Generational trends in the transition to womanhood in lowland rural Nepal: Changes in the meaning of early marriage.

OBJECTIVE: In South Asia, studies show secular trends toward slightly later women's marriage and first reproduction. However, data on related biological and social events, such as menarche and age of coresidence with husband, are often missing from these analyses. We assessed generational trends in key life events marking the transition to womanhood in rural lowland Nepal. METHODS: We used data on 110 co-resident mother-in-law (MIL) and daughter-in-law (DIL) dyads. We used paired t-tests and chi-squared tests to evaluate generational trends in women's education, and mean age at menarche, marriage, cohabitation with husband, and first reproduction of MIL and DIL dyads. We examined norms held by MILs and DILs on a daughter's life opportunities. RESULTS: On average, MIL was 29 years older than DIL (60 years vs. 31 years). Both groups experienced menarche at average age 13.8 years. MIL was married at average 12.4 years, before menarche, and cohabitated with husbands at average 14.8 years. DIL was simultaneously married and cohabitated with husbands after menarche, at average 15 years. DIL was marginally more educated than MIL but had their first child on average 0.8 years earlier (95% CI -1.4, -0.1). MIL and DIL held similar norms on daughters' education and marriage. CONCLUSION: While social norms remain similar, the meaning of "early marriage" and use of menarche in marriage decisions has changed in rural lowland Nepal. Compared to DIL, MIL who was married earlier transitioned to womanhood more gradually. However, DIL was still married young, and had an accelerated trajectory to childbearing.

Juvenile Dermatomyositis: what comes next? Long-term outcomes in childhood myositis from a patient perspective.

BACKGROUND: To describe long-term outcomes in JDM using patient questionnaires and link to longitudinal, prospectively collected data for each patient within the Juvenile Dermatomyositis Cohort and Biomarker Study, UK and Ireland (JDCBS) to determine outcome predictors.  METHODS: JDCBS participants aged ≥ 16y completed the SF36, HAQ and a questionnaire regarding current disease features, medications, education and employment. Data collected from the JDCBS included disease subtype, demographics, clinical and laboratory features. Intensity indices were calculated for physician VAS, modified skin DAS, CMAS and MMT8 by dividing area under the curve (AUC) from longitudinal score trajectories by duration of study follow-up (y). Relationships between questionnaire and JDCBS clinical / laboratory data were investigated fitting statistical models appropriate for cross sectional and longitudinal data. RESULTS: Of 190 questionnaires sent, 84 (44%) were returned. Average age of respondents was 20.6 years (SD 3.9), time since diagnosis was 12.4 years (SD 5.0), age at onset was 9.2 years (SD 4.3), female to male ratio 4.25:1. Forty-nine (59%) self-reported persistently active disease, 54 (65%) were still taking immunosuppressive medication. 14/32 at school/higher education reported myositis adversely affecting academic results. 18-24 year-olds were twice as likely to be unemployed compared the UK population (OR = 0.456, 95% CI 0.24, 0.84, p = 0.001). Participants ≥ 18 years were three times as likely to be living with a parent/guardian (OR = 3.39, p < 0.001). SF36 MCS and MMT8 intensity index scores were significantly correlated (ρ = 0.328, p = 0.007). CONCLUSIONS: After 12.4 years, questionnaire responders reported self-perceived high rates of persistently active disease and medication use, reduced rates of employment and were more likely to live with a parent/guardian. Perceived persistently active muscle disease appeared to affect quality of life in these patients and was the most significant contributor to long-term outcomes. Our findings highlight the importance of including the patient perspective in the assessment of long term outcomes, so that that we can start to target initial management strategies more effectively based on a combination of clinical and patient-reported data.

Is Month of Birth a Risk Factor for Colorectal Cancer?

