Effectiveness of a fourth SARS-CoV-2 vaccine dose in previously infected individuals from Austria.

INTRODUCTION: Evidence is limited on the effectiveness of a fourth vaccine dose against coronavirus disease 2019 (COVID-19) in populations with prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. We estimated the risk of COVID-19 deaths and SARS-CoV-2 infections according to vaccination status in previously infected individuals in Austria. METHODS: This is a nationwide retrospective observational study. We calculated age and gender adjusted Cox proportional hazard ratios (HRs) of COVID-19 deaths (primary outcome) and SARS-CoV-2 infections (secondary outcome) from 1 November to 31 December 2022, primarily comparing individuals with four versus three vaccine doses. Relative vaccine effectiveness (rVE) was calculated as (1-HR) X 100. RESULTS: Among 3,986,312 previously infected individuals, 281,291 (7,1%) had four and 1,545,242 (38.8%) had three vaccinations at baseline. We recorded 69 COVID-19 deaths and 89,056 SARS-CoV-2 infections. rVE for four versus three vaccine doses was -24% (95% CI: -120 to 30) against COVID-19 deaths, and 17% (95% CI: 14-19) against SARS-CoV-2 infections. This latter effect rapidly diminished over time and infection risk with four vaccinations was higher compared to less vaccinated individuals during extended follow-up until June 2023. Adjusted HR (95% CI) for all-cause mortality for four versus three vaccinations was 0.79 (0.74-0.85). DISCUSSION: In previously infected individuals, a fourth vaccination was not associated with COVID-19 death risk, but with transiently reduced risk of SARS-CoV-2 infections and reversal of this effect in longer follow-up. All-cause mortality data suggest healthy vaccinee bias.

Associations of free, bioavailable and total 25-hydroxyvitamin D with neonatal birth anthropometry and calcium homoeostasis in mother-child pairs in a sunny Mediterranean region.

Sufficient vitamin D status is crucial for successful pregnancy and fetal development. The assessment of 25-hydroxyvitamin D (25(OH)D) concentrations is commonly used to evaluate vitamin D status. Our objective was to examine the interrelated biodynamics of maternal and neonatal total, free and bioavailable 25(OH)D in maternal-neonatal dyads at birth and their associations with homeostasis and neonatal birth anthropometry. We analysed a cohort of seventy full-term mother-child pairs. We found positive associations between all neonatal measures of vitamin D status. Maternal forms exhibited a similar pattern of association, except for the bioavailable maternal form. In multivariate analysis, both total and free maternal 25(OH)D concentrations were correlated with all neonatal forms (neonatal total 25(OH)D: 1·29 (95 % CI, 1·12, 1·46) for maternal total 25(OH)D, 10·89 (8·16, 13·63) for maternal free 25(OH)D), (neonatal free 25(OH)D: 0·15 for maternal total 25(OH)D, 1·28 (95 % CI, 0·89, 1·68) for maternal free 25(OH)D) and (0·13 (95 % CI, 0·10, 0·16), 1·06 (95 % CI, 0·68, 1·43) for maternal free 25(OH)D), respectively, with the exclusion of the bioavailable maternal form. We observed no significant interactions within or between groups regarding maternal and neonatal vitamin D parameters and maternal calcium and parathyroid hormone concentrations, and neonatal birth anthropometry. Our study indicates that bioavailable maternal and neonatal 25(OH)D have no significant effects on vitamin D equilibrium, Ca homeostasis and neonatal anthropometry at birth. However, we observed an interaction between maternal and neonatal total and free 25(OH)D concentrations at the maternal-neonatal interface, with no associations observed with other calciotropic or anthropometric outcomes.

The role of functional vitamin D deficiency and low vitamin D reservoirs in relation to cardiovascular health and mortality.

