British Society of Gastroenterology guidelines for the management of hepatocellular carcinoma in adults.

Deaths from the majority of cancers are falling globally, but the incidence and mortality from hepatocellular carcinoma (HCC) is increasing in the United Kingdom and in other Western countries. HCC is a highly fatal cancer, often diagnosed late, with an incidence to mortality ratio that approaches 1. Despite there being a number of treatment options, including those associated with good medium to long-term survival, 5-year survival from HCC in the UK remains below 20%. Sex, ethnicity and deprivation are important demographics for the incidence of, and/or survival from, HCC. These clinical practice guidelines will provide evidence-based advice for the assessment and management of patients with HCC. The clinical and scientific data underpinning the recommendations we make are summarised in detail. Much of the content will have broad relevance, but the treatment algorithms are based on therapies that are available in the UK and have regulatory approval for use in the National Health Service.

Nivolumab with or without ipilimumab in patients with recurrent or metastatic cervical cancer (CheckMate 358): a phase 1-2, open-label, multicohort trial.

BACKGROUND: In preliminary findings from the recurrent or metastatic cervical cancer cohort of CheckMate 358, nivolumab showed durable anti-tumour responses, and the combination of nivolumab plus ipilimumab showed promising clinical activity. Here, we report long-term outcomes from this cohort. METHODS: CheckMate 358 was a phase 1-2, open-label, multicohort trial. The metastatic cervical cancer cohort enrolled patients from 30 hospitals and cancer centres across ten countries. Female patients aged 18 years or older with a histologically confirmed diagnosis of squamous cell carcinoma of the cervix with recurrent or metastatic disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, and up to two previous systemic therapies were enrolled into the nivolumab 240 mg every 2 weeks group, the randomised groups (nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks [NIVO3 plus IPI1] or nivolumab 1 mg/kg every 3 weeks plus ipilimumab 3 mg/kg every 3 weeks for four cycles then nivolumab 240 mg every 2 weeks [NIVO1 plus IPI3]), or the NIVO1 plus IPI3 expansion group. All doses were given intravenously. Patients were randomly assigned (1:1) to NIVO3 plus IPI1 or NIVO1 plus IPI3 via an interactive voice response system. Treatment continued until disease progression, unacceptable toxicity, or consent withdrawal, or for up to 24 months. The primary endpoint was investigator-assessed objective response rate. Anti-tumour activity and safety were analysed in all treated patients. This study is registered with ClinicalTrials.gov (NCT02488759) and is now completed. FINDINGS: Between October, 2015, and March, 2020, 193 patients were recruited in the recurrent or metastatic cervical cancer cohort of CheckMate 358, of whom 176 were treated. 19 patients received nivolumab monotherapy, 45 received NIVO3 plus IPI1, and 112 received NIVO1 plus IPI3 (45 in the randomised group and 67 in the expansion group). Median follow-up times were 19·9 months (IQR 8·2-44·8) with nivolumab, 12·6 months (7·8-37·1) with NIVO3 plus IPI1, and 16·7 months (7·2-27·5) with pooled NIVO1 plus IPI3. Objective response rates were 26% (95% CI 9-51; five of 19 patients) with nivolumab, 31% (18-47; 14 of 45 patients) with NIVO3 plus IPI1, 40% (26-56; 18 of 45 patients) with randomised NIVO1 plus IPI3, and 38% (29-48; 43 of 112 patients) with pooled NIVO1 plus IPI3. The most common grade 3-4 treatment-related adverse events were diarrhoea, hepatic cytolysis, hyponatraemia, pneumonitis, and syncope (one [5%] patient each; nivolumab group), diarrhoea, increased gamma-glutamyl transferase, increased lipase, and vomiting (two [4%] patients each; NIVO3 plus IPI1 group), and increased lipase (nine [8%] patients) and anaemia (seven [6%] patients; pooled NIVO1 plus IPI3 group). Serious treatment-related adverse events were reported in three (16%) patients in the nivolumab group, 12 (27%) patients in the NIVO3 plus IPI1 group, and 47 (42%) patients in the pooled NIVO1 plus IPI3 group. There was one treatment-related death due to immune-mediated colitis in the NIVO1 plus IPI3 group. INTERPRETATION: Nivolumab monotherapy and nivolumab plus ipilimumab combination therapy showed promise in the CheckMate 358 study as potential treatment options for recurrent or metastatic cervical cancer. Future randomised controlled trials of nivolumab plus ipilimumab or other dual immunotherapy regimens are warranted to confirm treatment benefit in this patient population. FUNDING: Bristol Myers Squibb and Ono Pharmaceutical.

