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For many cancer types, incidence rises rapidly with age as an apparent power law, supporting the idea that cancer is caused by a gradual accumulation of genetic mutations. Similarly, the incidence of many infectious diseases strongly increases with age. Here, combining data from immunology and epidemiology, we show that many of these dramatic age-related increases in incidence can be modeled based on immune system decline, rather than mutation accumulation. In humans, the thymus atrophies from infancy, resulting in an exponential decline in T cell production with a half-life of ∼16 years, which we use as the basis for a minimal mathematical model of disease incidence. Our model outperforms the power lawmodel with the same number of fitting parameters in describing cancer incidence data across a wide spectrum of different cancers, and provides excellent fits to infectious disease data. This framework provides mechanistic insight into cancer emergence, suggesting that age-related decline in T cell output is a major risk factor.

The forkhead transcription factor Foxn1 is indispensable for thymus development, but the mechanisms by which it mediates thymic epithelial cell (TEC) development are poorly understood. To examine the cellular and molecular basis of Foxn1 function, we generated a novel and revertible hypomorphic allele of Foxn1. By varying levels of its expression, we identified a number of features of the Foxn1 system. Here we show that Foxn1 is a powerful regulator of TEC differentiation that is required at multiple intermediate stages of TE lineage development in the fetal and adult thymus. We find no evidence for a role for Foxn1 in TEC fate-choice. Rather, we show it is required for stable entry into both the cortical and medullary TEC differentiation programmes and subsequently is needed at increasing dosage for progression through successive differentiation states in both cortical and medullary TEC. We further demonstrate regulation by Foxn1 of a suite of genes with diverse roles in thymus development and/or function, suggesting it acts as a master regulator of the core thymic epithelial programme rather than regulating a particular aspect of TEC biology. Overall, our data establish a genetics-based model of cellular hierarchies in the TE lineage and provide mechanistic insight relating titration of a single transcription factor to control of lineage progression. Our novel revertible hypomorph system may be similarly applied to analyzing other regulators of development.

Thymus function requires extensive cross-talk between developing T-cells and the thymic epithelium, which consists of cortical and medullary TEC. The transcription factor FOXN1 is the master regulator of TEC differentiation and function, and declining Foxn1 expression with age results in stereotypical thymic involution. Understanding of the dynamics of Foxn1 expression is, however, limited by a lack of single cell resolution data. We have generated a novel reporter of Foxn1 expression, Foxn1G, to monitor changes in Foxn1 expression during embryogenesis and involution. Our data reveal that early differentiation and maturation of cortical and medullary TEC coincides with precise sub-lineage-specific regulation of Foxn1 expression levels. We further show that initiation of thymic involution is associated with reduced cTEC functionality, and proportional expansion of FOXN1-negative TEC in both cortical and medullary sub-lineages. Cortex-specific down-regulation of Foxn1 between 1 and 3 months of age may therefore be a key driver of the early stages of age-related thymic involution.

ObjectiveTo explore graduate-entry medical students experiences of undergraduate training in the context of academic underperformance of medical students from ethnic minority backgrounds.DesignQualitative study using semi-structured focus groups.SettingA West Midlands medical school.Participants24 graduate-entry MBChB students were recruited using volunteer and snowball sampling; all students self-identified as being from Black and Minority Ethnic (BME) backgrounds.ResultsBME students reported facing a range of difficulties, throughout their undergraduate medical training, that they felt impeded their learning and performance. Their relationships with staff and clinicians, though also identified as facilitators to learning, were also perceived to have hindered progress, as many students felt that a lack of BME representation and lack of understanding of cultural differences among staff impacted their experience. Students also reported a lack of trust in the institution’s ability to support BME students, with many not seeking support. Students’ narratives indicated that they had to mask their identity to fit in among their peers and to avoid negative stereotyping. Although rare, students faced overt racism from their peers and from patients. Many students reported feelings of isolation, reduced self-confidence and low self-esteem.ConclusionsBME students in this study reported experiencing relationship issues with other students, academic and clinical staff, lack of trust in the institution and some racist events. Although it is not clear from this small study of one institution whether these findings would be replicated in other institutions, they nevertheless highlight important issues to be considered by the institution concerned and other institutions. These findings suggest that all stakeholders of graduate-entry undergraduate medical education should reflect on the current institutional practices intended to improve student–peer and student–staff relationships. Reviewing current proposals intended to diversify student and staff populations as well as evaluating guidance on tackling racism is likely to be beneficial.

