The earliest thymic T cell progenitors sustain B cell and myeloid lineage potential.

The stepwise commitment from hematopoietic stem cells in the bone marrow to T lymphocyte-restricted progenitors in the thymus represents a paradigm for understanding the requirement for distinct extrinsic cues during different stages of lineage restriction from multipotent to lineage-restricted progenitors. However, the commitment stage at which progenitors migrate from the bone marrow to the thymus remains unclear. Here we provide functional and molecular evidence at the single-cell level that the earliest progenitors in the neonatal thymus had combined granulocyte-monocyte, T lymphocyte and B lymphocyte lineage potential but not megakaryocyte-erythroid lineage potential. These potentials were identical to those of candidate thymus-seeding progenitors in the bone marrow, which were closely related at the molecular level. Our findings establish the distinct lineage-restriction stage at which the T cell lineage-commitment process transits from the bone marrow to the remote thymus.

Bridging the gap: Understanding the barriers and facilitators to performance for Black, Asian and Minority Ethnic medical students in the United Kingdom.

INTRODUCTION: Differential attainment is a well-known phenomenon in medical education. Despite a strong impetus for institutions and researchers to move away from a 'student deficit model' when exploring the attainment gap, little attention has been given to understanding the experiences of Black, Asian and Minority Ethnic (BAME) medical students. Informed by the social construction of learning theory, this is the first national study to explore how multiple dimensions of the medical school environment impact academic performance of BAME undergraduate medical students across the UK. METHODS: Using a sequential explanatory mixed-methods approach, the authors conducted a survey and facilitated three focus groups across medical schools in the UK between 2020-2021. Participants self-identified as being from BAME backgrounds. Quantitative analyses included descriptive statistics and bivariate analyses. Qualitative data were analysed using thematic analysis, subsequently identifying inductive themes. RESULTS: Three hundred sixty-two respondents completed the Phase 1 survey, and 17 participants participated in the Phase 2 focus groups. Although both survey and focus group participants identified facilitators to learning such as supportive relationships, students reported facing numerous barriers that they felt impeded their learning and performance. These barriers included limited access to educational resources, and undiversified curricula and medical school populations. Students also described both experiencing and witnessing various forms of racism throughout their educational journeys. DISCUSSION: Students encountered various difficulties throughout their medical training that they felt impacted their learning and performance. This study offers novel insights into the experiences of BAME students and builds upon previous research. It also reveals the pervasive nature of racism within medical schools, highlighting the urgent need for institutional changes. Educators and institutions must go beyond merely recognising these barriers and facilitators; they must proactively innovate and adapt. In doing so, they pave the way for inclusive learning environments that truly foster a sense of belonging for BAME students.

Thymic involution and rising disease incidence with age.

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 law model 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.

Does socioeconomic position affect knowledge of the risk factors and warning signs of stroke in the WHO European region? A systematic literature review.

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.

IL-17A-Induced PLET1 Expression Contributes to Tissue Repair and Colon Tumorigenesis.

This study identifies a novel mechanism linking IL-17A with colon tissue repair and tumor development. Abrogation of IL-17A signaling in mice attenuated tissue repair of dextran sulfate sodium (DSS)-induced damage in colon epithelium and markedly reduced tumor development in an azoxymethane/DSS model of colitis-associated cancer. A novel IL-17A target gene, PLET1 (a progenitor cell marker involved in wound healing), was highly induced in DSS-treated colon tissues and tumors in an IL-17RC-dependent manner. PLET1 expression was induced in LGR5+ colon epithelial cells after DSS treatment. LGR5+PLET1+ marks a highly proliferative cell population with enhanced expression of IL-17A target genes. PLET1 deficiency impaired tissue repair of DSS-induced damage in colon epithelium and reduced tumor formation in an azoxymethane/DSS model of colitis-associated cancer. Our results suggest that IL-17A-induced PLET1 expression contributes to tissue repair and colon tumorigenesis.

Changes in primary lymphoid organs with aging.

Aging is associated with decreased immune function that leads to increased morbidity and mortality in the elderly. Immune senescence is accompanied by age-related changes in two primary lymphoid organs, bone marrow and thymus, that result in decreased production and function of B and T lymphocytes. In bone marrow, hematopoietic stem cells exhibit reduced self-renewal potential, increased skewing toward myelopoiesis, and decreased production of lymphocytes with aging. These functional sequelae of aging are caused in part by increased oxidative stress, inflammation, adipocyte differentiation, and disruption of hypoxic osteoblastic niches. In thymus, aging is associated with tissue involution, exhibited by a disorganization of the thymic epithelial cell architecture and increased adiposity. This dysregulation correlates with a loss of stroma-thymocyte 'cross-talk', resulting in decreased export of naïve T cells. Mounting evidence argues that with aging, thymic inflammation, systemic stress, local Foxn1 and keratinocyte growth factor expression, and sex steroid levels play critical roles in actively driving thymic involution and overall adaptive immune senescence across the lifespan. With a better understanding of the complex mechanisms and pathways that mediate bone marrow and thymus involution with aging, potential increases for the development of safe and effective interventions to prevent or restore loss of immune function with aging.