Adjuvant and neoadjuvant therapies for hepatocellular carcinoma.

Immune-oncology-based regimens have shown efficacy in advanced HCC and have been implemented as standard of care as first-line therapy. Their efficacy, including high response rates, and safety justify their evaluation in earlier disease stages. Following negative results for adjuvant sorafenib in the global STORM trial in 2015, 4 global phase 3 trials, featuring different immune checkpoint inhibitor combinations, entered in parallel the race in the adjuvant setting. The IMbrave050 trial, comparing adjuvant atezolizumab in combination with bevacizumab to active surveillance following curative-intent resection or ablation, was the first to report, fast-tracking the results of the first interim analysis and demonstrating an improvement in recurrence-free survival. The trial has provoked a discussion on the horizon of expectations from adjuvant treatment and the clinical relevance of efficacy endpoints. Moreover, major pathological responses reported from early phase 2 data in the neoadjuvant setting provide a strong rationale for the evaluation of these concepts in phase 3 trials. In this review, we summarize current evidence and outline future directions for systemic therapies in early-stage HCC.

Immune Response to COVID-19 Vaccination in Elite Athletes.

Purpose: This study analyses the immune response of elite athletes after COVID-19 vaccination with double-dose mRNA and a single-dose vector vaccine. Methods: Immunoglobulin G (IgG) antibody titers, neutralizing activity, CD4 and CD8 T-cells were examined in blood samples from 72 athletes before and after vaccination against COVID-19 (56 mRNA (BNT162b2 / mRNA-1273), 16 vector (Ad26.COV.2) vaccines). Side effects and training time loss was also recorded. Results: Induction of IgG antibodies (mRNA : 5702 BAU/ml ; 4343 BAU/ml (hereafter: median), vector: 61 BAU/ml ; 52 BAU/ml, p<0.01), their neutralizing activity (99.7% ; 10.6%, p<0.01), and SARS-CoV-2 spike-specific CD4 T-cells (0.13% ; 0.05% ; p<0.01) after mRNA double-dose vaccines was significantly more pronounced than after a single-dose vector vaccine. SARS-CoV-2 spike-specific CD8 T-cell levels after a vector vaccine (0.15%) were significantly higher than after mRNA vaccines (0.02%; p<0.01). When athletes who had initially received the vector vaccine were boostered with an mRNA vaccine, IgG antibodies (to 3456 BAU/ml; p<0.01), neutralizing activity (to 100%; p<0.01), CD4 (to 0.13%; p<0.01) and CD8 T-cells (to 0.43%; p<0.01) significantly increased. When compared with dual-dose mRNA regimen, IgG antibody response was lower (p<0.01), the neutralizing activity (p<0.01) and CD8 T-cell (p<0.01) response higher and no significant difference in CD4 T-cell response (p=0.54) between the two regimens. Cumulative training loss (3 days) did not significantly differ between vaccination regimens (p=0.46). Conclusion: mRNA and vector vaccines against SARSCoV-2 appear to induce different patterns of immune response in athletes. Lower immune induction after a single-shot vector vaccine was clearly optimized by a heterologous booster. Vaccine reactions were mild and short-lived.

Side differences and reproducibility of the Moxy muscle oximeter during cycling in trained men.

PURPOSE: Portable near-infrared spectroscopy devices allow measurements of muscle oxygen saturation (SmO2) in real time and non-invasively. To use NIRS for typical applications including intensity control and load monitoring, the day-to-day variability needs to be known to interpret changes confidently. This study investigates the absolute and relative test-retest reliability of the Moxy Monitor and investigates side differences of SmO2 at the vastus lateralis muscle of both legs in cyclists. METHODS: Twelve trained cyclists and triathletes completed 3 incremental step tests with 5 min step duration starting at 1.0 W/kg with an increase of 0.5 W/kg separated by 2-7 days. SmO2 was averaged over the last minute of each stage. For all power outputs, the intra-class coefficient (ICC), the standard error of measurement (SEM) and the minimal detectable change (MDC) were calculated. Dominant and non-dominant leg SmO2 were compared using a three-factor ANOVA and limits of agreement (LoA). RESULTS: ANOVA showed no significant systematic differences between trials and side. For both legs and all intensities, the ICC ranged from 0.79 to 0.92, the SEM from 5 to 9% SmO2 and the MDC from 14 to 18% SmO2. The bias and LoA between both legs were -2.0% ± 19.9% SmO2. CONCLUSION: Relative reliability of SmO2 was numerically good to excellent according to current standards. However, it depends on the specific analytical goal whether the test-retest reliability is deemed sufficient. Wide LoA indicate side differences in muscle oxygenation during exercise unexplained by leg dominance.

