Falsely elevated parathyroid hormone in a patient with osteoporosis: a case report and review.

BACKGROUND: Parathyroid hormone (PTH) measurements can be falsely elevated due to the hormone binding to other molecules (macro-PTH) or immunoassay interference with heterophile, human anti-animal or other antibodies. This is rare but could lead to incorrect diagnosis, unnecessary investigations or avoidance of teriparatide treatment. We report a case of falsely high PTH levels due to assay interference and review the literature on cases of spuriously elevated PTH. CASE REPORT: An 87-year-old woman attending our bone health clinic with osteoporosis had persistently elevated PTH (383-784 pg/ml) using the Roche Cobas e801 immunoassay despite having normal serum calcium, phosphate, 25 hydroxyvitamin D (> 50 nmol/l) and eGFR (> 60 ml/min). To rule out falsely elevated PTH, a polyethylene glycol precipitation (PEG) test was performed which recovered less than 10% of the hormone resulting in a normal level. PTH was also tested on a different assay (Atellica Siemens) that identified a result of 27 pg/ml. The findings were consistent with immunoassay interference likely due to heterophile antibodies giving rise to a spuriously high PTH. DISCUSSION: The presence of unexpectedly high PTH levels should alert physicians to the possibility of false results due to assay interference or macro-PTH. This highlights the importance of clinically correlating results and of good communication with the testing laboratory. Here, we present the case of an 87-year-old woman with spuriously elevated PTH levels due to immunoassay interference likely mediated by heterophile antibodies. The presence of unexpectedly high PTH levels should prompt consideration of the possibility of false results due to assay interference or macro-PTH.

Vitamin D: determinants of status, indications for testing and knowledge in a convenience sample of Irish adults.

Vitamin D deficiency is common in Irish adults, though there is limited research on its determinants, knowledge of vitamin D or indications for testing. We aimed to explore the determinants of vitamin D status in adults and examine knowledge and reasons for testing. The study population comprised adults who had serum 25-hydroxyvitamin D tested by general practitioners request at a Dublin Hospital in 2020. Questionnaires detailing dietary intake, sun exposure, ethnicity, biophysical factors and vitamin D knowledge were sent to a sample stratified by age, sex and vitamin D status. In total, there were 383 participants, mean age 56·0 (sd 16·6) years. Wintertime deficiency disproportionally affected non-white v. white (60 % v. 24 %, P < 0·001). The greatest predictors of deficiency were low vitamin D intake (< 10 µg/d) (P < 0·001) and non-white ethnicity (P = 0·006), followed by sun avoidance (P = 0·022). It was also more prevalent in those with lower body exposure when outdoors. The majority (86 %) identified vitamin D as important for bone health. However, 40 % were tested for non-clinical indications and half were not aware of the recommended daily allowance (RDA). Low vitamin D intake was the most important determinant of deficiency, but ethnicity and sun exposure habits were also significant predictors. The majority had no clear indication for testing and were not aware of the RDA. Public health policies to improve knowledge and vitamin D intake, especially for those of non-white ethnicity and with reduced sun exposure, should be considered.

Low vitamin B12 but not folate is associated with incident depressive symptoms in community-dwelling older adults: a 4-year longitudinal study.

This was a longitudinal study utilising the Irish Longitudinal Study on Ageing (n 3849 aged ≥ 50 years) and investigated the relationship between blood plasma folate and B12 levels at baseline (wave 1) and incident depressive symptoms at 2 and 4 years (waves 2 and 3). A score ≥ 9 on the Center for Epidemiological Studies Depression Scale-8 at wave 2 or 3 was indicative of incident depressive symptoms. B12 status profiles (pmol/l) were defined as < 185, deficient low; 185 to < 258, low normal; > 258-601, normal and > 601 high. Folate status profiles (nmol/l) were defined as ≤ 10·0, deficient low; > 10-23·0, low normal; > 23·0-45·0, normal; >45·0, high. Logistic regression models were used to analyse the longitudinal associations. Both B12 and folate plasma concentrations were lower in the group with incident depressive symptoms v. non-depressed (folate: 21·4 v. 25·1 nmol/l; P = 0·0003; B12:315·7 v. 335·9 pmol/l; P = 0·0148). Regression models demonstrated that participants with deficient-low B12 status at baseline had a significantly higher likelihood of incident depression 4 years later (OR 1·51, 95 % CI 1·01, 2·27, P = 0·043). This finding remained robust after controlling for relevant covariates. No associations of folate status with incident depression were observed. Older adults with deficient-low B12 status had a 51 % increased likelihood of developing depressive symptoms over 4 years. The findings highlight the need to further explore the low-cost benefits of optimising vitamin B12 status for depression in older adults.

