Childhood cancer research in oxford III: The work of CCRG on ionising radiation.

BACKGROUND: High doses of ionising radiation are a known cause of childhood cancer and great public and professional interest attaches to possible links between childhood cancer and lower doses, particularly of man-made radiation. This paper describes work done by the Childhood Cancer Research Group (CCRG) on this topic METHODS: Most UK investigations have made use of the National Registry of Childhood Tumours and associated controls. Epidemiological investigations have included national incidence and mortality analyses, geographical investigations, record linkage and case-control studies. Dosimetric studies use biokinetic and dosimetric modelling. RESULTS: This paper reviews the work of the CCRG on the association between exposure to ionising radiation and childhood cancer, 1975-2014. CONCLUSION: The work of CCRG has been influential in developing understanding of the causes of 'clusters' of childhood cancer and the risks arising from exposure to ionising radiation both natural and man-made. Some clusters around nuclear installations have certainly been observed, but ionising radiation does not seem to be a plausible cause. The group's work has also been instrumental in discounting the hypothesis that paternal preconception irradiation was a cause of childhood cancers and has demonstrated an increased leukaemia risk for children exposed to higher levels of natural gamma-ray radiation.

Correlates of T-cell-mediated viral control and phenotype of CD8(+) T cells in HIV-2, a naturally contained human retroviral infection.

While a significant proportion of HIV-2-infected individuals are asymptomatic and maintain undetectable viral loads (controllers), 15% to 20% progress to AIDS and are predicted by detectable viremia. Identifying immune correlates that distinguish these 2 groups should provide insights into how a potentially pathogenic retrovirus can be naturally controlled. We performed a detailed study of HIV-2-specific cellular responses in a unique community cohort in Guinea-Bissau followed for over 2 decades. T-cell responses were compared between controllers (n = 33) and viremic subjects (n = 27) using overlapping peptides, major histocompatibility complex class I tetramers, and multiparameter flow cytometry. HIV-2 viral control was significantly associated with a high-magnitude, polyfunctional Gag-specific CD8(+) T-cell response but not with greater perforin upregulation. This potentially protective HIV-2-specific response is surprisingly narrow. HIV-2 Gag-specific CD8(+) T cells are at an earlier stage of differentiation than cytomegalovirus-specific CD8(+) T-cells, do not contain high levels of cytolytic markers, and exhibit low levels of activation and proliferation, representing distinct properties from CD8(+) T cells associated with HIV-1 control. These data reveal the potential T-cell correlates of HIV-2 control and the detailed phenotype of virus-specific CD8(+) T cells in a naturally contained retroviral infection.

Cross-space-time clustering of childhood cancer in Great Britain: evidence for a common aetiology.

Previously, we identified space-time clustering in certain childhood cancers. This study aimed to determine whether there was cross-space-time clustering between different diagnostic groups. A total of 32,295 cases were diagnosed during 1969-1993. Cross-space-time clustering was analyzed by a second-order procedure based on Diggle's method. Locations were birth and diagnosis addresses. The following space-time combinations were examined: address and date of birth; address at birth and date of diagnosis; address and date of diagnosis. Cross-space-time clustering analyses considered clustering pairs of cases from two different diagnostic groups. Formal statistical significance was taken as p < 0.00067 and marginal significance 0.01 > p ≥ 0.00067. Based on address at birth and date of diagnosis, there was statistically significant cross-clustering between cases of HL and intracranial and intraspinal embryonal tumors (IIET), both aged 0-14 years (p < 0.0001). Based on address and date of birth, there was marginally significant cross-clustering between cases of lymphoid leukemia (LL) aged 5-14 years and Hodgkin lymphoma (HL) aged 0-14 years (p = 0.0019). Based on address and date of diagnosis there was marginally significant cross-clustering between cases of LL aged 1-4 years and soft tissue sarcoma (STS) aged 0-14 years (p = 0.0041). Findings from this study are consistent with possible common aetiological factors between different diagnostic groups. They suggest a common aetiology for the following pairs of diagnostic groups: HL and IIET; older cases of LL and HL; younger cases of LL and STS. The possibility of common infectious mechanisms should be explored.

