Tobacco smoking and risk of 36 cardiovascular disease subtypes: fatal and non-fatal outcomes in a large prospective Australian study.

BACKGROUND: Tobacco smoking is a leading cause of cardiovascular disease (CVD) morbidity and mortality. Evidence on the relation of smoking to different subtypes of CVD, across fatal and non-fatal outcomes, is limited. METHODS: A prospective study of 188,167 CVD- and cancer-free individuals aged ≥ 45 years from the Australian general population joining the 45 and Up Study from 2006 to 2009, with linked questionnaire, hospitalisation and death data up to the end of 2015. Hazard ratios (HRs) for hospitalisation with or mortality from CVD among current and past versus never smokers were estimated, including according to intensity and recency of smoking, using Cox regression, adjusting for age, sex, urban/rural residence, alcohol consumption, income and education. Population-attributable fractions were estimated. RESULTS: During a mean 7.2 years follow-up (1.35 million person-years), 27,511 (crude rate 20.4/1000 person-years) incident fatal and non-fatal major CVD events occurred, including 4548 (3.2) acute myocardial infarction (AMI), 3991 (2.8) cerebrovascular disease, 3874 (2.7) heart failure and 2311 (1.6) peripheral arterial disease (PAD) events. At baseline, 8% of participants were current and 34% were past smokers. Of the 36 most common specific CVD subtypes, event rates for 29 were increased significantly in current smokers. Adjusted HRs in current versus never smokers were as follows: 1.63 (95%CI 1.56-1.71) for any major CVD, 2.45 (2.22-2.70) for AMI, 2.16 (1.93-2.42) for cerebrovascular disease, 2.23 (1.96-2.53) for heart failure, 5.06 (4.47-5.74) for PAD, 1.50 (1.24-1.80) for paroxysmal tachycardia, 1.31 (1.20-1.44) for atrial fibrillation/flutter, 1.41 (1.17-1.70) for pulmonary embolism, 2.79 (2.04-3.80) for AMI mortality, 2.26 (1.65-3.10) for cerebrovascular disease mortality and 2.75 (2.37-3.19) for total CVD mortality. CVD risks were elevated at almost all levels of current smoking intensity examined and increased with smoking intensity, with HRs for total CVD mortality in current versus never smokers of 1.92 (1.11-3.32) and 4.90 (3.79-6.34) for 4-6 and ≥ 25 cigarettes/day, respectively. Risks diminished with quitting, with excess risks largely avoided by quitting before age 45. Over one third of CVD deaths and one quarter of acute coronary syndrome hospitalisations in Australia aged < 65 can be attributed to smoking. CONCLUSIONS: Current smoking increases the risk of virtually all CVD subtypes, at least doubling the risk of many, including AMI, cerebrovascular disease and heart failure. Paroxysmal tachycardia is a newly identified smoking-related risk. Where comparisons are possible, smoking-associated relative risks for fatal and non-fatal outcomes are similar. Quitting reduces the risk substantially. In an established smoking epidemic, with declining and low current smoking prevalence, smoking accounts for a substantial proportion of premature CVD events.

Patterns of high-risk prescribing and other factors in relation to receipt of a home medicines review: a prospective cohort investigation among adults aged 45 years and over in Australia.