On-campus mental health services for Australian university students: A retrospective analysis of service utilisation.

OBJECTIVE: To investigate on-campus mental health service utilisation by Australian university students. METHOD: Retrospective analysis of clinical data from two on-campus health services (general practice and psychology and counselling service). Descriptive statistics include total consults, demographic factors, diagnoses, presenting concerns and rates of suicidal ideation. RESULTS: Mental health conditions account for the largest proportion of ongoing illness in on-campus health service users, representing 46% of all ongoing health conditions. Depression and anxiety were the most common diagnoses, and stress, anxiety and low mood were the most common presenting concerns. Females utilise mental health services more frequently than males, accounting for 65.3% and 60.1% of patients for the respective services. International students present for specific mental health consults less frequently than domestic students. Rates of suicidal ideation at presentation were high (37%). CONCLUSIONS: This retrospective analysis provides important information regarding the proportion and distribution of mental health conditions and service utilisation amongst Australian university students. There is clear scope for increased access to specialist care, renewed efforts to decrease stigma and increase rates of presentation (particularly amongst international students and males), greater support for general practitioners and more rigorous routine data collection and reporting, both within and across universities nationally.

Vitamin D retesting by general practitioners: a factor and cost analysis.

OBJECTIVES: Vitamin D testing by Primary Care doctors is increasing, placing greater workloads on healthcare systems. There is little data though on vitamin D retesting in Ireland. This study aims to investigate the factors associated with vitamin D retesting by Irish General Practitioners (GPs) and examine the resulting costs. METHODS: This is a retrospective analysis over 5 years (2014-2018) of GP requested 25-hydroxyvitamin D (25(OH)D) results in 36,458 patients at a major city hospital in Dublin, Ireland. Those with one test were compared with individuals who were retested and samples categorised to determine changes in status between tests. RESULTS: Nearly one in four patients (n=8,305) were retested. Positive predictors of retesting were female (p<0.001), age (60-69 years, p<0.001), location (Co. Kildare, p<0.001) and initial deficiency (<30 nmol/L, p<0.001) or insufficiency (30-49.9 nmol/L, p<0.001). Vitamin D status improved on retesting, with deficiency halving on first retest (9 vs. 18%, p<0.001) and dropping to 6% on further retests. About 12.2% of retests were done within 3 months and 29% had ≥2 retests within 1 year. 57% of retests were in those initially vitamin D replete (>50 nmol/L). The annual cost of inappropriate testing was €61,976. CONCLUSIONS: One in four patients were retested and this varied by age, gender and patient location. Over 10% of retests were inappropriately early (<3 months), a third too frequent and over half were in replete individuals incurring significant costs. Clear guidance for GPs on minimum retesting intervals is needed, as well as laboratory ordering systems to limit requests using pre-defined criteria.

Ambient UVB Dose and Sun Enjoyment Are Important Predictors of Vitamin D Status in an Older Population.

Background: UVB-induced skin synthesis is considered the key source of vitamin D, yet exposure to UVB is poorly accounted for in epidemiological studies.Objectives: The aim of this study was to examine the association of serum 25-hydroxyvitamin D [25(OH)D] concentration with accurately measured ambient UVB dose, sun enjoyment, supplements, and other factors.Methods: An all-Irish cohort of community-dwelling participants aged >60 y [median age: 73; 67% female; median 25(OH)D: 54.5 nmol/L] was used. Participants from this large, cross-sectional study completed a questionnaire to provide information on demographic factors and lifestyle (including supplement use and sun enjoyment). The Tropospheric Emission Monitoring Internet Service database was used to extract the daily ambient UVB dose at wavelengths that could induce vitamin D synthesis (D-UVB) over Ireland (latitude: 51°N-55°N). Blood sampling occurred throughout the year. Ambient exposure at the place of residence was calculated for each participant individually. Associations between determinants and serum 25(OH)D concentration were examined in a multivariate model. Random forest analysis was used to establish prediction models of vitamin D deficiency, and area under the curve (AUC) is shown.Results: In total, 5138 individuals were included. Median D-UVB was 63 mJ/cm2, which varied between seasons and latitudes, despite the small latitude differential. Vitamin D supplementation (ß = 27.7; P < 10 × 10-10), D-UVB (ß = 1.58 per 1000 mJ/cm2; P < 10 × 10-10), and sun enjoyment (ß = 6.6; P < 0.001) were strongly positively associated with serum 25(OH)D. Those who avoided sunshine were largely at risk of deficiency (<40 nmol/L), whereas those who enjoyed sunshine tended to be vitamin D sufficient (≥50 nmol/L). D-UVB and sun enjoyment improved prediction of deficiency in non-supplement-taking individuals; the overall AUC improved by 3.5%.Conclusion: D-UVB and sun enjoyment are important predictors of vitamin D status, even in this elderly population at northern latitudes. Accurate estimation of ambient UVB can help to further clarify the role of other determinants of vitamin D status and inform sunshine recommendation guidelines.

