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Abstract The human microbiome emerges as a promising reservoir for diagnostic markers and therapeutics. Since host-associated microbiomes at various body sites differ and diseases do not occur in isolation, a comprehensive analysis strategy highlighting the full potential of microbiomes should include diverse specimen types and various diseases. To ensure robust data quality and comparability across specimen types and diseases, we employ standardized protocols to generate sequencing data from 1931 prospectively collected specimens, including from saliva, plaque, skin, throat, eye, and stool, with an average sequencing depth of 5.3 gigabases. Collected from 515 patients, these samples yield an average of 3.7 metagenomes per patient. Our results suggest significant microbial variations across diseases and specimen types, including unexpected anatomical sites. We identify 583 unexplored species-level genome bins (SGBs) of which 189 are significantly disease-associated. Of note, the existence of microbial resistance genes in one specimen was indicative of the same resistance genes in other specimens of the same patient. Annotated and previously undescribed SGBs collectively harbor 28,315 potential biosynthetic gene clusters (BGCs), with 1050 significant correlations to diseases. Our combinatorial approach identifies distinct SGBs and BGCs, emphasizing the value of pan-body pan-disease microbiomics as a source for diagnostic and therapeutic strategies.

Introduction: Fibrolamellar carcinoma (FLC) displays upregulation of several oncogenes, including HER2, and multiple immune-suppressive mechanisms. We investigated the efficacy and safety of the pan-HER tyrosine kinase inhibitor neratinib as monotherapy (SUMMIT phase 2 basket study) or with immune checkpoint and/or mammalian target of rapamycin (mTOR) inhibitors (compassionate-use program) in patients with FLC. Methods: Patients received neratinib 240 mg/day orally in SUMMIT, or as doublet or triplet combinations with pembrolizumab 2 mg/kg intravenously every 3 weeks, nivolumab 240 mg intravenously every 2 weeks, everolimus 7.5 mg/day orally, or sunitinib 37.5 mg/day orally under compassionate use. The primary endpoint in SUMMIT was objective response rate; safety was a secondary endpoint. Results: Fifteen patients with FLC received neratinib monotherapy in SUMMIT. The objective response rate was 5% (95% confidence interval [CI]: 0–21.8) and the disease control rate was 13.3% (95% CI: 1.7–40.5). Upon progression, five had added immune checkpoint inhibitors with or without everolimus or sunitinib. Two additional patients received neratinib-based combinations outside of SUMMIT, for a total of 17 neratinib-treated patients. One patient who received neratinib plus pembrolizumab had a confirmed partial response, one treated with neratinib plus everolimus had stable disease lasting 6 months, and one who received neratinib plus pembrolizumab plus sunitinib had stable disease lasting 16 months. Grade 3/4 adverse events with neratinib monotherapy occurred in 10 (66.7%)/2 (13.3%) patients, respectively. Grade 3 adverse events with neratinib-based combinations were hyperglycemia (n = 1; neratinib plus pembrolizumab), hepatic failure, and anaphylaxis (n = 1 each, neratinib plus pembrolizumab plus everolimus). There were no grade 4 adverse events with combination therapy. Conclusion: In patients with FLC, single-agent neratinib had limited efficacy, but clinical benefit was observed with neratinib in combination with immunotherapy and/or mTOR-targeted agents.

The long-term health effects of football (soccer) have received significant attention in recent years. While brain health is currently the focus of this interest, potential long-term risks or benefits related to cardiovascular and metabolic diseases and cancer are also of interest to sports medicine professionals. However, studies assessing the overall health risks for professional football players remain scarce. We introduce ‘SoccHealth’, a satellite project to the German National Cohort (NAKO), Germany’s largest population-based cohort study. SoccHealth examined 348 former professional football players aged 40–69 using the infrastructure and comprehensive examination programme of NAKO. The German Statutory Accidental Insurance for Professional Athletes identified and invited male players, while female players were recruited among former national team members. Details of the examination programme and the sociodemographic and career-related characteristics of the participants are described. The identical examination programme for the NAKO participants provides the opportunity to draw general population controls according to various definitions and focus on the respective research question to be analysed. This report delineates one approach to evaluate the long-term health effects of football across a broad range of diseases.

Summary: Hepatocellular carcinoma (HCC) is a major global healthcare challenge, with >1 million patients predicted to be affected annually by 2025. In contrast to other cancers, both incidence and mortality rates continue to rise, and HCC is now the third leading cause of cancer-related death worldwide. Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for advanced HCC, with trials demonstrating a superior overall survival benefit compared to sorafenib in the first-line setting. Combination therapy with either atezolizumab (anti-PD-L1) and bevacizumab (anti-VEGF) or durvalumab (anti-PD-L1) and tremelimumab (anti-CTLA-4) is now recognised as standard of care for advanced HCC. More recently, two phase III studies of ICI-based combination therapy in the early and intermediate disease settings have successfully met their primary end points of improved recurrence- and progression-free survival, respectively. Despite these advances, and in contrast to other tumour types, there remain no validated predictive biomarkers of response to ICIs in HCC. Ongoing research efforts are focused on further characterising the tumour microenvironment in order to select patients most likely to benefit from ICI and identify novel therapeutic targets. Herein, we review the current understanding of the immune landscape in which HCC develops and the evidence for ICI-based therapeutic strategies in HCC. Additionally, we describe the state of biomarker development and novel immunotherapy approaches in HCC which have progressed beyond the pre-clinical stage and into early-phase trials.

In elite football, injury risk is considerable. Consequently, optimal rehabilitation and an adequate time point of return-to-play (RTP) are crucial. The elevated injury risk in the weeks after RTP (e.g. Orchard & Best, 2002; Wangensteen et al., 2016) and the time course of biological healing processes (Orchard & Best, 2002) nourished the speculation that players generally return to early. While the previously reported negative association between rehab time and injury risk after RTP (e.g. Beischer et al., 2020; Della Villa et al., 2021; Orchard & Best, 2002) points in the same direction, the truism “Correlation does not imply causation.” must be considered. To the best of our knowledge, the causal effect of rehab time on injury risk has not been investigated so far. This work aims to contribute towards closing this gap in knowledge. Specifically, to scrutinize if a reduction in injury risk may be expected when RTP is delayed. Previous time-loss injuries and match exposures of players currently playing in the European top leagues (Germany, Austria, France, Spain, Italy, Netherlands, United Kingdom) were collected from public sources and episodes (index injury-RTP-subsequent injury) constructed. Data analysis was conducted in R. Considering the time dependence of the excess injury risk after RTP, we analyzed injury occurrence after RTP within a fixed time frame (28 days). A robust scaling approach was used for making rehab time comparable between index injury diagnoses. Exposure within the 28-day period was adjusted for eventual time loss due to subsequent injury. The association between rehab time and injury was analyzed using logistic regression. Odds ratios (OR) were calculated from regression coefficients and adjusted for baseline probability to avoid overestimation of relative risk (RR). Two approaches were used to delineate a potential causal effect: (a) sensitivity analysis for the putative confounder (using Cornfield’s inequality) and (b) path analysis which due to the simple causal diagram could be implemented by including exposure in the logistic regression model. Eight thousand six hundred and forty-four episodes could be included among which 1,245 (14 %) had a subsequent injury within 28 days. There was a highly significant negative association between scaled rehab time and injury risk (RR 0,896), which was more pronounced for recurrences (RR 0,815). Cornfield’s inequality indicates that exposure would have to be lower by at least ~10% for every interquartile range of rehab time of the respective index injury to account for the observed association. While this is substantial, early return is in fact closely associated with higher exposure and this association accounts entirely for the observed association between rehab time and injury risk (Figure 1). Note that Figure 1 also shows that high exposures are observed exclusively after an early return. We conclude that the negative association between rehab time and injury risk is largely accounted for by higher exposures after early return. However, following from the limitations associated with predicting outside the range of previously observed values, the virtual absence of high exposures after long rehab (for the respective diagnosis) impedes on predicting the effect of prolonging rehab time. References Beischer, S., Gustavsson, L., Senorski, E. H., Karlsson, J., Thomee, C., Samuelsson, K., & Thomee, R. (2020). Young athletes who return to sport before 9 months after anterior cruciate ligament reconstruction have a rate of new injury 7 times that of those who delay return. Journal of Orthopaedic and Sports Physical Therapy, 50(2), 83-90. https://doi.org/10.2519/jospt.2020.9071 Della Villa, F., Hagglund, M., Della Villa, S., Ekstrand, J., & Walden, M. (2021). High rate of second ACL injury following ACL reconstruction in male professional footballers: An updated longitudinal analysis from 118 players in the UEFA Elite Club Injury Study. British Journal of Sports Medicine, 55(23), 1350-1356. https://doi.org/10.1136/bjsports-2020-103555 Orchard, J., & Best, T. M. (2002). The management of muscle strain injuries: An early return versus the risk of recurrence. Clinical Journal of Sport Medicine, 12(1), 3-5. https://doi.org/10.1097/00042752-200201000-00004 Wangensteen, A., Tol, J. L., Witvrouw, E., Van Linschoten, R., Almusa, E., Hamilton, B., & Bahr, R. (2016). Hamstring reinjuries occur at the same location and early after return to sport: A descriptive study of MRI-confirmed reinjuries. American Journal of Sports Medicine, 44(8), 2112-2121. https://doi.org/10.1177/0363546516646086