Is the onset of disabling chronic conditions in later childhood associated with exposure to social disadvantage in earlier childhood? A prospective cohort study using the ONS Longitudinal Study for England and Wales.

BACKGROUND: The aetiology of disabling chronic conditions in childhood in high income countries is not fully understood, particularly the association with socio-economic status (SES). Very few studies have used longitudinal datasets to examine whether exposure to social disadvantage in early childhood increases the risk of developing chronic conditions in later childhood. Here we examine this association, and its temporal ordering, with onset of all-cause disabling chronic later childhood in children reported as free from disability in early childhood. METHODS: The study comprised a prospective cohort study, using data from the Office for National Statistics Longitudinal Study (ONSLS) for England and Wales. The study sample included 52,839 children with complete data born between 1981-1991 with no disabling chronic condition/s in 1991. Index cases were children with disability recorded in 2001. Comparison cases were children with no recorded disability in 1991. A socio-economic disadvantage index (SDI) was constructed from data on social class, housing tenure and car/van access. Associations were explored with logistic regression modelling controlling sequentially for potentially confounding factors; age, gender, ethnicity and lone parenthood. RESULTS: By 2001, 2049 (4%) had at least one disability. Socio-economic disadvantage, age, gender and lone parenthood but not ethnicity were significantly associated with onset of disabling chronic conditions. The SDI showed a finely graded association with onset of disabling chronic conditions in the index group (most disadvantaged OR 2·11 [CI 1·76 to 2·53]; disadvantaged in two domains OR 1·45 [CI 1·20 to 1·75]; disadvantaged in one domain OR 1·14 [CI 0·93 to 1·39] that was unaffected by age, gender and ethnicity and slightly attenuated by lone parenthood. CONCLUSION: To our knowledge, this is the first study to identify socio-economic disadvantage in earlier childhood as a predisposing factor for onset of all-cause disabling chronic conditions in later childhood. Temporal ordering and gradation of the response indicate socio-economic disadvantage may play a causal role. This suggests that targeting preventative efforts to reduce socio-economic disadvantage in early childhood is likely to be an important public health strategy to decease health inequalities in later childhood and early adulthood.

'Where are you really from?': a qualitative study of racial microaggressions and the impact on medical students in the UK.

OBJECTIVE: To 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. DESIGN: Qualitative study using semistructured focus groups and group interviews. SETTING: UK. PARTICIPANTS: 20 graduate-entry medical students were recruited using volunteer and snowball sampling; all students self-identified as being from racially minoritised (RM) backgrounds. RESULTS: Participants 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. CONCLUSION: RM 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.

Childhood disability and socio-economic circumstances in low and middle income countries: systematic review.

BACKGROUND: The majority of children with disability live in low and middle income (LAMI) countries. Although a number of important reviews of childhood disability in LAMI countries have been published, these have not, to our knowledge, addressed the association between childhood disability and the home socio-economic circumstances (SEC). The objective of this study is to establish the current state of knowledge on the SECs of children with disability and their households in LAMI countries through a systematic review and quality assessment of existing research. METHODS: Electronic databases (MEDLINE; EMBASE; PUBMED; Web of Knowledge; PsycInfo; ASSIA; Virtual Health Library; POPLINE; Google scholar) were searched using terms specific to childhood disability and SECs in LAMI countries. Publications from organisations including the World Bank, UNICEF, International Monetary Fund were searched for. Primary studies and reviews from 1990 onwards were included. Studies were assessed for inclusion, categorisation and quality by 2 researchers. RESULTS: 24 primary studies and 13 reviews were identified. Evidence from the available literature on the association between childhood disability and SECs was inconsistent and inconclusive. Potential mechanisms by which poverty and low household SEC may be both a cause and consequence of disability are outlined in the reviews and the qualitative studies. The association of poor SECs with learning disability and behaviour problems was the most consistent finding and these studies had low/medium risk of bias. Where overall disability was the outcome of interest, findings were divergent and many studies had a high/medium risk of bias. Qualitative studies were methodologically weak. CONCLUSIONS: This review indicates that, despite socially and biologically plausible mechanisms underlying the association of low household SEC with childhood disability in LAMI countries, the empirical evidence from quantitative studies is inconsistent and contradictory. There is evidence for a bidirectional association of low household SEC and disability and longitudinal data is needed to clarify the nature of this association.

