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The literature linking adulthood criminality to cumulative disadvantage and early school misbehavior demonstrates that understanding the mechanisms underlying student behavior and the responses of teachers and administrators is crucial in comprehending racial/ethnic disparities in actual or perceived school misbehavior. We use data on 19,160 ninth graders from the nationally representative High School Longitudinal Study of 2009 to show that boys' and girls' negative achievement and negative experiences with teachers relate more closely to school misbehavior than the contextual measures (e.g., negative peer climate, proportion Black) that have often been emphasized as most salient for misbehavior. Differences in negative achievement and experiences completely explain Black boys', Latinx boys', and Black girls' heightened levels of school misbehavior relative to White youth, and Asian boys' and girls' lower levels of school misbehavior. In contrast, differences in negative achievement and experiences only partially explain Latinx girls' higher levels of school misbehavior relative to White girls.

The ^{244}Pu(^{50}Ti,xn)^{294-x}Lv reaction was investigated at Lawrence Berkeley National Laboratory's 88-Inch Cyclotron. The experiment was aimed at the production of a superheavy element with Z≥114 by irradiating an actinide target with a beam heavier than ^{48}Ca. Produced Lv ions were separated from the unwanted beam and nuclear reaction products using the Berkeley Gas-filled Separator and implanted into a newly commissioned focal-plane detector system. Two decay chains were observed and assigned to the decay of ^{290}Lv. The production cross section was measured to be σ_{prod}=0.44(_{-0.28}^{+0.58})  pb at a center-of-target center-of-mass energy of 220(3) MeV. This represents the first published measurement of the production of a superheavy element near the "island of stability," with a beam of ^{50}Ti and is an essential precursor in the pursuit of searching for new elements beyond Z=118.

ObjectiveSexual and physical abuse predict cardiovascular disease (CVD) among women in the general population. Women living with HIV (WLWH) report more abuse and have higher CVD risk compared with other women, yet associations between abuse history and CVD have not been considered among WLWH. This study fills this gap, and describes possible pathways linking abuse to CVD risk among WLWH and women living without HIV (WLWOH).MethodsUsing 25 years of data from the Women's Interagency HIV Study (WIHS; n  = 2734; WLWH n  = 1963; WLWOH n  = 771), we used longitudinal generalized estimating equations (GEE) to test associations between sexual and physical abuse with CVD risk. Framingham (FRS-H) and the American College of Cardiology/American Heart Association-Pooled Cohort Equation (ACC/AHA-PCE) scores were examined. Analyses were stratified by HIV-serostatus.ResultsAmong WLWH, childhood sexual abuse was associated with higher CVD risk ( βFRS-H  = 1.25, SE = 1.08, P  = 0.005; βACC/AHA-PCE  = 1.14, SE = 1.07, P  = 0.04) compared with no abuse. Adulthood sexual abuse was associated with higher CVD risk for WLWH ( βFRS-H  = 1.39, SE = 1.08, P

BACKGROUND: The effect of transdermal glyceryl trinitrate (GTN, a nitrovasodilator) on clinical outcome when administered before hospital admission in suspected stroke patients is unclear. Here, we assess the safety and efficacy of GTN in the prespecified subgroup of patients who had an ischaemic stroke within the Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial-2 (RIGHT-2). METHODS: RIGHT-2 was an ambulance-based multicentre sham-controlled blinded-endpoint study with patients randomised within 4 hours of onset. The primary outcome was a shift in scores on the modified Rankin scale (mRS) at day 90. Secondary outcomes included death; a global analysis (Wei-Lachin test) containing Barthel Index, EuroQol-5D, mRS, telephone interview for cognitive status-modified and Zung depression scale; and neuroimaging-determined brain frailty markers. Data were reported as n (%), mean (SD), median [IQR], adjusted common OR (acOR), mean difference or Mann-Whitney difference (MWD) with 95% CI. RESULTS: 597 of 1149 (52%) patients had a final diagnosis of ischaemic stroke; age 75 (12) years, premorbid mRS>2 107 (18%), Glasgow Coma Scale 14 (2) and time from onset to randomisation 67 [45, 108] min. Neuroimaging brain frailty was common: median score 2 [2, 3] (range 0-3). At day 90, GTN did not influence the primary outcome (acOR for increased disability 1.15, 95% CI 0.85 to 1.54), death or global analysis (MWD 0.00, 95% CI -0.10 to 0.09). In subgroup analyses, there were non-significant interactions suggesting GTN may be associated with more death and dependency in participants randomised within 1 hour of symptom onset and in those with more severe stroke. CONCLUSIONS: In patients who had an ischaemic stroke, ultra-acute administration of transdermal GTN in the ambulance did not improve clinical outcomes in a population with more clinical and radiological frailty than seen in previous in-hospital trials.