OBJECTIVES: The role of vitamin D deficiency in cardiovascular disease (CVD) is controversial. Inherent biological and analytical limitations compromise the specificity of widely used 25-hydroxyvitamin D [25(OH)D] cut-offs. Simultaneous determination of 25(OH)D and 24,25-dihydroxyvitamin D [24,25(OH)2D] permits a functional assessment of vitamin D metabolism. The present study compared the associations of functional vitamin D deficiency and low vitamin D reservoirs with CVD mortality and CVD burden. METHODS: 25(OH)D, 24,25(OH)2D, the degree of coronary obstruction on angiography, high-sensitive cardiac troponin T (hs-cTnT), N-terminal brain natriuretic peptide (NT-proBNP), and 10-year CVD mortality were obtained from 2,456 participants of the LURIC (Ludwigshafen Risk and Cardiovascular Health) study. RESULTS: Neither low 25(OH)D concentrations nor functional vitamin D deficiency were associated with the number of atherosclerotic coronary arteries or the degree of coronary obstruction. Over a median follow-up of 9.9 years, 454 participants died (23.6 %) due to CVD. CVD mortality was doubled in individuals with 25(OH)D concentrations below the widely used cut-off for deficiency of <50 nmol/L [20 ng/mL] (21.6 vs. 11.5 %). In individuals with and without functional vitamin D deficiency, CVD mortality was 25.0 and 16.7 %, respectively. NT-proBNP and heart failure prevalence were also higher in vitamin D deficient individuals. CONCLUSIONS: Vitamin D deficient individuals have markedly higher CVD mortality, but only marginally higher hs-cTnT concentrations. A higher prevalence of heart failure and higher NT-proBNP concentrations suggest a link between vitamin D deficiency and cardiac function. The traditional and metabolic assessment of vitamin D status showed comparable associations for the different parameters of cardiac health.

Functional Assessment of Vitamin D Status by a Novel Metabolic Approach: The Low Vitamin D Profile Concept.

BACKGROUND: Determining serum 25-hydroxyvitamin D [25(OH)D], 24,25-dihydroxyvitamin D [24,25(OH)2D] and the vitamin D metabolite ratio (VMR) allows the identification of individuals with a low vitamin D metabolite profile. Here, we evaluated if such a functional approach provides superior diagnostic information to serum 25(OH)D alone. METHODS: 25(OH)D, 24,25(OH)2D, and the VMR were determined in participants of the DESIRE (Desirable Vitamin D Concentrations, n = 2010) and the LURIC (Ludwigshafen Risk and Cardiovascular Health, n = 2456) studies. A low vitamin D metabolite profile (vitamin D insufficiency) was defined by a 24,25(OH)2D concentration <1.2 ng/mL (<3 nmol/L) and a VMR <4%. Parathyroid hormone (PTH) and bone turnover markers were measured in both cohorts, whereas 10-year mortality data was recorded in LURIC only. RESULTS: The median age in DESIRE and LURIC was 43.3 and 63.8 years, respectively. Median 25(OH)D concentrations were 27.2 ng/mL (68.0 nmol/L) and 15.5 ng/mL (38.8 nmol/L), respectively. Serum 25(OH)D deficiency, defined as <20.2 ng/mL (<50 nmol/L), was present in 483 (24.0%) and 1701 (69.3%) participants of DESIRE and LURIC, respectively. In contrast, only 77 (3.8%) and 521 (21.2%) participants had a low vitamin D metabolite profile. Regardless of the serum 25(OH)D concentration, a low vitamin D metabolite profile was associated with a significantly higher PTH, accelerated bone metabolism, and higher all-cause mortality than an unremarkable vitamin D metabolite profile. CONCLUSIONS: The personalized assessment of vitamin D status using a functional approach better identifies patients with accelerated bone metabolism and increased mortality than the use of a fixed 25(OH)D cutoff of 20 ng/mL (50 nmol/L).

Does natural and hybrid immunity obviate the need for frequent vaccine boosters against SARS-CoV-2 in the endemic phase?

