Hip and knee replacement as a proxy measure for lower limb osteoarthritis in Scottish military veterans.

INTRODUCTION: Physical activity is an important component of military training. Although injuries and musculoskeletal disorders are the most common cause of medical retirement from the Armed Forces, the long-term risk of lower limb osteoarthritis in veterans is unknown. We used data on hip and knee replacement in Scottish military veterans as a proxy measure. METHODS: Retrospective cohort study of 78 000 veterans born between 1945 and 1995 and a comparison group of 253 000 non-veterans, matched for age, sex and area of residence, followed up for up to 37 years, using survival analysis to examine the risk of hip and knee replacement. RESULTS: Veterans were significantly less likely to undergo hip replacement than non-veterans, Cox proportional HR 0.87, 95% CI 0.80 to 0.95, p<0.001. There was no significant difference between veterans and non-veterans in respect of knee replacement, HR 1.02, 95% CI 0.94 to 1.11, p=0.643, and there was no difference in the ages at which veterans and non-veterans underwent joint replacement. People who had served for longest in the military had similar risk to those with the shortest service. CONCLUSIONS: Based on the likelihood of undergoing joint replacement surgery in later life, we found no evidence of a positive association between military service and an increased risk of lower limb osteoarthritis.

Improving systems of care during and after a pregnancy complicated by hyperglycaemia: A protocol for a complex health systems intervention.

BACKGROUND: Many women with hyperglycaemia in pregnancy do not receive care during and after pregnancy according to standards recommended in international guidelines. The burden of hyperglycaemia in pregnancy falls disproportionately upon Indigenous peoples worldwide, including Aboriginal and Torres Strait Islander women in Australia. The remote and regional Australian context poses additional barriers to delivering healthcare, including high staff turnover and a socially disadvantaged population with a high prevalence of diabetes. METHODS: A complex health systems intervention to improve care for women during and after a pregnancy complicated by hyperglycaemia will be implemented in remote and regional Australia (the Northern Territory and Far North Queensland). The Theoretical Domains Framework was used during formative work with stakeholders to identify intervention components: (1) increasing workforce capacity, skills and knowledge and improving health literacy of health professionals and women; (2) improving access to healthcare through culturally and clinically appropriate pathways; (3) improving information management and communication; (4) enhancing policies and guidelines; (5) embedding use of a clinical register as a quality improvement tool. The intervention will be evaluated utilising the RE-AIM framework at two timepoints: firstly, a qualitative interim evaluation involving interviews with stakeholders (health professionals, champions and project implementers); and subsequently a mixed-methods final evaluation of outcomes and processes: interviews with stakeholders; survey of health professionals; an audit of electronic health records and clinical register; and a review of operational documents. Outcome measures include changes between pre- and post-intervention in: proportion of high risk women receiving recommended glucose screening in early pregnancy; diabetes-related birth outcomes; proportion of women receiving recommended postpartum care including glucose testing; health practitioner confidence in providing care, knowledge and use of relevant guidelines and referral pathways, and perception of care coordination and communication systems; changes to health systems including referral pathways and clinical guidelines. DISCUSSION: This study will provide insights into the impact of health systems changes in improving care for women with hyperglycaemia during and after pregnancy in a challenging setting. It will also provide detailed information on process measures in the implementation of such health system changes.

Healthy workers or less healthy leavers? Mortality in military veterans.