OBJECTIVES: To quantify the relationship between home medicines review (HMR) receipt in older adults and sociodemographic, medication-related and health factors. DESIGN: Prospective cohort analysis. SETTINGS, PARTICIPANTS, MEASUREMENTS: Questionnaire data from a population-based cohort study of individuals aged ≥45 years, Sydney, Australia were linked with primary healthcare data, medication and hospitalisation data, to ascertain factors associated with HMR receipt during the period July 2009-June 2014. Medication-related factors included exposure to five and more medications (polypharmacy), narrow therapeutic index medicines, potentially inappropriate prescribing defined using Beers Criteria medicines, and anticholinergic and sedative drugs, defined using the Drug Burden Index (DBI). Poisson and Cox regression models were used to evaluate HMR receipt in relation to sociodemographic, behavioural and health characteristics, and time-varying factors including medication use and hospitalisations. PRIMARY OUTCOME: HMR receipt during the 5-year study period. RESULTS: Over 5 years of follow-up, 4.7% (n=6115) of 131 483 participants received at least one HMR. Five-year HMR receipt was: 1.5% in people using <5 medications at baseline, 6.8% with 5-9 medications, 12.7% with ≥10 medications, 8.8% using Narrow Therapeutic Index medicines, 6.8% using Beers Criteria potentially inappropriate medicines and 7.4% using DBI medicines. Age-sex stratified HRs for HMR receipt were 6.07 (95% CI: 5.58 to 6.59) and 12.46 (11.42 to 13.59) for concurrent use of 5-9 and ≥10 versus <5 medications, respectively. The age-sex adjusted rate ratio for HMR receipt was 2.65 (2.51 to 2.80) with poor versus good self-reported health; this association was attenuated substantially following additional adjustment for polypharmacy. CONCLUSIONS: HMR was common in individuals using multiple medications, a formal indication for general practitioner referral and, to a lesser extent, with poorer health and other markers of high-risk prescribing. Despite this, HMR use over a 5-year period was generally below 10%, even in high-risk groups, suggesting substantial potential for improvement in uptake and targeting.

Diagnosis-based and external cause-based criteria to identify adverse drug reactions in hospital ICD-coded data: application to an Australia population-based study.

OBJECTIVES: External cause International Classification of Diseases (ICD) codes are commonly used to ascertain adverse drug reactions (ADRs) related to hospitalisation. We quantified ascertainment of ADR-related hospitalisation using external cause codes and additional ICD-based hospital diagnosis codes. METHODS: We reviewed the scientific literature to identify different ICD-based criteria for ADR-related hospitalisations, developed algorithms to capture ADRs based on candidate hospital ICD-10 diagnoses and external cause codes (Y40-Y59), and incorporated previously published causality ratings estimating the probability that a specific diagnosis was ADR related. We applied the algorithms to the NSW Admitted Patient Data Collection records of 45 and Up Study participants (2011-2013). RESULTS: Of 493 442 hospitalisations among 267 153 study participants during 2011-2013, 18.8% (n = 92 953) had hospital diagnosis codes that were potentially ADR related; 1.1% (n = 5305) had high/very high-probability ADR-related diagnosis codes (causality ratings: A1 and A2); and 2.0% (n = 10 039) had ADR-related external cause codes. Overall, 2.2% (n = 11 082) of cases were classified as including an ADR-based hospitalisation on either external cause codes or high/very high-probability ADR-related diagnosis codes. Hence, adding high/very high-probability ADR-related hospitalisation codes to standard external cause codes alone (Y40-Y59) increased the number of hospitalisations classified as having an ADR-related diagnosis by 10.4%. Only 6.7% of cases with high-probability ADR-related mental symptoms were captured by external cause codes. CONCLUSION: Selective use of high-probability ADR-related hospital diagnosis codes in addition to external cause codes yielded a modest increase in hospitalised ADR incidence, which is of potential clinical significance. Clinically validated combinations of diagnosis codes could potentially further enhance capture.

Variation in readmission and mortality following hospitalisation with a diagnosis of heart failure: prospective cohort study using linked data.

