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Article: Discovery by the Epistasis Project of an epistatic interaction between the GSTM3 gene and the HHEX/IDE/KIF11 locus in the risk of Alzheimer's disease.
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ABSTRACT: Despite recent discoveries in the genetics of sporadic Alzheimer's disease, there remains substantial "hidden heritability." It is thought that some of this missing heritability may be because of gene-gene, i.e., epistatic, interactions. We examined potential epistasis between 110 candidate polymorphisms in 1757 cases of Alzheimer's disease and 6294 control subjects of the Epistasis Project, divided between a discovery and a replication dataset. We found an epistatic interaction, between rs7483 in GSTM3 and rs1111875 in the HHEX/IDE/KIF11 gene cluster, with a closely similar, significant result in both datasets. The synergy factor (SF) in the combined dataset was 1.79, 95% confidence interval [CI], 1.35-2.36; p = 0.00004. Consistent interaction was also found in 7 out of the 8 additional subsets that we examined post hoc: i.e., it was shown in both North Europe and North Spain, in both men and women, in both those with and without the ε4 allele of apolipoprotein E, and in people older than 75 years (SF, 2.27; 95% CI, 1.60-3.20; p < 0.00001), but not in those younger than 75 years (SF, 1.06; 95% CI, 0.59-1.91; p = 0.84). The association with Alzheimer's disease was purely epistatic with neither polymorphism showing an independent effect: odds ratio, 1.0; p ≥ 0.7. Indeed, each factor was associated with protection in the absence of the other factor, but with risk in its presence. In conclusion, this epistatic interaction showed a high degree of consistency when stratifying by sex, the ε4 allele of apolipoprotein E genotype, and geographic region.Neurobiology of aging 10/2012; · 5.94 Impact Factor -
Article: Influence of short-course antenatal antiretroviral therapy on viral load and mother-to-child transmission in subsequent pregnancies among HIV-infected women.
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ABSTRACT: BACKGROUND: HIV-infected women not requiring treatment for their own health usually receive short-course antiretroviral therapy (ART) during pregnancy. Little is known about the effect of this on response to HAART in subsequent pregnancies. METHODS: We analysed data from the UK and Ireland's National Study of HIV in Pregnancy and Childhood for 2000-2010. Analyses were restricted to live births among women not on ART at conception but receiving antenatal HAART. We compared risk of detectable viral load at delivery and mother-to-child transmission in two pregnancy groups: 'ART-naive' and 'HAART-experienced' (≥7 days of HAART during previous pregnancy). Multivariable analyses were conducted using logistic regression. RESULTS: There were 5,372 pregnancies in the ART-naive group and 605 in the HAART-experienced group. Overall, there was weak evidence of an increased risk of detectable viral load in the HAART-experienced group (adjusted odds ratio [aOR] 1.27; 95% CI 1.01, 1.60); however, the increased risk was apparent only among women who previously received non-nucleoside reverse transcriptase inhibitor-based HAART (aOR 1.81; 95% CI 1.25, 2.63), and not among those with previous protease-inhibitor-based HAART exposure (aOR 1.08; 95% CI 0.81, 1.45). There was no difference in mother-to-child transmission risk between the ART-naive and HAART-experienced groups (aOR 0.42; 95% CI 0.10, 1.78), although the number of transmissions was small. CONCLUSIONS: We found no increased risk of detectable viral load at delivery among women exposed to short-course, protease-inhibitor-based HAART during a previous pregnancy. However, women with prior exposure to non-nucleoside reverse transcriptase inhibitor-based HAART appeared to be at increased risk of not adequately suppressing the virus. These findings highlight the need for careful management of HIV-infected women presenting with repeat pregnancies.Antiviral therapy 08/2012; · 3.16 Impact Factor -
Article: A toolkit for monitoring hospital-acquired bloodstream infection in neonatal intensive care.
