Safety of COVID-19 Vaccines Among the Paediatric Population: Analysis of the European Surveillance Systems and Pivotal Clinical Trials.

BACKGROUND AND OBJECTIVES: The European Medicine Agency extended the use of Comirnaty, Spikevax, and Nuvaxovid in paediatrics; thus, these vaccines require additional real-world safety evidence. Herein, we aimed to monitor the safety of COVID-19 vaccines through Covid-19 Vaccine Monitor (CVM) and EudraVigilance surveillance systems and the published pivotal clinical trials. METHODS: In a prospective cohort of vaccinees aged between 5 and 17 years, we measured the frequency of commonly reported (local/systemic solicited) and serious adverse drug events (ADRs) following the first and second doses of COVID-19 vaccines in Europe using data from the CVM cohort until April 2022. The results of previous pivotal clinical trials and data in the EudraVigilance were also analysed. RESULTS: The CVM study enrolled 658 first-dose vaccinees (children aged 5-11 years; n = 250 and adolescents aged 12-17 years; n = 408). Local/systemic solicited ADRs were common, whereas serious ADRs were uncommon. Among Comirnaty first and second dose recipients, 28.8% and 17.1% of children and 54.2% and 52.2% of adolescents experienced at least one ADR, respectively; injection-site pain (29.2% and 20.7%), fatigue (16.1% and 12.8%), and headache (22.1% and 19.3%) were the most frequent local and systemic ADRs. Results were consistent but slightly lower than in pivotal clinical trials. Reporting rates in Eudravigilance were lower by a factor of 1000. CONCLUSIONS: The CVM study showed high frequencies of local solicited reactions after vaccination but lower rates than in pivotal clinical trials. Injection-site pain, fatigue, and headache were the most commonly reported ADRs for clinical trials, but higher than spontaneously reported data.

Cohort Event Monitoring of Adverse Reactions to COVID-19 Vaccines in Seven European Countries: Pooled Results on First Dose.

INTRODUCTION: COVID-19 vaccines were rapidly authorised, thus requiring intense post-marketing re-evaluation of their benefit-risk profile. A multi-national European collaboration was established with the aim to prospectively monitor safety of the COVID-19 vaccines through web-based survey of vaccinees. METHODS: A prospective cohort event monitoring study was conducted with primary consented data collection in seven European countries. Through the web applications, participants received and completed baseline and up to six follow-up questionnaires on self-reported adverse reactions for at least 6 months following the first dose of COVID-19 vaccine (Netherlands, France, Belgium, UK, Italy) and baseline and up to ten follow-up questionnaires for one year in Germany and Croatia. Rates of adverse reactions have been described by type (solicited, non-solicited; serious/non-serious; and adverse events of special interest) and stratified by vaccine brand. We calculated the frequency of adverse reaction after dose 1 and prior to dose 2 among all vaccinees who completed at least one follow-up questionnaire. RESULTS: Overall, 117,791 participants were included and completed the first questionnaire in addition to the baseline: 88,196 (74.9%) from Germany, 27,588 (23.4%) from Netherlands, 984 (0.8%) from France, 570 (0.5%) from Italy, 326 (0.3%) from Croatia, 89 (0.1%) from the UK and 38 (0.03%) from Belgium. There were 89,377 (75.9%) respondents who had received AstraZeneca vaccines, 14,658 (12.4%) BioNTech/Pfizer, 11,266 (9.6%) Moderna and 2490 (2.1%) Janssen vaccines as a first dose. Median age category was 40-49 years for all vaccines except for Pfizer where median age was 70-79 years. Most vaccinees were female with a female-to-male ratio of 1.34, 1.96 and 2.50 for AstraZeneca, Moderna and Janssen, respectively. BioNtech/Pfizer had slightly more men with a ratio of 0.82. Fatigue and headache were the most commonly reported solicited systemic adverse reactions and injection-site pain was the most common solicited local reaction. The rates of adverse events of special interest (AESIs) were 0.1-0.2% across all vaccine brands. CONCLUSION: This large-scale prospective study of COVID-19 vaccine recipients showed, for all the studied vaccines, a high frequency of systemic reactions, related to the immunogenic response, and local reactions at the injection site, while serious reactions or AESIs were uncommon, consistent with those reported on product labels. This study demonstrated the feasibility of setting up and conducting cohort event monitoring across multiple European countries to collect safety data on novel vaccines that are rolled out at scale in populations which may not have been included in pivotal trials.

