Trans-driven variation in expression is common among detoxification genes in the extreme generalist herbivore Tetranychus urticae.

The extreme adaptation potential of the generalist herbivore Tetranychus urticae (the two-spotted spider mite) to pesticides as well as diverse host plants has been associated with clade-specific gene expansions in known detoxifying enzyme families, and with extensive and rapid transcriptional responses. However, how this broad transcriptional potential is regulated remains largely unknown. Using a parental/F1 design in which four inbred strains were crossed to a common inbred strain, we assessed the genetic basis and inheritance of gene expression variation in T. urticae. Mirroring known phenotypic variation in the progenitor strains of the inbreds, we confirmed that the inbred strains we created were genetically distinct, varied markedly in pesticide resistance, and also captured variation in host plant fitness as is commonly observed in this species. By examining differences in gene expression between parents and allele-specific expression in F1s, we found that variation in RNA abundance was more often explained in trans as compared to cis, with the former associated with dominance in inheritance. Strikingly, in a gene ontology analysis, detoxification genes of the cytochrome P450 monooxygenase (CYP) family, as well as dioxygenases (DOGs) acquired from horizontal gene transfer from fungi, were specifically enriched at the extremes of trans-driven up- and downregulation. In particular, multiple CYPs and DOGs with broad substrate-specificities for pesticides or plant specialized compounds were exceptionally highly upregulated as a result of trans-regulatory variation, or in some cases synergism of cis and trans, in the most multi-pesticide resistant strains. Collectively, our findings highlight the potential importance of trans-driven expression variation in genes associated with xenobiotic metabolism and host plant use for rapid adaptation in T. urticae, and also suggests modular control of these genes, a regulatory architecture that might ameliorate negative pleiotropic effects.

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.

Molecular Markers of Response to Anti-PD1 Therapy in Advanced Hepatocellular Carcinoma.

BACKGROUND & AIMS: Single-agent anti-PD1 checkpoint inhibitors convey outstanding clinical benefits in a small fraction (∼20%) of patients with advanced hepatocellular carcinoma (aHCC) but the molecular mechanisms determining response are unknown. To fill this gap, we herein analyze the molecular and immune traits of aHCC in patients treated with anti-PD1. METHODS: Overall, 111 tumor samples from patients with aHCC were obtained from 13 centers before systemic therapies. We performed molecular analysis and immune deconvolution using whole-genome expression data (n = 83), mutational analysis (n = 72), and histologic evaluation with an endpoint of objective response. RESULTS: Among 83 patients with transcriptomic data, 28 were treated in frontline, whereas 55 patients were treated after tyrosine kinase inhibitors (TKI) either in second or third line. Responders treated in frontline showed upregulated interferon-γ signaling and major histocompatibility complex II-related antigen presentation. We generated an 11-gene signature (IFNAP), capturing these molecular features, which predicts response and survival in patients treated with anti-PD1 in frontline. The signature was validated in a separate cohort of aHCC and >240 patients with other solid cancer types where it also predicted response and survival. Of note, the same signature was unable to predict response in archival tissue of patients treated with frontline TKIs, highlighting the need for fresh biopsies before immunotherapy. CONCLUSION: Interferon signaling and major histocompatibility complex-related genes are key molecular features of HCCs responding to anti-PD1. A novel 11-gene signature predicts response in frontline aHCC, but not in patients pretreated with TKIs. These results must be confirmed in prospective studies and highlights the need for biopsies before immunotherapy to identify biomarkers of response.

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.

Dicer-like 3a mediates intergenerational resistance against root-knot nematodes in rice via hormone responses.

