Reducing the socioeconomic gradient in uptake of the NHS bowel cancer screening Programme using a simplified supplementary information leaflet: a cluster-randomised trial.

BACKGROUND: Uptake of colorectal cancer screening is low in the English NHS Bowel Cancer Screening Programme (BCSP). Participation in screening is strongly associated with socioeconomic status. The aim of this study was to determine whether a supplementary leaflet providing the 'gist' of guaiac-based Faecal Occult Blood test (gFOBt) screening for colorectal cancer could reduce the socioeconomic status (SES) gradient in uptake in the English NHS BCSP. METHODS: The trial was integrated within routine BCSP operations in November 2012. Using a cluster randomised controlled design all adults aged 59-74 years who were being routinely invited to complete the gFOBt were randomised based on day of invitation. The Index of Multiple Deprivation was used to create SES quintiles. The control group received the standard information booklet ('SI'). The intervention group received the SI booklet and the Gist leaflet ('SI + Gist') which had been designed to help people with lower literacy engage with the invitation. Blinding of hubs was not possible and invited subjects were not made aware of a comparator condition. The primary outcome was the gradient in uptake across IMD quintiles. RESULTS: In November 2012, 163,525 individuals were allocated to either the 'SI' intervention (n = 79,104) or the 'SI + Gist' group (n = 84,421). Overall uptake was similar between the intervention and control groups (SI: 57.3% and SI + Gist: 57.6%; OR = 1.02, 95% CI: 0.92-1.13, p = 0.77). Uptake was 42.0% (SI) vs. 43.0% (SI + Gist) in the most deprived quintile and 65.6% vs. 65.8% in the least deprived quintile (interaction p = 0.48). The SES gradient in uptake was similar between the study groups within age, gender, hub and screening round sub-groups. CONCLUSIONS: Providing supplementary simplified information in addition to the standard information booklet did not reduce the SES gradient in uptake in the NHS BCSP. The effectiveness of the Gist leaflet when used alone should be explored in future research. TRIAL REGISTRATION: ISRCTN74121020 , registered: 17/20/2012.

Patient factors associated with non-attendance at colonoscopy after a positive screening faecal occult blood test.

Background Screening participants with abnormal faecal occult blood test results who do not attend further testing are at high risk of colorectal cancer, yet little is known about their reasons for non-attendance. Methods We conducted a medical record review of 170 patients from two English Bowel Cancer Screening Programme centres who had abnormal guaiac faecal occult blood test screening tests between November 2011 and April 2013 but did not undergo colonoscopy. Using information from patient records, we coded and categorized reasons for non-attendance. Results Of the 170 patients, 82 were eligible for review, of whom 66 had at least one recorded reason for lack of colonoscopy follow-up. Reasons fell into seven main categories: (i) other commitments, (ii) unwillingness to have the test, (iii) a feeling that the faecal occult blood test result was a false positive, (iv) another health issue taking priority, (v) failing to complete bowel preparation, (vi) practical barriers (e.g. lack of transport), and (vii) having had or planning colonoscopy elsewhere. The most common single reasons were unwillingness to have a colonoscopy and being away. Conclusions We identify a range of apparent reasons for colonoscopy non-attendance after a positive faecal occult blood test screening. Education regarding the interpretation of guaiac faecal occult blood test findings, offer of alternative confirmatory test options, and flexibility in the timing or location of subsequent testing might decrease non-attendance of diagnostic testing following positive faecal occult blood test.

A national cluster-randomised controlled trial to examine the effect of enhanced reminders on the socioeconomic gradient in uptake in bowel cancer screening.

BACKGROUND: The NHS Bowel Cancer Screening Programme in England offers biennial guaiac faecal occult blood testing (gFOBt). There is a socioeconomic gradient in participation and socioeconomically disadvantaged groups have worse colorectal cancer survival than more advantaged groups. We compared the effectiveness and cost of an enhanced reminder letter with the usual reminder letter on overall uptake of gFOBt and the socioeconomic gradient in uptake. METHODS: We enhanced the usual reminder by including a heading 'A reminder to you' and a short paragraph restating the offer of screening in simple language. We undertook a cluster-randomised trial of all 168 480 individuals who were due to receive a reminder over 20 days in 2013. Randomisation was based on the day of invitation. Blinding of individuals was not possible, but the possibility of bias was minimal owing to the lack of direct contact with participants. The enhanced reminder was sent to 78 067 individuals and 90 413 received the usual reminder. The primary outcome was the proportion of people adequately screened and its variation by quintile of Index of Multiple Deprivation. Data were analysed by logistic regression with conservative variance estimates to take account of cluster randomisation. RESULTS: There was a small but statistically significant (P=0.001) increase in participation with the enhanced reminder (25.8% vs 25.1%). There was significant (P=0.005) heterogeneity of the effect by socioeconomic status with an 11% increase in the odds of participation in the most deprived quintile (from 13.3 to 14.1%) and no increase in the least deprived. We estimated that implementing the enhanced reminder nationally could result in up to 80 more people with high or intermediate risk colorectal adenomas and up to 30 more cancers detected each year if it were implemented nationally. The intervention incurred a small one-off cost of £78 000 to modify the reminder letter. CONCLUSIONS: The enhanced reminder increases overall uptake and reduces the socioeconomic gradient in bowel cancer screening participation at little additional cost.