Monitoring performance, pituitary-adrenal hormones and mood profiles: how to diagnose non-functional over-reaching in male elite junior soccer players.

OBJECTIVE: To verify if in male elite junior soccer players a minimum 1-month performance decrease is accompanied by a mood profile and hormone levels typical of non-functional over-reaching (NFOR). DESIGN: A prospective case-control study using a monthly performance monitor with a standardised field test to detect the performance changes. Players with a performance decrease lasting at least 1 month were compared with control players without a performance decrease on mood scores and pre-exercise and postexercise levels of stress hormones. SETTING: Sporting field and sports medical laboratory. PARTICIPANTS: Ninety-four young elite soccer players were monitored during the 2006-2008 seasons. Twenty-one players were invited to the laboratory, seven of whom showed a significant performance decrease. MAIN OUTCOME MEASURES: Performance change over time, scores on the profile of mood states and premaximal and postmaximal exercise serum levels of adrenocorticotropic hormone (ACTH), growth hormone (GH) and cortisol. RESULTS: Players with a performance decrease showed psychological and hormonal changes typical of the non-functional state of over-reaching. Scores were higher on depression and anger, whereas the resting GH levels and ACTH levels after maximal exercise were reduced. ACTH and GH were capable of classifying all but one player correctly as either NFOR or control. CONCLUSIONS: Performance-related criteria in field tests are capable of identifying players with worsened mood and adaptations of the endocrine system that fit the definition of NFOR. Performance, mood and hormone levels may therefore be considered as valid instruments to diagnose NFOR in young elite soccer players.

Effectiveness of an injury prevention programme for adult male amateur soccer players: a cluster-randomised controlled trial.

BACKGROUND: The incidence rate of soccer injuries is among the highest in sports, particularly for adult male soccer players. PURPOSE: To investigate the effect of the 'The11' injury prevention programme on injury incidence and injury severity in adult male amateur soccer players. STUDY DESIGN: Cluster-randomised controlled trial. METHODS: Teams from two high-level amateur soccer competitions were randomly assigned to an intervention (n=11 teams, 223 players) or control group (n=12 teams, 233 players). The intervention group was instructed to perform The11 in each practice session during one soccer season. The11 focuses on core stability, eccentric training of thigh muscles, proprioceptive training, dynamic stabilisation and plyometrics with straight leg alignment. All participants of the control group continued their practice sessions as usual. RESULTS: In total, 427 injuries were recorded, affecting 274 of 456 players (60.1%). Compliance with the intervention programme was good (team compliance=73%, player compliance=71%). Contrary to the hypothesis, injury incidences were almost equal between the two study groups: 9.6 per 1000 sports hours (8.4-11.0) for the intervention group and 9.7 (8.5-11.1) for the control group. No significant differences were found in injury severity, but a significant difference was observed in the location of the injuries: players in the intervention group sustained significantly less knee injuries. CONCLUSIONS: This study did not find significant differences in the overall injury incidence or injury severity between the intervention and control group of adult male soccer players. More research is recommended, focusing on injury aetiology and risk factors in adult male amateur soccer players.

Effectiveness and cost-effectiveness of an injury prevention programme for adult male amateur soccer players: design of a cluster-randomised controlled trial.

BACKGROUND AND AIMS: Approximately 16% of all sports injuries in the Netherlands are caused by outdoor soccer. A cluster-randomised controlled trial has been designed to investigate the effectiveness and cost-effectiveness of an injury prevention programme ('The11') for male amateur soccer players. The injury prevention programme The11, developed with the support of the World Football Association FIFA, aims to reduce the impact of intrinsic injury risk factors in soccer. METHODS: Teams playing at first-class amateur level in two districts in the Netherlands are participating in the study. Teams in the intervention group were instructed to apply The11 during each practice session throughout the 2009-10 season. All participants of the control group continued their practice sessions as usual. All soccer-related injuries and related costs for each team were systematically reported online by a member of the medical staff. Player exposure to practice sessions and matches was reported weekly by the coaches. Also the use of The11 during the season after the intervention season will be monitored. DISCUSSION: Our hypothesis is that integrating the The11 exercises in the warm-up for each practice session is effective in terms of injury incidence, injury severity, healthcare use, and its associated costs and/or absenteeism. Prevention of soccer injuries is expected to be beneficial to adult soccer players, soccer clubs, the Royal Dutch Football Association (KNVB), health insurance companies and society.

