Spectrum of HLA associations: the case of medically refractory pediatric acute lymphoblastic leukemia

Although studies of HLA and disease now date back some 50 years, a principled understanding of that relationship has been slow to emerge. Here, we examine the associations of three HLA loci with medically refractory pediatric acute lymphoblastic leukemia (pALL) patients in a case–control study involving 2,438 cases and 41,750 controls. An analysis of alleles from the class I loci, HLA-A and HLA-B, and the class II locus DRB1 illuminates a spectrum of extremely significant allelic associations conferring both predisposition and protection. Genotypes constructed from predisposing, protective, and neutral allelic categories point to an additive mode of disease causation. For all three loci, genotypes homozygous for predisposing alleles are at highest disease risk while the favorable effect of homozygous protective genotypes is less striking. Analysis of A–B and B–DRB1 haplotypes reveals locus-specific differences in disease effects, while that all three loci influence pALL; the influence of HLA-B is greater than that of HLA-A, and the predisposing effect of DRB1 exceeds that of HLA-B. We propose that the continuum in disease susceptibility suggests a system in which many alleles take part in disease predisposition based on differences in binding affinity to one or a few peptides of exogenous origin. This work provides evidence that an immune response mediated by alleles from several HLA loci plays a critical role in the pathogenesis of pALL, adding to the numerous studies pointing to a role for an infectious origin in pALL

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Private schooling and labour market outcomes

Though a relative small part of the school sector, private schools have an important role in British society, and there are policy concerns about their negative effect on social mobility. Other studies show that individuals who have attended a private school go on to have higher levels of educational achievement, are more likely to secure a high-status occupation and also have higher wages. In this article we contribute new evidence on the magnitude of the wage premium, and address a puzzle found in previous studies: how to explain the direct pay premium whereby privately educated male workers have higher wages even than their similarly educated peers. It is commonly conjectured that the broader curriculum that private schools are able to deliver, coupled with the peer pressures of a partially segregated section of society, help to inculcate cultural capital, including some key ‘non-cognitive’ attributes. We focus here on leadership, organisational participation and an acceptance of hard work. We find that privately educated workers are in jobs that require significantly greater leadership skills, offer greater organisational participation and require greater work intensity. These associations are partially mediated by educational achievement. Collectively these factors contribute little, however, to explaining the direct pay premium. Rather, a more promising account arises from the finding that inclusion of a variable for industry reduces the private school premium to an insignificant amount, which is consistent with selective sorting of privately educated workers into high-paying industries.This work was supported by the ESRC‐funded LLAKES Centre at UCL Institute of Education

Learning Ethnography Through Doing Ethnography: Two Student—Researchers’ Insights

In this article, we present the accounts of the field experiences and challenges of two graduate student-researchers practising ethnographic methodology, conducting fieldwork, and writing up “post-modern” ethnographies that are both creative and “integrative”. We describe the complexities and tensions when two student-researchers negotiated many issues in the field and “behind the desk” as they transformed the texts: epistemology and ontology, reflexivity and auto-ethnography, and writing researchers and participants in and out of accounts. We conclude with a discussion on pedagogical implications, and consider the value of learning ethnography through doing ethnography

Mitochondrial function as a determinant of life span

Average human life expectancy has progressively increased over many decades largely due to improvements in nutrition, vaccination, antimicrobial agents, and effective treatment/prevention of cardiovascular disease, cancer, etc. Maximal life span, in contrast, has changed very little. Caloric restriction (CR) increases maximal life span in many species, in concert with improvements in mitochondrial function. These effects have yet to be demonstrated in humans, and the duration and level of CR required to extend life span in animals is not realistic in humans. Physical activity (voluntary exercise) continues to hold much promise for increasing healthy life expectancy in humans, but remains to show any impact to increase maximal life span. However, longevity in Caenorhabditis elegans is related to activity levels, possibly through maintenance of mitochondrial function throughout the life span. In humans, we reported a progressive decline in muscle mitochondrial DNA abundance and protein synthesis with age. Other investigators also noted age-related declines in muscle mitochondrial function, which are related to peak oxygen uptake. Long-term aerobic exercise largely prevented age-related declines in mitochondrial DNA abundance and function in humans and may increase spontaneous activity levels in mice. Notwithstanding, the impact of aerobic exercise and activity levels on maximal life span is uncertain. It is proposed that age-related declines in mitochondrial content and function not only affect physical function, but also play a major role in regulation of life span. Regular aerobic exercise and prevention of adiposity by healthy diet may increase healthy life expectancy and prolong life span through beneficial effects at the level of the mitochondrion

Oceanic Residual Depth Measurements, the Plate Cooling Model and Global Dynamic Topography

Convective circulation of the mantle causes deflections of the Earth's surface that vary as a function of space and time. Accurate measurements of this dynamic topography are complicated by the need to isolate and remove other sources of elevation, arising from flexure and lithospheric isostasy. The complex architecture of continental lithosphere means that measurement of present-day dynamic topography is more straightforward in the oceanic realm. Here, we present an updated methodology for calculating oceanic residual bathymetry, which is a proxy for dynamic topography. Corrections are applied that account for the effects of sedimentary loading and compaction, for anomalous crustal thickness variations, for subsidence of oceanic lithosphere as a function of age, and for non-hydrostatic geoid height variations. Errors are formally propagated to estimate measurement uncertainties. We apply this methodology to a global database of 1,936 seismic surveys located on oceanic crust and generate 2,297 spot measurements of residual topography, including 1,161 with crustal corrections. The resultant anomalies have amplitudes of ±1 km and wavelengths of ∼1,000 km. Spectral analysis of our database using cross-validation demonstrates that spherical harmonics up to and including degree 30 (i.e. wavelengths down to 1,300 km) are required to accurately represent these observations. Truncation of the expansion at a lower maximum degree erroneously increases the amplitude of inferred long-wavelength dynamic topography. There is a strong correlation between our observations and free-air gravity anomalies, magmatism, ridge seismicity, vertical motions of adjacent rifted margins, and global tomographic models. We infer that shorter wavelength components of the observed pattern of dynamic topography may be attributable to the presence of thermal anomalies within the shallow asthenospheric mantle.This research is supported by a BP-Cambridge collaboration