Structural basis for ligand reception by anaplastic lymphoma kinase.

The proto-oncogene ALK encodes anaplastic lymphoma kinase, a receptor tyrosine kinase that is expressed primarily in the developing nervous system. After development, ALK activity is associated with learning and memory1 and controls energy expenditure, and inhibition of ALK can prevent diet-induced obesity2. Aberrant ALK signalling causes numerous cancers3. In particular, full-length ALK is an important driver in paediatric neuroblastoma4,5, in which it is either mutated6 or activated by ligand7. Here we report crystal structures of the extracellular glycine-rich domain (GRD) of ALK, which regulates receptor activity by binding to activating peptides8,9. Fusing the ALK GRD to its ligand enabled us to capture a dimeric receptor complex that reveals how ALK responds to its regulatory ligands. We show that repetitive glycines in the GRD form rigid helices that separate the major ligand-binding site from a distal polyglycine extension loop (PXL) that mediates ALK dimerization. The PXL of one receptor acts as a sensor for the complex by interacting with a ligand-bound second receptor. ALK activation can be abolished through PXL mutation or with PXL-targeting antibodies. Together, these results explain how ALK uses its atypical architecture for its regulation, and suggest new therapeutic opportunities for ALK-expressing cancers such as paediatric neuroblastoma.

Process evaluation of implementation of the early stages of a whole systems approach to obesity in a small Island.

BACKGROUND: The small Atlantic island of St Helena is a United Kingdom Overseas Territory (UKOT) with a high prevalence of childhood obesity (over a quarter of 4-5 and 10-11 year olds) and, anecdotally, adulthood obesity and its associated health detriments. St Helena have taken a whole systems approach to obesity (WSAO) to address the issue. A WSAO recognises the factors that impact obesity as a complex system and requires a 'health in all policies' approach. UK academic and public health technical support was provided to the local St Helena delivery team. This process evaluation sought to explore the early stages of the WSAO implementation and implications for the transferability of the approach to other small island developing states and UKOT. METHODS: Data was collected via eight semi-structured interviews, paper based and online surveys, and document analysis. Thematic analysis was used to analyse the data. RESULTS: The analysis identified three factors which aided the first phase of WSAO implementation: (1) senior leaders support for the approach; (2) the academic support provided to establish and develop the approach; and (3) effective adaptation of UK Government resources to suit the local context. Key challenges of early implementation included: maintaining and broadening stakeholder engagement; limited local workforce capacity and baseline knowledge related to obesity and systems thinking; and limited capacity for support from the UK-based academic team due to contract terms and COVID-19 restrictions. CONCLUSIONS: Early stages of implementation of a WSAO in a UKOT can be successful when using UK's resources as a guide and adapting them to a small island context. All participants recommended other small islands adopt this approach. Continued senior support, dedicated leadership, and comprehensive community engagement is needed to progress implementation and provide the foundation for long-term impact. Small island developing states considering adopting a WSAO should consider political will, senior level buy-in and support, funding, and local workforce knowledge and capacity to enable the best chances of successful and sustainable implementation.

Allogeneic chondrogenic-induced mesenchymal stem cells for the treatment of tarsometatarsal lameness in horses.

OBJECTIVE: To assess the efficacy of commercial intra-articular blood-derived allogeneic-induced mesenchymal stem cells (CIMSCs) to treat tarsometatarsal lameness in horses. STUDY DESIGN: This was a retrospective cohort study. ANIMALS: Records from 167 adult light breed horses with bilateral tarsometatarsal lameness. METHODS: Horses with tarsometatarsal lameness were retrospectively selected from medical records. Diagnosis followed subjective graded lameness assessment before and after intra-articular analgesia, with graded radiographic tarsal examination. Horses were excluded if they were diagnosed or treated for any other concurrent lameness conditions during the study. Time to last follow-up and time of recurrence of lameness was recorded at veterinary re-assessment. RESULTS: A total of 67 horses were recruited to the CIMSC-treated group and 100 to the corticosteroid (CS)-treated group. Median age was 9 years, with no difference in signalment, use or radiographic grade between groups. First re-examination was 38 days (95% CI: 38-49), with no difference between groups, CIMSC 42 (35-45), control 34 (25-42). Median follow-up was 438 days for CIMSC, 546 for controls. Symptoms of lameness recurred in 86/100 controls compared to 17/67 (25%) CIMSC. Median time to lameness recurring in CIMSC was 336 days (95% CI: 239-400), control 90 days (95% CI: 80-108), p < .0001. Cox proportional hazard ratio for treatment was 8.35, 95% CI: 4.67 to 14.92, p < .0001. CONCLUSIONS: Lameness was abolished in all treated horses. It recurred significantly less often, and later, in CIMSC-treated horses. CLINICAL SIGNIFICANCE: Intra-articular CIMSC treatment results in prolonged soundness in horses with tarsometatarsal lameness.