Can we detect non-functional overreaching in young elite soccer players and middle-long distance runners using field performance tests?

OBJECTIVE: To study whether field performance tests can make a valid distinction between non-functionally overreaching (NFO) athletes and control athletes. DESIGN: Monthly field performance tests were used to determine a performance decrement (PD) throughout a season. Athletes with a minimum of 1 month PD were compared with control athletes without a PD on mood characteristics and resting levels of stress hormones. SETTING: Sporting field and sports medical laboratory. PARTICIPANTS: 129 young elite athletes, 77 soccer players and 52 middle-long distance runners were followed prospectively during the 2006-2007 season. Fifteen of them were invited to the laboratory. Eight athletes showed a performance decrease lasting longer than 1 month, and seven athletes without a performance decrease acted as their controls. MAIN OUTCOME MEASURES: Performance changes over time were measured using field tests. Profile of Mood States and resting levels of adrenocorticotrophic hormone (ACTH) and cortisol in blood were measured in the laboratory. RESULTS: PD athletes showed several symptoms typical of the non-functional state of overreaching (OR). The PD group scored higher on depression and anger than controls. They also showed a specific pattern of correlations between negative mood subscales (tension, fatigue and depression), which was absent in controls. ACTH levels at rest were similar, but lower cortisol levels in PD athletes pointed at a blunted cortisol response. Cortisol levels were decoupled from ACTH levels only in PD athletes. CONCLUSIONS: Implementing performance-related criteria in field tests can help coaches and sports physicians to distinguish NFO athletes from athletes with balanced workload and recovery.

Assessment of the effects of physical training in patients with chronic heart failure: the utility of effort-independent exercise variables.

Traditionally, the effects of physical training in patients with chronic heart failure (CHF) are evaluated by changes in peak oxygen uptake (peak VO(2)). The assessment of peak VO(2), however, is highly dependent on the patients' motivation. The aim of the present study was to evaluate the clinical utility of effort-independent exercise variables for detecting training effects in CHF patients. In a prospective controlled trial, patients with stable CHF were allocated to an intervention group (N = 30), performing a 12-week combined cycle interval and muscle resistance training program, or a control group (N = 18) that was matched for age, gender, body composition and left ventricular ejection fraction. The following effort-independent exercise variables were evaluated: the ventilatory anaerobic threshold (VAT), oxygen uptake efficiency slope (OUES), the V(E)/VCO(2) slope and the time constant of VO(2) kinetics during recovery from submaximal constant-load exercise (tau-rec). In addition to post-training increases in peak VO(2) and peak V(E), the intervention group showed significant within and between-group improvements in VAT, OUES and tau-rec. There were no significant differences between relative improvements of the effort-independent exercise variables in the intervention group. In contrast with VAT, which could not be determined in 9% of the patients, OUES and tau-rec were determined successfully in all patients. Therefore, we conclude that OUES and tau-rec are useful in clinical practice for the assessment of training effects in CHF patients, especially in cases of poor subject effort during symptom-limited exercise testing or when patients are unable to reach a maximal exercise level.

Monitoring load, recovery, and performance in young elite soccer players.

The purpose of this study was to investigate the relation between training load, recovery, and monthly field test performance in young elite soccer players to develop training guidelines to enhance performance. In a prospective, nonexperimental cohort design, 18 young elite soccer players registered training and match duration for a full competitive season by means of daily training logs. Furthermore, session rating of perceived exertion (RPE) and total quality of recovery (TQR) scores were recorded. Weekly duration (TL(d)), load (duration x session RPE = TL(rpe)), and TQR scores were calculated for 1 and 2 weeks before a monthly submaximal interval shuttle run tests to determine interval endurance capacity. Participants spent on average 394.4 +/- 134.9 minutes per week on training and game play with an average session RPE of 14.4 +/- 1.2 (somewhat hard) and TQR of 14.7 +/- 1.3 (good recovery). Random intercept models showed that every extra hour training or game play resulted in enhanced field test performance (p < 0.05). Session RPE and TQR scores did not contribute to the prediction of performance. The duration of training and game play in the week before field test performance is most strongly related to interval endurance capacity. Therefore, coaches should focus on training duration to improve interval endurance capacity in elite soccer players. To evaluate the group and individual training response, field tests should be frequently executed and be incorporated in the training program.

National survey on sports injuries in the Netherlands: target populations for sports injury prevention programs.