Background Strokes are one of the leading causes of death worldwide. People with a lower socioeconomic position (SEP) (i.e. with regards to education, income and occupation) are at a higher risk of having a stroke and have worse clinical outcomes compared to the general population. Good knowledge levels about stroke risk factors and warning signs are key to prolonging life and reducing health issues caused by stroke. This systematic review examined differences in knowledge of stroke risk factors and warning signs with regards to SEP in the WHO European region. Methods MEDLINE, Embase, Web of Science, PsycINFO and CINAHL were systematically searched using appropriate Medical Subject Headings (MeSH) terms and free text, combining search terms with Boolean operators. Two independent reviewers selected studies in two stages (title and abstract, and full-text), and screened reference lists of included studies. Only studies in English and based in the WHO European region were included. Results Screening identified 2118 records. In the final review, 20 articles were included, with 67,309 study participants between them. Out of 17 studies that looked at stroke risk factors, 11 found increasing knowledge to be associated with higher SEP, four found no difference by SEP, one showed a mixed pattern and one outlier study found increasing knowledge of risk factors to be associated with a lower SEP. Out of 19 studies that looked at stroke warning signs or symptoms, 15 found there to be better knowledge of warning signs with a higher SEP, three found there to be no difference, and the same outlier study found increasing knowledge of warning signs with a lower SEP. Studies that seemed to have a higher quality rating found increasing knowledge of stroke with a higher SEP. A meta-analysis was not possible due to heterogeneity of studies. Conclusions In the WHO European region, better knowledge of stroke risk factors and warning signs is associated with a higher SEP. Public health campaigns and educational interventions aiming to increase stroke knowledge should be targeted at people with a lower SEP.

ObjectiveTo determine the association of socioeconomic disadvantage with the prevalence of childhood disabling chronic conditions in high-income countries.Study designSystematic review and meta-analyses.Data sources6 electronic databases, relevant websites, reference lists and experts in the field.Study selection160 observational studies conducted in high-income countries with data on socioeconomic status and disabling chronic conditions in childhood, published between 1 January 1991 and 31 December 2013.Data extraction and synthesisAbstracts were reviewed, full papers obtained, and papers identified for inclusion by 2 independent reviewers. Inclusion decisions were checked by a third reviewer. Where reported, ORs were extracted for low versus high socioeconomic status. For studies reporting raw data but not ORs, ORs were calculated. Narrative analysis was undertaken for studies without data suitable for meta-analysis.Results126 studies had data suitable for meta-analysis. ORs for risk estimates were: all-cause disabling chronic conditions 1.72 (95% CI 1.48 to 2.01); psychological disorders 1.88 (95% CI 1.68 to 2.10); intellectual disability 2.41 (95% CI 2.03 to 2.86); activity-limiting asthma 2.20 (95% CI 1.87 to 2.85); cerebral palsy 1.42 (95% CI 1.26 to 1.61); congenital abnormalities 1.41 (95% CI 1.24 to 1.61); epilepsy 1.38 (95% CI 1.20 to 1.59); sensory impairment 1.70 (95% CI 1.39 to 2.07). Heterogeneity was high across most estimates (I2>75%). Of the 34 studies without data suitable for meta-analysis, 26 reported results consistent with increased risk associated with low socioeconomic status.ConclusionsThe findings indicate that, in high-income countries, childhood disabling chronic conditions are associated with social disadvantage. Although evidence of an association is consistent across different countries, the review provides limited evidence to explain the association; future research, using longitudinal data, will be required to distinguish low socioeconomic status as the cause or consequence of childhood disabling chronic conditions and the aetiological pathways and mechanisms.

ObjectiveTo explore graduate-entry medical students’ experiences of racial microaggressions, the impact of these on learning, performance and attainment, and their views on how these can be reduced.DesignQualitative study using semistructured focus groups and group interviews.SettingUK.Participants20 graduate-entry medical students were recruited using volunteer and snowball sampling; all students self-identified as being from racially minoritised (RM) backgrounds.ResultsParticipants reported experiencing numerous types of racial microaggressions during their time at medical school. Students’ accounts highlighted how these impacted directly and indirectly on their learning, performance and well-being. Students frequently reported feeling uncomfortable and out of place in teaching sessions and clinical placements. Students also reported feeling invisible and ignored in placements and not being offered the same learning opportunities as their white counterparts. This led to lack of access to learning experiences or disengagement from learning. Many participants described how being from an RM background was associated with feelings of apprehension and having their ‘guards up’, particularly at the start of new clinical placements. This was perceived to be an additional burden that was not experienced by their white counterparts. Students suggested that future interventions should focus on institutional changes to diversify student and staff populations; shifting the culture to build and maintain inclusive environments; encouraging open, transparent conversations around racism and promptly managing any student-reported racial experiences.ConclusionRM students in this study reported that their medical school experiences were regularly affected by racial microaggressions. Students believed these microaggressions impeded their learning, performance and well-being. It is imperative that institutions increase their awareness of the difficulties faced by RM students and provide appropriate support in challenging times. Fostering inclusion as well as embedding antiracist pedagogy into medical curricula is likely to be beneficial.

