Effects of evidence-based strategies to reduce the socioeconomic gradient of uptake in the English NHS Bowel Cancer Screening Programme (ASCEND): four cluster-randomised controlled trials.

BACKGROUND: Uptake in the national colorectal cancer screening programme in England varies by socioeconomic status. We assessed four interventions aimed at reducing this gradient, with the intention of improving the health benefits of screening. METHODS: All people eligible for screening (men and women aged 60-74 years) across England were included in four cluster-randomised trials. Randomisation was based on day of invitation. Each trial compared the standard information with the standard information plus the following supplementary interventions: trial 1 (November, 2012), a supplementary leaflet summarising the gist of the key information; trial 2 (March, 2012), a supplementary narrative leaflet describing people's stories; trial 3 (June, 2013), general practice endorsement of the programme on the invitation letter; and trial 4 (July-August, 2013) an enhanced reminder letter with a banner that reiterated the screening offer. Socioeconomic status was defined by the Index of Multiple Deprivation score for each home address. The primary outcome was the socioeconomic status gradient in uptake across deprivation quintiles. This study is registered, number ISRCTN74121020. FINDINGS: As all four trials were embedded in the screening programme, loss to follow-up was minimal (less than 0·5%). Trials 1 (n=163,525) and 2 (n=150,417) showed no effects on the socioeconomic gradient of uptake or overall uptake. Trial 3 (n=265 434) showed no effect on the socioeconomic gradient but was associated with increased overall uptake (adjusted odds ratio [OR] 1·07, 95% CI 1·04-1·10, p<0·0001). In trial 4 (n=168 480) a significant interaction was seen with socioeconomic status gradient (p=0·005), with a stronger effect in the most deprived quintile (adjusted OR 1·11, 95% CI 1·04-1·20, p=0·003) than in the least deprived (1·00, 0·94-1·06, p=0·98). Overall uptake was also increased (1·07, 1·03-1·11, p=0·001). INTERPRETATION: Of four evidence-based interventions, the enhanced reminder letter reduced the socioeconomic gradient in screening uptake, but further reducing inequalities in screening uptake through written materials alone will be challenging. FUNDING: National Institute for Health Research.

Impact of general practice endorsement on the social gradient in uptake in bowel cancer screening.

BACKGROUND: There is a socioeconomic gradient in the uptake of screening in the English NHS Bowel Cancer Screening Programme (BCSP), potentially leading to inequalities in outcomes. We tested whether endorsement of bowel cancer screening by an individual's general practice (GP endorsement; GPE) reduced this gradient. METHODS: A cluster-randomised controlled trial. Over 20 days, individuals eligible for screening in England from 6480 participating general practices were randomly allocated to receive a GP-endorsed or the standard invitation letter. The primary outcome was the proportion of people adequately screened and its variation by quintile of Index of Multiple Deprivation. RESULTS: We enrolled 265,434 individuals. Uptake was 58.2% in the intervention arm and 57.5% in the control arm. After adjusting for age, sex, hub and screening episode, GPE increased the overall odds of uptake (OR=1.07, 95% CI 1.04-1.10), but did not affect its socioeconomic gradient. We estimated that implementing GPE could result in up to 165 more people with high or intermediate risk colorectal adenomas and 61 cancers detected, and a small one-off cost to modify the standard invitation (£78,000). CONCLUSIONS: Although GPE did not improve its socioeconomic gradient, it offers a low-cost approach to enhancing overall screening uptake within the NHS BCSP.

Characterization of new transposable element sub-families from white clover (Trifolium repens) using PCR amplification.

Transposable elements (TEs) dominate the landscapes of most plant and animal genomes. Once considered junk DNA and genetic parasites, these interspersed, repetitive DNA elements are now known to play major roles in both genetic and epigenetic processes that sponsor genome variation and regulate gene expression. Knowledge of TE consensus sequences from elements in species whose genomes have not been sequenced is limited, and the individual TEs that are encountered in clones or short-reads rarely represent potentially canonical, let alone, functional representatives. In this study, we queried the Repbase database with eight BAC clones from white clover (Trifolium repens), identified a large number of candidate TEs, and used polymerase chain reaction and Sanger sequencing to create consensus sequences for three new TE families. The results show that TE family consensus sequences can be obtained experimentally in species for which just a single, full-length member of a TE family has been sequenced.

