Increased risk of cardiovascular and renal disease, and diabetes for all women diagnosed with gestational diabetes mellitus in New Zealand-A national retrospective cohort study.

BACKGROUND: Gestational diabetes mellitus increases the risk of developing type 2 diabetes. The aim of this study is to compare cardiometabolic and renal outcomes for all women in New Zealand with gestational diabetes (2001-2010) with women without diabetes, 10-20 years following delivery. METHODS: A retrospective cohort study, utilizing a national dataset providing information for all women who gave birth between 1 January 2001 and 31 December 2010 (n = 604 398). Adolescent girls <15 years, women ≥50 years and women with prepregnancy diabetes were excluded. In total 11 459 women were diagnosed with gestational diabetes and 11 447 were matched (for age and year of delivery) with 57 235 unexposed (control) women. A national hospital dataset was used to compare primary outcomes until 31 May 2021. RESULTS: After controlling for ethnicity, women with gestational diabetes were significantly more likely than control women to develop diabetes-adjusted hazard ratio (HR) 20.06 and 95% confidence interval (CI) 18.46-21.79; a first cardiovascular event 2.19 (1.86-2.58); renal disease 6.34 (5.35-7.51) and all-cause mortality 1.55 (1.31-1.83), all p values <.0001. The HR and 95% CI remained similar after controlling for significant covariates: diabetes 18.89 (17.36-20.56), cardiovascular events 1.79 (1.52-2.12), renal disease 5.42 (4.55-6.45), and all-cause mortality 1.44 (1.21-1.70). When time-dependent diabetes was added to the model, significance remained for cardiovascular events 1.33 (1.10-1.61), p = .003 and renal disease 2.33 (1.88-2.88), p < .0001 but not all-cause mortality. CONCLUSIONS: Women diagnosed with gestational diabetes have an increased risk of adverse cardiometabolic and renal outcomes. Findings highlight the importance of follow-up screening for diabetes, cardiovascular risk factors, and renal disease.

Trends in the primary healthcare nursing workforce in managing diabetes from two sample surveys in 2006-2008 and 2016 in Auckland, New Zealand.

AIM: To examine trends in the primary healthcare nursing workforce and their community management of diabetes. METHOD: Two representative surveys were carried out in 2006-2008 and 2016 among all primary healthcare nurses in Auckland. Nurses were randomly selected, and 26% (n=287) and 24% (n=336) completed a self-administered questionnaire and telephone survey. Biographical information, knowledge of diabetes, how valued nurses felt and diabetes care for patients was provided. RESULTS: Between surveys, numbers of practice nurses have significantly increased, and specialist nurse numbers decreased, while district nurse numbers remained the same. In 2016, practice nurses were younger, more ethnically diverse, more likely to undertake education and had increased knowledge of diabetes and diabetes-related complications (including stroke) compared to nurses in 2006-2008. More nurses consulted patients, conducted foot examinations, addressed serum glucose, medication management, tobacco use and followed up care independently of doctors. In 2016, only 37% of nurses felt sufficiently knowledgeable to discuss medications with patients, <20% could state that hypertension, smoking and dyslipidaemia were major risk factors for complications, and less nurses felt valued. CONCLUSION: Practice nurses have increased their capacity in diabetes management following global trends and require more support in meeting the complex healthcare needs of people with diabetes.

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 %.

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.

Metabolic syndrome severity score (MetSSS) associates with metabolic health status in multi-ethnic Aotearoa New Zealand cohorts.

AIM: To investigate the relationship of metabolic syndrome severity score (MetSSS) with glucose regulatory and cardiovascular disease (CVD) status in Aotearoa New Zealand. METHODS: MetSSS and MetSSS component coefficients were calculated for participants from the cross-sectional Workforce Diabetes Study (WDS) (n = 5,806) and Diabetes, Heart and Health Survey (DHAH) (n = 4,010) and compared by ethnicity (European, Maori, Pacific and Asian), glucose regulatory status [impaired fasting glucose, impaired glucose tolerance and type 2 diabetes) and history of cardiovascular disease. RESULTS: MetSSS positively associated with impaired glucose regulatory status and history of cardiovascular disease for all ethnic groups. Ethnicity significantly affected different coefficients of the MetSSS components, however all ethnicities had an approximately normal MetSSS distribution, with Maori and Pacific curves being right-shifted compared to European. While the MetSSS thresholds that capture 80% of participant with type 2 diabetes (T2D) were higher for Maori and Pacific, the difference in MetSSS between those participants with and without type 2 diabetes within an ethnicity group was similar across ethnicities. CONCLUSION: MetSSS may have utility as a tool to quantify an individual's cardiometabolic disease risk within the multi-ethnic population of Aotearoa New Zealand, however ethnic-specific categories for disease risk are likely to be required.

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.

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.

