Solar ultraviolet radiation exposure, and incidence of childhood acute lymphocytic leukaemia and non-Hodgkin lymphoma in a US population-based dataset.

BACKGROUND: Acute lymphocytic leukaemia (ALL) and non-Hodgkin lymphoma (NHL) are among the commonest types of childhood cancer. Some previous studies suggested that elevated ultraviolet radiation (UVR) exposures increase ALL risk; many more indicate NHL risk is reduced. METHODS: We assessed age<20 ALL/NHL incidence in Surveillance, Epidemiology and End Results data using AVGLO-derived UVR irradiance/cumulative radiant exposure measures, using quasi-likelihood models accounting for underdispersion, adjusted for age, sex, racial/ethnic group and other county-level socioeconomic variables. RESULTS: There were 30,349 cases of ALL and 8062 of NHL, with significant increasing trends of ALL with UVR irradiance (relative risk (RR) = 1.200/mW/cm2 (95% CI 1.060, 1.359, p = 0.0040)), but significant decreasing trends for NHL (RR = 0.646/mW/cm2 (95% CI 0.512, 0.816, p = 0.0002)). There was a borderline-significant increasing trend of ALL with UVR cumulative radiant exposure (RR = 1.444/MJ/cm2 (95% CI 0.949, 2.197, p = 0.0865)), and significant decreasing trends for NHL (RR = 0.284/MJ/cm2 (95% CI 0.166, 0.485, p < 0.0001)). ALL and NHL trend RR is substantially increased among those aged 0-3. All-age trend RRs are most extreme (increasing for ALL, decreasing for NHL) for Hispanics for both UVR measures. CONCLUSIONS: Our more novel finding, of excess UVR-related ALL risk, is consistent with some previous studies, but is not clear-cut, and in need of replication.

Vitamin D supplementation and major cardiovascular events: D-Health randomised controlled trial.

OBJECTIVE: To investigate whether supplementing older adults with monthly doses of vitamin D alters the incidence of major cardiovascular events. DESIGN: Randomised, double blind, placebo controlled trial of monthly vitamin D (the D-Health Trial). Computer generated permuted block randomisation was used to allocate treatments. SETTING: Australia from 2014 to 2020. PARTICIPANTS: 21 315 participants aged 60-84 years at enrolment. Exclusion criteria were self-reported hypercalcaemia, hyperparathyroidism, kidney stones, osteomalacia, sarcoidosis, taking >500 IU/day supplemental vitamin D, or unable to give consent because of language or cognitive impairment. INTERVENTION: 60 000 IU/month vitamin D3 (n=10 662) or placebo (n=10 653) taken orally for up to five years. 16 882 participants completed the intervention period: placebo 8270 (77.6%); vitamin D 8552 (80.2%). MAIN OUTCOME MEASURES: The main outcome for this analysis was the occurrence of a major cardiovascular event, including myocardial infarction, stroke, and coronary revascularisation, determined through linkage with administrative datasets. Each event was analysed separately as secondary outcomes. Flexible parametric survival models were used to estimate hazard ratios and 95% confidence intervals. RESULTS: 21 302 people were included in the analysis. The median intervention period was five years. 1336 participants experienced a major cardiovascular event (placebo 699 (6.6%); vitamin D 637 (6.0%)). The rate of major cardiovascular events was lower in the vitamin D group than in the placebo group (hazard ratio 0.91, 95% confidence interval 0.81 to 1.01), especially among those who were taking cardiovascular drugs at baseline (0.84, 0.74 to 0.97; P for interaction=0.12), although the P value for interaction was not significant (<0.05). Overall, the difference in standardised cause specific cumulative incidence at five years was -5.8 events per 1000 participants (95% confidence interval -12.2 to 0.5 per 1000 participants), resulting in a number needed to treat to avoid one major cardiovascular event of 172. The rate of myocardial infarction (hazard ratio 0.81, 95% confidence interval 0.67 to 0.98) and coronary revascularisation (0.89, 0.78 to 1.01) was lower in the vitamin D group, but there was no difference in the rate of stroke (0.99, 0.80 to 1.23). CONCLUSIONS: Vitamin D supplementation might reduce the incidence of major cardiovascular events, although the absolute risk difference was small and the confidence interval was consistent with a null finding. These findings could prompt further evaluation of the role of vitamin D supplementation, particularly in people taking drugs for prevention or treatment of cardiovascular disease. TRIAL REGISTRATION: ACTRN12613000743763.

Vitamin D supplementation and cognition-Results from analyses of the D-Health trial.

