Risk prediction of mortality for patients with heart failure in England: observational study in primary care.

AIMS: Many risk prediction models have been proposed for heart failure (HF), but few studies have used only information available to general practitioners (GPs) in primary care electronic health records (EHRs). We describe the predictors and performance of models built from GP-based EHRs in two cohorts of patients 10 years apart. METHODS AND RESULTS: Linked primary and secondary care data for incident HF cases in England were extracted from the Clinical Practice Research Datalink for 2001-02 and 2011-12. Time-to-event models for all-cause mortality were developed using a long list of potential baseline predictors. Discrimination and calibration were calculated. A total of 5966 patients in 156 general practices were diagnosed in 2001-02, and 12 827 patients in 331 practices were diagnosed in 2011-12. The 5-year survival rate was 40.0% in 2001-02 and 40.2% in 2011-12, though the latter population were older, frailer, and more comorbid; for 2001-02, the 10-year survival was 20.8% and 15-year survival 11.1%. Consistent predictors included age, male sex, systolic blood pressure, body mass index, GP domiciliary visits before diagnosis, and some comorbidities. Model performance for both time windows was modest (c = 0.70), but calibration was generally excellent in both time periods. CONCLUSIONS: Information routinely available to UK GPs at the time of diagnosis of HF gives only modest predictive accuracy of all-cause mortality, making it hard to decide on the type, place, and urgency of follow-up. More consistent recording of data relevant to HF (such as echocardiography and natriuretic peptide results) in GP EHRs is needed to support accurate prediction of healthcare needs in individuals with HF.

Changes in heart failure management and long-term mortality over 10 years: observational study.

OBJECTIVES: To estimate the long-term survival of two cohorts of people diagnosed with heart failure 10 years apart and to assess differences in patient characteristics, clinical guideline compliance and survival by diagnosis setting. METHODS: Data for patients aged 18 and over with a new diagnosis of heart failure in the Clinical Practice Research Datalink in 2001-2002 (5966 patients in 156 practices) and 2011-2012 (12 827 patients in 331 practices). Survival rates since diagnosis were described using Kaplan-Meier plots. Compliance with national guidelines was summarised. RESULTS: 2011/2012 patients were older than those diagnosed a decade before, with lower blood pressure and cholesterol but more comorbidity and healthcare contacts. For those diagnosed in 2001/2002, the 5-year survival was 40.0% (40.2% in the 2011/2012 cohort), 10-year survival was 20.8%, and 15-year survival 11.1%. Improvement in survival between the two time periods was seen only in those diagnosed in primary care (5-year survival 46.0% vs 57.4%, compared with 33.9% and 32.6% for hospital-diagnosed patients).Beta-blocker use rose from 24.3% to 39.1%; renin-angiotensin system blockers rose from 31.8% to 54.3% (both p<0.001). There was little change for loop diuretics and none for thiazide diuretics. For the 9963 patients with symptoms recorded by their general practitioner before diagnosis, brain natriuretic peptide (BNP) testing was low, but echocardiogram use rose from 8.3% to 19.3%, and specialist referral rose from 7.2% to 24.6% (all p<0.001). CONCLUSIONS: The 10 years saw some long-term survival gains but only modest improvement in national clinical guideline compliance, from a low baseline, despite the introduction of national initiatives.

Incident gout and weight change patterns: a retrospective cohort study of US adults.

BACKGROUND: Although the relationship between obesity and incident gout has been clarified, the influence of weight changes during the transition from early adulthood to midlife and the different weight change patterns in specific age ranges on the incidence of gout in later life remain unknown. Therefore, we aimed to investigate the association between weight change patterns across adulthood and incident gout. METHODS: Using data from the National Health and Nutrition Examination Survey (NHANES), we categorized individuals into four weight change patterns: those who remained obese (stable obese), those who moved from a non-obese body mass index (BMI) to an obese BMI (gaining), those who moved from an obese BMI to a non-obese BMI (losing), and those who remained non-obese (stable non-obese). Incident gout reflected its occurrence over the 10-year follow-up from the recalled midlife weight measure to the time of this survey. Hazard ratios (HRs) and 95% confidence intervals relating weight change patterns to incident gout over the 10-year follow-up period were calculated using Cox models adjusted for covariates. The hypothetical population attributable fraction (PAF) for the weight change patterns was calculated. RESULTS: Among our sample of adults aged 40-74 years at their midlife weight measure (n = 11,079), 320 developed gout. The highest risk of incident gout was found for participants with the stable obese pattern (HR 1.84; 1.08-3.14) and not for participants who remained stable non-obese during adulthood. Moreover, gaining weight was a significant risk factor for incident gout (HR 1.65; 1.19-2.29). No significant associations were found between losing weight change patterns and the risk of gout during the study period. If participants who gained weight had become non-obese during the 10-year follow-up, an estimated 3.2% (95% CI 0-6.3) of observed gout cases could have been averted. In addition, if the population had maintained a normal BMI, 32.9% (95% CI 18.2-44.9) cases could have been prevented during the 10 years. CONCLUSIONS: Gaining weight over adulthood was associated with an increased risk of gout. These findings have highlighted that maintaining non-obese weight and weight loss across adulthood is essential for the prevention and treatment of gout in adult life.