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.

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.

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.

Preformulated implementation intentions to promote colorectal cancer screening: a cluster-randomized trial.

OBJECTIVE: To evaluate an intervention based on implementation intention principles designed to increase uptake of colorectal cancer screening, and to examine differential efficacy by socioeconomic deprivation. METHOD: In England, adults aged between 60 and 69 years are invited for biennial fecal occult blood testing. A test kit and an information leaflet are mailed to each individual by the "Hubs" that deliver the national screening program. In the intervention group, three preformulated implementation intentions, based on known barriers to carrying out the test, were added to the information leaflet. Over a 12-week period, each week was randomly allocated to either the intervention (n = 12,414 invitations) or the control condition (n = 10,768), with uptake recorded at the Hub. Socioeconomic deprivation of each individual's area of residence was categorized into tertiles. RESULTS: There was no overall difference in uptake between control (40.4%) and intervention (39.7%) conditions, odds ratio (OR) = 0.97, 95% confidence interval (CI) [0.91, 1.04]. There was an interaction with deprivation, OR = 1.11, 95% CI [1.04, 1.18], but the positive effect observed in the lowest socioeconomic status (SES) tertile was small (35.2% vs. 33.0%), OR = 1.103, 95% CI [1.01, 1.21], and offset by a negative effect in the least deprived tertile (45.6% vs. 48.2%), OR = 0.90, 95% CI [0.82, 0.99]. The intervention had no significant effect in the middle tertile (38.9% vs. 40.8%), OR = 0.92, 95% CI [0.81, 1.04]. CONCLUSION: Preformulated implementation intentions did not increase overall colorectal cancer screening uptake and failed to make a sufficiently large impact on uptake among lower SES groups to merit their future use in this context.

Vitamin D deficiency in pregnancy - still a public health issue.

The objectives of this study were to quantify the prevalence of vitamin D insufficiency and deficiency in pregnancy, explore associated risk factors and discuss the public health implications. The study used retrospective analysis of randomly selected data. This is the first report on serum vitamin D levels in an unselected multi-ethnic population of pregnant women collected between April 2008 and March 2009. Women with sufficient stored serum were randomly selected from among all women who delivered between April 2008 and March 2009. Serum vitamin D levels were determined using liquid chromatography coupled to tandem mass spectrometry. Vitamin D levels were analysed with respect to ethnicity (marking skin tone), calendar quartile, body mass index (BMI), trimester and parity. Deficiency was defined as <25 nmol L(-1) , insufficiency 25-75 nmol L(-1) and adequacy >75 nmol L(-1) . Three hundred and forty-six women were included and represented the total population regarding skin tone, quartile, BMI, gestation and parity. Overall, 18% [95% confidence interval (CI): 15-23%] of sample women had adequate vitamin D levels; 36% were deficient, 45% insufficient. Among women with dark skin, only 8% (95% CI: 5-12%) had adequate levels compared with 43% (95% CI: 33-53%) of those with light skin. Obese women were found have significantly lower vitamin D levels than non-obese women. Vitamin D deficiency and insufficiency are prevalent year-round among pregnant women in North West London, especially those with darker skin. Existing supplementation guidelines should be supported; however, other measures are required to improve status among all women.

Cancer fatalism and poor self-rated health mediate the association between socioeconomic status and uptake of colorectal cancer screening in England.