BACKGROUND: Observational studies have consistently found a link between low serum 25-hydroxyvitamin D concentration and higher risk of cognitive impairment. Results from randomized controlled trials have been mixed, and few have been conducted in the general population. METHODS: We recruited 21,315 community-dwelling Australians aged between 60 and 84 years to participate in the D-Health Trial, a randomized, double-blind, placebo-controlled trial. The intervention was monthly oral doses of 60,000 international units of vitamin D or placebo for 5 years. We assessed cognitive function in a randomly sampled group of participants aged ≥70 years using the Telephone Interview for Cognitive Status (TICS) at 2 and 5 years after randomization. The primary outcome for this analysis was TICS score; the secondary outcome was the proportion of people who had cognitive impairment (defined as TICS score ≤25). We analyzed data using mixed models (linear and logistic). RESULTS: We interviewed 3887 participants at year 2 and 3614 participants at year 5. The mean TICS score at these time points was 32.3 and 32.2, respectively. Vitamin D supplementation did not affect cognitive function as measured by TICS score (mean difference between vitamin D and placebo groups 0.04; 95% CI -0.14 to 0.23), or alter risk of cognitive impairment (odds ratio 1.00; 95% CI 0.75 to 1.33). CONCLUSIONS: Monthly bolus doses of vitamin D supplementation neither enhanced nor hindered cognitive function among older adults. Population-wide vitamin D supplementation of older adults that are largely vitamin D replete is unlikely to substantially benefit cognition.

The effect of vitamin D supplementation on pain: an analysis of data from the D-Health randomised controlled trial.

Observational studies suggest that 25-hydroxy vitamin D (25(OH)D) concentration is inversely associated with pain. However, findings from intervention trials are inconsistent. We assessed the effect of vitamin D supplementation on pain using data from a large, double-blind, population-based, placebo-controlled trial (the D-Health Trial). 21 315 participants (aged 60-84 years) were randomly assigned to a monthly dose of 60 000 IU vitamin D3 or matching placebo. Pain was measured using the six-item Pain Impact Questionnaire (PIQ-6), administered 1, 2 and 5 years after enrolment. We used regression models (linear for continuous PIQ-6 score and log-binomial for binary categorisations of the score, namely 'some or more pain impact' and 'presence of any bodily pain') to estimate the effect of vitamin D on pain. We included 20 423 participants who completed ≥1 PIQ-6. In blood samples collected from 3943 randomly selected participants (∼800 per year), the mean (sd) 25(OH)D concentrations were 77 (sd 25) and 115 (sd 30) nmol/l in the placebo and vitamin D groups, respectively. Most (76 %) participants were predicted to have 25(OH)D concentration >50 nmol/l at baseline. The mean PIQ-6 was similar in all surveys (∼50·4). The adjusted mean difference in PIQ-6 score (vitamin D cf placebo) was 0·02 (95 % CI (-0·20, 0·25)). The proportion of participants with some or more pain impact and with the presence of bodily pain was also similar between groups (both prevalence ratios 1·01, 95 % CI (0·99, 1·03)). In conclusion, supplementation with 60 000 IU of vitamin D3/month had negligible effect on bodily pain.

Cutaneous melanoma, prostate-specific antigen testing and the subsequent risk of prostate cancer diagnosis: a prospective analysis of the 45 and Up Study.

BACKGROUND: The association between cutaneous melanoma and subsequent risk of prostate cancer (PC) was examined in a large population-based cohort study. METHODS: Male participants in the Sax Institute's 45 and Up Study (Australia) were recruited between 2006 and 2009. Questionnaire data and linked administrative health data from the Centre for Health Record Linkage and Services Australia identified melanomas diagnosed between 1/1/1994 and 12 months before Study recruitment (i.e., between 2005 and 2008), incident PCs, primary healthcare utilisation and prostate-specific antigen (PSA) tests. Men were excluded from the current analyses if they had a recorded PC or other cancer diagnosis other than melanoma and non-melanoma skin cancer prior to recruitment. Multivariable Cox regression was used to estimate hazard ratios (HRs) adjusting for PSA-testing frequency before PC diagnosis. RESULTS: Of 96,548 eligible men, 1899 were diagnosed with melanoma during the melanoma diagnosis period and 3677 incident PC diagnosed during follow-up (latest date 31/12/2013). Men with melanoma diagnosis had increased risk of a subsequent PC diagnoses (vs. no melanoma; fully adjusted HR = 1.32; 95% CI: 1.09-1.60). There was weak evidence of higher risks of a subsequent PC diagnosis for men diagnosed with more than one melanoma compared to men diagnosed with only one melanoma (p = 0.077), and if first melanoma diagnosis was 10 to 15 years before Study recruitment (fully adjusted HR = 2.05; 95% CI [1.35, 3.12]). CONCLUSION: Melanoma diagnosis was associated with increased risk of subsequent PC diagnosis, after adjusting for PSA testing and primary healthcare utilisation. While our ability to adjust for PC screening reduced risk of detection bias, we acknowledge that residual confounding from increased medical surveillance after melanoma diagnoses cannot be entirely ruled out.