Vitamin D3 supplementation using an oral spray solution resolves deficiency but has no effect on VO2 max in Gaelic footballers: results from a randomised, double-blind, placebo-controlled trial.

PURPOSE: Vitamin D inadequacy is a global health concern in athletes as well as the general population. Whilst the role of vitamin D in skeletal health is well defined, there remains uncertainty over whether vitamin D supplementation has an added benefit beyond bone health. METHODS: This randomised placebo-controlled trial in healthy male and female Gaelic footballers (n = 42) investigated the effect of vitamin D3 supplementation [3000 IU (75 µg) daily for 12 weeks, via an oral spray solution] on VO2 max which was the primary outcome measure. Secondary outcomes included skeletal muscle and lung function. RESULTS: Supplementation significantly increased total 25-hydroxyvitamin D concentrations compared to the placebo group (mean ± SD change from baseline, 36.31 ± 32.34 vs. 6.11 ± 23.93 nmol/L, respectively; P = 0.006). At baseline, 50 and 22 % of footballers presented with vitamin D insufficiency (31-49 nmol/L) and deficiency (<30 nmol/L), respectively. Total 25-hydroxyvitamin D concentration did not significantly correlate with any measure of physical performance. Analysis of covariance (ANCOVA) models demonstrated that vitamin D supplementation over 12 weeks had no significant effect on VO2 max (P = 0.375), vertical jump height (P = 0.797), left and right handgrip strength (P = 0.146 and P = 0.266, respectively), forced vital capacity (P = 0.573) or forced expiratory volume at 1 s (P = 0.665), after adjusting for confounders. The high prevalence of vitamin D inadequacy observed in this cohort of collegiate Gaelic footballers supports the need for vitamin D supplementation during wintertime to avoid being at risk of poor bone health. CONCLUSIONS: Twelve-week daily supplementation with 3000 IU (75 µg) vitamin D3 successfully resolved deficiency but did not have any significant effect on VO2 max, skeletal muscle or lung function.

Vitamin D3 supplementation in healthy adults: a comparison between capsule and oral spray solution as a method of delivery in a wintertime, randomised, open-label, cross-over study.

Vitamin D is typically supplied in capsule form, both in trials and in clinical practice. However, little is known regarding the efficacy of vitamin D administered via oral sprays - a method that primarily bypasses the gastrointestinal absorption route. This study aimed to compare the efficacy of vitamin D3 liquid capsules and oral spray solution in increasing wintertime total 25-hydroxyvitamin D (25(OH)D) concentrations. In this randomised, open-label, cross-over trial, healthy adults (n 22) received 3000 IU (75 µg) vitamin D3 daily for 4 weeks in either capsule or oral spray form. Following a 10-week washout phase, participants received the opposite treatment for a final 4 weeks. Anthropometrics and fasted blood samples were obtained before and after supplementation, with samples analysed for total 25(OH)D, creatinine, intact parathyroid hormone and adjusted Ca concentrations. At baseline, vitamin D sufficiency (total 25(OH)D>50 nmol/l), insufficiency (31-49 nmol/l) and clinical deficiency (<30 nmol/l) were evident in 59, 23 and 18 % of the participants, respectively. Overall, baseline total mean 25(OH)D concentration averaged 59·76 (sd 29·88) nmol/l, representing clinical sufficiency. ANCOVA revealed no significant difference in the mean and standard deviation change from baseline in total 25(OH)D concentrations between oral spray and capsule supplementation methods (26·15 (sd 17·85) v. 30·38 (sd 17·91) nmol/l, respectively; F=1·044, adjusted r 2 0·493, P=0·313). Oral spray vitamin D3 is an equally effective alternative to capsule supplementation in healthy adults.

Determinants of 25-hydroxyvitamin D in older Irish adults.