Abstract Background The main task of applied sport science is to inform decision-making in sports practice, that is, enabling practitioners to compare the expectable outcomes of different options (e.g. training programs). Main Body The “evidence” provided may range from group averages to multivariable prediction models. By contrast, many decisions are still largely based on the subjective, experience-based judgement of athletes and coaches. While for the research scientist this may seem “unscientific” and even “irrational”, it is important to realize the different perspectives: science values novelty, universal validity, methodological rigor, and contributions towards long-term advancement. Practitioners are judged by the performance outcomes of contemporary, specific athletes. This makes out-of-sample predictive accuracy and robustness decisive requirements for useful decision support. At this point, researchers must concede that under the framework conditions of sport (small samples, multifactorial outcomes etc.) near certainty is unattainable, even with cutting-edge methods that might theoretically enable near-perfect accuracy. Rather, the sport ecosystem favors simpler rules, learning by experience, human judgement, and integration across different sources of knowledge. In other words, the focus of practitioners on experience and human judgement, complemented—but not superseded—by scientific evidence is probably street-smart after all. A major downside of this human-driven approach is the lack of science-grade evaluation and transparency. However, methods are available to merge the assets of data- and human-driven strategies and mitigate biases. Short Conclusion This work presents the challenges of learning, forecasting and decision-making in sport as well as specific opportunities for turning the prevailing “evidence vs. eminence” contrast into a synergy.

Introduction: RATIONALE-301 (NCT03412773) was a global, phase 3 study comparing the efficacy and safety of tislelizumab with sorafenib as first-line (1L) treatment in adult patients with unresectable hepatocellular carcinoma (HCC) that met its primary endpoint of noninferiority in overall survival (OS). This analysis compared health-related quality-of-life (HRQOL) outcomes between the arms. Methods: Systemic therapy–naive adults with HCC were randomized 1:1 to receive tislelizumab n = 342) or sorafenib (n = 332). HRQOL was assessed using EORTC QLQ-C30, QLQ-HCC18, and EQ-5D-5L. At cycles 4 and 6, a mixed model for repeated measures was performed using key prespecified patient-reported outcome (PRO) endpoints of the QLQ-C30 and the QLQ-HCC18. Time to deterioration was analyzed with the Kaplan-Meier method using the PRO endpoints. Results: At cycles 4 and 6, patients in the tislelizumab arm had better HRQOL outcomes than the patients in the sorafenib arm per mean-change differences in GHS/QOL, QLQ-C30 physical functioning and fatigue, and QLQ-HCC18 symptom index; however, no differences for pain were observed. Patients in the tislelizumab arm had lower risk of deterioration in GHS/QOL (HR, 0.68; 95% CI, 0.49-0.94), QLQ-C30 physical functioning (HR, 0.46; 95% CI, 0.33-0.64) and fatigue (HR, 0.48; 95% CI, 0.37-0.63), QLQ-HCC18 symptom index (HR, 0.53; 95% CI, 0.34-0.81), and HCC-specific fatigue (HR, 0.60; 95% CI, 0.46-0.80). For pain, both arms had similar risk of deterioration (HR, 0.78; 95% CI, 0.56-1.09). At cycle 4 and 6, patients in the tislelizumab arm maintained in EQ-5D-5L visual analog scale, whereas scores decreased for the patients in the sorafenib arm. Conclusion: Patients with 1L HCC treated with tislelizumab had better HRQOL outcomes compared with patients treated with sorafenib, particularly in fatigue and physical functioning. These results, along with favorable safety profile, better response rate, and OS noninferiority, support tislelizumab as a potential 1L treatment option for unresectable HCC.

BackgroundThe cardiac stress for veteran football players during match is considerable. In this specific elderly population, the kinetics of exercise-induced cardiac troponin I (cTnI) and B-Type natriuretic peptide (BNP) could potentially be related to cardiovascular risk factors (CVRF) and cardiovascular disease and are therefore be investigated for their usefulness as an complement to established screening measures.MethodscTnI and BNP was measured in 112 veteran football players (age: 51 ± 10 years) within 30 minutes pre- and post-match. Players with elevated cTnI (cTnI-positive) and a control group (out of the 112 veteran players) with normal cTnI (cTnI-negative) underwent cardiac follow-up 4.2 ± 3.5 months post-match, comprising history, resting and stress ECG (including 30 minutes pre- and post cTnI and BNP), and echocardiography.ResultsIn 33 players (29%) cTnI and in 6 players BNP (5%) exceeded the upper range limit for increased risk of myocardial damage (cTnI ≥ 5 ng/l) and myocardial wall stress (BNP ≥ 100 pg/ml) post-match, respectively. No correlation was observed between Δ cTnI (pre- vs. post-match) and the number of CVRF (r = -0.06, p = 0.50). Follow-up was conducted in 62 players (31 cTnI-positive and 31 cTnI-negative players) of which 6 (10%, 3 cTnI positive and 3 cTnI negative players) had cardiac abnormalities (hypertrophic cardiomyopathy n = 2, coronary artery disease n = 2, coronary artery anomaly n = 1, hypertensive heart disease n = 1).ConclusionVeterans' football matches elicit increases in BNP and particularly cTnI in a considerable number of players. However, these biochemical alterations do not indicate acute cardiac damage as evidenced by follow-up. Routine determination of cardiac biomarkers is unlikely to improve cardiovascular screening in veteran football players.

IntroductionThe present study investigated the role of training intensity in the dose–response relationship between endurance training and cardiorespiratory fitness (CRF). The hypothesis was that beginners would benefit from an increase in training intensity after an initial training phase, even if the energy expenditure was not altered. For this purpose, 26 weeks of continuous moderate training (control group, CON) was compared to training with gradually increasing intensity (intervention group, INC) but constant energy expenditure.MethodsThirty-one healthy, untrained subjects (13 men, 18 women; 46 ± 8 years; body mass index 25.4 ± 3.3 kg m−2; maximum oxygen uptake, VO2max 34 ± 4 ml min−1 kg−1) trained for 10 weeks with moderate intensity [3 days/week for 50 min/session at 55% heart rate reserve (HRreserve)] before allocation to one of two groups. A minimization technique was used to ensure homogeneous groups. While group CON continued with moderate intensity for 16 weeks, the INC group trained at 70% HRreserve for 8 weeks and thereafter participated in a 4 × 4 training program (high-intensity interval training, HIIT) for 8 weeks. Constant energy expenditure was ensured by indirect calorimetry and corresponding adjustment of the training volume. Treadmill tests were performed at baseline and after 10, 18, and 26 weeks.ResultsThe INC group showed improved VO2max (3.4 ± 2.7 ml kg−1 min−1) to a significantly greater degree than the CON group (0.4 ± 2.9 ml kg−1 min−1) (P = 0.020). In addition, the INC group exhibited improved Vmax (1.7 ± 0.7 km h−1) to a significantly greater degree than the CON group (1.0 ± 0.5 km h−1) (P = 0.001). The reduction of resting HR was significantly larger in the INC group (7 ± 4 bpm) than in the CON group (2 ± 6 bpm) (P = 0.001). The mean heart rate in the submaximal exercise test was reduced significantly in the CON group (5 ± 6 bpm; P = 0.007) and in the INC group (8 ± 7 bpm; P = 0.001), without a significant interaction between group and time point.ConclusionIncreasing intensity leads to greater adaptations in CRF than continuing with moderate intensity, even without increased energy expenditure. After 26 weeks of training in the moderate- and higher-intensity domain, energy-matched HIIT elicited further adaptations in cardiorespiratory fitness. Thus, training intensity plays a crucial role in the dose–response relationship between endurance training and fitness in untrained but healthy individuals. Clinical Trial Registrationhttps://www.drks.de/DRKS00031445, identifier DRKS00031445.