Cancer Survivors' Long-Term Health Service Costs in Queensland, Australia: Results of a Population-Level Data Linkage Study (Cos-Q).

Worldwide, the number of cancer survivors is rapidly increasing. The aim of this study was to quantify long-term health service costs of cancer survivorship on a population level. The study cohort comprised residents of Queensland, Australia, diagnosed with a first primary malignancy between 1997 and 2015. Administrative databases were linked with cancer registry records to capture all health service utilization. Health service costs between 2013-2016 were analyzed using a bottom-up costing approach. The cumulative mean annual healthcare expenditure (2013-2016) for the cohort of N = 230,380 individuals was AU$3.66 billion. The highest costs were incurred by patients with a history of prostate (AU$538 m), breast (AU$496 m) or colorectal (AU$476 m) cancers. Costs by time since diagnosis were typically highest in the first year after diagnosis and decreased over time. Overall mean annual healthcare costs per person (2013-2016) were AU$15,889 (SD: AU$25,065) and highest costs per individual were for myeloma (AU$45,951), brain (AU$30,264) or liver cancer (AU$29,619) patients. Our results inform policy makers in Australia of the long-term health service costs of cancer survivors, provide data for economic evaluations and reinforce the benefits of investing in cancer prevention.

Vitamin D Supplementation and Antibiotic Use in Older Australian Adults: An Analysis of Data From the D-Health Trial.

BACKGROUND: Vitamin D supplementation may reduce the risk or severity of infection, but this has been investigated in few large population-based trials. We analyzed data from the D-Health Trial, using prescription of antibiotics as a surrogate for infection. METHODS: The D-Health Trial is a randomized, double-blind, placebo-controlled trial in which 21 315 Australians aged 60-84 years were randomized to 60 000 IU of supplementary vitamin D3 or placebo monthly for 5 years. For this analysis, the primary outcome was the number of antibiotic prescription episodes; secondary outcomes were total number of prescriptions, repeat prescription episodes, and antibiotics for urinary tract infection. We estimated incidence rate ratios (IRRs) using negative binomial regression, and odds ratios using logistic regression. RESULTS: Vitamin D supplementation slightly reduced the number of prescription episodes (IRR, 0.98; 95% confidence interval [CI], .95-1.01), total prescriptions (IRR, 0.97; 95% CI, .93-1.00), and repeat prescription episodes (IRR, 0.96; 95% CI, .93-1.00). There was stronger evidence of benefit in people predicted to have insufficient vitamin D at baseline (prescription episodes IRR, 0.93; 95% CI, .87-.99). CONCLUSIONS: Vitamin D may reduce the number of antibiotic prescriptions, particularly in people with low vitamin D status. This supports the hypothesis that vitamin D has a clinically relevant effect on the immune system. CLINICAL TRIALS REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12613000743763. https://www.anzctr.org.au/.

The D-Health Trial: a randomised controlled trial of the effect of vitamin D on mortality.

