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Coronavirus disease 2019 (COVID-19) resulted in sporting event suspensions and cancellations, affecting competition calendars worldwide during 2020 and 2021. This challenged high-performance athletes’ capacity to complete physical, technical, or tactical training during restricted movement measures (lockdown). With the Football World Cup organized in the last quarter of 2022, the past period of training and match disturbances challenged footballers concerning their performance and potential higher risk of injury at official matches’ resumption. There has been considerable debate about the management of resuming professional football (soccer) during the COVID-19 pandemic. Governing bodies worldwide implemented measures to ensure a safe resumption of football. These precautionary measures aimed to protect the health of players, their support staff, and officials around the pitch and ensure the enjoyment of the event by spectators in the football stadiums. We have therefore narratively reviewed scientific papers about how football has resumed on the pitch and in the stands with special focus on the COVID-19 infection control strategies allowing footballers to perform again and supporters to enjoy the game after the 2020 global stop to sport.

Acute illnesses affecting the respiratory tract are common and form a significant component of the work of Sport and Exercise Medicine (SEM) clinicians. Acute respiratory illness (ARill) can broadly be classified as non-infective ARill and acute respiratory infections (ARinf). The aim of this consensus is to provide the SEM clinician with an overview and practical clinical approach to ARinf in athletes. The International Olympic Committee (IOC) Medical and Scientific Commission appointed an international consensus group to review ARill (non-infective ARill and ARinf) in athletes. Six subgroups of the IOC Consensus group were initially established to review the following key areas of ARill in athletes: (1) epidemiology/risk factors for ARill, (2) ARinf, (3) non-infective ARill including ARill due to environmental exposure, (4) acute asthma and related conditions, (5) effects of ARill on exercise/sports performance, medical complications/return-to-sport and (6) acute nasal/vocal cord dysfunction presenting as ARill. Several systematic and narrative reviews were conducted by IOC consensus subgroups, and these then formed the basis of sections in the consensus documents. Drafting and internal review of sections were allocated to ‘core’ members of the consensus group, and an advanced draft of the consensus document was discussed during a meeting of the main consensus core group in Lausanne, Switzerland on 11 to 12 October 2021. Final edits were completed after the meeting. This consensus document (part 1) focusses on ARinf, which accounts for the majority of ARill in athletes. The first section of this consensus proposes a set of definitions and classifications of ARinf in athletes to standardise future data collection and reporting. The remainder of the consensus paper examines a wide range of clinical considerations related to ARinf in athletes: epidemiology, risk factors, pathology/pathophysiology, clinical presentation and diagnosis, management, prevention, medical considerations, risks of infection during exercise, effects of infection on exercise/sports performance and return-to-sport guidelines.

Acute respiratory illness (ARill) is common and threatens the health of athletes. ARill in athletes forms a significant component of the work of Sport and Exercise Medicine (SEM) clinicians. The aim of this consensus is to provide the SEM clinician with an overview and practical clinical approach to non-infective ARill in athletes. The International Olympic Committee (IOC) Medical and Scientific Committee appointed an international consensus group to review ARill in athletes. Key areas of ARill in athletes were originally identified and six subgroups of the IOC Consensus group established to review the following aspects: (1) epidemiology/risk factors for ARill, (2) infective ARill, (3) non-infective ARill, (4) acute asthma/exercise-induced bronchoconstriction and related conditions, (5) effects of ARill on exercise/sports performance, medical complications/return-to-sport (RTS) and (6) acute nasal/laryngeal obstruction presenting as ARill. Following several reviews conducted by subgroups, the sections of the consensus documents were allocated to ‘core’ members for drafting and internal review. An advanced draft of the consensus document was discussed during a meeting of the main consensus core group, and final edits were completed prior to submission of the manuscript. This document (part 2) of this consensus focuses on respiratory conditions causing non-infective ARill in athletes. These include non-inflammatory obstructive nasal, laryngeal, tracheal or bronchial conditions or non-infective inflammatory conditions of the respiratory epithelium that affect the upper and/or lower airways, frequently as a continuum. The following aspects of more common as well as lesser-known non-infective ARill in athletes are reviewed: epidemiology, risk factors, pathology/pathophysiology, clinical presentation and diagnosis, management, prevention, medical considerations and risks of illness during exercise, effects of illness on exercise/sports performance and RTS guidelines.

Objectives It is not uncommon for athletes to be diagnosed with iron deficiency, yet there remains uncertainty whether the prevalence of suboptimal iron status in elite athletes differs from the normal population or warrants routine screening. The purpose of this study is to describe the distribution of serum ferritin (SF) in a cohort of elite athletes. Design Retrospective cohort study. Methods Electronic health records of 1085 elite adult athletes (570 women, 515 men) from 2012–2017 were examined retrospectively. SF values were compared to published normal population data. The proportion of athletes meeting criterion values for iron deficiency or initiation of treatment was examined. Results SF distributions in male athletes were significantly lower than normal males aged 20 to 0.05) or aged 24 to 0.05). Using 35 ng/ml as the criterion value for stage one iron deficiency, 15% of male athletes and 52% of female athletes displayed suboptimal iron status. Conclusions Male athletes have a significantly lower population distribution of SF values as compared to normative data on healthy males, with 15% of male athletes having suboptimal SF status. The distribution of SF values in elite female athletes did not differ from population values, however approximately half women athletes were iron deficient. These data suggest that iron screening should be considered in both male and female athlete populations.

The efficient use of testing resources is crucial in the fight against doping in sports. The athlete biological passport relies on the need to identify the right athletes to test, and the right time to test them. Here we present an approach to longitudinal tracking of athlete performance to provide an additional, more intelligence-led approach to improve targeted antidoping testing. The performance results of athletes (male shot putters, male 100 m sprinters, and female 800 m runners) were obtained from a performance results database. Standardized performances, which adjust for average career performance, were calculated to determine the volatility in performance over an athlete's career. We then used a Bayesian spline model to statistically analyse changes within an athlete's standardized performance over the course of a career both for athletes who were presumed "clean" (not doped), and those previously convicted of doping offences. We used the model to investigate changes in the slope of each athlete's career performance trajectory and whether these changes can be linked to doping status. The model was able to identify differences in the standardized performance of clean and doped athletes, with the sign of the change able to provide some discrimination. Consistent patterns of standardized performance profile are seen across shot put, 100 m and 800 m for both the clean and doped athletes we investigated. This study demonstrates the potential for modeling athlete performance data to distinguish between the career trajectories of clean and doped athletes, and to enable the risk stratification of athletes on their risk of doping.