Efficacy of a new injury prevention programme (FUNBALL) in young male football (soccer) players: a cluster-randomised controlled trial.

OBJECTIVES: To evaluate the efficacy of a new multicomponent, exercise-based injury prevention programme in football players 13-19 years old. METHODS: Two-arm cluster-randomised controlled trial with clubs as the unit of randomisation. 55 football teams from Kosovo of the under 15, under 17 and under 19 age groups were randomly assigned to the intervention (INT; 28 teams) or the control group (CON; 27 teams) and were followed for one football season (August 2021-May 2022). The INT group performed the 'FUNBALL' programme after their usual warm-up at least twice per week, while the CON group followed their usual training routine. The primary outcome measure was the overall number of football-related injuries. Secondary outcomes were region-specific injuries of the lower limbs (hip/groin, thigh, knee, lower leg, ankle and foot) and injury severity. RESULTS: 319 injuries occurred, 132 in the INT and 187 in the CON group. The INT group used the 'FUNBALL' programme in 72.2% of all training sessions, on average 2.2 times per week. There was a significantly lower incidence in the INT group regarding the overall number of injuries (incidence rate ratio (IRR) 0.69, 95% CI 0.55 to 0.87), the number of thigh injuries (IRR 0.62, 95% CI 0.39 to 0.98), of moderate (time loss between 7 and 28 days) (IRR 0.65, 95% CI 0.44 to 0.97) and of severe injuries (time loss >28 days) (IRR 0.51, 95% CI 0.28 to 0.91). CONCLUSION: The 'FUNBALL' programme reduced the incidence of football-related injuries among male adolescent football players, and its regular use for injury prevention in this population is recommended. TRIAL REGISTRATION NUMBER: NCT05137015.

Efficacy of the FIFA cooling break heat policy during an intermittent treadmill football simulation in hot conditions in trained males.

OBJECTIVE: To evaluate the efficacy of the Fédération Internationale de Football Association (FIFA) cooling break policy against alternative cooling configurations in attenuating thermal strain during simulated football in the heat. METHODS: 12 males (age: 27±6 years, V̇O2peak: 61±7 mL/kg/min) completed five 90 min intermittent treadmill football match simulations in 40°C and 41% relative humidity (32°C wet-bulb globe temperature) with different cooling configurations: regular match without cooling breaks (REG), 3 min breaks without cooling (BRKno-cool), 3 min breaks with cooling (BRKcool: current FIFA policy; chilled fluid ingestion and ice towel across neck and shoulders), 5 min extended half-time without cooling breaks (ExtHTonly) and 3 min cooling breaks with 5 min ExtHT (ExtHTcool). Rectal temperature (Tre), heart rate, whole-body sweat rate (WBSR) and rating of perceived exertion (RPE) were recorded. Data are presented as mean (95% CIs). RESULTS: Final Tre was lower in BRKno-cool (0.20°C (0.01, 0.39), p=0.038), BRKcool (0.39°C (0.21, 0.57), p<0.001) and ExtHTcool (0.40°C (0.22, 0.58), p<0.001) than REG (39.1°C (38.8, 39.3)). Mean Tre was lower in ExtHTcool (38.2°C (38.0, 38.4)) than BRKcool (38.3°C (38.1, 38.5), p=0.018), BRKno-cool and ExtHTonly (38.4°C (38.2, 38.6), p<0.001) and REG (38.5°C (38.3, 38.7), p<0.001). Mean heart rate was lower during BRKcool (6 beats/min (4, 7), p<0.001) and ExtHTcool (7 beats/min (6, 8), p<0.001) compared with REG. WBSR was comparable across trials (p≥0.07) and RPE was attenuated during BRKcool (0.4 (0.1, 0.7), p=0.004) and ExtHTcool (0.5 (0.2, 0.7), p=0.002), compared with REG. CONCLUSION: BRKcool and ExtHTcool attenuated thermal, cardiovascular and perceptual strain during a simulated football match in the heat. Additional strategies may be required in field settings or under harsher conditions.