OBJECTIVE: To define target populations for sports injury prevention programs. DESIGN: A computer-assisted telephone survey on sports injuries and sports participation during 2000-2005 using a 3-month recall period. SETTING: Data obtained from a representative sample of Dutch citizens. PARTICIPANTS: Fifty-eight thousand four hundred five Dutch citizens aged older than 3 years. ASSESSMENT OF RISK FACTORS: Age, gender, and type of sports were used to distinguish subgroups with a substantial contribution to sports injuries. MAIN OUTCOME MEASURES: The absolute number of sports injuries, the incidence of sports injuries per 10,000 hours, the severity, and costs of sports injuries. RESULTS: Sports participation was associated with 1.5 million injuries per year and 10 injuries per 10,000 hours; of these, 50% had to be treated medically. Two-thirds of all medically treated sports injuries were associated with 9 sports (representing 18 subpopulations, all younger than 55 years): outdoor soccer (males 4-54 years and females 4-17 years), indoor soccer (males 18-34 years), tennis (males/females 35-54 years), volleyball (females 18-54 years), field hockey (males 18-34 years and females 4-17 years), running/jogging (males/females 35-54 years), gymnastics (males/females 4-17 years), skiing/snowboarding (males 4-17 years and females 18-34 years), and equestrian sports (females 18-34 years). These groups showed more than average injury rates and covered two-thirds of all direct and indirect costs (euro 400 million). CONCLUSIONS: The survey identified the most important (sports-, age-, and gender-specific) target populations for injury prevention programs in the Netherlands. Sports participants aged older than 55 years were excluded from these target groups because of their limited contribution to the total sports injury problem.

Factors associated with a more rapid recovery after anterior cruciate ligament reconstruction using multivariate analysis.

BACKGROUND: In the past, several studies investigated factors that are prognostic or associated with outcome after anterior cruciate ligament (ACL) reconstruction. A recent review showed that only limited evidence is available for most studied factors, and that insufficient analysis methods were used commonly. Therefore, the aim of this study was to add more weight to the existing evidence, about factors that are associated with a more rapid outcome after ACL reconstruction. The second aim was to use multivariate analysis to study the possible factors independently. METHODS: A cohort study was conducted with a follow-up of six months. Before surgery, patient variables were scored. Surgical variables were scored during arthroscopic ACL reconstructions with a single-bundle technique and hamstring autograft. The Lysholm score and subscales of the Knee Injury Osteoarthritis Outcome Score (KOOS) were assessed six months post surgery. A multiple analysis of variance (ANOVA) model was used to identify prognostic factors for outcome. RESULTS: In total, 118 patients were included. Patients, aged ≤30years, with a subjective knee score ≥ six, with normal flexion range of motion (ROM) of the knee, with flexion and extension strength deficit of ≤20%, and those with no previous knee surgery in the same knee at baseline scored significantly higher on outcome after multivariate analysis. No significant effect of surgical factors could be found. CONCLUSION: Younger age, higher subjective knee score, normal knee flexion, normal knee flexion and extension strength, and no previous knee surgery in the patients' history at baseline are associated with a more rapid recovery after ACL reconstruction. LEVEL OF EVIDENCE: Level III, prognostic study.

Effects of soft bracing or taping on a lateral ankle sprain: a non-randomised controlled trial evaluating recurrence rates and residual symptoms at one year.

BACKGROUND: After sustaining an ankle sprain, taping is often the standard treatment in primary care. Ankle braces are sometimes used as an alternative. This study aimed to compare the effects of four weeks of soft bracing or taping following acute lateral ankle ligamentous sprain (ALALS) on sprain recurrence rates and residual symptoms at one year. METHODS: In this pragmatic, non-randomised controlled trial, 157 adult participants with an ALALS caused by an inversion trauma were alternately allocated to a four week treatment with a soft brace (intervention group) or a four week treatment with ankle tape (control group) in order of presentation. The primary outcome was the 1-year incidence of the self-reported recurrence of ALALS. The secondary outcome was the occurrence of residual symptoms. RESULTS: Baseline characteristics did not differ appreciably between the treatment groups. Thirteen patients (17%) in the brace group reported a re-injury versus 11 patients (14%) treated with tape, corresponding to a risk difference of 3.1% (relative risk 1.2, 95% CI 0.6 to 2.6). Cox regression analysis showed a hazard ratio of self-reported ankle sprain recurrence within 52 weeks in the brace group compared to the tape group of 0.9 (95% CI 0.4 to 1.9). After one year, patients in the brace group had poorer scores on the manual anterior ankle test, corresponding to a risk difference of 15.4% (RR 2.4, 95% CI 1.1 to 5.0). CONCLUSION: ALALS recurrences and residual symptoms appear to be similar at one year when an ALALS is treated with four weeks of soft bracing or taping. TRIAL REGISTRATION: ISRCTN92030205.

