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Summary: Flaws in the conduct of randomized trials can lead to biased estimation of the intervention effect. Methods for adjustment of within‐trial biases in meta‐analysis include the use of empirical evidence from an external collection of meta‐analyses, and the use of expert opinion informed by the assessment of detailed trial information. Our aim is to present methods to combine these two approaches to gain the advantages of both. We make use of the risk of bias information that is routinely available in Cochrane reviews, by obtaining empirical distributions for the bias associated with particular bias profiles (combinations of risk of bias judgements). We propose three methods: a formal combination of empirical evidence and opinion in a Bayesian analysis; asking experts to give an opinion on bias informed by both summary trial information and a bias distribution from the empirical evidence, either numerically or by selecting areas of the empirical distribution. The methods are demonstrated through application to two example binary outcome meta‐analyses. Bias distributions based on opinion informed by trial information alone were most dispersed on average, and those based on opinions obtained by selecting areas of the empirical distribution were narrowest. Although the three methods for combining empirical evidence with opinion vary in ease and speed of implementation, they yielded similar results in the two examples. [ABSTRACT FROM AUTHOR]

Aggregated early warning scores (EWS) within these systems have evolved into the mutual language of ward and ICU teams. In the UK, most institutions have chosen to implement the National Early Warning Score (NEWS) in preference to local EWS. The ability of the National Early Warning Score (NEWS) to discriminate patients at risk of early cardiac arrest, unanticipated intensive care unit admission, and death. [Extracted from the article]

The collection of a subset of CFS/ME patient data as part of the.national CFS/ME collaborative was confirmed to be service evaluation by the North Somerset & Bristol Research Ethics Committee under REC reference 07/Q2006/48, and in a letter dated 29 January 2007 the Chair of the Research Ethics Committee had previously confirmed (a) that it would not be necessary to apply for ethical permission to use the data being collected as part of service evaluation for the national CFS/ME collaborative and (b) that if in future this data were to be used as part of a research project, this would be agreeable. The "Ethical Approval" section of this paper has been updated to read The data used in this study was originally collected and collated in the National Outcomes Database for the purposes of evaluation of CFS/ME services. [Extracted from the article]

Appropriate imputation inference requires both an unbiased imputation estimator and an unbiased variance estimator. The commonly used variance estimator, proposed by Rubin, can be biased when the imputation and analysis models are misspecified and/or incompatible. Robins and Wang proposed an alternative approach, which allows for such misspecification and incompatibility, but it is considerably more complex. It is unknown whether in practice Robins and Wang's multiple imputation procedure is an improvement over Rubin's multiple imputation. We conducted a critical review of these two multiple imputation approaches, a re-sampling method called full mechanism bootstrapping and our modified Rubin's multiple imputation procedure via simulations and an application to data. We explored four common scenarios of misspecification and incompatibility. In general, for a moderate sample size (n = 1000), Robins and Wang's multiple imputation produced the narrowest confidence intervals, with acceptable coverage. For a small sample size (n = 100) Rubin's multiple imputation, overall, outperformed the other methods. Full mechanism bootstrapping was inefficient relative to the other methods and required modelling of the missing data mechanism under the missing at random assumption. Our proposed modification showed an improvement over Rubin's multiple imputation in the presence of misspecification. Overall, Rubin's multiple imputation variance estimator can fail in the presence of incompatibility and/or misspecification. For unavoidable incompatibility and/or misspecification, Robins and Wang's multiple imputation could provide more robust inferences. [ABSTRACT FROM AUTHOR]

Background Studies have shown an inverse association of pet ownership with allergy but inconclusive findings for asthma. Objective To investigate whether pet ownership during pregnancy and childhood was associated with asthma and atopy at the age of 7 in a UK population-based birth cohort. Methods Data from the Avon Longitudinal Study of Parents and Children ( ALSPAC) were used to investigate associations of pet ownership at six time points from pregnancy to the age of 7 with asthma, atopy (grass, house dust mite, and cat skin prick test) and atopic vs. non-atopic asthma at the age of 7 using logistic regression models adjusted for child's sex, maternal history of asthma/atopy, maternal smoking during pregnancy, and family adversity. Results A total of 3768 children had complete data on pet ownership, asthma, and atopy. Compared with non-ownership, continuous ownership of any pet (before and after the age of 3) was associated with 52% lower odds of atopic asthma [odds ratio ( OR) 0.48, 95% CI 0.34-0.68]. Pet ownership tended to be associated with increased risk of non-atopic asthma, particularly rabbits ( OR 1.61, 1.04-2.51) and rodents ( OR 1.86, 1.15-3.01), comparing continuous vs. non-ownership. Pet ownership was consistently associated with lower odds of sensitization to grass, house dust mite, and cat allergens, but rodent ownership was associated with higher odds of sensitization to rodent allergen. Differential effects of pet ownership on atopic vs. non-atopic asthma were evident for all pet types. Conclusions and Clinical Relevance Pet ownership during pregnancy and childhood in this birth cohort was consistently associated with a reduced risk of aeroallergen sensitization and atopic asthma at the age of 7, but tended to be associated (particularly for rabbits and rodents) with an increased risk of non-atopic asthma. The opposing effects on atopy vs. non-atopic asthma might be considered by parents when they are deciding whether to acquire a pet. [ABSTRACT FROM AUTHOR]

