Could age increase the strength of inverse association between ultraviolet B exposure and colorectal cancer?

BACKGROUND: Vitamin D has been identified as a potential protective factor in the development of colorectal cancer (CRC). We expect to see a stronger association of ultraviolet B (UVB) exposure and CRC crude rates with increasing age since chronic vitamin D deficiency leads to sustained molecular changes that increase cancer risk. The DINOMIT (disjunction, initiation, natural selection, overgrowth, metastasis, involution, and transition) model postulates various stages of cancer development due to vitamin D deficiency and the associated latency period. The purpose of this study is to examine this age-dependent inverse relationship globally. METHODS: In this ecological study, a series of linear and polynomial regression tests were performed between country-specific UVB estimates adjusted for cloud cover and crude incidence rates of CRC for different age groups. Multiple linear regression was used to investigate the association between crude incidence rates of colorectal cancer and UVB estimate adjusting for urbanization, skin pigmentation, smoking, animal consumption, per capita GDP, and life expectancy. Statistical analysis was followed by geospatial visualization by producing choropleth maps. RESULTS: The inverse relationship between UVB exposure and CRC crude rates was stronger in older age groups at the country level. Quadratic curve fitting was preferred, and these models were statistically significant for all age groups. The inverse association between crude incidence rates of CRC and UVB exposure was statistically significant for age groups above 45 years, after controlling for covariates. CONCLUSION: The age-dependent inverse association between UVB exposure and incidence of colorectal cancer exhibits a greater effect size among older age groups in global analyses. Studying the effect of chronic vitamin D deficiency on colorectal cancer etiology will help in understanding the necessity for population-wide screening programs for vitamin D deficiency, especially in regions with inadequate UVB exposure. Further studies are required to assess the need for adequate public health programs such as selective supplementation and food fortification.

Effect of Vitamin D and Calcium Supplementation on Cancer Incidence in Older Women: A Randomized Clinical Trial.

Importance: Evidence suggests that low vitamin D status may increase the risk of cancer. Objective: To determine if dietary supplementation with vitamin D3 and calcium reduces the risk of cancer among older women. Design, Setting, and Participants: A 4-year, double-blind, placebo-controlled, population-based randomized clinical trial in 31 rural counties (June 24, 2009, to August 26, 2015-the final date of follow-up). A total of 2303 healthy postmenopausal women 55 years or older were randomized, 1156 to the treatment group and 1147 to the placebo group. Duration of treatment was 4 years. Interventions: The treatment group (vitamin D3 + calcium group) received 2000 IU/d of vitamin D3 and 1500 mg/d of calcium; the placebo group received identical placebos. Main Outcomes and Measures: The primary outcome was the incidence of all-type cancer (excluding nonmelanoma skin cancers), which was evaluated using Kaplan-Meier survival analysis and proportional hazards modeling. Results: Among 2303 randomized women (mean age, 65.2 years [SD, 7.0]; mean baseline serum 25-hydroxyvitamin D level, 32.8 ng/mL [SD, 10.5]), 2064 (90%) completed the study. At year 1, serum 25-hydroxyvitamin D levels were 43.9 ng/mL in the vitamin D3 + calcium group and 31.6 ng/mL in the placebo group. A new diagnosis of cancer was confirmed in 109 participants, 45 (3.89%) in the vitamin D3 + calcium group and 64 (5.58%) in the placebo group (difference, 1.69% [95% CI, -0.06% to 3.46%]; P = .06). Kaplan-Meier incidence over 4 years was 0.042 (95% CI, 0.032 to 0.056) in the vitamin D3 + calcium group and 0.060 (95% CI, 0.048 to 0.076) in the placebo group; P = .06. In unadjusted Cox proportional hazards regression, the hazard ratio was 0.70 (95% CI, 0.47 to 1.02). Adverse events potentially related to the study included renal calculi (16 participants in the vitamin D3 + calcium group and 10 in the placebo group), and elevated serum calcium levels (6 in the vitamin D3 + calcium group and 2 in the placebo group). Conclusions and Relevance: Among healthy postmenopausal older women with a mean baseline serum 25-hydroxyvitamin D level of 32.8 ng/mL, supplementation with vitamin D3 and calcium compared with placebo did not result in a significantly lower risk of all-type cancer at 4 years. Further research is necessary to assess the possible role of vitamin D in cancer prevention. Trial Registration: clinicaltrials.gov Identifier: NCT01052051.

25-Hydroxyvitamin D in the range of 20 to 100 ng/mL and incidence of kidney stones.