Defective tubulin detyrosination causes structural brain abnormalities with cognitive deficiency in humans and mice.

Reversible detyrosination of tubulin, the building block of microtubules, is crucial for neuronal physiology. Enzymes responsible for detyrosination were recently identified as complexes of vasohibins (VASHs) one or two with small VASH-binding protein (SVBP). Here we report three consanguineous families, each containing multiple individuals with biallelic inactivation of SVBP caused by truncating variants (p.Q28* and p.K13Nfs*18). Affected individuals show brain abnormalities with microcephaly, intellectual disability and delayed gross motor and speech development. Immunoblot testing in cells with pathogenic SVBP variants demonstrated that the encoded proteins were unstable and non-functional, resulting in a complete loss of VASH detyrosination activity. Svbp knockout mice exhibit drastic accumulation of tyrosinated tubulin and a reduction of detyrosinated tubulin in brain tissue. Similar alterations in tubulin tyrosination levels were observed in cultured neurons and associated with defects in axonal differentiation and architecture. Morphological analysis of the Svbp knockout mouse brains by anatomical magnetic resonance imaging showed a broad impact of SVBP loss, with a 7% brain volume decrease, numerous structural defects and a 30% reduction of some white matter tracts. Svbp knockout mice display behavioural defects, including mild hyperactivity, lower anxiety and impaired social behaviour. They do not, however, show prominent memory defects. Thus, SVBP-deficient mice recapitulate several features observed in human patients. Altogether, our data demonstrate that deleterious variants in SVBP cause this neurodevelopmental pathology, by leading to a major change in brain tubulin tyrosination and alteration of microtubule dynamics and neuron physiology.

National or population level interventions addressing the social determinants of mental health - an umbrella review.

BACKGROUND: Social circumstances in which people live and work impact the population's mental health. We aimed to synthesise evidence identifying effective interventions and policies that influence the social determinants of mental health at national or scaled population level. We searched five databases (Cochrane Library, Global Health, MEDLINE, EMBASE and PsycINFO) between Jan 1st 2000 and July 23rd 2019 to identify systematic reviews of population-level interventions or policies addressing a recognised social determinant of mental health and collected mental health outcomes. There were no restrictions on country, sub-population or age. A narrative overview of results is provided. Quality assessment was conducted using Assessment of Multiple Systematic Reviews (AMSTAR 2). This study was registered on PROSPERO (CRD42019140198). RESULTS: We identified 20 reviews for inclusion. Most reviews were of low or critically low quality. Primary studies were mostly observational and from higher income settings. Higher quality evidence indicates more generous welfare benefits may reduce socioeconomic inequalities in mental health outcomes. Lower quality evidence suggests unemployment insurance, warm housing interventions, neighbourhood renewal, paid parental leave, gender equality policies, community-based parenting programmes, and less restrictive migration policies are associated with improved mental health outcomes. Low quality evidence suggests restriction of access to lethal means and multi-component suicide prevention programmes are associated with reduced suicide risk. CONCLUSION: This umbrella review has identified a small and overall low-quality evidence base for population level interventions addressing the social determinants of mental health. There are significant gaps in the evidence base for key policy areas, which limit ability of national policymakers to understand how to effectively improve population mental health.

Analysis of loss to follow-up in 4099 multidrug-resistant pulmonary tuberculosis patients.