Doping control is an intrinsic element of any anti-doping programme. This chapter seeks to provide an overview of the strategies in place designed to control doping through the detection or determination of anti-doping rule violations and via a more preventative approach. It includes a comprehensive review of the analytical approaches including the processes involved in the detection of prohibited substances and in the detection of biomarkers as well as the recent focus towards non-analytical, intelligence-led approaches to doping control. An important aspect of an effective doping control programme is the development of a test distribution plan, which not only has the best chance of success but is also the most cost-effective. The chapter outlines the key stages and procedures for sample provision. Key stages in sample provision include: selection, notification, chaperoning, reporting to the doping control station and sample collection. These stages are carried out by authorised individuals typically known as doping control officers (DCOs).

ObjectivesThe risk of viral transmission associated with contact sports such as football (soccer) during the COVID-19 pandemic is unknown. The aim of this study was to describe the infective and immune status of professional football players, team staff and league officials over a truncated football season resumed at the height of the COVID-19 pandemic in a country with high infection rates and to investigate the clinical symptoms related to COVID-19 infection in professional football players.MethodsProspective cohort study of 1337 football players, staff and officials during a truncated football season (9 weeks) with a tailored infection control program based on preventive measures and regular SARS-CoV-2 PCR swab testing (every 3-5 days) combined with serology testing for immunity (every 4 weeks). Clinical symptoms in positive participants were recorded using a 26-item, Likert-scale-based scoring system.ResultsDuring the study period, 85 subjects returned positive (cycle threshold (cT)≤30) or reactive (30ConclusionFootball played outdoors involving close contact between athletes represents a limited risk for SARS-CoV-2 infection and severe illness when preventive measures are in place.

PurposeAssess the health status and heat preparation strategies of athletes competing in a World Cycling Championships held in hot ambient conditions (37°C, 25% relative humidity, wet-bulb-globe-temperature 27°C) and monitor the medical events arising during competition.Methods69 cyclists (~9% of the world championships participants) completed a pre-competition questionnaire. Illnesses and injuries encountered by the Athlete Medical Centre (AMC) were extracted from the race reports.Results22% of respondents reported illness symptoms in the 10 days preceding the Championships. 57% of respondents had previously experienced heat-related symptoms (cramping most commonly) while 17% had previously been diagnosed with exertional heat illness. 61% of the respondents had undergone some form of heat exposure prior to the Championships, with 38% acclimating for 5 to 30 days. In addition, several respondents declared to live in warm countries and all arrived in Qatar ~5 days prior to their event. 96% of the respondents used a pre-cooling strategy for the time trials and 74% did so before the road race (pConclusionsThe prevalence of previous heat illness in elite cyclists calls for team and event organisation doctors to be trained on heat illness management, including early diagnosis and rapid on-site cooling. Some cyclists had been exposed to the heat prior to the Championships, but few had a dedicated plan, calling for additional education on the importance of heat acclimation. Pre-cooling was widely adopted.

The purpose of this research was to evaluate the performances of female middle- and long-distance runners before and after the implementation of a new antidoping strategy (the Athlete Biological Passport [ABP]) in a country accused of systematic doping. A retrospective analysis of the results of Russian National Championships from 2008 to 2017 was performed. The 8 best female performances for the 800-m, 1500-m, 3000-m steeplechase, 5000-m, and 10,000-m events from the semifinals and finals were analyzed. The yearly number of athletes fulfilling standard qualifications for international competitions was also evaluated. Overall, numbers of athletes banned for doping in 2008–2017 were calculated. As a result, 4 events (800, 1500, 5000 [all P P

Fluctuations in plasma volume (PV) present potential confounders within the concentration-based markers of the haematological athlete biological passport (ABP). Here, a multi-parametric approach involving a simple blood test is applied to the current ABP adaptive model in an attempt to remove the influence of PV expansion, induced by a cycling stage race. Blood samples were obtained from 29 professional cyclists (14 male, 15 female) before, during and after 4-5 consecutive days of racing. Whole blood was analysed in accordance with the World Anti-Doping Agency ABP guidelines for haemoglobin ([Hb]) concentration and platelets. Serum and plasma were analysed for transferrin, albumin, calcium, creatinine, total protein and low-density lipoprotein. PV variation (Z-scores) was estimated using a multi-parametric model (consisting of the biomarkers mentioned earlier) and compared against calculated variations in PV (measured via CO-rebreathing). Significant reductions in [Hb] and the OFF-score were observed in female cyclists after 3 and 4 days of racing, with accompanying increases in PV, which returned to baseline values 4 days post competition. Similarly, a significant increase in PV was observed in male cyclists after 3 and 5 days of racing. When individual estimations of PV variance were applied to the adaptive model, the upper and lower reference predictions for [Hb] and the OFF-score were refined such that all outliers consistent with racing-induced PV changes were removed. The PV model appears capable of reducing the influence of PV on concentration-dependent markers during competition. This is an important step towards the inclusion of the PV correction in the ABP haematological module.

The integrity of the athlete biological passport (ABP) is underpinned by understanding normal fluctuations of its biomarkers to environmental or medical conditions, for example, altitude training or iron deficiency. The combined impact of altitude and iron supplementation on the ABP was evaluated in endurance-trained athletes (n = 34) undertaking 3 weeks of simulated live-high: train-low (14 h.d-1 , 3000 m). Athletes received either oral, intravenous (IV) or placebo iron supplementation, commencing 2 weeks prior and continuing throughout hypoxic exposure. Venous blood was sampled twice prior, weekly during, and up to 6 weeks after altitude. Individual ABP thresholds for haemoglobin concentration ([Hb]), reticulocyte percentage (%retic), and OFF score were calculated using the adaptive model and assessed at 99% and 99.9% specificity. Eleven athletes returned values outside of the calculated reference ranges at 99%, with 8 at 99.9%. The percentage of athletes exceeding the thresholds in each group was similar, but IV returned the most individual occurrences. A similar frequency of abnormalities occurred across the 3 biomarkers, with abnormal [Hb] and OFF score values arising mainly during-, and %retic values mainly post- altitude. Removing samples collected during altitude from the model resulted in 10 athletes returning abnormal values at 99% specificity, 2 of whom had not triggered the model previously. In summary, the abnormalities observed in response to iron supplementation and hypoxia were not systematic and mostly in line with expected physiological adaptations. They do not represent a uniform weakness in the ABP. Nevertheless, altitude training and iron supplementation should be carefully considered by experts evaluating abnormal ABP profiles.

