. Therapeutic efficacy of [131I]I-GMIB-4AH29 and [225Ac]Ac-DOTA-4AH29 was evaluated in an immunocompetent mouse model. Flow cytometry analysis of tumours from [225Ac]Ac-DOTA-4AH29 treated mice was performed. Treatment with [225Ac]Ac-DOTA-4AH29 was repeated in combination with PD-L1 ICB. RESULTS: The biodistribution showed high tumour uptake of [131I]I-GMIB-4AH29 with 3.5 ± 0.5% IA/g 1 h post-injection (p.i.) decreasing to 0.9 ± 0.1% IA/g after 24 h. Tumour uptake of [225Ac]Ac-DOTA-4AH29 was also relevant with 2.1 ± 0.5% IA/g 1 h p.i. with a less steep decrease to 1.7 ± 0.2% IA/g after 24 h. Survival was significantly improved after treatment with low and high doses [131I]I-GMIB-4AH29 or [225Ac]Ac-DOTA-4AH29 compared to vehicle solution. Moreover, we observed significantly higher PD-L1 expression in tumours of mice treated with [225Ac]Ac-DOTA-4AH29 compared to vehicle solution. Therefore, we combined high dose [225Ac]Ac-DOTA-4AH29 with PD-L1 ICB showing therapeutic synergy. CONCLUSION: [225Ac]Ac-DOTA-4AH29 and [131I]I-GMIB-4AH29 exhibit high and persistent tumour targeting, translating into prolonged survival in mice bearing aggressive tumours. Moreover, we demonstrate that the combination of PD-L1 ICB with [225Ac]Ac-DOTA-4AH29 TRT enhances its therapeutic efficacy.

The Dose-Response Relationship of an Exercise-Based Injury Prevention Program: A Secondary Analysis of a Randomized Controlled Trial on Athletics (Track-and-Field) Athletes Over a 39-Week Follow-Up.

Despite exercise-based injury prevention programs (EIPPs) being widely researched and used, several randomized controlled trials (RCTs) have failed to show their protective effect on injury risk. This is potentially due to underappreciating the EIPP dose-response relationship, by not controlling the analysis for the injuries sustained during the early EIPP implementation period, before the EIPP becomes efficacious. To determine the dose-response relationship of EIPP by controlling for the effects of injuries sustained before it became efficacious. We conducted a secondary analysis of an RCT analyzing the EIPP efficacy in athletics over a 39-week follow-up on 840 athletes, by including only those with 100% response rate. We controlled the statistical analyses for a range of lengths of early EIPP implementation period by either excluding the athletes with early injuries (i.e., exclusion approach) or adjusting for the early injuries' effects (i.e., inclusion approach). We estimated the EIPP's dose-response relationship by measuring the EIPP's effect at each length of the controlled period. When we considered no early controlled period, the EIPP showed no effect (OR = 0.85 [95% CI: 0.67-1.09]; p = 0.209). However, both exclusion and inclusion approaches showed that the EIPP effect increased significantly after 5-6 weeks of controlled period. This relationship plateaued at 7-12 weeks of controlled period, peaking at 10 weeks with the exclusion approach (OR = 0.28 [95% CI: 0.16-0.48]; p < 0.001), and 7 weeks with the inclusion approach (OR = 0.37 [95% CI: 0.25-0.55]; p < 0.001). Acknowledging the dose-response relationship of EIPPs could help researchers to design and analyze RCTs and practitioners to plan EIPP implementation timely. Trial Registration: ClinicalTrials.gov Identifier: NCT03307434.

How do sports injury epidemiological outcomes vary depending on athletes' response rates to a weekly online questionnaire? An analysis of 39-week follow-up from 391 athletics (track and field) athletes.