BACKGROUND: The 'healthy worker effect' predicts that longer employment is positively associated with reduced mortality, but few studies have examined mortality in military veterans irrespective of exposure to conflict. AIMS: To examine mortality in a large national cohort of Scottish veterans by length of service. METHODS: Retrospective cohort study comparing survival in up to 30-year follow-up among 57 000 veterans and 173 000 people with no record of service, matched for age, sex and area of residence, who were born between 1945 and 1985. We compared antecedent diagnoses in the two groups to provide information on probable risk factors. RESULTS: By the end of follow-up, 3520 (6%) veterans had died, compared with 10 947 (6%) non-veterans. Cox proportional hazard analysis confirmed no significant difference overall unadjusted or after adjusting for deprivation. On subgroup analysis, those who left prematurely (early service leavers) were at significantly increased risk of death (hazard ratio (HR) 1.16, 95% confidence interval (CI) 1.09-1.24, P < 0.001), although the increase became non-significant after adjusting for socioeconomic status (HR 1.05, 95% CI 0.99-1.12). Longer-serving veterans were at significantly lower risk of death than non-veterans; the risk decreased both with length of service and in more recent birth cohorts. Smoking-related disease was the greatest contributor to increased mortality in early leavers. CONCLUSIONS: Among longer-serving veterans, there was evidence of a HWE partly attributable to selective attrition of early service leavers, but birth cohort analysis suggests improvements over time which may also reflect a causal effect of improved in-service health promotion.

Peripheral arterial disease in Scottish military veterans: a retrospective cohort study of 57 000 veterans and 173 000 matched non-veterans.

BACKGROUND: While traumatic limb loss in military personnel is widely known, the threat posed by peripheral arterial disease (PAD) in those who have served is less well recognized. The aim of our study was to examine the risk of PAD in a Scotland-wide cohort of veterans who served between 1960 and 2012. METHODS: Retrospective 30-year cohort study of 56 205 veterans born 1945-85, and 172 741 non-veterans, matched for age, sex and area of residence, using Cox proportional hazard models to examine the association between veteran status, birth cohort, length of service and risk of PAD leading to hospitalization or death. RESULTS: Overall, veterans were at increased risk of PAD compared with non-veterans, unadjusted hazard ratio (HR) = 1.46, 95% confidence intervals (CI): 1.33-1.60, P < 0.001. The highest risk was in veterans born between 1950 and 1954, HR = 1.76, 95% CI: 1.50-2.07, P < 0.001, and in those with the shortest service (early service leavers), HR = 1.84, 95% CI: 1.49-2.27, P < 0.001. CONCLUSIONS: The findings provide evidence for a hidden burden of life- and limb-threatening PAD in older veterans and are consistent with the higher rates of military smoking which have been reported previously. The study emphasizes the need for vascular preventive measures in this group.

The association between driving time and unhealthy lifestyles: a cross-sectional, general population study of 386 493 UK Biobank participants.

BACKGROUND: Driving is a common type of sedentary behaviour; an independent risk factor for poor health. The study explores whether driving is also associated with other unhealthy lifestyle factors. METHODS: In a cross-sectional study of UK Biobank participants, driving time was treated as an ordinal variable and other lifestyle factors dichotomized into low/high risk based on guidelines. The associations were explored using chi-square tests for trend and binary logistic regression. RESULTS: Of the 386 493 participants who drove, 153 717 (39.8%) drove <1 h/day; 140 140 (36.3%) 1 h/day; 60 973 (15.8%) 2 h/day; and 31 663 (8.2%) ≥3 h/day. Following adjustment for potential confounders, driving ≥3 h/day was associated with being overweight/obese (OR = 1.74, 95% CI: 1.64-1.85), smoking (OR = 1.48, 95% CI: 1.37-1.63), insufficient sleep (1.70, 95% CI: 1.61-1.80), low fruit/vegetable intake (OR = 1.26, 95% CI: 1.18-1.35) and low physical activity (OR = 1.05, 95% CI: 1.00-1.11), with dose relationships for the first three, but was not associated with higher alcohol consumption (OR = 0.94, 95% CI: 0.87-1.02). CONCLUSIONS: Sedentary behaviour, such as driving, is known to have an independent association with adverse health outcomes. It may have additional impact mediated through its effect on other aspects of lifestyle. People with long driving times are at higher risk and might benefit from targeted interventions.

Men across a range of ethnicities have a higher prevalence of diabetes: findings from a cross-sectional study of 500 000 UK Biobank participants.

