The D-Health Trial: A randomized trial of vitamin D for prevention of mortality and cancer.

BACKGROUND: Vitamin D, specifically serum 25(OH)D has been associated with mortality, cancer and multiple other health endpoints in observational studies, but there is a paucity of clinical trial evidence sufficient to determine the safety and effectiveness of population-wide supplementation. We have therefore launched the D-Health Trial, a randomized trial of vitamin D supplementation for prevention of mortality and cancer. Here we report the methods and describe the trial cohort. METHODS: The D-Health Trial is a randomized placebo-controlled trial, with planned intervention for 5years and a further 5years of passive follow-up through linkage with health and death registers. Participants aged 65-84years were recruited from the general population of Australia. The intervention is monthly oral doses of 60,000IU of cholecalciferol or matching placebo. The primary outcome is all-cause mortality. Secondary outcomes are total cancer incidence and colorectal cancer incidence. RESULTS: We recruited 21,315 participants to the trial between February 2014 and May 2015. The participants in the two arms of the trial were well-balanced at baseline. Comparison with Australian population statistics shows that the trial participants were less likely to report being in fair or poor health, to be current smokers or to have diabetes than the Australian population. However, the proportion overweight or with health conditions such as arthritis and angina was similar. CONCLUSIONS: Observational data cannot be considered sufficient to support interventions delivered at a population level. Large-scale randomized trials such as the D-Health Trial are needed to inform public health policy and practice.

Associations between vitamin D metabolites, antiretroviral therapy and bone mineral density in people with HIV.

RATIONALE: To see if vitamin D and antiretroviral therapy are associated with bone mineral density (BMD) in people with HIV. RESULT: Lower hip BMD was associated with tenofovir (an antiretroviral medicine) in those with 25(OH)D ≥50 nmol/L. SIGNIFICANCE: The relationship between antiretroviral therapy and hip BMD differs depending on vitamin D status. INTRODUCTION: People with HIV have an increased risk of low BMD and fractures. Antiretroviral therapy contributes to this increased risk. The aim of this study was to evaluate associations between vitamin D metabolites and antiretroviral therapy on BMD. METHODS: The simplification of antiretroviral therapy with tenofovir-emtricitabine or abacavir-lamivudine trial (STEAL) was an open-label, prospective randomised non-inferiority study that compared simplification of current nucleoside reverse transcriptase inhibitors (NRTIs) to fixed-dose combination tenofovir-emtricitabine (TDF-FTC) or abacavir-lamivudine. Serum 25(OH)D and 1,25(OH)2D were measured in 160 individuals (90 receiving TDF-FTC, 70 receiving other NRTIs) at baseline from this study. Multivariable linear regression models were constructed to evaluate the covariates of 1,25(OH)2D and BMD. RESULTS: Protease inhibitor use (p = 0.02) and higher body mass index (BMI) (p = 0.002) were associated with lower 1,25(OH)2D levels in those with 25(OH)D <50 nmol/L. However, TDF-FTC use (p = 0.01) was associated with higher 1,25(OH)2D levels, but only in those with 25(OH)D ≥50 nmol/L. White ethnicity (p = 0.02) and lower BMI (p < 0.001) in those with 25(OH)D <50 nmol/L and with TDF-FTC use (p = 0.008) in those with 25(OH)D ≥50 nmol/L were associated with lower hip BMD. TDF-FTC use, higher serum calcium and serum ßCTX, winter, and lower bone-specific alkaline phosphatase (BALP) and BMI were associated with lower lumbar spine BMD. CONCLUSION: TDF-FTC use (versus non-TDF-FTC use) was associated with lower hip BMD, and this difference was more pronounced in those with 25(OH)D ≥50 nmol/L. Serum 25(OH)D <50 nmol/L was associated with lower hip BMD in all participants. Therefore, the associations between antiretroviral therapy and hip BMD differ depending on vitamin D status.

An internet based approach to improve general practitioners' knowledge and practices: the development and pilot testing of the "ABC's of vitamin D" program.

