Association of Arterial Stiffness with Chronic Kidney Disease: A Systematic Review.

INTRODUCTION: Significant kidney function may be lost before CKD is diagnosed. Arterial stiffness may be a risk factor for CKD and the relationship may be bi-directional. A systematic review of cohort studies was undertaken to ascertain the temporal relationship of arterial stiffness and CKD. METHODS: MEDLINE and Embase were searched to 4 October 2023 to identify studies that investigated whether arterial stiffness, as estimated by pulse wave velocity, was predictive of the development or progression of CKD, rapid decline in kidney function, and vice versa. The characteristics and outcomes of the included studies were set out in a qualitative summary. The review protocol is registered with PROSPERO (CRD42019129563). RESULTS: Forty-two studies were included, all of which were high quality with respect to bias. Thirteen of seventeen studies that investigated arterial stiffness as a predictor of incident CKD found a positive association (p < 0.05). Of the 10 studies that controlled for CKD risk factors, 6 found a positive association. Eight of seventeen studies that investigated arterial stiffness as a predictor of progression of CKD, and five out of eight studies, which investigated rapid kidney decline, found a positive association. One study of six found kidney function was able to predict future elevated arterial stiffness. CONCLUSION: Arterial stiffness may predict incident CKD and a rapid decline in CKD. It is uncertain if arterial stiffness is associated with CKD progression or whether reduced kidney function is predictive of increased arterial stiffness. Further longitudinal research is required.

Vitamin D for the management of chronic obstructive pulmonary disease.

BACKGROUND: COPD is a common, preventable and treatable airway disease, and is currently the third leading cause of death worldwide. About one billion people worldwide are estimated to have vitamin D deficiency or insufficiency. Vitamin D deficiency is common among people with COPD, and has been reported to be associated with reduced lung function and increased risk of acute exacerbations of COPD. Several clinical trials of vitamin D to prevent acute exacerbations of chronic obstructive pulmonary disease (AECOPD) and improve COPD control have been conducted, but an up-to-date meta-analysis of all double-blind, randomised, placebo-controlled trials of this intervention is lacking. OBJECTIVES: To assess the effects of vitamin D for the management of acute exacerbations and symptoms for people with COPD. SEARCH METHODS: We searched the Cochrane Airways Trials Register and reference lists of articles. We also searched trial registries directly, and contacted the authors of studies in order to identify additional trials. The date of the last search was 24 August 2022. SELECTION CRITERIA: We included double-blind, randomised, placebo-controlled trials of vitamin D or its hydroxylated metabolites, for adults with a clinical diagnosis of chronic obstructive pulmonary disease based on the presence of characteristic symptoms and irreversible airflow obstruction. We did not impose restrictions regarding disease severity or baseline vitamin D status, in order to maximise generalisability. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. The primary outcome was the rate of moderate or severe exacerbations (requiring systemic corticosteroids, antibiotics or both). We also performed subgroup analyses to determine whether the effect of vitamin D on the rate of moderate or severe exacerbations was modified by baseline vitamin D status, COPD severity or regular inhaled corticosteroid use. The main secondary outcomes of interest were the proportion of participants experiencing one or more exacerbations (moderate or severe), the change in forced expiratory volume in one second (FEV1, % predicted) and the proportion of participants with one or more serious adverse events of any cause, mortality (all-cause) and quality of life. We used GRADE to assess the certainty of evidence for each outcome. MAIN RESULTS: We included 10 double-blind, randomised, placebo-controlled trials in this review, involving a total of 1372 adults. Five studies contributed to the primary outcome analysis of the rate of moderate or severe exacerbations requiring systemic corticosteroids, antibiotics or both. The duration of studies ranged from six weeks to 40 months, and all investigated the effects of administering cholecalciferol (vitamin D3). One study included two intervention arms, one where vitamin D3 was given and one where calcitriol (1,25-dihydroxyvitamin D) was given. The majority of participants had mild to moderate COPD, and profound vitamin D deficiency (25-hydroxyvitamin D (25(OH)D) < 25 nmol/L) at baseline was rare (123 participants contributing data to subgroup analysis). Administration of vitamin D or its hydroxylated metabolites results in little to no change in the overall rate of exacerbations requiring systemic corticosteroids, antibiotics or both (rate ratio (RR) 0.98, 95% CI 0.86 to 1.11; 5 studies, 980 participants; high-certainty evidence). Vitamin D supplementation did not influence any meta-analysed secondary outcomes. These were all based on moderate- or high-certainty evidence aside from adverse events and quality of life, which were based on low-certainty evidence. We observed little to no change in the proportion of participants experiencing one or more moderate or severe exacerbations (odds ratio (OR) 0.94, 95% CI 0.72 to 1.24; 5 studies, 980 participants; high-certainty evidence). Additionally, vitamin D probably results in little to no difference in the inter-arm mean change in FEV1 (% predicted) (mean difference 2.82 higher in intervention arm, 95% CI -2.42 to 8.06; 7 studies, 1063 participants; moderate-certainty evidence). There was also probably no effect of vitamin D on the incidence of serious adverse events due to any cause; although we identified an anticipated absolute effect of 36 additional adverse events per 1000 people, the confidence interval included the null hypothesis of no effect (OR 1.19, 95% CI 0.82 to 1.71; 5 studies, 663 participants; moderate-certainty evidence). Vitamin D may have little to no effect on mortality (OR 1.13, 95% CI 0.57 to 2.21; 6 studies, 1019 participants; low-certainty evidence). It also may have little to no effect on quality of life as measured by validated instruments (narrative findings; 5 studies, 663 participants; low-certainty evidence). We assessed one study as being at high risk of bias in at least one domain; this did not contribute data to the meta-analysis of the primary outcome reported above. Sensitivity analysis that excluded this study from the meta-analysed outcome to which it contributed, the inter-arm mean change in FEV1, did not change the findings. AUTHORS' CONCLUSIONS: We found that administration of vitamin D results in little to no effect on the rate of moderate or severe exacerbations requiring systemic corticosteroids, antibiotics or both or the proportion of participants experiencing one or more exacerbations (moderate or severe) (both high-certainty evidence). Further, vitamin D probably has no effect on the inter-arm difference in change in lung volumes and the proportion of participants with one or more serious adverse event of any cause (both moderate-certainty evidence), and may make little to no difference to mortality or quality of life (both low-certainty evidence). We recommend further research on the balance of benefits and harms of vitamin D supplements in COPD for those with very low or very high starting vitamin D levels, because we assessed the available evidence as low-certainty for these groups.