The coronavirus disease 2019 (COVID-19) pandemic has entered its endemic phase and we observe significantly declining infection fatality rates due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). On this background, it is crucial but challenging to define current and future vaccine policy in a population with a high immunity against SARS-CoV-2 conferred by previous infections and/or vaccinations. Vaccine policy must consider the magnitude of the risks conferred by new infection(s) with current and evolving SARS-CoV-2 variants, how these risks vary in different groups of individuals, how to balance these risks against the apparently small, but existent, risks of harms of vaccination, and the cost-benefit of different options. More evidence from randomized controlled trials and continuously accumulating national health data is required to inform shared decision-making with people who consider vaccination options. Vaccine policy makers should cautiously weight what vaccination schedules are needed, and refrain from urging frequent vaccine boosters unless supported by sufficient evidence.

Long-term supplementation with 3200 to 4000 IU of vitamin D daily and adverse events: a systematic review and meta-analysis of randomized controlled trials.

PURPOSE: The upper tolerable intake level for vitamin D in the general population has been set at 4000 international units (IU) daily, but considerable uncertainty remains. We summarized reported harmful effects of a daily vitamin D supplement of 3200-4000 IU in trials lasting ≥ 6 months. METHODS: We performed a systematic review and meta-analysis of randomized controlled trials in several databases and identified 22 trials reporting safety data. Parameters of calcium metabolism, falls, hospitalization, and mortality were assessed. RESULTS: The selected trials comprised a total number of 12,952 participants. All trials used supplemental vitamin D3. The relative risk (RR) of hypercalcemia in the vitamin D vs. control arm was 2.21 (95%CI: 1.26-3.87; 10 studies), with a vitamin D-induced frequency of hypercalcemia of 4 cases per 1000 individuals. Subgroup analysis in trials with > 100 and ≤ 100 study participants revealed an RR of 2.63 (95%CI: 1.30-5.30; 7 studies) and 0.80 (95%CI: 0.24-2.62; 3 studies), respectively (Pinteraction = 0.06). Risks of falls and hospitalization were also significantly increased in the vitamin D arm with an RR of 1.25 (95%CI: 1.01-1.55; 4 studies) and 1.16 (95%CI: 1.01-1.33; 7 studies), respectively. Risks of hypercalciuria, kidney stones, and mortality did not differ significantly between study arms. Quality assessment revealed high risk of incomplete reporting of safety-related outcome data. CONCLUSION: Supplemental vitamin D doses of 3200-4000 IU/d appear to increase the risk of hypercalcemia and some other adverse events in a small proportion of individuals, indicating that this dose is not completely safe. In future studies, rigorous reporting of safety-related outcomes is needed when using moderately high doses of vitamin D.

SARS-CoV-2 reinfections: Overview of efficacy and duration of natural and hybrid immunity.

Seroprevalence surveys suggest that more than a third and possibly more than half of the global population has been infected with SARS-CoV-2 by early 2022. As large numbers of people continue to be infected, the efficacy and duration of natural immunity in terms of protection against SARS-CoV-2 reinfections and severe disease is of crucial significance for the future. This narrative review provides an overview on epidemiological studies addressing this issue. National surveys covering 2020-2021 documented that a previous SARS-CoV-2 infection is associated with a significantly reduced risk of reinfections with efficacy lasting for at least one year and only relatively moderate waning immunity. Importantly, natural immunity showed roughly similar effect sizes regarding protection against reinfection across different SARS-CoV-2 variants, with the exception of the Omicron variant for which data are just emerging before final conclusions can be drawn. Risk of hospitalizations and deaths was also reduced in SARS-CoV-2 reinfections versus primary infections. Observational studies indicate that natural immunity may offer equal or greater protection against SARS-CoV-2 infections compared to individuals receiving two doses of an mRNA vaccine, but data are not fully consistent. The combination of a previous SARS-CoV-2 infection and a respective vaccination, termed hybrid immunity, seems to confer the greatest protection against SARS-CoV-2 infections, but several knowledge gaps remain regarding this issue. Natural immunity should be considered for public health policy regarding SARS-CoV-2.

SARS-CoV-2 re-infection risk in Austria.