OBJECTIVE: To determine i) pain phenotypes (PP) in people with early-stage knee osteoarthritis (EKOA); ii) the longitudinal association between the phenotypes and pain worsening at two years. DESIGN: We studied participants with EKOA from the Multicenter Osteoarthritis Study defined as pain intensity ≤3/10, Kellgren and Lawrence grade ≤2, intermittent pain none to sometimes, and no constant pain. Two models of PP were explored. Model A included pressure pain thresholds, temporal summation, conditioned pain modulation, pain catastrophizing, sleep quality, depression, and widespread pain (WSP). In Model B, gait characteristics, quadriceps strength, comorbidities, and magnetic resonance imaging features were added to Model A. Latent Class Analysis was used to create phenotypes, and logistic regression was used to determine their association with pain worsening. RESULTS: 750 individuals (60% females), mean age [standard deviation (SD)]: 60.3 (9.4) were included in Model A and 333 individuals (60% females), mean age (SD): 59.4 (8.1) in Model B. 3-class and 4-class solutions were chosen for Model A and Model B. In Model A, the most severe phenotype was dominated by psychosocial factors, WSP, and measures of nervous system sensitization. Similarly in Model B, the Model A phenotype plus gait variables, quadriceps strength, and comorbidities were dominant. Surprisingly, none of the phenotypes in either model had a significant relationship with pain worsening. CONCLUSION: Phenotypes based upon various factors thought to be important for the pain experience were identified in those with EKOA but were not significantly related to pain worsening. These phenotypes require validation with clinically relevant endpoints.

Abstract Background Mechanobiological mechanisms of osteoarthritis (OA) are unclear. Our objectives were to explore: 1) changes in knee joint physiology using a large panel of synovial fluid biomarkers from before to one year after high tibial osteotomy (HTO) surgery, and 2) the association of changes in the synovial fluid biomarkers with the changes in MRI measures of knee effusion-synovitis and articular cartilage composition. Methods Twenty-six patients with symptomatic knee OA and varus alignment underwent synovial fluid aspirations and 3 T MRI before and one year after medial opening wedge HTO. Cytokine and growth factor levels in synovial fluid were measured with multiplex assays. Ontology and pathway enrichment was assessed using data protein sets with gene set enrichment analysis (GSEA), and analyzed using linear mixed effects models. MRIs were analyzed for effusion-synovitis and T2 cartilage relaxation time using manual segmentations. Changes in biomarker concentrations were correlated to changes in MRI effusion-synovitis volume and articular cartilage T2 relaxation times. Results Decreased enrichment in Toll-like receptor and TNF-α signalling was detected one year after HTO. The leading contributors to this reduction included IL-6, TNF-α and IL-1β, whereas the highest contributors to positive enrichment were EGF, PDGF-BB and FGF-2. Effusion-synovitis volume decreased (mean [95%CI]) one year after HTO (-2811.58 [-5094.40, -528.76mm3]). Effusion-synovitis volume was moderately correlated (r [95% CI]) with decreased MMP-1 (0.44 [0.05; 0.71]), IL-7 (0.41 [0.00; 0.69]) and IL-1β (0.59 [0.25; 0.80]) and increased MIP-1β (0.47 [0.10; 0.73]). Medial tibiofemoral articular cartilage T2 relaxation time decreased (mean [95% CI]) one year after HTO (-0.33 [-2.69; 2.05]ms). Decreased T2 relaxation time was moderately correlated to decreased Flt-3L (0.61 [0.28; 0.81]), IL-10 (0.47 [0.09; 0.73]), IP-10 (0.42; 0.03–0.70) and increased MMP-9 (-0.41 [-0.7; -0.03]) and IL-18 (-0.48 [-0.73; -0.10]). Conclusions Decreased aberrant knee mechanical loading in patients with OA is associated with decreased biological and imaging measures of inflammation (measured in synovial fluid and on MRI) and increased anabolic processes. These exploratory findings suggest that improvement in knee loading can produce long-term (one year) improvement in joint physiology.