Understanding low colorectal cancer screening uptake in South Asian faith communities in England--a qualitative study.

BACKGROUND: Colorectal cancer screening uptake within the South Asian population in England is approximately half that of the general population (33 % vs 61 %), and varies by Muslim (31.9 %), Sikh (34.6 %) and Hindu (43.7 %) faith background. This study sought to explore reasons for low uptake of CRC screening in South Asian communities and for the variability of low uptake between three faith communities; and to identify strategies by which uptake might be improved. METHODS: We interviewed 16 'key informants' representing communities from the three largest South Asian faith backgrounds (Islam, Hinduism and Sikhism) in London, England. RESULTS: Reasons for low colorectal cancer screening uptake were overwhelmingly shared across South Asian faith groups. These were: limitations posed by written English; limitations posed by any written language; reliance on younger family members; low awareness of colorectal cancer and screening; and difficulties associated with faeces. Non-written information delivered verbally and interactively within faith or community settings was preferred across faith communities. CONCLUSIONS: Efforts to increase accessibility to colorectal cancer screening in South Asian communities should use local language broadcasts on ethnic media and face-to-face approaches within community and faith settings to increase awareness of colorectal cancer and screening, and address challenges posed by written materials.

High adiponectin and increased risk of cardiovascular disease and mortality in asymptomatic older men: does NT-proBNP help to explain this association?

BACKGROUND: Raised adiponectin is associated with increased rather than decreased risk of cardiovascular disease (CVD) and mortality at older age. We examined whether N-terminal pro-brain natriuretic peptide (NT-proBNP), a marker of cardiac dysfunction, may help explain this relationship. METHODS AND RESULTS: A prospective study of 2879 men aged 60­79 years with no history of CVD at baseline followed-up for a mean of 9 years during which there were 196 major coronary heart disease events (fatal and non-fatal myocardial infarction) and 667 deaths (including 225 CVD deaths), whereas adiponectin concentration was inversely associated with several conventional CVD risk factors; it was significantly and positively associated with NT-proBNP concentration. After adjustment for several vascular risk factors, including renal function and muscle mass, relative risks associated with a top third versus bottom third comparison of adiponectin concentration were 1.51 (1.02­2.23) for coronary heart disease, 1.67 (1.15­2.41) for CVD mortality and 1.41 (1.13­1.95) for all cause mortality. Upon further adjustment for NT-proBNP, these relative risks attenuated to 1.31 (0.88­1.94), 1.31 (0.90­1.91) and 1.26 (1.01­1.59), respectively. CONCLUSION: We show for the first time that concomitantly elevated NT-proBNP concentration, at least, partially explains the apparently positive relationship between adiponectin concentration and risk of CVD and mortality in asymptomatic elderly men.

Prediction of coronary heart disease risk by Framingham and SCORE risk assessments varies by socioeconomic position: results from a study in British men.

AIM: Evidence is limited on performance of the Framingham risk score (FRS) in different socioeconomic groups; similar limitations apply to the Systematic Coronary Risk Evaluation (SCORE). We examined the performance of coronary risk prediction systems in different socioeconomic groups in British men. METHODS AND RESULTS: In a socially and geographically representative cohort of British men aged 40-59 between 1978 and 1980, predicted 10-year coronary heart disease (CHD) (fatal and non-fatal) risk was calculated using FRS, and CHD mortality using SCORE. Prevalent cardiovascular disease cases were excluded. Occupational social class ranged from I (professionals) to V (unskilled workers), and was summarized as non-manual (I, II, III non-manual) and manual (III manual, IV, V). Both FRS and SCORE over-estimated 10-year CHD risk; over-prediction by both was particularly marked in high social classes. With FRS, predicted/observed risk fell progressively from 2.30 in social class I to 1.19 in social class V. Sensitivity of FRS at a ≥20% threshold (27% of men) fell from 53% to 37% from social class I to V; specificity varied similarly. With SCORE, predicted/observed CHD mortality fell from 1.53 to 1.26 from social class I to V; sensitivity at a ≥5% threshold (29% of men) fell between non-manual (61%) and manual (57%) groups, as did specificity. However, including social class in FRS barely improved risk prediction (net reclassification improvement = 0.18%). CONCLUSIONS: Framingham and SCORE predictions varied between socioeconomic groups and are more likely to identify those at greater CHD risk in higher socioeconomic groups. To ensure equitable primary prevention, strategies to adequately estimate risk in lower socioeconomic groups (at increased CHD risk) should be developed.