Regulatory barriers to equity in a health system in transition: a qualitative study in Bulgaria.

BACKGROUND: Health reforms in Bulgaria have introduced major changes to the financing, delivery and regulation of health care. As in many other countries of Central and Eastern Europe, these included introducing general practice, establishing a health insurance system, reorganizing hospital services, and setting up new payment mechanisms for providers, including patient co-payments. Our study explored perceptions of regulatory barriers to equity in Bulgarian child health services. METHODS: 50 qualitative in-depth interviews with users, providers and policy-makers concerned with child health services in Bulgaria, conducted in two villages, one town of 70,000 inhabitants, and the capital Sofia. RESULTS: The participants in our study reported a variety of regulatory barriers which undermined the principles of equity and, as far as the health insurance system is concerned, solidarity. These included non-participation in the compulsory health insurance system, informal payments, and charging user fees to exempted patients. The participants also reported seemingly unnecessary treatments in the growing private sector. These regulatory failures were associated with the fast pace of reforms, lack of consultation, inadequate public financing of the health system, a perceived "commercialization" of medicine, and weak enforcement of legislation. A recurrent theme from the interviews was the need for better information about patient rights and services covered by the health insurance system. CONCLUSIONS: Regulatory barriers to equity and compliance in daily practice deserve more attention from policy-makers when embarking on health reforms. New financing sources and an increasing role of the private sector need to be accompanied by an appropriate and enforceable regulatory framework to control the behavior of health care providers and ensure equity in access to health services.

Real-time imaging of Leishmania mexicana-infected early phagosomes: a study using primary macrophages generated from green fluorescent protein-Rab5 transgenic mice.

The small GTPase Rab5 is a key regulator of endosome/phagosome maturation and in intravesicular infections marks a phagosome stage at which decisions over pathogen replication or destruction are integrated. It is currently unclear whether Leishmania-infected phagosomes uniformly pass through a Rab5(+) stage on their intracellular path to compartments with late endosomal/early lysosomal characteristics. Differences in routes and final compartments could have consequences for accessibility to antileishmanial drugs. Here, we generated a unique gfp-rab5 transgenic mouse model to visualize Rab5 recruitment to early parasite-containing phagosomes in primary host cells. Using real-time fluorescence imaging of phagosomes carrying Leishmania mexicana, we determined that parasite-infested phagosomes follow a uniform sequence of transient Rab5 recruitment. Residence in Rab5(+) compartments was much shorter compared with phagosomes harboring latex beads. Furthermore, a comparative analysis of parasite life-cycle stages and mutants deficient in lpg1, the gene encoding the enzyme required for synthesis of the dominant surface lipophosphoglycan, indicated that parasite surface ligands and host cell receptors modulate pathogen residence times in Rab5(+) phagosomes, but, as far as tested, had no significant effect on intracellular L. mexicana survival or replication.

Prevalence of childhood disability and the characteristics and circumstances of disabled children in the UK: secondary analysis of the Family Resources Survey.

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.

Policy challenges to the quality of child health services in Bulgaria.

BACKGROUND: Our study aimed to explore policy challenges to the quality of child health services in Bulgaria. METHODS: The study was based on qualitative in-depth interviews, analysis of regulatory documents, and review of the literature. Respondents included policy-makers, providers and users of health services, from both rural and urban areas. RESULTS: Problems identified included insufficient training of general practitioners, medical errors, delays in response to emergencies, inadequate information provided to patients, and underdeveloped child public health. A common view was that paediatricians provide better quality care than general practitioners. Respondents described a lack of clinical guidelines for rational use of pharmaceuticals, overprescribing of antibiotics, reliance on pharmaceutical companies for information, and unrestricted sales of drugs over-the-counter. 'Clinical pathways', introduced as a payment mechanism in hospitals, were perceived as lacking transparency, complicating clinical practice, and forcing doctors to record wrong diagnoses and conduct unnecessary investigations. CONCLUSIONS: Our findings indicate the need to develop evidence-based clinical guidelines for primary and secondary care, establish payment mechanisms that facilitate quality improvements, promote rational use of pharmaceuticals, improve continuing training of physicians and strengthen child public health.

Access to health care for Roma children in Central and Eastern Europe: findings from a qualitative study in Bulgaria.

BACKGROUND: Despite the attention the situation of the Roma in Central and Eastern Europe has received in the context of European Union enlargement, research on their access to health services is very limited, in particular with regard to child health services. METHODS: 50 qualitative in-depth interviews with users, providers and policy-makers concerned with child health services in Bulgaria, conducted in two villages, one town of 70,000 inhabitants, and the capital Sofia. RESULTS: Our findings provide important empirical evidence on the range of barriers Roma children face when accessing health services. Among the most important barriers are poverty, administrative and geographical obstacles, low levels of parental education, and lack of ways to accommodate the cultural, linguistic and religious specifics of this population group. CONCLUSION: Our research illustrates the complexity of the problems the Roma face. Access to health care cannot be discussed in isolation from other problems this population group experiences, such as poverty, restricted access to education, and social exclusion.