OBJECTIVE: To explore how sports injury epidemiological outcomes (i.e., prevalence, average prevalence, incidence, burden, and time to first injury) vary depending on the response rates to a weekly online self-reported questionnaire for athletes. METHODS: Weekly information on athletics injuries and exposure from 391 athletics (track and field) athletes was prospectively collected over 39 weeks (control group of the PREVATHLE randomized controlled trial) using an online self-reported questionnaire. The data were used to calculate sports injury epidemiological outcomes (i.e., prevalence, average prevalence, incidence, burden, and time to first injury) for sub-groups with different minimum individual athletes' response rates (i.e., from at least 100%, at least 97%, at least 95%, … to at least 0% response rate). We then calculated the relative variation between each sub-group and the sub-group with a 100% response rate as a reference. A substantial variation was considered when the relative variation was greater than one SD or 95% CI of the respective epidemiological outcome calculated in the sub-group with a 100% response rate. RESULTS: Of 15 249 expected weekly questionnaires, 7209 were completed and returned, resulting in an overall response rate of 47.3%. The individual athletes' response rates ranged from 0% (n = 51) to 100% (n = 100). The prevalence, average weekly prevalence, and time to first injury only varied substantially for the sub-groups below a 5%, 10% and 18% minimum individual response rate, respectively. The incidence and injury burden showed substantial variations for all sub-groups with a response rate below 100%. CONCLUSIONS: Epidemiological outcomes varied depending on the minimum individual athletes' response rate, with injury prevalence, average weekly prevalence, and time to first injury varying less than injury incidence and injury burden. This highlights the need to take into account the individual response rate when calculating epidemiological outcomes, and determining the optimal study-specific cut-offs of the minimum individual response rate needed.

French Athletics Stakeholders' Perceptions of Relevance and Expectations on Injury Prevention.

This study aimed to explore how stakeholders in athletics perceive the relevance of injury prevention, determine their communication preferences, and describe their expectations regarding injury prevention. We conducted a cross-sectional study using an exploratory online survey with high-level athletes (i. e. listed by the French ministry of sports), non-high-level athletes (i. e. all competitive level except high-level athletes), coaches, and health professionals licensed with the French Federation of Athletics. The survey was composed of three parts regarding stakeholder's characteristics (4 questions), perceived relevance (2 questions), communication preferences and expectations (3 questions) towards injury prevention. There were 2,864 responders to the survey. Almost all responders found that injury prevention is relevant (97.7% [95% CI 97.0% to 98.2%]), without any significant differences in the distribution between stakeholders' age, experience and sex (p>0.05). About three-quarters of the stakeholders preferred to find injury prevention information on a website (77.4%) without significant differences between stakeholders' categories (p>0.05); other media to find injury prevention information was chosen by less than 50% of responders. Expectations about injury prevention were mainly explanations, advice and tips about injury knowledge, management and prevention, based on expert opinion and/or scientific research. In conclusion, these results confirm that injury prevention is a challenge shared by numerous stakeholders in athletics, within France, and provide some orientation on how and what information to disseminate to these stakeholders.

Apparent temperature and heat-related illnesses during international athletic championships: A prospective cohort study.

International outdoor athletics championships are typically hosted during the summer season, frequently in hot and humid climatic conditions. Therefore, we analyzed the association between apparent temperature and heat-related illnesses occurrence during international outdoor athletics championships and compared its incidence rates between athletics disciplines. Heat-related illnesses were selected from illness data prospectively collected at seven international outdoor athletics championships between 2009 and 2018 using a standardized methodology. The Universal Thermal Climate Index (UTCI) was calculated as a measure of the apparent temperature based on weather data for each day of the championships. Heat-related illness numbers and (daily) incidence rates were calculated and analyzed in relation to the daily maximum UTCI temperature and between disciplines. During 50 championships days with UTCI temperatures between 15℃ and 37℃, 132 heat-related illnesses were recorded. Average incidence rate of heat-related illnesses was 11.7 (95%CI 9.7 to 13.7) per 1000 registered athletes. The expected daily incidence rate of heat-related illnesses increased significantly with UTCI temperature (0.12 more illnesses per 1000 registered athletes/°C; 95%CI 0.08-0.16) and was found to double from 25 to 35°C UTCI. Race walkers (RR = 45.5, 95%CI 21.6-96.0) and marathon runners (RR = 47.7, 95%CI 23.0-98.8) had higher heat-related illness rates than athletes competing in short-duration disciplines. Higher UTCI temperatures were associated with more heat-related illnesses, with marathon and race walking athletes having higher risk than athletes competing in short-duration disciplines. Heat-related illness prevention strategies should predominantly focus on marathon and race walking events of outdoor athletics championships when high temperatures are forecast.