BACKGROUND: Online continuing medical education (CME) offers a number of advantages for physicians including flexibility with regards to location and timing of use. In order to effect physician practices and improve patient outcomes, it is important that the development of online CME is theory and evidence-based. OBJECTIVES: This paper aims to describe the development of an online CME program for practising general practitioners (GPs) on vitamin D and sun health called "The ABC's of Vitamin D for GPs" using elements of design principles for physician-education web sites as a framework. The paper will also report the program's usability and acceptability pilot test results. METHODS: The ABC's of Vitamin D program was developed following nine principles: needs assessment; evidence-based content development; multimodal program and modularisation; clinical cases; tailoring and interactivity; audit and feedback; credibility of the web site host; patient education materials; ease of use and navigation. Among the 20 GPs invited, acceptability and useability was tested with 12 GPs (60%) who agreed to participate and were interviewed following use of the program. The study was conducted between 2011 and 2013. RESULTS: An online CME program consisting of eight modules was constructed. Of the 12 participating GPs, most (n=11) reported that the program was clear and easy to understand, logical, easy to navigate, and took a reasonable amount of time (estimated between 1 and 3h) to complete. Eleven of 12 participants said they would use the program as an accredited CME activity and all participants indicated that the program was 'very or somewhat' likely to lead to changes in the advice patients are given. CONCLUSION: This study found that a theory and evidence based approach for the development of an online CME program for GPs was acceptable to users. Further research is needed to examine whether the online CME program is effective at changing GP practices and improving patient outcomes.

Serum 25-hydroxy vitamin D concentrations are more deficient/insufficient in peritoneal dialysis than haemodialysis patients in a sunny climate.

BACKGROUND: Research has identified associations between serum 25(OH)D and a range of clinical outcomes in chronic kidney disease and wider populations. The present study aimed to investigate vitamin D deficiency/insufficiency in dialysis patients and the relationship with vitamin D intake and sun exposure. METHODS: A cross-sectional study was used. Participants included 30 peritoneal dialysis (PD) (43.3% male; 56.87 ± 16.16 years) and 26 haemodialysis (HD) (80.8% male; 63.58 ± 15.09 years) patients attending a department of renal medicine. Explanatory variables were usual vitamin D intake from diet/supplements (IU day(-1) ) and sun exposure (min day(-1) ). Vitamin D intake, sun exposure and ethnic background were assessed by questionnaire. Weight, malnutrition status and routine biochemistry were also assessed. Data were collected during usual department visits. The main outcome measure was serum 25(OH)D (nm). RESULTS: Prevalence of inadequate/insufficient vitamin D intake differed between dialysis modality, with 31% and 43% found to be insufficient (<50 nm) and 4% and 33% found to be deficient (<25 nm) in HD and PD patients, respectively (P < 0.001). In HD patients, there was a correlation between diet and supplemental vitamin D intake and 25(OH)D (ρ = 0.84, P < 0.001) and average sun exposure and 25(OH)D (ρ = 0.50, P < 0.02). There were no associations in PD patients. The results remained significant for vitamin D intake after multiple regression, adjusting for age, gender and sun exposure. CONCLUSIONS: The results highlight a strong association between vitamin D intake and 25(OH)D in HD but not PD patients, with implications for replacement recommendations. The findings indicate that, even in a sunny climate, many dialysis patients are vitamin D deficient, highlighting the need for exploration of determinants and consequences.

Incidence trends of keratinocytic skin cancers and melanoma in Israel 2006-11.

BACKGROUND: The incidence of melanoma and keratinocyte cancers (KCs) is rising worldwide. Squamous cell carcinomas (SCCs) and basal cell carcinoma (BCCs) are the most common of all cancers. OBJECTIVES: To determine trends in the incidence of melanoma, BCC and SCC among 1·7 million members of Maccabi Healthcare Services (MHS) from 2006 to 2011. METHODS: Data on patients newly diagnosed with melanoma, SCC and BCC were collected from the MHS Cancer Registry and based on histology reports from the centralized pathology laboratory. Age-specific and overall age-adjusted European standardized rates were computed. Trends were estimated by calculating average annual percentage change (AAPC). RESULTS: During the 6-year study period, 16,079 patients were diagnosed with at least one BCC, 4767 with SCC and 1264 with invasive melanoma. Age-standardized incidence rates were 188, 58 and 17 per 100,000 person years for BCC, SCC and melanoma, respectively. All lesions were more common among men and primarily affected the elderly. BCC rates were stable throughout the study period [AAPC -0·7%, 95% confidence interval (CI) -4·5 to 3·2], while the incidence of SCC increased significantly (AAPC 15·5%, 95% CI 2·6-30·0). In contrast, melanoma rates continuously decreased (AAPC -3·0%, 95%CI -4·5 to -0·1). CONCLUSIONS: The incidence of KC in Israel is high. The disparities in incidence trends between SCC, BCC and melanoma allude to their different aetiologies. These findings underscore the importance of continuous monitoring, education and prevention programmes in a growing high-risk population.