BACKGROUND: A key question concerning coronavirus disease 2019 (COVID-19) is how effective and long lasting immunity against this disease is in individuals who were previously infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We aimed to evaluate the risk of SARS-CoV-2 re-infections in the general population in Austria. METHODS: This is a retrospective observational study using national SARS-CoV-2 infection data from the Austrian epidemiological reporting system. As the primary outcome, we aim to compare the odds of SARS-CoV-2 re-infections of COVID-19 survivors of the first wave (February to April 30, 2020) versus the odds of first infections in the remainder general population by tracking polymerase chain reaction (PCR)-confirmed infections of both groups during the second wave from September 1 to November 30, 2020. Re-infection counts are tentative, since it cannot be excluded that the positive PCR in the first and/or second wave might have been a false positive. RESULTS: We recorded 40 tentative re-infections in 14 840 COVID-19 survivors of the first wave (0.27%) and 253 581 infections in 8 885 640 individuals of the remaining general population (2.85%) translating into an odds ratio (95% confidence interval) of 0.09 (0.07 to 0.13). CONCLUSIONS: We observed a relatively low re-infection rate of SARS-CoV-2 in Austria. Protection against SARS-CoV-2 after natural infection is comparable with the highest available estimates on vaccine efficacies. Further well-designed research on this issue is urgently needed for improving evidence-based decisions on public health measures and vaccination strategies.

Antifungal prophylaxis for prevention of COVID-19-associated pulmonary aspergillosis in critically ill patients: an observational study.

BACKGROUND: Coronavirus disease 19 (COVID-19)-associated pulmonary aspergillosis (CAPA) emerged as important fungal complications in patients with COVID-19-associated severe acute respiratory failure (ARF). Whether mould active antifungal prophylaxis (MAFP) can prevent CAPA remains elusive so far. METHODS: In this observational study, we included all consecutive patients admitted to intensive care units with COVID-19-associated ARF between September 1, 2020, and May 1, 2021. We compared patients with versus without antifungal prophylaxis with respect to CAPA incidence (primary outcome) and mortality (secondary outcome). Propensity score adjustment was performed to account for any imbalances in baseline characteristics. CAPA cases were classified according to European Confederation of Medical Mycology (ECMM)/International Society of Human and Animal Mycoses (ISHAM) consensus criteria. RESULTS: We included 132 patients, of whom 75 (57%) received antifungal prophylaxis (98% posaconazole). Ten CAPA cases were diagnosed, after a median of 6 days following ICU admission. Of those, 9 CAPA cases were recorded in the non-prophylaxis group and one in the prophylaxis group, respectively. However, no difference in 30-day ICU mortality could be observed. Thirty-day CAPA incidence estimates were 1.4% (95% CI 0.2-9.7) in the MAFP group and 17.5% (95% CI 9.6-31.4) in the group without MAFP (p = 0.002). The respective subdistributional hazard ratio (sHR) for CAPA incidence comparing the MAFP versus no MAFP group was of 0.08 (95% CI 0.01-0.63; p = 0.017). CONCLUSION: In ICU patients with COVID-19 ARF, antifungal prophylaxis was associated with significantly reduced CAPA incidence, but this did not translate into improved survival. Randomized controlled trials are warranted to evaluate the efficacy and safety of MAFP with respect to CAPA incidence and clinical outcomes.

Adverse body composition and lipid parameters in patients with prolactinoma: a case-control study.