Injury frequency and characteristics (location, type, cause and severity) differed significantly among athletics ('track and field') disciplines during 14 international championships (2007-2018): implications for medical service planning.

OBJECTIVE: To analyse differences between athletic disciplines in the frequency and characteristics of injuries during international athletics championships. METHODS: Study design, injury definition and data collection procedures were similar during the 14 international championships (2007-2018). National medical teams and local organising committee physicians reported all newly incurred injuries daily on a standardised injury report form. Results were presented as number of injuries and number of injuries per 1000 registered athletes, separately for male and female athletes, and for each discipline. RESULTS: From a total of 8925 male and 7614 female registered athletes, 928 injuries were reported in male and 597 in female athletes. The discipline accounting for the highest proportion of injuries was sprints, for both men (24%) and women (26%). The number of injuries per 1000 registered athletes varied between disciplines for men and women: highest in combined events for male athletes (235 (95% CI 189 to 281)) and female athletes (212 (95% CI 166 to 257)), and lowest for male throwers (47 (95% CI 35 to 59)) and female throwers (32 (95% CI 21 to 43)) and for female race walkers (42 (95% CI 19 to 66)). Injury characteristics varied significantly between disciplines for location, type, cause and severity in male and female athletes. Thigh muscle injuries were the main diagnoses in the disciplines sprints, hurdles, jumps, combined events and race walking, lower leg muscle injuries in marathon running, lower leg skin injury in middle and long distance running, and trunk muscle and lower leg muscle injuries in throws. CONCLUSIONS: Injury characteristics differed substantially between disciplines during international athletics championships. Strategies for medical service provision (eg, staff, facilities) during athletics championships should be discipline specific and be prepared for targeting the main injuries in each discipline.

Prosthetic groups for radioiodination and astatination of peptides and proteins: A comparative study of five potential bioorthogonal labeling strategies.

125I- and 211At-labeled azide and tetrazine based prosthetic groups for bioorthogonal conjugation were designed and tested in a comparative study of five bioorthogonal systems. All five bioconjugation reactions conducted on a model clickable peptide led to quantitative yields within less than a minute to several hours depending on the system used. Transferability to the labeling of an IgG was demonstrated with one of the bioorthogonal system. This study provides several new alternatives to the conventional and suboptimal approach currently in use for radioiodination and astatination of biomolecules and should accelerate the development of new probes with these radionuclides for applications in nuclear imaging and targeted alpha-therapy.

A new Strategy to Improve Drug Delivery to the Maxillary Sinuses: The Frequency Sweep Acoustic Airflow.

PURPOSE: Enhancement of intranasal sinus deposition involves nebulization of a drug superimposed by an acoustic airflow. We investigated the impact of fixed frequency versus frequency sweep acoustic airflow on the improvement of aerosolized drug penetration into maxillary sinuses. METHODS: Fixed frequency and frequency sweep acoustic airflow were generated using a nebulizing system of variable frequency. The effect of sweep cycle and intensity variation was studied on the intranasal sinus deposition. We used a nasal replica created from CT scans using 3D printing. Sodium fluoride and gentamicin were chosen as markers. RESULTS: Studies performed using fixed frequency acoustic airflow showed that each of maxillary sinuses of the nasal replica required specific frequency for the optimal aerosol deposition. Intranasal sinus drug deposition experiments under the effect of the frequency sweep acoustic airflow showed an optimal aerosol deposition into both maxillary sinus of the nasal replica. Studies on the effect of the duration of the sweep cycle showed that the shorter the cycle the better the deposition. CONCLUSIONS: We demonstrate the benefit of frequency sweep acoustic airflow on drug deposition into maxillary sinuses. However further in vivo studies have to be conducted since delivery rates cannot be obviously determined from a nasal replica.

A data-driven computational methodology towards a pre-hospital Acute Ischaemic Stroke screening tool using haemodynamics waveforms.