Abstract Background Standardized training prescriptions often result in large variation in training response with a substantial number of individuals that show little or no response at all. The present study examined whether the response in markers of cardiorespiratory fitness (CRF) to moderate intensity endurance training can be elevated by an increase in training intensity. Methods Thirty-one healthy, untrained participants (46 ± 8 years, BMI 25.4 ± 3.3 kg m−2 and $${\dot{\text{V}}}$$ V ˙ O2max 34 ± 4 mL min−1 kg−1) trained for 10 weeks with moderate intensity (3 day week−1 for 50 min per session at 55% HRreserve). Hereafter, the allocation into two groups was performed by stratified randomization for age, gender and VO2max response. CON (continuous moderate intensity) trained for another 16 weeks at moderate intensity, INC (increased intensity) trained energy-equivalent for 8 weeks at 70% HRreserve and then performed high-intensity interval training (4 × 4) for another 8 weeks. Responders were identified as participants with VO2max increase above the technical measurement error. Results There was a significant difference in $${\dot{\text{V}}}$$ V ˙ O2max response between INC (3.4 ± 2.7 mL kg−1 min−1) and CON (0.4 ± 2.9 mL kg−1 min−1) after 26 weeks of training (P = 0.020). After 10 weeks of moderate training, in total 16 of 31 participants were classified as VO2max responders (52%). After another 16 weeks continuous moderate intensity training, no further increase of responders was observed in CON. In contrast, the energy equivalent training with increasing training intensity in INC significantly (P = 0.031) increased the number of responders to 13 of 15 (87%). The energy equivalent higher training intensities increased the rate of responders more effectively than continued moderate training intensities (P = 0.012). Conclusion High-intensity interval training increases the rate of response in VO2max to endurance training even when the total energy expenditure is held constant. Maintaining moderate endurance training intensities might not be the best choice to optimize training gains. Trial Registration German Clinical Trials Register, DRKS00031445, Registered 08 March 2023—Retrospectively registered, https://www.drks.de/DRKS00031445

The study aim was to assess whether match-derived external-to-internal load ratios are a valid and reliable tool to measure physical fitness. Sixteen elite youth soccer players (17±1 years) performed two maximal fitness tests. Subsequently, players participated in three intra squad soccer matches in three consecutive weeks. Three GPS-based parameters of external load (total distance, PlayerLoad, high-intensity distance) were divided by three heart rate based parameters of internal load (iTRIMP, Banister TRIMP, average percentage heart rate reserve) for the ratio calculations. Validity was established by comparing the ratios with results of the fitness tests, while between-athlete and within-athlete reliability were quantified. Most integrated load ratios were moderately-to-largely correlated with the various fitness parameters. Overall, a ratio consisting of PlayerLoad and average percentage heart rate reserve demonstrated the mostconsistentcorrelations with maximum treadmill speed (r = 0.69, P = 0.003) and the speeds associated with 4 mmol/L of blood lactate (r = 0.56, P = 0.024) and 80% of heart rate reserve (r = 0.54, P = 0.031). Most of the ratios displayed acceptable levels of reproducibility (intraclass correlation coefficient > 0.8 and coefficient of variation < 10%), with the minimal detectable change of all ratios ranging between 7.1 and 37.8%. Given their associations with physical fitness and non-invasive nature, certain external-to-internal load ratios may be used to monitor physical fitness in soccer players. However, the ratios may not be sensitive enough to detect small yet practically relevant alterations in player fitness.

Abstract Background This study describes the implementation of a standardised, prospective injury database covering the entire 1st male German football league (“Bundesliga”) based on publicly available media data. For the first time, various media sources were used simultaneously as the external validity of media-generated data was low in the past compared to data obtained by way of the “gold standard”, i.e. by the teams’ medical staffs. Methods The study covers 7 consecutive seasons (2014/15–2020/21). The primary data source was the online version of the sport-specific journal “kicker Sportmagazin™” complemented by further publicly available media data. Injury data collection followed the Fuller consensus statement on football injury studies. Results During the 7 seasons, 6653 injuries occurred, thereof 3821 in training and 2832 in matches. The injury incidence rates (IRs) per 1000 football hours were 5.5 [95% CI 5.3–5.6], 25.9 [25.0–26.9] per 1000 match, and 3.4 [3.3–3.6] per 1000 training hours. Twenty-four per cent of the injuries (n = 1569, IR 1.3 [1.2–1.4]) affected the thigh, 15% (n = 1023, IR 0.8 [0.8–0.9]) the knee, and 13% (n = 856, IR 0.7 [0.7–0.8]) the ankle. Muscle/tendon injuries contributed 49% (n = 3288, IR 2.7 [2.6–2.8]), joint/ligament injuries 17% (n = 1152, IR 0.9 [0.9–1.0]), and contusions 13% (n = 855, IR 0.7 [0.7–0.8]). Compared to studies using injury reports from the clubs’ medical staff, media data revealed similar proportional distributions of the injuries, but the IRs tended towards the lower end. Obtaining specific locations or diagnosis especially with regard to minor injuries is difficult. Conclusions Media data are convenient for investigating the quantity of injuries of an entire league, for identifying injuries for further subanalysis, and for analysing complex injuries. Future studies will focus on the identification of inter- and intraseasonal trends, players' individual injury histories, and risk factors for subsequent injuries. Furthermore, these data will be used in a complex system approach for developing a clinical decision support system, e.g. for return to play decisions.

Background: Treatment with lenvatinib (dosing for patients who weigh ≥60 kg was 12 mg/day; for patients who weigh

ABSTRACTBackground: Refugees with exposure to multiple traumatic events are at high risk for developing posttraumatic stress disorder (PTSD) and depression. Narrative exposure therapy (NET) is an effective treatment for the core symptoms of PTSD, but it does not reliably reduce depressive symptoms. Endurance exercise on the other hand was consistently found to be effective in treating depression making it a promising adjunct to NET. Up to date, no studies exist investigating the combination of NET and endurance exercise in a sample of refugees with PTSD and comorbid depression.Objectives: In the proposed randomized controlled trial, we aim to investigate whether a combination of NET and moderate-intensity aerobic exercise training (MAET) enhances treatment outcome for refugees with PTSD and comorbid depressive symptoms. We expect a greater improvement in psychopathology in participants who receive the combined treatment.Methods and analysis: 68 refugees and asylum seekers with PTSD and clinically relevant depressive symptoms will be recruited in the proposed study. Participants will be randomly assigned to receive either NET only (NET-group) or NET plus MAET (NET+-group). All participants will receive 10 NET sessions. Participants in the NET+-group will additionally take part in MAET. Primary (PTSD, depression) and secondary (general mental distress, agoraphobia and somatoform complaints, sleep quality) outcome measures will be assessed before treatment, after treatment, and at six-month follow-up. The hypotheses will be tested with multiple 2 × 3 mixed ANOVA's.Trial registration: German Clinical Trials Register identifier: DRKS00022145.

ObjectivesThe present study aimed to assess the perception and change of mental and physical fatigue and to examine acute effects of mental recovery strategies in air rifle athletes across simulated competition days with two consecutive competition bouts.DesignWe conducted a randomized counterbalanced crossover study.Method22 development air rifle athletes (Mage = 17.77 ± 4.0) of a regional squad participate in the study. The Short Recovery and Stress Scale (SRSS), perception of mental fatigue, physical fatigue, concentration and motivation as well as differential Ratings of Perceived Exertion (RPE) were used to assess recovery-stress states and fatigue states. During a recovery break, participants underwent two mental recovery strategies (powernap, systematic breathing) or a control condition. Total shooting scores were recorded for both competition bouts.ResultsStudy results revealed a significant increase of post ratings for mental (p

Abstract Background Patients with hepatocellular carcinoma (HCC) and Child–Pugh B liver cirrhosis have poor prognosis and are underrepresented in clinical trials. The CELESTIAL trial, in which cabozantinib improved overall survival (OS) and progression-free survival (PFS) versus placebo in patients with HCC and Child–Pugh A liver cirrhosis at baseline, was evaluated for outcomes in patients who had Child–Pugh B cirrhosis at Week 8. Methods This was a retrospective analysis of adult patients with previously treated advanced HCC. Child–Pugh B status was assessed by the investigator. Patients were randomised 2:1 to cabozantinib (60 mg once daily) or placebo. Results Fifty-one patients receiving cabozantinib and 22 receiving placebo had Child–Pugh B cirrhosis at Week 8. Safety and tolerability of cabozantinib for the Child–Pugh B subgroup were consistent with the overall population. For cabozantinib- versus placebo-treated patients, median OS from randomisation was 8.5 versus 3.8 months (HR 0.32, 95% CI 0.18–0.58), median PFS was 3.7 versus 1.9 months (HR 0.44, 95% CI 0.25–0.76), and best response was stable disease in 57% versus 23% of patients. Conclusions These encouraging results with cabozantinib support the initiation of prospective studies in patients with advanced HCC and Child–Pugh B liver function. Clinical Trial Registration: NCT01908426.