Physical Demands of Walking Football in Patients With Cardiovascular Risk Factors and Diseases.

OBJECTIVE: To compare the exercise intensity of walking football (WF) with walking (WA) and to describe specific movement characteristics of WF. DESIGN: Cross-sectional study. SETTING: Sports facilities Saarland University, Germany. PATIENTS: Eighteen patients with cardiovascular risk factors CVRFs and diseases (13 men and 5 women, age: 69 ± 10 years). INDEPENDENT VARIABLES: Patients completed a WF match and WA session of 2 x 10 min each. Video analysis was used to characterize movements during WF. MAIN OUTCOME MEASURES: Rate of perceived exertion (RPE, Borg Scale 6-20), % maximum heart rate (HRmax), musculoskeletal pain on a visual analog scale (VAS, 1-100 mm) before and up to 72 hours after exercise, and movement patterns during WF. RESULTS: The mean RPE during WF (12.1 ± 2.7) and WA (11.9 ± 3.0) did not differ (P = 0.63). The mean HR during WF (79 ± 12% of HRmax) was higher than during WA (71% ± 11%; P < 0.01). The HR variability coefficient of variation during WF (10.3% ± 5.8%) and WA (7.1 ± 5.5%) did not differ (P = 0.13). There was no influence of exercise mode (WF vs WA) on musculoskeletal pain perception (P = 0.96 for interaction). Injury-inciting activities such as lunges (median: 0.5 [interquartile range (IQR) 0-1.3]) and goal kicks (median: 4 [IQR: 1.8-5.3]) occurred rarely during WF. CONCLUSIONS: Walking football might represent an alternative to WA for health prevention programs in patients with CVRF and diseases as it is characterized by a manageable cardiocirculatory strain, moderate RPE, low pain induction, and a low number of injury-inciting activities.

Quantitative transcriptomic and epigenomic data analysis: a primer.

The advent of microarray and second generation sequencing technology has revolutionized the field of molecular biology, allowing researchers to quantitatively assess transcriptomic and epigenomic features in a comprehensive and cost-efficient manner. Moreover, technical advancements have pushed the resolution of these sequencing techniques to the single cell level. As a result, the bottleneck of molecular biology research has shifted from the bench to the subsequent omics data analysis. Even though most methodologies share the same general strategy, state-of-the-art literature typically focuses on data type specific approaches and already assumes expert knowledge. Here, however, we aim at providing conceptual insight in the principles of genome-wide quantitative transcriptomic and epigenomic (including open chromatin assay) data analysis by describing a generic workflow. By starting from a general framework and its assumptions, the need for alternative or additional data-analytical solutions when working with specific data types becomes clear, and are hence introduced. Thus, we aim to enable readers with basic omics expertise to deepen their conceptual and statistical understanding of general strategies and pitfalls in omics data analysis and to facilitate subsequent progression to more specialized literature.

Epidemiology of football-related injuries in young male football players. An additional analysis of data from a cluster-randomised controlled trial.

Football carries a high risk of injury for youth players. The aim of this study was to investigate the epidemiology of football-related injuries in young male players. The data stems from a previously conducted cluster-randomised controlled trial that investigated the efficacy of 'FUNBALL', a new injury prevention programme. This study contains the data of the 503 players of the control arm. The players belonged to 22 football teams of the Under-(U)15, U17 and U19 age groups. The time-loss injuries were recorded during the season 2021-2022 according to the Football Consensus Statement. An analysis on the injury incidence (IR, calculated per 1000 hours of exposure), location, severity, category, and type was performed. Incidence rate ratios (IRRs) were used to compare the variables between the specific age groups. 187 injuries (96 in training and 91 in matches) occurred during 52 938 hours of exposure. The overall IR was 3.53 injuries/1000 h (95% confidence intervals (CI) 3.06 to 4.07). The training IR was 2.16 injuries/1000 h (95% CI 1.17 to 2.64). The match IR was 10.50 injuries/1000 h (95% CI 8.55 to 12.89). In the U19s, the overall IRR was higher compared to the U17s (IRR 1.57, CI 1.12 to 2.19; p = 0.008) and compared to the U15s (IRR 1.82, 95% CI 1.25 to 2.62; p = 0.001). The thigh was the most commonly affected body region (IR 0.92/1000 h, 95% CI 0.69 to 1.22). Muscle injuries were the most common injury type (IR 1.05/1000 h, 95% CI 0.81 to 1.37). Injury burden was 74 lost days/1000 h. The findings of this study indicate a lower injury incidence in youth players than in adult ones. We observed a higher injury incidence towards the older age groups.