BACKGROUND AND OBJECTIVE: Acute Ischaemic Stroke (AIS), a significant global health concern, results from occlusions in cerebral arteries, causing irreversible brain damage. Different type of treatments exist depending on the size and location of the occlusion. Challenges persist in achieving faster diagnosis and treatment, which needs to happen in the first hours after the onset of symptoms to maximize the chances of patient recovery. The current diagnostic pipeline, i.e. "drip and ship", involves diagnostic via advanced imaging tools, only available in large clinical facilities, which poses important delays. This study investigates the feasibility of developing a machine learning model to diagnose and locate occluding blood clots from velocity waveforms, which can be easily be obtained with portable devices such as Doppler Ultrasound. The goal is to explore this approach as a cost-effective and time-efficient alternative to advanced imaging techniques typically available only in large hospitals. METHODS: Simulated haemodynamic data is used to conduct blood flow simulations representing healthy and different AIS scenarios using a population-based database. A Machine Learning classification model is trained to solve the inverse problem, this is, detect and locate a potentially occluding thrombus from measured waveforms. The classification process involves two steps. First, the region where the thrombus is located is classified into nine groups, including healthy, left or right large vessel occlusion, left or right anterior cerebral artery, and left or right posterior cerebral artery. In a second step, the bifurcation generation of the thrombus location is classified as small, medium, or large vessel occlusion. RESULTS: The proposed methodology is evaluated for data without noise, achieving a true prediction rate exceeding 95% for both classification steps mentioned above. The inclusion of up to 20% noise reduces the true prediction rate to 80% for region detection and 70% for bifurcation generation detection. CONCLUSIONS: This study demonstrates the potential effectiveness and efficiency of using haemodynamic data and machine learning to detect and locate occluding thrombi in AIS patients. Although the geometric and topological data used in this study are idealized, the results suggest that this approach could be applicable in real-world situations with appropriate adjustments. Source code is available in https://github.com/ahmetsenemse/Acute-Ischaemic-Stroke-screening-tool-.

Physics-Informed Graph Neural Networks to solve 1-D equations of blood flow.

BACKGROUND AND OBJECTIVE: Computational models of hemodynamics can contribute to optimizing surgical plans, and improve our understanding of cardiovascular diseases. Recently, machine learning methods have become essential to reduce the computational cost of these models. In this study, we propose a method that integrates 1-D blood flow equations with Physics-Informed Graph Neural Networks (PIGNNs) to estimate the propagation of blood flow velocity and lumen area pulse waves along arteries. METHODS: Our methodology involves the creation of a graph based on arterial topology, where each 1-D line represents edges and nodes in the blood flow analysis. The innovation lies in decoding the mathematical data connecting the nodes, where each node has velocity and lumen area pulse waveform outputs. The training protocol for PIGNNs involves measurement data, specifically velocity waves measured from inlet and outlet vessels and diastolic lumen area measurements from each vessel. To optimize the learning process, our approach incorporates fundamental physical principles directly into the loss function. This comprehensive training strategy not only harnesses the power of machine learning but also ensures that PIGNNs respect fundamental laws governing fluid dynamics. RESULTS: The accuracy was validated in silico with different arterial networks, where PIGNNs achieved a coefficient of determination (R2) consistently above 0.99, comparable to numerical methods like the discontinuous Galerkin scheme. Moreover, with in vivo data, the prediction reached R2 values greater than 0.80, demonstrating the method's effectiveness in predicting flow and lumen dynamics using minimal data. CONCLUSIONS: This study showcased the ability to calculate lumen area and blood flow rate in blood vessels within a given topology by seamlessly integrating 1-D blood flow with PIGNNs, using only blood flow velocity measurements. Moreover, this study is the first to compare the PIGNNs method with other classic Physics-Informed Neural Network (PINNs) approaches for blood flow simulation. Our findings highlight the potential to use this cost-effective and proficient tool to estimate real-time arterial pulse waves.

Educating and promoting athletes' health protection through infographics on injury and illness prevention during an international competition: a prospective study during the 2024 European Athletics Championships.