Loss to follow-up (LFU) of ≥2 consecutive months contributes to the poor levels of treatment success in multidrug-resistant tuberculosis (MDR-TB) reported by TB programmes. We explored the timing of when LFU occurs by month of MDR-TB treatment and identified patient-level risk factors associated with LFU.We analysed a dataset of individual MDR-TB patient data (4099 patients from 22 countries). We used Kaplan-Meier survival curves to plot time to LFU and a Cox proportional hazards model to explore the association of potential risk factors with LFU.Around one-sixth (n=702) of patients were recorded as LFU. Median (interquartile range) time to LFU was 7 (3-11) months. The majority of LFU occurred in the initial phase of treatment (75% in the first 11 months). Major risk factors associated with LFU were: age 36-50 years (HR 1.3, 95% CI 1.0-1.6; p=0.04) compared with age 0-25 years, being HIV positive (HR 1.8, 95% CI 1.2-2.7; p<0.01) compared with HIV negative, on an individualised treatment regimen (HR 0.7, 95% CI 0.6-1.0; p=0.03) compared with a standardised regimen and a recorded serious adverse event (HR 0.5, 95% CI 0.4-0.6; p<0.01) compared with no serious adverse event.Both patient- and regimen-related factors were associated with LFU, which may guide interventions to improve treatment adherence, particularly in the first 11 months.

Space-based bias of covert visual attention in complex regional pain syndrome.

See Legrain (doi:10.1093/awx188) for a scientific commentary on this article. Some patients with complex regional pain syndrome report that movements of the affected limb are slow, more effortful, and lack automaticity. These symptoms have been likened to the syndrome that sometimes follows brain injury called hemispatial neglect, in which patients exhibit attentional impairments and problems with movements affecting the contralesional side of the body and space. Psychophysical testing of patients with complex regional pain syndrome has found evidence for spatial biases when judging visual targets distanced at 2 m, but not in directions that indicate reduced attention to the affected side. In contrast, when judging visual or tactile stimuli presented on their own body surface, or pictures of hands and feet within arm's reach, patients with complex regional pain syndrome exhibited a bias away from the affected side. What is not yet known is whether patients with complex regional pain syndrome only have biased attention for bodily-specific information in the space within arm's reach, or whether they also show a bias for information that is not associated with the body, suggesting a more generalized attention deficit. Using a temporal order judgement task, we found that patients with complex regional pain syndrome processed visual stimuli more slowly on the affected side (relative to the unaffected side) when the lights were projected onto a blank surface (i.e. when no bodily information was visible), and when the lights were projected onto the dorsal surfaces of their uncrossed hands. However, with the arms crossed (such that the left and right lights projected onto the right and left hands, respectively), patients' responses were no different than controls. These results provide the first demonstration of a generalized attention bias away from the affected side of space in complex regional pain syndrome patients that is not specifically related to bodily information. They also suggest a separate and additional bias of visual attention away from the affected hand. The strength of attention bias was predicted by scores on a self-report measure of body perception distortion; but not by pain intensity, time since diagnosis, or affected body side (left or right). At an individual level, those patients whose upper limbs were most affected had a higher incidence of inattention than those whose lower limbs were most affected. However, at a group level, affected limb (upper or lower) did not predict bias magnitude; nor did three measures designed to assess possible asymmetries in the distribution of movements across space. It is concluded that inattention in near space in complex regional pain syndrome may arise in parallel with a distorted perception of the body.10.1093/brain/awx152_video1awx152media15495542665001.

A critical scoping review of the connections between social mission and medical school admissions: BEME Guide No. 47.

BACKGROUND: Despite a growing focus on the social accountability of medical schools, there has been no substantive review of admissions related to the social mission of medical schools. This paper reports on a critical scoping review of the connections between social mission and medical school admissions. METHODS: Searches of seven bibliographic databases identified 1258 unique articles. After filtering for relevance, 71 articles were considered for final review. The results of the data extraction were synthesized using a combination of qualitative and quantitative techniques. RESULTS: Five reviewers conducted 149 data extractions from 71 papers. Social missions tended to focus either on access and equity issues for applicants from underrepresented populations or on the career choices of medical graduates and how they meet particular social needs. The connection between social missions and admissions was often implied but rarely considered or evaluated directly. There was a notable absence of empirical evidence, with calls for reform or program descriptions far outweighing the number of papers based on empirical findings. CONCLUSIONS: Despite the move to social missions in medical education, there remains little direct connection between missions and admissions and little evidence reflecting the efficacy or impacts of making this connection.

Using affective judgement to increase physical activity in British adults.