OBJECTIVES: Increasing 25-hydroxyvitamin D serum levels can prevent a wide range of diseases. There is a concern about increasing kidney stone risk with vitamin D supplementation. We used GrassrootsHealth data to examine the relationship between vitamin D status and kidney stone incidence. METHODS: The study included 2012 participants followed prospectively for a median of 19 months. Thirteen individuals self-reported kidney stones during the study period. Multivariate logistic regression was applied to assess the association between vitamin D status and kidney stones. RESULTS: We found no statistically significant association between serum 25-hydroxyvitamin D and kidney stones (P = .42). Body mass index was significantly associated with kidney stone risk (odds ratio = 3.5; 95% confidence interval = 1.1, 11.3). CONCLUSIONS: We concluded that a serum 25-hydroxyvitamin D level of 20 to 100 nanograms per milliliter has no significant association with kidney stone incidence.

Meta-analysis of all-cause mortality according to serum 25-hydroxyvitamin D.

We examined the relationship between serum 25-hydroxyvitamin D (25[OH]D) and all-cause mortality. We searched biomedical databases for articles that assessed 2 or more categories of 25(OH)D from January 1, 1966, to January 15, 2013. We identified 32 studies and pooled the data. The hazard ratio for all-cause mortality comparing the lowest (0-9 nanograms per milliliter [ng/mL]) to the highest (> 30 ng/mL) category of 25(OH)D was 1.9 (95% confidence interval = 1.6, 2.2; P < .001). Serum 25(OH)D concentrations less than or equal to 30 ng/mL were associated with higher all-cause mortality than concentrations greater than 30 ng/mL (P < .01). Our findings agree with a National Academy of Sciences report, except the cutoff point for all-cause mortality reduction in this analysis was greater than 30 ng/mL rather than greater than 20 ng/mL.

A prospective study of factors affecting recovery from musculoskeletal injuries.

PURPOSE: Research suggests the importance of psychosocial factors in recovery from musculoskeletal injuries. The objective of this study was to identify predictors of recovery among U.S. Marines who had musculoskeletal injuries of the back, knee, or shoulder. METHODS: A sample of 134 participants was assessed at baseline and followed for 1 year to determine outcome information. RESULTS: The strongest predictor of injury recovery at the 1-year follow-up was recovery expectations. In a multivariate logistic model with key demographic and psychosocial factors controlled, individuals who had high recovery expectations at baseline were over five times as likely to be recovered at follow-up as individuals who had low expectations (OR = 5.18, p\.01). CONCLUSIONS: This finding is consistent with a large body of research that has linked recovery expectations with better recovery outcomes in patients with musculoskeletal injuries as well as with research linking recovery expectations with better outcomes across a wide range of medical conditions.Applied to military populations, interventions designed to modify recovery expectations may have the potential to improve rates of return to duty and to reduce rates of disability discharge.

Serum 25-hydroxyvitamin D and breast cancer in the military: a case-control study utilizing pre-diagnostic serum.

PURPOSE: The objective of this study was to ascertain whether a relationship exists between pre-diagnostic serum levels of 25-hydroxyvitamin D (25(OH)D) and risk of breast cancer in young women. METHODS: About 600 incident cases of breast cancer were matched to 600 controls as part of a nested case-control study that utilized pre-diagnostic sera. Logistic regression was used to assess the relationship between serum 25(OH)D concentration and breast cancer risk, controlling for race and age. RESULTS: According to the conditional logistic regression for all subjects, odds ratios for breast cancer by quintile of serum 25(OH)D from lowest to highest were 1.2, 1.0, 0.9, 1.1, and 1.0 (reference) (p trend = 0.72). After multivariate regression for subjects whose blood had been collected within 90 days preceding diagnosis, odds ratios for breast cancer by quintile of serum 25(OH)D from lowest to highest were 3.3, 1.9, 1.7, 2.6, and 1.0 (reference) (p trend = 0.09). CONCLUSIONS: An inverse association between serum 25(OH)D concentration and risk of breast cancer was not present in the principal analysis, although an inverse association was present in a small subgroup analysis of subjects whose blood had been collected within 90 days preceding diagnosis. Further prospective studies of 25(OH)D and breast cancer risk are needed.

Predictors of psychiatric disorders in combat veterans.