Theories of student engagement for dropout and school completion are proposed to begin as early as age five. Student engagement in elementary-age students has been linked to school completion, post-secondary education, and achievement. However, there is little research examining patterns and profiles of student engagement in this population. In an effort to provide more individualized support and intervention, work in the field of student engagement has begun to examine profiles of student engagement and disengagement or disaffection. This study explored the identification of distinguishable groups based on student engagement in a sample of third-grade students and those groups' associations with demographic and outcome variables. Consistent with findings of research with older students, four distinct profiles of student engagement were found for males and females: Engaged, Cognitively/Affectively Disengaged, Behaviorally Disengaged, Disaffected. An additional class characterized by high absences was found for males. Demographic characteristics were associated with cluster attributes for males (Free or Reduced Lunch, special education, English Learner, and race-ethnicity) and female (El status). Cluster affiliation was significantly associated with seventh grade Math and Language Arts grades for both males and females and absences for males. Implications and future directions for research are discussed. The findings from the current study indicate there are discernible classes of student engagement and disengagement that can be identified as early as the third grade. These results may aid in the early identification of those at risk for dropping out of school and more effectively link students to targeted early interventions.

Schools' overt or explicit practices are a dominant lens through which education researchers and policymakers attempt to understand how schools are racially inequitable. Yet, Lewis and Diamond argue that contemporary racial inequalities are largely sustained through implicit factors, like institutional practices and structural inequalities. Ray's framework on racialized organizations similarly outlines how our racialized sociopolitical structure becomes embedded in organizations, legitimating and perpetuating the racialized hierarchy. We apply illustrative cluster analysis techniques to rich data on schools, teachers, and students from the nationally representative High School Longitudinal Study of 2009 to find that structural inequities (e.g., student body, sector, average achievement) appear to be most salient in delineating the racialization of US high schools, whereas the characteristics of schools and teachers that are typically emphasized for closing racial inequities in educational outcomes (e.g., teacher qualifications, courses offered, stratification practices) are not salient differentiators across schools.

The percentage of care-experienced young people in England progressing to university by the age of 19 currently stands at around 12-13% with a further 10% of care-experienced adults attending university during their 20s and 30s. This figure remains lower than both the general population and other groups of disadvantaged learners. It is well established that the educational attainment of care-experienced young people can be impacted by a range of barriers to learning. Existing research often focuses on the importance of key adults and their role in supporting young people in care. A small number of studies examine the reflexive capacities of the young people themselves through the lens of sociologist Margaret Archer's model of modes of reflexivity and internal conversations. Archer's theory can be utilised to understand how care-experienced young people navigate their circumstances. The notion of the internal conversation offers a way to understand how some young people growing up in care develop more stable modes of reflexivity, namely autonomous, communicative or meta-reflexive. Here we contribute to new knowledge by considering care-experienced young people who develop communicative and autonomous aspects to their day-to-day life functioning. This paper draws on findings and analysis from interviews conducted as part of the first author's PhD (2020) which considered the reflexive capacities of care-experienced young people who self-identified as higher achievers. We utilise Archer's modes of reflexivity to explore participants' internal conversations and to develop our understanding of the relationships, experiences and personal skills that underpin successful educational journeys.