Objective: To investigate the feasibility, perceived relevance and usefulness of providing injury and illness prevention information through infographics to athletes and medical teams before and during an international athletics championship, and its potential impact on injury and illness risk during the same championship. Methods: We conducted a prospective cohort study during the 2024 European Athletics Championships in Roma with (1) dissemination of infographics, (2) data collection on perceived relevance (yes/no) and perceived usefulness (score from 0 to 100) of infographics among athletes and medical teams using an online questionnaire and (3) data collection by medical teams of newly incurred injuries and illnesses among athletes during the championship. Results: Among the 124 athletes who completed the questionnaire, 35.5% had access to the infographics, of which 86.4% found the information relevant, and their perceived usefulness scores to reduce their risk were 51.8±23.9 (range: 2.9-100.0) for injuries and 50.6±23.0 (range: 0.0-100.0) for illnesses. Among the registered physicians and physiotherapists, 44 replied to the survey, 70.5% had access to the infographics, of which 83.9% found it relevant, and their perceived usefulness scores to reduce risk were 55.6±28.0 (range: 6.0-100.0) for injuries and 52.9±28.0 (range: 0.0-100.0) for illnesses. The logistic regression showed that a higher perceived usefulness score was associated with a lower risk of in-championship injury (OR 0.950; 95% CI 0.877 to 0.996). Conclusions: Promoting the health protection of athletes through infographics on injury and illness prevention in the context of international athletics championships was feasible and may represent an additional prevention approach.

Perceptions and beliefs on sports injury prediction as an injury risk reduction strategy: An online survey on elite athletics (track and field) athletes, coaches, and health professionals.

OBJECTIVES: To explore perceptions and beliefs of elite athletics (track and field) athletes, coaches, and health professionals, towards the use of injury prediction as an injury risk reduction strategy. DESIGN: Cross-sectional study. METHOD: During the 2022 European Athletics Championships in Munich, registered athletes, coaches, and health professionals were asked to complete an online questionnaire on their perceptions and beliefs of injury prediction use as an injury risk reduction strategy. The perceived level of interest, intent to use, help, potential stress (psychological impact) and dissemination were assessed by a score from 0 to 100. RESULTS: We collected 54 responses from 17 countries. Elite athletics stakeholders expressed a perceived level of interest, intent to use, and help of injury prediction of (mean ± SD) 85 ± 16, 84 ± 16, and 85 ± 15, respectively. The perceived level of potential stress was 41 ± 33 (range from 0 to 100), with an important inter-individual variability in each elite athletics stakeholder's category. CONCLUSIONS: This was the first study investigating the perceptions and beliefs of elite athletics stakeholders regarding the use of injury prediction as an injury risk reduction strategy. Regardless of the stakeholders, there was a high perceived level of interest, intent to use and help reported in this potential strategy.

Optimizing the Therapeutic Index of sdAb-Based Radiopharmaceuticals Using Pretargeting.

Single-domain antibodies (sdAbs) demonstrate favorable pharmacokinetic profiles for molecular imaging applications. However, their renal excretion and retention are obstacles for applications in targeted radionuclide therapy (TRT). Methods: Using a click-chemistry-based pretargeting approach, we aimed to reduce kidney retention of a fibroblast activation protein α (FAP)-targeted sdAb, 4AH29, for 177Lu-TRT. Key pretargeting parameters (sdAb-injected mass and lag time) were optimized in healthy mice and U87MG (FAP+) xenografts. A TRT study in a pancreatic ductal adenocarcinoma (PDAC) patient-derived xenograft (PDX) model was performed as a pilot study for sdAb-based pretargeting applications. Results: Modification of 4AH29 with trans-cyclooctene (TCO) moieties did not modify the sdAb pharmacokinetic profile. A 200-µg injected mass of 4AH29-TCO and an 8-h lag time for the injection of [177Lu]Lu-DOTA-PEG7-tetrazine resulted in the highest kidney therapeutic index (2.0 ± 0.4), which was 5-fold higher than that of [177Lu]Lu-DOTA-4AH29 (0.4 ± 0.1). FAP expression in the tumor microenvironment was validated in a PDAC PDX model with both immunohistochemistry and PET/CT imaging. Mice treated with the pretargeting high-activity approach (4AH29-TCO + [177Lu]Lu-DOTA-PEG7-tetrazine; 3 × 88 MBq, 1 injection per week for 3 wk) demonstrated prolonged survival compared with the vehicle control and conventionally treated ([177Lu]Lu-DOTA-4AH29; 3 × 37 MBq, 1 injection per week for 3 wk) mice. Mesangial expansion was reported in 7 of 10 mice in the conventional cohort, suggesting treatment-related kidney morphologic changes, but was not observed in the pretargeting cohort. Conclusion: This study validates pretargeting to mitigate sdAbs' kidney retention with no observation of morphologic changes on therapy regimen at early time points. Clinical translation of click-chemistry-based pre-TRT is warranted on the basis of its ability to alleviate toxicities related to biovectors' intrinsic pharmacokinetic profiles. The absence of representative animal models with extensive stroma and high FAP expression on cancer-associated fibroblasts led to a low mean tumor-absorbed dose even with high injected activity and consequently to modest survival benefit in this PDAC PDX.