A case of right middle cerebral artery 'tendonectomy' following mitral valve replacement surgery.

Following mechanical mitral valve replacement surgery, a 69-year-old woman had an ischemic stroke in the right middle cerebral artery territory. Mechanical thrombectomy showed the embolus to be a piece of chordae tendineae excised during the valve replacement surgery.

A case of right middle cerebral artery 'tendonectomy' following mitral valve replacement surgery.

Following mechanical mitral valve replacement surgery, a 69-year-old woman had an ischemic stroke in the right middle cerebral artery territory. Mechanical thrombectomy showed the embolus to be a piece of chordae tendineae excised during the valve replacement surgery.

Reducing the Social Gradient in Uptake of the NHS Colorectal Cancer Screening Programme Using a Narrative-Based Information Leaflet: A Cluster-Randomised Trial.

Objective. To test the effectiveness of adding a narrative leaflet to the current information material delivered by the NHS English colorectal cancer (CRC) screening programme on reducing socioeconomic inequalities in uptake. Participants. 150,417 adults (59-74 years) routinely invited to complete the guaiac Faecal Occult Blood test (gFOBt) in March 2013. Design. A cluster randomised controlled trial (ISRCTN74121020) to compare uptake between two arms. The control arm received the standard NHS CRC screening information material (SI) and the intervention arm received the standard information plus a supplementary narrative leaflet, which had previously been shown to increase screening intentions (SI + N). Between group comparisons were made for uptake overall and across socioeconomic status (SES). Results. Uptake was 57.7% and did not differ significantly between the two trial arms (SI: 58.5%; SI + N: 56.7%; odds ratio = 0.93; 95% confidence interval: 0.81-1.06; p = 0.27). There was no interaction between group and SES quintile (p = 0.44). Conclusions. Adding a narrative leaflet to existing information materials does not reduce the SES gradient in uptake. Despite the benefits of using a pragmatic trial design, the need to add to, rather than replace, existing information may have limited the true value of an evidence-based intervention on behaviour.

Agnathia-otocephaly complex: report of three cases with involvement of two different Carnegie stages.

Three fetuses with agnathia-otocephaly complex representing different degrees of embryonic maldevelopment are reported. The study of the three cases and of the anterior embryonic disc supports the concept that an altered embryologic development might have taken place at Carnegie stages 10 (embryonic days 22 or 23) and 11 (embryonic days 23-26). Karyotypic abnormalities and aberrant gene expression of sonic hedgehog and paired-related homeobox genes are discussed as the cytogenetic and molecular basis of agnathia-otocephaly complex.

Double null cells reveal that CBP and p300 are dispensable for p53 targets p21 and Mdm2 but variably required for target genes of other signaling pathways.

The histone acetyltransferase coactivators CBP (CREBBP) and p300 (EP300) have more than 400 described protein interaction partners and are implicated in numerous transcriptional pathways. We have shown previously that CBP and p300 double knockout mutations in mouse embryonic fibroblasts (dKO MEFs) result in mixed effects on cAMP-inducible gene expression, with many CREB target genes requiring CBP/p300 for full expression, while others are unaffected or expressed better in their absence. Here we used CBP and p300 dKO MEFs to examine gene expression in response to four other signals: DNA damage (via p53), double-stranded RNA, serum, and retinoic acid. We found that while retinoic acid-inducible gene expression tends to be uniformly dependent on CBP/p300, dsRNA- and serum-inducible genes displayed non-uniform requirements for CBP/p300, with the dsRNA-inducible expression of Ifnb1 (interferon-ß) being particularly dependent on CBP/p300. Surprisingly, the p53-dependent genes Cdkn1a (p21/CIP/WAF) and Mdm2 did not require CBP/p300 for their expression. As with cAMP-responsive CREB targets, we propose that the signal-responsive recruitment of CBP and p300 does not necessarily indicate a requirement for these coactivators at a locus. Rather, target gene context (e.g. DNA sequence) influences the extent to which transcription requires CBP/p300 versus other coactivators, which may not be HATs.