Plasma volume and red cell mass are key health markers used to monitor numerous disease states, such as heart failure, kidney disease, or sepsis. Nevertheless, there is currently no practically applicable method to easily measure absolute plasma or red cell volumes in a clinical setting. Here, a novel marker for plasma volume and red cell mass was developed through analysis of the observed variability caused by plasma volume shifts in common biochemical measures, selected based on their propensity to present with low variations over time. Once a month for 6 months, serum and whole blood samples were collected from 33 active males. Concurrently, the CO-rebreathing method was applied to determine target levels of hemoglobin mass (HbM) and blood volumes. The variability of 18 common chemistry markers and 27 Full Blood Count variables was investigated and matched to the observed plasma volume variation. After the removal of between-subject variations using a Bayesian model, multivariate analysis identified two sets of 8 and 15 biomarkers explaining 68% and 69% of plasma volume variance, respectively. The final multiparametric model contains a weighting function to allow for isolated abnormalities in single biomarkers. This proof-of-concept investigation describes a novel approach to estimate absolute vascular volumes, with a simple blood test. Despite the physiological instability of critically ill patients, it is hypothesized the model, with its multiparametric approach and weighting function, maintains the capacity to describe vascular volumes. This model has potential to transform volume management in clinical settings. Am. J. Hematol. 92:62-67, 2017. © 2016 Wiley Periodicals, Inc.

ObjectiveTo characterise the core temperature response and power output profile of elite male and female cyclists during the 2016 UCI Road World Championships. This may contribute to formulating environmental heat stress policies.MethodsCore temperature was recorded via an ingestible capsule in 10, 15 and 15 cyclists during the team time trial (TTT), individual time trial (ITT) and road race (RR), respectively. Power output and heart rate were extracted from individual cycling computers. Ambient conditions in direct sunlight were hot (37°C±3°C) but dry (25%±16% relative humidity), corresponding to a wet-bulb globe temperature of 27°C±2°C.ResultsCore temperature increased during all races (pConclusion85% of the cyclists participating in the study (ie, 34 of 40) reached a core temperature of at least 39°C with 25% (ie, 10 of 40) exceeding 40°C. Higher core temperatures were reached during the time trials than the RR.

It is well described that numerous environmental factors, including exercise, modulate plasma volume (PV). These modulations prove problematic when a number of haematological markers are measured as a concentration in blood plasma. A primary example is haemoglobin concentration ([Hb]), a marker of erythropoiesis commonly used within medicine and also used to detect blood doping. Natural changes in PV can confound [Hb] values when a volume change is detected rather than a true change in haemoglobin mass (Hbmass) (e.g. volume expansion resulting in a [Hb] decrease and pseudo-anemia vs. Hbmass decline resulting in anaemia). Currently, there is no simple solution to correct for PV shifts, and this has proven problematic when monitoring volumetric health markers in clinical and anti-doping settings. This narrative review explores the influence that PV shifts have on volumetric biomarkers, such as [Hb]. The progressive expansion in PV observed during multi-day endurance events will be summarised, and the observed impact PV variance has on concentration-based markers will be quantified. From this, the need for alternative methods to correct [Hb] for volume fluctuations is highlighted. Available methods for calculating intravascular volumes are then discussed, with a focus on a recently developed approach using a panel of 'volume descriptive' biomarkers from a standard blood test. Finally, the practical applications of this novel PV blood test within both anti-doping and clinical settings will be examined.

Given the large impact on performance, manipulations of the blood have always been appealing to athletes and have widely been abused in all endurance sports over the last decades. Only in 1986 was the manipulation of blood included in the list of forbidden substances and methods. Since then, the definition of “blood manipulation” or “blood doping” has constantly evolved as new methods and substances were developed and have entered the world of sports. World Anti-Doping Agency (WADA) addresses the entity of blood manipulations in two sections of the prohibited list. The main section M1 Manipulation of Blood and Blood Components and section S2 Peptide Hormones, Growth Factors, Related Substances, and Mimetics, where certain blood modulating substances are specified. Given that in autologous blood transfusions the additional blood cells used by the doping athlete originate from the athlete himself, and are thus identical to the ones in his normal circulation, there is currently no direct test for this type of manipulation.

Altitude is a confounding factor within the Athlete Biological Passport (ABP) due, in part, to the plasma volume (PV) response to hypoxia. Here, a newly developed PV blood test is applied to assess the possible efficacy of reducing the influence of PV on the volumetric ABP markers; haemoglobin concentration ([Hb]) and the OFF‐score. Endurance athletes (n=34) completed a 21‐night simulated live‐high train‐low (LHTL) protocol (14 h.d‐1 at 3000 m). Bloods were collected twice pre‐altitude; at days 3, 8, and 15 at altitude; and 1, 7, 21, and 42 days post‐altitude. A full blood count was performed on the whole blood sample. Serum was analysed for transferrin, albumin, calcium, creatinine, total protein, and low‐density lipoprotein. The PV blood test (consisting of the serum markers, [Hb] and platelets) was applied to the ABP adaptive model and new reference predictions were calculated for [Hb] and the OFF‐score, thereby reducing the PV variance component. The PV correction refined the ABP reference predictions. The number of atypical passport findings (ATPFs) for [Hb] was reduced from 7 of 5 subjects to 6 of 3 subjects. The OFF‐score ATPFs increased with the PV correction (from 9 to 13, 99% specificity); most likely the result of more specific reference limit predictions combined with the altitude‐induced increase in red cell production. Importantly, all abnormal biomarker values were identified by a low confidence value. Although the multifaceted, individual physiological response to altitude confounded some results, the PV model appears capable of reducing the impact of PV fluctuations on [Hb].