AIMS: Studies show that white men have a higher prevalence of Type 2 diabetes mellitus than women at a given age and BMI, but equivalent standardized data for other ethnic groups in the UK are sparse. METHODS: This cross-sectional study analysed UK Biobank data from 489 079 participants to compare the prevalence of diabetes mellitus across four major ethnic groups including: 471 700 (96.4%) white, 7871 (1.6%) South Asian, 7974 (1.6%) black and 1534 (0.3%) Chinese participants, before and after standardizing for age, socio-economic status (SES), BMI and lifestyle factors including physical activity, TV viewing, fruit and vegetable intake, processed meat, red meat, oily fish, alcohol intake and smoking. A subgroup analysis of South Asians was also undertaken. RESULTS: Crude diabetes prevalence was higher in men across all four ethnicities. After standardizing for age, SES, BMI and lifestyle factors, a significant sex difference in diabetes prevalence persisted in white (men 6.0% vs. women 3.6%), South Asian (21.0% vs. 13.8%) and black individuals (13.3% vs. 9.7%) (P < 0.0001); there was a non-significant difference between Chinese men and women (7.1% vs. 5.5%) (P = 0.211). Sex differences persisted across South Asian subgroups. CONCLUSIONS: Men across a range of major ethnic groups including white, South Asian and black, have a higher prevalence of diabetes compared with women of similar age, BMI, SES and lifestyle in the UK.

Tobacco exposure and sleep disturbance in 498 208 UK Biobank participants.

Background: The prevalence of sleep disturbance is high and increasing. The study investigated whether active, former and passive smoking were associated with sleep disturbance. Methods: This cross-sectional study used data from the UK Biobank: a cohort study of 502 655 participants, of whom 498 208 provided self-reported data on smoking and sleep characteristics. Multivariable multinomial and logistic regression models were used to examine the associations between smoking and sleep disturbance. Results: Long-sleep duration (>9 h) was more common among current smokers [odds ratio (OR): 1.47; 95% confidence interval (CI): 1.17-1.85; probability value (P) = 0.001] than never smokers, especially heavy (>20/day) smokers (OR: 2.85; 95% CI: 1.66-4.89; P < 0.001). Former heavy (>20/day) smokers were also more likely to report short (<6 h) sleep duration (OR: 1.41; 95% CI: 1.25-1.60; P < 0.001), long-sleep duration (OR: 1.99; 95% CI: 1.47-2.71; P < 0.001) and sleeplessness (OR: 1.47; 95% CI: 1.38-1.57; P < 0.001) than never smokers. Among never smokers, those who lived with more than one smoker had higher odds of long-sleep duration than those not cohabitating with a smoker (OR: 2.71; 95% CI: 1.26-5.82; P = 0.011). Conclusions: Active and passive exposure to high levels of tobacco smoke are associated with sleep disturbance. Existing global tobacco control interventions need to be enforced.

Chronic obstructive pulmonary disease in Scottish military veterans.

INTRODUCTION: Smoking is a major risk factor for chronic obstructive pulmonary disease (COPD). Serving military personnel have previously been shown to be more likely to smoke, and to smoke more heavily, than civilians, but there is no clear consensus as to whether in later life, as veterans, they experience a higher prevalence and mortality from COPD than do non-veterans. We examined the risk of COPD in Scottish veterans and assessed the impact of changes in military smoking. METHODS: Retrospective 30-year cohort study of 56 205 veterans born 1945-1985, and 172 741 people with no record of military service, matched for age, sex and area of residence, using Cox proportional hazard models to examine the association between veteran status, birth cohort, length of service and risk of COPD resulting in hospitalisation or death. RESULTS: There were 1966 (3.52%) cases of COPD meeting the definition in veterans, compared with 5434 (3.19%) in non-veterans. The difference was statistically significant (p=0.001) in the unadjusted model although it became non-significant after adjusting for deprivation. The highest risk was seen in the oldest (1945-1949) birth cohort and in veterans with the shortest service (Early Service Leavers). The risk was significantly reduced in veterans born from 1960, and in those with over 12 years' service. CONCLUSIONS: Our findings are consistent with falling rates of military smoking since the 1960s, and with the reduction in smoking with longer service. The oldest veterans, and those with the shortest service, are least likely to have benefited from this, as reflected in their higher risk for COPD.