Delivering and evaluating a scalable training model for strengthening family medicine in resource-limited environments: the Gaza experience. A mixed-methods evaluation.

BACKGROUND: Since 2007, Gaza Palestine has been subject to blockade affecting over 1.9 million people. This denies health professionals access to continuing professional development (CPD). In Gaza, family physicians are scarce, and their level of training does not meet the needs of United Nations Relief and Works Agency's (UNRWA) Family Health Team (FHT) model for better population health. AIM: This study sought to develop a postgraduate training programme for Gazan doctors via a Diploma in Family Medicine (FM PG), and evaluate its impact on physicians and patients. DESIGN & SETTING: A mixed-methods evaluation of a postgraduate diploma in Gaza Palestine. METHOD: The programme was delivered over 1 year, to 15 primary care doctors. The impact was evaluated through focus group discussions and patient feedback questionnaire survey comparing FM PG graduate doctors and doctors without the FM PG Diploma. RESULTS: All participating doctors graduated successfully and found the experience extremely positive. Trainees felt that the Diploma helped them take more individualised approach to patients; have a better understanding of psychosocial elements affecting patient health; feel more inclined towards team-working and collaborative approaches to health care; and more insight into non-verbal communication such as active listening and tactile gestures. Statistical analysis of patients' feedback showed significantly improved patient-reported outcomes and satisfaction when treated by course diplomates compared to non-diplomates. CONCLUSION: Where there are limited training opportunities, investment in a structured postgraduate diploma training programme can improve quality of health service delivery. UNRWA's experience in Gaza demonstrates the value of a scalable model in resource-limited settings.

Correction to: Associations between post-operative rehabilitation of hip fracture and outcomes: national database analysis.

Following publication of the original article [1], the author reported an error in the Title. The original article has been corrected.

Associations between post-operative rehabilitation of hip fracture and outcomes: national database analysis (90 characters).

BACKGROUND: Rehabilitation programmes are used to improve hip fracture outcomes. There is little published trial clinical trial or population-based data on the effects of the type or provider of rehabilitation treatments on hip fracture outcomes. We evaluated the associations of rehabilitation interventions with post-operative hip fracture outcomes. METHODS: Cross-sectional (2013-2015) analysis of data from the English National Hip Fracture Database (NHFD) from all 191 English hospitals treating hip fractures. Of 62,844 NHFD patients, we included 17,708 patients with rehabilitation treatment and 30-day mobility data, and 34,142 patients with rehabilitation treatment and discharge destination data. The intervention was early mobilisation rehabilitation treatments delivered by a physiotherapist (PT, physical therapist in North America) or other clinical staff as identifiable in NHFD. We used ordinal logistic and propensity scoring regression models to adjust for confounding variables including age, sex, pre-fracture mobility, operative delay, and cognitive function and peri-operative risk scores. RESULTS: In both the adjusted multivariate and propensity-weighted analyses, mobilisation on the day or the day following surgery is associated with better mobility function 30 days after discharge. However patients mobilised by a PT did not have better mobility compared to mobilisation by other professionals. Patients who received a PT assessment were not protected from poorer mobility 30 days after discharge, compared with those who did not receive an assessment. The discharge destination outcome is also better in mobilised than unmobilised patients, whether done by a PT or another health professional, and the difference persists, slightly attenuated, after propensity weighting. CONCLUSIONS: In addition to the type of health professional initiating mobilisation, data on rehabilitation treatment activity and post-operative gait speed is needed to determine optimum rehabilitation dosage and functional outcome. After adjustment patients mobilised by non-PTs did as well as patients mobilised by PTs, suggesting that PTs' current roles in very early rehabilitation should be reconsidered, with a view to redeploying them to more specialised later rehabilitation activity.