BACKGROUND: The effect of supplementing unscreened adults with vitamin D3 on mortality is unclear. We aimed to determine whether monthly doses of vitamin D3 influenced mortality in older Australians. METHODS: We did a randomised, double-blind, placebo-controlled trial of oral vitamin D3 supplementation (60 000 IU per month) in Australians 60 years or older who were recruited across the country via the Commonwealth electoral roll. Participants were randomly assigned (1:1), using automated computer-generated permuted block randomisation, to receive one oral gel capsule of either 60 000 IU vitamin D3 or placebo once a month for 5 years. Participants, staff, and investigators were blinded to study group allocation. The primary endpoint was all-cause mortality assessed in all participants who were randomly assigned. We also analysed mortality from cancer, cardiovascular disease, and other causes. Hazard ratios (HRs) and 95% CIs were generated using flexible parametric survival models. This trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12613000743763. FINDINGS: Between Feb 14, 2014, and June 17, 2015, we randomly assigned 21 315 participants, including 10 662 to the vitamin D group and 10 653 to the placebo group. In 4441 blood samples collected from randomly sampled participants (N=3943) during follow-up, mean serum 25-hydroxy-vitamin D concentrations were 77 (SD 25) in the placebo group and 115 (SD 30) nmol/L in the vitamin D group. Following 5 years of intervention (median follow-up 5·7 years [IQR 5·4-6·7]), 1100 deaths were recorded (placebo 538 [5·1%]; vitamin D 562 [5·3%]). 10 661 participants in the vitamin D group and 10 649 participants in the placebo group were included in the primary analysis. Five participants (one in the vitamin D group and four in the placebo group) were not included as they requested to be withdrawn and their data to be destroyed. The HR of vitamin D3 effect on all-cause mortality was 1.04 [95% CI 0·93 to 1·18]; p=0·47)and the HR of vitamin D3 effect on cardiovascular disease mortality was 0·96 (95% CI 0·72 to 1·28; p=0·77). The HR for cancer mortality was 1·15 (95% CI 0·96 to 1·39; p=0·13) and for mortality from other causes it was 0·83 (95% CI 0·65 to 1·07; p=0·15). The odds ratio for the per-protocol analysis was OR 1·18 (95% CI 1·00 to 1·40; p=0·06). In exploratory analyses excluding the first 2 years of follow-up, those randomly assigned to receive vitamin D had a numerically higher hazard of cancer mortality than those in the placebo group (HR 1·24 [95% CI 1·01-1·54]; p=0·05). INTERPRETATION: Administering vitamin D3 monthly to unscreened older people did not reduce all-cause mortality. Point estimates and exploratory analyses excluding the early follow-up period were consistent with an increased risk of death from cancer. Pending further evidence, the precautionary principle would suggest that this dosing regimen might not be appropriate in people who are vitamin D-replete. FUNDING: The D-Health Trial is funded by National Health and Medical Research Council.

Vitamin D supplementation and risk of falling: outcomes from the randomized, placebo-controlled D-Health Trial.

BACKGROUND: Falls cause considerable morbidity and mortality in older people. It is unclear how vitamin D supplementation affects falls risk, particularly when taken at high doses. We sought to determine whether monthly high-dose vitamin D supplementation reduces risk and incidence of falls. METHODS: We used data from the randomized, double-blind, placebo-controlled D-Health Trial conducted in Australia. Between February 2014 and May 2015, 21 315 participants aged 60-84 years were randomized (1:1) to monthly doses of either 60 000 IU of colecalciferol or placebo for a maximum of 5 years. People who reported a history of osteomalacia, sarcoidosis, hyperparathyroidism, hypercalcaemia or kidney stones or who were taking >500 IU/day supplementary vitamin D were ineligible. Each year, we collected blood samples from ~450 randomly sampled participants from each trial arm and measured 25-hydroxyvitamin D [25(OH)D]. Falls, a prespecified tertiary outcome, were ascertained using annual surveys and, for a subset of participants, 3-month falls diaries. The primary outcome for this analysis was any fall in the month before completing an annual survey. As part of our process to maintain blinding, we used random samples of participants (surveys, n = 16 000; diaries, n = 2400), with equal numbers per group. Participants with no outcome data were excluded. Following an intention-to-treat approach, we analysed outcomes using logistic, ordinal and negative binomial regression. Registration: Australian New Zealand Clinical Trials Registry (ACTRN12613000743763); registered 4 July 2013. RESULTS: Mean treatment duration was 4.3 years (standard deviation [SD] = 1.4 years). Mean serum 25(OH)D concentrations during the trial were 114.8 (SD 30.3) nmol/L and 77.5 (SD 25.2) nmol/L in the vitamin D and placebo groups, respectively. Survey and diary analytic sets included 15 416 and 2200 participants, respectively; approximately half were randomized to vitamin D (surveys: 50.1%; diaries: 50.4%). Vitamin D had no effect on falling in the past month (odds ratio [OR] 1.02, 95% confidence interval [CI] 0.95-1.10). There was an interaction with body mass index (BMI) (P-interaction = 0.001); vitamin D increased risk in participants with BMI < 25 kg/m2 (OR 1.25, 95% CI 1.09-1.43), but there was no effect in those with BMI ≥ 25 kg/m2 (OR 0.95, 95% CI 0.87-1.04). Analyses of diary data were consistent with these findings. The incidence of hypercalcaemia and kidney stones did not differ between groups. CONCLUSIONS: Monthly high-dose vitamin D supplementation did not reduce risk of falling. A possible increased risk of falling with vitamin D supplementation in people with normal BMI warrants further investigation.

Impact of personal genomic risk information on melanoma prevention behaviors and psychological outcomes: a randomized controlled trial.