Effect of Monthly High-Dose Vitamin D Supplementation on Acute Respiratory Infections in Older Adults: A Randomized Controlled Trial.

BACKGROUND: Although adults with low vitamin D status are at increased risk of acute respiratory infection (ARI), randomized controlled trials of vitamin D supplementation have provided inconsistent results. METHODS: We performed a randomized, double-blinded, placebo-controlled trial of 5110 adults aged 50-84 years. In 2011-2012, participants were randomized to an initial oral dose of 200 000 IU vitamin D3 followed by 100 000 IU monthly (n = 2558) or placebo (n = 2552) until late 2013 (median follow-up, 1.6 years). Participants reported upper and lower ARIs on monthly questionnaires. Cox models analyzed time to first ARI (upper or lower) by treatment group. RESULTS: Participants' mean age was 66 years and 58% were male; 83% were of European/other ethnicity, with the rest Maori, Polynesian, or South Asian. Mean (SD) baseline blood 25-hydroxyvitamin D [25(OH)D] level was 63 (24) nmol/L; 25% were <50 nmol/L. In a random sample (n = 441), vitamin D supplementation increased mean 25(OH)D to 135 nmol/L at 3 years, while those on placebo remained at 63 nmol/L. During follow-up, 3737 participants reported ≥1 ARI: 74.1% in the vitamin D group versus 73.7% in the placebo group. The hazard ratio for vitamin D compared with placebo was 1.01 (95% CI, 0.94, 1.07). Similar results were seen in most subgroups, including those with baseline 25(OH)D <50 nmol/L and in analyses of the upper/lower components of the ARI outcome. CONCLUSIONS: Monthly high-dose vitamin D supplementation does not prevent ARI in older adults with a low prevalence of profound vitamin D deficiency at baseline. Whether effects of daily or weekly dosing differ requires further study. CLINICAL TRIALS REGISTRATION: Australian New Zealand Clinical Trials Registry, identifier ACTRN12611000402943.

Evidence of a Bi-Directional Relationship between Arterial Stiffness and Diabetes: A Systematic Review and Meta-Analysis of Cohort Studies.

BACKGROUND: There are numerous cross-sectional studies showing an association between arterial stiffness and diabetes, but the temporality of the association is unclear. OBJECTIVE: To investigate the temporal relationship between arterial stiffness and diabetes. METHODS: We searched MEDLINE and Embase from inception to 31 August 2023, to identify cohort studies that assessed whether arterial stiffness, as measured by pulse wave velocity (PWV), was predictive of the development of diabetes and vice versa. We summarised study data, and where possible undertook meta-analysis. RESULTS: We identified 19 studies that included people with type 1, type 2 and gestational diabetes. All 11 studies investigating arterial stiffness as a predictor of diabetes found a significant relationship. Six of those studies were suitable for meta-analysis. The risk of developing diabetes was greater in people with higher PWV at baseline than lower PWV (RR = 2.14, 95%CI 1.65 to 2.79, p < 0.00001) and the mean difference in baseline PWV was higher in people who developed diabetes than those who did not (mean difference: 0.77 m/s, 95%CI 0.47 to 1.06, p < 0.00001). Of 8 studies investigating diabetes as a predictor of arterial stiffness, 7 found a significant relationship. CONCLUSION: There is evidence of a bidirectional relationship between arterial stiffness and diabetes. Arterial stiffness may provide a causal link between diabetes and future cardiovascular disease.