Combined healthy lifestyle behaviours and incident disability in an elderly population: the Ohsaki Cohort 2006 Study.

BACKGROUND: The joint impact of healthy lifestyle behaviours (HLBs) on incident disability among elderly populations is still uncertain. This cohort study was conducted to estimate the population-attributable fraction (PAF) of combined HLBs for disability reduction in elderly Japanese. METHODS: We analysed 10-year follow-up data for 9910 community-dwelling elderly people (≥65 years) in a prospective cohort study. Information on lifestyle behaviours and food consumption was collected via a questionnaire in 2006. The exposure variable was defined as a healthy lifestyle index (HLI), which represented the summed number of HLBs ('never or former smoker', 'time spent walking ≥0.5 hour/day' and 'vegetable and fruit consumption volume ≥median'). Data on incident disability were retrieved from the public Long term Care Insurance database. HRs and 95% CIs were estimated by Cox proportional regression and the PAFs and their 95% CIs were estimated with the multivariate-adjusted model. RESULTS: The 10-year incidence of disability was 35.7%. An inverse dose-response relationship was observed (HR (95% CI): 0.85(0.81 to 0.90) for each one-point increase of the HLI score, p-trend <0.001). Based on multivariate-adjustment, adherence to each one additional HLB gives PAF of 10.5%(95% CI 9.0% to 12.0%) for disability reduction. The PAF would have been 25.9%(14.2% to 36.0%) if all subjects had adhered to all three HLBs. CONCLUSION: Combined HLBs may have a substantial impact on reducing the risk of incident disability among elderly people. Even having one more healthy lifestyle habit may bring considerable benefit.

Prevalence of asthma-like symptoms with ageing.

BACKGROUND: Change in the prevalence of asthma-like symptoms in populations of ageing adults is likely to be influenced by smoking, asthma treatment and atopy. METHODS: The European Community Respiratory Health Survey collected information on prevalent asthma-like symptoms from representative samples of adults aged 20-44 years (29 centres in 13 European countries and Australia) at baseline and 10 and 20 years later (n=7844). Net changes in symptom prevalence were determined using generalised estimating equations (accounting for non-response through inverse probability weighting), followed by meta-analysis of centre level estimates. FINDINGS: Over 20 years the prevalence of 'wheeze' and 'wheeze in the absence of a cold' decreased (-2.4%, 95% CI -3.5 to -1.3%; -1.5%, 95% CI -2.4 to -0.6%, respectively) but the prevalence of asthma attacks, use of asthma medication and hay fever/nasal allergies increased (0.6%, 95% CI 0.1 to 1.11; 3.6%, 95% CI 3.0 to 4.2; 2.7%, 95% CI 1.7 to 3.7). Changes were similar in the first 10 years compared with the second 10 years, except for hay fever/nasal allergies (increase seen in the first 10 years only). Decreases in these wheeze-related symptoms were largely seen in the group who gave up smoking, and were seen in those who reported hay fever/nasal allergies at baseline. INTERPRETATION: European adults born between 1946 and 1970 have, over the last 20 years, experienced less wheeze, although they were more likely to report asthma attacks, use of asthma medication and hay fever. Decrease in wheeze is largely attributable to smoking cessation, rather than improved treatment of asthma. It may also be influenced by reductions in atopy with ageing.

Effects of Pulmonary Rehabilitation on Exacerbation Number and Severity in People With COPD: An Historical Cohort Study Using Electronic Health Records.

BACKGROUND: In previous systematic reviews (predominantly of randomized controlled trials), pulmonary rehabilitation (PR) has been shown to reduce hospital admissions for acute exacerbations of COPD (AECOPD). However, findings have been less consistent for cohort studies. The goal of this study was to compare rates of hospitalized and general practice (GP)-treated AECOPD prior to and following PR. METHODS: Using anonymized data from the Clinical Practice Research Datalink and Hospital Episode Statistics, hospital admissions and GP visits for AECOPD were compared 1 year prior to and 1 year following PR in patients referred for PR. Exacerbation rates were also compared between individuals eligible and referred for PR vs those eligible and not referred. RESULTS: A total of 69,089 (64%) of the patients with COPD in the cohort were eligible for PR. Of these, only 6,436 (9.3%) were recorded as having been referred for rehabilitation. A total of 62,019 (89.8%) were not referred, and 634 (0.98%) declined referral. When combining GP and hospital exacerbations, patients who were eligible and referred for PR had a slightly higher but not statistically significant exacerbation rate (2.83 exacerbations/patient-year; 95% CI, 2.66-3.00) than those who were eligible but not referred (2.17 exacerbations/patient-year; 95% CI, 2.11-2.24). CONCLUSIONS: This study found that < 10% of patients who were eligible for PR were actually referred. Patients who were eligible and referred for (but not necessarily completed) PR did not have fewer GP visits and hospitalizations for AECOPD in the year following PR compared with those not referred or compared with the year prior to PR.