Abstract We aimed to analyze the number and type of contacts involving the risk of respiratory disease transmission during football match play. We analysed 50 matches from different playing levels. Two reviewers evaluated the contacts of all players in each match. We focused on between-player contacts, crowding, actions with potentially increased aerosol and droplet production and within-player hand-to-head contacts. We categorized the duels with direct contact into frontal and other ones and measured contact duration. The number of between-player contacts were similar between playing levels (median 28.3 [IQR 22.6, 33] contacts per player-hour). Frontal contacts summed up to 8% of all contacts. Contacts involving the head occurred less than once per player and match with none lasting longer than 3 s. Crowding included between two and six players and the duration was mostly less than 10 s. Aerosol and droplet producing activities were three to four times more frequent in adult compared to youth players. Our results suggest that the risk of respiratory pathogen transmission is low during football matches. This conclusion is based on the finding that most close contact situations are of short duration and on the fact that it is an outdoor sport.

Introduction: Cabozantinib, an inhibitor of MET, AXL, and VEGF receptors, significantly improved overall survival (OS) and progression-free survival (PFS) versus placebo in patients with previously treated advanced hepatocellular carcinoma (HCC). In this exploratory analysis, outcomes were evaluated according to plasma biomarker levels. Methods: Baseline plasma levels were evaluated for MET, AXL, VEGFR2, HGF, GAS6, VEGF-A, PlGF, IL-8, EPO, ANG2, IGF-1, VEGF-C, and c-KIT for 674/707 randomized patients; and Week 4 levels were evaluated for MET, AXL, VEGFR2, HGF, GAS6, VEGF-A, PlGF, IL-8, and EPO for 614 patients. OS and PFS were analyzed by baseline levels as dichotomized or continuous variables and by on-treatment changes at Week 4 as continuous variables; biomarkers were considered potentially prognostic if p < 0.05 and predictive if p < 0.05 for the interaction between treatment and the biomarker. Multivariable analyses adjusting for clinical covariates were also performed. Results: In the placebo group, high levels of MET, HGF, GAS6, IL-8, and ANG2 and low levels of IGF-1 were associated with shorter OS in univariate and multivariable analyses; these associations were also observed for MET, IL-8, and ANG2 in the cabozantinib group. Hazard ratios for OS and PFS favored cabozantinib over the placebo at low and high baseline levels for all biomarkers. No baseline biomarkers were predictive of a treatment benefit. Cabozantinib promoted pharmacodynamic changes in several biomarkers, including increases in VEGF-A, PlGF, AXL, and GAS6 levels and decreases in VEGFR2 and HGF levels; these changes were not associated with OS or PFS. Conclusion: Cabozantinib improved OS and PFS versus placebo at high and low baseline concentrations for all biomarkers analyzed. Low baseline levels of MET, HGF, GAS6, IL-8, and ANG2 and high levels of IGF-1 were identified as potential favorable prognostic biomarkers for survival in previously treated advanced HCC. Although cabozantinib promoted pharmacodynamic changes in several biomarkers, these changes were not associated with survival.

Positional tracking data allows football practitioners to derive features that describe patterns of player behavior and quantify performance. Existing research using tracking data has mostly focused on what occurred on the pitch, such as the determinants of effective passing. There have yet to be studies attempting to use findings from data science to improve performance. Therefore, 24 professional players (mean age = 21.6 years, SD = 5.7) were divided into a control team and an intervention team which competed against each other in a pre-test match. Metrics were gathered via notational analysis (number of passes, penalty box entries, shots on goal), and positional tracking data including pass length, pass velocity, defensive disruption (D-Def), and the number of outplayed opponents (NOO). D-Def and NOO were used to extract video clips from the pre-test that were shown to the intervention team as a teaching tool for 2 weeks prior to the post-test match. The results in the post-test showed no significant improvements from the pre-test between the Intervention Team and the Control Team for D-Def (F = 1.100, p = 0.308, η2 = 0.058) or NOO (F = 0.347, p = 0.563, η2 = 0.019). However, the Intervention Team made greater numerical increases for number of passes, penalty box entries, and shots on goal in the post-test match. Despite a positive tendency from the intervention, results indicate the transfer of knowledge from data science to performance was lacking. Future studies should aim to include coaches' input and use the metrics to design training exercises that encourage the desired behavior.

Introduction: Tislelizumab (anti-programmed cell death protein 1 antibody) showed preliminary antitumor activity and tolerability in patients with advanced solid tumors, including hepatocellular carcinoma (HCC). This study aimed to assess the efficacy and safety of tislelizumab in patients with previously treated advanced HCC. Methods: The multi-regional phase 2 study, RATIONALE-208, examined single-agent tislelizumab (200 mg intravenously every three weeks) in patients with advanced HCC with Child-Pugh A, Barcelona Clinic Liver Cancer stage B or C, and who had received one or more prior lines of systemic therapy. The primary endpoint was objective response rate (ORR), radiologically confirmed per Response Evaluation Criteria in Solid Tumors version 1.1 by Independent Review Committee. Safety was assessed in patients who received ≥1 dose of tislelizumab. Results: Between April 9, 2018 and February 27, 2019, 249 eligible patients were enrolled and treated. After a median study follow-up of 12.7 months, ORR was 13% (n = 32/249; 95% confidence interval [CI], 9–18), including five complete and 27 partial responses. Number of prior lines of therapy did not impact ORR (one prior line, 13% [95% CI, 8–20]; two or more prior lines, 13% [95% CI, 7–20]). Median duration of response was not reached. Disease control rate was 53% and median overall survival was 13.2 months. Of the 249 total patients, grade ≥3 treatment-related adverse events were reported in 38 (15%) patients; the most common was liver transaminase elevations in 10 (4%) patients. Treatment-related adverse events led to treatment discontinuation in 13 (5%) patients or dose delay in 46 (19%) patients. No deaths were attributed to the treatment per investigator assessment. Conclusion: Tislelizumab demonstrated durable objective responses, regardless of the number of prior lines of therapy, and acceptable tolerability in patients with previously treated advanced HCC.

PurposeThe aim of this study was to assess the short-term responsiveness of measurement instruments aiming at quantifying the acute psycho-physiological response to load in high-level adolescent soccer players.MethodsData were collected from 16 high-level male youth soccer players from the Under 15 age group. Players were assessed on two occasions during the week: after 2 days of load accumulation (“high load”) and after at least 48 h of rest. Measurements consisted of the Short Recovery and Stress Scale (SRSS), a countermovement jump (CMJ) and a sub-maximal run to assess exercise heart-rate (HRex) and heart-rate recovery (HRR60s). Training load was quantified using total distance and high-speed running distance to express external and sRPE training load to express internal load. It was expected that good instruments can distinguish reliably between high load and rest.ResultsOdd ratios (0.74–1.73) of rating one unit higher or lower were very low for athlete-reported ratings of stress and recovery of the SRSS. Standardized mean high load vs. rest differences for CMJ parameters were trivial to small (−0.31 to 0.34). The degree of evidence against the null hypothesis that changes are interchangeable ranged from p = 0.04 to p = 0.83. Moderate changes were observed for HRex (−0.62; 90% Cl −0.78 to −0.47; p = 3.24 × 10−9), while small changes were evident for HRR60s (0.45; 90% Cl 0.08–0.80; p = 0.04). Only small to moderate repeated-measures correlations were found between the accumulation of load and acute responses across all measurement instruments. The strongest relationships were observed between HRex and total distance (rm-r = −0.48; 90% Cl −0.76 to −0.25).ConclusionResults suggest that most of the investigated measurement instruments to assess acute psycho-physiological responses in adolescent soccer players have limited short-term responsiveness. This questions their potential usefulness to detect meaningful changes and manage subsequent training load and program adequate recovery.

Shared metabolic pathways could allow simultaneous manipulation of T cells, viruses and tumours. Here the authors show targeting cholesterol esterification restrains hepatitis B in vitro, whilst bolstering exhausted antigen-specific T cell responses from human liver and hepatocellular carcinoma.

This study describes the design of the TARGET‐hepatocellular carcinoma (HCC) cohort and descriptive characteristics of the patient population at diagnosis among those who were enrolled in the cohort across academic and community clinical centers. TARGET‐HCC is a 5‐year, longitudinal, observational cohort of patients with HCC receiving care in usual clinical practice. Redacted clinical information, obtained from medical records, captures the natural history and management of the disease, including the safety and efficacy of treatment interventions used in usual clinical practice. Patients can complete patient‐reported outcome measures and provide biological specimens for future translational studies. The TARGET‐HCC study includes adults with histologic, cytologic, or radiologic diagnosis of HCC from academic and community centers in both the United States and Europe. A total of 1,841 participants were enrolled between January 9, 2017, and July 23, 2019, at 67 sites in the United States and Europe. To date, the most common liver disease etiology in the cohort continues to be hepatitis C, although nearly half had a nonviral etiology, including alcohol‐related liver disease or nonalcoholic steatohepatitis. Most included patients were diagnosed at an early stage (Barcelona Clinic Liver Cancer Stage [BCLC] 0/A), but only approximately one third underwent curative treatment. Systemic therapy has been used in 7.3% of enrolled patients, including 45.7% of those with BCLC stage C tumors. Conclusion: Overall, the TARGET‐HCC cohort allows for the assessment of patient characteristics and investigation of new treatment paradigms and sequencing with existing agents as well as novel regimens for HCC.