The Athlete Biological Passport (ABP) estimates individualized reference ranges for key blood markers, such as haemoglobin concentration ([Hb]), using predetermined population mean, between- and within-subject variances. Here, we aim to reassess previously published estimates for within-subject [Hb] variance and determine whether sex-, analyzer-, sport-, or season-specific values are required. Our reference population contains 7723 male (mean ± SD, 22.3 ± 4.6 years of age) and 6164 female (21.6 ± 4.3) athlete observations from 49 sports. [Hb] was calculated using one of three cytometers; Bayer-H3 (1997–1999, n = 4554), ADVIA-120 (1999–2010, n = 8636) and Sysmex XT-2000i (2010–2012, n = 697). The final model was a linear mixed model for [Hb] with analyzer (H3, ADVIA, Sysmex), sex (male, female), sport (power-endurance, endurance, skill, team, disabled and non-athletes), season (summer, winter), and the interaction between sex and sport as fixed effects and athlete as a random effect. The model included an exponential correlation structure to allow for within-subject autocorrelation, and allowed different within-subject variances for each sport. Within-subject [Hb] variance (g2/L2) was significantly less for power endurance (35.09, 95% CI 33.50 to 36.76), disabled (25.82, 95% CI 21.71 to 35.28) and non-athletes (34.30, 95% CI 28.53 to 35.87) than for endurance (40.35, 95% CI 39.62 to 47.22) and team sports (38.70, 95% CI 37.68 to 39.76) athletes. No new evidence was found to justify adjusting the current within-subject [Hb] variance estimate. Copyright © 2015 John Wiley & Sons, Ltd.

Some recent studies have characterized the stability of blood variables commonly measured for the Athlete Biological Passport. The aim of this study was to characterize the impact of different shipments conditions and the quality of the results returned by the haematological analyzer. Twenty-two healthy male subjects provided five EDTA tubes each. Four shipment conditions (24, 36, 48, 72 h) under refrigerated conditions were tested and compared to a set of samples left in the laboratory also under refrigerated conditions (group control). All measurements were conducted using two Sysmex XT-2000i analyzers. Haemoglobin concentration, reticulocytes percentage, and OFF-score numerical data were the same for samples analyzed just after collection and after a shipment under refrigerated conditions up to 72 h. Detailed information reported especially by the differential (DIFF) channel scatterplot of the Sysmex XT-2000i indicated that there were signs of blood deterioration, but were not of relevance for the variables used in the Athlete Biological Passport. As long as the cold chain is guaranteed, the time delay between the collection and the analyses of blood variables can be extended. Copyright© 2015 John Wiley & Sons, Ltd.

Performance profiling is a new area of research that could potentially open new frontiers in the fight against doping. Even beyond exposing unnatural and pharmacology aided performances, there are other potential applications and benefits of performance modeling for the protection of the integrity of sports. The backbone of performance modeling in anti-doping is the individual tracking of performance through competition results or other metrics of sporting achievements. Since performance improvement is the primary goal of doping, it is expected that doping will affect competition results. Thus, individual tracking of performance could potentially expose suspicious cases that deserve more scrutiny from anti-doping officials and help to adjust targeted testing. On the other hand changes in performance levels could also be used to assess the efficiency of new anti-doping strategies. Another application of performance analysis is to develop unified classifications of athletes according to their level of performance. This classification has numerous practical meanings, but from anti-doping perspective it provides an opportunity to set exact criteria for athletes belonging to national and international testing pools and thus estimate the number of tests needed in different countries based on the number of athletes at ascertain performance level. At the moment, in the absence of unified and comprehensive criteria for national and international testing pools, there are no definitive regulations regarding exact doping test numbers needed. Thus, it creates inequality between nations and affects the credibility of the anti-doping system worldwide. Such classification would allow a more efficient use of anti-doping resources. Since doping is not the only threat to the integrity of sports, performance modeling can also help to reveal cases of other misbehavior in sports, like match fixing or result manipulation. In summary, performance modeling and its application to various fields is a new method to improve the efficiency of systems to safeguard the integrity of sports at different levels.

Altitude training is associated with changes in blood markers, which can confound results of the Athlete?s Biological Passport (ABP). This meta‐analysis aims to describe the fluctuations during‐ and post‐altitude in key ABP variables; hemoglobin concentration ([Hb]), square‐root transformed reticulocyte percentage (sqrt(retic%)) and the OFF‐score. Individual de‐identified raw data were provided from 17 studies. Separate linear mixed effects analyses were performed for delta values from baseline for [Hb], sqrt(retic%) and OFF‐score, by altitude phase (during and post). Mixed models were fitted with the hierarchical structure: study and subject within study as random effects. Delta values as response variables and altitude dose (in kilometer hours; km.hr = altitude (m) / 1000 x hours), sex, age, protocol and baseline values as fixed effects. Allowances were made for potential autocorrelation. Within two days at natural altitude [Hb] rapidly increased. Subsequent delta [Hb] values increased with altitude dose, reaching a plateau of 0.94 g/dL [95%CI (0.69, 1.20)] at ~1000 km.hr. Delta sqrt(retic%) and OFF‐score were the first to identify an erythrocyte response, with respective increases and decreases observed within 100 to 200 km.hr. Post‐altitude, [Hb] remained elevated for two weeks. Delta sqrt(retic%) declined below baseline, the magnitude of change was dependent on altitude dose. Baseline values were a significant covariate (p < 0.05). The response to altitude is complex resulting in a wide range of individual responses, influenced primarily by altitude dose and baseline values. Improved knowledge of the plausible hematological variations during‐ and post‐altitude provides fundamental information for both the ABP expert and sports physician.

For decades, drug testing has been the main instrument at the disposal of anti-doping authorities. The availability in the 1980s of substances identical to those produced by the human body, including the "big 3" (erythropoietin, testosterone, and growth hormone), necessitated a new paradigm in anti-doping. The athlete biological passport (ABP) is a new paradigm, complementary to traditional drug testing, based on the personalized monitoring of doping biomarkers. Athletes who abuse doping substances do so to trigger physiological changes that provide performance enhancement. The ABP aims to detect these changes through its 3 hematological, steroidal, and endocrine modules. Any deviation of a biomarker from what is expected in a healthy physiological condition can be attributable to doping or a medical condition, which, interestingly, is also the criterion used to define a banned substance. Recent advances in proteomics and metabolomics offer immense opportunities to enhance the ABP. The ABP shares multiple aspects with the present customization of health care and personalized medicine.