Introduction. The developmental origins of health and disease hypothesis and season of birth have been linked to a wide variety of later life conditions including cancer. Whether any relationship between month and season of birth and colorectal cancer exists is unknown. Methods. A case-control study was performed with month of birth extracted from a dedicated colorectal cancer database. Age and gender matched patients were used as a control group. Generalised linear models were fitted with Poisson and negative binomial responses and logarithmic links. A forward stepwise approach was followed adding seasonal components with 6- and 12-month periods. Results. 1019 colorectal cancer patients and 1277 randomly selected age and gender matched controls were included. For both men and women there is an excess of colorectal cancer in those born in autumn and a corresponding reduction of risk among those born in spring (p = 0.026). For the identified September peak, the excess risk for colorectal cancer was 14.8% (95% CI 5.6-32.3%) larger than the spring trough. Conclusion. There is a seasonal effect in the monthly birth rates of people who are operated for colorectal cancer with a disproportionate excess of cancer in those born in September. Further large studies are required to validate these findings.

Presentation for care and antenatal management of HIV in the UK, 2009-2014.

OBJECTIVES: Despite very low rates of vertical transmission of HIV in the UK overall, rates are higher among women starting antenatal antiretroviral therapy (ART) late. We investigated the timing of key elements of the care of HIV-positive pregnant women [antenatal care booking, HIV laboratory assessment (CD4 count and HIV viral load) and antenatal ART initiation], to assess whether clinical practice is changing in line with recommendations, and to investigate factors associated with delayed care. METHODS: We used the UK's National Study of HIV in Pregnancy and Childhood for 2009-2014. Data were analysed by fitting logistic regression and Cox proportional hazards models. RESULTS: A total of 5693 births were reported; 79.5% were in women diagnosed with HIV prior to that pregnancy. Median gestation at antenatal booking was 12.1 weeks [interquartile range (IQR) 10.0-15.6 weeks] and booking was significantly earlier during 2012-2014 vs. 2009-2011 (P < 0.001), although only in previously diagnosed women. Overall, 42.2% of pregnancies were booked late (≥ 13 gestational weeks). Among women not already on treatment, antenatal ART commenced at a median of 21.4 (IQR18.1-24.5) weeks and started significantly earlier in the most recent time period (P < 0.001). Compared with previously diagnosed women, those newly diagnosed during the current pregnancy booked later for antenatal care and started antenatal ART later (both P < 0.001). Multivariable analyses revealed demographic variations in access to or uptake of care, with groups including migrants and parous women initiating care later. CONCLUSIONS: Although women are accessing antenatal and HIV care earlier in pregnancy, some continue to face barriers to timely initiation of antenatal care and ART.

New generalized poisson mixture model for bimodal count data with drug effect: An application to rodent brief-access taste aversion experiments.

Pharmacodynamic (PD) count data can exhibit bimodality and nonequidispersion complicating the inclusion of drug effect. The purpose of this study was to explore four different mixture distribution models for bimodal count data by including both drug effect and distribution truncation. An example dataset, which exhibited bimodal pattern, was from rodent brief-access taste aversion (BATA) experiments to assess the bitterness of ascending concentrations of an aversive tasting drug. The two generalized Poisson mixture models performed the best and was flexible to explain both under and overdispersion. A sigmoid maximum effect (Emax ) model with logistic transformation was introduced to link the drug effect to the data partition within each distribution. Predicted density-histogram plot is suggested as a model evaluation tool due to its capability to directly compare the model predicted density with the histogram from raw data. The modeling approach presented here could form a useful strategy for modeling similar count data types.

Hepatitis C virus seroprevalence in pregnant women delivering live-born infants in North Thames, England in 2012.