Arterial stiffness and incident chronic kidney disease: a large population-based cohort study.

BACKGROUND/AIMS: Evidence from large population-based cohorts as to the association of arterial stiffness and incident chronic kidney disease (CKD) is mixed. This large population-based study aimed to investigate whether arterial stiffness, assessed oscillometrically, was associated with incident CKD. METHODS: The study population comprised 4838 participants from the Vitamin D Assessment (ViDA) Study without known CKD (mean ± SD age = 66 ± 8). Arterial stiffness was assessed from 5 April, 2011 to 6 November, 2012 by way of aortic pulse wave velocity, estimated carotid-femoral pulse wave velocity, and aortic pulse pressure. Incident CKD was determined by linkage to national hospital discharge registers. Cox proportional hazards regression was used to assess the risk of CKD in relation to chosen arterial stiffness measures over the continuum and quartiles of values. RESULTS: During a mean ± SD follow-up of 10.5 ± 0.4 years, 376 participants developed incident CKD. Following adjustment for potential confounders, aortic pulse wave velocity (hazard ratio (HR) per SD increase 1.69, 95% CI 1.45-1.97), estimated carotid-femoral pulse wave velocity (HR per SD increase 1.84, 95% CI 1.54-2.19), and aortic pulse pressure (HR per SD increase 1.37, 95% CI 1.22-1.53) were associated with the incidence of CKD. The risk of incident CKD was, compared to the first quartile, higher in the fourth quartile of aortic pulse wave velocity (HR 4.72, 95% CI 2.69-8.27; Ptrend < 0.001), estimated carotid-femoral pulse wave velocity (HR 4.28, 95% CI 2.45-7.50; Ptrend < 0.001) and aortic pulse pressure (HR 2.71, 95% CI 1.88-3.91; Ptrend < 0.001). CONCLUSIONS: Arterial stiffness, as measured by aortic pulse wave velocity, estimated carotid-femoral pulse wave velocity, and aortic pulse pressure may be utilised in clinical practice to help identify people at risk of future CKD. TRIAL REGISTRATION: www.anzctr.org.au identifier:ACTRN12611000402943.

Arterial Stiffness and Incident Glaucoma: A Large Population-Based Cohort Study.

PURPOSE: To investigate whether arterial stiffness, assessed oscillometrically, is associated with incident glaucoma in the Vitamin D Assessment (ViDA) Study cohort, aged 50 to 84 years. DESIGN: Prospective, population-based cohort study. METHODS: Arterial stiffness was assessed in 4,713 participants without known glaucoma (mean ± SD age = 66 ± 8 years) from 5 April 2011 to 6 November 2012 by way of aortic PWV (aPWV), estimated carotid-femoral PWV (ePWV) and aortic PP (aPP). Incident glaucoma was identified through linkage to national prescription and hospital discharge registers. Relative risks of glaucoma for each arterial stiffness measure were estimated by Cox proportional hazards regression, over the continuum of values and by quartiles. RESULTS: During a mean ± SD follow-up of 10.5±0.4 years, 301 participants developed glaucoma. Arterial stiffness, as measured by aPWV (Hazard ratio (HR) per SD increase, 1.36, 95% CI 1.14-1.62) and ePWV (HR per SD increase, 1.40, 95% CI 1.14-1.71) but not aPP (HR per SD increase, 1.06, 95% CI 0.92-1.23) was associated with incident glaucoma. When arterial stiffness was analyzed as a categorical variable, the highest quartiles of aPWV (HR, 2.62, 95% CI 1.52-4.52; Ptrend = .007), ePWV (HR, 2.42, 95%CI 1.37-4.27; Ptrend = .03), and aPP (HR, 1.68, 95%CI 1.10-2.5; Ptrend = .02) were associated with the development of glaucoma. CONCLUSIONS: Arterial stiffness measured with a simple oscillometric device predicted the development of glaucoma and could potentially be used in clinical practice to help identify people at risk of this condition. It may also present a new therapeutic research avenue, including in respect of systemic antihypertensives.

Sizing the association between lifestyle behaviours and fatness in a large, heterogeneous sample of youth of multiple ethnicities from 4 countries.