BACKGROUND: Most previous research that has examined mental health among Operation Enduring Freedom and Operation Iraqi Freedom (OEF/OIF) combatants has relied on self-report measures to assess mental health outcomes; few studies have examined predictors of actual mental health diagnoses. The objective of this longitudinal investigation was to identify predictors of psychiatric disorders among Marines who deployed to combat in Iraq and Afghanistan. METHODS: The study sample consisted of 1113 Marines who had deployed to Iraq or Afghanistan. Demographic and psychosocial predictor variables from a survey that all Marines in the sample had completed were studied in relation to subsequent psychiatric diagnoses. Univariate and multivariate logistic regression were used to determine the influence of the predictors on the occurrence of psychiatric disorders. RESULTS: In a sample of Marines with no previous psychiatric disorder diagnoses, 18% were diagnosed with a new-onset psychiatric disorder. Adjusting for other variables, the strongest predictors of overall psychiatric disorders were female gender, mild traumatic brain injury symptoms, and satisfaction with leadership. Service members who expressed greater satisfaction with leadership were about half as likely to develop a mental disorder as those who were not satisfied. Unique predictors of specific types of mental disorders were also identified. CONCLUSIONS: Overall, the study's most relevant result was that two potentially modifiable factors, low satisfaction with leadership and low organizational commitment, predicted mental disorder diagnoses in a military sample. Additional research should aim to clarify the nature and impact of these factors on combatant mental health.

Anxiety and depression in Marines sent to war in Iraq and Afghanistan.

Although the effects of combat deployment on posttraumatic stress disorder have been extensively studied, little is known about the effects of combat deployment on depression and anxiety. This study examined the factors associated with anxiety and depression in a sample of 1560 US Marines who were deployed to Iraq and Afghanistan. Eleven demographic and psychosocial factors were studied in relation to depression and anxiety. Five factors emerged as significant in relation to depression: deployment-related stressors, combat exposure, attitudes toward leadership, mild traumatic brain injury symptoms, and marital status. The same factors, with the exception of marital status, emerged as significant in relation to anxiety. Deployment-related stressors had a stronger association with both depression and anxiety than any other variable, including combat exposure. This finding is important because deployment-related stressors are potentially modifiable by the military.

Low ultraviolet B and increased risk of brain cancer: an ecological study of 175 countries.

BACKGROUND: The purpose of this study was to determine whether an inverse association exists between latitude, solar ultraviolet B (UVB) irradiance, modeled 25-hydroxyvitamin D [25(OH)D] levels and incidence rates of cancer of the brain. METHODS: Associations of latitude and UVB irradiance with age-standardized incidence rates of cancer of the brain were analyzed for 175 countries while controlling for proportion of population overweight, energy from animal sources, fish consumption, cigarette and alcohol consumption and per capita health expenditures, using multiple regression. Serum 25(OH)D levels were modeled for each country, and their association with brain cancer also was determined. RESULTS: The incidence rates of brain cancer were higher at higher latitudes (R(2) for males = 0.45, p ≤ 0.0001; R(2) for females = 0.35, p < 0.0001). After adjustment for potential confounders, UVB irradiance (p ≤ 0.0001) and modeled serum 25(OH)D were inversely associated with incidence rates. CONCLUSIONS: Countries with low solar UVB irradiance and estimated mean serum 25(OH)D levels generally had higher age-standardized incidence rates of brain cancer. Since this was an ecological study, further research would be worthwhile on the association of prediagnostic serum 25(OH)D with incidence rate in studies of cohorts of individuals.

Psychiatric diagnoses and punishment for misconduct: the effects of PTSD in combat-deployed Marines.

BACKGROUND: Research on Vietnam veterans suggests an association between psychological problems, including posttraumatic stress disorder (PTSD), and misconduct; however, this has rarely been studied in veterans of Operation Iraqi Freedom or Operation Enduring Freedom. The objective of this study was to investigate whether psychological problems were associated with three types of misconduct outcomes (demotions, drug-related discharges, and punitive discharges.) METHODS: A population-based study was conducted on all U.S. Marines who entered the military between October 1, 2001, and September 30, 2006, and deployed outside of the United States before the end of the study period, September 30, 2007. Demographic, psychiatric, deployment, and personnel information was collected from military records. Cox proportional hazards regression analysis was conducted to investigate associations between the independent variables and the three types of misconduct in war-deployed (n = 77,998) and non-war-deployed (n = 13,944) Marines. RESULTS: Marines in both the war-deployed and non-war-deployed cohorts with a non-PTSD psychiatric diagnosis had an elevated risk for all three misconduct outcomes (hazard ratios ranged from 3.93 to 5.65). PTSD was a significant predictor of drug-related discharges in both the war-deployed and non-war-deployed cohorts. In the war-deployed cohort only, a specific diagnosis of PTSD was associated with an increased risk for both demotions (hazard ratio, 8.60; 95% confidence interval, 6.95 to 10.64) and punitive discharges (HR, 11.06; 95% CI, 8.06 to 15.16). CONCLUSIONS: These results provide evidence of an association between PTSD and behavior problems in Marines deployed to war. Moreover, because misconduct can lead to disqualification for some Veterans Administration benefits, personnel with the most serious manifestations of PTSD may face additional barriers to care.