Abstract In digital agriculture, accurate crop detection is fundamental to developing automated systems for efficient plantation management. For oil palm, the main challenge lies in developing robust models that perform well in different environmental conditions. This study addresses the feasibility of using GAN augmentation methods to improve palm detection models. For this purpose, drone images of young palms ( 5 year-old), both models also achieved similar accuracies, with baseline model achieving precision and recall of 93.1% and 99.4%, and GAN-based model achieving 95.7% and 99.4%. As for the challenge dataset 2 consisting of storm affected palms, the baseline model achieved precision of 100% but recall was only 13%. The GAN-based model achieved a significantly better result, with a precision and recall values of 98.7% and 95.3%. This result demonstrates that images generated by GANs have the potential to enhance the accuracies of palm detection models.

Abstract The dynamic interaction between cliff, beach and shore-platform is key to assessing the sediment balance for coastal erosion risk assessments, but this is poorly understood. We present a dataset containing daily, 3D,colour LiDAR scans of a 450 m coastal section at Happisburgh, Norfolk, UK. This previously para-glaciated region comprises mixed sand-gravel sediments, which are less well-understood and well-studied than sandy beaches. From Apr-Dec 2019, 236 daily surveys were carried out. The dataset presented includes: survey areas, transects LiDAR scans, georeferenced orthophotos, meteorological- and oceanographical conditions during the Apr-Dec observation period. Full LiDAR point-clouds are available for 67 scans (Oct-Dec). Hourly time-series of offshore sea-state parameters (significant wave height, mean propagation direction, selected spectral periods) were obtained by downscaling the ERA5 global reanalysis data (global atmosphere, land surface and ocean waves) using the numerical model Simulating Waves Nearshore (SWAN). We indicate how to obtain hourly precipitation time-series by interpolating ERA5 data. This dataset is important for researchers understanding the interaction between cliff, beach and shore-platform in open-coast mixed-sand-gravel environments.

Abstract Background Orthorexia Nervosa (ON) is a disordered eating style involving an unhealthy obsession with ‘healthy’ or ‘clean’ eating. Its aetiology is still poorly understood and is not yet recognised in diagnostic manuals. While ON has been associated with Obsessive Compulsive (OC) symptoms and perfectionism, no study to date has looked at the relationship between OC symptoms and ON tendencies via perfectionism, or the influence of two facets of perfectionism in this relationship, namely evaluative concern and achievement striving. Examining the potential role of perfectionism helps to understand the aetiology of ON as well as inform potential treatments tailored specifically for ON and comorbid OC symptoms. Methods In this cross sectional study, we tested 507 participants (n = 70 males, n = 69 at risk of ON) on questionnaires measuring OC symptoms, perfectionism and ON symptoms. We ran two mediation analyses to look at the overall relationship between perfectionism and OC and ON symptoms (Model 1) as well as the specific contribution of evaluative concern and achievement striving in the relationship between OC and ON symptoms (Model 2). Results We found that perfectionism partially mediated the relationship between OC and ON symptoms. Specifically, we found that while achievement striving and evaluative concern were associated with OC symptoms, only achievement striving was significantly associated with ON symptoms, mediating the relationship between OC and ON symptoms. Conclusions This study highlighted the role of one key facet of perfectionism (achievement striving) in the aetiology of ON. The role of achievement striving was indicated as a transdiagnostic construct explaining the link between ON and OC symptoms. These findings are discussed in terms of their implications for treatment models, specifically in terms of the potential role of targeting perfectionism in ON treatment.