BACKGROUND: Hyperprolactinaemia might cause adverse metabolic effects. The aim of our study was to compare parameters of body composition, glucose and lipid metabolism between untreated patients with prolactinoma and controls and to assess changes after initiation of cabergoline. METHODS: Case-control study with a retrospectively analyzed follow-up in patients with prolactinoma after initiation of cabergoline therapy. RESULTS: 21 patients with prolactinoma (9 micro- and 12 macroprolactinomas; 7 females) and 30 controls were analyzed. Patients with prolactinoma had significantly higher BMI than controls; fat mass did not differ between groups. Only men - but not women - with prolactinoma had significantly higher fat mass at all six sites measured compared to controls. Levels of LDL (130 (107-147.5) vs. 94.5 (80-127.5) mg/dl, p < 0.001) were significantly higher, levels of HDL (56 ± 16.7 vs. 69.2 ± 14.6 mg/dl, p = 0.004) significantly lower than in controls. Fasting glucose, HOMA-IR, HbA1c, adiponectin, CRP, and homocysteine did not differ between groups. After a median of 10 weeks (IQR 7-18 weeks) after initiation of cabergoline, total (from 212.5 ± 36.2 to 196.9 ± 40.6 mg/dl, p = 0.018) and LDL cholesterol (130 (107-147.5) to 106.5 (94.3-148) mg/dl, p = 0.018) had significantly decreased. Analyzing men and women separately, this change occurred in men only. CONCLUSIONS: Reasons for the association between prolactin and metabolic parameters include direct effects of prolactin on adipose tissue, hyperprolactinaemia-triggered hypogonadism and dopamine-agonist therapy per se. Altered lipid metabolism in patients with prolactinoma might imply an increased cardiovascular risk, highlighting the necessity to monitor metabolic parameters in these patients.

Randomized trial of vitamin D versus placebo supplementation on markers of systemic inflammation in hypertensive patients.

BACKGROUND AND AIMS: Animal and cell models indicated that vitamin D modulates inflammatory activity, which is considered relevant in the pathogenesis of arterial hypertension and cardiovascular diseases. We therefore aimed to investigate the effect of vitamin D supplementation on systemic markers of inflammation in a cohort of hypertensive patients. METHODS AND RESULTS: The Styrian Vitamin D Hypertension Trial is a single-centre, double-blind, placebo-controlled study conducted from 2011 to 2014 in Austria. We enrolled 200 study participants with arterial hypertension and 25-hydroxy-vitamin-D (25(OH)D) concentration below 30 ng/mL. Study participants were randomized to receive either 2800 IU of vitamin D3 per day or placebo for 8 weeks. The present investigation is a post-hoc analysis using analysis of co-variance (ANCOVA). Outcome measures were biomarkers of inflammation including CRP, leukocytes including subtypes and leukocyte-to-lymphocyte ratio, leucine and kynurenic acid. A total of 187 participants (mean age 60.1 ± 11.3years; 47% women; mean baseline 25(OH)D 21.1 ± 5.6 ng/mL) completed the trial. ANCOVA revealed a mean treatment effect for none of the respective outcomes and no significant results were detected in various subgroup analyses. CONCLUSION: Vitamin D3 supplementation in hypertensive patients with insufficient 25(OH)D concentrations has no significant effect on lowering markers of systemic inflammation. Further studies investigating the effect of vitamin D on other inflammatory pathways and in populations with severe vitamin D deficiency and a significant inflammatory burden are required. REGISTRATION: ClinicalTrials.gov Identifier: NCT02136771; EudraCT No. 2009-018,125-70. Start Date: 2011-04-06.

Vitamin D and Cardiovascular Disease: An Updated Narrative Review.

During the last two decades, the potential impact of vitamin D on the risk of cardiovascular disease (CVD) has been rigorously studied. Data regarding the effect of vitamin D on CVD risk are puzzling: observational data indicate an inverse nonlinear association between vitamin D status and CVD events, with the highest CVD risk at severe vitamin D deficiency; however, preclinical data and randomized controlled trials (RCTs) show several beneficial effects of vitamin D on the surrogate parameters of vascular and cardiac function. By contrast, Mendelian randomization studies and large RCTs in the general population and in patients with chronic kidney disease, a high-risk group for CVD events, largely report no significant beneficial effect of vitamin D treatment on CVD events. In patients with rickets and osteomalacia, cardiovascular complications are infrequently reported, except for an increased risk of heart failure. In conclusion, there is no strong evidence for beneficial vitamin D effects on CVD risk, either in the general population or in high-risk groups. Whether some subgroups such as individuals with severe vitamin D deficiency or a combination of low vitamin D status with specific gene variants and/or certain nutrition/lifestyle factors would benefit from vitamin D (metabolite) administration, remains to be studied.