BACKGROUND: The magnitude of the relationship between lifestyle risk factors for obesity and adiposity is not clear. The aim of this study was to clarify this in order to determine the level of importance of lifestyle factors in obesity aetiology. METHODS: A cross-sectional analysis was carried out on data on youth who were not trying to change weight (n = 5714), aged 12 to 22 years and from 8 ethnic groups living in New Zealand, Australia, Fiji and Tonga. Demographic and lifestyle data were measured by questionnaires. Fatness was measured by body mass index (BMI), BMI z-score and bioimpedance analysis, which was used to estimate percent body fat and total fat mass (TFM). Associations between lifestyle and body composition variables were examined using linear regression and forest plots. RESULTS: TV watching was positively related to fatness in a dose-dependent manner. Strong, dose-dependent associations were observed between fatness and soft drink consumption (positive relationship), breakfast consumption (inverse relationship) and after-school physical activity (inverse relationship). Breakfast consumption-fatness associations varied in size across ethnic groups. Lifestyle risk factors for obesity were associated with percentage differences in body composition variables that were greatest for TFM and smallest for BMI. CONCLUSIONS: Lifestyle factors were most strongly related to TFM, which suggests that studies that use BMI alone to quantify fatness underestimate the full effect of lifestyle on adiposity. This study clarifies the size of lifestyle-fatness relationships observed in previous studies.

Association of arterial stiffness and neuropathy in diabetes: a systematic review and meta-analysis.

Evidence is still emerging on the relationships of arterial stiffness with cardiac autonomic neuropathy (CAN) and peripheral neuropathy (PN). To our knowledge no systematic reviews or meta-analyses of these associations have been published. The purpose of our review was to assess the association of arterial stiffness with each type of neuropathy. Medline and Embase were systematically searched for observational studies of arterial stiffness and neuropathy.The systematic review of 60 studies (25 for CAN and 37 for PN), 59 including people with diabetes, showed arterial stiffness overall was higher in people with neuropathy than people without neuropathy. Forty-three studies were included in the meta-analysis. For CAN (19 studies), arterial stiffness was increased in people with neuropathy compared with without, as measured by pulse wave velocity (PWV) (mean difference: 1.32 m/s, 95% CI 0.82 to 1.81, p<0.00001), pulse pressure (PP) (mean difference: 6.25 mmHg, 95% CI 4.51 to 7.99, p<0.00001) or augmentation index (mean difference: 5.52%, 95% CI 3.46 to 7.58, p<0.0001). For PN (26 studies), arterial stiffness was increased in people with neuropathy compared with those without, as measured by PWV (mean difference: 1.22 m/s, 95% CI 0.87 to 1.58, p<0.00001) or PP (mean difference: 4.59 mmHg, 95% CI 2.96 to 6.22, p<0.00001). Only two cohort studies were located so the temporality of the association between arterial stiffness and neuropathy remains unclear. Increased arterial stiffness is associated with CAN and PN.PROSPERO registration number: CRD42019129563.

Diabetes in the Cook Islands: a clinical audit.

Introduction The global burden of diabetes mellitus (diabetes) is significant and of increasing concern with more pregnant women being diagnosed with gestational diabetes mellitus (GDM). The Cook Islands face mounting pressures to address diabetes alongside competing population health needs and priorities. Cook Islands residents frequently travel to New Zealand to access health services. Inadequate information systems also make it difficult for countries to prioritise preventative measures for investment. In the absence of good data to inform effective diabetes preventative and treatment measures, people with diabetes are likely to progress to complications which will burden society and health systems in the Cook Islands and New Zealand. Aim To determine the prevalence of diabetes and prediabetes, and incidence of GDM, in the Cook Islands. Methods We analysed two Te Marae Ora Cook Islands Ministry of Health datasets, the Non-Communicable Diseases (NCD) register examining demographic data for the period 1967 to December 2018 and same for the GDM register from January 2009 to December 2018. Results Of the 1270 diabetes cases, 53% were female and half were aged 45-64 years. There were 54 pre-diabetes cases and 146 GDM. Of the 20 GDM cases who developed type 2 diabetes, 80% were diagnosed before the age of 40 years. Data quality was poor. Discussion The Cook Islands diabetes registers provide important data to inform priorities for diabetes-related preventative and treatment measures. A data analyst has been employed to ensure quality, regularly audited data and information systems.

Priority Health Needs and Challenges in New Zealand Pacific Communities-A Qualitative Analysis of Healthcare Delivery during the COVID-19 Pandemic.

BACKGROUND: The Pacific community in New Zealand experienced an increased risk of COVID-19 transmission due to delayed contact tracing, along with a disproportionate prevalence of health challenges. The community is representative of a diverse population who proudly identify with the vibrant Pacific Island nations of Samoa, Tonga, Cook Islands, Niue, Fiji, etc. Pacific communities in New Zealand face a higher burden of health challenges compared to other groups. These challenges include obesity, high blood pressure, diabetes, mental health disorders, respiratory issues, smoking, excessive alcohol consumption, disabilities, and chronic conditions. Concerns were raised regarding the oversight of Pacific community views in the initial pandemic response planning. Pacific healthcare professionals expressed concerns about inadequate state support and the need for active involvement in decision making. METHODS: This article reports thematic analyses of text data gained from open-ended questions from a purposive anonymous online survey completed by Pacific healthcare professionals in New Zealand. RESULTS: The participants shared their experiences and opinions, which generated four major themes highlighting priority health needs and challenges. These themes included the necessity for a culturally appropriate healthcare plan, adequate resourcing, addressing discrimination, and emphasising a united and collaborative effort for consistency. The research's limitation is the narrow scope of open-ended questions in the questionnaire survey. However, conducting semi-structured face-to-face interviews can provide more in-depth data and offer further insights beyond the four broad themes identified in the analysis. CONCLUSIONS: The findings can inform the development of future research to provide more in-depth data and offer further insights beyond the four broad themes identified in the analysis. This will help develop future tailored healthcare delivery plans that address specific Pacific community needs.