To estimate HCV seroprevalence in subpopulations of women delivering live-born infants in the North Thames region in England in 2012, an unlinked anonymous (UA) cross-sectional survey of neonatal dried blood spot samples was conducted. Data were available from 31467 samples from live-born infants received by the North Thames screening laboratory. Thirty neonatal samples had HCV antibodies, corresponding to a maternal seroprevalence of 0·095% (95% confidence interval 0·067-0·136). Estimated HCV seroprevalences in women born in Eastern Europe, Southern Asia and the UK were 0·366%, 0·162% and 0·019%, respectively. For women born in Eastern Europe seroprevalence was highest in those aged around 27 years, while in women born in the UK and Asia-Pacific region, seroprevalence increased significantly with age. HCV seroprevalence in UK-born women whose infant's father was also UK-born was 0·016%. One of the 30 HCV-seropositive women was HIV-1 seropositive. Estimated HCV seroprevalence for women delivering live-born infants in North Thames in 2012 (0·095%) was significantly lower than that reported in an earlier UA survey in 1997-1998 (0·191%). Data indicate that the cohort of UK-born HCV-seropositive women is ageing and that, in this area of England, most perinatally HCV-exposed infants were born to women themselves born in Southern Asia or Eastern Europe.

Risk-adjusted comparisons of bloodstream infection rates in neonatal intensive-care units.

Comparisons of bloodstream infection (BSI) rates between neonatal intensive-care units (NICUs) should take into account differences in babies' vulnerability and invasive procedures that can introduce infection. Our aim was to investigate which risk factors recorded in routine records should be adjusted for when NICUs are compared. This was a retrospective cohort study using routine records for two London NICUs. We analysed rates of BSI with Poisson regression models. The level of neonatal care used by the National Health Service was the strongest predictor of BSI incidence. The rate ratios for BSI, adjusted for birthweight, inborn/outborn status, and postnatal age, were 3.15 (95% CI 2.01-4.94) for intensive care and 6.58 (95% CI 4.18-10.36) for high-dependency care, relative to special care. Total parenteral nutrition was significantly associated with BSI incidence, but explained less of the variance among babies than level of care. A case-control study with the same dataset gave similar results. Further multicentre studies are required to confirm our predictive model. Until then, we recommend that comparisons of BSI rates between NICUs should include adjustments for level of care, birthweight, inborn/outborn status, and postnatal age, with the use of routinely recorded standardized measures in hospital administrative data.

Modelling psychiatric measures using Skew-Normal distributions.

Data from psychiatric research frequently exhibit departures from Normality. Methods which utilise the data optimally to model the distribution directly are available. We highlight the issue of modelling skewness, resulting from screening instruments where the majority of respondents are healthy individuals and few participants have a value reflecting particular disorders.

Antiretroviral therapy and preterm delivery-a pooled analysis of data from the United States and Europe.

OBJECTIVE: To investigate reported differences in the association between highly active antiretroviral therapy (HAART) in pregnancy and the risk of preterm delivery among HIV-infected women. DESIGN: Combined analysis of data from three observational studies. SETTING: USA and Europe. POPULATION: A total of 19, 585 singleton infants born to HIV-infected women, 1990-2006. METHODS: Data from the Pediatric Spectrum of HIV Disease project (PSD), a US monitoring study, the European Collaborative Study (ECS), a consented cohort study, and the National Study of HIV in Pregnancy and Childhood (NSHPC), the United Kingdom and Ireland surveillance study. MAIN OUTCOME MEASURE: Preterm delivery rate (<37 weeks of gestation). RESULTS: Compared with monotherapy, HAART was associated with increased preterm delivery risk in the ECS (adjusted odds ratio [AOR] 2.40, 95% CI 1.49-3.86) and NSHPC (AOR 1.43, 95% CI 1.10-1.86), but not in the PSD (AOR 0.92, 95% CI 0.67-1.26), after adjusting for relevant covariates. Because of heterogeneity, data were not pooled for this comparison, but heterogeneity disappeared when HAART was compared with dual therapy (P = 0.26). In a pooled analysis, HAART was associated with 1.5-fold increased odds of preterm delivery compared with dual therapy (95% CI 1.19-1.87, P=0.001), after adjusting for covariates. CONCLUSIONS: Heterogeneity in the association between HAART and preterm delivery was not explained by study design, adjustment for confounders or a standard analytical approach, but may have been the result of substantial differences in populations and data collected. The pooled analysis comparing HAART with dual therapy showed an increased risk of preterm delivery associated with HAART.