BACKGROUND: Little is known about the psychological predictors of colorectal screening uptake in England and mediators of associations between uptake and socioeconomic status (SES). This study tested the hypotheses that although higher threat and efficacy beliefs, lower cancer fatalism, lower depression, and better self-rated health would predict higher screening uptake, only efficacy beliefs, fatalism, depression, and self-rated health would mediate associations between uptake and SES. METHODS: Data from 529 adults aged 60 to 69 who had completed a postal survey in 2005-2006 were linked with data on fecal occult blood test (FOBt) uptake recorded at the screening "hub" following its introduction in 2007, resulting in a prospective study. RESULTS: Screening uptake was 56% and was higher among people with higher SES, better self-rated health, higher self-efficacy beliefs, and lower cancer fatalism in univariate analyses. Path analysis on participants with complete data (n = 515) showed that both better self-rated health and lower cancer fatalism were directly associated with higher uptake of FOBt screening and significantly mediated pathways from SES to uptake. Lower depression only had an indirect effect on uptake through better self-rated health. Efficacy beliefs did not mediate the relationship between SES and uptake. CONCLUSION: SES differences in uptake of FOBt in England are partially explained by differences in cancer fatalism, self-rated health, and depression. IMPACT: This is one of only a few studies to examine mediators of the relationship between SES and screening uptake, and future research could test the effectiveness of interventions to reduce fatalistic beliefs to increase equality of uptake.

Inequalities in participation in an organized national colorectal cancer screening programme: results from the first 2.6 million invitations in England.

BACKGROUND: An organized, population-based, colorectal cancer screening programme was initiated in England in 2006 offering biennial faecal occult blood testing (FOBT) to adults aged 60-69 years. Organized screening programmes with no associated financial costs to the individual should minimize barriers to access for lower socio-economic status (SES) groups. However, SES differences in uptake were observed in the pilot centres of the UK programme, so the aim of this analysis was to identify the extent of inequalities in uptake by SES, ethnic diversity, gender and age in the first 28 months of the programme. Design Cross-sectional analysis of colorectal cancer screening uptake data. METHODS: Between October 2006 and January 2009, over 2.6 million adults aged 60-69 years were mailed a first FOBT kit by the five regional screening hubs. Uptake was defined as return of a test kit within 13 weeks. We used multivariate generalized linear regression to examine variation by area-based socioeconomic deprivation, area-based ethnicity, gender and age. RESULTS: Uptake was 54%, but showed a gradient across quintiles of deprivation, ranging from 35% in the most deprived quintile to 61% in the least deprived. Multivariate analyses confirmed an independent effect of deprivation, with stronger effects in women and older people. The most ethnically diverse areas also had lower uptake (38%) than other areas (52-58%) independent of SES, age, gender and regional screening hub. Ethnic disparities were more pronounced in men but equivalent across age groups. More women than men returned a kit (56 vs 51%), but there was also an interaction with age, with uptake increasing with age in men (49% at 60-64 years; 53% at 65-69 years) but not women (57 vs 56%). CONCLUSIONS: Overall uptake rates in this organized screening programme were encouraging, but nonetheless there was low uptake in the most ethnically diverse areas and a striking gradient by SES. Action to promote equality of uptake is needed to avoid widening inequalities in cancer mortality.

A single dose of vitamin D enhances immunity to mycobacteria.

RATIONALE: Vitamin D was used to treat tuberculosis (TB) in the preantibiotic era. Prospective studies to evaluate the effect of vitamin D supplementation on antimycobacterial immunity have not previously been performed. OBJECTIVES: To determine the effect of vitamin D supplementation on antimycobacterial immunity and vitamin D status. METHODS: A double-blind randomized controlled trial was conducted in 192 healthy adult TB contacts in London, United Kingdom. Participants were randomized to receive a single oral dose of 2.5 mg vitamin D or placebo and followed up at 6 weeks. MEASUREMENTS AND MAIN RESULTS: The primary outcome measure was assessed with a functional whole blood assay (BCG-lux assay), which measures the ability of whole blood to restrict luminescence, and thus growth, of recombinant reporter mycobacteria in vitro; the readout is expressed as a luminescence ratio (luminescence postinfection/baseline luminescence). IFN-gamma responses to the Mycobacterium tuberculosis antigens early secretory antigenic target-6 and culture filtrate protein 10 were determined with a second whole blood assay. Vitamin D supplementation significantly enhanced the ability of participants' whole blood to restrict BCG-lux luminescence in vitro compared with placebo (mean luminescence ratio at follow-up, 0.57, vs. 0.71, respectively; 95% confidence interval for difference, 0.01-0.25; p=0.03) but did not affect antigen-stimulated IFN-gamma secretion. CONCLUSIONS: A single oral dose of 2.5 mg vitamin D significantly enhanced the ability of participants' whole blood to restrict BCG-lux luminescence in vitro without affecting antigen-stimulated IFN-gamma responses. Clinical trials should be performed to determine whether vitamin D supplementation prevents reactivation of latent TB infection. Clinical trial registered with www.clinicaltrials.gov (NCT 00157066).