Mobile phone apps have been shown to increase physical activity (PA), but existing apps fail to target the emotional aspects of PA, which influence whether individuals are active. We developed an app that encourages individuals to focus on the emotional aspects of PA. We aimed to assess the acceptability of this app, and conduct a preliminary evaluation of efficacy. The app was developed in collaboration with users through focus groups. Seven users tested the app over 4 months and provided feedback on acceptability, aesthetics and functionality in a follow-up focus group. Results were summarized descriptively. Before testing the app, participants completed a questionnaire assessing their current PA and psychological antecedents of PA. A second questionnaire was completed at the follow-up focus group. Change scores are reported for each participant and overall.The social and reminder aspects facilitated motivation to be active and many found it easy to integrate into their lives. Most suggested modifications. Small improvements in number of minutes spent walking per week were observed (overall mean change +25 min) and some psychological antecedents of PA (overall mean change for social support for PA +0.14, self-efficacy for PA +0.17, outcome expectations about PA +0.20; all five-point scales), but reductions were seen in other domains. The app was acceptable to users, although developments are required. Testing with a small number of individuals, offering preliminary evidence of efficacy of this app, provides justification for further evaluation on a larger scale.

Cognitive Behaviour Therapy for Health Anxiety: A Systematic Review and Meta-Analysis.

BACKGROUND: Health anxiety (HA), or hypochondriasis, is a psychological problem characterized by a preoccupation with the belief that one is physically unwell. A 2007 Cochrane review (Thomson and Page, 2007) found cognitive behavioural therapy (CBT) to be an effective intervention for individuals with HA. Similar findings were reported in a recent meta-analysis (Olatunji et al., 2014), which did not employ a systematic search strategy. The current review aimed to investigate the efficacy of CBT for HA, and to update the existing reviews. METHOD: A systematic search was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance, including randomized controlled trials that compared CBT with a control condition for people with HA. Five hundred and sixty-seven studies were found in the original search, of which 14 were included in the meta-analysis. RESULTS: Meta-analysis was conducted on 21 comparisons and a large effect size for CBT compared with a control condition was found at post therapy d = 1.01 (95% confidence interval 0.77-1.25), as well as at 6- and 12-month follow-up. CONCLUSIONS: This systematic review and meta-analysis provides support for the hypothesis that CBT is an effective intervention for HA when compared with a variety of control conditions, e.g. treatment-as-usual, waiting list, medication, and other psychological therapies.

Wearing a Bicycle Helmet Can Increase Risk Taking and Sensation Seeking in Adults.

Humans adapt their risk-taking behavior on the basis of perceptions of safety; this risk-compensation phenomenon is typified by people taking increased risks when using protective equipment. Existing studies have looked at people who know they are using safety equipment and have specifically focused on changes in behaviors for which that equipment might reduce risk. Here, we demonstrated that risk taking increases in people who are not explicitly aware they are wearing protective equipment; furthermore, this happens for behaviors that could not be made safer by that equipment. In a controlled study in which a helmet, compared with a baseball cap, was used as the head mount for an eye tracker, participants scored significantly higher on laboratory measures of both risk taking and sensation seeking. This happened despite there being no risk for the helmet to ameliorate and despite it being introduced purely as an eye tracker. The results suggest that unconscious activation of safety-related concepts primes globally increased risk propensity.

The effect of noncognitive traits on health behaviours in adolescence.

This paper investigates the relationship between personality traits and health behaviours in adolescence using a large and recent cohort study. In particular, we investigate the impact of locus of control, self-esteem and work ethics at ages 15-16 years on the incidence of health behaviours such as alcohol consumption, cannabis and other drug use, unprotected and early sexual activity and sports and physical activity. We use matching methods to control for a very rich set of adolescent and family characteristics, and we find that personality traits do affect health behaviours. In particular, individuals with external locus of control, low self-esteem or with low levels of work ethics seem more likely in engage in risky health behaviours.

Nonlinear response of summer temperature to Holocene insolation forcing in Alaska.

Regional climate responses to large-scale forcings, such as precessional changes in solar irradiation and increases in anthropogenic greenhouse gases, may be nonlinear as a result of complex interactions among earth system components. Such nonlinear behaviors constitute a major source of climate "surprises" with important socioeconomic and ecological implications. Paleorecords are key for elucidating patterns and mechanisms of nonlinear responses to radiative forcing, but their utility has been greatly limited by the paucity of quantitative temperature reconstructions. Here we present Holocene July temperature reconstructions on the basis of midge analysis of sediment cores from three Alaskan lakes. Results show that summer temperatures during 10,000-5,500 calibrated years (cal) B.P. were generally lower than modern and that peak summer temperatures around 5,000 were followed by a decreasing trend toward the present. These patterns stand in stark contrast with the trend of precessional insolation, which decreased by ∼10% from 10,000 y ago to the present. Cool summers before 5,500 cal B.P. coincided with extensive summer ice cover in the western Arctic Ocean, persistence of a positive phase of the Arctic Oscillation, predominantly La Niña-like conditions, and variation in the position of the Alaskan treeline. These results illustrate nonlinear responses of summer temperatures to Holocene insolation radiative forcing in the Alaskan sub-Arctic, possibly because of state changes in the Arctic Oscillation and El Niño-Southern Oscillation and associated land-atmosphere-ocean feedbacks.