Background The assessment of biological maturity status plays an important role in talent identification and development programs. Aim To compare age at predicted adult height and BAUS skeletal age as indicators of biological maturity status in youth soccer players using a construct-validity approach. Subjects and methods Participants were 114 players from the U12 to U17 age groups of a professional youth soccer academy. Maturity status was determined via percentage of predicted adult height based upon the Khamis-Roche method (somatic maturity) and assessed via the SonicBone BAUSTM system (skeletal maturity). Convergent and known-groups validity were evaluated between maturity assessment methods and by comparing maturity-related selection biases across age groups. Results Although maturity status indicators were largely interrelated (r = .94, 95%CL 0.91–0.96), concordance (κ = 0.31 to 0.39) and Spearman’s rank-order correlations (ρ = 0.45–0.52) of classification methods were moderate. A selection bias towards early maturing players emerged in the U14 age group which remained relatively consistent through to the U17 age group. Conclusions Results confirm the construct-validity of both methods to assess biological maturity status although further validation relative to established indicators of biological maturity is needed. Furthermore, caution is also warranted when interpreting maturity status classification methods interchangeably given the poor concordance between classification methods.

Nasopharyngeal carcinoma (NPC) lacks effective diagnostic and therapeutic strategies, in particular at advanced stages. Here, the authors show that expression of the somatostatin receptor 2 is induced by Epstein-Barr virus in NPC and has a key role in the diagnosis, imaging, targeted therapies and prognosis of NPC.

Morbidity and mortality of COVID-19 is increased in patients with inborn errors of immunity (IEI). Age and comorbidities and also impaired type I interferon immunity were identified as relevant risk factors. In patients with primary antibody deficiency (PAD) and lack of specific humoral immune response to SARS-CoV-2, clinical disease outcome is very heterogeneous. Despite extensive clinical reports, underlying immunological mechanisms are poorly characterized and levels of T cellular and innate immunity in severe cases remain to be determined. In the present study, we report clinical and immunological findings of 5 PAD patients with severe and fatal COVID-19 and undetectable specific humoral immune response to SARS-CoV-2. Reactive T cells to SARS-CoV-2 spike (S) and nucleocapsid (NCAP) peptide pools were analyzed comparatively by flow cytometry in PAD patients, convalescents and naïve healthy individuals. All examined PAD patients developed a robust T cell response. The presence of polyfunctional cytokine producing activated CD4+ T cells indicates a memory-like phenotype. An analysis of innate immune response revealed elevated CD169 (SIGLEC1) expression on monocytes, a surrogate marker for type I interferon response, and presence of type I interferon autoantibodies was excluded. SARS-CoV-2 RNA was detectable in peripheral blood in three severe COVID-19 patients with PAD. Viral clearance in blood was observed after treatment with COVID-19 convalescent plasma/monoclonal antibody administration. However, prolonged mucosal viral shedding was observed in all patients (median 67 days) with maximum duration of 127 days. PAD patients without specific humoral SARS-CoV-2 immunity may suffer from severe or fatal COVID-19 despite robust T cell and normal innate immune response. Intensified monitoring for long persistence of SARS-CoV-2 viral shedding and (prophylactic) convalescent plasma/specific IgG as beneficial treatment option in severe cases with RNAemia should be considered in seronegative PAD patients.

While sample sizes in elite sports are necessarily small, so are the effects that may be relevant. This conundrum is complicated by an understandable reluctance of athletes to comply with extensive study requirements. In Bayesian analyses, pre-existing knowledge (e.g., from sub-elite trials) can be formally included to supplement scarce data. Moreover, some design specifics for small sample research extend to the extreme case of a single subject. This provides the basis for actionable feedback (e.g., about individual responses) thereby incentivising participation. As a proof-of-concept, we conducted a replicated cross-over trial on the effect of cold-water immersion (CWI) on sprint performance recovery in soccer players. Times for 30 m linear sprint and the initial 5 m section, respectively, were measured by light gates before and 24 h after induction of fatigue. Data were analysed by Bayesian and by standard frequentist methods. Informative priors are based on a published metaanalysis. Seven players completed the trial. Sprint performance was 4.156 ± 0.193 s for 30 m linear sprint and 0.978 ± 0.064 s for the initial 5 m section. CWI improved recovery of sprint time for the initial 5 m section (difference to control: −0.060 ± 0.060 s, p = 0.004) but not for the full 30 m sprint (0.002 ± 0.115 s, p = 0.959), with general agreement between Bayesian and frequentist interval estimates. On the individual level, relevant differences between analytical approaches were present for most players. Changes in the two performance measures are correlated (p = 0.009) with a fairly good reproducibility of individual response patterns. Bayesian analyses with informative priors may be a practicable and meaningful option particularly for very small samples and when the analytical aim is decision making (use / don't use in the specific setting) rather than generalizable inference.

Abstract The consecutive three-component Suzuki-Knoevenagel condensation (SuKnoCon) synthesis is an efficient, modular one-pot synthetic approach to donor-substituted merocyanines with carboxylic acid functionality. A library of 19 dyes is readily accessible and their electronic properties can be assessed by cyclic voltammetry and absorption and emission spectroscopy. In addition, for illustration of the utility of this concise one-pot concept, several dyes from this library were identified to be well suited as DSSC dyes with relative efficiencies reaching up to 93% of Grätzel's dye N3.

Objective: It is unclear whether and to what extent COVID-19 infection poses health risks and a chronic impairment of performance in athletes. Identification of individual health risk is an important decision-making basis for managing the pandemic risk of infection with SARS-CoV-2 in sports and return to play (RTP).Methods: This study aims 1) to analyze the longitudinal rate of seroprevalence of SARS-CoV-2 in German athletes, 2) to assess health-related consequences in athletes infected with SARS-CoV-2, and 3) to reveal effects of the COVID-19 pandemic in general and of a cleared SARS-CoV-2 infection on exercise performance. CoSmo-S is a prospective observational multicenter study establishing two cohorts: 1) athletes diagnosed positive for COVID-19 (cohort 1) and 2) federal squad athletes who perform their annual sports medical preparticipation screening (cohort 2). Comprehensive diagnostics including physical examination, laboratory blood analyses and blood biobanking, resting and exercise electrocardiogram (ECG), echocardiography, spirometry and exercise testing added by questionnaires are conducted at baseline and follow-up.Results and Conclusion: We expect that the results obtained, will allow us to formulate recommendations regarding RTP on a more evidence-based level.

SARS-CoV-2 testing is dominated by PCR to guide treatment and individual as well as public health preventive measures. Among 1700 football (soccer) players and staff of the German Bundesliga and Bundesliga 2 who were regularly tested by PCR twice weekly, 98 individuals had a positive PCR (May 2020 to mid-January 2021). A subset of these were retested shortly after the initial positive result. Among those, 11 subjects were identified who only had a transient single positive PCR of low viral load. All individuals were asymptomatic and none developed long COVID. We tested SARS-CoV-2 IgG and IgA as well as SARS-CoV-2 specific CD4 und CD8 positive T cells, and showed that only one out of 11 individuals developed SARS-CoV-2 specific cellular and humoral immunity after the positive PCR, whereas a specific immunity was undetectable in all other individuals. Thus, a single positive PCR might indicate that transient colonization of the upper respiratory tract with SARS-CoV-2 may occur without systemic induction of specific adaptive immunity. Together with test artifacts as another potential reason for a transiently positive test, this finding may favor cautious interpretation of positive PCR results or retesting before initiating intervening treatment or infection control measures in some cases.

Introduction We conducted a systematic literature review to assess the utility of liver function assessments for predicting disease prognosis and response to systemic anticancer therapy in patients with advanced hepatocellular carcinoma (aHCC). Methods This was a PRISMA-standard review and was registered with PROSPERO (CRD42021244588). MEDLINE and Embase were systematically searched (March 24, 2021) to identify publications reporting the efficacy and/or safety of systemic anticancer therapy (vs any/no comparator) in liver-function-defined subgroups in phase 2 or 3 aHCC trials. Screening was completed by a single reviewer, with uncertainties resolved by a second reviewer and/or the authors. English-language full-text articles and congress abstracts were eligible for inclusion. Included publications were described and assessed for risk of bias using the GRADE methodology. Results Twenty (of 2579) screened publications were eligible; seven categorised liver function using the albumin–bilirubin system, nine using the Child–Pugh system, four using both. GRADE assessment classified ten, nine, and one publication(s) as reporting moderate-quality, low-quality, and very-low-quality evidence, respectively. Analyses of cross-trial trends of within-exposure arm analyses (active and control) reported a positive relationship between baseline liver function and overall survival and progression-free survival, supporting liver function as a prognostic marker in aHCC. There were also signals for a modest relationship between more preserved baseline liver function and extent of systemic treatment benefit, and with more preserved liver function and lower incidence of safety events. Conclusion This review supports liver function as a prognostic variable in aHCC, and highlights the value of a priori stratification of patients by baseline liver function in aHCC trials. The predictive value of liver function warrants further study. Findings were limited by the quality of available data.

