Recent research in rodents has demonstrated that exposure to bacterial endotoxin during the neonatal period alters the development of the hypothalamic-pituitary-adrenal axis resulting in hypersecretion of corticosterone after stress-exposure in adulthood. Given the known interactions between glucocorticoids and the immune system it was hypothesized that such alterations may impact on immune outcomes. Fischer 344 rats were treated with endotoxin (50 g/kg Salmonella enteritidis, i.p.) or the vehicle on postpartum d 1, 3, 5, and 7. In adulthood, animals were subjected to chronic stress (6 ϫ 10 h/d restraint stress), and the effect on resistance to tumor colonization (experiment 1) and natural killer cell activity (experiment 2) was assessed. Experiment 3 assessed corticosterone responses to acute stress in adulthood after neonatal endotoxin or saline treatment. Neonatal endotoxin exposure resulted in a 2-fold increase in tumor colonization (p Ͻ 0.001) and a significant impairment in the activity of natural killer cells (p Ͻ 0.01), cells critically involved in the surveillance and eradication of tumor cells. Neonatal endotoxin exposure also resulted in a significant decrease in gain weight that persisted into adulthood (p Ͻ 0.05), and potentiation of corticosterone responses to acute stress in adulthood (p Ͻ 0.05). We conclude that neonatal endotoxin exposure produces longterm changes in the hypothalamic-pituitary-adrenal axis, and has significant long-term effects on immune function, specifically in terms of resistance to tumor colonization in adulthood. Development of the fetus is determined by interactions between, among others, the neurochemical, immune, and endocrine systems. Cell-mediated and humoral immunity continue to develop throughout the early postnatal period and are dependent on appropriate immune-endocrine signaling (1, 2), and normal development of the HPA and hypothalamicgonadal axes is influenced by early immune activation (3, 4). Exposure to stress during this postnatal period influences stress responsivity in adulthood. For instance, exposure of neonatal rat pups to bacterial endotoxin, or separation of pups from their dam, results in hyperresponsivity of the HPA axis to stress when these animals, as adults, are exposed to stress (5-9). There is a common hypothesis concerning the mechanism behind these long-term changes, that exposure of the neonate to stress, at a period when there is considerable neural plasticity, alters glucocorticoid receptor numbers producing changes in HPA sensitivity (6,10,11). Consistent with this hypothesis, both neonatal endotoxin exposure and maternal separation induce high levels of ACTH and corticosterone in neonatal rodent pups (12)(13)(14). This is associated with reduced glucocorticoid receptor density in the hypothalamus, hippocampus, and frontal cortex (5), increased hypothalamic corticotropinreleasing hormone mRNA levels (6), and increased plasma corticosterone levels (6, 7, 9) in adulthood. This downregulation in receptor concentration results in reduced gluc...

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Background Medical student burnout is a prevalent problem with adverse long-term outcomes. Incorporating psychological resource-building interventions into comprehensive burnout prevention approaches during medical training is an identified priority among educators. These interventions could reduce burnout risk by buffering students against nonmodifiable career stressors. However, there is a need for rigorous investigation into optimal intervention targets and methods. Psychological flexibility (PF) is an adaptive behavioral skill set that has demonstrated relationships with medical student burnout and well-being. More broadly, there is evidence that PF mediates burnout and well-being outcomes and may be a protective factor. Efficacy studies assessing the benefits of interventions targeting PF among medical students are needed. Research also supports the need to establish optimal methods for increasing intervention efficacy in the context of individual differences in burnout and PF by using individualized approaches. Objective This study aims to assess whether an app-delivered PF intervention (Acceptance and Commitment Training) reduces burnout and improves well-being among medical students. We will examine whether changes in burnout and well-being are mediated by changes in PF. The potential benefits of an individualized version of the app versus those of a nonindividualized version will also be evaluated. Methods In this 3-arm, parallel, randomized controlled study, a sample of medical students will be randomly allocated to 1 of 3 intervention arms (individualized, nonindividualized, and waiting list) by using a 1:1:1 allocation ratio. Participants in the individualized and nonindividualized intervention arms will have 5 weeks to access the app, which includes a PF concepts training session (stage 1) and access to short PF skill activities on demand (stage 2). Stage 2 will be either individualized to meet participants’ identified PF training needs at each log-in or nonindividualized. Results Burnout, well-being, and PF will be assessed at baseline and after the intervention. Quantitative analyses will include descriptive and inferential statistics. We hypothesize that the Acceptance and Commitment Training intervention app will be effective in improving burnout and well-being and that changes in these outcomes will be mediated by changes in PF. We further hypothesize that participants in the individualized intervention group will demonstrate greater improvements in burnout and well-being outcomes than those in the nonindividualized group. Conclusions The findings of this study could guide the development of burnout prevention and well-being initiatives for medical students. Identifying PF as a mediating process would provide support for the delivery of preventive intervention programs that train individuals to strengthen this psychological resource before burnout symptoms emerge. This would be an important step in addressing and potentially offsetting the significant costs of burnout among medical students and physicians. Demonstrating the superiority of an individualized version of the app over a nonindividualized version would have implications for enhancing intervention precision and efficacy by using scalable interventions. Trial Registration Australian New Zealand Clinical Trials Registry ANZCTR 12621000911897; https://www.anzctr.org.au/ACTRN12621000911897.aspx International Registered Report Identifier (IRRID) PRR1-10.2196/32992

Background Medical students are at higher risk of burnout than the general population. Interventions that facilitate adaptive coping behaviors (eg, Psychological Flexibility) in the context of inherent stressors associated with medical training could mitigate burnout risk and improve well-being. Delivering these interventions using smartphone apps offers advantages such as accessibility, scalability, mitigation of time and stigma barriers, and facilitation of individual tailoring (individualization). There is a need for feasibility trials with medical students in this emerging field. Formal evaluations of user experiences of app-based psychological skill training are required to identify barriers to and facilitators of engagement and optimize intervention development before implementation in efficacy trials and real-world settings. Objective This study aimed to assess the feasibility of delivering an individualized Psychological Flexibility skill training intervention (Acceptance and Commitment Training [ACTraining]) to medical students using an app-based delivery format. We further aimed to explore how formal evaluation of user experiences might inform and guide the development of this app before implementation in an efficacy trial and future research involving app-delivered psychological skill training for medical students. Methods This single-arm study was an early-phase feasibility trial of a stand-alone ACTraining app conducted with a sample of Australian medical students (n=11). We collected app usability and user experience data across a broad range of domains (eg, perceived helpfulness and relevance, learning experiences, and self-efficacy) using self-report questionnaires (quantitative and qualitative) and behavioral engagement outcomes. Results Behavioral engagement data demonstrated that the app delivered the assessment procedures and individualized ACTraining intervention to medical students as intended. The subjective feedback provided by students who actively engaged with the app was generally positive across several indicators, including usability, perceived relevance and helpfulness, accessibility, maintenance of privacy, and opportunity for self-reflection. Disengagement from the app was an identified challenge throughout the trial. Participant feedback identified several factors that may have affected engagement, such as time, expectations regarding app interface functioning, and individual differences in confidence and self-efficacy when implementing skills. Conclusions This study reports user experience data that have been largely absent from the literature on digital psychological interventions for medical students. Our findings demonstrate the preliminary feasibility of an app-delivered ACTraining intervention for medical student well-being and burnout and support the value of future assessment of the efficacy of this approach with larger samples. We consider subjective feedback from medical students in relation to observed engagement and propose how this information might be used to inform the development of this app and future research in this nascent field.