Serum 25(OH)D Concentration, Vitamin D Supplementation, and Risk of Cardiovascular Disease and Mortality in Patients with Type 2 Diabetes or Prediabetes: a Systematic Review and Dose-Response Meta-Analysis.

BACKGROUND: Evidence is uncertain about the association between serum 25-hydroxyvitamin D (25(OH)D) concentration and health outcomes in people with type 2 diabetes. OBJECTIVES: We aimed to assess the association between vitamin D status and all-cause mortality and cardiovascular disease in people with type 2 diabetes. METHODS: We did a systematic search in PubMed, Scopus, CENTRAL, and Web of Science until May 2022. We selected 1) cohort studies investigating the association between serum 25(OH)D concentration and mortality or cardiovascular disease in people with type 2 diabetes or prediabetes and 2) randomized trials of vitamin D supplementation in these patients. We used random-effects pairwise meta-analyses to calculate summary relative risks (RRs) and 95% confidence intervals (CI). RESULTS: 21 cohort studies and 6 randomized trials were included. Compared with sufficient vitamin D status (≥50 nmol/L), the RR of all-cause mortality was 1.36 (95% CI: 1.23, 1.49; n = 11 studies, GRADE = moderate) for vitamin D insufficiency (25 to <50 nmol/L), and 1.58 (1.33, 1.83; n = 16, GRADE = moderate) for deficiency (<25 nmol/L). Similar findings were observed for cardiovascular mortality and morbidity but not for cancer mortality. The certainty of evidence ranged from very low to moderate. Dose-response meta-analyses indicated nonlinear associations, with the lowest risk at 25(OH)D ∼60 nmol/L for all-cause and cardiovascular mortality. Supplementation with vitamin D did not reduce the risk of all-cause mortality (RR: 0.96, 95% CI: 0.79, 1.16; risk difference per 1000 patients: 3 fewer, 95% CI: 16 fewer, 12 more; n = 6 trials with 7316 participants; GRADE = low) or the risk of cardiovascular mortality and morbidity (very low- to low-certainty evidence). CONCLUSIONS: Vitamin D deficiency and insufficiency are associated with a higher risk of all-cause and cardiovascular mortality in patients with type 2 diabetes or prediabetes. Vitamin D deficiency should be corrected in patients with type 2 diabetes to reach normal serum 25(OH)D concentrations, preferably 60 nmol/L. SYSTEMATIC REVIEW REGISTRATION: This systemic review was registered at PROSPERO as CRD42022326429 (=https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=326429).

Efficacy of vitamin D3 supplementation on cancer mortality: Systematic review and individual patient data meta-analysis of randomised controlled trials.

To evaluate the effect of vitamin D3 supplementation on cancer mortality in the general population and on prognosis in cancer patients, a systematic review and meta-analysis of randomised, placebo-controlled trials (RCTs) and individual patient data (IPD) was conducted. Overall, 14 RCTs with a total of 104,727 participants (2015 cancer deaths) were identified and 7 RCTs, including 90 % of all study participants (n = 94,068), could be included in the IPD meta-analyses. The main meta-analysis of the 14 RCTs yielded a statistically non-significant reduction in cancer mortality by 6 % (risk ratio (RR) [95%-confidence interval (95%CI)]: 0.94 [0.86-1.02]). Subgroup analyses revealed a 12 % lower cancer mortality in the vitamin D3 group compared with the placebo group in 10 trials with a daily dosing regimen (RR [95%CI]: 0.88 [0.78-0.98]), whereas no mortality reduction was seen in 4 trials using a bolus regimen (RR [95%CI]: 1.07 [0.91-1.24]; p-value for interaction: 0.042). The IPD meta-analysis (RR [95%CI]: 0.93 [0.84; 1.02]) confirmed the finding of all trials. The IPD were used to test effect modification by age, sex, body mass index, ethnicity, baseline serum 25-hydroxyvitamin D concentration, adherence and cancer-related factors but no statistically significant findings were obtained in meta-analyses of all trials. When restricted to trials with daily dosing in a post-hoc analysis, adults aged ≥ 70 years (RR [95%CI]: 0.83 [0.77; 0.98]) and subjects with vitamin D3 therapy initiation before cancer diagnosis (RR [95%CI]: 0.87 [0.69; 0.99]) appeared to benefit most from daily vitamin D3 supplementation. Measurements of baseline 25-hydroxyvitamin D levels and inclusion of other than non-Hispanic White adults were too sparse in the trials to draw conclusions. Results for all-cause and cancer-specific survival of participants with cancer were comparable to those obtained in the general population for cancer mortality. In conclusion, vitamin D3 did not reduce cancer mortality in the main meta-analysis of all RCTs because the observed risk reduction by 6 % was not statistically significant. However, a subgroup analysis revealed that vitamin D3 administered daily, in contrast to bolus supplementation, reduced cancer mortality by 12 %.