Impact of health reforms on child health services in Europe: the case of Bulgaria.

BACKGROUND: In the last two decades, all countries in Europe have embarked on substantial health reforms, introducing new models of financing and provision of health services. Using Bulgaria as a case study, this article examines the impact of the reforms on child health services. METHODS: This is the first of a series of papers drawing on a broader research on inequalities in access to child health services, using Bulgaria as a case study. Multiple methods and data sources were used, including a review of the literature and existing epidemiological data, 50 qualitative in-depth interviews and an analysis of regulatory documents. This article presents the findings of the documentary analysis. RESULTS: Primary health services for children are now provided by general practitioners. Children are exempted from health insurance contributions and user fees and are formally entitled to free health care. During the first years of the reform general practitioners still had insufficient training in child health. Restrictions on the number of referrals to paediatricians and discontinuation of community services at a time when general practice was not well established, undermined access to quality care. CONCLUSION: While many of these issues have been subsequently addressed, the reform process was far from linear. Challenges remain in ensuring access to quality child health services to the rural population and marginalized groups, such as the Roma minority and children with disabilities. Throughout Europe, health reforms need to be based on solid evidence of what works best for improving quality of and access to child health services.

Student perspectives on barriers to performance for black and minority ethnic graduate-entry medical students: a qualitative study in a West Midlands medical school.

OBJECTIVE: To explore graduate-entry medical students experiences of undergraduate training in the context of academic underperformance of medical students from ethnic minority backgrounds. DESIGN: Qualitative study using semi-structured focus groups. SETTING: A West Midlands medical school. PARTICIPANTS: 24 graduate-entry MBChB students were recruited using volunteer and snowball sampling; all students self-identified as being from Black and Minority Ethnic (BME) backgrounds. RESULTS: BME 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. CONCLUSIONS: BME 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.

Contact us for more information: an analysis of public enquiries about stem cells.

Aim: This study examines online enquiries received by two prominent stem cell science initiatives operating in different geographical jurisdictions. Materials & methods: Combined quantitative and qualitative analysis undertaken of internet-based queries (n = 1047) received by Stem Cells Australia and EuroStemCell from members of the public over a two-year period (May 2014-2016). Results: Findings reveal striking similarities between the two datasets and highlight the range of uncertainties, priorities and needs of those seeking information about stem cells online. Conclusion: Sustained and in-depth tailored guidance is needed to effectively meet the diverse stem cell-related information-based needs of communities internationally. Such efforts should be prioritized by regenerative medicine research initiatives and organizations, given the trust and hope diverse publics appear to place in these groups.

Marketing of unproven stem cell-based interventions: A call to action.

Commercial promotion of unsupported therapeutic uses of stem cells is a global problem that has proven resistant to regulatory efforts. Here, we suggest a coordinated approach at the national and international levels focused on engagement, harmonization, and enforcement to reduce the risks associated with direct-to-consumer marketing of unproven stem cell treatments.

Heterologous expression of the filarial nematode alt gene products reveals their potential to inhibit immune function.

BACKGROUND: Parasites exploit sophisticated strategies to evade host immunity that require both adaptation of existing genes and evolution of new gene families. We have addressed this question by testing the immunological function of novel genes from helminth parasites, in which conventional transgenesis is not yet possible. We investigated two such novel genes from Brugia malayi termed abundant larval transcript (alt), expression of which reaches ~5% of total transcript at the time parasites enter the human host. RESULTS: To test the hypothesis that ALT proteins modulate host immunity, we adopted an alternative transfection strategy to express these products in the protozoan parasite Leishmania mexicana. We then followed the course of infection in vitro in macrophages and in vivo in mice. Expression of ALT proteins, but not a truncated mutant, conferred greater infectivity of macrophages in vitro, reaching 3-fold higher parasite densities. alt-transfected parasites also caused accelerated disease in vivo, and fewer mice were able to clear infection of organisms expressing ALT. alt-transfected parasites were more resistant to IFN-gamma-induced killing by macrophages. Expression profiling of macrophages infected with transgenic L. mexicana revealed consistently higher levels of GATA-3 and SOCS-1 transcripts, both associated with the Th2-type response observed in in vivo filarial infection. CONCLUSION: Leishmania transfection is a tractable and informative approach to determining immunological functions of single genes from heterologous organisms. In the case of the filarial ALT proteins, our data suggest that they may participate in the Th2 bias observed in the response to parasite infection by modulating cytokine-induced signalling within immune system cells.