Lung function and risk of type 2 diabetes and fatal and nonfatal major coronary heart disease events: possible associations with inflammation.

OBJECTIVE: We prospectively examined the relationship between lung function and risk of type-2 diabetes and fatal and nonfatal coronary heart disease (CHD) events and investigated the hypothesis that inflammation may underlie these associations. RESEARCH DESIGN AND METHODS: A prospective study of 4,434 men aged 40-59 years with no history of cardiovascular disease (CHD or stroke) or diabetes drawn from general practices in 24 British towns and followed up for 20 years. RESULTS: There were 680 major CHD events (276 fatal, 404 nonfatal) and 256 incident type 2 diabetes during the 20 years follow-up. Forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV(1)) but not FEV(1)-to-FVC ratio were significantly and inversely associated with incident type 2 diabetes and fatal CHD events (not nonfatal events) after adjustment for age, potential confounders, and metabolic risk factors. The adjusted relative risk (RR) for type 2 diabetes (Quartile 1 vs. Quartile 4) were 1.59 (1.07-2.56) and 1.74 (1.16-2.61) for FVC and FEV(1), respectively (P = 0.03 and P = 0.04 for trend). The corresponding RR for fatal CHD were 1.48 (1.00-2.21) and 1.81 (1.19-2.76) (P = 0.002 and P = 0.0003 for trend). Lung function was significantly and inversely associated with C-reactive protein and interleukin-6; the inverse associations with type 2 diabetes for FVC and FEV(1) were attenuated after further adjustment for these factors (P = 0.14 and P = 0.11 for trend) but remained significant for fatal CHD (P = 0.03 and P = 0.01, respectively). CONCLUSIONS: Restrictive rather than obstructive impairment of lung function is associated with incident type 2 diabetes (and fatal CHD) with both associations partially explained by traditional and metabolic risk factors and inflammation.

Is the recent rise in type 2 diabetes incidence from 1984 to 2007 explained by the trend in increasing BMI?: evidence from a prospective study of British men.

OBJECTIVE: To estimate the extent to which increasing BMI may explain the rise in type 2 diabetes incidence in British men from 1984 to 2007. RESEARCH DESIGN AND METHODS: A representative cohort ratio of 6,460 British men was followed-up for type 2 diabetes incidence between 1984 (aged 45-65 years) and 2007 (aged 67-89 years). BMI was ascertained at regular intervals before and during the follow-up. RESULTS: Between 1984-1992 and 1999-2007, the age-adjusted hazard of type 2 diabetes more than doubled (hazard ratio 2.33 [95% CI 1.75-3.10]). Mean BMI rose by 1.42 kg/m(2) (95% CI 1.10-1.74) between 1984 and 1999; this could explain 26% (95% CI 17-38) of the type 2 diabetes increase. CONCLUSIONS: An appreciable portion of the rise in type 2 diabetes can be attributed to BMI changes. A substantial portion remains unexplained, possibly associated with other determinants such as physical activity. This merits further research.

Associations between dietary fiber and inflammation, hepatic function, and risk of type 2 diabetes in older men: potential mechanisms for the benefits of fiber on diabetes risk.

OBJECTIVE: To examine the relationship between dietary fiber and the risk of type 2 diabetes in older men and the role of hepatic and inflammatory markers. RESEARCH DESIGN AND METHODS: The study was performed prospectively and included 3,428 nondiabetic men (age 60-79 years) followed up for 7 years, during which there were 162 incident cases of type 2 diabetes. RESULTS: Low total dietary fiber (lowest quartile < or =20 g/day) was associated with increased risk of diabetes after adjustment for total calorie intake and potential confounders (relative risk -1.47 [95% CI 1.03-2.11]). This increased risk was seen separately for both low cereal and low vegetable fiber intake. Dietary fiber was inversely associated with inflammatory markers (C-reactive protein, interleukin-6) and with tissue plasminogen activator and gamma-glutamyl transferase. Adjustment for these markers attenuated the increased risk (1.28 [0.88-1.86]). CONCLUSIONS: Dietary fiber is associated with reduced diabetes risk, which may be partly explained by inflammatory markers and hepatic fat deposition.

Do socioeconomic characteristics of neighbourhood of residence independently influence incidence of coronary heart disease and all-cause mortality in older British men?