BACKGROUND: vitamin D deficiency is prevalent in older adults living in Northern Europe and is influenced by several factors which may vary significantly with age. OBJECTIVE: we aimed to investigate the determinants of 25-hydroxyvitamin D [25(OH)D] in older Irish adults and in particular to examine the effect of supplement use and surrogate markers of sun exposure. METHODS: subjects were non-institutionalised community dwelling Irish adults aged over 60 years who were participants of a large cross-sectional study comprising three disease defined cohorts. Serum 25(OH)D was measured by liquid chromatography mass spectroscopy. Associations between 25(OH)D and potential confounders were explored in forward regression models in each cohort. RESULTS: the three cohorts comprised 1895, 1233 and 1316 participants (respective mean ages 70.1, 71.0 and 80.4 years). Statistical models explained between a fifth to a third of the variation in 25(OH)D. Supplement use and global solar radiation were positive predictors of 25(OH)D in all cohorts whereas the only universal negative predictor was body mass index. Supplement use was associated with a mean increase in 25(OH)D of between 21.4 and 35.4 nmol/l. The other main predictors varied by cohort but included sun holiday travel, enjoyment of sunshine when outside, use of vitamin D fortified milk, smoking, oily fish and egg consumption and physical frailty. CONCLUSION: supplement use was the most important determinant of vitamin D status. Vitamin D fortified milk and spending time in the sun, even in the oldest old may also be useful strategies to improve 25(OH)D.

Adalimumab Therapy Has a Beneficial Effect on Bone Metabolism in Patients with Crohn's Disease.

BACKGROUND: Infliximab has been shown to have beneficial effects on bone metabolism in patients with Crohn's disease (CD) although as yet the exact mechanisms have not been fully elucidated. AIM: To evaluate the impact of adalimumab therapy on bone metabolism using a combined in vivo and in vitro model. METHODS: Parathyroid hormone, vitamin D, bone formation markers, bone resorption marker, pro-inflammatory cytokines, anti-inflammatory cytokines, osteoprotegerin, and sRANKL were measured in control patients and pre- and post-treatment with adalimumab in CD patients. The effect of control patients' and pre- and post-treatment CD patients' sera on human osteoblasts (hFOB 1.19) in vitro cell viability and differentiation was also analyzed. RESULTS: There was a significant increase in bone formation markers osteocalcin (P < 0.05) and procollagen type 1 N-terminal propeptide (P < 0.01) at 1 and 3 months post-treatment. Moreover, there was a sustained but not significant fall in serum CTx, a bone resorption marker. No significant change was seen over time with other parameters measured. Serum from CD patients pre-treated with adalimumab showed increased osteoblast viability compared with that of post-treated patients at 6 months (P = 0.002) and controls. However, post-adalimumab treatment sera at 6 months appeared to increase osteoblast differentiation (P = 0.001), which is likely to be important in new bone formation. CONCLUSIONS: This first study evaluating the role of adalimumab as a possible bone protector in Crohn's disease patients has shown that similar to infliximab, adalimumab has complex and potentially beneficial effects on bone metabolism.

Vitamin D Status Is Associated with Intestinal Inflammation as Measured by Fecal Calprotectin in Crohn's Disease in Clinical Remission.

BACKGROUND: Vitamin D, as potential immune modulator, has been implicated as an environmental risk factor for Crohn's disease (CD). Vitamin D status may be associated with disease risk, severity, activity, and progression. While associations between circulating 25OHD and markers of disease activity and inflammation in CD have been reported, the results are inconsistent. AIM: To determine the association between vitamin D status and markers of disease activity and inflammation in CD. METHODS: One hundred and nineteen CD patients' active and inactive diseases were enrolled in the cross-sectional study. Subject demographics and clinical data were collected. A serum sample was collected for 25OHD and CRP analysis, and a stool sample was collected for fecal calprotectin (FC) measurement. RESULTS: The mean serum 25OHD concentration of the group was 59.8 (24.9) nmol/L. After controlling for confounding variables, serum 25OHD inversely correlated with FC (r = -0.207, P = 0.030), particularly among those in clinical remission (r = -0.242, P = 0.022). The association between FC and 25OHD was further confirmed by linear regression (r = 31.3 %, P < 0.001). FC was lower in patients with 25OHD levels ≥75 nmol/L compared with levels <25 nmol/L [FC: 32.2 (16.3-98.2) vs 100.0 (34.4-213.5) µg/g, P = 0.004]. In the current study, however, 25OHD was not significantly associated with either CRP or CDAI. CONCLUSION: Circulating 25OHD was significantly inversely associated with intestinal inflammation as determined by FC in CD. Subgroup analysis confirmed the association among those in clinical remission, but not in those with active disease. 25OHD was not associated with disease activity score (CDAI) or systemic inflammation (CRP). Vitamin D intervention studies are warranted to determine whether raising serum 25OHD levels in patients with CD may reduce intestinal inflammation as measured by FC.