Identifying metabolic syndrome in migrant Asian Indian adults with anthropometric and visceral fat action points.

BACKGROUND: Metabolic syndrome (MetS) is a clustering of metabolic risk factors, including large waist circumference (WC). Other anthropometric parameters and visceral fat mass (VFM) predicted from these may improve MetS detection. Our aim was to assess the ability of such parameters to predict this clustering in a cross-sectional, diagnostic study. METHOD: Participants were 82 males and 86 females, aged 20-74 years, of Asian Indian ethnicity. VFM was estimated by dual-energy X-ray absorptiometry (DXA) through identification of abdominal subcutaneous fat layer boundaries. Non-anthropometric metabolic risk factors (triglycerides, HDL cholesterol, blood pressure and glucose) were defined using MetS criteria. We estimated the ability of anthropometry and VFM to detect ≥ 2 of these factors by receiver operating characteristic (ROC) and precision-recall curves. RESULTS: Two or more non-anthropometric metabolic risk factors were present in 45 (55%) males and 29 (34%) females. The area under the ROC curve (AUC) to predict ≥ 2 of these factors using WC was 0.67 (95% confidence interval: 0.55-0.79) in males and 0.65 (0.53-0.77) in females. Optimal WC cut-points were 92 cm for males (63% accuracy) and 79 cm for females (53% accuracy). VFM, DXA-measured sagittal diameter and suprailiac skinfold thickness yielded higher AUC point estimates (by up to 0.06), especially in females where these measures improved accuracy to 69%, 69% and 65%, respectively. Pairwise combinations that included WC further improved accuracy. CONCLUSION: Our findings indicate that cut-points for readily obtained measures other than WC, or in combination with WC, may provide improved detection of MetS risk factor clusters.

Prediction of Vitamin D Deficiency in Older Adults: The Role of Machine Learning Models.

CONTEXT: Conventional prediction models for vitamin D deficiency have limited accuracy. BACKGROUND: Using cross-sectional data, we developed models based on machine learning (ML) and compared their performance with those based on a conventional approach. METHODS: Participants were 5106 community-resident adults (50-84 years; 58% male). In the randomly sampled training set (65%), we constructed 5 ML models: lasso regression, elastic net regression, random forest, gradient boosted decision tree, and dense neural network. The reference model was a logistic regression model. Outcomes were deseasonalized serum 25-hydroxyvitamin D (25(OH)D) <50 nmol/L (yes/no) and <25 nmol/L (yes/no). In the test set (the remaining 35%), we evaluated predictive performance of each model, including area under the receiver operating characteristic curve (AUC) and net benefit (decision curves). RESULTS: Overall, 1270 (25%) and 91 (2%) had 25(OH)D <50 and <25 nmol/L, respectively. Compared with the reference model, the ML models predicted 25(OH)D <50 nmol/L with similar accuracy. However, for prediction of 25(OH)D <25 nmol/L, all ML models had higher AUC point estimates than the reference model by up to 0.14. AUC was highest for elastic net regression (0.93; 95% CI 0.90-0.96), compared with 0.81 (95% CI 0.71-0.91) for the reference model. In the decision curve analysis, ML models mostly achieved a greater net benefit across a range of thresholds. CONCLUSION: Compared with conventional models, ML models predicted 25(OH)D <50 nmol/L with similar accuracy but they predicted 25(OH)D <25 nmol/L with greater accuracy. The latter finding suggests a role for ML models in participant selection for vitamin D supplement trials.

Genetic control of serum 25(OH)D levels and its association with ethnicity.

BACKGROUND: Identified DNA variants associated with serum 25-hydroxyvitamin vitamin D (25[OH]D) concentration may provide mechanistic insights into the vitamin D metabolic pathway in individuals. Our aim was to further characterise participants and their serum 25(OH)D concentration at baseline using candidate single nucleotide polymorphism (SNP) genotyping. METHODS: 5110 participants, aged 50-84 years, were recruited from the community. Blood samples were collected at baseline to measure serum 25(OH)D by liquid chromatography mass spectrometry and the participants were genotyped for four markers close to or within genes in the vitamin D metabolic pathway known to be associated with differences in 25(OH)D. The markers and their associated genes were rs12785878 (DHCR7), rs10741657 (CYP2R1), rs4588 (DBP) and rs2228570 (VDR). RESULTS: All four markers had significantly different genotype distributions and minor allele frequencies between the four self-determined ethnicities (European/Other, Maori, Pacific, and South Asian). For example, the frequency in each ethnic group of the G allele for the marker rs12785878 was 0.26, 0.71, 0.89, and 0.78 respectively. Using multivariable regression in the full cohort, three out of four markers were significantly associated with baseline concentrations of 25(OH)D (mean differences: 2.9-10.9 nmol/L). Collectively, the four markers explained 8.4% of the variation in 25(OH)D concentrations. CONCLUSION: Significant ethnic variations exist in the distribution of alleles associated with serum 25(OH)D concentration, particularly rs12785878, in a multi-ethnic community sample from New Zealand.