Qualitative study of the impact of an authentic electronic portfolio in undergraduate medical education.

BACKGROUND: Portfolios are increasingly used in undergraduate and postgraduate medical education. Four medical schools have collaborated with an established NHS electronic portfolio provider to develop and implement an authentic professional electronic portfolio for undergraduate students. We hypothesized that using an authentic portfolio would have significant advantages for students, particularly in familiarizing them with the tool many will continue to use for years after graduation. This paper describes the early evaluation of this undergraduate portfolio at two participating medical schools. METHODS: To gather data, a questionnaire survey with extensive free text comments was used at School 1, and three focus groups were held at School 2. This paper reports thematic analysis of students' opinions expressed in the free text comments and focus groups. RESULTS: Five main themes, common across both schools were identified. These concerned the purpose, use and acceptability of the portfolio, advantages of and barriers to the use of the portfolio, and the impacts on both learning and professional identity. CONCLUSIONS: An authentic portfolio mitigated some of the negative aspects of using a portfolio, and had a positive effect on students' perception of themselves as becoming past of the profession. However, significant barriers to portfolio use remained, including a lack of understanding of the purpose of a portfolio and a perceived damaging effect on feedback.

Small-area analyses of bone cancer diagnosed in Great Britain provide clues to aetiology.

BACKGROUND: The aetiology of bone cancers is poorly understood. This study examined geographical patterning in incidence of primary bone cancers diagnosed in 0-49 year olds in Great Britain during 1980-2005 to provide information on factors linked with disease development. We investigated putative associations with deprivation and population density. METHODS: Data on osteosarcoma and Ewing sarcoma were obtained from national population-based registries. Negative binomial regression was used to examine the relationship between incidence rates and the Townsend deprivation score (and its component variables) and small-area population density. RESULTS: The study analyzed 2566 osteosarcoma and 1650 Ewing sarcoma cases. For females with osteosarcoma, statistically significant decreased risk was associated with higher levels of deprivation (relative risk [RR] per unit increase in deprivation score = 0.969; 95% confidence interval [CI] 0.946-0.993). For all Ewing sarcoma combined, statistically significant decreased risk was associated with greater area-level population density and higher levels of non-car ownership (RR per person per hectare increase = 0.984; 95% CI 0.976-0.993, RR per 1% increase in non-car ownership = 0.994; 95% CI 0.991-0.998). CONCLUSIONS: Higher incidence of osteosarcoma was observed for females in areas with lower deprivation levels indicating increased risk is linked to some aspect of affluent living. Higher incidence of Ewing sarcoma occurred in areas of low population density and where more people owned cars, both characteristic of rural environments. The study adds substantially to evidence associating Ewing sarcoma risk with rural environmental exposures. Putative risk factors include agricultural exposures, such as pesticides and zoonotic agents.

Immunophenotype and cytogenetic characteristics in the relationship between birth weight and childhood leukemia.

BACKGROUND: High birth weight increases the risk of childhood acute lymphoid leukemia (ALL) through unknown mechanisms. Whether this risk is specific to ALL subtypes is unknown, and low case numbers have prevented investigation of the rarer leukemias. Here we address these associations using a large population-based dataset. PROCEDURE: Using the National Registry of Childhood Tumors, birth weights of 7,826 leukemia cases, defined by immunophenotype and cytogenetic subgroup, were compared with those of 10,785 controls born in England and Wales between 1980 and 2007. RESULTS: The risk for overall leukemia increases 7% with each 0.5 kg increase in birth weight (OR 1.07, 95%CI 1.04-1.10). This risk is limited to the lymphoid leukemias (OR 1.08, 95%CI 1.05-1.12) diagnosed between 1 and 9 years of age. Analysis by cytogenetic feature reveals that there appears to be association with specific chromosomal abnormality: the risk of tumors with high hyperdiploid karyotypes increases 12% per 0.5 kg increase in birth weight (OR 1.12, 95%CI 1.05-1.20), and t(1;19) tumors show an increased risk of 41% per 0.5 kg increase (OR 1.41, 95%CI 1.09-1.84). The risk of acute myeloid leukemia is elevated in high and low birth weight babies. There is no significant risk relationship to other leukemias or myeloproliferative diseases. CONCLUSIONS: Birth weight is a risk factor for ALL and AML. Other subtypes of the disease are not significantly affected. There appears to be association with specific chromosomal abnormality, which may aid our understanding of the development of childhood leukemia in utero.