Secondary hyperparathyroidism: Predictors and relationship with vitamin D status, bone turnover markers and bone mineral density.

INTRODUCTION: Secondary hyperparathyroidism (SHPT) has adverse implications for bone health but is relatively understudied. In this study we examine the prevalence and determinants of SHPT and describe the relationship of SHPT with bone turnover markers and bone mineral density (BMD) in older Irish adults. METHOD: Eligible participants (n = 4139) were identified from the Trinity-Ulster-Department of Agriculture (TUDA) study, a cohort of Irish adults aged ≥60 years. Exclusion criteria included an estimated glomerular filtration rate (eGFR) <30 ml/min and serum calcium >2.5 mmol/l to remove hyperparathyroidism due to advanced chronic kidney disease (CKD) and primary hyperparathyroidism respectively. The relationship between SHPT and bone turnover markers and BMD (measured by densitometry) was examined in a subsample (n = 1488). Vitamin D deficiency was defined as 25-hydroxyvitamin D [25 (OH)D] <30 nmol/l. RESULTS: Participants had a mean age of 73.6 ± 7.9 years, 65.1 % were female and 19.4 % were found to be vitamin D deficient. The prevalence of SHPT decreased as vitamin D increased, from 30.6 % in those deficient to 9.8 % in those with 25(OH)D ≥ 50 nmol/l and increased with declining kidney function. In non­calcium supplement users, principal determinants of SHPT were vitamin D deficiency (OR 4.18, CI 3.05-5.73, p < 0.001), eGFR 30-44 ml/min (OR 3.69, CI 2.44-5.57, p < 0.001), loop diuretic use (OR 3.52, CI 2.59-4.79, p < 0.001) and to a lesser extent body mass index (p = 0.001), eGFR 45-59 ml/min (p < 0.001) and 25(OH)D level 30-49 nmol/l (p = 0.002). Similar findings were observed in calcium supplement users, though proton pump inhibitors were also associated with SHPT (OR 1.55, CI 1.08-2.22, p = 0.018) while vitamin D 30-49 nmol/l was not. In participants with SHPT versus those without, bone turnover markers were higher: bone alkaline phosphatase (p = 0.017) and tartrate-resistant acid phosphatase (p = 0.033), whilst there was lower BMD at the neck of femur (0.880 vs. 0.903 g/cm2, p = 0.033) and total hip (0.968 vs. 0.995 g/cm2, P = 0.017). DISCUSSION: The results show that up to one in six older Irish adults had SHPT and this was associated with lower BMD and higher concentrations of bone turnover markers. Both vitamin D deficiency and 25(OH)D level 30-49 nmol/l were important predictors of SHPT. Loop diuretics and PPIs may also increase the risk of SHPT, and their use may need to be carefully considered in this population. Further studies examining the potential impact of these factors on bone health in similar populations to our study sample are warranted.

Vitamin D intake and status in Ireland: a narrative review.

Vitamin D is crucial for musculoskeletal health, with evidence suggesting non-skeletal benefits. Cutaneous vitamin D synthesis is limited in Ireland due to its northern latitude (52-55°N) and the population is dependent on dietary sources, yet intakes are inadequate. No study to-date has comprehensively examined vitamin D intakes and status in Ireland (Northern Ireland and the Republic). We aimed to review the evidence since 2010 and summarise the results in subgroups of the Irish population. We found that in the largest studies prevalence of deficiency [25-hydroxyvitamin D (25(OH)D) < 30 nm/l] was 15-17% in pregnancy, 15-23% in children and 13% in adults. Approximately half the population had 25(OH)D < 50 nm/l. There were only four small studies in an ethnic population with the largest in Southeast Asians finding that 67% were deficient. All studies found higher rates of deficiency and levels <50 nm/l in winter v. summer. Vitamin D intake was lowest in children (mean 2⋅3-4⋅2 µg/d) and pregnant women (mean 1⋅9-5⋅1 µg/d) and highest in older adults (6⋅9 µg/d), with over 90% of the population not meeting the recommended daily allowance. This review indicates that low vitamin D status and dietary vitamin D intake are widespread with children, adolescents, younger adults, pregnant women and ethnic minorities most at-risk. However, data are sparse in at-risk groups including the Travelling community, non-Europeans and institutionalised adults. Given the significant prevalence of deficiency, public health policies to promote better awareness of recommended vitamin D intakes and explore the options of food fortification are needed to address this issue.