The relationship between ambient ultraviolet radiation (UVR) and objectively measured personal UVR exposure dose is modified by season and latitude.

Despite the widespread use of ambient ultraviolet radiation (UVR) as a proxy measure of personal exposure to UVR, the relationship between the two is not well-defined. This paper examines the effects of season and latitude on the relationship between ambient UVR and personal UVR exposure. We used data from the AusD Study, a multi-centre cross-sectional study among Australian adults (18-75 years), where personal UVR exposure was objectively measured using polysulphone dosimeters. Data were analysed for 991 participants from 4 Australian cities of different latitude: Townsville (19.3°S), Brisbane (27.5°S), Canberra (35.3°S) and Hobart (42.8°S). Daily personal UVR exposure varied from 0.01 to 21 Standard Erythemal Doses (median = 1.1, IQR: 0.5-2.1), on average accounting for 5% of the total available ambient dose. There was an overall positive correlation between ambient UVR and personal UVR exposure (r = 0.23, p < 0.001). However, the correlations varied according to season and study location: from strong correlations in winter (r = 0.50) and at high latitudes (Hobart, r = 0.50; Canberra, r = 0.39), to null or even slightly negative correlations, in summer (r = 0.01) and at low latitudes (Townsville, r = -0.06; Brisbane, r = -0.16). Multiple regression models showed significant effect modification by season and location. Personal exposure fraction of total available ambient dose was highest in winter (7%) and amongst Hobart participants (7%) and lowest in summer (1%) and in Townsville (4%). These results suggest season and latitude modify the relationship between ambient UVR and personal UVR exposure. Ambient UVR may not be a good indicator for personal exposure dose under some circumstances.

Exposure to solar ultraviolet radiation is associated with a decreased folate status in women of childbearing age.

In vitro studies indicate that folate in collected human blood is vulnerable to degradation after exposure to ultraviolet (UV) radiation. This has raised concerns about folate depletion in individuals with high sun exposure. Here, we investigate the association between personal solar UV radiation exposure and serum folate concentration, using a three-week prospective study that was undertaken in females aged 18-47years in Brisbane, Australia (153 E, 27 S). Following two weeks of supplementation with 500µg of folic acid daily, the change in serum folate status was assessed over a 7-day period of measured personal sun exposure. Compared to participants with personal UV exposures of <200 Joules per day, participants with personal UV exposures of 200-599 and >600 Joules per day had significantly higher depletion of serum folate (p=0.015). Multivariable analysis revealed personal UV exposure as the strongest predictor accounting for 20% of the overall change in serum folate (Standardised B=-0.49; t=-3.75; p=<0.01). These data show that increasing solar UV radiation exposures reduces the effectiveness of folic acid supplementation. The consequences of this association may be most pronounced for vulnerable individuals, such as women who are pregnant or of childbearing age with high sun exposures.

The AusD Study: a population-based study of the determinants of serum 25-hydroxyvitamin D concentration across a broad latitude range.

Observational studies suggest that people with a high serum 25-hydroxyvitamin D (25(OH)D) concentration may have reduced risk of chronic diseases such as osteoporosis, multiple sclerosis, type 1 diabetes, cardiovascular disease, and some cancers. The AusD Study (A Quantitative Assessment of Solar UV Exposure for Vitamin D Synthesis in Australian Adults) was conducted to clarify the relationships between ultraviolet (UV) radiation exposure, dietary intake of vitamin D, and serum 25(OH)D concentration among Australian adults residing in Townsville (19.3°S), Brisbane (27.5°S), Canberra (35.3°S), and Hobart (42.8°S). Participants aged 18-75 years were recruited from the Australian Electoral Roll between 2009 and 2010. Measurements were made of height, weight, waist:hip ratio, skin, hair, and eye color, blood pressure, and grip strength. Participants completed a questionnaire on sun exposure and vitamin D intake, together with 10 days of personal UV dosimetry and an associated sun-exposure and physical-activity diary that was temporally linked to a blood test for measurement of 25(OH)D concentration. Ambient solar UV radiation was also monitored at all study sites. We collected comprehensive, high-quality data from 1,002 participants (459 males, 543 females) assessed simultaneously across a range of latitudes and through all seasons. Here we describe the scientific and methodological issues considered in designing the AusD Study.