Background: Historical cohort studies in England have found that impaired fetal growth and lower respiratory tract infections in early childhood are associated with lower levels of lung function in late adult life. These relations are investigated in a similar study in Scotland.Methods: In 1985-86 a follow up study was carried out of 1070 children who had been born in St Andrew's from 1921 to 1935 and followed from birth to 14 years of age by the Mackenzie Institute for Medical Research. Recorded information included birth weight and respiratory illnesses. The lung function of 239 of these individuals was measured.Results: There was no association between birth weight and lung function. Pneumonia before two years of age was associated with a difference in mean forced expiratory volume in one second (FEV1) of -0.39 litres (95% confidence interval (CI) -0.67, -0.11; p = 0.007) and in mean forced vital capacity (FVC) of -0.60 litres (95% CI -0.92, -0.28; p < 0.001), after controlling for age, sex, height, smoking, type of spirometer, and other illnesses before two years. Similar reductions were seen in men and women. Bronchitis before two years was associated with smaller deficits in FEV1 and FVC. Asthma or wheeze at two years and older and cough after five years were also associated with a reduction in FEV1.Conclusions: The relation between impaired fetal growth and lower lung function in late adult life seen in previous studies was not confirmed in this cohort. The deficits in FEV1 and FVC associated with pneumonia and bronchitis in the first two years of life are consistent with a causal relation. [ABSTRACT FROM AUTHOR]

Background:Screening for prostate cancer continues to generate controversy because of concerns about over-diagnosis and unnecessary treatment. We describe the rationale, design and recruitment of the Cluster randomised triAl of PSA testing for Prostate cancer (CAP) trial, a UK-wide cluster randomised controlled trial investigating the effectiveness and cost-effectiveness of prostate-specific antigen (PSA) testing.Methods:Seven hundred and eighty-five general practitioner (GP) practices in England and Wales were randomised to a population-based PSA testing or standard care and then approached for consent to participate. In the intervention arm, men aged 50-69 years were invited to undergo PSA testing, and those diagnosed with localised prostate cancer were invited into a treatment trial. Control arm practices undertook standard UK management. All men were flagged with the Health and Social Care Information Centre for deaths and cancer registrations. The primary outcome is prostate cancer mortality at a median 10-year-follow-up.Results:Among randomised practices, 271 (68%) in the intervention arm (198 114 men) and 302 (78%) in the control arm (221 929 men) consented to participate, meeting pre-specified power requirements. There was little evidence of differences between trial arms in measured baseline characteristics of the consenting GP practices (or men within those practices).Conclusions:The CAP trial successfully met its recruitment targets and will make an important contribution to international understanding of PSA-based prostate cancer screening. [ABSTRACT FROM AUTHOR]

Background: Chronic fatigue syndrome (CFS) is relatively common and disabling. Over 8000 patients attend adult services each year, yet little is known about the outcome of patients attending NHS services. Aim: Investigate the outcome of patients with CFS and what factors predict outcome. Design: Longitudinal patient cohort. Methods: We used data from six CFS/ME (myalgic encephalomyelitis) specialist services to measure changes in fatigue (Chalder Fatigue Scale), physical function (SF-36), anxiety and depression (Hospital Anxiety and Depression Scale) and pain (visual analogue pain rating scale) between clinical assessment and 8-20 months of follow-up. We used multivariable linear regression to investigate baseline factors associated with outcomes at follow-up. Results: Baseline data obtained at clinical assessment were available for 1643 patients, of whom 834 (51%) had complete follow-up data. There were improvements in fatigue [mean difference from assessment to outcome: -6.8; 95% confidence interval (CI) -7.4 to -6.2; P < 0.001]; physical function (4.4; 95% CI 3.0-5.8; P < 0.001), anxiety (-0.6; 95% CI -0.9 to -0.3; P < 0.001), depression (-1.6; 95% CI -1.9 to -1.4; P < 0.001) and pain (-5.3; 95% CI -7.0 to -3.6; P < 0.001). Worse fatigue, physical function and pain at clinical assessment predicted a worse outcome for fatigue at follow-up. Older age, increased pain and physical function at assessment were associated with poorer physical function at follow-up. Conclusions: Patients who attend NHS specialist CFS/ME services can expect similar improvements in fatigue, anxiety and depression to participants receiving cognitive behavioural therapy and graded exercise therapy in a recent trial, but are likely to experience less improvement in physical function. Outcomes were predicted by fatigue, disability and pain at assessment. [ABSTRACT FROM AUTHOR]

Longitudinal studies, where data are repeatedly collected on subjects over a period, are common in medical research. When estimating the effect of a time-varying treatment or exposure on an outcome of interest measured at a later time, standard methods fail to give consistent estimators in the presence of time-varying confounders if those confounders are themselves affected by the treatment. Robins and colleagues have proposed several alternative methods that, provided certain assumptions hold, avoid the problems associated with standard approaches. They include the g-computation formula, inverse probability weighted estimation of marginal structural models and g-estimation of structural nested models. In this tutorial, we give a description of each of these methods, exploring the links and differences between them and the reasons for choosing one over the others in different settings. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Most previous studies have examined the association between mortality and deprivation at only one point in time. However, risk accumulates over the life course. The design of the study was ecological. Its aims were to explain inequalities in total and cause-specific mortality between geographical areas in relation to the lifestyle and health behaviours of the resident populations and the area levels of deprivation in 1981 and in 1921-40. Methods: Data on health behaviour from the 1985 Heartbeat Wales Community Survey were evaluated in light of Welsh mortality rates for the period 1981-99, 1981 census data on socioeconomic position and the infant mortality rates in 1921-40. Negative binomial models were carried out to investigate the district-level association of mortality with deprivation (infant mortality in 1921-40, Carstairs score in 1981, combined index of deprivation) independently from the personal habits and characteristics of the resident population. Results: There was an increased risk of death in deprived areas compared with more wealthy ones. Both infant mortality (a proxy of material deprivation during the time in which the 50-59-gear-old individuals were born or were children) and Carstairs scores )a proxy of deprivation during adulthood) were strongly associated with recent mortality. Deprivation had stronger effects in women than in men, the only exception being the effects of later life deprivation on lung cancer. Conclusions: Area characteristics at different points of time may help to explain geographical inequality in mortality. [ABSTRACT FROM AUTHOR]