Vitamin D status & associations with inflammation in older adults.

Research studies have observed associations of vitamin D with inflammation but data in representative older adult studies is lacking. We aimed to investigate the association of C-reactive protein (CRP) with vitamin D status in a representative sample of the older Irish population. The concentrations of 25-hydroxyvitamin D (25(OH)D) and CRP was measured in 5,381 community dwelling Irish adults aged ≥50 years from the Irish Longitudinal Study on Ageing (TILDA). Demographic, health and lifestyle variables were assessed by questionnaire and categorical proportions of CRP were generated by vitamin D status and age. Multi-nominal logistic regression was used to investigate the association of 25(OH)D and CRP status. The prevalence (mean; 95% confidence interval (95% CI)) of normal CRP status (0-5 mg/dL) was 83.9% (82.6-85.0%), elevated status (5-10 mg/dL) 11.0% (9.9-12.0%) and high status (>10 mg/dL) was 5.1% (4.5-5.8%). Mean (95% CI) CRP concentrations were lower in those with normal vs. deficient 25(OH)D status (2.02 mg/dL (1.95-2.08) vs. 2.60 mg/dL (2.41-2.82); p<0.0001). In a logistic regression analysis, those with insufficient or sufficient 25(OH)D status were less likely to have a high CRP status compared to those with deficient 25(OH)D status (insufficient: coefficient (CE) -0.732, 95% CI -1.12-0.33, p<0.0001; sufficient: CE -0.599, 95% CI -0.95-0.24, p = 0.001). In conclusion older adults with deficient vitamin D status had higher levels of inflammation as measured by CRP. Given that inflammation is an important pathological driver of chronic diseases of ageing, and that emerging evidence suggests that vitamin D therapy can reduce inflammation in some disease settings, optimising vitamin D status could represent an effective low risk/low-cost pathway to modulate inflammation in community dwelling older adults.

Vitamin D and orthostatic hypotension.

INTRODUCTION: we aimed to investigate on the potential relationship between vitamin D and orthostatic hypotension (OH) in a case-control model in older adults. METHODS: all participants were community-dwelling adults who were not taking vitamin D supplements. Cases were subjects aged 64 or older who were diagnosed with OH at a Falls and Blackout Unit. Controls were age- (within 5 years) and gender-matched subjects who had no history of blackouts, falls or orthostatic dizziness in the preceding year. OH was defined according to standard criteria and was diagnosed with an active stand test. Serum vitamin D [25(OH)D] was measured by radioimmunoassay. RESULTS: seventy-six subjects were included in the analysis (38 controls and 38 cases). Twenty-four in each group were female and mean age was between 78 and 79 years. Subjects with OH had lower serum 25(OH)D compared to controls (mean difference = 20.6 nmol/l, P = 0.0002). Lower vitamin D status was associated with an increased risk of OH after adjustment for season, body mass index, presence of stroke, diabetes and angina (P = 0.035) but not with impaired orthostatic haemodynamics. DISCUSSION: findings suggest that vitamin D may play a role in the aetiology of OH. Further studies will be required to explore on this relationship.

Low socioeconomic status predicts vitamin D status in a cross-section of Irish children.

Vitamin D is essential for bone and muscle health with adequate status in childhood crucial for normal skeletal development. We aimed to investigate vitamin D status in a convenience sample (n = 1226) of Irish children (aged 1-17 years) who had serum 25-hydroxyvitamin D (25(OH)D) tested by request of their GP at a Dublin Hospital between 2014 and 2020. We examined predictors including age, sex, season and socioeconomic status (SES). Vitamin D deficiency (<30 nmol/l) was prevalent affecting 23 % and was more common in disadvantaged areas (34 %) and in those aged >12 v. ≤12 years (24 % v. 16 %, P = 0⋅033). The greatest predictor was SES (disadvantaged v. affluent, OR 2⋅18, CI 1⋅34, 3⋅53, P = 0⋅002), followed by female sex (OR 1⋅57, CI 1⋅15, 2⋅14, P = 0⋅005) and winter season (October to February, OR 1⋅40, CI 1⋅07, 1⋅84, P = 0⋅015). A quarter of our sample of children were deficient, rising to one-third in those in disadvantaged areas. Females and those aged over 12 years had a higher prevalence of deficiency. Public health strategies to improve vitamin D status in Irish children, including systematic food fortification may need to be considered to address this issue.