Vitamin D status and musculoskeletal health in adolescent male ballet dancers a pilot study.

Adequate vitamin D levels during growth are critical to ensuring optimal bone development. Vitamin D synthesis requires sun exposure; thus, athletes engaged in indoor activities such as ballet dancing may be at relatively high risk of vitamin D insufficiency. The objective of this study was to investigate the prevalence of low vitamin D levels in young male ballet dancers and its impact on musculoskeletal health. Eighteen male ballet dancers, aged 10 to 19 years and training for at least 6 hours per week, were recruited from the Australian Ballet School, Melbourne, Australia. Serum 25(OH)D and intact PTH were measured in winter (July) from a non-fasting blood sample. Pubertal stage was determined using self-assessed Tanner criteria. Body composition and areal bone mineral density (aBMD) at the whole body and lumbar spine were measured using dual-energy x-ray absorptiometry (DXA). Injury history and physical activity levels were assessed by questionnaire. Blood samples were obtained from 16 participants. Serum 25(OH)D levels ranged from 20.8 to 94.3 nmol/L, with a group mean of 50.5 nmol/L. Two participants (12.5%) showed vitamin D deficiency [serum 25(OH)D level < 25 nmol/L], seven dancers (44%) had vitamin D insufficiency (25 to 50 nmol/L), and the remaining seven dancers (44%) had normal levels (> 50 nmol/L). No relationship was found between vitamin D status, PTH levels, body composition, and aBMD. The most commonly reported injuries were muscle tears and back pain. The average number of injuries reported by each dancer was 1.9 ± 0.4 (range: 0 to 5). There was no difference in the frequency of reported injuries between subjects with vitamin D deficiency or insufficiency (2.1 ± 0.6 injuries) and those with normal vitamin D levels (1.4 ± 0.6 injuries). This pilot study showed that more than half of highly-trained young male ballet dancers presented with low levels of vitamin D in winter. Further investigations in larger samples of adolescent athletes are needed to determine if this could negatively impact bone growth and place them at higher risk for musculoskeletal injuries.

Influence of solar UVA on erythemal irradiances.

Many materials in everyday use such as window glass in homes and offices, glass in sunrooms and greenhouses, vehicle glass and some brands of sunscreens act as a barrier to the shorter UVB wavelengths while transmitting some of the longer UVA wavelengths. This paper reports on the erythemal exposures due to the UVA waveband encountered over a 12-month period for a solar zenith angle (SZA) range of 4 degrees to 80 degrees and the resulting times required for an erythemal exposure of one standard erythemal dose (SED) due to the erythemal exposures to the UVA wavelengths. The minimum time for an exposure of one SED due to the UVA wavelengths in winter is approximately double that what it is in summer. The time period of 40 to 60 min was the most frequent length of time for an exposure of one SED with 60 to 80 min the next frequent length of time required for a one SED exposure.

Potential of phenothiazine as a thin film dosimeter for UVA exposures.

The research reported in this paper on the changes in absorbance and the calibration of a proposed UVA (320-400 nm) dosimeter have established the phenothiazine-mylar combination as a potential UVA dosimeter for population studies of UVA exposures. The change in optical absorbance at 370 nm was employed to quantify the UVA exposures. This change starts to saturate at a change in absorbance of approximately 0.3. This relates to solar UVA exposures at a sub-tropical site on a horizontal plane of approximately three to four hours. The shape of this calibration curve varies with the season. This can be overcome in the same manner as for polysulfone where the dosimeter is calibrated for the conditions that it will be employed to measure the UVA exposures.

Vitamin D effective ultraviolet wavelengths due to scattering in shade.