Exposure to tobacco smoke in utero or during early childhood and risk of hypomania: Prospective birth cohort study.

OBJECTIVES: Using data from a prospective birth cohort, we aimed to test for an association between exposure to tobacco smoke in utero or during early development and the experience of hypomania assessed in young adulthood. METHODS: We used data on 2957 participants from a large birth cohort (Avon longitudinal study of parents and children [ALSPAC]). The primary outcome of interest was hypomania, and the secondary outcome was "hypomania plus previous psychotic experiences (PE)". Maternally-reported smoking during pregnancy, paternal smoking and exposure to environmental tobacco smoke (ETS) in childhood were the exposures of interest. Multivariable logistic regression was used and estimates of association were adjusted for socio-economic, lifestyle and obstetric factors. RESULTS: There was weak evidence of an association between exposure to maternal smoking in utero and lifetime hypomania. However, there was a strong association of maternal smoking during pregnancy within the sub-group of individuals with hypomania who had also experienced psychotic symptoms (OR=3.45; 95% CI: 1.49-7.98; P=0.004). There was no association between paternal smoking, or exposure to ETS during childhood, and hypomania outcomes. CONCLUSIONS: Exposure to smoking in utero may be a risk factor for more severe forms of psychopathology on the mood-psychosis spectrum, rather than DSM-defined bipolar disorder.

Tuberculosis in Scottish military veterans: evidence from a retrospective cohort study of 57†000 veterans and 173†000 matched non-veterans.

OBJECTIVE: Tuberculosis was a major cause of morbidity and manpower loss in the Armed Forces during World War II. Military control programmes commenced in the 1950s but were initially limited in scope by the many recruits who were already tuberculin positive on enlistment. The aim of our study was to examine whether veterans have an increased risk of tuberculosis compared with non-veterans. METHODS: Retrospective cohort study of 57 000 veterans born 1945-1985, and 173 000 people with no record of military service, resident in Scotland, matched for age, sex and area of residence, using Cox proportional hazard analysis to compare the risk of tuberculosis overall, by birth cohort, length of service and year of diagnosis and to examine comorbidities. RESULTS: Over mean 29 years follow-up, 69 (0.12%) veterans were recorded as having tuberculosis, compared with 267 (0.15%) non-veterans (unadjusted HR 0.90, 95% CIs 0.69 to 1.19, p=0.463). Only the 1945-1949 veterans' birth cohort was at higher risk, unadjusted HR 1.54, 95% CIs 0.98 to 2.45, p=0.061, although the difference in risk did not achieve significance. Veterans born from 1950 were at significantly reduced risk of tuberculosis compared with non-veterans after adjusting for deprivation, HR 0.67, 95% CI 0.47 to 0.95, p=0.026. The most common comorbidities were smoking-related and alcohol-related disease. The risk of comorbid hepatitis B or C was very low, in both veterans and non-veterans. No length of service was associated with an increased risk of tuberculosis in comparison with non-veterans. CONCLUSIONS: Scottish veterans born before 1950 are at moderately increased risk of tuberculosis compared with age, sex and geographically matched civilians with no record of service, although the difference is not statistically significant. Scottish veterans born from 1950 show a reduction in risk compared with civilians. Tuberculosis should be considered in the differential diagnosis of respiratory disease in the older veteran.

Childhood interleukin-6, C-reactive protein and atopic disorders as risk factors for hypomanic symptoms in young adulthood: a longitudinal birth cohort study.