In a continuously changing and challenging environment, passing down the memory of encountered stress factors to offspring could provide an evolutionary advantage. In this study, we demonstrate the existence of "intergenerational acquired resistance" in the progeny of rice (Oryza sativa) plants attacked by the belowground parasitic nematode Meloidogyne graminicola. Transcriptome analyses revealed that genes involved in defense pathways are generally downregulated in progeny of nematode-infected plants under uninfected conditions but show a stronger induction upon nematode infection. This phenomenon was termed "spring loading" and depends on initial downregulation by the 24-nucleotide (nt) siRNA biogenesis gene dicer-like 3a (dcl3a) involved in the RNA-directed DNA methylation pathway. Knockdown of dcl3a led to increased nematode susceptibility and abolished intergenerational acquired resistance, as well as jasmonic acid/ethylene spring loading in the offspring of infected plants. The importance of ethylene signaling in intergenerational resistance was confirmed by experiments on a knockdown line of ethylene insensitive 2 (ein2b), which lacks intergenerational acquired resistance. Taken together, these data indicate a role for DCL3a in regulating plant defense pathways during both within-generation and intergenerational resistance against nematodes in rice.

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.

Lenvatinib plus pembrolizumab versus lenvatinib plus placebo for advanced hepatocellular carcinoma (LEAP-002): a randomised, double-blind, phase 3 trial.

BACKGROUND: Systemic therapies have improved the management of hepatocellular carcinoma, but there is still a need to further enhance overall survival in first-line advanced stages. This study aimed to evaluate the addition of pembrolizumab to lenvatinib versus lenvatinib plus placebo in the first-line setting for unresectable hepatocellular carcinoma. METHODS: In this global, randomised, double-blind, phase 3 study (LEAP-002), patients aged 18 years or older with unresectable hepatocellular carcinoma, Child Pugh class A liver disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no previous systemic treatment were enrolled at 172 global sites. Patients were randomly assigned (1:1) with a central interactive voice-response system (block size of 4) to receive lenvatinib (bodyweight <60 kg, 8 mg/day; bodyweight ≥60 kg, 12 mg/day) plus pembrolizumab (200 mg every 3 weeks) or lenvatinib plus placebo. Randomisation was stratified by geographical region, macrovascular portal vein invasion or extrahepatic spread or both, α-fetoprotein concentration, and Eastern Cooperative Oncology Group performance status. Dual primary endpoints were overall survival (superiority threshold at final overall survival analysis, one-sided p=0·019; final analysis to occur after 532 events) and progression-free survival (superiority threshold one-sided p=0·002; final analysis to occur after 571 events) in the intention-to-treat population. Results from the final analysis are reported. This study is registered with ClinicalTrials.gov, NCT03713593, and is active but not recruiting. FINDINGS: Between Jan 17, 2019, and April 28, 2020, of 1309 patients assessed, 794 were randomly assigned to lenvatinib plus pembrolizumab (n=395) or lenvatinib plus placebo (n=399). Median age was 66·0 years (IQR 57·0-72·0), 644 (81%) of 794 were male, 150 (19%) were female, 345 (43%) were Asian, 345 (43%) were White, 22 (3%) were multiple races, 21 (3%) were American Indian or Alaska Native, 21 (3%) were Native Hawaiian or other Pacific Islander, 13 (2%) were Black or African American, and 46 (6%) did not have available race data. Median follow up as of data cutoff for the final analysis (June 21, 2022) was 32·1 months (IQR 29·4-35·3). Median overall survival was 21·2 months (95% CI 19·0-23·6; 252 [64%] of 395 died) with lenvatinib plus pembrolizumab versus 19·0 months (17·2-21·7; 282 [71%] of 399 died) with lenvatinib plus placebo (hazard ratio [HR] 0·84; 95% CI 0·71-1·00; stratified log-rank p=0·023). As of data cutoff for the progression-free survival final analysis (April 5, 2021), median progression-free survival was 8·2 months (95% CI 6·4-8·4; 270 events occurred [42 deaths; 228 progressions]) with lenvatinib plus pembrolizumab versus 8·0 months (6·3-8·2; 301 events occurred [36 deaths; 265 progressions]) with lenvatinib plus placebo (HR 0·87; 95% CI 0·73-1·02; stratified log-rank p=0·047). The most common treatment-related grade 3-4 adverse events were hypertension (69 [17%] of 395 patients in the lenvatinib plus pembrolizumab group vs 68 [17%] of 395 patients) in the lenvatinib plus placebo group), increased aspartate aminotransferase (27 [7%] vs 17 [4%]), and diarrhoea (25 [6%] vs 15 [4%]). Treatment-related deaths occurred in four (1%) patients in the lenvatinib plus pembrolizumab group (due to gastrointestinal haemorrhage and hepatorenal syndrome [n=1 each] and hepatic encephalopathy [n=2]) and in three (1%) patients in the lenvatinib plus placebo group (due to gastrointestinal haemorrhage, hepatorenal syndrome, and cerebrovascular accident [n=1 each]). INTERPRETATION: In earlier studies, the addition of pembrolizumab to lenvatinib as first-line therapy for advanced hepatocellular carcinoma has shown promising clinical activity; however, lenvatinib plus pembrolizumab did not meet prespecified significance for improved overall survival and progression-free survival versus lenvatinib plus placebo. Our findings do not support a change in clinical practice. FUNDING: Eisai US, and Merck Sharp & Dohme, a subsidiary of Merck.