Solar UVB radiation (280-320 nm) is an initiator of Vitamin D3 production in the human skin. While numerous studies have been conducted in relation to the biological impact of UV exposure in full sun, less research has investigated the irradiances in shade. The purpose of this study was to determine the levels of UV radiation in relation to Vitamin D3 induction with six commonly encountered shade environments for the larger solar zenith angles observed during autumn and winter. Spectral UV irradiance measurements were made under relatively clear sky conditions at a sub-tropical Southern Hemisphere site for six specific shade environments and solar zenith angle between 35 degrees and 60 degrees to investigate the biologically effective UV irradiances for pre-Vitamin D3 production. Data from this research indicates that pre-Vitamin D3 effective UV wavelengths in the shade were most significant for tree shade and a shade umbrella. Compared to that in full sun, pre-Vitamin D3 effective UV wavelengths were at levels of approximately 52 and 55%, respectively, beneath the shade umbrella and in tree shade. UVB irradiance levels in the shade of a northern facing covered veranda and in a car with windows closed were significantly less than those beneath the shade umbrella, with levels of approximately 11 and 0%, respectively, of those in full sun. Shade is important as a UV minimisation strategy; however, it may also play an important role in providing the human body with adequate levels of UVB radiation for pre-Vitamin D3 production without experiencing the relatively higher levels of UVA irradiances present in full sun.

Optical properties of poly(2,6-dimethyl-1,4-phenylene oxide) film and its potential for a long-term solar ultraviolet dosimeter.

The optical properties of poly(2,6-dimethyl-1,4-phenylene oxide) (PPO) film have been characterized in order to develop an alternative method for UV dosimetry with a focus on long-term human exposure measurements. The dynamic range of PPO film was found to extend to 2 MJ m(-2) of broadband UV exposure independently of film thickness, providing an exposure range of roughly four summer days at subtropical latitudes. The sensitivity of the film to UV exposure was positively related to film thickness in the 20-40 microm range. Films of 40 microm thickness proved to be the most suitable for long-term human UV exposure measurements. The temperature independence of the response of 40 microm PPO film was established from 1.5 degrees C to 50 degrees C within a dosimeter response uncertainty of 6.5%. Dose-rate independence was also demonstrated within 8% of the mean dosimeter response. The spectral response approximates the CIE erythemal action spectrum between 300 and 340 nm, with a peak response at 305 nm. A large deviation from this action spectrum was observed at shorter wavelengths. Investigation of the angular response in both the azimuth and altitude planes showed a cosine error of less than 6.2% between 0 degrees and 40 degrees, and did not exceed 13.3% at any angle greater than 40 degrees. These results indicate that PPO film satisfies the requirements for use as a UV dosimeter, and may be employed in long-term human exposure measurements.

Comparison of human facial UV exposure at high and low latitudes and the potential impact on dermal vitamin D production.

The results presented in this paper allow for the estimation of the monthly UV exposure of the human facial region at various locations across the earth. The technique allows a graphical representation of the UV exposures over the face. The erythemal UV exposures as well as the vitamin D exposures to the human facial region have been investigated. The results gained in this paper, for a clear sky and constant ozone indicate that the sun's capability to promote the development of vitamin D in the human body does not follow the erythemal UV irradiances, in particular at high latitudes. For Amsterdam (52 degrees N) in late winter, approximately 20% more UV is required to produce 215 J m(-2) of vitamin D weighted UV than erythemal UV.

Comparison of biologically damaging spectral solar ultraviolet radiation at a southern hemisphere sub-tropical site.

The first dataset of a complete year of biologically damaging spectral UV at a sub-tropical latitude in the southern hemisphere has been presented. The new data provides a baseline dataset against which comparisons can be made in the future to establish if there have been any long term trends in the biologically damaging UV. The general shape of the variation of the daily biologically damaging exposures through the year depends on the relative response of the various action spectra at the different wavelengths. The ratio of the daily erythemal to actinic exposures drops by approximately 20 to 25% from winter to summer. The ratio of the erythemal to DNA exposures drops by approximately 50% over the same period. In contrast, the ratio of the erythemal to plant damage exposures is higher in summer compared to winter. This is due to the changes in the relative proportion of UVA to UVB wavebands and relative responses of the different action spectra. The relative changes for the different action spectra show that the erythemal action spectrum cannot be used as a proxy for other biologically damaging responses.

Lower body anatomical distribution of solar ultraviolet radiation on the human form in standing and sitting postures.