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ABSTRACT: In neonatal intensive care units (NICUs), monitoring hospital-acquired bloodstream infection (BSI) is critical to alert clinicians to variations in the incidence of infection between units and over time. We demonstrate a toolkit of monitoring techniques that account for case mix and could be implemented using routinely available clinical data. This toolkit could enable quality of care comparisons between hospitals to facilitate the sharing of improved practices. Prospective study over 4 years. Babies admitted to 2 tertiary London NICUs. We derived expected numbers of BSI episodes using a Poisson regression risk model adjusting for variations in birth weight, transfers to the NICU from other hospitals, postnatal age, and days spent at each National Health Service level of care. We compared observed and expected numbers of BSI episodes using 2 monitoring techniques: standardized infection ratios (SIRs) and the sequential probability ratio test (SPRT). Using the SIR method, observed BSI incidence increased over expected incidence in 2002 at both NICUs, but this increase did not reach statistical significance at the 1% level. Using the SPRT method, neither unit showed a clinically important increase or decrease, defined as a 30% deviation from expected incidence. Risk-adjusted BSI monitoring can be performed using routine hospital data. NICUs could use SIRs for an annual look back at infection incidence and SPRTs for prospective, quarterly monitoring. The SIR and the SPRT methods have different strengths, and both could help clinicians improve infection control and patient care in NICUs.Infection Control and Hospital Epidemiology 08/2012; 33(8):831-6. · 3.67 Impact Factor -
Article: The association between ethnicity and late presentation to antenatal care among pregnant women living with HIV in the UK and Ireland.
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ABSTRACT: UK and Ireland guidelines state that all pregnant women should have their first antenatal care appointment by 13 weeks of pregnancy (antenatal booking). We present the results of an analysis looking at the association between maternal ethnicity and late antenatal booking in HIV-positive women in the UK and Ireland. We analysed data from the National Study of HIV in Pregnancy and Childhood (NSHPC). We included all pregnancies in women who were diagnosed with HIV before delivery and had an estimated delivery date between 1 January 2008 and 31 December 2009. Late booking was defined as antenatal booking at 13 weeks or later. The baseline reference group for all analyses comprised women of "white" ethnicity. Logistic regression models were fitted to estimate adjusted odds ratios (AOR). There were 2721 eligible reported pregnancies; 63% (1709) had data available on antenatal care booking date. In just over 50% of pregnancies (871/1709), the antenatal booking date was ≥13 weeks of pregnancy (i.e., late booking). Women diagnosed with HIV during the current pregnancy were more likely to present for antenatal care late than those previously diagnosed (59.1% vs. 47.5%, p<0.001). Where women knew their HIV status prior to becoming pregnant, the risk of late booking was raised for those of African ethnicity (AOR 1.80; 95% confidence interval (CI) 1.14, 2.82; p=0.011). In women diagnosed with HIV during pregnancy, the risk of late booking was also higher for women of African ethnicity (AOR 2.98: 95% CI 1.45, 6.11; p=0.003) and for women of other black ethnicity (AOR 3.74: 95% CI 1.28, 10.94; p=0.016). Overall, women of African or other black ethnicity were more likely to book late for antenatal care compared with white women, regardless of timing of diagnosis. This may have an adverse effect on maternal and infant outcomes, including mother-to-child transmission of HIV.AIDS Care 04/2012; 24(8):978-85. · 1.60 Impact Factor -
Article: Incidence, patterns, and predictors of repeat pregnancies among HIV-infected women in the United Kingdom and Ireland, 1990-2009.
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ABSTRACT: To explore the pattern of repeat pregnancies among diagnosed HIV-infected women in the United Kingdom and Ireland, estimate the rate of these sequential pregnancies, and investigate the demographic and clinical characteristics of women experiencing them. Diagnosed HIV-infected pregnant women are reported through an active confidential reporting scheme to the National Study of HIV in Pregnancy and Childhood. Pregnancies occurring during 1990-2009 were included. Multivariable analyses were conducted fitting Cox proportional hazards models. There were 14,096 pregnancies in 10,568 women; 2737 (25.9%) had 2 or more pregnancies reported. The rate of repeat pregnancies was 6.7 (95% confidence interval: 6.5 to 7.0) per 100 woman-years. The proportion of pregnancies in women who already had at least 1 pregnancy reported increased from 20.3% (32 of 158) in 1997 to 38.6% (565 of 1465) in 2009 (P < 0.001). In multivariable analysis, the probability of repeat pregnancy significantly declined with increasing age at first pregnancy. Parity was also inversely associated with repeat pregnancy. Compared with women born in the United Kingdom or Ireland, those from Europe, Eastern Africa, and Southern Africa were less likely to have a repeat pregnancy, whereas women from Middle Africa and Western Africa were more likely to. Maternal health at first pregnancy was not associated with repeat pregnancy. The number of diagnosed HIV-infected women in the United Kingdom and Ireland experiencing repeat pregnancies is increasing. Variations in the probability of repeat pregnancies, according to demographic and clinical characteristics, are an important consideration when planning reproductive health services and HIV care for people living with HIV.JAIDS Journal of Acquired Immune Deficiency Syndromes 03/2012; 59(3):287-93. · 4.43 Impact Factor