Title: Understanding a Low Vitamin D State in the Context of COVID-19.

While a low vitamin D state has been associated with an increased risk of infection by SARS-CoV-2 in addition to an increased severity of COVID-19 disease, a causal role is not yet established. Here, we review the evidence relating to i) vitamin D and its role in SARS-CoV-2 infection and COVID-19 disease ii) the vitamin D status in the Irish adult population iii) the use of supplemental vitamin D to treat a deficient status and iv) the application of the Bradford-Hill causation criteria. We conclude that reverse causality probably makes a minimal contribution to the presence of low vitamin D states in the setting of COVID-19. Applying the Bradford-Hill criteria, however, the collective literature supports a causal association between low vitamin D status, SARS-CoV-2 infection, and severe COVID-19 (respiratory failure, requirement for ventilation and mortality). A biologically plausible rationale exists for these findings, given vitamin D's role in immune regulation. The thresholds which define low, deficient, and replete vitamin D states vary according to the disease studied, underscoring the complexities for determining the goals for supplementation. All are currently unknown in the setting of COVID-19. The design of vitamin D randomised controlled trials is notoriously problematic and these trials commonly fail for a number of behavioural and methodological reasons. In Ireland, as in most other countries, low vitamin D status is common in older adults, adults in institutions, and with obesity, dark skin, low UVB exposure, diabetes and low socio-economic status. Physiological vitamin D levels for optimal immune function are considerably higher than those that can be achieved from food and sunlight exposure alone in Ireland. A window exists in which a significant number of adults could benefit from vitamin D supplementation, not least because of recent data demonstrating an association between vitamin D status and COVID-19. During the COVID pandemic, we believe that supplementation with 20-25ug (800-1000 IU)/day or more may be required for adults with apparently normal immune systems to improve immunity against SARS-CoV-2. We expect that higher monitored doses of 37.5-50 ug (1,500-2,000)/day may be needed for vulnerable groups (e.g., those with obesity, darker skin, diabetes mellitus and older adults). Such doses are within the safe daily intakes cited by international advisory agencies.

Association between vitamin D deficiency and the risk of prevalent type 2 diabetes and incident prediabetes: A prospective cohort study using data from The Irish Longitudinal Study on Ageing (TILDA).

Background: It is hypothesized that vitamin D contributes to the aetiology of type 2 diabetes mellitus (diabetes). This study's objective was to examine the relationships between baseline vitamin D status (as measured by plasma 25-hydroxyvitamin D concentration) and both prevalent diabetes and prospective risk of developing diabetes, including prediabetes, in a population with historically low levels of vitamin D. Methods: In this prospective cohort study, data from The Irish Longitudinal Study on Ageing (TILDA), a nationally representative cohort of adults aged ≥50 years residing in Ireland were analysed, including wave 1 (October 2009-June 2011) (n = 5272) and wave 3 (March 2014-October 2015) (n = 3828). Those aged <50 years at baseline or who did not complete the health assessment were excluded. Logistic regression models examined the associations between baseline vitamin D concentration (nmol/L) with prevalent diabetes status and incident diabetes/prediabetes collected at a 4-year follow-up. Models were adjusted for age, sex, education, body mass index, smoking history, physical activity, use of statins, and the season in which the vitamin D concentration was sampled. Findings: Deficient baseline vitamin D concentration was cross-sectionally associated with an increased likelihood of having prevalent diabetes (Relative Risk Ratio [RRR] 1·5, 95% CI: 1·03, 2·18; p = 0·037). In longitudinal analyses evaluating diabetes status 4 years later, there was a 62% increased likelihood (RRR: 1·62, 95% CI: 1·12, 2·35; p = 0·011) of developing prediabetes for those with vitamin D <30 nmol/L compared to those with ≥75 nmol/L. The rate of progression from prediabetes to diabetes between wave 1 and 3 was observed to be 32·5%. Interpretation: Those with lower concentrations of vitamin D, as measured by 25-hydroxyvitamin D, may have different risk profiles with regards to their glycaemic status. Our study had limited power due to the low incidence of diabetes but showed strong associations with incident prediabetes, so further research is required. Optimising vitamin D status at a population level may significantly reduce diabetes. Funding: TILDA is funded by Atlantic Philanthropies, the Irish Department of Health, and Irish Life, while additional funding was provided by the Irish Department of Agriculture, Food and the Marine (13F492) to cover the cost of 25-hydroxyvitamin D analysis.