For decades, drug testing has been the main instrument at the disposal of anti-doping authorities. The availability in the 1980s of substances identical to those produced by the human body, including the "big 3" (erythropoietin, testosterone, and growth hormone), necessitated a new paradigm in anti-doping. The athlete biological passport (ABP) is a new paradigm, complementary to traditional drug testing, based on the personalized monitoring of doping biomarkers. Athletes who abuse doping substances do so to trigger physiological changes that provide performance enhancement. The ABP aims to detect these changes through its 3 hematological, steroidal, and endocrine modules. Any deviation of a biomarker from what is expected in a healthy physiological condition can be attributable to doping or a medical condition, which, interestingly, is also the criterion used to define a banned substance. Recent advances in proteomics and metabolomics offer immense opportunities to enhance the ABP. The ABP shares multiple aspects with the present customization of health care and personalized medicine.

The Athlete Biological Passport (ABP) detects blood doping in athletes through longitudinal monitoring of erythropoietic markers. Mathematical algorithms are used to define individual reference ranges for these markers for each athlete. It is unclear if altitude and exercise can affect the variables included in these calculations in a way that the changes might be mistaken for blood manipulation. The aim of this study was to investigate the influence of the simultaneous strenuous exercise and low to high altitude exposure on the calculation algorithms of the ABP. 14 sea level (SL) and 11 altitude native (ALT) highly trained athletes participated in a 14-day cycling stage race taking place at an average altitude of 2496 m above sea level (min. 1014 m, max. 4120 m), race distances ranged between 96 and 227 km per day. ABP blood measures were taken on days -1,3,6,10,14 (SL) and -1,9,15 (ALT) of the race. Four results from three samples of two different SL athletes exceeded the individual limits at the 99% specificity threshold and one value at 99.9%. In ALT, three results from three samples of three different athletes were beyond the individual limits at 99%, one at 99.9%. The variations could be explained by the expected physiological reaction to exercise and altitude. In summary, the abnormalities observed in the haematological ABP´s of well-trained athletes during extensive exercise at altitude are limited and in line with expected physiological changes. Copyright © 2014 John Wiley & Sons, Ltd.

The major objective of this study was to investigate the effects of several days of intense exercise on the growth hormone marker approach to detect doping with human growth hormone (hGH). In addition we investigated the effect of changes in plasma volume on the test. Fifteen male athletes performed a simulated nine-day cycling stage race. Blood samples were collected twice daily over a period of 15 days (stage race + three days before and after). Plasma volumes were estimated by the optimized CO Rebreathing method. IGF-1 and P-III-NP were analyzed by Siemens Immulite and Cisbio Assays, respectively. All measured GH 2000 scores were far below the published decision limits for an adverse analytical finding. The period of exercise did not increase the GH-scores; however the accompanying effect of the increase in Plasma Volume yielded in essentially lower GH-scores. We could demonstrate that a period of heavy, long-term exercise with changes in plasma volume does not interfere with the decision limits for an adverse analytical finding. Copyright © 2014 John Wiley & Sons, Ltd.

Despite the limited research on the effects of altitude (or hypoxic) training interventions on team-sport performance, players from all around the world engaged in these sports are now using altitude training more than ever before. In March 2013, an Altitude Training and Team Sports conference was held in Doha, Qatar, to establish a forum of research and practical insights into this rapidly growing field. A round-table meeting in which the panellists engaged in focused discussions concluded this conference. This has resulted in the present position statement, designed to highlight some key issues raised during the debates and to integrate the ideas into a shared conceptual framework. The present signposting document has been developed for use by support teams (coaches, performance scientists, physicians, strength and conditioning staff ) and other professionals who have an interest in the practical application of altitude training for team sports. After more than four decades of research, there is still no consensus on the optimal strategies to elicit the best results from altitude training in a team-sport population. However, there are some recommended strategies discussed in this position statement to adopt for improving the acclimatisation process when training/competing at altitude and for potentially enhancing sealevel performance. It is our hope that this information will be intriguing, balanced and, more importantly, stimulating to the point that it promotes constructive discussion and serves as a guide for future research aimed at advancing the bourgeoning body of knowledge in the area of altitude training for team sports. Refereed/Peer-reviewed

During the last 30 years, the artificial increase of red blood cell volume ("blood doping") has changed the level of performance in all endurance sports. Many doping scandals have shown the extent of the problem. The detection of blood doping relies on two different approaches: the direct detection of exogenous manipulating substances (erythropoietic stimulants) or red cells (homologous transfusion) and the indirect detection, where not the doping substance or technique itself, but its effect on certain biomarkers is measured. Whereas direct detection using standard laboratory procedures such as isoelectric focusing can identify erythropoietic stimulants, homologous blood transfusion is identified through mismatches in minor blood group antigens by flow cytometry. Indirect methods such as the athlete biological passport are the only means to detect autologous transfusion and may also be used for the detection of erythropoietic stimulants or homologous transfusion. New techniques to unmask blood doping include the use of high-throughput 'omics' technologies (proteomics/metabolomics) and the combination of different biomarkers with the help of mathematical approaches. Future strategies should aim at improving the use of the available data and resources by applying pattern recognition algorithms to recognize suspicious athletes and, on the basis of these findings, use the appropriate testing method. Different types of information should be combined in the quest for a forensic approach to anti-doping.

Despite increased control on the use of performance-enhancing drugs both ‘in’ and ‘out’ of competition, as well as increasing punishments for those found contravening the rules, there remains those athletes willing to risk using substances to improve their performance and/or aid their recovery (Yesalis and Bahrke, 2002). The World Anti-Doping Agency (WADA) strictly regulates the use of pharmaceutical products in competitive sport. WADA produces and regularly updates the World Anti-Doping Code that includes a prohibited drug list. This list dictates what is and is not acceptable, from a doping perspective, within sport (Table 1). In addition to using these restrictions to promote the Olympic ideal of free and fair competition, they are also in place for the protection of athletes and to help prevent the negative health consequences associated with the use of many substances on the list. This chapter shall therefore examine impact of performance enhancing drugs from a range of categories on cardiovascular health.