Abstract BackgroundDespite accessibility and clinical benefits, open access trials of self-guided digital health interventions (DHIs) for young people have been plagued by high drop-out rates, with some DHIs recording completion rates of less than 3%. ObjectiveThe aim of this study was to explore how young people motivate themselves to complete an unpleasant task and to explore perceived motivators and demotivators for engaging with a DHI. MethodsIn this qualitative research study, 30 children and adolescents aged between 7 and 17 years were recruited to participate in 7 focus groups conducted over a 3-month period. Focus group activities and discussions explored sources of motivation to complete tasks and engage in a hypothetical 6-week DHI for anxiety. ResultsChildren (aged 7-11 years) reported greater reliance on external motivators such as following parent instruction to complete unpleasant tasks, while adolescents (aged 12-17 years) reported greater internal motivation such as self-discipline. Program factors, such as engaging content, were the most commonly mentioned motivators for engaging with a DHI across both age groups. After that, internal sources of motivation were most commonly mentioned, such as perceived future benefits. External factors were the most commonly mentioned demotivators across all ages, with time commitment being the most frequently mentioned. ConclusionsThe study’s findings have implications for enhancing adherence in future DHIs targeted to children and adolescents. Recommendations include the need for supportive parental involvement for children, while adolescents would likely benefit from mechanisms that promote autonomy, establish a supportive environment, and align with personal interests and values. Belief that a DHI will provide short-term benefits is important to both children and adolescents, as well as having confidence that future benefits will be realized.

The neutron-rich rare isotope 190W is discussed as a candidate for a prolate-oblate transitional nucleus with maximum γ-softness. The collectivity of this isotope is assessed for the first time by the measurement of the reduced E2 transition probability of its first 2+ state to the ground state. The experiment employed the FAst TIming Array (FATIMA), comprised of 36 LaBr3(Ce) scintillators, which was part of the DESPEC setup at GSI, Darmstadt. The 41+ and 21+ states of 190W were populated subsequently to the decay of its 127(12) μs isomeric Jπ=10− state. The mean lifetime of the 21+ state was determined to be τ=274(28) ps, which corresponds to a B(E2;21+→01+) value of 95(10) W.u. The results motivated a revision of previous calculations within an energy-density functional-based interacting boson model-2 approach, yielding E2 transition properties and spectroscopic quadrupole moments for tungsten isotopes. From comparison to theory, the new data suggest that 190W is at the transition from prolate to oblate structure along the W isotopic chain, which had previously been discussed as a nuclear shape-phase transition.

Abstract Background Vagus nerve stimulation (VNS) is an established therapy for treating a variety of chronic diseases, such as epilepsy, depression, obesity, and for stroke rehabilitation. However, lack of precision and side-effects have hindered its efficacy and extension to new conditions. Achieving a better understanding of the relationship between VNS parameters and neural and physiological responses is therefore necessary to enable the design of personalized dosing procedures and improve precision and efficacy of VNS therapies. Methods We used biomarkers from recorded evoked fiber activity and short-term physiological responses (throat muscle, cardiac and respiratory activity) to understand the response to a wide range of VNS parameters in anaesthetised pigs. Using signal processing, Gaussian processes (GP) and parametric regression models we analyse the relationship between VNS parameters and neural and physiological responses. Results Firstly, we illustrate how considering multiple stimulation parameters in VNS dosing can improve the efficacy and precision of VNS therapies. Secondly, we describe the relationship between different VNS parameters and the evoked fiber activity and show how spatially selective electrodes can be used to improve fiber recruitment. Thirdly, we provide a detailed exploration of the relationship between the activations of neural fiber types and different physiological effects. Finally, based on these results, we discuss how recordings of evoked fiber activity can help design VNS dosing procedures that optimize short-term physiological effects safely and efficiently. Conclusion Understanding of evoked fiber activity during VNS provide powerful biomarkers that could improve the precision, safety and efficacy of VNS therapies.

A 2022 canine gastroenteritis outbreak in the United Kingdom was associated with circulation of a new canine enteric coronavirus closely related to a 2020 variant with an additional spike gene recombination. The variants are unrelated to canine enteric coronavirus–like viruses associated with human disease but represent a model for coronavirus population adaptation.