Hepatocellular carcinoma.

Hepatocellular carcinoma is one of the most common cancers worldwide and represents a major global health-care challenge. Although viral hepatitis and alcohol remain important risk factors, non-alcoholic fatty liver disease is rapidly becoming a dominant cause of hepatocellular carcinoma. A broad range of treatment options are available for patients with hepatocellular carcinoma, including liver transplantation, surgical resection, percutaneous ablation, and radiation, as well as transarterial and systemic therapies. As such, clinical decision making requires a multidisciplinary team that longitudinally adapts the individual treatment strategy according to the patient's tumour stage, liver function, and performance status. With the approval of new first-line agents and second-line agents, as well as the establishment of immune checkpoint inhibitor-based therapies as standard of care, the treatment landscape of advanced hepatocellular carcinoma is more diversified than ever. Consequently, the outlook for patients with hepatocellular carcinoma has improved. However, the optimal sequencing of drugs remains to be defined, and predictive biomarkers are urgently needed to inform treatment selection. In this Seminar, we present an update on the causes, diagnosis, molecular classification, and treatment of hepatocellular carcinoma.

Liver transcriptomic and methylomic analyses identify transcriptional mitogen-activated protein kinase regulation in facultative hibernation of Syrian hamster.

Hibernation consists of alternating torpor-arousal phases, during which animals cope with repetitive hypothermia and ischaemia-reperfusion. Due to limited transcriptomic and methylomic information for facultative hibernators, we here conducted RNA and whole-genome bisulfide sequencing in liver of hibernating Syrian hamster (Mesocricetus auratus). Gene ontology analysis was performed on 844 differentially expressed genes and confirmed the shift in metabolic fuel utilization, inhibition of RNA transcription and cell cycle regulation as found in seasonal hibernators. Additionally, we showed a so far unreported suppression of mitogen-activated protein kinase (MAPK) and protein phosphatase 1 pathways during torpor. Notably, hibernating hamsters showed upregulation of MAPK inhibitors (dual-specificity phosphatases and sproutys) and reduced levels of MAPK-induced transcription factors (TFs). Promoter methylation was found to modulate the expression of genes targeted by these TFs. In conclusion, we document gene regulation between hibernation phases, which may aid the identification of pathways and targets to prevent organ damage in transplantation or ischaemia-reperfusion.

Concurrent invasions of European starlings in Australia and North America reveal population-specific differentiation in shared genomic regions.