Humans undertake their daily activities in a number of different postures. This paper aims to compare the anatomical distribution of the solar erythemal UV to human legs for standing and sitting postures. The exposure ratios to the legs (ratio of the UV exposure to a particular anatomical site compared to the ambient) have been measured with UV dosimeters for standing and sitting postures of a manikin. The exposure ratios for the legs ranged from 0 to 0.75 for the different anatomical sites for the sitting posture in summer (December through February) compared to 0.14 to 0.39 for the standing posture. In winter (June through August) the exposure ratios ranged from 0.01 to 0.91 for sitting to 0.17 to 0.81 for standing. For the anterior thigh and shin, the erythemal UV exposures increased by a factor of approximately 3 for sitting compared to standing postures. The exposure ratios to specific anatomical sites have been multiplied by the ambient erythemal UV exposures for each day to calculate the annual exposures. The annual erythemal exposures to the anterior thigh and ankle were predicted to be higher than 800 MED for humans sitting outdoors each day between noon and 13:00 h Australian Eastern Standard Time (EST). For humans standing outdoors during this time, the annual erythemal UV exposure averaged over each leg site was 436 MED, whereas, the averaged annual erythemal UV exposure was 512 MED for the sitting posture. Similarly, the annual erythemal UV exposure averaged over each of the sites was 173 MED for humans standing outdoors between 09:00 h EST and noon each Saturday morning and 205 MED for humans sitting outdoors during this time. These results show that there is increased risk of non-melanoma skin cancer and malignant melanoma to the lower body if no UV preventative strategies are employed while in a sitting posture compared to a standing posture.

Comparison of the solar spectral ultraviolet irradiance in motor vehicles with windows in an open and closed position.

The solar ultraviolet (UV) spectrum was measured by a spectroradiometer located inside two common Australian vehicles: a family wagon and a four-wheel-drive vehicle. The entrance optics of the spectroradiometer was orientated, in turn, on a horizontal plane, towards the driver and passenger windows and towards the windshield. UV spectra were recorded when the vehicles' windows were in an open and closed position. For a typical Australian family wagon, on a horizontal plane inside the vehicle, closing the windows decreased, the total UV irradiance by a factor of 3.2, whilst in a four-wheel drive the irradiance decreased by a factor of 2.1. In order to reduce the likelihood of developing of UV-related eye and skin disorders, drivers should use appropriate UV protection whilst driving a vehicle with the windows in an open position. Results gained from this research provide new findings on the exposure of humans to UV in a vehicle.

Understanding the UVA environment at a sub-tropical site and its consequent impact on human UVA exposure.

Daily UVA and erythemal irradiance data on a horizontal plane at a sub-tropical site were measured during a period from March 2000 to February 2001. On a relative basis, UVA radiation was shown to be a greater concern to human exposure during the winter months than summer months. In summer (December to February), the peak daily UVA exposure was 205 J cm(-2) and in winter (June to August), the minimum daily value was 19 J cm(-2). The peak daily UVery exposure was 37 MED in summer and the winter minimum was 4 MED. The occupational work day UVA exposure to the vertex of the head was estimated using the collected UV data. The outdoor workers received 89% of the available UVA radiation whilst the home workers received 18% of the available ambient UVA radiation. This result parallels the exposure patterns of these two population groups, with the outdoor workers spending most of the working week outdoors, whilst the home workers spend small, intermittent time periods outdoors in the sun.

Usage of real-time ultraviolet radiation data to modify the daily erythemal exposure of primary schoolchildren.

BACKGROUND/AIMS: Primary schoolchildren in their everyday school life are exposed to solar ultraviolet radiation. This may be through time spent outdoors whilst having meal breaks, physical education classes and other class orientated outdoor activities. METHODS: This research investigates the UV exposure of primary schoolchildren and the effect real-time UV irradiances data and an associated software package, UVGUIDE, have on UV exposure. This software utilises scientifically collected data, such as facial distribution of UV, as well as accessing real-time on-line UV irradiances data to estimate the UV distribution to the head region. The students can also enter other parameters such as hat usage and hat type to show the effect of using such a UV protective device on their facial UV distribution. CONCLUSIONS: The results from this study found that the average 3-day erythemal UV exposure in late summer and early autumn to the left shoulder was 33% higher for the students not having access to the on-line UV data and software package.