PURPOSE: We evaluated the impact of personal melanoma genomic risk information on sun-related behaviors and psychological outcomes. METHODS: In this parallel group, open, randomized controlled trial, 1,025 Australians of European ancestry without melanoma and aged 18-69 years were recruited via the Medicare database (3% consent). Participants were randomized to the intervention (n = 513; saliva sample for genetic testing, personalized melanoma risk booklet based on a 40-variant polygenic risk score, telephone-based genetic counseling, educational booklet) or control (n = 512; educational booklet). Wrist-worn ultraviolet (UV) radiation dosimeters (10-day wear) and questionnaires were administered at baseline, 1 month postintervention, and 12 months postbaseline. RESULTS: At 12 months, 948 (92%) participants completed dosimetry and 973 (95%) the questionnaire. For the primary outcome, there was no effect of the genomic risk intervention on objectively measured UV exposure at 12 months, irrespective of traditional risk factors. For secondary outcomes at 12 months, the intervention reduced sunburns (risk ratio: 0.72, 95% confidence interval: 0.54-0.96), and increased skin examinations among women. Melanoma-related worry was reduced. There was no overall impact on general psychological distress. CONCLUSION: Personalized genomic risk information did not influence sun exposure patterns but did improve some skin cancer prevention and early detection behaviors, suggesting it may be useful for precision prevention. There was no evidence of psychological harm.

Lifetime Ambient UV Radiation Exposure and Risk of Basal Cell Carcinoma by Anatomic Site in a Nationwide U.S. Cohort, 1983-2005.

BACKGROUND: Cutaneous basal cell carcinoma (BCC) has long been associated with UV radiation (UVR) exposure, but data are limited on risks by anatomic site. METHODS: We followed 63,912 cancer-free White U.S. radiologic technologists from cohort entry (1983-1989/1994-1998) to exit (date first BCC via 2003-2005 questionnaire). We estimated associations between cumulative ambient UVR and relative/absolute risks of self-reported BCC by anatomic location via Poisson models. RESULTS: For incident first primary BCC in 2,124 subjects (mean follow-up, 16.9 years) log[excess relative risks] (ERR) of BCC per unit cumulative ambient UVR = 1.27/MJ cm-2 [95% confidence interval (CI): 0.86-1.68; P trend < 0.001] did not vary by anatomic site (P = 0.153). However, excess absolute risks of BCC per unit cumulative ambient UVR were large for the head/neck = 5.46/MJ cm-2/104 person-year (95% CI: 2.92-7.36; P trend < 0.001), smaller for the trunk (2.56; 95% CI: 1.26-3.33; P trend = 0.003), with lesser increases elsewhere. There were lower relative risks, but higher absolute risks, for those with Gaelic ancestry (P < 0.001), also higher absolute risks among those with fair complexion, but relative and absolute risks were not generally modified by other constitutional, lifestyle or medical factors for any anatomic sites. Excess absolute and relative risk was concentrated 5-15 years before time of follow-up. CONCLUSIONS: BCC relative and absolute risk rose with increasing cumulative ambient UVR exposure, with absolute risk highest for the head/neck, to a lesser extent in the trunk. IMPACT: These associations should be evaluated in other White and other racial/ethnic populations along with assessment of possible modification by time outdoors, protective, and behavioral factors.

Predicting deseasonalised serum 25 hydroxy vitamin D concentrations in the D-Health Trial: An analysis using boosted regression trees.

BACKGROUND: The D-Health Trial aims to determine whether monthly high-dose vitamin D supplementation can reduce the mortality rate and prevent cancer. We did not have adequate statistical power for subgroup analyses, so could not justify the high cost of collecting blood samples at baseline. To enable future exploratory analyses stratified by baseline vitamin D status, we developed models to predict baseline serum 25 hydroxy vitamin D [25(OH)D] concentration. METHODS: We used data and serum 25(OH)D concentrations from participants who gave a blood sample during the trial for compliance monitoring and were randomised to placebo. Data were partitioned into training (80%) and validation (20%) datasets. Deseasonalised serum 25(OH)D concentrations were dichotomised using cut-points of 50, 60 and 75 nmol/L. We fitted boosted regression tree models, based on 13 predictors, and evaluated model performance using the validation data. RESULTS: The training and validation datasets had 1788 (10.5% <50 nmol/L, 23.1% <60 nmol, 48.8 <75 nmol/L) and 447 (11.9% <50 nmol/L, 25.7% <60 nmol/L, and 49.2% <75 nmol/L) samples, respectively. Ambient UV radiation and total intake of vitamin D were the strongest predictors of 'low' serum 25(OH)D concentration. The area under the receiver operating characteristic curves were 0.71, 0.70, and 0.66 for cut-points of <50, <60 and <75 nmol/L respectively. CONCLUSIONS: We exploited compliance monitoring data to develop models to predict serum 25(OH)D concentration for D-Health participants at baseline. This approach may prove useful in other trial settings where there is an obstacle to exhaustive data collection.