A species' success during the invasion of new areas hinges on an interplay between the demographic processes common to invasions and the specific ecological context of the novel environment. Evolutionary genetic studies of invasive species can investigate how genetic bottlenecks and ecological conditions shape genetic variation in invasions, and our study pairs two invasive populations that are hypothesized to be from the same source population to compare how each population evolved during and after introduction. Invasive European starlings (Sturnus vulgaris) established populations in both Australia and North America in the 19th century. Here, we compare whole-genome sequences among native and independently introduced European starling populations to determine how demographic processes interact with rapid evolution to generate similar genetic patterns in these recent and replicated invasions. Demographic models indicate that both invasive populations experienced genetic bottlenecks as expected based on invasion history, and we find that specific genomic regions have differentiated even on this short evolutionary timescale. Despite genetic bottlenecks, we suggest that genetic drift alone cannot explain differentiation in at least two of these regions. The demographic boom intrinsic to many invasions as well as potential inversions may have led to high population-specific differentiation, although the patterns of genetic variation are also consistent with the hypothesis that this infamous and highly mobile invader adapted to novel selection (e.g., extrinsic factors). We use targeted sampling of replicated invasions to identify and evaluate support for multiple, interacting evolutionary mechanisms that lead to differentiation during the invasion process.

Sports-related sudden cardiac arrest in young adults.

AIMS: Data on sports-related sudden cardiac arrest (SrSCA) among young adults in the general population are scarce. We aimed to determine the overall SrSCA incidence, characteristics, and outcomes in young adults. METHODS AND RESULTS: Prospective cohort study of all cases of SrSCA between 2012 and 2019 in Germany and Paris area, France, involving subjects aged 18-35 years. Detection of SrSCA was achieved via multiple sources, including emergency medical services (EMS) reporting and web-based screening of media releases. Cases and aetiologies were centrally adjudicated. Overall, a total of 147 SrSCA (mean age 28.1 ± 4.8 years, 95.2% males) occurred, with an overall burden of 4.77 [95% confidence interval (CI) 2.85-6.68] cases per million-year, including 12 (8.2%) cases in young competitive athletes. While bystander cardiopulmonary resuscitation (CPR) was initiated in 114 (82.6%), automated external defibrillator (AED) use by bystanders occurred only in a minority (7.5%). Public AED use prior to EMS arrival (odds ratio 6.25, 95% CI 1.48-43.20, P = 0.02) was the strongest independent predictor of survival at hospital discharge (38.1%). Among cases that benefited from both immediate bystander CPR and AED use, survival rate was 90.9%. Coronary artery disease was the most frequent aetiology (25.8%), mainly through acute coronary syndrome (86.9%). CONCLUSION: Sports-related sudden cardiac arrest in the young occurs mainly in recreational male sports participants. Public AED use remains disappointingly low, although survival may reach 90% among those who benefit from both bystander CPR and early defibrillation. Coronary artery disease is the most prevalent cause of SrSCA in young adults.

Minimally Invasive Ways to Monitor Changes in Cardiocirculatory Fitness in Running-based Sports: A Systematic Review.

This systematic review provides a synthesis of research investigating submaximal protocols to monitor changes in cardiocirculatory fitness in running-based sports. Following PRISMA guidelines, 2,452 records were identified and 14 studies, representing 515 athletes, satisfied the eligibility criteria. While most studies found large associations between changes in heart rate at standardized, submaximal running speeds and changes in aerobic fitness (r=0.51-0.88), three studies failed to establish a relationship (r=0.19-0.35). The intensity of the submaximal protocols seems to be relevant, with changes in running speeds at 90% of maximal heart rate showing larger relationships with changes in aerobic fitness (r=0.52-0.79) compared to 70% of maximal heart rate (r=0.24-0.52). Conversely, changes in post-exercise heart rate variability were very largely associated with changes in aerobic fitness when the testing protocols were less intense (70% of maximal heart rate) (r=0.76-0.88), but not when the test required participants to achieve 90% of their maximal heart rate (r=-0.02-0.06). Studies on post-exercise heart rate recovery revealed inconclusive results (r=-0.01- -0.55), while rate of heart rate increase may be a promising athlete monitoring metric (r=0.08- -0.84) but requires further research. In summary, when executed, analyzed, and interpreted appropriately, submaximal protocols can provide valuable information regarding changes in athlete cardiocirculatory fitness.