We present models for the combined analysis of evidence from randomized controlled trials categorized as being at either low or high risk of bias due to a flaw in their conduct. We formulate a bias model that incorporates between-study and between-meta-analysis heterogeneity in bias, and uncertainty in overall mean bias. We obtain algebraic expressions for the posterior distribution of the bias-adjusted treatment effect, which provide limiting values for the information that can be obtained from studies at high risk of bias. The parameters of the bias model can be estimated from collections of previously published meta-analyses. We explore alternative models for such data, and alternative methods for introducing prior information on the bias parameters into a new meta-analysis. Results from an illustrative example show that the bias-adjusted treatment effect estimates are sensitive to the way in which the meta-epidemiological data are modelled, but that using point estimates for bias parameters provides an adequate approximation to using a full joint prior distribution. A sensitivity analysis shows that the gain in precision from including studies at high risk of bias is likely to be low, however numerous or large their size, and that little is gained by incorporating such studies, unless the information from studies at low risk of bias is limited. We discuss approaches that might increase the value of including studies at high risk of bias, and the acceptability of the methods in the evaluation of health care interventions. [ABSTRACT FROM AUTHOR]

Background: Patterns of wheezing during early childhood may indicate differences in aetiology and prognosis of respiratory illnesses. Improved characterisation of wheezing phenotypes could lead to the identification of environmental influences on the development of asthma and airway diseases in predisposed individuals.Methods: Data collected on wheezing at seven time points from birth to 7 years from 6265 children in a longitudinal birth cohort (the ALSPAC study) were analysed. Latent class analysis was used to assign phenotypes based on patterns of wheezing. Measures of atopy, airway function (forced expiratory volume in 1 s (FEV(1)), mid forced expiratory flow (FEF(25-75))) and bronchial responsiveness were made at 7-9 years of age.Results: Six phenotypes were identified. The strongest associations with atopy and airway responsiveness were found for intermediate onset (18 months) wheezing (OR for atopy 8.36, 95% CI 5.2 to 13.4; mean difference in dose response to methacholine 1.76, 95% CI 1.41 to 2.12 %FEV(1) per mumol, compared with infrequent/never wheeze phenotype). Late onset wheezing (after 42 months) was also associated with atopy (OR 6.6, 95% CI 4.7 to 9.4) and airway responsiveness (mean difference 1.61, 95% CI 1.37 to 1.85 %FEV(1) per mumol). Transient and prolonged early wheeze were not associated with atopy but were weakly associated with increased airway responsiveness and persistent wheeze had intermediate associations with these outcomes.Conclusions: The wheezing phenotypes most strongly associated with atopy and airway responsiveness were characterised by onset after age 18 months. This has potential implications for the timing of environmental influences on the initiation of atopic wheezing in early childhood. [ABSTRACT FROM AUTHOR]

Background A recent study suggested a link between folate metabolism and atopy, based on a positive association between a common polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene and allergic sensitization in Danish adults. Objective We investigated the associations between MTHFR C677T and allergy or atopy in a large, population-based birth cohort of children and their mothers, the Avon Longitudinal Study of Parents and Children (ALSPAC). We also looked for evidence of a pre-natal effect of maternal folate metabolism on subsequent atopic disease in the offspring. Methods Mothers were recruited in pregnancy and the children followed from birth. Atopy in the child was assessed at 7–8 years of age by skin prick tests to common allergens. Asthma was defined as a physician diagnosis and current symptoms at 71/2 years of age. Asthma and allergy status of the mothers were obtained from self-completion questionnaires. Results Data on MTHFR C677T genotype and allergy were available for 5364 children and on allergy and/or asthma for 7356 mothers. In children, the prevalence of atopy was 20.0% and asthma 10.0% whereas in mothers, the prevalence of self-reported allergy was 42.7% and asthma 11.5%. Atopy in the child was associated with male gender ( P<0.001), less tobacco smoke exposure and higher maternal education. MTHFR C677T genotype was not associated with social factors or dietary folate intake. We found no evidence of associations between the MTHFR C677T variant allele and atopy, allergy or asthma in mothers or children. There was no evidence to support an effect of maternal MTHFR C677T genotype on atopy in the offspring. Conclusion The results of this study do not support the hypothesis that impaired folate metabolism is associated with allergy in adults or children in this population. [ABSTRACT FROM AUTHOR]

Objectives. To estimate changes in coronary risk factors and their implications for coronary heart disease (CHD) rates in men starting highly active antiretroviral therapy (HAART). Methods. Men participating in the Swiss HIV Cohort Study with measurements of coronary risk factors both before and up to 3 years after starting HAART were identified. Fractional polynomial regression was used to graph associations between risk factors and time on HAART. Mean risk factor changes associated with starting HAART were estimated using multilevel models. A prognostic model was used to predict corresponding CHD rate ratios. Results. Of 556 eligible men, 259 (47%) started a nonnucleoside reverse transcriptase inhibitor (NNRTI) and 297 a protease inhibitor (PI) based regimen. Levels of most risk factors increased sharply during the first 3 months on HAART, then more slowly. Increases were greater with PI- than NNRTI-based HAART for total cholesterol (1.18 vs. 0.98 mmol L−1), systolic blood pressure (3.6 vs. 0 mmHg) and BMI (1.04 vs. 0.55 kg m2) but not HDL cholesterol (0.24 vs. 0.32 mmol L−1) or glucose (1.02 vs. 1.03 mmol L−1). Predicted CHD rate ratios were 1.40 (95% CI 1.13–1.75) and 1.17 (0.95–1.47) for PI- and NNRTI-based HAART respectively. Conclusions. Coronary heart disease rates will increase in a majority of patients starting HAART: however the increases corresponding to typical changes in risk factors are relatively modest and could be offset by lifestyle changes. [ABSTRACT FROM AUTHOR]

