Periodontal Disease and Other Adverse Health Outcomes Share Risk Factors, including Dietary Factors and Vitamin D Status.

For nearly a century, researchers have associated periodontal disease (PD) with risks of other adverse health outcomes such as cardiovascular disease, diabetes mellitus, and respiratory diseases, as well as adverse pregnancy outcomes. Those findings have led to the hypothesis that PD causes those adverse health outcomes either by increasing systemic inflammation or by the action of periodontopathic bacteria. However, experiments largely failed to support that hypothesis. Instead, the association is casual, not causal, and is due to shared underlying modifiable risk factors, including smoking, diet, obesity, low levels of physical activity, and low vitamin D status. Diabetes mellitus is also considered a risk factor for PD, whereas red and processed meat are the most important dietary risk factors for diabetes. Because PD generally develops before other adverse health outcomes, a diagnosis of PD can alert patients that they could reduce the risk of adverse health outcomes with lifestyle changes. In addition, type 2 diabetes mellitus can often be reversed rapidly by adopting an anti-inflammatory, nonhyperinsulinemic diet that emphasizes healthful, whole plant-based foods. This review describes the evidence that proinflammatory and prohyperinsulinemia diets and low vitamin D status are important risk factors for PD and other adverse health outcomes. We also make recommendations regarding dietary patterns, food groups, and serum 25-hydroxyvitamin D concentrations. Oral health professionals should routinely inform patients with PD that they could reduce their risk of severe PD as well as the risks of many other adverse health outcomes by making appropriate lifestyle changes.

Evidence That Increasing Serum 25(OH)D Concentrations to 30 ng/mL in the Kingdom of Saudi Arabia and the United Arab Emirates Could Greatly Improve Health Outcomes.

Accumulating evidence supports the potential protective effects of vitamin D against chronic diseases such as Alzheimer's disease, autoimmune diseases, cancers, cardiovascular disease (ischaemic heart disease and stroke), type 2 diabetes, hypertension, chronic kidney disease, stroke, and infectious diseases such as acute respiratory tract diseases, COVID-19, influenza, and pneumonia, as well as adverse pregnancy outcomes. The respective evidence is based on ecological and observational studies, randomized controlled trials, mechanistic studies, and Mendelian randomization studies. However, randomized controlled trials on vitamin D supplementation have largely failed to show benefits, probably due to poor design and analysis. In this work, we aim to use the best available evidence on the potential beneficial effects of vitamin D to estimate the expected reduction in incidence and mortality rates of vitamin D-related diseases in the Kingdom of Saudi Arabia and the United Arab Emirates if minimum serum 25(OH)D concentrations were to be raised to 30 ng/mL. Estimated reductions by 25% for myocardial infarction incidence, 35% for stroke incidence, 20 to 35% for cardiovascular disease mortality, and 35% for cancer mortality rates depicted a promising potential for raising serum 25(OH)D. Methods to increase serum 25(OH)D concentrations at the population level could include food fortification with vitamin D3, vitamin D supplementation, improved dietary vitamin D intake, and sensible sun exposure.

Vitamin D deficiency in British South Asians, a persistent but avoidable problem associated with many health risks (including rickets, T2DM, CVD, COVID-19 and pregnancy complications): the case for correcting this deficiency.

High vitamin D deficiency rates, with rickets and osteomalacia, have been common in South Asians (SAs) arriving in Britain since the 1950s with preventable infant deaths from hypocalcaemic status-epilepticus and cardiomyopathy. Vitamin D deficiency increases common SA disorders (type 2 diabetes and cardiovascular disease), recent trials and non-linear Mendelian randomisation studies having shown deficiency to be causal for both disorders. Ethnic minority, obesity, diabetes and social deprivation are recognised COVID-19 risk factors, but vitamin D deficiency is not, despite convincing mechanistic evidence of it. Adjusting analyses for obesity/ethnicity abolishes vitamin D deficiency in COVID-19 risk prediction, but both factors lower serum 25(OH)D specifically. Social deprivation inadequately explains increased ethnic minority COVID-19 risks. SA vitamin D deficiency remains uncorrected after 70 years, official bodies using 'education', 'assimilation' and 'diet' as 'proxies' for ethnic differences and increasing pressures to assimilate. Meanwhile, English rickets was abolished from ~1940 by free 'welfare foods' (meat, milk, eggs, cod liver oil), for all pregnant/nursing mothers and young children (<5 years old). Cod liver oil was withdrawn from antenatal clinics in 1994 (for excessive vitamin A teratogenicity), without alternative provision. The take-up of the 2006 'Healthy-Start' scheme of food-vouchers for low-income families with young children (<3 years old) has been poor, being inaccessible and poorly publicised. COVID-19 pandemic advice for UK adults in 'lockdown' was '400 IU vitamin D/day', inadequate for correcting the deficiency seen winter/summer at 17.5%/5.9% in White, 38.5%/30% in Black and 57.2%/50.8% in SA people in representative UK Biobank subjects when recruited ~14 years ago and remaining similar in 2018. Vitamin D inadequacy worsens many non-skeletal health risks. Not providing vitamin D for preventing SA rickets and osteomalacia continues to be unacceptable, as deficiency-related health risks increase ethnic health disparities, while abolishing vitamin D deficiency would be easier and more cost-effective than correcting any other factor worsening ethnic minority health in Britain.