Plasma volume and red cell mass are key health markers used to monitor numerous disease states, such as heart failure, kidney disease, or sepsis. Nevertheless, there is currently no practically applicable method to easily measure absolute plasma or red cell volumes in a clinical setting. Here, a novel marker for plasma volume and red cell mass was developed through analysis of the observed variability caused by plasma volume shifts in common biochemical measures, selected based on their propensity to present with low variations over time. Once a month for 6 months, serum and whole blood samples were collected from 33 active males. Concurrently, the CO-rebreathing method was applied to determine target levels of hemoglobin mass (HbM) and blood volumes. The variability of 18 common chemistry markers and 27 Full Blood Count variables was investigated and matched to the observed plasma volume variation. After the removal of between-subject variations using a Bayesian model, multivariate analysis identified two sets of 8 and 15 biomarkers explaining 68% and 69% of plasma volume variance, respectively. The final multiparametric model contains a weighting function to allow for isolated abnormalities in single biomarkers. This proof-of-concept investigation describes a novel approach to estimate absolute vascular volumes, with a simple blood test. Despite the physiological instability of critically ill patients, it is hypothesized the model, with its multiparametric approach and weighting function, maintains the capacity to describe vascular volumes. This model has potential to transform volume management in clinical settings. Am. J. Hematol. 92:62-67, 2017. © 2016 Wiley Periodicals, Inc.

Summary Introduction Dehydration, fluid shifts or changes in coagulation occurring during air travel can trigger distinct reactions in the haematological system. Athletes are concerned that these effects might impair sporting performance, increase the risk of thrombosis or cause abnormalities in blood values that might be mistaken for doping in the ‘Athlete′s biological passport’ (ABP) a longitudinal monitoring of haematological variables in antidoping. The aim of the study was to investigate key variables of the ABP before and after a long-haul flight in athletes. Methods Fifteen endurance athletes were submitted to ABP blood samples in the morning before and after arrival of an 8 h flight. Two additional samples were obtained in the morning and the evening 3 days after the travel. Twelve nontravelling subjects served as controls. Results Haemoglobin concentration was higher before than after travel in athletes (+0.5 g/dL, P = 0.038), a similar pattern was observed 3 days after the travel. No difference was observed in the control group. Reticulocyte% did not show any significant changes in neither of the groups. Conclusion The observed changes are in line with normal diurnal variations. There is no indication that travel will affect haematological variables in way that might be mistaken for blood doping.

Biomarker monitoring can be considered a new era in the effort against doping. Opposed to the old concept in doping control of direct detection of a prohibited substance in a biological sample such as urine or blood, the new paradigm allows a personalized longitudinal monitoring of biomarkers that indicate non-physiological responses independently of the used doping technique or substance, and may cause sanctioning of illicit practices. This review presents the development of biomarker monitoring in sports doping control and focuses on the implementation of the Athlete Biological Passport as the current concept of the World Anti Doping Agency for the detection of blood doping (hematological module). The scope of the article extends to the description of novel biomarkers and future concepts of application.

The increase of the body's capacity to transport oxygen is a prime target for doping athletes in all endurance sports. For this pupose, blood transfusions or erythropoiesis stimulating agents (ESA), such as erythropoietin, NESP, and CERA are used. As direct detection of such manipulations is difficult, biomarkers that are connected to the haematopoietic system (haemoglobin concentration, reticulocytes) are monitored over time (Athlete Biological Passport (ABP)) and analyzed using mathematical models to identify patterns suspicious of doping. With this information, athletes can either be sanctioned directly based on their profile or targeted with conventional doping tests. Key issues for the appropriate use of the ABP are correct targeting and use of all available information (e.g. whereabouts, cross sectional population data) in a forensic manner. Future developments of the passport include the correction of all concentration-based variables for shifts in plasma volume, which might considerably increase sensitivity. New passport markers from the genomic, proteomic, and metabolomic level might add further information, but need to be validated before integration into the passport procedure. A first assessment of blood data of federations that have implemented the passport show encouraging signs of a decreased blood-doping prevalence in their athletes, which adds scientific credibility to this innovative concept in the fight against ESA- and blood doping.

The Race Across America, a 4800-km nonstop cycle race, is one of the most demanding endurance sports events. We display the racing strategy, power output, HR, hormonal levels, and inflammatory markers of an athlete before and during the race, which he completed in 10 d 23 h.The athlete showed physiological characteristics of a well-trained (nonelite) cyclist (V˙O2peak=63 mL·min·kg, heart volume=11.3 mL·kg). The race was mainly performed at low intensities (mean ± SD: power output=141 ± 76 W, HR=117 ± 14 bpm). During the race, testosterone levels dropped initially by 30-40% and returned to baseline toward the end. Cortisol remained elevated throughout (+75%-90% compared with baseline). Markers of inflammation (C-reactive protein), dehydration, and protein catabolism (albumin) were not affected. The athlete used a race strategy with regular sleeping breaks (total rest=91 h, 45 h of sleep).Contrasting conventional racing strategies for the Race Across America, which aim at minimizing sleep and maximizing ride time, our case demonstrates that by emphasizing regular recovery and sleep, such alternative strategy might lead an equally successful race result.

BACKGROUND: Since no direct detection method for autologous blood transfusions exists, the most promising attempt is the Athlete Biological Passport (ABP) and its adaptive model that enables a longitudinal monitoring of hematologic measures to identify patterns of blood manipulations. The purpose therefore was to evaluate the performance of this adaptive model for the detection of autologous blood transfusions in a longitudinal blinded setting. STUDY DESIGN AND METHODS: Twenty-one subjects were divided into a doped group (multiple transfusions of 1-2 units of red blood cells, n = 11) and a control group (n = 10). The time course of a cycling season (42 weeks) was simulated including three major competitions (Classics, Grand Tour, World Championships). Up to 10 venous blood samples were ordered per subject by a blinded investigator mimicking the intelligent approach in obtaining hematologic data for the adaptive model (hemoglobin [Hb] concentration, reticulocyte percentage, OFF-score). RESULTS: Retrospective analysis allowed identification of four (probability >99%) or three (probability >99.9%) abnormal samples for Hb and eight (probability >99%) or five (probability >99.9%) abnormal samples for OFF-hr in doped subjects. Four doped subjects (36%) presented an abnormal OFF-hr sequence and three doped subjects (27%) an abnormal Hb sequence; there were no false-positive sequence results. The best possible sensitivity was 82% when a combination of all tests was used. CONCLUSIONS: This investigation provides evidence that the adaptive model allows detection of autologous blood transfusions with a good sensitivity. An intelligent testing approach and the adherence to World Anti-Doping Agency's ABP operating guidelines are nevertheless determinant in the success.