Keypoints •It has been suggested that the link between human papillomavirus (HPV) and head and neck squamous cell carcinoma (HNSCC) is specific to carcinoma of the tonsil. • We systematically reviewed studies that tested for HPV16 exposure in anatomically defined sites in the head and neck and a control group. • The association between HPV16 and cancer was strongest for tonsil (OR: 15.1, 95% CI: 6.8–33.7), intermediate for oropharynx (OR: 4.3, 95% CI: 2.1–8.9) and weakest for oral (OR: 2.0, 95% CI: 1.2–3.4) and larynx (OR: 2.0, 95% CI: 1.0–4.2). • To investigate heterogeneity, further stratification by method of HPV16 detection, suggested that variation in the magnitude of the HPV-cancer association with cancer site was restricted to studies using ELISA: among studies using PCR, the magnitude of the summary odds ratios was similar across the four sites. • The association between HPV16 infection and HNSCC in specific sites suggests the strongest and most consistent association is with tonsil cancer, and the magnitude of this association is consistent with an infectious aetiology. • However, the method of viral detection may be an important source of heterogeneity. Resolution of this issue will require further studies using both methods, examining associations separately in different sites. [ABSTRACT FROM AUTHOR]

Objective: To estimate the cumulative incidence of severe complications associated with genital chlamydia infection in the general female population. Methods: The Uppsala Women's Cohort Study was a retrospective population based cohort study in Sweden, linking laboratory, hospital, and population registers. We estimated the cumulative incidence of hospital diagnosed pelvic inflammatory disease, ectopic pregnancy, and infertility, and used multivariable regression models to estimate hazard ratios according to screening status. Results: We analysed complete data from 43 715 women in Uppsala aged 15–24 years between January 1985 and December 1989. Follow up until the end of 1999 included 709 000 woman years and 3025 events. The cumulative incidence of pelvic inflammatory disease by age 35 years was 3.9% (95% CI 3.7% to 4.0%) overall: 5.6% (4.7% to 6.7%) in women who ever tested positive for chlamydia, 4.0% (3.7% to 4.4%) in those with negative tests, and 2.9% (2.7% to 3.2%) in those who were never screened. The corresponding figures were: for ectopic pregnancy, 2.3% (2.2% to 2.5%) overall, 2.7% (2.1% to 3.5%), 2.0% (1.8% to 2.3%), and 1.9% (1.7% to 2.1%); and for infertility, 4.1% (3.9% to 4.3%) overall, 6.7% (5.7% to 7.9%), 4.7% (4.4% to 5.1%), and 3.1% (2.8% to 3.3%). Low educational attainment was strongly associated with the development of all outcomes. Conclusions: The incidence of severe chlamydia associated complications estimated from ours, and other population based studies, was lower than expected. Studies that incorporate data about pelvic inflammatory disease diagnosed in primary care and behavioural risk factors would further improve our understanding of the natural history of chlamydia. Our results provide reassurance for patients, but mean that the benefits of chlamydia screening programmes might have been overestimated. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the association of parental history of atopic disease with childhood atopic dermatitis, and to examine the relative strength of associations with maternal and paternal disease. Design: Mothers were recruited to the Avon longitudinal study of parents and children (ALSPAC) from the eighth week of pregnancy. Before parturition, both parents were asked, separately, to report their lifetime history of eczema, asthma, and hayfever. Parents reported symptoms of atopic dermatitis in their children at ages 6, 18, 30, and 42 months. Results: Of 8530 children with complete information on rash at ages 6, 18, 30, and 42 months, 7969 had complete information on maternal atopic disease and 5658 on maternal and paternal atopic disease. There was a strong association between parental eczema and childhood atopic dermatitis: odds ratio 1.69 (95% confidence interval, 1.47 to 1.95) for maternal eczema only, 1.74 (1.44 to 2.09) For paternal eczema only, and 2.72 (2.09 to 3.53) for eczema in both parents. Associations with parental asthma or hayfever were attenuated after controlling for parental eczema. There was no evidence that associations with maternal atopy were stronger than with paternal. Conclusions: Associations between parents' atopic disease and the risk of atopic dermatitis in offspring vary according to the type of atopic disease in the parents, but not according to parental sex. These results are at variance with previous studies reporting stronger associations with maternal than paternal atopy, and suggest that there is no "parent-of-origin" effect in atopic dermatitis. Parental eczema may be a better marker than parental asthma/hayfever in predisposing to childhood eczema. [ABSTRACT FROM AUTHOR]