Mobile Medical Education (MoMEd) - how mobile information resources contribute to learning for undergraduate clinical students - a mixed methods study.

BACKGROUND: Mobile technology is increasingly being used by clinicians to access up-to-date information for patient care. These offer learning opportunities in the clinical setting for medical students but the underlying pedagogic theories are not clear. A conceptual framework is needed to understand these further. Our initial questions were how the medical students used the technology, how it enabled them to learn and what theoretical underpinning supported the learning. METHODS: 387 medical students were provided with a personal digital assistant (PDA) loaded with medical resources for the duration of their clinical studies. Outcomes were assessed by a mixed-methods triangulation approach using qualitative and quantitative analysis of surveys, focus groups and usage tracking data. RESULTS: Learning occurred in context with timely access to key facts and through consolidation of knowledge via repetition. The PDA was an important addition to the learning ecology rather than a replacement. Contextual factors impacted on use both positively and negatively. Barriers included concerns of interrupting the clinical interaction and of negative responses from teachers and patients. Students preferred a future involving smartphone platforms. CONCLUSIONS: This is the first study to describe the learning ecology and pedagogic basis behind the use of mobile learning technologies in a large cohort of undergraduate medical students in the clinical environment. We have developed a model for mobile learning in the clinical setting that shows how different theories contribute to its use taking into account positive and negative contextual factors.The lessons from this study are transferable internationally, to other health care professions and to the development of similar initiatives with newer technology such as smartphones or tablet computers.

Influence of HLA class I and HLA-KIR compound genotypes on HIV-2 infection and markers of disease progression in a Manjako community in West Africa.

Overall, the time to AIDS after HIV-2 infection is longer than with HIV-1, and many individuals infected with HIV-2 virus remain healthy throughout their lives. Multiple HLA and KIR gene products have been implicated in the control of HIV-1, but the effect of variation at these loci on HIV-2 disease is unknown. We show here for the first time that HLA-B*1503 is associated significantly with poor prognosis after HIV-2 infection and that HLA-B*0801 is associated with susceptibility to infection. Interestingly, previous data indicate that HLA-B*1503 is associated with low viral loads in HIV-1 clade B infection but has no significant effect on viral load in clade C infection. In general, alleles strongly associated with HIV-1 disease showed no effect in HIV-2 disease. These data emphasize the unique nature of the effects of HLA and HLA/KIR combinations on HIV-2 immune responses relative to HIV-1, which could be related to their distinct clinical course.

Neurologic manifestations of human immunodeficiency virus-2: dementia, myelopathy, and neuropathy in West Africa.