Hip fractures inflict heightened morbidity and mortality upon older adults. Although previous studies have explored the impact of individual demographic factors on hip fracture risk, a comprehensive review can help reconcile disparities among these factors. This meta-analysis encompassed 69 studies involving 976,677 participants and 99,298 cases of hip fractures. We found that age ≥ 85 (OR = 1.75), BMI < 18.5 (OR 1.72), female sex (OR = 1.23), history of falls (OR = 1.88), previous fractures (OR = 3.16), menopause (OR 7.21), history of maternal hip fractures (OR = 1.61), single and unmarried status (OR = 1.70), divorced status (OR 1.38), residing in a residential care facility (OR = 5.30), and living alone (OR = 1.47) were significantly associated with an increased incidence of hip fracture. Conversely, BMI ranging from 25 to 30 (OR = 0.59), BMI > 30 (OR = 0.38), parity (OR = 0.79), non-Caucasian descent (overall OR = 0.4, Asian OR 0.36, Black OR = 0.39, and Hispanic OR = 0.45), and rural residence (OR = 0.95) were significantly associated with a diminished risk of hip fracture. Hip fracture patients exhibited significantly lower weight and BMI than the non-fracture group, while their age was significantly higher. However, age at menopause and height did not significantly differ between the two groups.

Abstract Background Elder abuse often goes unreported and undetected. Older people may be ashamed, fearful, or otherwise reticent to disclose abuse, and many health providers are not confident in asking about it. In the No More Shame study, we will evaluate a co-designed, multi-component intervention that aims to improve health providers’ recognition, response, and referral of elder abuse. Methods This is a single-blinded, pragmatic, cluster randomised controlled trial. Ten subacute hospital sites (i.e. clusters) across Australia will be allocated 1:1, stratified by state to a multi-component intervention comprising a training programme for health providers, implementation of a screening tool and use of site champions, or no additional training or support. Outcomes will be collected at baseline, 4 and 9 months. Our co-primary outcomes are change in health providers’ knowledge of responding to elder abuse and older people’s sense of safety and quality of life. We will include all inpatients at participating sites, aged 65 + (or aged 50 + if Aboriginal or Torres Strait Islander), who are able to provide informed consent and all unit staff who provide direct care to older people; a sample size of at least 92 health providers and 612 older people will provide sufficient power for primary analyses. Discussion This will be one of the first trials in the world to evaluate a multi-component elder abuse intervention. If successful, it will provide the most robust evidence base to date for health providers to draw on to create a safe environment for reporting, response, and referral. Trial registration ANZCTR, ACTRN12623000676617p . Registered 22 June 2023.

Abstract Background Prenatal exposure to the Zika virus can lead to microcephaly and adverse developmental outcomes, even in children without evident birth defects. The social environment plays a crucial role in infant health and developmental trajectories, especially during periods of heightened brain plasticity. The study aimed to assess socioenvironmental factors as predictors of developmental outcomes of 36-month-old children exposed to Zika virus prenatally. Study design This cross-sectional study included 53 mothers and 55 children enrolled in the Pediatric Outcomes of Prenatal Zika Exposure cohort study in Puerto Rico. The study performs follow-up developmental assessments of children born to mothers with confirmed and probable Zika virus infection during pregnancy. Mothers completed socioenvironmental questionnaires (e.g., Perceived Neighborhood Scale and US Household Food Insecurity Survey). Children’s developmental outcomes were assessed with the Bayley Scales of Infant and Toddler Development: Third Edition, the Ages and Stages Questionnaires: Third Edition, the Ages and Stages Questionnaire-Socioemotional: Second Edition, and the Child Adjustment and Parent Efficacy Scale. Results Linear regression models, adjusting for a child’s sex and age and maternal education, revealed that early life exposure to food insecurity and maternal pregnancy stressors were significantly associated with poorer developmental outcomes in Zika virus-exposed children at 36 months of age. Maternal resilience representation of adaptive ability was associated with the preservation of adequate developmental outcomes in children. Conclusions Pregnancy and early childhood are critical life periods for ensuring optimal brain development in children. While the mechanisms in the interaction of children with their environment are complex, the risk and protective factors identified in the study are modifiable through public policy and preventive initiatives. Implementation of comprehensive strategies that improve access to social support programs, educational and nutritional interventions, and mental health services during pregnancy and early childhood can enhance the developmental potential of vulnerable children.