Discordance between CD4 cell count and CD4 cell percentage: implications for when to start antiretroviral therapy in HIV-1 infected children.

OBJECTIVE: Antiretroviral therapy (ART) guidelines for HIV-1-infected children specify both absolute CD4 cell count and CD4 percentage thresholds at which consideration should be given to initiating ART. This leads to clinical dilemma when one marker is below the threshold, whereas the other is above. DESIGN: Data were obtained on a large group of children followed longitudinally in trials and cohort studies in Europe and the USA. Follow-up was censored 6 months after the start of any antiretroviral drug other than zidovudine monotherapy. METHODS: Discordance between CD4 cell count and percentage was defined in relation to ART initiation thresholds in World Health Organization (WHO) and European paediatric treatment guidelines. The relative prognostic value of CD4 cell count and percentage for progression to AIDS/death was investigated using time-updated Cox proportional hazards models, stratified by age. RESULTS: Among 3345 children, with a total of 21,815 pairs of CD4 measurements analysed, 980 developed AIDS and/or died after a median follow-up of 1.7 years. Over one-half of children had discordant values of CD4 cell markers at the first visit when one or both treatment thresholds were crossed and approximately one-third had the same pattern of discordance at a subsequent measurement. Models suggested that CD4 percentage had little or no prognostic value over and above that contained in CD4 cell count, irrespective of age. CONCLUSIONS: More emphasis should be placed on CD4 cell count than on CD4 percentage in deciding when to start ART in HIV-1-infected children.

Association study of MICA and MICB in Alzheimer's disease.

Following the replication of the association of the human leucocyte antigen (HLA) allele, HLA-B*07, with Alzheimer's disease (AD) in the cohort of the Oxford Project to Investigate Memory and Ageing (OPTIMA) in a previous study, we examined whether that association could be due to linkage disequilibrium with MICA or MICB alleles. We found a possible association of MICA*00801 heterozygotes with AD in subjects positive for the epsilon 4 allele of apolipoprotein E. This finding was supported by Hardy-Weinberg analysis, by stratified association analysis and by interaction analysis, but did not survive correction for multiple testing. In any case, these results do not explain our previously reported association of HLA-B*07 with AD.

Epidemiology of biliary atresia in England and Wales (1999-2006).

OBJECTIVE: To identify the epidemiological characteristics of infants with biliary atresia in England and Wales, since centralisation of its management in 1999. METHODS: The care of infants with biliary atresia (BA) in England and Wales is centralised to only three centres. All infants (treated from January 1999 to December 2006) were identified from a prospective national database; demographic details were ascertained from medical records and compared between two groups based on presumed aetiology (isolated biliary atresia (IBA) and developmental biliary atresia (DBA) (for example, syndromic infants, biliary atresia splenic malformation, cystic biliary atresia)). RESULTS: There were 302 (133 male (44%)) infants with BA that could be divided into IBA (n = 219, 73%) and DBA (n = 76, 25%). The overall incidence was 0.58/10 000 (1 in 17,049) live births with marked regional differences along a north-west/south-east axis varying from 0.38 (north-west England) to 0.78 (south-east England)/10,000 live births (OR 2.05 (95% CI 1.26-3.41); p = 0.002). The commonest month of birth was September with December being the least common, although there was no evidence for significant seasonal variation (p = 0.2). Infants with DBA were more likely to be female (p<0.001), of white background (p = 0.01), first-born (p = 0.04) and to be formula-fed (p = 0.07). Infants of south Asian origin came to surgery at an older age (59 (IQ 45-75) versus 52 (IQ 42-65) days; p = 0.03). CONCLUSIONS: There is a remarkable variation of incidence of biliary atresia within England and Wales, some of which may have been caused by factors related to a different aetiological and racial background.

