Sandra Rainbow

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).

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.

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.

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.

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.