High-dose vitamin D supplementation to prevent prostate cancer progression in localised cases with low-to-intermediate risk of progression on active surveillance (ProsD): protocol of a phase II randomised controlled trial.

INTRODUCTION: Active surveillance (AS) for patients with prostate cancer (PC) with low risk of PC death is an alternative to radical treatment. A major drawback of AS is the uncertainty whether a patient truly has low risk PC based on biopsy alone. Multiparametric MRI scan together with biopsy, appears useful in separating patients who need curative therapy from those for whom AS may be safe. Two small clinical trials have shown short-term high-dose vitamin D supplementation may prevent PC progression. There is no substantial evidence for its long-term safety and efficacy, hence its use in the care of men with PC on AS needs assessment. This protocol describes the ProsD clinical trial which aims to determine if oral high-dose vitamin D supplementation taken monthly for 2 years can prevent PC progression in cases with low-to-intermediate risk of progression. METHOD AND ANALYSIS: This is an Australian national multicentre, 2:1 double-blinded placebo-controlled phase II randomised controlled trial of monthly oral high-dose vitamin D supplementation (50 000 IU cholecalciferol), in men diagnosed with localised PC who have low-to-intermediate risk of disease progression and are being managed by AS. This trial will assess the feasibility, efficacy and safety of supplementing men with an initial oral loading dose of 500 000 IU cholecalciferol, followed by a monthly oral dose of 50 000 IU during the 24 months of AS. The primary trial outcome is the commencement of active therapy for clinical or non-clinical reason, within 2 years of AS. ETHICS AND DISSEMINATION: This trial is approved by Bellberry Ethics Committee (2016-06-459). All results will be reported in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ACTRN12616001707459.

The effect of vitamin D supplementation on acute respiratory tract infection in older Australian adults: an analysis of data from the D-Health Trial.

BACKGROUND: Observational studies have linked vitamin D deficiency with acute respiratory tract infection, but results from randomised controlled trials are heterogeneous. We analysed data from the D-Health Trial to determine whether supplementing older Australian adults, recruited from the general population, with monthly doses of vitamin D reduced the risk, duration, and severity of acute respiratory tract infections. METHODS: We used data from the D-Health Trial, a randomised, double-blind, placebo-controlled trial of monthly vitamin D supplementation, for which acute respiratory infection was a pre-specified trial outcome. Participants were supplemented and followed for up to 5 years. The trial was set within the Australian general population, using the Commonwealth Electoral Roll as the sampling frame, but also allowing some volunteers to participate. Participants were men and women aged 60 to 79 years (with volunteers up to age 84 years). Participants were randomly assigned to receive either vitamin D or placebo (1:1) using computer-generated permuted block randomisation, which was stratified by age, sex, and state. This was an automated process and the assignment list was not visible to study staff or investigators. Active and placebo gel capsules, identical in appearance to ensure masking, were labelled A and B and the code was not available to study staff or investigators. Participants were asked to report occurrence of acute respiratory symptoms over the previous month via annual surveys, and a subset of participants completed 8-week respiratory symptom diaries in winter. As part of our process to maintain blinding, a random sample of participants was selected for analysis of survey data and a separate sample selected for analysis of diary data. Blood samples were obtained from a random sample of participants (about 450 per group per year) and serum 25-hydroxy vitamin D (25[OH]D) concentrations were measured to monitor adherence. We used regression models to estimate odds ratios (OR), rate ratios, and rate differences. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12613000743763. FINDINGS: Between Jan 13, 2014, and May 26, 2015, 421 207 invitations were sent, 40 824 people were interested in participating, and 21 315 participants were recruited and randomised. Of the 16 000 participants selected for potential analysis of survey data, 15 373 were included in the analysis; 295 in the vitamin D group and 332 in the placebo group who were missing data for all five annual surveys were excluded from the analysis. Of the 3800 selected for potential analysis of diary data, 3070 were invited to complete the diaries because 730 had already withdrawn. 2598 people were included in the analysis; 218 people in the vitamin D group and 254 in the placebo group were missing data and were therefore excluded from the analysis. In blood samples collected from randomly sampled participants throughout the trial, the mean serum 25(OH)D concentration was 114·8 (SD 30·3) nmol/L in the vitamin D group and 77·5 (25·2) nmol/L in the placebo group. Vitamin D supplementation did not reduce the risk of acute respiratory tract infection (survey OR 0·98, 95% CI 0·93 to 1·02; diary OR 0·98, 0·83 to 1·15). Analyses of diary data showed reductions in the overall duration of symptoms and of severe symptoms, but these were small and unlikely to be clinically significant. INTERPRETATION: Monthly bolus doses of 60 000 IU of vitamin D did not reduce the overall risk of acute respiratory tract infection, but could slightly reduce the duration of symptoms in the general population. These findings suggest that routine vitamin D supplementation of a population that is largely vitamin D replete is unlikely to have a clinically relevant effect on acute respiratory tract infection. FUNDING: National Health and Medical Research Council.