Pharmacogenomics (PGx) studies how a person’s genes affect the response to medications and is quickly becoming a significant part of precision medicine. The clinical application of PGx principles has consistently been cited as a major opportunity for improving therapeutic outcomes. Several recent studies have demonstrated that most individuals (> 90%) harbor PGx variants that would be clinically actionable if prescribed a medication relevant to that gene. In multiple well-conducted studies, the results of PGx testing have been shown to guide therapy choice and dosing modifications which improve treatment efficacy and reduce the incidence of adverse drug reactions (ADRs). Although the value of PGx testing is evident, its successful implementation in a clinical setting presents a number of challenges to molecular diagnostic laboratories, healthcare systems, providers and patients. Different molecular methods can be applied to identify PGx variants and the design of the assay is therefore extremely important. Once the genotyping results are available the biggest technical challenge lies in turning this complex genetic information into phenotypes and actionable recommendations that a busy clinician can effectively utilize to provide better medical care, in a cost-effective, efficient and reliable manner. In this paper we describe a successful and highly collaborative implementation of the PGx testing program at the University of Minnesota and MHealth Fairview Molecular Diagnostic Laboratory and selected Pharmacies and Clinics. We offer detailed descriptions of the necessary components of the pharmacogenomic testing implementation, the development and technical validation of the in-house SNP based multiplex PCR based assay targeting 20 genes and 48 SNPs as well as a separate CYP2D6 copy number assay along with the process of PGx report design, results of the provider and pharmacists usability studies, and the development of the software tool for genotype-phenotype translation and gene-phenotype-drug CPIC-based recommendations. Finally, we outline the process of developing the clinical workflow that connects the providers with the PGx experts within the Molecular Diagnostic Laboratory and the Pharmacy.

Background & Aims: The coronavirus disease 2019 (COVID-19) pandemic has posed unprecedented challenges to healthcare systems and it may have heavily impacted patients with liver cancer (LC). Herein, we evaluated whether the schedule of LC screening or procedures has been interrupted or delayed because of the COVID-19 pandemic. Methods: An international survey evaluated the impact of the COVID-19 pandemic on clinical practice and clinical trials from March 2020 to June 2020, as the first phase of a multicentre, international, and observational project. The focus was on patients with hepatocellular carcinoma or intrahepatic cholangiocarcinoma, cared for around the world during the first COVID-19 pandemic wave. Results: Ninety-one centres expressed interest to participate and 76 were included in the analysis, from Europe, South America, North America, Asia, and Africa (73.7%, 17.1%, 5.3%, 2.6%, and 1.3% per continent, respectively). Eighty-seven percent of the centres modified their clinical practice: 40.8% the diagnostic procedures, 80.9% the screening programme, 50% cancelled curative and/or palliative treatments for LC, and 41.7% modified the liver transplantation programme. Forty-five out of 69 (65.2%) centres in which clinical trials were running modified their treatments in that setting, but 58.1% were able to recruit new patients. The phone call service was modified in 51.4% of centres which had this service before the COVID-19 pandemic (n = 19/37). Conclusions: The first wave of the COVID-19 pandemic had a tremendous impact on the routine care of patients with liver cancer. Modifications in screening, diagnostic, and treatment algorithms may have significantly impaired the outcome of patients. Ongoing data collection and future analyses will report the benefits and disadvantages of the strategies implemented, aiding future decision-making. Lay summary: The coronavirus disease 2019 (COVID-19) pandemic has posed unprecedented challenges to healthcare systems globally. Herein, we assessed the impact of the first wave pandemic on patients with liver cancer and found that routine care for these patients has been majorly disrupted, which could have a significant impact on outcomes.

Both daily demands as well as training and competition characteristics in sports can result in a psychobiological state of mental fatigue leading to feelings of tiredness, lack of energy, an increased perception of effort, and performance decrements. Moreover, optimal performance will only be achievable if the balance between recovery and stress states is re-established. Consequently, recovery strategies are needed aiming at mental aspects of recovery. The aim of the study was to examine acute effects of potential mental recovery strategies (MR) on subjective-psychological and on cognitive performance outcomes after a mentally fatiguing task. A laboratory-based randomized cross-over study with twenty-four students (22.8 ± 3.6 years) was applied. Participants were run through a powernap intervention (PN), a systematic breathing intervention (SB), a systematic breathing plus mental imagery intervention (SB+), and a control condition (CC) with one trial a week over four consecutive weeks. Mental fatigue was induced by completion of the 60-min version of the AX-continuous performance test (AX-CPT). The Short Recovery and Stress Scale (SRSS) and Visual Analog Scales (VAS) were assessed to measure effects on perceptual outcomes. Cognitive performance was measured with a reaction time test of the Vienna Test System (VTS). During all three recovery interventions and CC portable polysomnography was applied. Results showed a significant increase from pre-AX-CPT to pre-MR on fatigue states and recovery-stress states indicating that the induction of mental fatigue was effective. Moreover, results underlined that analysis yielded no significant differences between recovery interventions and the control condition but they revealed significant time effects for VAS, SRSS items, and cognitive performance. However, it could be derived that the application of a rest break with 20 min of mental recovery strategies appears to enhance recovery on a mainly mental and emotional level and to reduce perceived mental fatigue.

Hepatocellular carcinoma (HCC) remains a leading cause of cancer death worldwide, and despite recent immunotherapeutic advances there remains a need for improved diagnostic, prognostic, and therapeutic tools. UL-16 binding protein 1 (ULBP1) is a ligand of the activatory receptor Natural Killer cell Group 2 receptor D (NKG2D) and is found as a cell-surface protein on some malignant cells including on human hepatocellular carcinomas. We aimed to explore the biological and clinical significance of NKG2D ligands in the circulation of patients with HCC. We measured ULBP1 in the serum of two retrospective cohorts of patients with HCC from the PROLIFICA cohort in The Gambia (n = 43) and from a tertiary care setting in the UK (n = 72) by sandwich ELISA. Exosome isolation by size exclusion was used to compare ULBP1 concentration in exosomes and as free protein. Survival analysis was performed and multiple linear regression and Poisson regression were used to assess the independent effect of ULBP1 concentration. ULBP1 was raised in both cohorts with HCC regardless of the underlying liver disease, and was not associated with markers of cirrhosis such as platelet count or serum albumin. ULBP1 was present predominantly as free protein rather than bound to exosomes. Serum ULBP1 > 2000 pg/ml was associated with a significantly reduced survival in both cohorts (hazard ratios in Gambian and UK cohorts 2.37 and 2.1, respectively). The effect remained significant after adjustment for BCLC staging (p = 0.03). These data suggest that ULBP1 merits further investigation as a prognostic marker in HCC in diverse settings and should also be explored as a therapeutic target.

Summary: This protocol describes a robust method for the generation of engineered human myocardium (EHM) from pluripotent stem cells (PSCs) in a multi-well plate under defined, serum-free conditions. By parallel culture of up to 48 EHM in one plate, contractile heart muscle can be obtained to serve numerous applications, including drug screening and disease modelling. This protocol has been successfully applied to human embryonic stem (HES) cell- and induced PSC-derived cardiomyocytes, subtype-specific, i.e., atrial and ventricular, and commercially available cardiomyocyte preparations. For complete details on the use and execution of this protocol, please refer to Tiburcy et al. (2017).

Isolation of circulating tumor cells (CTCs) allows for non-invasive disease monitoring and characterization. Here the authors describe an alternative CTC isolation method based on the ability of the malaria rVAR2 protein to specifically bind oncofetal chondroitin sulfate, which is expressed by all cancer cells

Abstract Practicing sport at the highest level is typically accompanied by several stressors and restrictions on personal life. Elite athletes’ lifestyle delivers a significant challenge to sleep, due to both the physiological and psychological demands, and the training and competition schedules. Inter-individual variability of sleep patterns (e.g., sleep requirements, chronotype) may have important implications not only for recovery and training schedules but also for the choice of measures to possibly improve sleep. This article provides a review of the current available literature regarding the variability of sleep among elite athletes and factors possibly responsible for this phenomenon. We also provide methodological approaches to better address the inter-individual variability of sleep in future studies with elite athletes. There is currently little scientific evidence supporting a specific influence of one particular type of sport on sleep; sleep disorders may be, however, more common in strength/power and contact sports. Sleep behavior may notably vary depending on the athlete’s typical daily schedule. The specificity of training and competition schedules possibly accounts for the single most influential factor leading to inconsistency in sleep among elite athletes (e.g., “social jet lag”). Additionally, athletes are affected by extensive exposure to electric light and evening use of electronic media devices. Therefore, the influence of ordinary sleep, poor sleep, and extended sleep as important additional contributors to training load should be studied. Future experimental studies on sleep and elite sport performance should systematically report the seasonal phase. Boarding conditions may provide a good option to standardize as many variables as possible without the inconvenience of laboratory. The use of interdisciplinary mixed-method approaches should be encouraged in future studies on sleep and elite sport. Finally, high inter- and intra-individual variability in the athletes’ sleep characteristics suggests a need for providing individual responses in addition to group means.