Objectives: To investigate ethnic differences in rates of gonorrhoea using empirical sexual behaviour data in a simple mathematical model. To explore the impact of different intervention strategies in this simulated population. Methods: The findings from cross sectional studies of gonorrhoea rates and sexual behaviour in three ethnic groups in south east London were used to determine the parameters for a deterministic, mathematical model of gonorrhoea transmission dynamics, in a population stratified by sex, sexual activity (rate of partner change), and ethnic group (white, black African, and black Caribbean). We compared predicted and observed rates of infection and simulated the effects of targeted and population- wide intervention strategies. Results: In model simulations the reported sexual behaviours and mixing patterns generated major differences in the rates of gonorrhoea experienced by each subpopulation. The fit of the model to observed data was sensitive to assumptions about the degree of mixing by level of sexual activity, the numbers of sexual partnerships reported by men and women, and the degree to which observed data underestimate female infection rates. Interventions to reduce duration of infection were most effective when targeted at black Caribbeans. Conclusions: Average measures of sexual behaviour in large populations are inadequate descriptors for the epidemiology of gonorrhoea. The consistency between the model results and empirical data shows that profound differences in gonorrhoea rates between ethnic groups can be explained by modest differences in a limited number of sexual behaviours and mixing patterns. Targeting effective services to particular ethnic groups can have a disproportionate influence on disease reduction in the whole community. [ABSTRACT FROM AUTHOR]

Background: Screening has been recommended to reduce the prevalence and morbidity associated with genital chlamydia infection in the United Kingdom. Methods: We describe the rationale and study design of the Chlamydia Screening Studies (ClaSS), a collaborative project designed to evaluate screening outside genitourinary medicine clinics. A non- selective, active screening approach in 16-39 year olds randomly sampled from 27 general practice lists in the Bristol and Birmingham areas formed the basis of interlinked studies: a case-control study was used to investigate factors to improve the targeting of screening; participants with chlamydia were invited to enrol in a randomised controlled trial to evaluate partner notification conducted in primary care; and laboratory based studies were used to assess the best specimens and tests. We also explored psychosocial effects of screening and partner notification and modelled the cost effectiveness of the programme. Conclusion: Results from four pilot practices show that mailing of specimens for chlamydia testing is feasible but that it is difficult to achieve high response rates with postal screening. The high prevalence of asymptomatic infection in men suggests that efforts to screen men for chlamydia should be strengthened. [ABSTRACT FROM AUTHOR]

There is strong evidence that the incidence and prevalence of atopic diseases is increasing. However, estimates of the prevalence of atopic dermatitis (AD) have varied greatly in the U.K. and most parts of the developed world. The aim of the study was to estimate the prevalence and incidence of AD between the ages of 0 and 42 months in children born in the 1990s in a defined population in the U.K. We used data from the Avon Longitudinal Study of Pregnancy and Childhood (ALSPAC), a large population-based study in the U.K. that enrolled all pregnant mothers who were resident in Avon and had their delivery date falling between 1 April 1991 and 31 December 1992. Since then ALSPAC has collected a wide range of data from the newborns and their parents. Data reported here were collected at 6, 18, 30 and 42 months using parental reports in a postal questionnaire. Of the 14 009 children originally enrolled 8530 provided information on AD in each of the four follow-up questionnaires. We defined AD as a report of rash in at least two of the four questionnaires. Incidence risk was defined as the percentage of new cases of AD between follow-up questionnaires, out of the total number of children whose parents had not reported that they had AD by the time of the previous follow-up. Period prevalence of 21·0%, 25·6%, 23·2% and 19·9% were observed at ages 0–6, 6–18, 18–30 and 30–42 months, respectively. The corresponding incidence risks were 21·0%, 11·2% and 3·8%, at 0–6, 6–18 and 18–30 months, respectively. There were no gender differences in either the incidence or prevalence of the disease. Results from this large, prospective study are consistent with recent reports of increased incidence and prevalence of AD. Health planners can use our estimates of incidence and prevalence to project the number of children likely to suffer from AD during infancy and early childhood, and thus to determine the human and financial resources required. [ABSTRACT FROM AUTHOR]

Periodontal disease has been suggested to be an important risk factor for preterm low birthweight (PLBW). Here we report a case-control study of 236 cases (infants < 37 wks and weighing < 2499 g) and a daily random sample of 507 controls (⩾ 38 wks and weighing ⩾ 2500 g). Clinical periodontal indices were measured on the labor wards. Associated risk factors for periodontal disease and PLBW were ascertained by means of a structured questionnaire and maternity notes. The risk for PLBW decreased with increasing pocket depth (odds ratio [OR] 0.83, 95% confidence interval [CI] 0.68 to 1.00). After adjustment for maternal age, ethnicity, maternal education, smoking, alcohol consumption, infections, and hypertension during pregnancy, this decreased further (OR 0.78, 95% CI 0.64 to 0.99). We found no evidence for an association between PLBW and periodontal disease. Our results do not support a specific drive to improve periodontal health of pregnant women as a means of improving pregnancy outcomes. [ABSTRACT FROM AUTHOR]