Reduced transition probabilities have been extracted between excited, yrast states in the N=Z+2 nucleus 94Pd. The transitions of interest were observed following decays of the Iπ=14+, Ex=2129-keV isomeric state, which was populated following the projectile fragmentation of a 124Xe primary beam at the GSI Helmholtzzentrum für Schwerionenforschung accelerator facility as part of FAIR Phase-0. Experimental information regarding the reduced E2 transition strengths for the decays of the yrast 8+ and 6+ states was determined following isomer-delayed Eγ1−Eγ2−△T2,1 coincidence method, using the LaBr3(Ce)-based FATIMA fast-timing coincidence gamma-ray array, which allowed direct determination of lifetimes of states in 94Pd using the Generalized Centroid Difference (GCD) method. The experimental value for the half-life of the yrast 8+ state of 755(106) ps results in a reduced transition probability of B(E2:8→+6+) = 205−25+34 e2fm4, which enables a precise verification of shell-model calculations for this unique system, lying directly between the N=Z line and the N=50 neutron shell closure. The determined B(E2) value provides an insight into the purity of (g9/2)n configurations in competition with admixtures from excitations between the (lower) N=3pf and (higher) N=4gds orbitals for the first time. The results indicate weak collectivity expected for near-zero quadrupole deformation and an increasing importance of the T=0 proton-neutron interaction at N=48.

Background Over the past decade, cancer immunotherapies have revolutionized the treatment of melanoma; however, responses vary across patient populations. Recently, baseline tumor size has been identified as an independent prognostic factor for overall survival in patients with melanoma receiving immune checkpoint inhibitors. MG1 is a novel oncolytic agent with broad tumor tropism that has recently entered early-phase clinical trials. The aim of this study was to characterize T-cell responses in human and mouse melanoma models following MG1 treatment and to establish if features of the tumor immune microenvironment (TIME) at two distinct tumor burdens would impact the efficacy of oncolytic virotherapy.Methods Human three-dimensional in vitro priming assays were performed to measure antitumor and antiviral T-cell responses following MG1 infection. T-cell receptor (TCR) sequencing, T2 killing assay, and peptide recall assays were used to assess the evolution of the TCR repertoire, and measure specific T-cell responses, respectively. In vivo, subcutaneous 4434 melanomas were characterized using RNA sequencing, immunohistochemistry, and flow cytometry. The effectiveness of intratumoral MG1 was assessed in advancing 4434 tumors and the generation of antitumor and antiviral T cells measured by splenocyte recall assays. Finally, combination MG1 and programmed cell death protein-1 antibody (αPD-1) therapy was investigated in advanced 4434 tumors.Results MG1 effectively supported priming of functional cytotoxic T cells (CTLs) against tumor-associated antigens as well as virus-derived peptides, as assessed using peptide recall and T2 killing assays, respectively. TCR sequencing revealed that MG1-primed CTL comprised larger clusters of similar CDR3 amino acid sequences compared with controls. In vivo testing of MG1 demonstrated that MG1 monotherapy was highly effective at treating early disease, resulting in 90% cures; however, the efficacy of MG1 reduced as the disease burden (local tumor size) increased, and the addition of αPD-1 was required to overcome resistance in more advanced disease. Differential gene expression profiles revealed that increased tumor burden was associated with an immunologically colder TIME. Furthermore, analysis of TCR signaling in advancing tumors demonstrated a different dynamic of TCR engagement compared with smaller tumors, in particular a shift in antigen recognition by CD4+ cells, from conventional to regulatory subsets.Conclusion Addition of αPD-1 to MG1 is required to overcome viral therapy resistance in immunologically ‘colder’ more advanced melanoma, highlighting the importance of tumor burden to different types of immunotherapy.