The effect of forced even pacing and an opponent on end-spurt behaviour in freestyle pool swimming.

To investigate the effect of forced even pacing through virtual pacing assistance and an opponent in a competitive setting on end-spurt behaviour in freestyle swimmers, including related physiological underpinnings. Twenty-seven competitive swimmers and triathletes were recruited. There were four 1500 m freestyle trials: (i) familiarisation time trial, (ii) self-paced time trial (STT), (iii) head-to-head competition time trial (CTT) and (iv) forced even pacing through virtual pacing assistance time trial (FET). Eventually, 12 swimmers met the criteria for the CTT and FET to be included in the analysis. Changes in end-spurt behaviour, finishing time and physiological parameters (lactate, cortisol, noradrenaline and heart rate) were analysed using a linear mixed model with fixed effects for trials and a random effect for swimmer identity. A separate linear model was computed for competition outcome. The end-spurt for each race was determined by means of an end-spurt indicator (ESI; ESI > 0 greater end-spurt). Swimmers demonstrated a significantly greater ESI in FET (+2.6; p < 0.001) and CTT (+1.4; p = 0.022) compared to STT. Blood lactate concentration in FET (+1.0 mmol L-1; p < 0.001) and CTT (+1.6 mmol L-1; p < 0.001) was significantly higher than in STT. Winners had a significantly greater ESI than losers in CTT (+1.6 and p = 0.005). Swimmers utilised a greater end-spurt through metabolically optimal forced even pacing by virtual pacing assistance and in a head-to-head competition due a larger mobilisation of anaerobic reserves as indicated by greater blood lactate concentrations. Winners had a significantly greater end-spurt than losers despite similar metabolic disturbances.

Quality Criteria for Studies Assessing the Acute Effects of Heading: Results from a UEFA Expert Panel.

There is increasing concern regarding the effects of heading in football on brain health including cognitive, behavioural and neuromotor function, with research suggesting an association between repeated ball-head impacts and neurodegenerative disease. While longitudinal studies to determine the long-term consequences of heading are challenging, there have been short-term 'acute' studies conducted, with some studies lacking appropriate methodology to ensure valid results. The Union of European Football Associations (UEFA) established a panel of experts to determine methodological recommendations for the conduct of studies that explore the acute effects of heading (defined as a single session of heading conducted either in a laboratory setting or following match play or a training session). The aim of this panel was to create quality criteria for acute heading studies that will form part of the eligibility assessment when applying for UEFA research funding (although the criteria can be applied to the conduct of acute heading research more widely). This process was deemed necessary to counter studies with poor methodological quality that used heading trials that did not accurately represent player exposure to ball-head impacts through football practice and match play (such as small sample sizes, unrealistically high heading exposure, and a lack of consideration of confounding variables). The panel identified core design decisions that authors should consider when designing and conducting acute heading research, with key methodological requirements for each domain pertaining to participants, heading trials, confounding variables, statistics and dependent/target variables and their measurement. After two rounds of reviews, the final list of quality criteria was agreed by the panel and will be applied to the next round of UEFA grant applications.

Cardiovascular risk of veterans' football: An observational cohort study with follow-up.

BACKGROUND: The 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. METHODS: cTnI 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. RESULTS: In 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). CONCLUSION: Veterans' 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.

What is the most appropriate age for the first cardiac screening of athletes?