BACKGROUND: Hospitalisation for heart failure is common and post-discharge outcomes, including readmission and mortality, are often poor and are poorly understood. The purpose of this study was to examine patient- and hospital-level variation in the risk of 30-day unplanned readmission and mortality following discharge from hospital with a diagnosis of heart failure. METHODS: Prospective cohort study using data from the Sax Institute's 45 and Up Study, linking baseline survey (Jan 2006-April 2009) to hospital and mortality data (to Dec 2011). Primary outcomes in those admitted to hospital with heart failure included unplanned readmission, mortality and combined unplanned readmission/mortality, within 30 days of discharge. Multilevel models quantified the variation in outcomes between hospitals and examined associations with patient- and hospital-level characteristics. RESULTS: There were 5074 participants with a heart failure admission discharged from 251 hospitals; 1052 (21%) had unplanned readmissions, 186 (3.7%) died, and 1146 (23%) had either/both outcomes within 30 days of discharge. Crude outcomes varied across hospitals, but between-hospital variation explained little of the total variation in outcomes (intraclass correlation coefficients (ICC) after inclusion of patient factors: 30-day unplanned readmission ICC = 0.0125 (p = 0.24); death ICC = 0.0000 (p > 0.99); unplanned readmission/death ICC = 0.0266 (p = 0.07)). Patient characteristics associated with a higher risk of unplanned readmission included: being male (male vs female, adjusted odds ratio (aOR) = 1.18, 95% CI: 1.00-1.37); prior hospitalisation for cardiovascular disease (aOR = 1.44, 1.08-1.91) and for anemia (aOR = 1.36, 1.14-1.63); comorbidities at admission (severe vs none: aOR = 1.26, 1.03-1.54); lower body-mass-index (obese vs normal weight: aOR = 0.77, 0.63-0.94); and lower social interaction scores. Similarly, risk of 30-day mortality was associated with patient- rather than hospital-level factors, in particular age (≥85y vs 45-< 75y: aOR = 3.23, 1.93-5.41) and comorbidity (severe vs none: aOR = 2.68, 1.82-3.94). CONCLUSIONS: The issue of high readmission and mortality rates in people with heart failure appear to be system-wide, with the variation in these outcomes essentially attributable to variation between patients rather than hospitals. The findings suggest that there are limitations in using these outcomes as hospital performance measures in this patient population and support the need for patient-centred strategies to optimise heart failure management and outcomes.

Cousin marriage in south-western England in the nineteenth century.

Knowledge of inbreeding levels in historical times is necessary to estimate the health consequences of past inbreeding, and to contextualize the current public debate about cousin marriage in Britain. This research aims to calculate the level of cousin marriage using the intensive technique of multi-source parish reconstitution and to determine whether village organization, religion and occupational class influenced the level of consanguineous marriage. A wide variety of documentary sources were used to create extensive pedigrees of spouses in over 800 marriages in the 19th century in the rural villages of Stourton and Kilmington. The closed village of Stourton had higher levels of inbreeding than the open village of Kilmington. Catholics had lower rates of 1st cousin marriage but higher rates of 2nd cousin marriage than Protestants. Farmers had higher levels of 1st cousin marriage than labourers. The levels of consanguinity in south-western Wiltshire in the 19th century were related to the economic structure of the villages and the religion and social class of the spouses.

Geographical mobility in Wiltshire, 1754-1914.

The aim of this paper is to determine the birthplaces, rather than residences, of spouses married in two parishes in England and to consider the effect of local topography, religion and occupation on pre-marital geographic mobility. A wide array of primary documentary sources was used to construct a database of over 22,000 individuals who lived in south-west Wiltshire in the eighteenth, nineteenth and twentieth centuries. Individuals were arranged in family groups and pedigrees traced for several generations. Data were included on birthplace, religious affiliation, occupation and many other variables. Geographical mobility calculated from birthplace was higher than estimates derived from residence prior to marriage. Brides had shorter marital distances than grooms. There were noticeable changes in the frequency of marital distance at 4 miles and 11 miles. Spouses born outside the parish of marriage were more likely to come from certain villages in ways which cannot be explained merely by distance and size. The Somerset-Wiltshire border formed a barrier, although a porous one, to the flow of marriage partners. Occupation influenced geographical mobility: grooms from higher-status occupational groups were more likely to be born further away than grooms from lower-status occupational groups. Catholic grooms were more likely to be born in the parish of marriage than Protestant grooms, but were also more likely to be born more than 11 miles away.

Aberrant methylation of the eyes absent 4 gene in ulcerative colitis-associated dysplasia.