Do Sports-related Concussions Induce Subsequent Injuries in Elite Male Football Players?

To assess the players' risk of a subsequent injury after sustaining concussive injuries and their return-to-competition in German professional men's football. A prospective injury database in the 1st Bundesliga was created encompassing 7 seasons (2014/15-2020/21). Cox proportional hazard model analyzed whether a concussive injury increased the risk of a subsequent injury in the first year after the index injury. 6,651 injuries were reported (n=182 concussive injuries). The incidence rate was 0.15 (95% CI 0.13-0.17) per 1000 football hours. A concussive injury was associated with only a slightly numerical higher risk of 7% (HR=1.07, 95% CI 0.78-1.47) in the subsequent year after the injury compared to a randomly selected non-concussive injury, but the effect was not significant. The risk was higher after 6-12 months post-SRC reaching 70% (HR=1.70, 95% CI 1.15-2.52). For 0-3 months (HR=0.76, 95% CI 0.48-1.20) and 3-6 months (HR=0.97, 95% CI 0.62-1.50) the injury risk was lower. The present data do not confirm previously published investigations about an increased injury risk after SRC. Contrasting effects of lower hazard ratios were found early after SRC, followed by an increase after 6-12 months. Further research should look into compliance rates with regards to return-to-competition protocols.

Incidence, characteristics and cost of head, neck and dental injuries in non-professional football (soccer) using 3 years of sports injury insurance data.

AIM: This descriptive epidemiological study aimed to quantify the incidence, characteristics and costs of head, neck and dental injuries in non-professional football players. METHODS: Injury data were coded (using Orchard Sports Injury and Illness Classification System) from a de-identified insurance database containing three seasons (2018-2020) of data. Cost data included direct and indirect costs presented by type of injury, age group and sex using means ± SD, range of costs ($AU) and total costs ± SE. Chi-squared tests were used to analyse the data (significance level p < .05) with injury incidence rates (IR) calculated per 1000 match hours and per 1000 injury insurance claims. RESULTS: A total of 388 injuries affecting 240 players were sustained. Of these, 43% (n = 102) of players also sustained one or more secondary injuries, mainly to the head or neck area. Dental injuries (n = 143, 39%, IR = 0.008) accounted for the highest number of primary and secondary injuries and the highest mean direct cost per injury ($AU1152), while head and facial injuries accounted for the highest proportion of total costs ($AU434,101). Players who sustained one or more secondary injuries had the highest direct and indirect mean cost per injury. CONCLUSIONS: Given the frequency and cost of dental injuries in non-professional football players, injury prevention initiatives warrant further investigation.

Mouse tracking performance: A new approach to analyzing continuous mouse tracking data.

Mouse tracking is an important source of data in cognitive science. Most contemporary mouse tracking studies use binary-choice tasks and analyze the curvature or velocity of an individual mouse movement during an experimental trial as participants select from one of the two options. However, there are many types of mouse tracking data available beyond what is produced in a binary-choice task, including naturalistic data from web users. In order to utilize these data, cognitive scientists need tools that are robust to the lack of trial-by-trial structure in most normal computer tasks. We use singular value decomposition (SVD) and detrended fluctuation analysis (DFA) to analyze whole time series of unstructured mouse movement data. We also introduce a new technique for describing two-dimensional mouse traces as complex-valued time series, which allows SVD and DFA to be applied in a straightforward way without losing important spatial information. We find that there is useful information at the level of whole time series, and we use this information to predict performance in an online task. We also discuss how the implications of these results can advance the use of mouse tracking research in cognitive science.