Factors associated with self-reported sun exposure in a multi-ethnic community sample from New Zealand.

Sun exposure, the main source of vitamin D, may have beneficial effects in humans, including for cardiovascular health. However, little is known about the characteristics related to sun exposure. Previous studies have surveyed participants with a demographic profile that is restricted by sex and ethnicity. We carried out an analysis to identify factors associated with self-reported sun exposure in a large multi-ethnic study of men and women. The study was a cross-sectional analysis of baseline data collected in a large vitamin D supplementation randomized controlled trial. The weekly amount of sun exposure in the past three months was assessed using a questionnaire. Multivariable prevalence ratios (PR) of high sun exposure (≥ 15 h/ week) associated with demographic and lifestyle variables were calculated using Poisson regression to adjust for covariates. A P-value of < 0.05 (2-tail) was used to determine statistical significance. A total of 5039 participants aged 50-84 years were analysed, who comprised 330 Pacific Islanders, 267 Maori, 242 South Asian and 4200 Other ethnicities (mostly European ancestry). For demographic variables, high sun exposure was associated with sex (higher in males), ethnicity (highest in Maori, lowest in South Asian), and education (highest in those completing secondary level education), but was lowest in the oldest age-group (80-84 years). For lifestyle variables, high sun exposure was associated with higher levels of alcohol drinking, TV watching and physical activity, but was not associated with tobacco smoking. Weekly sun exposure was lower in participants who were overweight or obese (compared to those with normal body mass index), and in those who reported a skin reaction to sun exposure of burning only (compared to those who reported tanning). These associations remained when all variables were included in the same model. In conclusion, several demographic and lifestyle factors were associated independently with the sun exposure, the primary source of vitamin D. Understanding how these factors are associated with sun exposure may refine strategies to minimise vitamin D deficiency.

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.

Nurse's contribution to the diabetes annual review and funded programmes in Auckland, New Zealand.

AIMS: Examine trends in nurse's contribution to diabetes funded programmes,estimate total nurse consultations, and document the division of diabetes care between doctors and nurses in general practice. METHODS: All primary health care nurses in Auckland were identified in 2006-8 and 2016 and 26% and 24% were randomly surveyed, achieving response rates of 86%and 73%, respectively. Participants completed a self-administered and telephone questionnaire detailing their contribution to diabetes funded programmes. RESULTS: In response to more people with diabetes, significantly more nurses in 2016 consulted patients, provided follow-up care, completed Diabetes Annual Reviews independently of doctors (48%), accessed more educational resources (including theinternet) and 63% felt supported, compared with 27% and 55% of nurses respectively,in 2006-8. The main reason nurses surveyed did not participate in diabetes reviews was because designated nurses conducted them, with more reporting this in 2016 (55%) compared to 32% in 2006-8. Most nurses in the 2016 survey addressed cardiovascular risk such as blood pressure, smoking cessation, physical activity and nutrition during the review. CONCLUSIONS: Nurses conducted more diabetes consultations and reviews, addressed cardiovascular risk in 2016 and reported increased support for participating in diabetes reviews within general practice, compared with nurses in 2006-8.

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.

Trends in diabetes care and education by primary health care nurses in Auckland, New Zealand.

AIMS: To examine trends in the management of patients with diabetes by primary health care nurses, its association with diabetes education and how valued and supported nurses feel in Auckland, New Zealand. METHODS: Two representative cross-sectional surveys of all nurses providing community-based care, and patients with diabetes they consult, were conducted in 2006-8 and 2016. All participants completed a self-administered questionnaire on biographical details and a telephone interview on their provision of diabetes care. RESULTS: Significantly more nurses discussed serum glucose and medications with patients, planned follow-up and scheduled practice nurse appointments in 2016 compared with 2006-8, and fewer specialist diabetologist appointments were made (12% versus 2%). Fewer nurses in 2016 than in 2006-8 felt valued (62% versus 75%) and supported (78% versus 89%) when managing patients (p-values = 0.0004). Nurses diabetes education was associated with recommended practice and feeling valued. Significantly more patients were prescribed metformin (81%) and insulin (46%) in 2016 compared with 58% and 30% in 2006-8. Despite this, HbA1c levels remained unchanged. CONCLUSIONS: Prescribed glycaemic-related medications increased, and more nurses engaged with patients about glycaemic control and medications in 2016 compared with 2006-8. Nurses undertaking diabetes education was strongly associated with best management practices and nurses feeling valued.

Vitamin D supplementation to prevent acute respiratory infections: a systematic review and meta-analysis of aggregate data from randomised controlled trials.