BACKGROUND & AIMS: This study explored the eyes absent 4 (EYA4) gene promoter methylation in noncolitic colorectal tissues and assessed its discrimination for neoplasia in chronic ulcerative colitis (CUC). METHODS: The methylation status of noncolitic specimens was confirmed by direct bisulfite sequencing. Methylation-specific polymerase chain reaction (MSP) primers were designed to evaluate colorectal tissues, including 50 noncolitic patients comprising 24 normal epithelia, 14 polyps, and 12 cancers. The assay was tested on tissues from 67 CUC patients including 31 surveillance neoplasia-positive patients and nonneoplastic controls including 22 CUC surveillance-negative and 14 CUC short-disease duration. Remote colonic tissue was included from each of 27 of the 31 CUC neoplasia cases. The expression of EYA4 was quantified in cell lines by use of reverse-transcription polymerase chain reaction. RESULTS: Within noncolitic tissues, bisulfite sequencing showed EYA4 promoter hypermethylation in 80% (8 of 10) of colorectal cancers but in none (0 of 9) of the normal tissues. MSP was positive in 81% (21 of 26) of cancers and polyps and in only 4% (1 of 14) of normal mucosa. In CUC, MSP was positive in 81% (25 of 31) of neoplastic cases but in none (0 of 36) of the nonneoplastic controls. RNA expression was decreased in methylated compared with unmethylated cell lines (P < .001). Treatment with 5-Aza-2'-deoxycytidine (DAC)/Trichostatin (TSA) increased the overall messenger RNA expression (P = .005). CONCLUSIONS: The EYA4 gene promoter is hypermethylated commonly in sporadic and colitic neoplasia and may be associated with gene silencing. EYA4 methylation represents a candidate marker for CUC surveillance.

Molecular analysis of APC promoter methylation and protein expression in colorectal cancer metastasis.

APC (adenomatous polyposis coli) promoter methylation has been linked to the early development of colorectal cancers. However, the role of APC methylation and its effect on protein expression in colon cancer metastasis is largely unknown. In this study, we investigated APC promoter methylation by Methylight analysis and analysed the APC protein levels by immunohistochemistry and western blot analysis in 24 liver metastasis and 39 primary colorectal cancers. Promoter methylation of the APC gene was found to be a frequent event in liver metastasis (10/24) and significantly more frequent compared with primary colorectal cancer (7/39, P = 0.047). APC methylation was not found in 14 matched normal colon tissues. APC protein was detected in the cytoplasm of primary and metastatic cancer cells and non-tumorous colon epithelium. By western blot analysis, APC protein levels were found to be decreased in primary tumour tissues compared with the normal colon mucosa. In contrast, APC protein levels were not decreased in the cancer cells that had metastasized to the liver. APC protein levels were independent of the presence of APC promoter methylation or gene mutations. In summary, APC promoter methylation is a frequent epigenetic alteration in colorectal cancer metastasis. However, we observed no significant association between APC promoter methylation or gene mutation and APC protein expression in colorectal metastasis. Therefore, metastatic cancer cells seem to harbour a heterogenous genetic and epigenetic background, in which cancer cells may exhibit APC promoter methylation that is independent of APC expression.

Identification and characterization of an isoform of murine Mpl.

A new isoform of the full-length murine thrombopoietin (Tpo) receptor was isolated from a murine spleen cDNA library. This isoform, c-mpl-II, differs from full-length c-mpl (c-mpl-I) by virtue of deletion of 180 nucleotides that encode 60 amino acids located in the extracellular domain of Mpl. Normal murine megakaryocytes were found to express both c-mpl-I and c-mpl-II transcripts. BaF3 cells transfected with c-mpl-I expressed a 95 kDa protein that was displayed on the cell surface and bound 125I-Tpo. BaF3 cells transfected with c-mpl-II expressed a 70 kDa protein. However, these cells were not able to bind 125I-Tpo and surface display of Mpl-II could not be detected. In summary, c-mpl-II is an isoform of murine Mpl expressed by megakaryocytes that lacks a 60 amino acid region required for surface expression of the protein.