BACKGROUND: There are no existing longitudinal studies of inflammatory markers and atopic disorders in childhood and risk of hypomanic symptoms in adulthood. This study examined if childhood: (1) serum interleukin-6 (IL-6) and C-reactive protein (CRP); and (2) asthma and/or eczema are associated with features of hypomania in young adulthood. METHOD: Participants in the Avon Longitudinal Study of Parents and Children, a prospective general population UK birth cohort, had non-fasting blood samples for IL-6 and CRP measurement at the age of 9 years (n = 4645), and parents answered a question about doctor-diagnosed atopic illness before the age of 10 years (n = 7809). These participants completed the Hypomania Checklist at age 22 years (n = 3361). RESULTS: After adjusting for age, sex, ethnicity, socio-economic status, past psychological and behavioural problems, body mass index and maternal postnatal depression, participants in the top third of IL-6 values at 9 years, compared with the bottom third, had an increased risk of hypomanic symptoms by age 22 years [adjusted odds ratio 1.77, 95% confidence interval (CI) 1.10-2.85, p < 0.001]. Higher IL-6 levels in childhood were associated with adult hypomania features in a dose-response fashion. After further adjustment for depression at the age of 18 years this association remained (adjusted odds ratio 1.70, 95% CI 1.03-2.81, p = 0.038). There was no evidence of an association of hypomanic symptoms with CRP levels, asthma or eczema in childhood. CONCLUSIONS: Higher levels of systemic inflammatory marker IL-6 in childhood were associated with hypomanic symptoms in young adulthood, suggesting that inflammation may play a role in the pathophysiology of mania. Inflammatory pathways may be suitable targets for the prevention and intervention for bipolar disorder.

Early adoption of screening and the changing pattern of cervical cancer in UK military women: evidence from the Scottish Veterans Health Study.

OBJECTIVE: To examine the risk of cervical cancer in a large national cohort of military veteran women followed up for up to 30 years. METHODS: Retrospective cohort study of 5235 veteran women born between 1945 and 1985, and 20 703 women with no record of service matched for age and area of residence, using Cox proportional hazard models to compare the overall risk of cervical cancer and by year of birth. RESULTS: During the follow-up period 1981-2012, there were 18 (0.34%) cases of cervical cancer in the veteran women compared with 81 (0.39%) in the non-veterans. The difference was not statistically significant overall (adjusted HR 0.95, 95% CI 0.57 to 1.59). When analysed by the year of birth, veteran women born in 1958 and earlier had a non-significantly higher risk than non-veterans (adjusted HR 1.24, 95% CI 0.68 to 2.26), while veteran women born after 1958 had a non-significant reduction in risk (adjusted HR 0.51, 95% CI 0.18 to 1.44). CONCLUSIONS: Women born after 1958 who have served in the Armed Forces are at reduced risk of cervical cancer compared with women who have never served, and compared with older veteran women. Small numbers of cases precluded statistical significance. The change in risk pattern in veteran women coincided with the introduction of cervical screening in the Armed Forces, which predated the UK national programme, and provides evidence for the long-term effectiveness of the Armed Forces' sexual health strategy. The impact of recent changes in the screening age, and of human papillomavirus immunisation, should be monitored in the future.

Profound parental bias associated with chromosome 14 acquired uniparental disomy indicates targeting of an imprinted locus.

Acquired uniparental disomy (aUPD) is a common finding in myeloid malignancies and typically acts to convert a somatically acquired heterozygous mutation to homozygosity. We sought to identify the target of chromosome 14 aUPD (aUPD14), a recurrent abnormality in myeloid neoplasms and population cohorts of elderly individuals. We identified 29 cases with aUPD14q that defined a minimal affected region (MAR) of 11.2 Mb running from 14q32.12 to the telomere. Exome sequencing (n=7) did not identify recurrently mutated genes, but methylation-specific PCR at the imprinted MEG3-DLK1 locus located within the MAR demonstrated loss of maternal chromosome 14 and gain of paternal chromosome 14 (P<0.0001), with the degree of methylation imbalance correlating with the level of aUPD (r=0.76; P=0.0001). The absence of driver gene mutations in the exomes of three individuals with aUPD14q but no known haematological disorder suggests that aUPD14q may be sufficient to drive clonal haemopoiesis. Analysis of cases with both aUPD14q and JAK2 V617F (n=11) indicated that aUPD14q may be an early event in some cases but a late event in others. We conclude that aUPD14q is a recurrent abnormality that targets an imprinted locus and may promote clonal haemopoiesis either as an initiating event or as a secondary change.

Association between salivary cotinine and cardiovascular biomarkers among nonsmokers and current smokers: cross-sectional study of 10,081 participants.