BACKGROUND: A 2017 meta-analysis of data from 25 randomised controlled trials (RCTs) of vitamin D supplementation for the prevention of acute respiratory infections (ARIs) revealed a protective effect of this intervention. We aimed to examine the link between vitamin D supplementation and prevention of ARIs in an updated meta-analysis. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, and the ClinicalTrials.gov registry for studies listed from database inception to May 1, 2020. Double-blind RCTs of vitamin D3, vitamin D2, or 25-hydroxyvitamin D (25[OH]D) supplementation for any duration, with a placebo or low-dose vitamin D control, were eligible if they had been approved by a research ethics committee, and if ARI incidence was collected prospectively and prespecified as an efficacy outcome. Studies reporting results of long-term follow-up of primary RCTs were excluded. Aggregated study-level data, stratified by baseline 25(OH)D concentration and age, were obtained from study authors. Using the proportion of participants in each trial who had one or more ARIs, we did a random-effects meta-analysis to obtain pooled odds ratios (ORs) and 95% CIs to estimate the effect of vitamin D supplementation on the risk of having one or more ARIs (primary outcome) compared with placebo. Subgroup analyses were done to estimate whether the effects of vitamin D supplementation on the risk of ARI varied according to baseline 25(OH)D concentration (<25 nmol/L vs 25·0-49·9 nmol/L vs 50·0-74·9 nmol/L vs >75·0 nmol/L), vitamin D dose (daily equivalent of <400 international units [IU] vs 400-1000 IU vs 1001-2000 IU vs >2000 IU), dosing frequency (daily vs weekly vs once per month to once every 3 months), trial duration (≤12 months vs >12 months), age at enrolment (<1·00 years vs 1·00-15·99 years vs 16·00-64·99 years vs ≥65·00 years), and presence versus absence of airway disease (ie, asthma only, COPD only, or unrestricted). Risk of bias was assessed with the Cochrane Collaboration Risk of Bias Tool. The study was registered with PROSPERO, CRD42020190633. FINDINGS: We identified 1528 articles, of which 46 RCTs (75 541 participants) were eligible. Data for the primary outcome were obtained for 48 488 (98·1%) of 49 419 participants (aged 0-95 years) in 43 studies. A significantly lower proportion of participants in the vitamin D supplementation group had one or more ARIs (14 332 [61·3%] of 23 364 participants) than in the placebo group (14 217 [62·3%] of 22 802 participants), with an OR of 0·92 (95% CI 0·86-0·99; 37 studies; I2=35·6%, pheterogeneity=0·018). No significant effect of vitamin D supplementation on the risk of having one or more ARIs was observed for any of the subgroups defined by baseline 25(OH)D concentration. However, protective effects of supplementation were observed in trials in which vitamin D was given in a daily dosing regimen (OR 0·78 [95% CI 0·65-0·94]; 19 studies; I2=53·5%, pheterogeneity=0·003), at daily dose equivalents of 400-1000 IU (0·70 [0·55-0·89]; ten studies; I2=31·2%, pheterogeneity=0·16), for a duration of 12 months or less (0·82 [0·72-0·93]; 29 studies; I2=38·1%, pheterogeneity=0·021), and to participants aged 1·00-15·99 years at enrolment (0·71 [0·57-0·90]; 15 studies; I2=46·0%, pheterogeneity=0·027). No significant interaction between allocation to the vitamin D supplementation group versus the placebo group and dose, dose frequency, study duration, or age was observed. In addition, no significant difference in the proportion of participants who had at least one serious adverse event in the vitamin supplementation group compared with the placebo group was observed (0·97 [0·86-1·07]; 36 studies; I2=0·0%, pheterogeneity=0·99). Risk of bias within individual studies was assessed as being low for all but three trials. INTERPRETATION: Despite evidence of significant heterogeneity across trials, vitamin D supplementation was safe and overall reduced the risk of ARI compared with placebo, although the risk reduction was small. Protection was associated with administration of daily doses of 400-1000 IU for up to 12 months, and age at enrolment of 1·00-15·99 years. The relevance of these findings to COVID-19 is not known and requires further investigation. FUNDING: None.

Effect of monthly vitamin D supplementation on antibiotic prescribing in older adults: a post hoc analysis of a randomized controlled trial.