For sporting organisations that conduct screening of athletes, there are very few consistent guidelines on the age at which to start. Our review found the total rate of sudden cardiac arrest or death is very low between the ages of 8-11 years (less than 1/100,000/year), increasing to 1-2/100,000/year in both elite athletes and community athletes aged 12-15 years and then steadily increases with age. The conditions associated with sudden cardiac death in paediatric athletes and young adult athletes are very similar with some evidence that death from coronary artery abnormalities occurs more frequently in athletes 10-14 years old. The decision when to begin a screening program involves a complex interplay between requirements and usual practices in a country, the rules of different leagues and programs, the age of entry into an elite program, the underlying risk of the population and the resources available. Given the incidence of sudden cardiac arrest or death in young people, we recommend beginning cardiac screening no earlier than 12 years (not later than 16 years). The risk increases with age, therefore, starting a program at any point after age 12 has added value. Importantly, anyone with concerning symptoms (e.g. collapse on exercise) or family history of an inherited cardiac condition should see a physician irrespective of age. Finally, no screening program can capture all abnormalities, and it is essential for organisations to implement a cardiac emergency plan including training on recognition and response to sudden cardiac arrest and prompt access to resuscitation, including defibrillators.

Heading in football: a systematic review of descriptors, definitions, and reporting methods used in heading incidence studies.

The primary objective of this systematic review was to describe the number and type of heading descriptors used in all published studies which report on heading incidence in football. The secondary objective was to detail the data collection and reporting methods used in the included studies to present heading incidence data. Eligible studies were identified through searches of five electronic databases: Ovid MEDLINE, CINAHL, EMBASE, SPORTDiscus, and Web of Science, using a combination of free-text keywords (inception to 12th September 2023). Manual searching of reference lists and retrieved systematic reviews was also performed. A descriptive overview and synthesis of the results is presented. From 1620 potentially eligible studies, 71 studies were included, with the following key findings: 1) only 61% of studies defined a header with even fewer (23%) providing an operational definition of a header within the methods; 2) important study and player demographic data including year and country were often not reported; 3) reported heading descriptors and their coding options varied greatly; 4) visual identification of headers was essential when inertial measurement units were used to collect heading incidence data; and 5) there was a lack of standardisation in the reporting methods used in heading incidence studies making comparison between studies challenging. To address these findings, the development of a standardised, internationally supported, operational definition of a header and related heading descriptors should be prioritised. Further recommendations include the development of minimum reporting criteria for heading incidence research.

The phenylalanine ammonia-lyase inhibitor AIP induces rice defence against the root-knot nematode Meloidogyne graminicola.

The phenylalanine ammonia-lyase (PAL) enzyme catalyses the conversion of l-phenylalanine to trans-cinnamic acid. This conversion is the first step in phenylpropanoid biosynthesis in plants. The phenylpropanoid pathway produces diverse plant metabolites that play essential roles in various processes, including structural support and defence. Previous studies have shown that mutation of the PAL genes enhances disease susceptibility. Here, we investigated the functions of the rice PAL genes using 2-aminoindan-2-phosphonic acid (AIP), a strong competitive inhibitor of PAL enzymes. We show that the application of AIP can significantly reduce the PAL activity of rice crude protein extracts in vitro. However, when AIP was applied to intact rice plants, it reduced infection of the root-knot nematode Meloidogyne graminicola. RNA-seq showed that AIP treatment resulted in a rapid but transient upregulation of defence-related genes in roots. Moreover, targeted metabolomics demonstrated higher levels of jasmonates and antimicrobial flavonoids and diterpenoids accumulating after AIP treatment. Furthermore, chemical inhibition of the jasmonate pathway abolished the effect of AIP on nematode infection. Our results show that disturbance of the phenylpropanoid pathway by the PAL inhibitor AIP induces defence in rice against M. graminicola by activating jasmonate-mediated defence.

A Phase 1b Study of Lenvatinib plus Pembrolizumab in Patients with Unresectable Hepatocellular Carcinoma: Extended Analysis of Study 116.