OBJECTIVE: Both active smoking and exposure to secondhand smoke (SHS) are associated with cardiovascular disease, but sidestream smoke contains higher levels of small particles and toxic gases than mainstream smoke. The relationship between the concentration of cotinine and a number of cardiovascular biomarkers among nonsmokers and active smokers was examined. METHODS: A cross-sectional study using the Scottish Health Surveys conducted between 1998 and 2010 was undertaken. Inclusion was restricted to participants aged ≥16 years who had provided saliva and blood samples. Uni- and multivariate regression models were used to examine the relationships between the concentration of cotinine and C-reactive protein (CRP), high-density lipoprotein (HDL) cholesterol, and fibrinogen concentrations, as well as total:HDL cholesterol ratios. RESULTS: Of the 10,018 eligible participants, 7,345 (73.3%) were confirmed to be nonsmokers (cotinine <15.0 ng/mL) and 2,673 (26.7%) were confirmed to be current smokers (cotinine ≥15.0 ng/mL). CRP and total:HDL cholesterol increased, and HDL cholesterol decreased, with increasing cotinine concentration across nonsmokers and smokers (all p < .001). However, there were step changes at the interface, whereby nonsmokers with a high exposure to SHS had lower concentrations of cotinine than light active smokers but comparable concentrations of CRP (p = .709), HDL cholesterol (p = .931), and total:HDL cholesterol (p = .405). Fibrinogen concentrations were significantly raised in moderate and heavy active smokers only (both p < .001). CONCLUSION: Exposure to SHS is associated with disproportionately higher biomarkers of cardiovascular risk compared with active smoking. Protection from exposure to SHS should be a public health priority.

Meta-analysis of the association between cigarette smoking and peripheral arterial disease.

CONTEXT: Smoking is an important risk factor for peripheral arterial disease (PAD). OBJECTIVE: To undertake a meta-analysis of the association between cigarette smoking and PAD. DATA SOURCES: Medline, Embase, PubMed and Web of Science databases. STUDY SELECTION: Relevant studies published up to 30 April 2012 were identified. DATA EXTRACTION: Performed by two researchers. Overall and stratified random effects meta-analyses, cumulative meta-analyses and metaregression analyses were conducted. Heterogeneity was tested using the I(2) test, and publication and small study bias using funnel plots and Egger's test. RESULTS: Fifty-five eligible studies were identified: 43 cross-sectional, 10 cohort and 2 case-control. Of the 68 results for current smokers, 59 (86.8%) were statistically significant and the pooled OR was 2.71 (95% CI 2.28 to 3.21). There was a high level of heterogeneity (I(2) 94.9%, p<0.001) and Egger's test was significant (p=0.023). The association with smoking was significant among both general (OR 3.08, 95% CI 2.56 to 3.69) and disease populations (OR 1.54, 95% CI 1.31 to 1.83). Of the 40 results for ex-smokers, 29 (72.5%) were statistically significant and the pooled OR was 1.67 (95% CI 1.54 to 1.81). There was moderate heterogeneity (I(2) 54.7%, p<0.001) and Egger's test was significant (p<0.001). CONCLUSIONS: There is now substantial evidence of an association between active smoking and PAD. The magnitude of the association is greater than that reported for coronary heart disease. The risk is lower among ex-smokers but, nonetheless, significantly increased compared with never smokers. The results highlight the need for interventions both to encourage quitting among existing smokers and discourage commencement among never smokers.

Meta-analysis of the association between secondhand smoke exposure and stroke.