Effect of monthly vitamin D supplementation on cardiac biomarkers: A post-hoc analysis of a randomized controlled trial.

The effects of vitamin D supplementation on cardiovascular diseases are controversial. Data on effects of vitamin D upon cardiac biomarkers, as surrogate endpoints of cardiovascular diseases, are limited and inconclusive. Therefore, we carried out a post-hoc analysis of sub-samples of a randomized, double-blinded, placebo-controlled trial with community-based older adults who were randomized to receive monthly 100,000-IU vitamin D or placebo, to determine effect of monthly vitamin D supplementation on high-sensitivity cardiac troponin I (hs-cTnI), troponin T (hs-cTnT) and N-terminal-pro-B-type natriuretic peptide (NT-proBNP). Adjusted relative difference (aRD) of follow-up geometric mean of biomarkers and adjusted relative risk (aRR) of elevated biomarkers between two groups were calculated. A total of 779 participants aged 50-84 y, randomized to vitamin D (n = 395) or placebo (n = 384) groups underwent sampling for measurement of plasma biomarkers at baseline and after one or two years treatment. Over a mean follow-up of 1.6 years, we did not find significant relative difference of geometric mean levels of three biomarkers at follow-up between vitamin D and placebo groups: hs-cTnI (aRD=1.03, 95%CI=0.97-1.09), hs-cTnT (aRD=0.99, 95%CI=0.95-1.04), and NT-proBNP (aRD=1.01, 95%CI=0.92-1.10). No significant differences were found in likelihood of clinically elevated biomarkers between two groups: hs-cTnI (aRR=0.92, 95%CI=0.51-1.69), hs-cTnT (aRR=1.11, 95%CI=0.86-1.42), and NT-proBNP (aRR=1.03,95%CI=0.89-1.20). However, among participants with initial low vitamin D status (<50 nmol/L, n = 200), follow-up NT-proBNP were significantly lower in the vitamin D group compared to placebo (geometric mean 75.9 vs 94.5 pg/mL, respectively; aRD=0.84, 95%CI=0.71-<1.00). The same results were observed for the NT-proBNP levels change from baseline between two groups. Overall, in older adults, monthly vitamin D supplementation did not reduce concentrations of hs-cTnI, hs-cTnT, and NT-proBNP. In those with low vitamin D status, vitamin D treatment was associated, on follow up and change from baseline, with lower plasma NT-proBNP compared with placebo. This potentially signals reduced risk of subsequent heart failure within this sub-group. However, we acknowledge that these findings need to be considered exploratory. Further research is required to replicate them.

Circulating cardiac biomarkers improve risk stratification for incident cardiovascular disease in community dwelling populations.

BACKGROUND: Plasma cardiac markers may assist in prediction of incident cardiovascular disease. METHODS: The incremental value of cardiac Troponins (T and I) and NT-proBNP added to risk factors in the PREDICT score for incident cardiovascular disease (CVD) in primary care, was assessed in 4102 asymptomatic participants in a randomised controlled trial of Vitamin D (ViDA). Findings were corroborated in 2528 participants in a separate community-based observational registry of CVD-free volunteers (HVOLS). FINDINGS: Hazard ratios for first cardiovascular events adjusted for PREDICT risk factors, comparing fifth to first quintiles of marker plasma concentrations, were 2.57 (95% CI 1.47-4.49); 3.01 (1.66-5.48) and 3.38 (2.04-5.60) for hs-cTnI, hs-cTnT and NT-proBNP respectively. The C statistic for discrimination of the primary endpoint increased from 0.755 to 0.771 (+0.016, p = 0.01). Cardiac marker data correctly reclassified risk upwards in 6.7% of patients and downwards in 3.3%. These findings were corroborated by results from HVOLS. INTERPRETATION: Increments in plasma cardiac biomarkers robustly and reproducibly predicted increased hazard of incident CVD, independent of established risk factors, in two community-dwelling populations. Cardiac markers may augment risk assessment for onset of CVD in primary care. FUNDING: ViDA was funded by the Health Research Council of New Zealand (grant 10/400) and the Accident Compensation Corporation. HVOLS was funded by the Health Research Council of NZ Programme Grants (grants 02/152 and 08/070) and by grants from the Heart Foundation of NZ and the Christchurch Heart Institute Trust. Roche Diagnostics provided in-kind support for NT-proBNP and hs-cTnT assays and Abbott Laboratories for hs-cTnI assays.