Optic nerve sheath diameter and eyeball transverse diameter in severe head injury and its correlation with intracranial pressure.

BACKGROUND: Gold standard for determining intracranial pressure (ICP), intraventricular catheter, is invasive with associated risks. Non-invasive investigations like magnetic resonance imaging and ultrasonography have demonstrated correlation between optic nerve sheath diameter (ONSD) and raised ICP. However, computed tomography (CT) is accessible and less operator-dependent. Literature shows variable results regarding correlations between ICP and ONSD on CT. The study aimed to investigate correlations between raised ICP and ONSD, eyeball transverse diameter (ETD), and ONSD/ETD ratios on CT scan(s) of severe head injuries. METHODS: A retrospective review of a three-year prospectively-maintained database of severe traumatic head injuries in patients who had ICP measurements and CT scans was conducted. Glasgow Coma Score (GCS), ICP, ONSD 3 mm and 9 mm behind the globe, ETD, ONSD/ETD ratios, CT Marshall Grade, and Glasgow Outcome Score (GOS) were recorded. Statistical analysis assessed correlations between ICP and CT measurements. RESULTS: Seventy-four patients were assessed; mortality rate: 36.5 %. Assault (48.6 %) and pedestrian-vehicle collisions (21.6 %) were the most common mechanisms. CT Marshall Grade correlated significantly with 3 mm and 9 mm ONSD, ONSD/ETD ratios, GCS, and GCS motor score, which correlated significantly with GOS. No significant correlation was found between ICP and ONSD, ETD or ONSD/ETD ratios. Marshall Grade was not significantly associated with ICP measurements but correlated with injury severity. CONCLUSIONS: Unlike previous studies, our study not only investigated the correlation between ICP and single variables (ONSD and ETD) but also the ONSD/ETD ratios. No correlations were observed between raised ICP and ONSD, ETD or ONSD/ETD ratio on CT in neurotrauma patients.

Lessons on food security from the COVID-19 pandemic in Bermuda.

Compared with other OECD countries, Bermuda ranks third globally in terms of income inequality globally. During the COVID-19 pandemic, anecdotal evidence suggested, significant fluctuations in the food demand and supply. We aimed to examine the impact of the COVID-19 pandemic on food insecurity, with a focus on the availability and affordability of various foods in Bermuda. We utilized a cross-sectional study design to investigate potential drivers of food insecurity within the local population. To gauge the level of household food insecurity we relied on the Bermuda Omnibus survey (N = 400) undertaken by Total Research Associates Ltd via telephone. To assess changes in food availability and affordability we conducted semi-structured interviews with key stakeholders who played pivotal roles in shaping food accessibility availability and affordability of food in Bermuda. These interviews were systematically analysed using the framework method. We performed analyses of food retail and import data to evaluate fluctuations in food prices and their impact on food availability and affordability. We found statistically significant associations between changes in food consumption, household income, and government aid. Food aid beneficiaries ate fewer fruits and vegetables by 50% [95% CI:17%-83%] and less fresh meat and fish by 39% [95 CI:3%-75%] compared with residents who did not receive any aid during the COVID-19 period from March 2020 to March 2021. Although we did not identify statistically significant food price increases feeding programmes played a pivotal role in preventing food insecurity during the pandemic in Bermuda. However, a lack of monitoring regarding the nutritional quality within the programmes, allowed a wide availability of foods high in sugar, salts, and fats, disproportionately affected low-income populations. In conclusion, food availability in Bermuda remained largely unaffected during the pandemic. Nevertheless, the surge in demand for feeding programs underscores underlying food security challenges in Bermuda and warrants further attention.

Drug experience epigenetically primes Fosb gene inducibility in rat nucleus accumbens.