Psychosocial predictors of military misconduct.

The objective of this longitudinal study was to determine psychosocial predictors of military misconduct in a cohort of Marine Corps war veterans. The study included data from 20,746 male Marines who completed a life history questionnaire during initial basic training and were subsequently deployed to a combat zone. Associations between psychosocial variables, psychiatric diagnoses, and subsequent misconduct outcomes were analyzed using Cox proportional hazards regression. The strongest predictors of misconduct outcomes (bad conduct discharges and military demotions) were psychiatric diagnoses and young age at first combat deployment. The results indicate that combat-related psychological disorders may manifest in numerous harmful ways, including impulsive, disruptive, and antisocial behavior. We recommend that the association between misconduct and psychiatric disorders be more explicitly acknowledged in research and treatment efforts involving military war veterans and other trauma victims.

Correlates of posttraumatic stress disorder symptoms in Marines back from war.

The effect of combat and operational stress on the mental health of military personnel is a major concern. The objective of this study was to identify factors associated with possible posttraumatic stress disorder (PTSD). A questionnaire was completed by 1,569 Marines who deployed in support of conflicts in Iraq and Afghanistan (2002-2007). Using the PTSD Checklist with a cutoff score of 44, 17.1% of the sample screened positive for possible PTSD. Of 9 demographic and psychosocial factors examined in relation to PTSD, 4 were significant in a multivariate analysis: deployment-related stressors, combat exposure, marital status, and education. Deployment-related stressors had a stronger association with PTSD than any other variable. This is an important finding because deployment-related stressors are potentially modifiable.

Factors associated with antisocial behavior in combat veterans.

The objective of this study was to identify factors associated with antisocial behavior in 1,543 Marines who deployed to combat zones in support of conflicts in Iraq and Afghanistan during 2002-2007. Five factors were associated with antisocial behavior in multivariate analyses: post-traumatic stress disorder (PTSD) symptoms, deployment-related stressors, combat exposure, younger age, and being divorced. PTSD symptoms had a stronger association with antisocial behavior than any other variable. A unique and important finding of this study was the association between deployment-related stressors and a higher incidence of antisocial behavior. Because deployment-related stressors are potentially modifiable, the military may be able to address them in concrete ways such as by shortening deployments and improving communication with home.

Insufficient Sun Exposure Has Become a Real Public Health Problem.

This article aims to alert the medical community and public health authorities to accumulating evidence on health benefits from sun exposure, which suggests that insufficient sun exposure is a significant public health problem. Studies in the past decade indicate that insufficient sun exposure may be responsible for 340,000 deaths in the United States and 480,000 deaths in Europe per year, and an increased incidence of breast cancer, colorectal cancer, hypertension, cardiovascular disease, metabolic syndrome, multiple sclerosis, Alzheimer's disease, autism, asthma, type 1 diabetes and myopia. Vitamin D has long been considered the principal mediator of beneficial effects of sun exposure. However, oral vitamin D supplementation has not been convincingly shown to prevent the above conditions; thus, serum 25(OH)D as an indicator of vitamin D status may be a proxy for and not a mediator of beneficial effects of sun exposure. New candidate mechanisms include the release of nitric oxide from the skin and direct effects of ultraviolet radiation (UVR) on peripheral blood cells. Collectively, this evidence indicates it would be wise for people living outside the tropics to ensure they expose their skin sufficiently to the sun. To minimize the harms of excessive sun exposure, great care must be taken to avoid sunburn, and sun exposure during high ambient UVR seasons should be obtained incrementally at not more than 5-30 min a day (depending on skin type and UV index), in season-appropriate clothing and with eyes closed or protected by sunglasses that filter UVR.

Calcium plus vitamin D supplementation and the risk of colorectal cancer.