Incidence of early-onset glaucoma after infant cataract extraction with and without intraocular lens implantation.

AIMS: To determine the incidence of glaucoma, with onset within 1 year after the date of cataract surgery (early onset) performed in the first year of life, with or without intraocular lens (IOL) implantation. METHODS: A retrospective review of a single surgeon's cohort from 1999 to 2006. Glaucoma onset risk, comparison of aphakic/pseudophakic eyes and IOL type were analysed together with microcornea, persistent fetal vasculature (PFV) and age < or =4 weeks at surgery. RESULTS: Ninety-eight eyes (62 patients; mean age 2.88 months) were included with 61 eyes (36 patients) aphakic (57 planned and four failed implantations), and 37 eyes (26 patients) pseudophakic. At a mean follow-up of 2.51 years,15.3% (12.2% within 1 year) of all eyes, 9.8% of eyes (6.6% within 1 year) in the planned aphakic group, all four eyes with failed implantation and 13.5% of the pseudophakic eyes (10.8% within 1 year) developed glaucoma. Glaucoma incidence stratified by absence or presence of IOL showed no statistically significant difference, but eyes in the rigid polymethylmethacrylate group had an increased glaucoma risk compared with the Acrysof group (p = 0.002). Microcornea, PFV and age < or =4 weeks at surgery were not significant predictors of early-onset glaucoma. CONCLUSIONS: In this single surgeon study of infant cataract surgery only, age < or =4 weeks at surgery was not a predictor of early-onset glaucoma. The rate of aphakic and pseudophakic early-onset glaucoma was not found to be statistically different, but we found a statistically different rate of glaucoma between the two IOL types which needs further evaluation, given that this is a retrospective review. Excessive surgical trauma influences incidence of glaucoma.

Causes of deafness in British Bangladeshi children: a prevalence twice that of the UK population cannot be accounted for by consanguinity alone.

OBJECTIVE: To study the causes and prevalence of sensorineural deafness in Bangladeshi children resident in East London. METHODS: This was a cross sectional survey of children of Bangladeshi origin living in East London with bilateral sensorineural hearing loss of 40 db HL or more. In this study, 134 patients were included. The study looked primarily at the causes of sensorineural hearing loss in this population. RESULTS: The prevalence of deafness in Bangladeshi children in East London is approximately 3.86 per 1000 [95% confidence intervals (CI) 3.20, 4.65] which is significantly greater than the average UK prevalence of 1.65 per 1000. The prevalence of deafness in these Bangladeshi children belonging to non-consanguineous families only, the prevalence falls to 2.73 per 1000 (95% CI 2.19, 3.41). In 60% cases the cause of deafness was genetic. The single most common cause of sensorineural hearing loss in this population was mutations in the GJB2 gene (Connexin 26) in 20 of these patients (17%). Parents were consanguineous in 33% of the families. CONCLUSION: This study concludes that prevalence of sensorineural deafness in Bangladeshi children is at least 2.3 times the national average. This study also concludes that genetic causes are the common cause of deafness in this ethnic group, with nearly 30% of children with non-syndromic deafness having mutations in GJB2. Although parental consanguinity was very high in this population it did not account for the whole increase in prevalence.

Rubella seroprevalence in pregnant women in North Thames: estimates based on newborn screening samples.