The Suzuki coupling Knoevenagel condensation one-pot synthesis of boronic acids/esters, (hetero)aromatic bromo aldehydes and methylene active compounds is a highly practical consecutive three-component process to provide substance libraries with 60 donor-π-bridge-acceptor molecules, i.e., merocyanines in a broader sense, in moderate to excellent yield. As already seen with the naked eye, a broad variation of the optical properties becomes accessible using this practical synthetic tool. More systematically, correlation analyses upon plotting the optical band gaps against the first oxidation potentials of redox active systems of consanguineous series furnishes linear correlations and, by extension, two parameter plots (oxidation potential and emission maximum) planar correlations with the optical band gaps.

Despite the general consensus regarding the implementation of self-report measures in the training monitoring, there is a lack of research about their applicability and comprehensibility among developing athletes. However, this target group needs special considerations to manage the increasing training demands while maintaining health and performance. This study deals with challenges of applying recovery-stress questionnaires which were validated with adult populations among developing athletes and presents a possible approach to enhance their applicability. In two phases, the Acute Recovery and Stress Scale (ARSS), a 32-adjective list covering eight scales, and the 8-item derived version, the Short Recovery and Stress Scale (SRSS) were answered by 1052 athletes between 10 and 16 years. Phase 1 included 302 14- to 16-year-old athletes who used the original questionnaires with the additional option to mark “I don’t understand,” while modified versions with additional explanations (phase 2) were applied to 438 adolescents (14.7 ± 0.6 years) and 312 child athletes (11.8 ± 1.1 years). Data of the original validation sample (n = 442) were reanalyzed to examine measurement invariance between adults and adolescents. The results showed comparable psychometric properties to the validation sample (e.g., rit > 0.30) and acceptable fit indices via confirmatory factor analyses (CFA), although more difficulties and limitations were present within the younger groups (e.g., Cronbach’s α between 0.50 and 0.87), especially among 10- and 11-year-olds. The original as well as the modified SRSS, on the other hand, indicated good applicability (Cronbach’s α between 0.72 and 0.80). Multigroup CFA revealed measurement invariance of the original ARSS among adults and adolescents and of the modified ARSS among adolescents and children. Overall, the present study confirmed the assumption that questionnaires designed by and for adults cannot be directly transferred to younger athletes. The peculiarities and differences in the cognitive and affective development of each age group need to be considered. Future research needs to identify a cut-off age to start the proper use of psychometric tools, especially for state-oriented assessments for routine application in training monitoring. Further modifications and long-term investigations are necessary to implement psychometric monitoring in high-performance environments within youth sport.

Purpose: Individualized reference ranges for serum creatine kinase (CK) and urea are a promising tool for the assessment of recovery status in high-level endurance athletes. In this study, we investigated the application of this approach in racket sports, specifically for the monitoring of elite badminton players during the preparation for their world championships.Methods: Seventeen elite badminton players were enrolled of which 15 could be included in the final analysis. Repeated measurements of CK and urea at recovered (R) and non-recovered (NR) time points were used for the stepwise individualization of group-based, prior reference ranges as well as for the evaluation of classificatory performance. Specifically, blood samples were collected in the morning following a day off (R) or following four consecutive training days (NR), respectively. Group based reference ranges were derived from the same data. Error rates were compared between the group-based and individualized approaches using the Fisher exact test.Results: Error rates were numerically lower for the individualized as compared to the group-based approach in all cases. Improvements reached statistical significance for urea (test-pass error rate: p = 0.007; test-fail error rate: p = 0.002) but not for CK (p vs. group-based: test-pass error rate: p = 0.275, test-fail error rate: p = 0.291). Regardless of the chosen approach, the use of CK was associated with lower error rates as compared to urea.Conclusion and Practical Applications: Individualized reference ranges seem to offer diagnostic benefits in the monitoring of muscle recovery in elite badminton. The lack of significant improvements in error rates for CK is likely due to the large difference between R and NR for this parameter with error rates that are already low for the group-based approach.

Objective: In two independent study arms, we determine the effects of strength training (ST) and high-intensity interval training (HIIT) overload on cardiac autonomic modulation by measuring heart rate (HR) and vagal heart rate variability (HRV).Methods: In the study, 37 well-trained athletes (ST: 7 female, 12 male; HIIT: 9 female, 9 male) were subjected to orthostatic tests (HR and HRV recordings) each day during a 4-day baseline period, a 6-day overload microcycle, and a 4-day recovery period. Discipline-specific performance was assessed before and 1 and 4 days after training.Results: Following ST overload, supine HR, and vagal HRV (Ln RMSSD) were clearly increased and decreased (small effects), respectively, and the standing recordings remained unchanged. In contrast, HIIT overload resulted in decreased HR and increased Ln RMSSD in the standing position (small effects), whereas supine recordings remained unaltered. During the recovery period, these responses were reversed (ST: small effects, HIIT: trivial to small effects). The correlations between changes in HR, vagal HRV measures, and performance were weak or inconsistent. At the group and individual levels, moderate to strong negative correlations were found between HR and Ln RMSSD when analyzing changes between testing days (ST: supine and standing position, HIIT: standing position) and individual time series, respectively. Use of rolling 2–4-day averages enabled more precise estimation of mean changes with smaller confidence intervals compared to single-day values of HR or Ln RMSSD. However, the use of averaged values displayed unclear effects for evaluating associations between HR, vagal HRV measures, and performance changes, and have the potential to be detrimental for classification of individual short-term responses.Conclusion: Measures of HR and Ln RMSSD during an orthostatic test could reveal different autonomic responses following ST or HIIT which may not be discovered by supine or standing measures alone. However, these autonomic changes were not consistently related to short-term changes in performance and the use of rolling averages may alter these relationships differently on group and individual level.

Foam rolling is thought to improve muscular performance and flexibility as well as to alleviate muscle fatigue and soreness. For this reason, foam rolling has become a popular intervention in all kinds of sport settings used to increase the efficiency of training or competition preparation as well as to speed post-exercise recovery. The objective of this meta-analysis was to compare the effects of foam rolling applied before (pre-rolling as a warm-up activity) and after (post-rolling as a recovery strategy) exercise on sprint, jump, and strength performance as well as on flexibility and muscle pain outcomes and to identify whether self-massage with a foam roller or a roller massager is more effective. A comprehensive and structured literature search was performed using the PubMed, Google Scholar, PEDro, and Cochrane Library search engines. Twenty-one studies were located that met the inclusion criteria. Fourteen studies used pre-rolling, while seven studies used post-rolling. Pre-rolling resulted in a small improvement in sprint performance (+0.7%, g = 0.28) and flexibility (+4.0%, g = 0.34), whereas the effect on jump (−1.9%, g = 0.09) and strength performance (+1.8%, g = 0.12) was negligible. Post-rolling slightly attenuated exercise-induced decreases in sprint (+3.1%, g = 0.34) and strength performance (+3.9 %, g = 0.21). It also reduced muscle pain perception (+6.0%, g = 0.47), whereas its effect on jump performance (−0.2%, g = 0.06) was trivial. Of the twenty-one studies, fourteen used foam rollers, while the other seven used roller massage bars/sticks. A tendency was found for foam rollers to offer larger effects on the recovery of strength performance (+5.6%, g = 0.27 vs. −0.1%, g = −0.01) than roller massagers. The differences in the effects between foam rolling devices in terms of pre-rolling did not seem to be of practical relevance (overall performance: +2.7 %, g = 0.11 vs. +0.4%, g = 0.21; flexibility: +5.0%, g = 0.32 vs. +1.6%, g = 0.39). Overall, it was determined that the effects of foam rolling on performance and recovery are rather minor and partly negligible, but can be relevant in some cases (e.g., to increase sprint performance and flexibility or to reduce muscle pain sensation). Evidence seems to justify the widespread use of foam rolling as a warm-up activity rather than a recovery tool.