Associations of Thyroid Hormones and Resting Heart Rate in Patients Referred to Coronary Angiography.

Resting heart rate (RHR) is associated with increased risk of cardiovascular morbidity and mortality. Thyroid hormones exert several effects on the cardiovascular system, but the relation between thyroid function and RHR remains to be further established. We evaluated whether measures of thyroid hormone status are associated with RHR in patients referred to coronary angiography. Thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxin (FT4), and RHR were determined in 2795 participants of the Ludwigshafen Risk and Cardiovascular Health (LURIC) Study. Median (25th to 75th percentile) serum concentrations were 1.25 (0.76-1.92) mU/l for TSH, 4.8 (4.2-5.3) pmol/l for FT3 and 17.1 (15.4-19.0) pmol/l for FT4, and mean (±standard deviation) RHR was 68.8 (±11.7) beats/min. Comparing the highest versus the lowest quartile, RHR (beats/min) was significantly higher in the fourth FT4 quartile [3.48, 95% confidence interval (CI): 2.23-4.73; p <0.001] and in the fourth FT3 quartile (2.30, 95% CI: 1.06-3.55; p <0.001), but there was no significant difference for TSH quartiles. In multiple linear regression analyses adjusting for various potential confounders, FT3 and FT4 were significant predictors of RHR (p <0.001 for both). In subgroups restricted to TSH, FT3, and FT4 values within the reference range, both FT3 and FT4 remained significant predictors of RHR (p <0.001 for all). In conclusion, in patients referred to coronary angiography, FT3 and FT4 but not TSH were positively associated with RHR. The relationship between free thyroid hormones and RHR warrants further investigations regarding its diagnostic and therapeutic implications.

Serum 25-hydroxyvitamin D response to vitamin D supplementation in infants: a systematic review and meta-analysis of clinical intervention trials.

PURPOSE: For the prevention of nutritional rickets, 400 IU vitamin D daily and circulating 25-hydroxyvitamin D (25OHD) concentrations > 50 nmol/L are recommended, whereas the toxicity threshold is set at 250 nmol/L. We synthesized the evidence for the effect of vitamin D supplementation on incremental 25OHD in infants up to 1 year of age. METHODS: We performed a systematic review and meta-analysis of intervention trials in several databases. A total of 87 records were identified for full-text review and 27 articles with 61 studies were included in the final analysis. RESULTS: The selected 61 studies included 1828 participants. Nineteen cohorts had already mean baseline 25OHD levels ≥ 50 nmol/L. The weighted mean difference in 25OHD following vitamin D supplementation was + 49.4 nmol/L (95% CI 43.6-55.3 nmol/L; P < 0.001). The increment was dose-dependent (P = 0.002), was higher in full-term than in pre-term infants (P < 0.001), was higher in infants with baseline 25OHD < 50 nmol/L as compared to ≥ 50 nmol/L (P = 0.001), and was marginally influenced by the 25OHD test procedure (P = 0.080). Vitamin D3 doses of 400 IU/day were sufficient to achieve 25OHD concentrations ≥ 50 nmol/L in most full-term infants. A 25OHD level of 250 nmol/L was not exceeded in ≥ 97.5% of infants at doses between 200 and 1200 IU/day, but potentially in ≥ 2.5% of infants at a dose of 1600 IU/day. CONCLUSIONS: Vitamin D supplementation of 400 IU/day is sufficient for achieving 25OHD concentrations able to prevent nutritional rickets. A more personalized vitamin D dosing strategy would require 25OHD testing, but also assay standardization.

Vitamin D supplementation during pregnancy: an overview.