While well documented in human immunodeficiency virus (HIV)-1, neurologic sequelae have not been systematically evaluated in HIV-2. After excluding for confounding comorbidities, 67 individuals from a rural cohort in Guinea-Bissau (22 HIV-2 participants, 45 seronegative controls) were evaluated. HIV + individuals were divided into CD4 < 350 and CD4 ≥ 350 for analysis. HIV-associated neurocognitive disorders (HAND), assessed by the International HIV Dementia Scale (IHDS), distal sensory polyneuropathy (DSPN), and myelopathy were the main outcome variables. In univariate analysis, there was no difference in IHDS scores among groups. When analyzed by primary education attainment, IHDS scores were nonsignificantly higher (p = 0.06) with more education. There was no significant difference in DSPN prevalence among groups; overall, 45% of participants had DSPN. There were no cases of myelopathy. In multivariate linear regression, higher IHDS scores were significantly correlated with older age (coefficient = -0.11, p < 0.001). Logistic regression analysis showed that older age (odds ratio (OR) 95% CI 1.04-1.20), lower CD4 count (OR 95% CI 0.996-0.999), and higher BMI (OR 95% CI 1.02-1.43) significantly predicted the presence of DSPN. While a significant increase in cognitive impairment was not observed in HIV-2-infected individuals, the study suggests the IHDS may be a less effective screening tool for HAND in settings of lower educational attainment as encountered in rural Guinea-Bissau. Similar to HIV-1, DSPN seems to occur with lower CD4 counts in HIV-2. Further study of the viral-host interactions in HIV-2 and its consequent neurological diseases may provide an avenue for understanding the epidemic problems of HIV-1.

An Online Teaching Resource to Support UK Medical Student Education During the COVID-19 Pandemic: A Descriptive Account.

This paper describes the development and use of the bespoke digital learning resource CAPSULE (Clinical and Professional Studies Unique Learning Environment) which was launched UK wide in May 2020 to facilitate the delivery of core learning content for UK medical students during the COVID-19 pandemic. CAPSULE is a digital learning resource comprising case-based scenarios and multiple-choice questions, encompassing all undergraduate medical specialities and supported by a pan-speciality editorial board. Following the COVID-19 pandemic lockdown and loss of face-to-face learning opportunities, CAPSULE was made available to all UK medical schools in May 2020. Following a global content review and edit and UK wide rollout, over 41,000 medical students and 3200 faculty registered as users. Approximately 1.5 million cases were completed in the first 12 months of use by up to 4500 distinct monthly users. Feedback from both students and faculty has been highly positive. CAPSULE continues to be used within UK medical schools and has allowed an entire cohort of medical students to access core curriculum content and progress their studies during the COVID-19 pandemic. Future directions may include further integration into UK medical school curricula, enhancement of platform functionality and potential expansion on an international scale.

HTLV-1 in rural Guinea-Bissau: prevalence, incidence and a continued association with HIV between 1990 and 2007.

BACKGROUND: HTLV-1 is endemic in Guinea-Bissau, and the highest prevalence in the adult population (5.2%) was observed in a rural area, Caió, in 1990. HIV-1 and HIV-2 are both prevalent in this area as well. Cross-sectional associations have been reported for HTLV-1 with HIV infection, but the trends in prevalence of HTLV-1 and HIV associations are largely unknown, especially in Sub Saharan Africa. In the current study, data from three cross-sectional community surveys performed in 1990, 1997 and 2007, were used to assess changes in HTLV-1 prevalence, incidence and its associations with HIV-1 and HIV-2 and potential risk factors. RESULTS: HTLV-1 prevalence was 5.2% in 1990, 5.9% in 1997 and 4.6% in 2007. Prevalence was higher among women than men in all 3 surveys and increased with age. The Odds Ratio (OR) of being infected with HTLV-1 was significantly higher for HIV positive subjects in all surveys after adjustment for potential confounding factors. The risk of HTLV-1 infection was higher in subjects with an HTLV-1 positive mother versus an uninfected mother (OR 4.6, CI 2.6-8.0). The HTLV-1 incidence was stable between 1990-1997 (Incidence Rate (IR) 1.8/1,000 pyo) and 1997-2007 (IR 1.6/1,000 pyo) (Incidence Rate Ratio (IRR) 0.9, CI 0.4-1.7). The incidence of HTLV-1 among HIV-positive individuals was higher compared to HIV negative individuals (IRR 2.5, CI 1.0-6.2), while the HIV incidence did not differ by HTLV-1 status (IRR 1.2, CI 0.5-2.7). CONCLUSIONS: To our knowledge, this is the largest community based study that has reported on HTLV-1 prevalence and associations with HIV. HTLV-1 is endemic in this rural community in West Africa with a stable incidence and a high prevalence. The prevalence increases with age and is higher in women than men. HTLV-1 infection is associated with HIV infection, and longitudinal data indicate HIV infection may be a risk factor for acquiring HTLV-1, but not vice versa. Mother to child transmission is likely to contribute to the epidemic.