Post-treatment levels of plasma 25- and 1,25-dihydroxy vitamin D and mortality in men with aggressive prostate cancer.

Vitamin D may reduce mortality from prostate cancer (PC). We examined the associations of post-treatment plasma 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D concentrations with PC mortality. Participants were PC cases from the New South Wales Prostate Cancer Care. All contactable and consenting participants, at 4.9 to 8.6 years after diagnosis, were interviewed and had plasma 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D) measured in blood specimens. Cox regression allowing for left-truncation was used to calculate adjusted mortality hazards ratios (HR) and 95% confidence intervals (95% CI) for all-cause and PC-specific mortality in relation to vitamin D levels and other potentially-predictive variables. Of the participants (n = 111; 75·9% response rate), there were 198 deaths from any cause and 41 from PC in the study period. Plasma 25(OH)D was not associated with all-cause or PC-specific mortality (p-values > 0·10). Plasma 1,25(OH)2D was inversely associated with all-cause mortality (HR for highest relative to lowest quartile = 0·45; 95% CI: 0·29-0·69), and PC-specific mortality (HR = 0·40; 95% CI: 0·14-1·19). These associations were apparent only in men with aggressive PC: all-cause mortality HR = 0·28 (95% CI·0·15-0·52; p-interaction = 0·07) and PC-specific mortality HR = 0·26 (95% CI: 0·07-1.00). Time spent outdoors was also associated with lower all-cause (HR for 4th relative to 1st exposure quartile = 0·42; 95% CI: 0·24-0·75) and PC-specific (HR = 0·48; 95% CI: 0·14-1·64) mortality, although the 95% CI for the latter was wide. The inverse association between post-treatment plasma 1,25(OH)2D levels and all-cause and PC-specific mortality in men with aggressive PC, suggest a possible beneficial effect of vitamin D supplementation in these men.

Lifetime Costs of Surviving Cancer-A Queensland Study (COS-Q): Protocol of a Large Healthcare Data Linkage Study.

Australia-wide, there are currently more than one million cancer survivors. There are over 32 million world-wide. A trend of increasing cancer incidence, medical innovations and extended survival places growing pressure on healthcare systems to manage the ongoing and late effects of cancer treatment. There are no published studies of the long-term health service use and cost of cancer survivorship on a population basis in Australia. All residents of the state of Queensland, Australia, diagnosed with a first primary malignancy from 1997-2015 formed the cohort of interest. State and national healthcare databases are linked with cancer registry records to capture all health service utilization and healthcare costs for 20 years (or death, if this occurs first), starting from the date of cancer diagnosis, including hospital admissions, emergency presentations, healthcare costing data, Medicare services and pharmaceuticals. Data analyses include regression and economic modeling. We capture the whole journey of health service contact and estimate long-term costs of all cancer patients diagnosed and treated in Queensland by linking routinely collected state and national healthcare data. Our results may improve the understanding of lifetime health effects faced by cancer survivors and estimate related healthcare costs. Research outcomes may inform policy and facilitate future planning for the allocation of healthcare resources according to the burden of disease.

Cumulative solar ultraviolet radiation exposure and basal cell carcinoma of the skin in a nationwide US cohort using satellite and ground-based measures.