Objectives: To examine differences in population based rates of gonorrhoea and chlamydia between black ethnic groups in Lambeth, Southwark and Lewisham Health Authority.Methods: Episodes of gonorrhoea or chlamydia recorded among attenders at 11 genitourinary clinics in south and central London from 1 January 1994 to 31 December 1995 were retrieved. Complete data on chlamydia were only available for women. Ethnic group was assigned according to census categories--white, black Caribbean, black African, black other, Asian, or other. We calculated yearly incidence rates for episodes of gonorrhoea and chlamydia in residents of Lambeth, Southwark and Lewisham Health Authority. Random effects Poisson regression models were used to examine associations between infection rates and age, ethnic group, and material deprivation.Results: During the study period there were 1996 episodes of gonorrhoea in men and women and 1376 episodes of chlamydia in women with complete data. For both infections rates among individuals from black Caribbean and black other ethnic groups were markedly higher than among black Africans. In men, the gonorrhoea rate among black Caribbean 20-24 year olds was 2348 (95% CI 1965 to 2831) episodes per 100,000 compared with 931 (95% CI 690 to 1288) in black African men and 111 (95% CI 100 to 124) per 100,000 in white men of the same age. Among women gonorrhoea rates were highest in black Caribbean 15-19 year olds (2612, 95% CI 2161 to 3190 per 100,000). In contrast, rates in black African women of the same age (331, 95% CI 154 to 846 per 100,000) were similar to those of white women (222, 95% CI 163 to 312). Chlamydia rates were also highest in black Caribbean 15-19 year old women (4579, 95% CI 3966 to 5314 per 100,000), compared with 1286 (95% CI 907 to 1888) in black African and 433 (95% CI 349 to 544) per 100,000 white women. Controlling for material deprivation and age only attenuated differences in rates between ethnic groups slightly.Conclusions: There are marked differences in rates of gonorrhoea and chlamydia between different black ethnic groups, with higher rates in black Caribbeans than black Africans. This study supports the hypothesis that assortative sexual mixing patterns can restrict epidemics of sexually transmitted infections within ethnic groups. Differences in disease occurrence between black ethnic groups should be explored before combining data, even when numbers of episodes are small. [ABSTRACT FROM AUTHOR]

Background: The pulmonary antioxidant glutathione may limit airway inflammation in asthma. Since paracetamol (acetaminophen) depletes the lung of glutathione in animals, a study was undertaken to investigate whether frequent use in humans was associated with asthma.Methods: Information was collected on the use of analgesics as part of a population based case-control study of dietary antioxidants and asthma in adults aged 16-49 years registered with 40 general practices in Greenwich, South London. The frequency of use of paracetamol and aspirin was compared in 664 individuals with asthma and in 910 without asthma. Asthma was defined by positive responses to questions about asthma attacks, asthma medication, or waking at night with shortness of breath. The association between analgesic use and severity of disease amongst asthma cases, as measured by a quality of life score, was also examined.Results: Paracetamol use was positively associated with asthma. After controlling for potential confounding factors the odds ratio for asthma, compared with never users, was 1.06 (95% CI 0.77 to 1.45) in infrequent users (Conclusions: Frequent use of paracetamol may contribute to asthma morbidity and rhinitis in adults. [ABSTRACT FROM AUTHOR]

Background: Impaired fetal growth may be a risk factor for asthma although evidence in children is conflicting and there are few data in adults. Little is known about risk factors which may influence asthma in late childhood or early adult life. Whilst there are clues that fatness may be important, this has been little studied in young adults. The relations between birth weight and childhood and adult anthropometry and asthma, wheeze, hayfever, and eczema were investigated in a nationally representative sample of young British adults.Methods: A total of 8960 individuals from the 1970 British Cohort Study (BCS70) were studied. They had recently responded to a questionnaire at 26 years of age in which they were asked whether they had suffered from asthma, wheeze, hayfever, and eczema in the previous 12 months. Adult body mass index (BMI) was calculated from reported height and weight.Results: The prevalence of asthma at 26 years fell with increasing birth weight. After controlling for potential confounding factors, the odds ratio comparing the lowest birth weight group (<2 kg) with the modal group (3-3.5 kg) was 1.99 (95% CI 0.96 to 4.12). The prevalence of asthma increased with increasing adult BMI. After controlling for birth weight and other confounders, the odds ratio comparing highest with lowest quintile was 1.72 (95% CI 1.29 to 2.29). The association between fatness and asthma was stronger in women; odds ratios comparing overweight women (BMI 25-29.99) and obese women (BMI >/=30) with those of normal weight (BMI <25) were 1.51 (95% CI 1.11 to 2.06) and 1.84 (95% CI 1. 19 to 2.84), respectively. The BMI at 10 years was not related to adult asthma. Similar associations with birth weight and adult BMI were present for wheeze but not for hayfever or eczema.Conclusions: Impaired fetal growth and adult fatness are risk factors for adult asthma. [ABSTRACT FROM AUTHOR]

We have measured the opsonic capacity of serum for the phagocytosis of Porphyromonas (Bacteroides) gingivalis by polymorphonuclear leucocytes (PMN) in 35 patients with a history of destructive periodontitis and 35 matched control subjects. The serum from cases, tested concentrations of 8% and 0.8% opsonised P. gingivalis for phagocytosis by PMN to a level significantly greater than controls (p< 0.0001 and <0.01 respectively). IgG antibody levels to P. gingivalis whole cells estimated by ELISA were also significantly higher in the cases (p<0.0001). The IgG antibody levels correlated significantly with the opsonic capacity of the serum tested at 8% concentration in controls (r-0.371, p. 0.03) but not in eases (r=0.235, p=0.17); in 0.8 % serum, the opsonic capacity of the cases and controls were not significantly correlated. Elevated opsonisation by serum was a significant predictor that a subject was a case rather than a control, even after allowing for the effect of elevated IgG antibody in the cases. The data suggest that an elevated capacity of serum to opsonise P. gingivalis is a distinctive feature in patients with past destructive periodontal disease. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Clinical Periodontology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Journal of Clinical Periodontology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Journal of Clinical Periodontology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Journal of Clinical Periodontology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Journal of Clinical Periodontology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Journal of Clinical Periodontology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Journal of Clinical Periodontology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Journal of Clinical Periodontology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Journal of Clinical Periodontology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Journal of Clinical Periodontology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Mycobacterium leprae (M. leprae) soluble antigen (MLSA) reagents have been developed with the aim of finding a reagent, comparable to tuberculin, which could identify individuals infected with the leprosy bacillus. They have yet to be evaluated fully in human populations.Methods: More than 15000 individuals living in a leprosy endemic area of northern Malawi were skin tested with one of five batches of MLSA prepared using two different protocols. The main difference in preparation was the introduction of a high G centrifugation step in the preparation of the last three ('second-generation') batches.Results: The prevalence of skin-test positivity (delayed-type hypersensitivity (DTH)) and association with the presence of a BCG scar were greater for first (batches A6, A22) than second (batches AB53, CD5, CD19) generation reagents. The association of positivity with M. leprae infection was investigated by comparing results among known (household) contacts of leprosy cases, and among newly diagnosed leprosy patients with those in the general population. While positivity to 'first-generation' antigens appeared to be associated with M. leprae infection, positivity to later antigens was unrelated either to exposure to leprosy cases or presence of leprosy disease. There were geographical differences in the prevalence of DTH to the various batches, probably reflecting exposure to various mycobacteria in the environment.Conclusions: Our results suggest that the 'second-generation' batches have lost antigens that can detect M. leprae infections, but that they retain one or more antigens which are shared between M. leprae and environmental mycobacteria. Natural exposure to these both sensitizes individuals and provides natural protection against M. leprae infection or disease. Identification of antigens present in these groups of skin test reagents may assist in production of improved skin test reagents. [ABSTRACT FROM AUTHOR]