BACKGROUND: The relationship between coronary heart disease (CHD) incidence and death, and individual sociodemographic status is well established. Our aim was to examine whether neighbourhood deprivation scores predict CHD and death in older men, independently of individual sociodemographic status. METHODS: Prospective study of 5049 men, born between 1918 and 1939, recruited from 24 British towns encompassing 969 electoral wards, without documented evidence of previous major CHD when responding to a questionnaire in 1992, and followed up for incidence of major CHD and death. RESULTS: Four hundred and seventy-two new major CHD events (1.08% pa), and 1021 deaths (2.28% pa) occurred over an average of 9.75 years. When men were divided into fifths according to increasing neighbourhood deprivation score, CHD incidences (% pa) were 0.92, 0.89, 0.99, 1.33 and 1.29. When modelling continuous trends, the rate ratio for men in the top fifth compared with the bottom fifth was 1.55 (95% confidence interval 1.19-2.00) for CHD. This rate ratio was, however, no longer statistically significant [1.22 (95% confidence interval 0.92-1.61)] when effects of individual sociodemographic status measures (car ownership, housing, longest held occupation, marital status and social networks) were accounted for. CONCLUSION: Little evidence of an independent relationship of neighbourhood deprivation with CHD incidence was found once individual measures of sociodemographic status had been adjusted for.

Arf-induced turnover of the nucleolar nucleophosmin-associated SUMO-2/3 protease Senp3.

The stabilization and subcellular localization of the p19(Arf) tumor suppressor protein and the SUMO-2/3 deconjugating protease Senp3 each depend upon their binding to the abundant nucleolar protein nucleophosmin (Npm/B23). Senp3 and p19(Arf) antagonize each other's functions in regulating the SUMOylation of target proteins including Npm itself. The p19(Arf) protein triggers the sequential phosphorylation, polyubiquitination and rapid proteasomal degradation of Senp3, and this ability of p19(Arf) to accelerate Senp3 turnover also depends on the presence of Npm. In turn, endogenous p19(Arf) and Senp3 are both destabilized in viable Npm-null mouse embryo fibroblasts (that also lack p53), and reintroduction of the human NPM protein into these cells reverses this phenotype. NPM mutants that retain their acidic and oligomerization domains can re-stabilize both p19(Arf) and Senp3 in this setting, but the nucleolar localization of NPM is not strictly required for these effects. Knockdown of Senp3 with shRNAs mimics the antiproliferative functions of p19(Arf) in cells that lack p53 alone or in triple knock-out cells that lack the Arf, Mdm2 and p53 genes. These findings reinforce the hypothesis that the p53-independent tumor suppressive functions of p19(Arf) may be mediated by its ability to antagonize Senp3, thereby inducing cell cycle arrest by abnormally elevating the cellular levels of SUMOylated proteins.

Missed opportunities for secondary prevention of cerebrovascular disease in elderly British men from 1999 to 2005: a population-based study.

OBJECTIVE: We examined patterns in medication use for secondary prevention of cerebrovascular disease in older British men from 1999 to 2005, and investigated socio-demographic and disease-related influences on medication use. METHODS: Percentage use of antiplatelet drugs, blood pressure-lowering drugs and statins use was calculated in men, aged 65-87 years in 2005, who had been diagnosed with stroke or transient ischaemic attack (TIA) from a population-based cohort based in one general practice in each of 24 British towns. RESULTS: In 1999, most men with cerebrovascular disease received antiplatelet drugs (67%). However, a few received blood pressure-lowering drugs (50%) and statins (13%). By 2005, the use of all drug types had increased; at least half of the patients received each type of drug. However, only one-third of patients received all three medication types and combined blood pressure treatment was limited. Older age, a diagnosis of TIA rather than stroke and absence of co-existing coronary heart disease were associated with lower rates of use of specific medication categories. CONCLUSION: Despite improvements in secondary prevention medication use, there is scope for achieving the full potential of these medications, particularly by increasing combination blood pressure treatment and statin use and ensuring that older patients receive the benefits of prevention.

The general transcription machinery and general cofactors.