Routine isotope-dilution liquid chromatography-tandem mass spectrometry assay for simultaneous measurement of the 25-hydroxy metabolites of vitamins D2 and D3.

BACKGROUND: Measurement of 25-hydroxyvitamin D2 and D3 (25-OH D2 and D3) is essential for investigating vitamin D deficiency. Competitive binding techniques are unable to distinguish between the 2 metabolites and suffer from interference from other hydroxy metabolites of vitamin D. METHODS: We used isotope-dilution liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS) for routine determination of 25-OH D2 and D3 with a stable-isotope-labeled internal standard (IS). Serum samples (100 microL) were denatured with methanol-propanol containing IS, vortex-mixed, extracted into hexane, and dried under nitrogen. The reconstituted extract was chromatographed on a BDS C8 HPLC column, and the metabolites and IS were detected by electrospray ionization MS/MS in multiple-reaction monitoring mode. RESULTS: 25-OH D2 and D3 and the IS nearly coeluted, whereas 1alpha-hydroxyvitamin D3 was separated; total run time was 8 min. The interassay CVs for 25-OH D2 were 9.5% and 8.4% at 52 and 76 nmol/L, respectively, and for 25-OH D3 were 5.1% and 5.6% at 55 and 87 nmol/L, respectively. The detection limit of the present method was <4 nmol/L for both metabolites. Method comparison with a commercial RIA measuring total 25-hydroxyvitamin D showed good correlation: y=0.97x - 2.7 nmol/L (r=0.91). The analytical system can assay 100 samples in 12.5 h. CONCLUSIONS: This simple robust interference-free LC-MS/MS assay is suitable for routine measurement of the 25-hydroxy metabolites of vitamins D2 and D3 in human serum. The assay has been in use for 9 months and has been used to assay more than 6000 routine samples.

Advanced glycation end products modulate the maturation and function of peripheral blood dendritic cells.

Advanced glycation end products (AGEs), a complex and heterogeneous group of posttranslational modifications of proteins in vivo, have been widely studied for their involvement in diabetic complications; these complications are largely vascular and accompanied by inflammation. Because dendritic cells (DCs) initiate and modulate inflammatory responses, we hypothesized that AGEs might exert immunomodulatory effects via antigen-presenting DCs. To test this hypothesis, we investigated effects of the AGE peptide, compared with the naked peptide, on maturation, costimulatory molecule expression, and function of DCs in peripheral blood. From flow cytometry, we found a dose-dependent inhibition in CD83 expression on DCs exposed for 2.5 h to each of two synthetic AGE peptides. A similar culture for 24 h additionally produced an inhibition of CD80 expression, whereas exposure to AGEs for 3 days induced a large increase in DC numbers and a concomitant loss of monocyte/macrophages. Exposure of DCs to AGEs resulted in a dose-dependent loss in their capacity to stimulate primary proliferation of allogeneic T-cells. We conclude that AGEs promote development of DCs but that these DCs fail to express maturation markers and lose the capacity to stimulate primary T-cell responses. Effects of AGEs on DCs could be instrumental in the immunological changes associated with diabetes.

Continuous glucose monitoring and haemoglobin A(1c).

BACKGROUND: Measurement of HbA(1c) is the standard test for assessment of glycaemic control in diabetic subjects. Using new glucose sensing technology we re-evaluated the significance of HbA(1c) in terms of the aspects of the blood profile it measures in patients with diabetes. METHODS: In a group of 27 patients with type 1 diabetes, interstitial fluid glucose concentrations were monitored for a mean of 2.6 days using the Continuous Glucose Monitoring System trade mark (MiniMed Inc, CA, USA). Results were correlated with an HBA(1c) measurement taken at the time of sensor insertion. RESULTS: Results were available in 25 subjects, two datasets being lost due to patient error. There was a correlation between mean sensor glucose value, and the HbA(1c) value (r = 0.59, P = 0.002). The correlation with standard deviation of the readings was weaker (r = 0.3, P = 0.15). No other descriptor of the sensor glucose concentration correlated with HbA(1c). CONCLUSION: The mean interstitial glucose concentration recorded with the Continuous Glucose Monitoring System correlates with HbA(1c) level recorded at the time, but with no other marker of glucose control in diabetic subjects. These results have implications for the interpretation of HbA(1c) concentrations in type 1 diabetes.