Is the risk of muscle injuries higher in the finals than in previous rounds of the 100 m, 200 m and 400 m sprints of international athletics championships?

OBJECTIVES: To compare incidence rates of lower limb muscle injuries (LLMIs) and hamstring muscle injuries (HMIs) in 100 m, 200 m and 400 m sprints disciplines between finals, semi-finals and heats of international athletics championships. DESIGN: Prospective total population study. METHODS: We analysed in-competition LLMIs and HMIs of female and male athletes during eight championships between 2009 and 2022. RESULTS: LLMI and HMI incidence rates in 100 m finals were significantly higher than in heats and semi-finals for female and male athletes. HMI incidence rates were significantly higher in 200 m finals than heats and semi-finals for male athletes. CONCLUSIONS: LLMI and HMI risk was higher in finals compared to previous rounds during international athletics championships.

Generic semi-automated radiofluorination strategy for single domain antibodies: [18F]FB-labelled single domain antibodies for PET imaging of fibroblast activation protein-α or folate receptor-α overexpression in cancer.

BACKGROUND: Radiofluorination of single domain antibodies (sdAbs) via N-succinimidyl-4-[18F]fluorobenzoate ([18F]SFB) has shown to be a promising strategy in the development of sdAb-based PET tracers. While automation of the prosthetic group (PG) [18F]SFB production, has been successfully reported, no practical method for large scale sdAb labelling has been reported. Therefore, we optimized and automated the PG production, enabling a subsequently efficient manual conjugation reaction to an anti-fibroblast activation protein (FAP)-α sdAb (4AH29) and an anti-folate receptor (FR)-α sdAb (2BD42). Both the alpha isoform of FAP and the FR are established tumour markers. FAP-α is known to be overexpressed mainly by cancer-associated fibroblasts in breast, ovarian, and other cancers, while its expression in normal tissues is low or undetectable. FR-α has an elevated expression in epithelial cancers, such as ovarian, brain and lung cancers. Non-invasive imaging techniques, such as PET-imaging, using tracers targeting specific tumour markers can provide molecular information over both the tumour and its environment, which aides in the diagnosis, therapy selection and assessment of the cancer treatment. RESULTS: [18F]SFB was synthesized using a fully automated three-step, one-pot reaction. The total procedure time was 54 min and results in [18F]SFB with a RCP > 90% and a RCY d.c. of 44 ± 4% (n = 13). The manual conjugation reaction after purification produced [18F]FB-sdAbs with a RCP > 95%, an end of synthesis activity > 600 MBq and an apparent molar activity > 10 GBq/µmol. Overall RCY d.c., corrected to the trapping of [18F]F- on the QMA, were 9% (n = 1) and 5 ± 2% (n = 3) for [18F]FB-2BD42 and [18F]FB-4AH29, respectively. CONCLUSION: [18F]SFB synthesis was successfully automated and upscaled on a Trasis AllInOne module. The anti-hFAP-α and anti-hFR-α sdAbs were radiofluorinated, yielding similar RCYs d.c. and RCPs, showing the potential of this method as a generic radiofluorination strategy for sdAbs. The radiofluorinated sdAbs showed a favourable biodistribution pattern and are attractive for further characterization as new PET tracers for FAP-α and FR-α imaging.

Risk factors for injury complaints leading to restricted participation in Athletics (Track and Field): a secondary analysis of data from 320 athletes over one season.