PURPOSE OF REVIEW: Examine recent evidence of randomized controlled trials and meta-analyses regarding the effect of maternal vitamin D status and supplementation over obstetrical and offspring outcomes. RECENT FINDINGS: Maternal serum 25-hydroxyvitamin [25(OH)D] progressively declines during pregnancy because of fetal physiological demands and adjustments. Vitamin D supplementation during pregnancy in women with low vitamin D status may improve fetal growth and reduce the risks for small-for-gestational-age, preeclampsia, preterm birth, and gestational diabetes. Mothers with sufficient vitamin D levels have offsprings with less enamel defects and less attention deficit and hyperactive disorders and autism. All pregnant women should be supplemented with 600 IU/day of vitamin D3. We discuss evidence indicating that higher vitamin D doses (1000-4000 IU/day) may be convenient to achieve better maternal and infant outcomes. Low maternal vitamin D status during pregnancy may be associated in infants with a higher risk for lower bone mineral content, enamel defects and attention deficit hyperactive disorder. SUMMARY: Recent evidence from vitamin D intervention studies and meta-analyses of a large number of studies support vitamin D supplementation during pregnancy to improve maternal, fetal and, immediate and later offspring health.

Iron Metabolism, Hepcidin, and Mortality (the Ludwigshafen Risk and Cardiovascular Health Study).

BACKGROUND: Anemia has been shown to be a risk factor for coronary artery disease (CAD) and mortality, whereas the role of iron metabolism remains controversial. METHODS: We analyzed iron metabolism and its associations with cardiovascular death and total mortality in patients undergoing coronary angiography with a median follow-up of 9.9 years. Hemoglobin and iron status were determined in 1480 patients with stable CAD and in 682 individuals in whom significant CAD had been excluded by angiography. RESULTS: Multivariate-adjusted hazard ratios (HRs) for total mortality in the lowest quartiles of iron, transferrin saturation, ferritin, soluble transferrin receptor (sTfR), and hemoglobin were 1.22 (95% CI, 0.96-1.60), 1.23 (95% CI, 0.97-1.56), 1.27 (95% CI, 1.02-1.58), 1.26 (95% CI, 0.97-1.65), and 0.99 (95% CI, 0.79-1.24), respectively, compared to the second or third quartile, which served as reference (1.00) because of a J-shaped association. The corresponding HRs for total mortality in the highest quartiles were 1.44 (95% CI, 1.10-1.87), 1.37 (95% CI, 1.05-1.77), 1.17 (95% CI, 0.92-1.50), 1.76 (95% CI, 1.39-2.22), and 0.83 (95% CI, 0.63-1.09). HRs for cardiovascular death were similar. For hepcidin, the adjusted HRs for total mortality and cardiovascular deaths were 0.62 (95% CI, 0.49-0.78) and 0.70 (95% CI, 0.52-0.90) in the highest quartile compared to the lowest one. CONCLUSIONS: In stable patients undergoing angiography, serum iron, transferrin saturation, sTfR, and ferritin had J-shaped associations and hemoglobin only a marginal association with cardiovascular and total mortality. Hepcidin was continuously and inversely related to mortality.

Effects of vitamin D supplementation on androgens in men with low testosterone levels: a randomized controlled trial.

PURPOSE: It has been hypothesized that vitamin D is associated with androgen levels in men. We, therefore, aimed to evaluate whether vitamin D supplementation increases serum total testosterone (TT) levels in men with low TT levels at baseline. METHODS: The Graz Vitamin D&TT-RCT is a single-center, double-blind, randomized placebo-controlled trial conducted between March 2013 and November 2017 at the endocrine outpatient clinic at the Medical University of Graz, Austria. One-hundred healthy men with serum TT levels < 10.4 nmol/l and 25-hydroxyvitamin D [25(OH)D] levels < 75 nmol/l participated in the trial. Subjects were randomized to receive 20,000 IU of vitamin D3/week (n = 50) or placebo (n = 50) for 12 weeks. Primary outcome was TT measured using mass spectrometry. Secondary outcomes were free testosterone, free androgen index, sex hormone-binding globulin, estradiol, follicle-stimulating hormone, luteinizing hormone, metabolic characteristics, and body composition. RESULTS: Ninety-four men [mean age and 25(OH)D: 47 (± 12) years and 56.3 (± 18.3) nmol/l, respectively] completed the study. We found no significant treatment effect on serum TT or on the remaining secondary outcome variables. CONCLUSION: Vitamin D treatment had no effect on serum TT levels in middle-aged healthy men with low TT levels.