Pulmonary Rehabilitation as a Mechanism to Reduce Hospitalizations for Acute Exacerbations of COPD: A Systematic Review and Meta-Analysis.

BACKGROUND: Acute exacerbation of COPD (AECOPD) has a significant impact on health-care use, including physician visits and hospitalizations. Previous studies and reviews have shown that pulmonary rehabilitation (PR) has many benefits, but the effect on hospitalizations for AECOPD is inconclusive. METHODS: A literature search was carried out to find studies that might help determine, using a meta-analysis, the impact of PR on AECOPD, defined as unscheduled or emergency hospitalizations and ED visits. Cohort studies and randomized controlled trials (RCTs) reporting hospitalizations for AECOPD as an outcome were included. Meta-analyses compared hospitalization rates between eligible PR recipients and nonrecipients before and after rehabilitation. RESULTS: Eighteen studies were included in the meta-analysis. Results from 10 RCTs showed that the control groups had a higher overall rate of hospitalization than did the PR groups (control groups: 0.97 hospitalizations/patient-year; 95% CI, 0.67-1.40; PR groups: 0.62 hospitalizations/patient-year; 95% CI, 0.33-1.16). Five studies compared admission numbers in the 12 months before and after rehabilitation, finding a significantly higher admission rate before compared with after (before: 1.24 hospitalizations/patient-year; 95% CI, 0.66-2.34; after: 0.47 hospitalizations/patient-year; 95% CI, 0.28-0.79). The pooled result of three cohort studies found that the reference group had a lower admission rate compared with the PR group (0.18 hospitalizations/patient-year; 95% CI, 0.11-0.32 for reference group vs 0.28 hospitalizations/patient-year; 95% CI, 0.25-0.32 for the PR group). CONCLUSIONS: Although results from RCTs suggested that PR reduces subsequent admissions, pooled results from the cohort studies did not, likely reflecting the heterogeneous nature of individuals included in observational research and the varying standard of PR programs.

Changes in IgE sensitization and total IgE levels over 20 years of follow-up.

BACKGROUND: Cross-sectional studies have reported a lower prevalence of sensitization in older adults, but few longitudinal studies have examined whether this is an aging or a year-of-birth cohort effect. OBJECTIVE: We sought to assess changes in sensitization and total IgE levels in a cohort of European adults as they aged over a 20-year period. METHODS: Levels of serum specific IgE to common aeroallergens (house dust mite, cat, and grass) and total IgE levels were measured in 3206 adults from 25 centers in the European Community Respiratory Health Survey on 3 occasions over 20 years. Changes in sensitization and total IgE levels were analyzed by using regression analysis corrected for potential differences in laboratory equipment and by using inverse sampling probability weights to account for nonresponse. RESULTS: Over the 20-year follow-up, the prevalence of sensitization to at least 1 of the 3 allergens decreased from 29.4% to 24.8% (-4.6%; 95% CI, -7.0% to -2.1%). The prevalence of sensitization to house dust mite (-4.3%; 95% CI, -6.0% to -2.6%) and cat (-2.1%; 95% CI, -3.6% to -0.7%) decreased more than sensitization to grass (-0.6%; 95% CI, -2.5% to 1.3%). Age-specific prevalence of sensitization to house dust mite and cat did not differ between year-of-birth cohorts, but sensitization to grass was most prevalent in the most recent ones. Overall, total IgE levels decreased significantly (geometric mean ratio, 0.63; 95% CI, 0.58-0.68) at all ages in all year-of-birth cohorts. CONCLUSION: Aging was associated with lower levels of sensitization, especially to house dust mite and cat, after the age of 20 years.

Are primary care factors associated with hospital episodes for adverse drug reactions? A national observational study.