Undetectable plasma viral load predicts normal survival in HIV-2-infected people in a West African village.

BACKGROUND: There have been no previous studies of the long-term survival and temporal changes in plasma viral load among HIV-2 infected subjects. METHODS: 133 HIV-2 infected and 158 HIV-uninfected subjects from a rural area in North-west Guinea-Bissau, West Africa were enrolled into a prospective cohort study in 1991 and followed-up to mid-2009. Data were collected on four occasions during that period on HIV antibodies, CD4% and HIV-2 plasma viral load. RESULTS: Median age (interquartile range [IQR]) of HIV-2 infected subjects at time of enrollment was 47 (36, 60) years, similar to that of HIV-uninfected control subjects, 49 (38, 62) (p = 0.4). Median (IQR) plasma viral load and CD4 percentage were 347 (50, 4,300) copies/ml and 29 (22, 35) respectively.Overall loss to follow-up to assess vital status was small, at 6.7% and 6.3% for HIV-2 infected and uninfected subjects respectively. An additional 17 (12.8%) and 16 (10.1%) of HIV-2 infected and uninfected subjects respectively were censored during follow-up due to infection with HIV-1. The mortality rate per 100 person-years (95% CI) was 4.5 (3.6, 5.8) among HIV-2 infected subjects compared to 2.1 (1.6, 2.9) among HIV-uninfected (age-sex adjusted rate ratio 1.9 (1.3, 2.8, p < 0.001) representing a 2-fold excess mortality rate associated with HIV-2 infection.Viral load measurements were available for 98%, 78%, 77% and 61% HIV-2 infected subjects who were alive and had not become super-infected with HIV-1, in 1991, 1996, 2003 and 2006 respectively. Median plasma viral load (RNA copies per ml) (IQR) did not change significantly over time, being 150 (50, 1,554; n = 77) in 1996, 203 (50, 2,837; n = 47) in 2003 and 171 (50, 497; n = 31) in 2006. Thirty seven percent of HIV-2 subjects had undetectable viraemia (<100 copies/ml) at baseline: strikingly, mortality in this group was similar to that of the general population. CONCLUSIONS: A substantial proportion of HIV-2 infected subjects in this cohort have stable plasma viral load, and those with an undetectable viral load (37%) at study entry had a normal survival rate. However, the sequential laboratory findings need to be interpreted with caution given the number of individuals who could not be re-examined.

Robust Gag-specific T cell responses characterize viremia control in HIV-2 infection.

HIV-2 infection in the majority of infected subjects follows an attenuated disease course that distinguishes it from infection with HIV-1. Antigen-specific T cells are pivotal in the management of chronic viral infections but are not sufficient to control viral replication in HIV-1-positive subjects, and their function in HIV-2 infection is not fully established. In a community-based cohort of HIV-2 long-term nonprogressors in rural Guinea-Bissau, we performed what we believe is the first comprehensive analysis of HIV-2-specific immune responses. We demonstrate that Gag is the most immunogenic protein. The magnitude of the IFN-gamma immune response to the HIV-2 proteome was inversely correlated with HIV-2 viremia, and this relationship was specifically due to the targeting of Gag. Furthermore, patients with undetectable viremia had greater Gag-specific responses compared with patients with high viral replication. The most frequently recognized peptides clustered within a defined region of Gag, and responses to a single peptide in this region were associated with low viral burden. The consistent relationship between Gag-specific immune responses and viremia control suggests that T cell responses are vital in determining the superior outcome of HIV-2 infection. A better understanding of how HIV-2 infection is controlled may identify correlates of effective protective immunity essential for the design of HIV vaccines.

Presence of a multidrug-resistance mutation in an HIV-2 variant infecting a treatment-naive individual in Caio, Guinea Bissau.