Objective: To investigate if several potential risk factors were associated with time to injury complaints leading to participation restriction in Athletics (ICPR). Methods: We performed a secondary analysis of data collected during 39 weeks of the 2017-2018 Athletics season in a cluster-randomised controlled trial ('PREVATHLE'). Univariate and multivariable analyses using Cox regression models were performed to analyse the association between the time to first ICPR and potential risk factors collected (1) at baseline: sex, age, height, body mass, discipline, the usual duration of Athletics training and non-specific sports training, ICPR in the preceding season (yes/no), ICPR at baseline (yes/no); (2) weekly during the season: duration and intensity of Athletics training and competition, and non-specific sports training, fitness subjective state, sleep duration and illness (yes/no); and (3) combined. Results: Data from 320 athletes were included; 138 (43.1%) athletes reported at least one ICPR during the study follow-up. The combined multivariable analyses revealed that the risk of ICPR at any given time was significantly higher in athletes with a pre-existing ICPR (hazard rate ratio, HRR 1.90, 95% CI 1.15 to 3.15; p=0.012) and lower in athletes with a higher fitness subjective state (HRR 0.63, 95% CI 0.55 to 0.73; p<0.001) and who had had at least one illness during the season (HRR 0.42, 95% CI 0.29 to 0.62; p<0.001). Conclusions: Our results provide new insights into injury risk factors in Athletics that could help with potential injury risk reduction strategies. These could be to explore the pre-existing injury presence at the season's beginning and to monitor the fitness subjective state and illnesses occurrence during the season. Trial registration: ClinicalTrials.gov Identifier: NCT03307434.

Relationship between a daily injury risk estimation feedback (I-REF) based on machine learning techniques and actual injury risk in athletics (track and field): protocol for a prospective cohort study over an athletics season.

INTRODUCTION: Two-thirds of athletes (65%) have at least one injury complaint leading to participation restriction (ICPR) in athletics (track and field) during one season. The emerging practice of medicine and public health supported by electronic processes and communication in sports medicine represents an opportunity for developing new injury risk reduction strategies. Modelling and predicting the risk of injury in real-time through artificial intelligence using machine learning techniques might represent an innovative injury risk reduction strategy. Thus, the primary aim of this study will be to analyse the relationship between the level of Injury Risk Estimation Feedback (I-REF) use (average score of athletes' self-declared level of I-REF consideration for their athletics activity) and the ICPR burden during an athletics season. METHOD AND ANALYSIS: We will conduct a prospective cohort study, called Injury Prediction with Artificial Intelligence (IPredict-AI), over one 38-week athletics season (from September 2022 to July 2023) involving competitive athletics athletes licensed with the French Federation of Athletics. All athletes will be asked to complete daily questionnaires on their athletics activity, their psychological state, their sleep, the level of I-REF use and any ICPR. I-REF will present a daily estimation of the ICPR risk ranging from 0% (no risk for injury) to 100% (maximal risk for injury) for the following day. All athletes will be free to see I-REF and to adapt their athletics activity according to I-REF. The primary outcome will be the ICPR burden over the follow-up (over an athletics season), defined as the number of days lost from training and/or competition due to ICPR per 1000 hours of athletics activity. The relationship between ICPR burden and the level of I-REF use will be explored by using linear regression models. ETHICS AND DISSEMINATION: This prospective cohort study was reviewed and approved by the Saint-Etienne University Hospital Ethical Committee (Institutional Review Board: IORG0007394, IRBN1062022/CHUSTE). Results of the study will be disseminated in peer-reviewed journals and in international scientific congresses, as well as to the included participants.

Preclinical Evaluation of a Radiotheranostic Single-Domain Antibody Against Fibroblast Activation Protein α.