Comparing the Evidence from Observational Studies and Randomized Controlled Trials for Nonskeletal Health Effects of Vitamin D.

Although observational studies of health outcomes generally suggest beneficial effects with, or following, higher serum 25-hydroxyvitamin D [25(OH)D] concentrations, randomized controlled trials (RCTs) have generally not supported those findings. Here we review results from observational studies and RCTs regarding how vitamin D status affects several nonskeletal health outcomes, including Alzheimer's disease and dementia, autoimmune diseases, cancers, cardiovascular disease, COVID-19, major depressive disorder, type 2 diabetes, arterial hypertension, all-cause mortality, respiratory tract infections, and pregnancy outcomes. We also consider relevant findings from ecological, Mendelian randomization, and mechanistic studies. Although clear discrepancies exist between findings of observational studies and RCTs on vitamin D and human health benefits these findings should be interpreted cautiously. Bias and confounding are seen in observational studies and vitamin D RCTs have several limitations, largely due to being designed like RCTs of therapeutic drugs, thereby neglecting vitamin D's being a nutrient with a unique metabolism that requires specific consideration in trial design. Thus, RCTs of vitamin D can fail for several reasons: few participants' having low baseline 25(OH)D concentrations, relatively small vitamin D doses, participants' having other sources of vitamin D, and results being analyzed without consideration of achieved 25(OH)D concentrations. Vitamin D status and its relevance for health outcomes can usefully be examined using Hill's criteria for causality in a biological system from results of observational and other types of studies before further RCTs are considered and those findings would be useful in developing medical and public health policy, as they were for nonsmoking policies. A promising approach for future RCT design is adjustable vitamin D supplementation based on interval serum 25(OH)D concentrations to achieve target 25(OH)D levels suggested by findings from observational studies.

An Exploration of How Solar Radiation Affects the Seasonal Variation of Human Mortality Rates and the Seasonal Variation in Some Other Common Disorders.

Many diseases have large seasonal variations in which winter overall mortality rates are about 25% higher than in summer in mid-latitude countries, with cardiovascular diseases and respiratory infections and conditions accounting for most of the variation. Cancers, by contrast, do not usually have pronounced seasonal variations in incidence or mortality rates. This narrative review examines the epidemiological evidence for seasonal variations in blood pressure, cardiovascular disease rates and respiratory viral infections in relation to atmospheric temperature and humidity, and solar UV exposure through vitamin D production and increased blood concentrations of nitric oxide. However, additional mechanisms most likely exist by which solar radiation reduces the risk of seasonally varying diseases. Some studies have been reported with respect to temperature without considering solar UV doses, although studies regarding solar UV doses, such as for respiratory infections, often consider whether temperature can affect the findings. More research is indicated to evaluate the relative effects of temperature and sun exposure on the seasonality of mortality rates for several diseases. Since solar ultraviolet-B (UVB) doses decrease to vanishingly small values at higher latitudes in winter, the use of safe UVB lamps for indoor use in winter may warrant consideration.

A Narrative Review of the Evidence for Variations in Serum 25-Hydroxyvitamin D Concentration Thresholds for Optimal Health.

Vitamin D3 has many important health benefits. Unfortunately, these benefits are not widely known among health care personnel and the general public. As a result, most of the world's population has serum 25-hydroxyvitamin D (25(OH)D) concentrations far below optimal values. This narrative review examines the evidence for the major causes of death including cardiovascular disease, hypertension, cancer, type 2 diabetes mellitus, and COVID-19 with regard to sub-optimal 25(OH)D concentrations. Evidence for the beneficial effects comes from a variety of approaches including ecological and observational studies, studies of mechanisms, and Mendelian randomization studies. Although randomized controlled trials (RCTs) are generally considered the strongest form of evidence for pharmaceutical drugs, the study designs and the conduct of RCTs performed for vitamin D have mostly been flawed for the following reasons: they have been based on vitamin D dose rather than on baseline and achieved 25(OH)D concentrations; they have involved participants with 25(OH)D concentrations above the population mean; they have given low vitamin D doses; and they have permitted other sources of vitamin D. Thus, the strongest evidence generally comes from the other types of studies. The general finding is that optimal 25(OH)D concentrations to support health and wellbeing are above 30 ng/mL (75 nmol/L) for cardiovascular disease and all-cause mortality rate, whereas the thresholds for several other outcomes appear to range up to 40 or 50 ng/mL. The most efficient way to achieve these concentrations is through vitamin D supplementation. Although additional studies are warranted, raising serum 25(OH)D concentrations to optimal concentrations will result in a significant reduction in preventable illness and death.

Determinants of circulating 25-hydroxyvitamin D concentration and its association with musculoskeletal health in midlife: Findings from the Hertfordshire Cohort Study.