We report the possible transmission of drug-resistant human immunodeficiency virus type 2. A 66-year-old woman from rural Guinea Bissau who had no obvious antiretroviral exposure was found to harbor a variant with the multidrug-resistance mutation Q151M. Finding this mutation among a drug-naive population presents an important public health issue that needs to be addressed for treatment to be effective.

Spatial clustering of childhood cancer in Great Britain during the period 1969-1993.

The aetiology of childhood cancer is poorly understood. Both genetic and environmental factors are likely to be involved. The presence of spatial clustering is indicative of a very localized environmental component to aetiology. Spatial clustering is present when there are a small number of areas with greatly increased incidence or a large number of areas with moderately increased incidence. To determine whether localized environmental factors may play a part in childhood cancer aetiology, we analyzed for spatial clustering using a large set of national population-based data from Great Britain diagnosed 1969-1993. The Potthoff-Whittinghill method was used to test for extra-Poisson variation (EPV). Thirty-two thousand three hundred and twenty-three cases were allocated to 10,444 wards using diagnosis addresses. Analyses showed statistically significant evidence of clustering for acute lymphoblastic leukaemia (ALL) over the whole age range (estimate of EPV = 0.05, p = 0.002) and for ages 1-4 years (estimate of EPV = 0.03, p = 0.015). Soft-tissue sarcoma (estimate of EPV = 0.03, p = 0.04) and Wilms tumours (estimate of EPV = 0.04, p = 0.007) also showed significant clustering. Clustering tended to persist across different time periods for cases of ALL (estimate of between-time period EPV = 0.04, p =0.003). In conclusion, we observed low level spatial clustering that is attributable to a limited number of cases. This suggests that environmental factors, which in some locations display localized clustering, may be important aetiological agents in these diseases. For ALL and soft tissue sarcoma, but not Wilms tumour, common infectious agents may be likely candidates.

Space-time clustering of childhood cancer around the residence at birth.

Previously, we identified space-time clustering in certain childhood cancers around diagnosis residence. These findings provided support for the involvement of environmental agents in etiological processes occurring close to diagnosis. We have reanalyzed the same British population-based dataset. The aim of the study was to determine whether there was space-time clustering around the residence at birth in relation to time of birth and separately from time of diagnosis. A total of 29,553 cases, diagnosed during the period 1969-1993, were examined by a second-order procedure based on K-functions. Locations were birth addresses, but separately, both dates of birth and diagnosis were analyzed. There was statistically significant space-time clustering for Hodgkin lymphoma (HL) and central nervous system (CNS) tumors (p=0.047 and 0.01, respectively, based on birth date) and for total leukemia at ages 1-4 years only, Non-Hodgkin lymphoma (NHL) and Wilms tumor (p=0.01, 0.02 and 0.006, respectively, based on diagnosis date). These results, interpreted together with other epidemiological evidence, suggest an etiological role for environmental factors focused around birth address for certain childhood cancers. For HL and CNS tumors, findings suggest that etiological exposures occurred at similar ages or in utero. For leukemia, NHL and Wilms tumor there is support for exposures occurring at similar times before diagnosis. For leukemia, HL, NHL and CNS tumors, but not Wilms tumor, the findings are consistent with infectious hypotheses.

Power-frequency electric and magnetic fields in the light of Draper et al. 2005.

Power-frequency electric and magnetic fields are produced wherever electricity is used; exposure is ubiquitous. Epidemiologic studies find an association between children living in homes with the highest magnetic fields and childhood leukemia, but bias is a possible alternative to a causal explanation. A new study, Draper et al., looks at residence close to high-voltage power lines, one source of exposure to such fields, and its design avoids any obvious bias. It finds elevated childhood leukemia rates, but extending too far from the power lines to be straightforwardly compatible with the existing literature. This leads to an examination of alternative explanations: magnetic fields, other physical factors, such as corona ions, the characteristics of the areas power lines pass through, bias, and chance. The conclusion is that there is currently no single preferred explanation, but that this is a serious body of science that needs further work until an explanation is found.