OBJECTIVE: Identification of primary care factors associated with hospital admissions for adverse drug reactions (ADRs). DESIGN AND SETTING: Cross-sectional analysis of 2010-2012 data from all National Health Service hospitals and 7664 of 8358 general practices in England. METHOD: We identified all hospital episodes with an International Classification of Diseases (ICD) 10 code indicative of an ADR, in the 2010-2012 English Hospital Episode Statistics (HES) admissions database. These episodes were linked to contemporary data describing the associated general practice, including general practitioner (GP) and patient demographics, an estimate of overall patient population morbidity, measures of primary care supply, and Quality and Outcomes Framework (QOF) quality scores. Poisson regression models were used to examine associations between primary care factors and ADR-related episode rates. RESULTS: 212,813 ADR-related HES episodes were identified. Rates of episodes were relatively high among the very young, older and female subgroups. In fully adjusted models, the following primary care factors were associated with increased likelihood of episode: higher deprivation scores (population attributable fraction (PAF)=0.084, 95% CI 0.067 to 0.100) and relatively poor glycated haemoglobin (HbA1c) control among patients with diabetes (PAF=0.372; 0.218 to 0.496). The following were associated with reduced episode likelihood: lower GP supply (PAF=-0.016; -0.026 to -0.005), a lower proportion of GPs with UK qualifications (PAF=-0.035; -0.058 to -0.012), lower total QOF achievement rates (PAF=-0.021; -0.042 to 0.000) and relatively poor blood pressure control among patients with diabetes (PAF=-0.144; -0.280 to -0.022). CONCLUSIONS: Various aspects of primary care are associated with ADR-related hospital episodes, including achievement of particular QOF indicators. Further investigation with individual level data would help develop understanding of the associations identified. Interventions in primary care could help reduce the ADR burden. ADRs are candidates for primary care sensitive conditions.

Global and regional trends in COPD mortality, 1990-2010.

Between 1990 and 2010, chronic obstructive pulmonary disease (COPD) moved from the fourth to third most common cause of death worldwide. Using data from the Global Burden of Disease programme we quantified regional changes in the number of COPD deaths and COPD mortality rates between 1990 and 2010. We estimated the proportion of the change that was attributable to gross national income per capita and an index of cumulative smoking exposure, and quantified the difference in mortality rates attributable to demographic changes. Despite a substantial decrease in COPD mortality rates, COPD deaths fell only slightly, from three million in 1990 to 2.8 million in 2010, because the mean age of the population increased. The number of COPD deaths in 2010 would have risen to 5.2 million if the age- and sex-specific mortality rates had remained constant. Changes in smoking led to only a small increase in age- and sex-specific mortality rates, which were strongly associated with changes in gross national income. The increased burden of COPD mortality was mainly driven by changes in age distribution, but age- and sex-specific rates fell as incomes rose. The rapid response to increasing affluence suggests that changes in COPD mortality are not entirely explained by changes in early life.

Cardiovascular disease mortality and years of life lost attributable to non-optimal systolic blood pressure and hypertension in northeastern Iran.

BACKGROUND: High blood pressure is the second most important risk factor of cardiovascular diseases (CVDs) in Iran. It is imperative to estimate the burden of CVDs that can be averted if high blood pressure is controlled at the population level. The aim of the current study was to estimate the avertable CVD mortality in the setting of Golestan Cohort Study (GCS). METHODS: Over 50,000 participants were recruited and followed for a median of 7 years. The exposures of interest in this study were non-optimal systolic blood pressure (SBP) and hypertension measured at baseline. Deaths by cause have been precisely recorded. The Population Attributable Fraction (PAF) of deaths and Years of Life Lost (YLLs) due to CVDs attributable to exposures of interest were calculated. RESULTS: Overall, 223 deaths due to ischemic heart disease (IHD), 207 deaths due to cerebrovascular accidents (CVA), and 460 deaths due to all CVDs could be averted if the SBP of all subjects in the study were optimal. Similarly, 5,560 YLLs due to IHD, 4,771 YLLs due to CVA, and 11,135 YLLs due to CVDs could be prevented if SBP were optimal. In all age groups, the avertable deaths and YLLs were higher due to IHD compared with CVA. Deaths and YLLs attributable to non-optimal SBP in women were less than men. CONCLUSIONS: A very large proportion of CVD deaths can be averted if blood pressure is controlled in Iran. Effective interventions in primary and secondary health care setting are mandatory to be implemented as early as possible.