Background: The World Health Organization (WHO) recommended the use of high titre measles vaccine in 1989. Subsequent long term follow-up of several trials yielded results suggesting higher mortality among children inoculated with medium and high titre vaccines compared to standard titre vaccines, although none of the individual trials found significant differences in mortality.Methods: Long term survival after standard, medium and high titre measles vaccines has been investigated in a combined analysis of all West African trials with mortality data. In trials from Guinea-Bissau, The Gambia and Senegal, children received medium or high titre vaccines from 4 months of age and were compared to control groups recruited at the same time later receiving standard titre vaccine from 9 months of age. All children were followed up to at least 3 years old.Results: Combining trials of high titre vaccines showed higher mortality among the high titre group compared to the standard group: mortality ratio (MR) = 1.33 (95% CI : 1.02-1. 73). Mortality among recipients of medium titre vaccines was not different from that in the standard vaccine group, MR = 1.11 (95% CI: 0.54-2.27). In a combined analysis by sex, the adjusted mortality ratios comparing high titre vaccine with standard vaccine were 1.86 (95% CI : 1.28-2.70) for females and 0.91 (95% CI : 0.61-1.35) for males. The trials were not designed to study long term mortality. Adjustments for several possible sources of bias did not alter the results.Conclusions: The combined analysis showed a decreased survival related to high titre measles vaccine compared with standard titre vaccines, though solely among females. As a result of these studies from West Africa and a study from Haiti, WHO has recommended that high titre measles vaccine no longer be used. [ABSTRACT FROM AUTHOR]

Background: Geographical differences in leprosy risk are not understood, but may provide clues about the natural history of the disease. We report an analysis of the geographical distribution of leprosy in Karonga District, a rural area of Northern Malawi, between 1979 and 1989.Methods: Cohort study of the incidence of leprosy based on two total population surveys. Area of residence was determined using aerial photographs, which allowed identification of households, as well as location of roads, rivers and the lake shore.Results: Incidence rates were between two and three times higher in the north compared to the south of the district, and lowest in the semi-urban district capital. The most obvious environmental difference between these regions is the north's higher rainfall and more fertile soil. There was no overall association between leprosy incidence and population density, although highest rates were observed in the least densely populated areas. Looking at the entire district, incidence rates increased with increasing distance from a main road, but declined with increasing distance from a river or from the shore of Lake Malawi. The negative association with proximity to rivers may reflect the larger number of rivers in the north of the district. Apparent differences in incidence rates between groups speaking different languages reflected confounding by area of residence.Conclusions: There is a marked variation, not explained by socioeconomic or cultural factors, in the incidence of leprosy within Karonga District. Our results are consistent with a theme in the literature associating the environment, particularly proximity to water, with leprosy. [ABSTRACT FROM AUTHOR]

An initial parenteral injection of adrenalin-thyroxin (1 injection daily for 5 days) followed by a high lipid diet induces an unusual, rapidly occuring atheroma in the rabbit aorta. Previous ultrastructural and histoenzymologic studies of the same model have shown obvious intimal and medial changes, apparently due to the hormonal treatment alone. Repair occurs quickly. The mechanism of atherogenesis is uncertain. The present study reports the occurence of obvious atherosclerosis at later stages in this model, when studied by the same methods. The changes are compared with those induced by hormonal treatment alone, allowing some insight into the additional effects of adrenalin and cholesterol on rabbit aorta: [ABSTRACT FROM AUTHOR]

The first stages of the atherosclerotic lesions induced in the rabbit aorta by adrenalin- thyroxine, with (or without) an hypercholesterolic diet, have been studied on the 6th, 13th, and 22nd day. Major parietal changes, barely demonstrable with light microscopic standard techniques, were detected, as soon as the 6th day, by electronmicroscopy and histoenzymology. These changes were probably due solely to the hormonal treatment. In the early stage, they consisted of some fragmentations of the elastic sheets and some smooth muscle cell lysis. The oxidative and ATPase activities were greatly reduced. The increased lysosomal hydrolase activities of the outer layers of the vessel could be related to the increased vascular permeability and consecutive increased perfusion gradient induced by these lesions. Later, an obvious repair process was seen. The smooth muscle cells bearing numerous processes were bound by many microfilaments and by some elastic material. The energetic enzymatic activities were increased. The part taken by the lipidic diet in these changes, apart from the increase of the esterase activity, did not seem yet of significance in this first stage of atherosclerosis. However, one cannot exclude that the intensively accumulating lipids might, at some later stages, potentiate the consequences of the vascular lesions or impede the repair process. [ABSTRACT FROM AUTHOR]