Fibroblast activation protein α (FAP) is highly expressed on cancer-associated fibroblasts of epithelial-derived cancers. Breast, colon, and pancreatic tumors often show strong desmoplastic reactions, which result in a dominant presence of stromal cells. FAP has gained interest as a target for molecular imaging and targeted therapies. Single-domain antibodies (sdAbs) are the smallest antibody-derived fragments with beneficial pharmacokinetic properties for molecular imaging and targeted therapy. Methods: We describe the generation, selection, and characterization of a sdAb against FAP. In mice, we assessed its imaging and therapeutic potential after radiolabeling with tracer-dose 131I and 68Ga for SPECT and PET imaging, respectively, and with 131I and 225Ac for targeted radionuclide therapy. Results: The lead sdAb, 4AH29, exhibiting picomolar affinity for a distinct FAP epitope, recognized both purified and membrane-bound FAP protein. Radiolabeled versions, including [68Ga]Ga-DOTA-4AH29, [225Ac]Ac-DOTA-4AH29, and [131I]I-guanidinomethyl iodobenzoate (GMIB)-4AH29, displayed radiochemical purities exceeding 95% and effectively bound to recombinant human FAP protein and FAP-positive GM05389 human fibroblasts. These radiolabeled compounds exhibited rapid and specific accumulation in human FAP-positive U87-MG glioblastoma tumors, with low but specific uptake in lymph nodes, uterus, bone, and skin (∼2-3 percentage injected activity per gram of tissue [%IA/g]). Kidney clearance of unbound [131I]I-GMIB-4AH29 was fast (<1 %IA/g after 24 h), whereas [225Ac]Ac-DOTA-4AH29 exhibited slower clearance (8.07 ± 1.39 %IA/g after 24 h and 2.47 ± 0.18 %IA/g after 96 h). Mice treated with [225Ac]Ac-DOTA-4AH29 and [131I]I-GMIB-4AH29 demonstrated prolonged survival compared with those receiving vehicle solution. Conclusion: [68Ga]Ga-DOTA-4AH29 and [131I]I-GMIB-4AH29 enable precise FAP-positive tumor detection in mice. Therapeutic [225Ac]Ac-DOTA-4AH29 and [131I]I-GMIB-4AH29 exhibit strong and sustained tumor targeting, resulting in dose-dependent therapeutic effects in FAP-positive tumor-bearing mice, albeit with kidney toxicity observed later for [225Ac]Ac-DOTA-4AH29. This study confirms the potential of radiolabeled sdAb 4AH29 as a radiotheranostic agent for FAP-positive cancers, warranting clinical evaluation.

Relationships Between Performance and Injury Occurrence in Athletics (Track and Field): A Pilot Study on 8 National-Level Athletes From Sprints, Jumps and Combined Events Followed During at Least Five Consecutive Seasons.

Background: Performance success or failure in athletics (Track and Field) and the capacity to succeed are driven at the adult level, like in other sports, by many factors, injury being one of them. More information regarding the potential relationships between performance and injuries in athletics is needed. Objective: To analyse the potential association between performance and occurrence of injuries in national-level athletics athletes from sprints, jumps and combined events through several seasons. Methods: We performed a retrospective analysis of performance and injury data collected prospectively in 8 national-level athletics athletes followed during at least five consecutive seasons from 2009 to 2019. For each athlete, injuries data [total injuries (injuries) and time-loss injuries (TLI)] were collected by the same sports medicine physician throughout the study period using a medical attention injury definition. Performances during official competitions were collected on the French Federation of Athletics website, and included (i) any participation in national championships, (ii) any participation in an international competition (i.e., being national team member for an international competition), (iii) any podium at the national championships, (iv) any podium at an international competition, and (v) performance metrics normalised to the world record (WR) of the respective athletics speciality (%WR). For each athlete, we performed a descriptive analysis of the performances and injuries. We also performed four binomial logistic regressions with (1) national championships participation (yes/no) or (2) international competition participation (yes/no) as dependent variables, and injuries (yes/no) or TLI (yes/no) as independent variables, adjusted for individual athlete and number of seasons, and in models on participation in international competitions, was also adjusted for national championship participation (yes/no), with Odd Ratios (OR) with 95% confidence intervals (95%CI). Results: Among the 8 national-level athletics athletes included in the present study, cumulated 155 injuries, including 52 TLI (33.5%). There was an average of 2.7 ± 1.7 injuries and 0.9 ± 0.6 TLI per athlete per season over the study period. The occurrence of injuries was significantly associated with higher odds of national championships participation (OR = 4.85 [95% CI 3.10 to 3050.5], p = 0.021). The occurrence of TLI was significantly associated with higher odds of national championships participation (OR = 133.6 [95% CI 4.92 to 14251.5], p = 0.013). The occurrence of injuries or TLI were associated with insignificantly lower odds of international championships participation. Conclusions: Our present pilot study confirms that injuries are part of an athletes' life. The occurrence of at least one injury was associated with higher odds of participation in a national championship, whereas the absence of at least one injury was associated with higher odds of participation in an international championship. We hypothesised that the length of the season can play a role in the risk of injury occurrence, but if the athlete wants to reach his/her highest level, decreasing the risk of injuries seems to be of importance. Despite the caution that should be taken in the interpretation of our results, our present study confirms the interest and relevance of injury risk reduction approach in athletics.