Vitamin D supplementation does not prevent the testosterone decline in males with advanced heart failure: the EVITA trial.

PURPOSE: Observational studies indicate a positive association between circulating 25-hydroxyvitamin D (25OHD) and testosterone (T) concentrations. Because low 25OHD concentrations and T deficiency are considered to be a generalized phenomenon in patients with advanced heart failure (HF), we aimed to investigate whether vitamin D supplementation has beneficial effects on T indices in these patients. METHODS: In a pre-specified secondary analysis of the EVITA (effect of vitamin D on mortality in heart failure) randomized controlled trial, we analyzed in male subjects with 25OHD concentrations < 75 nmol/L the effect of a daily vitamin D3 supplement of 4000 IU for 3 years (n = 71) vs. placebo (n = 62) on total T (TT), sex hormone-binding globulin (SHBG), free T (fT), and bioactive T (BAT). We assessed changes from baseline until study termination and between-group differences at study termination. RESULTS: 25OHD increased in the placebo group from 36.6 nmol/L by 9.2 nmol/L (95% CI 3.2-15.1 nmol/L; P = 0.003) and in the vitamin D group from 36.5 nmol/L by 63.9 nmol/L (95% CI 52.6-75.3 nmol/L; P < 0.001), with a significant between-group difference at study termination (P < 0.001). TT and SHBG concentrations did not change significantly, neither in the placebo group nor in the vitamin D group (P = 0.845-0.082), but concentrations of fT and BAT declined significantly in both groups (P = 0.025-0.008). At study termination, there were no between-group differences in TT (P = 0.612), SHBG (P = 0.393), fT (P = 0.861), or BAT (P = 0.960). CONCLUSIONS: In male patients with advanced HF and low 25OHD concentrations, a daily vitamin D3 supplement of 4000 IU for 3 years did not prevent the decline in testosterone indices.

LC-MS/MS based 25(OH)D status in a large Southern European outpatient cohort: gender- and age-specific differences.

BACKGROUND: Developed countries have a high prevalence of vitamin D deficiency. In previous studies, 25(OH)D was predominantly measured by immunoassays. The present study assessed serum 25(OH)D in a very large Southern European outpatient cohort by liquid chromatography tandem mass spectrometry (LC-MS/MS). MATERIALS AND METHODS: 74,235 serum 25(OH)D results generated under routine conditions between 2015 and 2016 were extracted from the laboratory information system of the Department of Clinical Pathology at Bolzano Hospital (Italy). In 3801 cases, parathyroid hormone (PTH) was requested in parallel. Serum 25(OH)D was measured by a NIST-972 aligned commercial LC-MS/MS method. The distribution of serum 25(OH)D concentrations in males and females of different age groups, the prevalence of 25(OH)D2 and seasonal variability were studied. RESULTS: The average 25(OH)D concentration in the entire cohort was 68.6 nmol/L (7.5-1880 nmol/L). Females had a 7 nmol/L higher average 25(OH)D concentration than males, which increased significantly with age. 37.9 and 28.3% of males and females, respectively, had a deficient 25(OH)D concentration of < 50 nmol/L. 620 samples (0.84%) had measureable amounts of 25(OH)D2. In samples with a normal PTH, 25(OH)D was 11 nmol/L higher than in the entire cohort. Seasonal variation ranged between 20 and 30% and was most pronounced in young individuals. 25(OH)D2 remained constant throughout the year. CONCLUSION: Average serum 25(OH)D in South Tyrol is higher than in other parts of Europe. 25(OH)D and PTH show a continuous inverse relationship. Seasonal variation of serum 25(OH)D is an important aspect in young and middle-aged adults, but becomes less relevant in elderly subjects. 25(OH)D2 is of minor practical importance in South Tyrol.