Consequences of exposure to peri-articular injections of micro- and nano-particulate cobalt-chromium alloy.

Metal hip replacements generate both metal particles and ions. The biological effects of peri-articular exposure to nanometre and micron sized cobalt chrome (CoCr) wear particles were investigated in a mouse model. Mice received injections of two clinically relevant doses of nanoparticles (32 nm), one of micron sized (2.9 µm) CoCr particles or vehicle alone into the right knee joint at 0, 6, 12 and 18 weeks. Mice were analysed for genotoxic and immunological effects 1, 4 and 40 weeks post exposure. Nanoparticles but not micron particles progressively corroded at the injection site. Micron sized particles were physically removed. No increase of Co or Cr was seen in peripheral blood between 1 and 40 weeks post exposure to particles. No significant inflammatory changes were observed in the knee tissues including ALVAL or necrosis. DNA damage was increased in bone marrow at one and forty weeks and in cells isolated from frontal cortex at 40 weeks after injection with nanoparticles. Mice exposed to the micron sized, but not nanoparticles became immunologically sensitized to Cr(III), Cr (VI) and Ni(II) over the 40 week period as determined by lymphocyte transformation and ELISpot (IFN-γ and IL-2) assays. The data indicated that the response to the micron sized particles was Th1 driven, indicative of type IV hypersensitivity. This study adds to understanding of the potential adverse biological reactions to metal wear products.

The association of asthma with BMI and menarche in the 1958 British Birth Cohort.

BACKGROUND: Obesity and early menarche have been associated with asthma. In this report, we assess the association of asthma with BMI and with changes in BMI from childhood to early adulthood. In addition, we determine if, in girls, any observed association of asthma with menarche can be explained by BMI. METHODS: In a large national birth cohort, the associations of asthma at age 7, 11, 16 and 33 years with BMI, and of, asthma at age 33 years with changes in BMI from age 7 to age 33 years was assessed using logistic and mixed effects models as appropriate. Associations of asthma with age of menarche in girls were similarly assessed with and without adjustment for BMI. RESULTS: Information on asthma, BMI, onset of menarche and confounders at all assessments was available for 1968 girls and 2223 boys. Obesity was relatively uncommon (<2%) in childhood. Overweight (BMI 25+) girls had more asthma. Girls with early menarche were more likely to be overweight. At age 11 years, asthma was associated with early menarche (OR = 1.70, 95% CI 1.17-2.47, after adjustment for BMI OR = 1.60, 95% CI 1.10-2.34). Across all ages, asthma was significantly associated with BMI (OR = 1.50, 95% CI 1.18-1.90) but not with early menarche (OR = 1.24, 95% CI 0.95-1.63). CONCLUSION: Asthma is more common in overweight girls. Early menarche is more common in overweight girls but this does not explain its association with asthma at age 11 years. Early menarche is not a risk factor for asthma at age 33 years in this cohort.

Prenatal and infant acetaminophen exposure, antioxidant gene polymorphisms, and childhood asthma.

BACKGROUND: Prenatal and infant acetaminophen exposure has been associated with an increased risk of childhood asthma phenotypes. Demonstration of biologically plausible interactions between these exposures and maternal and child antioxidant gene polymorphisms would strengthen causal inference. OBJECTIVE: To explore potential interactions between prenatal and infant acetaminophen exposure and antioxidant genotypes on childhood asthma. METHODS: In the Avon Longitudinal Study of Parents and Children, we typed a functional nuclear erythroid 2 p45-related factor 2 (Nrf2) polymorphism and glutathione S-transferase (GST) M1, T1, and P1 polymorphisms. Effects of prenatal and infant acetaminophen exposure on asthma phenotypes at 7 years were stratified by genotype in >4000 mothers and >5000 children. RESULTS: Risk of asthma and wheezing associated with early gestation acetaminophen exposure was increased when maternal copies of the minor T allele of Nrf2 were present (P interactions, .02 and .04, respectively). Risk of asthma associated with late gestation exposure was higher when maternal GSTT1 genotype was present rather than absent (P interaction, .006), and risk of wheezing was increased when maternal GSTM1 was present (P interaction, .04). Although acetaminophen use in infancy was associated with an increased risk of atopy, child antioxidant genotype did not modify associations between infant acetaminophen use and asthma phenotypes. However, the increased risk of asthma and wheezing associated with late gestation acetaminophen exposure in the presence of maternal GSTM1 was further enhanced when GSTM1 was also present in the child. CONCLUSION: Maternal antioxidant gene polymorphisms may modify the relation between prenatal acetaminophen exposure and childhood asthma, strengthening evidence for a causal association. In contrast, relations between infant acetaminophen use and asthma and atopy were not modified by child genotype and may be confounded by pre-existing wheeze or allergy.