INTRODUCTION: Several studies have reported the importance of vitamin D status to musculoskeletal health in populations of older adults. Here we report relationships between circulating serum 25(OH)D and musculoskeletal health in a community cohort of UK adults in midlife and investigate whether environmental (dietary intake, use of supplements) and/or genetic factors (4 SNPs previously related to vitamin D status) play more significant roles in determining vitamin D status in this population. METHODS: Participants were recruited from the Hertfordshire Cohort Study, an established longitudinal cohort study of community dwelling adults and were seen at baseline and follow up 9-12 years later. Lumbar spine and total femur BMD were measured at baseline using a Hologic QDR 4500 instrument. Osteoarthritis (OA) was defined by radiographs of the knees graded according to Kellgren & Lawrence at both time points. Serum 25(OH)D concentrations were measured using a DiaSorin Liaison chemiluminescent assay. Genotyping of 4 SNPs previously associated with 25(OH)D values were assessed: (rs12785878 (DHCR7), rs10741657 (CYP2R1) and rs6013897 (CYP24A1)) and a fourth SNP (rs4588), described as "a near-perfect proxy (i.e. substitute) for rs2282679 on the GC gene". RESULTS: 820 subjects (397 men, 423 women) participated at baseline, and 339 of these 820 subjects (164 men; 175 women) participated in a follow up study of OA progression. The median (IQR) age of participants at baseline was 64.0 (61.8-66.5) and 65.5 (63.3-67.6) for men and women respectively. Median circulating levels of 25(OH)D were 44.6 (35.0-63.0) nmol/L and 41.3 (29.8-53.5) nmol/L in men and women respectively. Circulating 25(OH)D was strongly associated with season of blood testing (p < 0.001). The greatest variance in a model of vitamin D status that included the four SNPs measured, season, and whether participants reported taking vitamin D supplements was explained by season of assay (17.9% men; 15.8% women). Higher femoral neck BMD was observed in men with higher baseline vitamin D status, after adjustment for age, season, BMI, smoker status, alcohol consumption, physical activity and social class (p = 0.01). Associations between 25(OH)D and BMD in women were not statistically significant in this population. There were no associations between circulating 25(OH)D and radiographic knee OA at either time point after adjustment for confounders and for duration of follow-up. CONCLUSION: Circulating 25(OH)D levels were generally lower than is recommended in community dwelling adults in midlife, with marked seasonal variation observed, but relationships with reported vitamin D supplementation were weaker. Circulating 25(OH)D was directly associated with hip BMD in men but relationships with BMD in women and radiographic OA were not seen in this sample.

Areca catechu-(Betel-nut)-induced whole transcriptome changes in a human monocyte cell line that may have relevance to diabetes and obesity; a pilot study.

BACKGROUND: Betel-nut consumption is the fourth most common addictive habit globally and there is good evidence linking the habit to obesity, type 2 diabetes (T2D) and the metabolic syndrome. The aim of our pilot study was to identify gene expression relevant to obesity, T2D and the metabolic syndrome using a genome-wide transcriptomic approach in a human monocyte cell line incubated with arecoline and its nitrosated products. RESULTS: The THP1 monocyte cell line was incubated separately with arecoline and 3-methylnitrosaminopropionaldehyde (MNPA) in triplicate for 24 h and pooled cDNA indexed paired-end libraries were sequenced (Illumina NextSeq 500). After incubation with arecoline and MNPA, 15 and 39 genes respectively had significant changes in their expression (q < 0.05, log fold change 1.5). Eighteen of those genes have reported associations with T2D and obesity in humans; of these genes there was most marked evidence for CLEC10A, MAPK8IP1, NEGR1, NQ01 and INHBE genes. CONCLUSIONS: Our preliminary studies have identified a large number of genes relevant to obesity, T2D and metabolic syndrome whose expression was changed significantly in human TPH1 cells following incubation with betel-nut derived arecoline or with MNPA. These findings require validation by further cell-based work and investigation amongst betel-chewing communities.

Why do so many trials of vitamin D supplementation fail?

Our knowledge of vitamin D has come a long way since the 100 years it took for doctors to accept, between 1860 and 1890, that both sunlight and cod liver oil (a well-known folk remedy) cured and prevented rickets. Vitamins D2/D3 were discovered exactly a hundred years ago, and over the last 50 years vitamin D has been found to have many effects on virtually all human tissues and not just on bone health, while mechanisms affecting the actions of vitamin D at the cellular level are increasingly understood, but deficiency persists globally. Observational studies in humans have shown that better provision of vitamin D is strongly associated, dose-wise, with reductions in current and future health risks in line with the known actions of vitamin D. Randomised controlled trials, commonly accepted as providing a 'gold standard' for assessing the efficacy of new forms of treatment, have frequently failed to provide supportive evidence for the expected health benefits of supplementation. Such RCTs, however, have used designs evolved for testing drugs while vitamin D is a nutrient; the appreciation of this difference is critical to identifying health benefits from existing RCT data and for improving future RCT design. This report aims, therefore, to provide a brief overview of the evidence for a range of non-bony health benefits of vitamin D repletion; to discuss specific aspects of vitamin D biology that can confound RCT design and how to allow for them.