ΔFosB, a Fosb gene product, is induced in nucleus accumbens (NAc) and caudate-putamen (CPu) by repeated exposure to drugs of abuse such as cocaine. This induction contributes to aberrant patterns of gene expression and behavioral abnormalities seen with repeated drug exposure. Here, we assessed whether a remote history of cocaine exposure in rats might alter inducibility of the Fosb gene elicited by subsequent drug exposure. We show that prior chronic cocaine administration, followed by extended withdrawal, increases inducibility of Fosb in NAc, as evidenced by greater acute induction of ΔFosB mRNA and faster accumulation of ΔFosB protein after repeated cocaine reexposure. No such primed Fosb induction was observed in CPu; in fact, subsequent acute induction of ΔFosB mRNA was suppressed in CPu. These abnormal patterns of Fosb expression are associated with chromatin modifications at the Fosb gene promoter. Prior chronic cocaine administration induces a long-lasting increase in RNA polymerase II (Pol II) binding at the Fosb promoter in NAc only, suggesting that Pol II "stalling" primes Fosb for induction in this region upon reexposure to cocaine. A cocaine challenge then triggers the release of Pol II from the gene promoter, allowing for more rapid Fosb transcription. A cocaine challenge also decreases repressive histone modifications at the Fosb promoter in NAc, but increases such repressive marks and decreases activating marks in CPu. These results provide new insight into the chromatin dynamics at the Fosb promoter and reveal a novel mechanism for primed Fosb induction in NAc upon reexposure to cocaine.

COVID-19 vaccination intentions and subsequent uptake: An analysis of the role of marginalisation in society using British longitudinal data.

COVID-19 vaccine hesitancy has previously been modelled using data on intentions - expressed prior to vaccine availability. Once vaccines became widely available, it became possible to model hesitancy using actual vaccination uptake data. This paper estimates the determinants of the joint distribution of COVID-19 vaccination intentions (declared before the release of any vaccine) and actual vaccination take-up (when it was widely available across the age distribution). We use high quality longitudinal data (UK Household Longitudinal Study) collected during the pandemic in the UK, merged to a wide variety of individual characteristics collected prior to the COVID-19 pandemic. Our estimation draws on pre-Covid values of variables for a sample that includes 10,073 observations from the September 2021 wave. The contribution of this paper is to model hesitancy and uptake jointly. The work shows that people who might be regarded as marginalised in society (measured, before the pandemic began) are less likely to say that they intend to be vaccinated and they go on to also be more likely to actually remain unvaccinated. It also shows that there is a large positive correlation between the unobservable determinants of intention and of uptake. This high positive correlation has an important implication - that information campaigns can be reasonably well profiled to target specific groups on the basis of intention data alone. We also show that changing one's mind is not correlated with observable data. This is consistent with two explanations. Firstly, the new information available on the arrival of vaccines, that they are safe and effective, may be more optimistic than was originally assumed. Secondly, individuals may have been more pessimistic about the effects associated with infection before vaccines became available.

Active travel to school: a longitudinal millennium cohort study of schooling outcomes.

OBJECTIVES: Assess longitudinal associations between active travel during the school commute and later educational outcomes. SETTING: England, Wales and Northern Ireland. PARTICIPANTS: 6778 children, surveyed at ages 7, 11, 14 and 17. PRIMARY AND SECONDARY OUTCOMES: School-leaver General Certificate of Secondary Education exam scores summed to provide a single measure of educational success. RESULTS: Controlling a range of sociodemographic and health variables, using active versus passive travel modes during a child's commute to school during earlier years predicted differences in school-leaver exam performance at age 16. These effects were mediated through changes in self-esteem, emotional difficulties and behavioural difficulties. Examples include: being driven to school at 11 was associated with improved exam performance at 16 mediated through enhanced self-esteem at 14 (ab=0.08, 95% CI=0.01 to 0.20, p=0.05) and cycling at 14 was associated with better exam scores at 16 mediated through reduced emotional difficulty at 16 (ab=0.10, 95% CI=0.01 to 0.30, p=0.05). The relationship between travel mode and exam performance was moderated by household income quintile, most notably with poorer exam performance seen in high-income children who were driven to school. Importantly, although our model predicted 21% of variance in exam performance, removing travel mode barely reduced its ability to predict exam scores (ΔR 2=-0.005, F 20,6469 = 2.50, p<0.001). CONCLUSION: There are differences in school-leaver exam performance linked to travel mode choices earlier in the school career, but these differences are extremely small. There appears to be no realistic educational disadvantage from any given travel mode, strengthening the case for cleaner, healthier modes to become the default.