BACKGROUND: Higher intake of calcium and vitamin D has been associated with a reduced risk of colorectal cancer in epidemiologic studies and polyp recurrence in polyp-prevention trials. However, randomized-trial evidence that calcium with vitamin D supplementation is beneficial in the primary prevention of colorectal cancer is lacking. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 36,282 postmenopausal women from 40 Women's Health Initiative centers: 18,176 women received 500 mg of elemental calcium as calcium carbonate with 200 IU of vitamin D3 [corrected] twice daily (1000 mg of elemental calcium and 400 IU of vitamin D3) and 18,106 received a matching placebo for an average of 7.0 years. The incidence of pathologically confirmed colorectal cancer was the designated secondary outcome. Baseline levels of serum 25-hydroxyvitamin D were assessed in a nested case-control study. RESULTS: The incidence of invasive colorectal cancer did not differ significantly between women assigned to calcium plus vitamin D supplementation and those assigned to placebo (168 and 154 cases; hazard ratio, 1.08; 95 percent confidence interval, 0.86 to 1.34; P=0.51), and the tumor characteristics were similar in the two groups. The frequency of colorectal-cancer screening and abdominal symptoms was similar in the two groups. There were no significant treatment interactions with baseline characteristics. CONCLUSIONS: Daily supplementation of calcium with vitamin D for seven years had no effect on the incidence of colorectal cancer among postmenopausal women. The long latency associated with the development of colorectal cancer, along with the seven-year duration of the trial, may have contributed to this null finding. Ongoing follow-up will assess the longer-term effect of this intervention. (ClinicalTrials.gov number, NCT00000611.).

Commentary. On the epidemiology of influenza: reply to Radonovich et al.

On the epidemiology of influenza: reply to Radonovich LJ, Martinello RA, Hodgson M, Milton DK, Nardell EA. Influenza and ultraviolet germicidal irradiation. Virol J. 2008, 5:149.

Vitamin D and prevention of colorectal adenoma: a meta-analysis.

BACKGROUND: Vitamin D status is associated inversely with risk of colorectal cancer, but the association with adenoma risk is less clear. This meta-analysis examined the overall relationship between circulating (plasma or serum) 25-hydroxyvitamin D [25(OH)D], vitamin D intake (dietary, supplemental, or total), and colorectal adenoma incidence in published studies. METHODS: A meta-analysis composed of 17 epidemiologic studies [1 cross-sectional, 9 case-control, and 7 cohort or nested case-control studies; 7 on 25(OH)D and 12 on vitamin D intake] published before December 2007 was done to examine the association between circulating 25(OH)D, vitamin D intake, and colorectal adenomas. Summary Peto odds ratios (OR) were computed for overall and stratified analyses. RESULTS: Circulating 25(OH)D was inversely associated with risk of colorectal adenomas: the OR was 0.70 [95% confidence interval (95% CI), 0.56-0.87] for high versus low circulating 25(OH)D. The highest quintile of vitamin D intake was associated with an 11% marginally decreased risk of colorectal adenomas compared with low vitamin D intake (OR, 0.89; 95% CI, 0.78-1.02). For recurrent adenomas, there was a decreased risk of 12% (95% CI, 0.72-1.07) among individuals with high versus low vitamin D intake. The inverse associations appeared stronger for advanced adenoma [OR, 0.64; 95% CI, 0.45-0.90 for serum 25(OH)D and OR, 0.77; 95% CI, 0.63-0.95 for vitamin D intake], but the number of studies was small. CONCLUSIONS: Both circulating 25(OH)D and vitamin D intake were inversely associated with colorectal adenoma incidence and recurrent adenomas. These results further support a role of vitamin D in prevention of colorectal adenoma incidence and recurrence.

Conjugated equine estrogens and colorectal cancer incidence and survival: the Women's Health Initiative randomized clinical trial.

BACKGROUND: In separate Women's Health Initiative randomized trials, combined hormone therapy with estrogen plus progestin reduced colorectal cancer incidence but estrogen alone in women with hysterectomy did not. We now analyze features of the colorectal cancers that developed and examine the survival of women following colorectal cancer diagnosis in the latter trial. PARTICIPANTS AND METHODS: 10,739 postmenopausal women who were 50 to 79 years of age and had undergone hysterectomy were randomized to conjugated equine estrogens (0.625 mg/d) or matching placebo. Colorectal cancer incidence was a component of the monitoring global index of the study but was not a primary study endpoint. Colorectal cancers were verified by central medical record and pathology report review. Bowel exam frequency was not protocol defined, but information on their use was collected. RESULTS: After a median 7.1 years, there were 58 invasive colorectal cancers in the hormone group and 53 in the placebo group [hazard ratio, 1.12; 95% confidence interval (95% CI), 0.77-1.63]. Tumor size, stage, and grade were comparable in the two randomization groups. Bowel exam frequency was also comparable in the two groups. The cumulative mortality following colorectal cancer diagnosis among women in the conjugated equine estrogen group was 34% compared with 30% in the placebo group (hazard ratio, 1.34; 95% CI, 0.58-3.19). CONCLUSIONS: In contrast to the preponderance of observational studies, conjugated equine estrogens in a randomized clinical trial did not reduce colorectal cancer incidence nor improve survival after diagnosis.