Second-generation mammalian target of rapamycin (mTOR) inhibitors such as CC-223 may have theoretical advantages over first-generation drugs by inhibiting TOR kinase in mTOR complex 1 (mTORC1) and 2 (mTORC2), potentially improving clinical efficacy for well-differentiated neuroendocrine tumors (NET).Enrolled patients had metastatic, well-differentiated NET of non-pancreatic gastrointestinal or unknown origin, with/without carcinoid symptoms, had failed ≥1 systemic chemotherapy, and were taking a somatostatin analog (SSA). Oral once-daily CC-223 was administered in 28-day cycles starting at 45 mg (n = 24), with a subsequent cohort starting at 30 mg (n = 23). Objectives were to evaluate tolerability, preliminary efficacy, and pharmacokinetic and biomarker profiles of CC-223. Forty-seven patients completed the study, with mean treatment duration of 378 days and mean dose of 26 mg; 26% of patients remained on the starting dose. Most frequent grade ≥3 toxicities were diarrhea (38%), fatigue (21%), and stomatitis (11%). By investigator, 3 of 41 evaluable patients (7%) showed partial response (PR) and 34 (83%) had stable disease (SD) for a disease control rate (DCR) of 90% (95% confidence interval [CI] 76.9-97.3%). Duration of PR was 125-401 days; median SD duration was 297 days (min-max, 50-1519 days). Median progression-free survival was 19.5 months (95% CI 10.4-28.5 months). Carcinoid symptoms of flushing, diarrhea, or both improved in 50%, 41%, and 39% of affected patients, respectively. For the first time, this study describes that a second-generation mTOR pathway inhibitor can result in highly durable tumor regression and control of NET carcinoid symptoms. The manageable safety profile, high DCR, and durable response, coupled with reduction in carcinoid symptoms refractory to SSA, make CC-223 a promising agent for further development.

Randomized controlled trials (RCTs) can be regarded as gold standard in investigating dose-response and causal relationships in exercise science. Recommendations for exercise training routines and efficacy analyses of certain training regimen require valid data derived from robust RCTs. Moreover, meta-analyses rely on RCTs and both RCTs and meta-analyses are considered the highest level of scientific evidence. Beyond general study design a variety of methodological aspects and notable pitfalls has to be considered. Therefore, exercise training studies should be carefully constructed focusing on the consistency of the whole design “package” from an explicit hypothesis or research question over study design and methodology to data analysis and interpretation. The present scoping review covers all main aspects of planning, conducting, and analyzing exercise based RCTs. We aim to focus on relevant aspects regarding study design, statistical power, training planning and documentation as well as traditional and recent statistical approaches. We intend to provide a comprehensive hands-on paper for conceptualizing future exercise training studies and hope to stimulate and encourage researchers to conduct sound and valid RCTs in the field of exercise training.

Background: The relation between training load, especially internal load, and the recovery-stress state is of central importance for avoiding negative adaptations in high-performance sports like swimming. The aim of this study was to analyze the individual time-delayed linear effect relationship between training load and recovery-stress state with single case time series methods and to monitor the acute recovery-stress state of high-performance swimmers in an economical and multidimensional manner over a macro cycle. The Acute Recovery and Stress Scale (ARSS) was used for daily monitoring of the recovery-stress state. The methods session-RPE (sRPE) and acute:chronic workload-ratio (ACWR) were used to compare different methods for quantifying the internal training load with regard to their interrelationship with the recovery-stress state.Methods: Internal load and recovery-stress state of five highly trained female swimmers [with a training frequency of 13.6 ± 0.8 sessions per week and specializing in sprint (50 and 100 m), middle-distance (200 and 400 m), or long distance (800 and 1,500 m) events] were daily documented over 17 weeks. Two different types of sRPE were applied: RPE∗duration (sRPEh) and RPE∗volume (sRPEkm). Subsequently, we calculated the ratios ACWRh and ACWRkm (sRPE last week: 4-week exponentially weighted moving average). The recovery-stress state was measured by using the ARSS, consisting of eight scales, four of which are related to recovery [Physical Performance Capability (PPC), Mental Performance Capability (MPC), Emotional Balance (EB), Overall Recovery (OR)], and four to stress [Muscular Stress (MS), Lack of Activation (LA), Negative Emotional State (NES), Overall Stress (OS)]. To examine the relation between training load and recovery-stress state a cross correlation (CCC) was conducted with sRPEh, sRPEkm, ACWRh, and ACWRkm as lead and the eight ARSS-scales as lag variables.Results: A large variation of training load can be observed in the individual week-to-week fluctuations whereby the single fluctuations can significantly differ from the overall mean of the group. The range also shows that the CCC individually reaches values above 0.3, especially with sRPEkm as lead variable. Overall, there is a large range with significant differences between the recovery and stress dimensions of the ARSS and between the training load methods, with sRPEkm having the largest span (Range = 1.16). High inter-individual differences between the athletes lie in strength and direction of the correlation | 0.66|≤ CCC ≥|-0.50|. The time delayed effects (lags 0–7) are highly individual, however, clear patterns can be observed.Conclusion: The ARSS, especially the physical and overall-related scales (PPC, OR, MS, OS), is a suitable tool for monitoring the acute recovery-stress state in swimmers. MPC, EB, LA, and NES are less affected by training induced changes. Comparably high CCC and Ranges result from the four internal load methods, whereby sRPE, especially sRPEkm, shows a stronger relation to recovery-stress state than ACWR. Based on these results and the individual differences in terms of time delay in training response, we recommend for swimming to use sRPE to monitor the internal training load and to use the ARSS, with a focus at the physical and overall-scales, to monitor the recovery-stress state.

A comprehensive monitoring of fitness, fatigue, and performance is crucial for understanding an athlete's individual responses to training to optimize the scheduling of training and recovery strategies. Resting and exercise-related heart rate measures have received growing interest in recent decades and are considered potentially useful within multivariate response monitoring, as they provide non-invasive and time-efficient insights into the status of the autonomic nervous system (ANS) and aerobic fitness. In team sports, the practical implementation of athlete monitoring systems poses a particular challenge due to the complex and multidimensional structure of game demands and player and team performance, as well as logistic reasons, such as the typically large number of players and busy training and competition schedules. In this regard, exercise-related heart rate measures are likely the most applicable markers, as they can be routinely assessed during warm-ups using short (3–5 min) submaximal exercise protocols for an entire squad with common chest strap-based team monitoring devices. However, a comprehensive and meaningful monitoring of the training process requires the accurate separation of various types of responses, such as strain, recovery, and adaptation, which may all affect heart rate measures. Therefore, additional information on the training context (such as the training phase, training load, and intensity distribution) combined with multivariate analysis, which includes markers of (perceived) wellness and fatigue, should be considered when interpreting changes in heart rate indices. The aim of this article is to outline current limitations of heart rate monitoring, discuss methodological considerations of univariate and multivariate approaches, illustrate the influence of different analytical concepts on assessing meaningful changes in heart rate responses, and provide case examples for contextualizing heart rate measures using simple heuristics. To overcome current knowledge deficits and methodological inconsistencies, future investigations should systematically evaluate the validity and usefulness of the various approaches available to guide and improve the implementation of decision-support systems in (team) sports practice.

Objective: High-intensity interval training (HIIT) can be extremely demanding and can consequently produce high blood lactate levels. Previous studies have shown that lactate is a potent metabolic stimulus, which is important for adaptation. Active recovery (ACT) after intensive exercise, however, enhances blood lactate removal in comparison with passive recovery (PAS) and, consequently, may attenuate endurance performance improvements. Therefore, the aim of this study was to examine the influence of regular ACT on training adaptations during a HIIT mesocycle.Methods: Twenty-six well-trained male intermittent sport athletes (age: 23.5 ± 2.5 years; O2max: 55.36 ± 3.69 ml min kg-1) participated in a randomized controlled trial consisting of 4 weeks of a running-based HIIT mesocycle with a total of 12 HIIT sessions. After each training session, participants completed 15 min of either moderate jogging (ACT) or PAS. Subjects were matched to the ACT or PAS groups according to age and performance. Before the HIIT program and 1 week after the last training session, the athletes performed a progressive incremental exercise test on a motor-driven treadmill to determine O2max, maximum running velocity (vmax), the running velocity at which O2max occurs (vO2max), and anaerobic lactate threshold (AT). Furthermore, repeated sprint ability (RSA) were determined.Results: In the whole group the HIIT mesocycle induced significant or small to moderate changes in vmax (p < 0.001, effect size [ES] = 0.65,), vO2max (p < 0.001, ES = 0.62), and AT (p < 0.001, ES = 0.56) compared with the values before the intervention. O2max and RSA remained unchanged throughout the study. In addition, no significant differences in the changes were noted in any of the parameters between ACT and PAS except for AT (p < 0.05, ES = 0.57).Conclusion: Regular use of individualized ACT did not attenuate training adaptations during a HIIT mesocycle compared to PAS. Interestingly, we found that the ACT group obtained a significantly higher AT following the training program compared to the PAS group. This could be because ACT allows a continuation of the training at a low intensity and may activate specific adaptive mechanisms that are not triggered during PAS.