Summary and conclusion Our results revealed a strong rise of iron concentration in EDTA-plasma sample after blood transf usion. We reasoned that the strongincreasewasduetothechelatoreffectofEDTAthatreducedthebase-line values of iron concentration in non-transfused plasma samples.The detection window of the observed change was up to one dayafter blood transfusion (10-fold increase) with a high speci ficity. Sinceiron is very stable, only very few co nfounding factors can interferewith the measurement. Thus, the measurement of iron in plasma-EDTA samples might provide supporting information for the ABPtesting to detect autologous and homologous blood transfusion.AcknowledgementsThis research was supported by the AntiDoping SwitzerlandFoundation (Bern, Switzerland). The authors would like toacknowledge Siemens Healthcare Diagnostics SA (Zurich,Switzerland) for providing the tests. References [1] N. Monfort, R. Ventura, A. Latorre, V. Belalcazar, M. Lopez, J. Segura.Urinary di-(2-ethylhexyl)phthalate metabolites in athletes as screen-ing measure for illicit blood doping: A comparison study withpatients receiving blood transfusion. Transfusion 2010, 50, 145.[2] Y.O. Schumacher, M. Saugy, T. Pottgiesser, N. Robinson. Detection ofEPO doping and blood doping: The haematological module of theathlete biological passport. Drug Test. Anal. 2012, 4, 846.[3] D.B. Kim-Shapiro, J. Lee, M.T. Gladwin. Storage lesion: Role of redblood cell breakdown. Transfusion 2011, 51, 844.[4] E.A. Hod, G.M. Brittenham, G.B. Billote, R.O. Francis, Y.Z. Ginzburg,J.E. Hendrickson, J. Jhang, J. Schwartz, S. Sharma, S. Sheth, A.N. Sireci,H.L. Stephens, B.A. Stotler, B.S. Wojczyk, J.C. Zimring, S.L. Spitalnik.Transfusion of human volunteers with older, stored redblood cells produces extravascular hemolysis and circulatingnon-transferrin-bound iron. Blood 2011, 118,6675.[5] N. Leuenberger, Y.O. Schumacher, S. Pradervand, T. Sander,M. Saugy, T. Pottgiesser. Circulating microRNAs as biomarkers fordetection of autologous blood transfusion. PLoS One 2013, 8, e66309.[6] F.E. Smith, J. Herbert, J. Gaudin, D.J. Hennessy, G.R. Reid. Serum irondetermination using ferene triazine. Clin. Biochem. 1984, 17, 306.[7] B. Berglund. Development of techniques for the detection of blooddoping in sport. Sports Med. 1988, 5, 127.[8] M.V.L. Rao, L.V.L. Sastry, M. Srinivasan, V. Subrahmanyan. Inhibition ofoxidation of ascorbic acid by EDTA. J. Sci. Food Agric. 1959, 10, 436.[9] S. Eskelinen, M. Haikonen, S. Raisanen. Ferene-S as the chromogen forserum iron determinations. Scand. J. Clin. Lab. Invest. 1983, 43, 453.[10] A. Jaspers, F. Baron, E. Willems, L. Seidel, E.T. Wiegerinck, D.W. Swinkels,Y. Beguin. Serum hepcidin following autologous hematopoietic celltransplantation: An illustration of the interplay of iron status, erythropoi-esis and inflammation. Haematologica 2014, 99,e35–e37.

The haematological module of the "Athletes Biological Passport" (ABP) is used to detect blood doping through the longitudinal variation of blood variables, such as haemoglobin concentration (Hb). Sporting federations have opened disciplinary procedures against athletes based on ABP results. Suspicious athletes try to explain the variations in their blood values with dehydration caused by gastrointestinal (GI) problems. The aim of the present report is to describe haemoglobin concentration, a key variable of the ABP, during acute gastroenteritis in athletes. 5 athletes with severe gastroenteritis were studied in retrospective. Blood test results (Hb, white blood cell count (WBC) and differential, CRP) obtained on hospital admission for GI problems were compared to data obtained from the same athletes in states of good health on previous occasions. During GI problems, athletes displayed marked inflammatory constellations with increased CRP and typical WBC shifts. Hb was not affected and remained mostly unchanged. This is in line with basic physiologic fluid regulation, where plasma volume is kept constant, even under conditions of severe dehydration. It is therefore unlikely that fluid loss associated with gastroenteritis will cause athletes blood data to reach levels of abnormality that will be suspicious of blood doping.

Haemoglobin (Hb) and haematocrit (Hct) are measured as indirect markers of doping in athletes. We studied the effect of posture on these parameters in a typical antidoping setting. Venous blood samples were obtained from nine endurance athletes (six males, three females) and nine control subjects (six males, three females) immediately and after 5, 10, 15, 20 and 30 min after having adopted a seated position from normal daily activity. Hb (CV 0.72%) and Hct (CV 0.87%) were determined using an automated cell counter, plasma volume changes were calculated. Differences between the time points, gender and groups were calculated using a mixed-model procedure. Significant changes were observed in the first 10 min after sitting down but no further changes were noted between 10 and 30 min. Mean directional change for Hb and Hct between 0 min and the average of the period from 10 to 30 min was -2.4% (-0.35 g/dl) for Hb and -2.7% (-1.2%) for Hct. Plasma volume increased accordingly. Neither group nor gender had significant effects. Under typical conditions encountered during blood testing in doping control, a period of 10 min in a seated position is sufficient for the vascular volumes to re-equilibrate and to adapt to the new posture.

Summary Introduction: With the setting up of the newly Athlete’s Biological Passport antidoping programme, novel guidelines have been introduced to guarantee results beyond reproach. We investigated in this context, the effect of storage time on the variables commonly measured for the haematological passport. We also wanted to assess for these variables, the within and between analyzer variations. Methods: Blood samples were obtained from top level male professional cyclists (27 samples for the first part of the study and 102 for the second part) taking part to major stage races. After collection, they were transported under refrigerated conditions (2 °C < T 48 h) and the technical comparison of the haematology analyzer demonstrated excellent results. Conclusion: In conclusion, our data clearly demonstrate that as long as the World Anti-Doping Agency’s guidelines are followed rigorously, all blood results reach the quality level required in the antidoping context.