BACKGROUND: Observational studies have reported that low vitamin D status is associated with increased risk of antibiotic use. However, trials on the effect of vitamin D supplementation on antibiotics are limited and inconclusive. OBJECTIVES: The main objective of this study was to determine the effect of monthly vitamin D supplementation on the proportion of adults with ≥1 prescriptions of antibiotics. The secondary outcomes were to determine the effect of monthly vitamin D supplementation on the number of antibiotic prescriptions and the number of days on antibiotics. METHODS: This was a post hoc analysis of a randomized, double-blinded, placebo-controlled trial with community-based older adults who were randomly assigned to receive monthly 100,000 IU of vitamin D or identical placebo. All analyses were based on the principle of "intention to treat." RR from log-binomial models and the incidence rate ratio (IRR) from negative binomial models were estimated for primary and secondary outcomes after adjusting for age, sex, and ethnicity. RESULTS: A total of 5108 participants aged 50-84 y were randomly assigned to vitamin D supplementation (n = 2558) or placebo (n = 2550) groups. During a median follow-up of 3.3 y, 4211 (82%) participants were prescribed antibiotics. There was no difference in the proportion of participants prescribed antibiotics between vitamin D (82%) and placebo (83%) groups (adjusted RR: 0.99; 95% CI: 0.97, 1.01; P = 0.42). Similarly, the number of antibiotic prescriptions per person-year did not differ between the 2 treatment groups (adjusted IRR: 0.98; 95% CI: 0.93, 1.04; P = 0.58). However, the number of days on antibiotics per person-year was significantly lower in the vitamin D group (mean ± SEM: 15 ± 0.7) compared with the placebo group (mean ± SEM: 17 ± 0.8) (adjusted IRR: 0.90; 95% CI: 0.82, 0.98; P = 0.01), especially for the tetracyclines (IRR: 0.65; 95% CI: 0.50, 0.85; P = 0.002). CONCLUSIONS: Long-term, monthly, high-dose vitamin D3 supplementation did not prevent antibiotic prescribing in older adults, but the vitamin D group had fewer days per person-year on antibiotics. Further research is required to replicate these findings. This trial was registered at www.anzctr.org.au as ACTRN12611000402943.

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.

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.

Effect of Monthly Vitamin D Supplementation on Preventing Exacerbations of Asthma or Chronic Obstructive Pulmonary Disease in Older Adults: Post Hoc Analysis of a Randomized Controlled Trial.

Randomized controlled trials have suggested that vitamin D supplementation can prevent asthma and chronic obstructive pulmonary disease (COPD) exacerbations. For COPD, the benefit appears to be limited to individuals with baseline 25-hydroxyvitamin D (25OHD) levels <25 nmol/L. We performed a post hoc analysis of data from a randomized, double-blinded, placebo-controlled trial to investigate the effect that monthly, high-dose vitamin D supplementation (versus placebo) had on older adults with asthma and/or COPD. Specifically, we investigated whether vitamin D supplementation prevented exacerbations of these conditions. Participants were randomly assigned either to an initial oral dose of 200,000 IU vitamin D3 followed by 100,000 IU monthly or to placebo, with an average follow-up period of 3.3 years. Among the 5110 participants, 775 had asthma or COPD at the beginning of the study, and were eligible for inclusion in this analysis. Exacerbations were defined by the prescription of a short-burst of oral corticosteroids. The mean age of the participants was 67 years old, and 56% were male. The mean baseline blood 25OHD level was 63 nmol/L; 2.3% were <25 nmol/L. Overall, we found that vitamin D supplementation did not affect the exacerbation risk (hazard ratio 1.08; 95%CI 0.84-1.39). Among those with baseline 25OHD <25 nmol/L, however, the hazard ratio was 0.11 (95%CI 0.02-0.51); p for interaction = 0.001. Although monthly vitamin D supplementation had no overall impact on risk of exacerbations of asthma or COPD, we found evidence of a probable benefit among those with severe vitamin D deficiency.

Exocrine Pancreatic Dysfunction Increases the Risk of New-Onset Diabetes Mellitus: Results of a Nationwide Cohort Study.

It is well established that individuals with diabetes mellitus (DM) may develop exocrine pancreatic dysfunction (EPD) requiring pancreatic enzyme replacement therapy, whereas the converse relationship has been poorly studied. Pancreatitis is a disease that is well suited to investigate the latter as it is often characterized by the development of EPD and/or new-onset DM. The aim was to investigate the association between EPD and the risk of new-onset DM in individuals after the first attack of pancreatitis. Using nationwide pharmaceutical dispensing data and hospital discharge data, this cohort study included a total of 9,124 post-pancreatitis individuals. EPD was defined as having two or more dispensing records of pancreatic enzymes. Considering EPD as a time-dependent variable, multivariable Cox regression analysis was conducted. A 1-year lag period between EPD and DM was introduced to minimize reverse causality. Age, sex, ethnicity, alcohol consumption, tobacco smoking, social deprivation index, Charlson comorbidity index, and use of proton pump inhibitors were adjusted for. In the overall cohort, EPD was associated with a significantly higher risk for new-onset DM (adjusted hazard ratio, 3.83; 95% confidence interval, 2.37-6.18). The association remained statistically significant when a 1-year lag period was applied (adjusted hazard ratio, 2.51; 95% confidence interval, 1.38-4.58), as well as when the analysis was constrained to mild acute pancreatitis (4.65; 2.18-9.93). The findings suggest that individuals with EPD, even those without extensive mechanistic destruction of the pancreas, are at an increased risk for new-onset DM. Purposely designed studies are warranted to investigate mechanisms behind the association and if the mechanisms could be targeted therapeutically.