OBJECTIVES: Routine screening for rubella susceptibility is recommended in the UK so that women found to be susceptible can be offered immunization in the post partum period. We demonstrate the use of newborn dried blood spot samples linked to routine vital statistics datasets to monitor rubella susceptibility in pregnant women and to investigate maternal characteristics as determinants of rubella seronegativity. SETTING: North Thames region of England (including large parts of inner London). METHODS: Maternally acquired rubella IgG antibody levels were measured in 18882 newborn screening blood spot samples. Latent class regression finite mixture models were used to classify samples as seronegative to rubella. Data on maternal country of birth were available through linkage to birth registration data. RESULTS: An estimated 2.7% (95% CI 2.4%-3.0%) of newly delivered women in North Thames were found to be seronegative. Mothers born abroad, particularly in Sub-Saharan Africa and South Asia, were more likely to be seronegative than UK-born mothers, with adjusted odds ratios of 4.2 (95% CI 3.1-5.6) and 5.0 (3.8-6.5), respectively. Mothers under 20 years were more likely to be seronegative than those aged 30 to 34. CONCLUSION: Our findings highlight the need for vaccination to be targeted specifically at migrant women and their families to ensure that they are protected from rubella in pregnancy and its serious consequences.

Ethnicity of children with homozygous c.985A>G medium-chain acyl-CoA dehydrogenase deficiency: findings from screening approximately 1.1 million newborn infants.

OBJECTIVES: It has been suggested that homozygous c.985A>G medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is a disease of White ethnic origin but little is known regarding its ethnic distribution. We estimated ethnic-specific homozygous c.985A>G MCADD birth prevalence from a large-scale UK newborn screening study. METHODS: Homozygous c.985A>G MCADD cases were ascertained in six English newborn screening centres between 1 March 2004 and 28 February 2007 by screening approximately 1.1 million newborns using tandem mass spectrometry analysis of underivatised blood spot samples to quantitate octanoylcarnitine (C8). Follow-up biochemistry and mutation analyses for cases (mean triplicate C8 value >/=0.5 micromol/L) were reviewed to confirm diagnosis. Ethnicity was ascertained from clinician report and denominators from 2001 UK Census estimates of ethnic group of children less than one year. RESULTS: Sixty-four infants were c.985A>G MCADD homozygotes (overall prevalence 5.8 per 100,000 live births; 95% CI 4.4-7.2). Sixty (93%) were White, two (3%) were mixed/other and two were of unknown ethnic origin. No Asian or Black homozygotes were identified. Proportions of White, mixed/other, Asian and Black births in screening regions were estimated, yielding homozygous c.985A>G MCADD birth prevalence of 6.9 per 100,000 (95% CI 5.2-8.8) in White, and 95% CI estimates of 0-2.7 per 100,000 in Asian and 0-5.8 in Black populations. The c.985A>G carrier frequency in the White group was estimated at one in 65 (95% CI 1/74, 1/61) under Hardy-Weinberg conditions. CONCLUSION: c.985A>G homozygous MCADD is not found in Black and Asian ethnic groups that have been screened at birth in England. This is consistent with the earlier published observations suggesting that MCADD due to the c.985A>G mutation is a disease of White ethnic origin.

Risk-adjusted surveillance of hospital-acquired infections in neonatal intensive care units: a systematic review.

Comparisons of bacteraemia incidence between neonatal intensive care units (NICUs) can identify centres with effective infection control, whose practices can be shared with other units. For fair comparisons, infection incidence must be risk-adjusted to control for differences between centres in the vulnerability of babies and the intensity of invasive procedures which can introduce infection. We reviewed risk adjustment methods for between-NICU comparisons of bacteraemia incidence, both in the published literature and in regional and national NICU infection monitoring systems. PubMed and Embase were searched for studies reporting risk-adjusted bacteraemia incidence in more than one NICU. An internet search found NICU infection monitoring systems in Western industrialised countries. In all nine studies that met the inclusion criteria, risk adjustment reduced but did not eliminate variation in bacteraemia incidence between NICUs. In both the studies and the regional monitoring systems, adjustment for baby susceptibility generally involved stratification by factors measured at birth. Adjustment for Length of stay and invasive procedures involved reporting incidence by days with a device, such as central venous catheter days. Methods for NICU infection monitoring lack consistency. Adjustment for factors measured at birth fails to capture changes in susceptibility throughout admission and adjustment for device days does not adequately reflect risk to babies not treated with the device. Further research should address variation in risk for all babies throughout their NICU stay.