During a large epidemiologic study in the Karonga District of northern Malawi, serum samples from 139 patients with incident leprosy, 124 with newly diagnosed leprosy, 277 patients with incident tuberculosis, and 2296 controls were tested for antibodies to human immunodeficiency virus. Sera were tested according to a four-test protocol using two ELISAs and two particle agglutination assays. Overall, 188 samples were considered positive, 2634 were considered negative, and 14 were indeterminate. All 18 available positive specimens from leprosy patients, a random sample of 14 positive specimens from tuberculosis patients, and 15 positive specimens from controls were tested by Western blot. There was no evidence of substantial numbers of ELISA false-positives in any patient group or among controls. [ABSTRACT FROM PUBLISHER]

LA 2851 (2-4-diamino-7-methyl-pyrazolo (1,5-a), 1,3,5-triazine), a bronchodilator and antiallergic compound, in type I hypersensitivity, has been tested orally for activity against carrageenan oedema and complement dependent, reverse passive Arthus (RPA) and zymosan oedema in rats. Pharmacokinetic determinations were also realized in order to correlate plasma blood levels and pharmacological activity. LA 2851 was found active in the first test but showed a more marked effect in the immunologically mediated RPA reaction and zymosan oedema. Among reference drugs tested, theophylline showed the same pattern in contrast with non-steroidal anti-inflammatory agents. LA 2851 and theophylline, using a superfused lung preparation, were found ineffective on the synthesis of cyclooxygenase products from arachidonic acid. LA 2851 as theophylline inhibited cAMP phosphodiesterase (PDE) but this inhibition does not seem to be involved in their anti-inflammatory activity since papaverine, a potent inhibitor of PDE, was totally inactive. The activity on RPA and zymosan inflammation was achieved at the drug plasma level in the range of those required to relax the trachea. The same antagonism was obtained with the 2 drugs at a lower plasma level with LA 2851 than with theophylline for the same dose administered (25 mg/kg). LA 2851 and theophylline did not inhibit all the components of the inflammatory process since maximum inhibition did not exceed 60% up to 200 mg/kg and 100 mg/kg respectively. [ABSTRACT FROM AUTHOR]

Gingival crevicular fluid (GCF) is a promising source for markers of destructive periodontal disease activity. As the initial stage of a longitudinal study into the characterization of disease markers, GCF sampled from 104 sites in 74 adolescents was examined via sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS/PAGE). In this population, which had varying degrees of gingivitis but little evidence of destructive periodontitis, there was a highly homologous GCF protein profile. The Plasma components, albumin, transferrin and IgG, were major constituents of all samples. In addition, a second group of non-plasma derived proteins, with molecular weights 37 kDA, 47 kDA, 57 kDA and 59 kDA, was also commonly detected. The high frequency of occurrence of these components suggests that they may represent products of normal turnover of the periodontal tissues. Analysis of GCF sampled from patients with progressing destructive disease revealed a different SDS/PAGE profile particularly with respect of proteins of non-plasma origin. It is anticipated that the major metabolic changes which accompany the destruction of the tissues during future disease episodes in the adolescent study population will be discernible as alterations to the GCF protein profile. [ABSTRACT FROM AUTHOR]

Although periodontal disease status and progression may vary at different sites in the same subject, statistical models of data from periodontal research must not assume independence of different observations made on the same subject. Methods to analyze appropriate statistical models for data from periodontal research exist, but have hitherto required the data set to be generally balanced. Algorithms for the estimation of `variance components' or `multilevel' models for the analysis of unbalanced data which possess a nested structure have, however, recently been developed. The use of a simple variance components model is illustrated using data from a periodontal clinical trial. The conclusions reached differed from those reached by the original analysis, which did not take account of within-subject differences. Such models may be generalized, for instance to allow for random effects or Longitudinal data. These models will be useful in the study of the etiology and pathogenesis of periodontal diseases, [ABSTRACT FROM AUTHOR]

Improving early warning scores - more data, better validation, the same response: a reply We thank Mackay et al. [1] for their comments on our editorial [2], which accompanied the article by Chiu et al. [3] and agree with the definition of external validation that they provide. Randomly selected patients whose data are not included in the training data used to develop the prediction model and used for validation are similar to, and subject to, the same sampling processes as patients in the development dataset. [Extracted from the article]

With the advent of evidence-based medicine, medical students, doctors and other healthcare professionals are required to be more skilled in the interpretation and manipulation of numerical data. The authors observed that undergraduate students without A-level mathematics expressed concern as to their ability to cope with an epidemiology and biostatistics course. It was hypothesized that these anxieties reflected differences in attitudes to numerical manipulation rather than any real lack of competence. Mean exam performance scores were compared for 498 first-year medical students between 2000 and 2002 depending on whether the students did or did not have A-level mathematics. The data revealed no difference in performance. Students without mathematics A-level scored marginally worse (-1.1%, 95% CI -3.1% to 0.8%, p =0.20) but were no more likely to fail the exam (odds ratio=0.98, 95% CI 0.40 to 2.6, p =0.9). It is concluded that some students experience 'numerophobia'-- a perceived and, it is thought, disproportionate fear of numbers and simple mathematical manipulation. This may act as a psychological barrier for future evidence-based practitioners. [ABSTRACT FROM AUTHOR]