Prenatal paracetamol exposure and asthma: further evidence against confounding.

BACKGROUND: Observational studies have reported an association between maternal use of paracetamol in pregnancy and childhood asthma, which was not explained by measured confounding factors. However, it is possible that this relation might be confounded by unmeasured behavioural factors linked to paracetamol usage; if that were the case, effects of similar magnitude of partner's paracetamol use and/or postnatal maternal use would be expected. METHODS: In the Avon Longitudinal Study of Parents and Children (ALSPAC), a population-based birth cohort, we compared the univariate effects of maternal use of paracetamol in pregnancy on risk of doctor-diagnosed asthma, wheeze and elevated immunoglobulin E (IgE) in the offspring at 7 years of age, with the univariate effects of partner's use and postnatal maternal use on these phenotypes. RESULTS: Maternal use of paracetamol in pregnancy was strongly associated with all outcomes. Partner's use was very weakly associated with asthma but not associated with wheezing or IgE. Postnatal maternal use was associated with asthma and wheezing, though less strongly than was prenatal use, and was not associated with IgE. On mutual adjustment, the effects of maternal use in pregnancy on all outcomes were not substantially attenuated, whereas the effects of partner's use on asthma, and of postnatal maternal use on asthma and wheezing, were reduced. CONCLUSIONS: These findings suggest that the relation between maternal use of paracetamol in pregnancy and childhood asthma is unlikely to be confounded by unmeasured behavioural factors linked to paracetamol use.

The genotoxicity of physiological concentrations of chromium (Cr(III) and Cr(VI)) and cobalt (Co(II)): an in vitro study.

Humans are exposed to chromium and cobalt in industry, from the environment and after joint replacement surgery from the CoCr alloy in the implant. In this study we have investigated whether Cr(III), Cr(VI), Co(II) and Cr in combination with Co could induce chromosome aberrations in human fibroblasts in vitro at the same concentrations that have been found in the peripheral blood of exposed humans. We used 24 colour M-FISH as a sensitive way to detect translocations and aneuploidy and examined the effects of a 24-h exposure and its consequences up to 30 days after the exposure in order to record genomic instability and/or repair. At these physiological doses the metals induced predominantly numerical rather than structural aberrations. Co was the least reactive and Cr(VI) especially in combination with Co the most. All metals at the highest physiological doses caused simple (gain or loss of 3 or less chromosomes) and complex (more than 49 chromosomes) aneuploidy. All metals at the lowest physiological dose caused a significant increase of total aberrations. Cr(VI) was much more effective than Cr(III) in causing chromosome fragments, which were only induced at the highest doses. There was a slow resolution of aneuploidy with time after exposure. This involved a reduction in the proportion of aneuploid cells and a reduction of the number of chromosomes within cells showing complex aneuploidy. We conclude that these metal ions can cause chromosome aberrations at physiological concentrations and that their main effect is aneugenic.

DNA damaging bystander signalling from stem cells, cancer cells and fibroblasts after Cr(VI) exposure and its dependence on telomerase.

The bystander effect is a feature of low dose radiation exposure and is characterized by a signaling process from irradiated cells to non irradiated cells, which causes DNA and chromosome damage in these 'nearest neighbour' cells. Here we show that a low and short dose of Cr(VI) can induce stem cells, cancer cells and fibroblasts to chronically secrete bystander signals, which cause DNA damage in neighboring cells. The Cr(VI) induced bystander signaling depended on the telomerase status of either cell. Telomerase negative fibroblasts were able to receive DNA damaging signals from telomerase positive or negative fibroblasts or telomerase positive cancer cells. However telomerase positive fibroblasts were resistant to signals from Cr(VI) exposed telomerase positive fibroblasts or cancer cells. Human embryonic stem cells, with positive Oct4 staining as a marker of pluripotency, showed no significant increase of DNA damage from adjacent Cr and mitomycin C exposed fibroblasts whilst those cells that were negatively stained did. This selectivity of DNA damaging bystander signaling could be an important consideration in developing therapies against cancer and in the safety and effectiveness of tissue engineering and transplantation using stem cells.