Injury prevention target groups in soccer: injury characteristics and incidence rates in male junior and senior players.

To identify target groups for injury prevention in male amateur soccer players under 35 years of age. A computer-assisted telephone survey with a 12-month recall period for injuries in a representative sample of Dutch citizens from the Injuries and Physical Activity Netherlands (IPAN)-database. A comparison of the volume of soccer injuries, the incidence and the need for medical attention per level of exposure and age category. The incidence in seniors was twice that of juniors (17.5% versus 8.1%; odds ratio (OR=2.4). In juniors the overall incidence was lowest in the category with the least amount of soccer exposure time (0-3 h: 2.9%; 3-5 h: 13.0%; 5+ h: 12.3%). A comparable result was found in seniors: (0-3 h: 12.0%; 3-5 h: 21.6%; 5+ h: 21.5%). Within each level of soccer exposure, a different incidence was found in juniors and seniors (0-3 h: OR=4.6; 3-5 h: OR=1.8; 5+ h: OR=1.9). Ankle, knee and upper leg injuries were most common (59.9%). Contusions, strains and sprains dominated (78.1%). Body region and type of injuries were similar in both age categories. Medical treatment for injuries was equally necessary in both age groups. Senior male amateur soccer players and particularly the more skilled seniors (involved in soccer at least 3 h per week), should be primarily targeted for studies on injury risk factors and prevention programs.

Evaluation and opportunities in overtraining approaches.

Overtraining (OT) as a sports phenomenon can be caused by stressors on various levels (physical, emotional, psychological, and social) and evokes responses on these levels. This study evaluated research and new opportunities in the field of OT by introducing an integrated multidisciplinary approach, based on the single and multistressors approach. The single stressor approach focuses on the training load-recovery imbalance, which results in a stagnating performance, excluding the etiology by nonsport-related factors. The multistressors approach includes all factors as relevant in the etiology of a stagnating performance. In future studies on OT an integrative approach should not only highlight changes in training regimes and specific responses to training stressors but also focus on the role of training-related recovery, the impact of stressors, and personality factors influencing stress appraisal. This will provide a better insight into the etiology and consequences of OT necessary for prevention and treatment in sport practice, and enhance the focus on adequate recovery (good sleep, sufficient rest periods) and athletes' stress-related responses.

Predicting effects of exercise training in patients with heart failure secondary to ischemic or idiopathic dilated cardiomyopathy.

The purpose of this study was to investigate which patient characteristics may predict training effects on maximal and submaximal exercise performance in patients with heart failure. Together with commonly used clinical and performance-related variables, oxygen uptake kinetics during exercise recovery were included as possible predictors. Fifty patients with heart failure (New York Heart Association class II or III) performed a 12-week training program (cycle interval and resistance training). Training effects were expressed as changes in peak oxygen uptake (Vo(2)), Vo(2) at ventilatory threshold (VT), and the time constant of Vo(2) recovery after submaximal exercise (tau-rec). After training, peak Vo(2), Vo(2) at VT, and tau-rec improved significantly, with a wide variety in training responses. Changes in peak Vo(2) were related to changes in VT (r = 0.79, p <0.001), but both changes were not related to changes in tau-rec. Using multivariate regression analyses, post-training changes in peak Vo(2) could be predicted by recovery halftime of peak Vo(2) (T1/2), peak Vo(2) (percentage of predicted), and peak respiratory exchange ratio (R(2) = 36%). Post-training changes in VT could be predicted by T1/2 and VT (predicted) (R(2) = 29%), whereas changes in tau-rec could be predicted only by tau-rec at baseline (R(2) = 34%). In conclusion, oxygen recovery kinetics after maximal and submaximal exercise substantially add to the prediction of training effects in patients with heart failure, presumably because of their relations with, respectively, central and peripheral impairments of exercise capacity. However, the explained variance in training effects is not sufficient to make a definite distinction between training responders and nonresponders.