BACKGROUND: Active smoking is a recognized risk factor for stroke. We determined the evidence for an association with secondhand smoke exposure. METHODS: A systematic review was undertaken according to PRISMA guidelines. Random effects meta-analysis provided a pooled estimate of risk, and heterogeneity quantified using I(2) values. Potential publication and study bias were assessed using a funnel plot and Egger's test. Meta-regression analyses were used to investigate sources of heterogeneity. RESULTS: The 20 eligible studies provided 35 estimates of risk derived from 885 307 participants, of whom 5894 (0.7%) suffered a stroke. The pooled estimate of risk was 1.25 (95% CI: 1.12-1.38) with no evidence of significant publication or small-study bias. There was moderate heterogeneity (I(2) = 54.2%, P < 0.001) but no study characteristics were statistically significant in the meta-regression analysis. There was a non-linear dose relationship. The relative risk increased from 1.16 (95% CI: 1.06-1.27) for exposure to 5 cigarettes/day to 1.56 (95% CI: 1.25-1.96) for exposure to 40 cigarettes/day. CONCLUSIONS: There is evidence of a strong, consistent and dose-dependent association between exposure to secondhand smoke and risk of stroke, suggestive of a causal relationship, with disproportionately high risk at low levels of exposure suggesting no safe lower limit of exposure.

Meta-analysis of the effect of comprehensive smoke-free legislation on acute coronary events.

OBJECTIVE: To assess the evidence for a reduced risk of acute coronary events following comprehensive smoke-free legislation. METHODS: Two independent systematic reviews were undertaken using PubMed, Embase and Science Direct with no date restrictions imposed. Meta-analysis was undertaken using a random effects model to obtain a pooled estimate of the relative risk. Linear regression was used to examine possible bias and meta-regression was used to investigate possible causes of heterogeneity. MAIN OUTCOME MEASURE: Acute coronary events. RESULTS: The 17 eligible studies (10 from North America, 6 from Europe and 1 from Australasia) provided 35 estimates of effect size. Apart from five subgroup analyses, all of the published results suggested a reduction in the incidence of acute coronary events following the introduction of smoke-free legislation. Meta-analysis produced a pooled estimate of the relative risk of 0.90 (95% CI 0.86 to 0.94). There was significant heterogeneity (overall I(2)=95.1%, p<0.001) but there was no evidence of small study bias (p=0.714). On univariate random effects meta-regression analysis, studies with longer data collection following legislation produced greater estimates of risk reduction and remained significant after adjustment for other study characteristics (adjusted coefficient -0.005, 95% CI -0.007 to -0.002, multiplicity adjusted p=0.006). CONCLUSIONS: There is now a large body of evidence supporting a reduction in acute coronary events following the implementation of comprehensive smoke-free legislation, with the effect increasing over time from implementation. Countries that have not yet adopted smoke-free legislation should be encouraged to do so.

Further refinement of the critical minimal genetic region for the imprinting disorder 6q24 transient neonatal diabetes.

AIMS/HYPOTHESIS: Transient neonatal diabetes (TND) is associated with overexpression of genes within a critical region on 6q24. This study aims to refine the boundaries of this region to reduce the number of potential candidate genes for 6q24 TND. METHODS: Fifteen patients with transient neonatal diabetes and submicroscopic chromosome 6 duplications were investigated. The duplications were confirmed by microsatellite analysis and subsequently mapped using tiled chromosome 6 array Comparative Genomic Hybridisation (aCGH) and MLPA. Duplication boundaries were compared to identify the minimal shared region of duplication. These data were then used with available clinical data to identify associations between size of 6q24 duplication and severity of TND phenotype. RESULTS: Alignment of the minimal region of duplication to the human genome reduced the minimal TND critical region, formerly estimated at 440 kb, to 160-173 kb, revealing PLAGL1 (pleiomorphic adenoma gene-like 1) and HYMAI (imprinted in hydatidiform mole) to be the only genes wholly included therein. Additionally, the complete paternal duplication of a region containing the theoretical protein FAM164B was associated with the severe growth restriction observed in 6q24 duplication patients. CONCLUSIONS/INTERPRETATION: This study has significantly reduced the critical region associated with 6q24 TND. It has eliminated several previous TND candidate genes, leaving the overlapping imprinted genes PLAGL1 and HYMAI as the only remaining complete candidate genes for 6q24 TND. Moreover, these data provide the first evidence that an additional region, encompassing the theoretical protein FAM164B, may have a critical role in the growth restriction phenotype observed in many 6q24 TND patients.