Seasonal variation of serum vitamin D and the effect of vitamin D supplementation in Irish community-dwelling older people.

BACKGROUND: Ireland is at 53°N, and its population risk of vitamin D deficiency is high. Previous Irish studies suggested a significant seasonality of serum 25-hydroxyvitamin D [25(OH)D] and a beneficial effect of supplementation in raising 25(OH)D levels. However, in Irish older people, little is known about the magnitude of the supplementation effect and whether supplementation affects 25(OH)D seasonality. DESIGN: cross-sectional observational. SETTING: outpatient clinic. SUBJECTS: five hundred and forty-six community-dwelling subjects (mean age 73.0, SD 7.4; 68.5% females) were assessed between September 2007 and May 2009. METHODS: for supplemented and non-supplemented: 'cosinor' analysis (Pulse_XP®) of monthly 25(OH)D. Period global solar radiation (GSR) and solar elevation angle (SEA) data were collected as proxy markers of ultraviolet-B radiation exposure. Multivariate linear regression was conducted to investigate the independent effect of GSR and SEA on 25(OH)D, controlling for confounders. RESULTS: supplemented group (N = 183): 89.1% were on cholecalciferol 800 IU/day. Mean 25(OH)D = 64.1 (95% confidence interval: 52.2-75.8) nmol/l, with no significant seasonality; regression: neither GSR nor SEA predicted 25(OH)D. Non-supplemented group (N = 363): mean 25(OH)D = 40.3 (35.5-45.0) nmol/l, with significant seasonality (55.5% variance remaining), peak in August, amplitude = 6.0 (3.1-8.8) nmol/l; regression: both GSR (P = 0.002) and the interaction GSR * SEA (P = 0.018) predicted 25(OH)D. CONCLUSIONS: vitamin D supplementation was associated with a mean serum 25(OH)D increase of 23.8 nmol/l. Interestingly, supplementation seemed to blunt seasonality. In the supplemented group, 72.1% had individual 25(OH)D levels below the recommended 75 nmol/l. There is a case for universal supplementation in Irish older people, probably at a higher dose. Further research is needed to establish the optimum dose.

Maternal obesity and baseline vitamin D insufficiency alter the response to vitamin D supplementation: a double-blind, randomized trial in pregnant women.

BACKGROUND: The achievement of target 25-hydroxyvitamin D [25(OH)D] concentrations in pregnancy may be altered by maternal obesity. OBJECTIVE: The authors examined the effects of maternal supplementation of 10 µg compared with 20 µg vitamin D3/d on maternal and umbilical cord 25(OH)D. The secondary aim was to investigate the influence of maternal BMI (in kg/m2) on the response of the primary outcomes. METHODS: The authors performed a 2-arm parallel double-blind randomized trial with 240 pregnant women recruited throughout the year in Northern Ireland. Women were stratified by BMI to receive 10 or 20 µg vitamin D3/d from 12 gestational wk (GW) until delivery. Maternal blood samples collected at 12, 28, and 36 GW and from the umbilical cord were analyzed for total serum 25(OH)D. A total of 166 women completed the study. RESULTS: Mean ± SD 25(OH)D at 36 GW was 80.8 ± 28.2 compared with 94.4 ± 33.2 nmol/L (P < 0.001) (10 compared with 20 µg vitamin D3/d, respectively). In those classified with 25(OH)D <50 nmol/L at baseline and assigned 10 µg vitamin D3/d, mean 25(OH)D concentrations remained <50 nmol/L at 36 GW, whereas those <50 nmol/L at baseline and assigned 20 µg vitamin D3/d, had mean 25(OH)D concentrations ≥50 nmol/L at 28 and 36 GW. In women with obesity and 25(OH)D <50 nmol/L at baseline, the related mean umbilical cord 25(OH)D was deficient (<25 nmol/L) in both treatment groups, whereas those with obesity and 25(OH)D ≥50 nmol/L at baseline had an average umbilical cord 25(OH)D between 25 and 50 nmol/L in both treatment groups. CONCLUSIONS: Supplementation of 20 µg vitamin D3/d is needed to attain maternal and umbilical cord 25(OH)D concentrations ≥50 nmol/L on average, in those who start pregnancy with low 25(OH)D concentrations (<50 nmol/L). Under current recommendations, women with obesity and low 25(OH)D in early pregnancy are particularly vulnerable to maintaining a low 25(OH)D concentration throughout pregnancy and having an infant born with deficient 25(OH)D concentrations. This trial was registered at ClinicalTrials.gov as NCT02713009.