Variation with socioeconomic status of indoor radon levels in Great Britain: The less affluent have less radon.

We demonstrate a strong correlation between domestic radon levels and socio-economic status (SES) in Great Britain, so that radon levels in homes of people with lower SES are, on average, only about two thirds of those of the more affluent. This trend is apparent using small area measures of SES and also using individual social classes. The reasons for these differences are not known with certainty, but may be connected with greater underpressure in warmer and better-sealed dwellings. There is also a variation of indoor radon levels with the design of the house (detached, terraced, etc.). In part this is probably an effect of SES, but it appears to have other causes as well. Data from other countries are also reviewed, and broadly similar effects seen in the United States for SES, and in other European countries for detached vs other types of housing. Because of correlations with smoking, this tendency for the lower SES groups to experience lower radon levels may underlie the negative association between radon levels and lung cancer rates in a well-known ecological study based on US Counties. Those conducting epidemiological studies of radon should be alert for this effect and control adequately for SES.

Immunological predictors of survival in HIV type 2-infected rural villagers in Guinea-Bissau.

We investigated the association between beta2-microglobulin, neopterin, serum levels of soluble urokinase-type plasminogen activator receptor (suPAR), CD4 count, and plasma viremia with survival in 133 HIV-2-infected villagers and 160 controls living in rural Guinea-Bissau. Subjects were recruited in 1991 and visited at home every 3-6 months until 1998. Median beta2-microglobulin, neopterin, and suPAR were significantly higher and CD4% significantly lower among HIV-2-infected individuals than controls. Thirty-one HIV-2-infected individuals died and 7 were lost to follow-up. beta2-Microglobulin, CD4%, and plasma viral load were associated independently with survival in multivariate analyses. Neopterin and suPAR did not reach statistical significance. These findings suggest that immune activation is central to the pathogenesis of HIV. They also have important implications for resource-poor settings where CD4 count and plasma viral load are unaffordable.

Infant birthweight and risk of childhood cancer: international population-based case control studies of 40 000 cases.

BACKGROUND: High birthweight is an established risk factor for childhood leukaemia. Its association with other childhood cancers is less clear, with studies hampered by low case numbers. METHODS: We used two large independent datasets to explore risk associations between birthweight and all subtypes of childhood cancer. Data for 16 554 cases and 53 716 controls were obtained by linkage of birth to cancer registration records across five US states, and 23 772 cases and 33 206 controls were obtained from the UK National Registry of Childhood Tumours. US, but not UK, data were adjusted for gestational age, birth order, plurality, and maternal age and race/ethnicity. RESULTS: Risk associations were found between birthweight and several childhood cancers, with strikingly similar results between datasets. Total cancer risk increased linearly with each 0.5 kg increase in birthweight in both the US [odds ratio 1.06 (95% confidence interval 1.04, 1.08)] and UK [1.06 (1.05, 1.08)] datasets. Risk was strongest for leukaemia [USA: 1.10 (1.06, 1.13), UK: 1.07 (1.04, 1.10)], tumours of the central nervous system [USA: 1.05 (1.01, 1.08), UK: 1.07 (1.04, 1.10)], renal tumours [USA: 1.17 (1.10, 1.24), UK: 1.12 (1.06, 1.19)] and soft tissue sarcomas [USA: 1.12 (1.05, 1.20), UK: 1.07 (1.00, 1.13)]. In contrast, increasing birthweight decreased the risk of hepatic tumours [USA: 0.77 (0.69, 0.85), UK: 0.79 (0.71, 0.89) per 0.5 kg increase]. Associations were also observed between high birthweight and risk of neuroblastoma, lymphomas, germ cell tumours and malignant melanomas. For some cancer subtypes, risk associations with birthweight were non-linear. We observed no association between birthweight and risk of retinoblastoma or bone tumours. CONCLUSIONS: Approximately half of all childhood cancers exhibit associations with birthweight. The apparent independence from other factors indicates the importance of intrauterine growth regulation in the aetiology of these diseases.