Is There Proof of Extraskeletal Benefits From Vitamin D Supplementation From Recent Mega Trials of Vitamin D?

Scientific interest in possible extraskeletal effects of vitamin D first appeared in the 1930s soon after the structure of vitamin D was characterized, and increased in the 1980s with the development of assays of 25-hydroxyvitamin D status as a marker of vitamin D status, which in observational epidemiological studies was shown to be inversely associated with many nonskeletal diseases. This resulted in the start of seven large randomized controlled trials (n > 2000 participants in each) of vitamin D supplementation giving higher doses than previously used. The intervention periods in these trials collectively started in 2009 and continued to 2020. They have recruited participants, mostly of both sexes and over the age of 50 years, from many countries and have given either daily or monthly doses of vitamin D. Collectively, the trials have a wide range of outcomes with the main focus on the prevention of cancer, cardiovascular disease, and fractures, besides many other outcomes. The findings of four trials have been published, and they have shown that vitamin D supplementation does not prevent hard-disease endpoints, such as cardiovascular disease, cancer, fractures, or falls, aside from a possible beneficial effect against cancer mortality. In contrast, beneficial effects were seen for intermediate outcomes such as BMD of spine and hips, arterial function, and lung function, especially in people with vitamin D deficiency. The finding of a benefit primarily in people with vitamin D deficiency, if confirmed by the other trials, would support a population approach to preventing vitamin D deficiency using fortification rather than the high-risk approach of screening for deficiency combined with supplementation. The findings on other outcomes from the three published trials, along with the findings from the four unpublished trials, are expected within the next 2 to 3 years to clarify the role of vitamin D supplementation in preventing nonskeletal disease. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Vitamin D and Clinical Cancer Outcomes: A Review of Meta-Analyses.

The relationship between vitamin D status or supplementation and cancer outcomes has been examined in several meta-analyses. To address remaining knowledge gaps, we conducted a systematic overview and critical appraisal of pertinent meta-analyses. For meta-analyses of trials, we assessed their quality using AMSTAR-2 (A Measurement Tool to Assess Systematic Reviews), strength of associations using umbrella review methodology and credibility of evidence using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) criteria. Meta-analyses of observational studies reported inverse associations of 25OHD with risk of cancer incidence and cancer mortality and, particularly for colorectal cancer, fulfilled some of Bradford-Hill's causation criteria. In meta-analyses of trials, vitamin D supplementation did not affect cancer incidence. However, we found credible evidence that vitamin D supplementation reduced total cancer mortality risk, with five out of six meta-analyses reporting a relative risk (RR) reduction of up to 16%: RR, 0.84 (95% CI, 0.74-0.95). The strength of the association, however, was classified as weak. This was true among meta-analyses of high, moderate, and lower quality (AMSTAR-2-rated). Trials did not include large numbers of vitamin D-deficient participants; many tested relatively low doses and lacked sufficiently powered data on site-specific cancers. In conclusion, meta-analyses show that, although observational evidence indicates that low vitamin D status is associated with a higher risk of cancer outcomes, randomized trials show that vitamin D supplementation reduces total cancer mortality, but not cancer incidence. However, trials with larger proportions of vitamin D-insufficient participants and longer durations of follow-up, plus adequately powered data on site-specific common cancers, would provide further insight into the evidence base. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Atrial fibrillation detection in primary care during blood pressure measurements and using a smartphone cardiac monitor.

Improved atrial fibrillation (AF) screening methods are required. We detected AF with pulse rate variability (PRV) parameters using a blood pressure device (BP+; Uscom, Sydney, Australia) and with a Kardia Mobile Cardiac Monitor (KMCM; AliveCor, Mountain View, CA). In 421 primary care patients (mean (range) age: 72 (31-99) years), we diagnosed AF (n = 133) from 12-lead electrocardiogram recordings, and performed PRV and KMCM measurements. PRV parameters detected AF with area under curve (AUC) values of up to 0.92. Using the mean of two sequential readings increased AUC to up to 0.94 and improved positive predictive value at a given sensitivity (by up to 18%). The KMCM detected AF with 83% sensitivity and 68% specificity. 89 KMCM recordings were "unclassified" or blank, and PRV detected AF in these with AUC values of up to 0.88. When non-AF arrhythmias (n = 56) were excluded, the KMCM device had increased specificity (73%) and PRV had higher discrimination performance (maximum AUC = 0.96). In decision curve analysis, all PRV parameters consistently achieved a positive net benefit across the range of clinical thresholds. In primary care, AF can be detected by PRV accurately and by KMCM, especially in the absence of non-AF arrhythmias or when combinations of measurements are used.