Die metabolisch-physiologische Leistungsdiagnostik beinhaltet Methoden zur objektiven Messung der Ausdauerleistungsfahigkeit von Sporttreibenden oder der kardiopulmonalen Funktion von Patienten. Die korrekte Anwendung metabolischer Leistungsdiagnostik setzt eine detaillierte Kenntnis der Belastungsphysiologie und Erfahrung im Umgang mit den Methoden der Leistungsdiagnostik voraus. Die Basismethode zur Leistungsdiagnostik ist die Ergometrie mit gleichzeitiger Erfassung physiologischer Messgrosen wie der Herzfrequenz, der Blutlaktatkonzentration oder der Atemgasanalyse (Spiroergometrie). Zur Interpretation der Leistungsdiagnostik und Trainingssteuerung stehen verschiedene Konzepte und Softwareverfahren zur Verfugung. Neuere Ansatze implementieren statistisch-prognostische Methoden in die automatisierten Auswertungsalgorithmen.

Haemoglobin (Hb) and Reticulocytes (Ret) are measured as indirect markers of doping in athletes. We studied the diurnal variation, the impact of exercise, fluid intake and ambient temperature in athletes on these parameters. Hourly venous blood samples were obtained from 36 male athletes of different disciplines (endurance (END) and non-endurance (NON-END)) over 12 h during a typical training day. Seven inactive subjects served as controls (CON). Hb and Ret were determined. A mixed model procedure was used to analyse the data. At baseline, Hb was similar for all groups, END showed lower Ret than NON-END and CON. Exercise showed a significant impact on Hb (+0.46 g/dl, p

The haematological module of the Athlete's Biological Passport (ABP) has significantly impacted the prevalence of blood manipulations in elite sports. However, the ABP relies on a number of concentration-based markers of erythropoiesis, such as haemoglobin concentration ([Hb]), which are influenced by shifts in plasma volume (PV). Fluctuations in PV contribute to the majority of biological variance associated with volumetric ABP markers. Our laboratory recently identified a panel of common chemistry markers (from a simple blood test) capable of describing ca 67% of PV variance, presenting an applicable method to account for volume shifts within anti-doping practices. Here, this novel PV marker was included into the ABP adaptive model. Over a six-month period (one test per month), 33 healthy, active males provided blood samples and performed the CO-rebreathing method to record PV (control). In the final month participants performed a single maximal exercise effort to promote a PV shift (mean PV decrease -17%, 95% CI -9.75 to -18.13%). Applying the ABP adaptive model, individualized reference limits for [Hb] and the OFF-score were created, with and without the PV correction. With the PV correction, an average of 66% of [Hb] within-subject variance is explained, narrowing the predicted reference limits, and reducing the number of atypical ABP findings post-exercise. Despite an increase in sensitivity there was no observed loss of specificity with the addition of the PV correction. The novel PV marker presented here has the potential to improve the ABP's rate of correct doping detection by removing the confounding effects of PV variance.

Haemoglobin mass is a main determinant of maximal oxygen uptake. Blood doping aims at increasing this variable. Limits for haematocrit and haemoglobin concentration are used as indicators of blood doping. However, these variables are measures of concentration, do not represent total haemoglobin mass and are altered by vascular volumes shifts. Direct estimation of haemoglobin mass could improve blood tests. It is unknown if physical exercise alters haemoglobin mass. The purpose of this study was to investigate the reaction of haemoglobin mass and other vascular compartments to heavy exercise in athletes. Haemoglobin mass and vascular compartments were evaluated using the optimised CO rebreathing method in 7 elite cyclists during a stage race. Simultaneously, haemoglobin concentration and haematocrit were analysed. Haemoglobin mass (pre-race 958 +/- 123 g, end race 948 +/- 106 g) and red cell volume did not change significantly over the study period, while plasma volume and blood volume tended to increase. Haematocrit (pre-race 44.1 +/- 2.5 %, end race 40.9 +/- 1.59 %) and haemoglobin concentration (pre race 15.8 +/- 0.9 g/dl, end race 14.7 +/- 0.7 g/dl) decreased. During the study, a plasma volume expansion as adaptation to prolonged exercise occurred. Haemoglobin concentration and haematocrit decreased accordingly, whereas haemoglobin mass remained stable. Haemoglobin mass might therefore be a suitable screening tool for blood manipulations.

The aim of the study was to report the relationship between cadence and power developed by professional cyclists during high mountain ascents of the Tour de France. From the 10 cyclists (30 +/- 4 years, 178 +/- 8 cm, 69 +/- 6 kg) involved in the study, 108 ascents were recorded and analyzed using a mobile power measurement device (SRM Training Systems, Jülich, Germany). Based on topographic characteristics, the ascents were categorized into 1st and Hors Category (HC) climbs. During the ascents of the 1st Category climbs, power output averaged 312 +/- 43 W (4.5 +/- 0.6 W/kg) with a mean cadence of 73 +/- 6 rpm and a mean duration of 37 : 41 +/- 16 : 16 min. Power output averaged 294 +/- 36 W (4.3 +/- 0.6 W/kg) at a mean cadence of 70 +/- 6 rpm during 57 : 40 +/- 10 : 32 min on HC climbs. The maximal mean power for long durations (1800 s) showed a mean power output of 327 W and 346 W for the 1st and HC climbs, respectively. The evaluation of the cadence-power output and the distance per pedaling cycle-power output relationship shows that high power outputs are mainly yielded by higher pedaling cadences and higher gears.

Cancer is a life-threatening condition. We describe the case of a 22-yr-old world-class endurance athlete who presented with mild local lymphadenopathy but without any systemic complaints or impaired performance. He was subsequently diagnosed with stage III A (S) Hodgkin's lymphoma. A complete physiological workup before the diagnosis revealed high aerobic capacity. Immediately after six courses of escalated BEACOPP chemotherapy in an identical test setting, aerobic capacity was markedly reduced (-42%), mainly because of a decrease in total hemoglobin mass (-37%), despite maintaining a certain amount of endurance training. Other potentially performance-limiting systems such as heart, lung, or aerobic metabolism did not show any signs of impairment. Two months after chemotherapy, the athlete had recovered his hemoglobin mass, and his aerobic performance was almost back to pretherapy levels. This case illustrates that advanced malignancies can be present in elite athletes without affecting performance, and that aerobic capacity can be regained within a short time after systemic chemotherapy.