Background Robust data on the prevalence of childhood disability and the circumstances and characteristics of disabled children is crucial to understanding the relationship between impairment and social disadvantage. It is also crucial for public policy development aimed at reducing the prevalence of childhood disability and providing appropriate and timely service provision. This paper reports prevalence rates for childhood disability in the United Kingdom (UK) and describes the social and household circumstances of disabled children, comparing these where appropriate to those of non-disabled children. Methods Data were generated from secondary analysis of the Family Resources Survey, a national UK cross-sectional survey, (2004/5) which had data on 16,012 children aged 0-18 years. Children were defined as disabled if they met the Disability Discrimination Act (DDA) definition (1995 and 2005). Frequency distributions and cross-tabulations were run to establish prevalence estimates, and describe the circumstances of disabled children. To establish the association between individual social and material factors and childhood disability when other factors were controlled for, logistic regression models were fitted on the dependent variable 'DDA defined disability'. Results 7.3% (CI 6.9, 7.7) of UK children were reported by as disabled according to the DDA definition. Patterns of disability differed between sexes with boys having a higher rate overall and more likely than girls to experience difficulties with physical coordination; memory, concentration and learning; communication. Disabled children lived in different personal situations from their non-disabled counterparts, and were more likely to live with low-income, deprivation, debt and poor housing. This was particularly the case for disabled children from black/minority ethnic/mixed parentage groups and lone-parent households. Childhood disability was associated with lone parenthood and parental disability and these associations persisted when social disadvantage was controlled for. Conclusion These analyses suggest that UK disabled children experience higher levels of poverty and personal and social disadvantage than other children. Further research is required to establish accurate prevalence estimates of childhood disability among different black and minority ethnic groups and to understand the associations between childhood disability and lone parenthood and the higher rates of sibling and parental disability in households with disabled children.

During development, cortical (c) and medullary (m) thymic epithelial cells (TEC) arise from the third pharyngeal pouch endoderm. Current models suggest that within the thymic primordium most TEC exist in a bipotent/common thymic epithelial progenitor cell (TEPC) state able to generate both cTEC and mTEC, at least until embryonic day 12.5 (E12.5) in the mouse. This view, however, is challenged by recent transcriptomics and genetic evidence. We therefore set out to investigate the fate and potency of TEC in the early thymus. Here using single cell (sc) RNAseq we identify a candidate mTEC progenitor population at E12.5, consistent with recent reports. Via lineage-tracing we demonstrate this population as mTEC fate-restricted, validating our bioinformatics prediction. Using potency analyses we also establish that most E11.5 and E12.5 progenitor TEC are cTEC-fated. Finally we show that overnight culture causes most if not all E12.5 cTEC-fated TEPC to acquire functional bipotency, and provide a likely molecular mechanism for this changed differentiation potential. Collectively, our data overturn the widely held view that a common TEPC predominates in the E12.5 thymus, showing instead that sublineage-primed progenitors are present from the earliest stages of thymus organogenesis but that these early fetal TEPC exhibit cell-fate plasticity in response to extrinsic factors. Our data provide a significant advance in the understanding of fetal thymic epithelial development and thus have implications for thymus-related clinical research, in particular research focussed on generating TEC from pluripotent stem cells

Palmer et al comments on the criticisms of their study exploring the relationship between thymic involution and rising disease incidence with age. There are experiments from the 1970s in which athymic mice are measured to have similar cancer risk to normal mice, while having increased risk of infectious diseases. Furthermore, individuals with DiGeorge syndrome often have thymus problems and a higher risk of infectious diseases, yet some reports find that they have similar cancer risk. On the other hand, there are experiments in which thymectomized mice displayed a higher cancer risk and others in which thymus grafts on nude mice induce cancer remission. In addition, there is an association between low T cell receptor excision circles (a by-product of T cell production) and certain cancers, and a perspective study found that short leukocyte telomeres predict cancer risk. They stresses that their article provide statistical support for thymic T cell output strongly influencing cancer incidence.