Introduction: Lenvatinib (dosing for patients who weigh ≥60 kg was 12 mg/day; for patients who weigh <60 kg, the dose was 8 mg/day) plus pembrolizumab 200 mg once every 3 weeks demonstrated antitumor activity and a manageable safety profile in patients with first-line unresectable hepatocellular carcinoma (uHCC) in the open-label phase 1b Study 116/KEYNOTE-524 (primary analysis data cutoff date: October 31, 2019; median follow-up: 10.6 months). This analysis (updated data cutoff date: March 31, 2021) reports efficacy results from 17 months of additional follow-up time. Methods: 100 patients with uHCC were included in the primary analysis (median follow-up: 27.6 months). Endpoints included overall survival (OS), investigator-assessed progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR) per modified RECIST. Landmark analyses of OS by the best response at 3 and 9 months were performed. Pembrolizumab antidrug antibodies (ADAs) and concentrations were also measured (cutoff date: August 7, 2020). Results: ORR was 43.0% (95% CI 33.1-53.3%) and median DOR was 17.1 months (95% CI 6.9-19.3 months). Median PFS and OS were 9.3 months (95% CI 7.4-9.8 months) and 20.4 months (95% CI 14.4-25.9 months), respectively. No treatment-emergent ADAs were detected. Conclusion: Results show a sustained treatment effect with lenvatinib plus pembrolizumab in patients with uHCC in the first-line setting.

COVID-19 in Female and Male Athletes: Symptoms, Clinical Findings, Outcome, and Prolonged Exercise Intolerance-A Prospective, Observational, Multicenter Cohort Study (CoSmo-S).

BACKGROUND: An infection with SARS-CoV-2 can lead to a variety of symptoms and complications, which can impair athletic activity. OBJECTIVE: We aimed to assess the clinical symptom patterns, diagnostic findings, and the extent of impairment in sport practice in a large cohort of athletes infected with SARS-CoV-2, both initially after infection and at follow-up. Additionally, we investigated whether baseline factors that may contribute to reduced exercise tolerance at follow-up can be identified. METHODS: In this prospective, observational, multicenter study, we recruited German COVID elite-athletes (cEAs, n = 444) and COVID non-elite athletes (cNEAs, n = 481) who tested positive for SARS-CoV-2 by PCR (polymerase chain reaction test). Athletes from the federal squad with no evidence of SARS-CoV-2 infection served as healthy controls (EAcon, n = 501). Questionnaires were used to assess load and duration of infectious symptoms, other complaints, exercise tolerance, and duration of training interruption at baseline and at follow-up 6 months after baseline. Diagnostic tests conducted at baseline included resting and exercise electrocardiogram (ECG), echocardiography, spirometry, and blood analyses. RESULTS: Most acute and infection-related symptoms and other complaints were more prevalent in cNEA than in cEAs. Compared to cEAs, EAcon had a low symptom load. In cNEAs, female athletes had a higher prevalence of complaints such as palpitations, dizziness, chest pain, myalgia, sleeping disturbances, mood swings, and concentration problems compared to male athletes (p < 0.05). Until follow-up, leading symptoms were drop in performance, concentration problems, and dyspnea on exertion. Female athletes had significantly higher prevalence for symptoms until follow-up compared to male. Pathological findings in ECG, echocardiography, and spirometry, attributed to SARS-CoV-2 infection, were rare in infected athletes. Most athletes reported a training interruption between 2 and 4 weeks (cNEAs: 52.9%, cEAs: 52.4%), while more cNEAs (27.1%) compared to cEAs (5.1%) had a training interruption lasting more than 4 weeks (p < 0.001). At follow-up, 13.8% of cNEAs and 9.9% of cEAs (p = 0.24) reported their current exercise tolerance to be under 70% compared to pre-infection state. A persistent loss of exercise tolerance at follow-up was associated with persistent complaints at baseline, female sex, a longer break in training, and age > 38 years. Periodical dichotomization of the data set showed a higher prevalence of infectious symptoms such as cough, sore throat, and coryza in the second phase of the pandemic, while a number of neuropsychiatric symptoms as well as dyspnea on exertion were less frequent in this period. CONCLUSIONS: Compared to recreational athletes, elite athletes seem to be at lower risk of being or remaining symptomatic after SARS-CoV-2 infection. It remains to be determined whether persistent complaints after SARS-CoV-2 infection without evidence of accompanying organ damage may have a negative impact on further health and career in athletes. Identifying risk factors for an extended recovery period such as female sex and ongoing neuropsychological symptoms could help to identify athletes, who may require a more cautious approach to rebuilding their training regimen. TRIAL REGISTRATION NUMBER: DRKS00023717; 06.15.2021-retrospectively registered.

Effects on cardiorespiratory fitness of moderate-intensity training vs. energy-matched training with increasing intensity.

Introduction: The 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. Methods: Thirty-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. Results: The 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. Conclusion: Increasing 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 Registration: https://www.drks.de/DRKS00031445, identifier DRKS00031445.