BACKGROUND: Basal cell carcinoma of the skin (BCC) is the most common cancer in populations of European ancestry. Although consistently linked with basal cell carcinoma of the skin in case-control studies, few prospective cohort studies have evaluated the shape of the exposure-response of basal cell carcinoma associated with cumulative radiant solar ultraviolet exposure (UVR). METHODS: We followed 63,912 white cancer-free US radiologic technologists from entry (1983-1998) to exit (2003-2005) with known ultraviolet irradiance at up to 5 residential locations. Using generalized-additive and relative risk models we analyzed the exposure-response of basal cell carcinomas associated with ambient cumulative ultraviolet radiant exposure using ground-based National Solar Radiation database Average Daily Total Global data and satellite-based National Aeronautics and Space Administration Total Ozone Mapping Spectrometer data. RESULTS: There were 2151 technologists with an incident primary basal cell carcinoma. Risk of basal cell carcinoma rose with increasing cumulative ultraviolet radiation exposure using both measures, such that 1 MJ cm- 2 increased basal cell carcinoma risk by 8.48 (95% CI 5.22, 11.09, p < 0.001) and by 10.15 (95% CI 6.67, 13.10, p < 0.001) per 10,000 persons per year using the Average Daily Total Global and Total Ozone Mapping Spectrometer ultraviolet data, respectively; relative risk was likewise elevated. There was some evidence of upward curvature in the cumulative ultraviolet exposure response using both exposure measures with a greater increase in risk of basal cell carcinoma at higher levels of ultraviolet radiation exposure, but less evidence for curvature in relative risk. There are indications of substantial variation of relative risk with time after exposure and age at exposure, so that risk is highest for the period 10-14 years after ultraviolet radiation exposure and for those exposed under the age of 25. CONCLUSIONS: We observed increases in risk of basal cell carcinoma and a similar exposure-response for ground-based and satellite ultraviolet radiation measures. Our observations suggest that interventions should concentrate on persons with higher levels of ultraviolet radiation exposure.

Risk attitudes and sun protection behaviour: Can behaviour be altered by using a melanoma genomic risk intervention?

BACKGROUND: Exposure to ultraviolet radiation from sunlight is directly associated with melanoma skin cancer, however reducing sun-exposure can be difficult to achieve at a population level. METHODS: Using a genomic risk information behaviour change trial for melanoma prevention, we classified participants as risk-seeking, risk-neutral or risk-averse for domain-specific risk taking (DOSPERT). One-way ANOVA determined the association between socio-demographic characteristics and risk-taking score, and multivariable linear regression ascertained impact of an individual's underlying risk propensity on an objective measure of sun-exposure, standard erythemal dose (SED), at 3-months follow-up. RESULTS: Of 119 participants, mean age 53 years; 50% males, 87% had a personal/family history of cancer; 19% were classified risk-seeking, 57% risk-neutral. The mean risk-taking score was significantly higher in younger participants (≤50 years: 13.86 vs. >50 years: 11.11, p = 0.003); and lower in those with a personal/family history of skin cancer versus without (10.55 vs 13.33, p = 0.009). Risk averse individuals had lower weekly mean SEDs at 3-months than risk neutral and risk seeking individuals (2.56, 5.81, 4.81 respectively, p = 0.01). Risk seekers showed fewer sun protective habits (p < 0.001); and higher intentional tanning, (p = 0.01). At 3-months, risk seekers attained 16%-54% lower SEDs in the genomic information group compared with controls, however this was not significantly different across risk groups (interaction p = 0.13). CONCLUSION: An individual's underlying risk attitude is likely associated with sun-exposure behaviours, and may modify the effect of a genomic risk information behaviour change intervention. Young people and risk seekers may benefit most from being given information on their genetic risk of melanoma.

A randomized placebo-controlled trial of vitamin D supplementation for reduction of mortality and cancer: Statistical analysis plan for the D-Health Trial.

BACKGROUND: Many observational studies have reported an association between vitamin D and non-skeletal health outcomes. The D-Health Trial was launched to determine if supplementing the older population with high monthly doses of Vitamin D can prevent cancer and premature mortality. The intervention is ongoing but here we provide a detailed statistical analysis plan for the primary and secondary outcomes of the D-Health Trial. METHODS/DESIGN: The D-Health Trial is a double-blind, randomized, placebo-controlled trial. Between February 2014 and May 2015, 21,315 people were randomized in a 1:1 ratio to receive monthly doses of either 60,000 IU of cholecalciferol (vitamin D3) or placebo for five years. The primary outcome is all-cause mortality and the secondary outcomes are total cancer incidence and colorectal cancer incidence. These will be ascertained via linkage to death and cancer registries. The primary analysis for each outcome will follow an intention-to-treat approach; we will use flexible parametric survival models to investigate the association between supplementation and time to an event. We describe in detail sophisticated secondary analyses that consider non-compliance and contamination due to off-study supplementation. CONCLUSIONS: Publication of this statistical analysis plan in advance of the intervention's completion, and adherence to it, will avoid data-driven analyses of the primary and secondary outcomes and ensure robust reporting of outcomes. CLINICAL TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry: ACTRN12613000743763. Registered on 4 July 2013.