In eukaryotes, the core promoter serves as a platform for the assembly of transcription preinitiation complex (PIC) that includes TFIIA, TFIIB, TFIID, TFIIE, TFIIF, TFIIH, and RNA polymerase II (pol II), which function collectively to specify the transcription start site. PIC formation usually begins with TFIID binding to the TATA box, initiator, and/or downstream promoter element (DPE) found in most core promoters, followed by the entry of other general transcription factors (GTFs) and pol II through either a sequential assembly or a preassembled pol II holoenzyme pathway. Formation of this promoter-bound complex is sufficient for a basal level of transcription. However, for activator-dependent (or regulated) transcription, general cofactors are often required to transmit regulatory signals between gene-specific activators and the general transcription machinery. Three classes of general cofactors, including TBP-associated factors (TAFs), Mediator, and upstream stimulatory activity (USA)-derived positive cofactors (PC1/PARP-1, PC2, PC3/DNA topoisomerase I, and PC4) and negative cofactor 1 (NC1/HMGB1), normally function independently or in combination to fine-tune the promoter activity in a gene-specific or cell-type-specific manner. In addition, other cofactors, such as TAF1, BTAF1, and negative cofactor 2 (NC2), can also modulate TBP or TFIID binding to the core promoter. In general, these cofactors are capable of repressing basal transcription when activators are absent and stimulating transcription in the presence of activators. Here we review the roles of these cofactors and GTFs, as well as TBP-related factors (TRFs), TAF-containing complexes (TFTC, SAGA, SLIK/SALSA, STAGA, and PRC1) and TAF variants, in pol II-mediated transcription, with emphasis on the events occurring after the chromatin has been remodeled but prior to the formation of the first phosphodiester bond.

Secondary prevention of coronary heart disease in older patients after the national service framework: population based study.

OBJECTIVE: To examine the extent of uptake of medication for secondary prevention of coronary heart disease in older British men and women before (1998-2001) and after (2003) the implementation of the national service framework. DESIGN: Two population based, longitudinal studies of men and women aged 60-79 in 1998-2001, based in one general practice in each of 24 British towns. PARTICIPANTS: Men and women with established coronary heart disease at the two time points (respectively 817 and 465 in 1998-2001, 857 and 548 in 2003), aged 60-79 in 1998-2001. MAIN OUTCOME MEASURES: Prevalence of use of antiplatelet medication, statins, beta blockers, angiotensin converting enzyme (ACE) inhibitors, and other blood pressure lowering treatments (individually and in combination) assessed in 1998-2001 and 2003. RESULTS: Between 1998-2001 and 2003, the use of all individual drugs had increased in both men and women, especially for statins (from 34% to 65% in men and from 48% to 67% in women with myocardial infarction). However, less than half received beta blockers and ACE inhibitors, even by 2003. Prevalences of medication use were lower in patients with angina than in those with myocardial infarction. The proportions of patients receiving more than one drug increased over time; by 2003 about half of patients with myocardial infarction and a third of those with angina were receiving antiplatelet medication, statins, and blood pressure lowering treatments. CONCLUSIONS: Between 1998-2001 and 2003, statin uptake and the use of combined drug treatment in elderly men and women increased markedly. Further potential exists, however, for reducing the risk of recurrent coronary heart disease in older patients, particularly by improving the uptake of medication among angina patients, and by more extensive use of blood pressure lowering treatment (particularly with beta blockers and ACE inhibitors).

E6 oncoprotein represses p53-dependent gene activation via inhibition of protein acetylation independently of inducing p53 degradation.

The mechanism employed by DNA tumor viruses to inhibit p53-dependent transcription from chromatin is poorly understood. Here, we use in vitro-reconstituted chromatin and UV-irradiated cells to define the mechanism of human papillomavirus E6 oncoprotein in repressing p53-dependent transcription. We demonstrate that E6 does not prevent p53 or p300 recruitment to the chromatin but inhibits p300-mediated acetylation on p53 and nucleosomal core histones. This suppression of protein acetylation requires the E6-interacting regions of p300. Moreover, E6 mutants unable to interact with p53 or p300, but not deficient in inducing p53 degradation, fail to inhibit p53-mediated activation, indicating that a p53-E6-p300-containing protein complex is critical for repressing p53-targeted gene activation. That E6 acts as a molecular switch converting p53-p300 from an activating complex to a repressing entity on the chromatin, which occurs independently of E6AP-mediated protein degradation pathway, may represent a general mechanism for gene regulation.