Use of levothyroxine for euthyroid, thyroid antibody positive women with infertility: Analyses of aggregate data from a survey of European thyroid specialists (Treatment of Hypothyroidism in Europe by Specialists: An International Survey).

OBJECTIVES: The use of levothyroxine (LT4) treatment aiming to improve fertility in euthyroid women with positive thyroid peroxidase antibodies (TPOAb) is not supported by the available evidence. The aim of the study was to document the use of LT4 by European thyroid specialists in such patients. DESIGN: The data presented derive from Treatment of Hypothyroidism in Europe by Specialists, an International Survey (THESIS), a questionnaire conducted between 2019 and 2021 to document the management of hypothyroidism by European thyroid specialists. Here, we report the aggregate results on the use of LT4 in infertile, euthyroid women with positive TPOAb. RESULTS: A total of 2316/5406 (42.8%) respondents stated that LT4 may be indicated in TPOAb positive euthyroid women with infertility. The proportion of those replying positively to this question varied widely across different countries (median 39.4, range 22.9%-83.7%). In multivariate analyses males (OR: 0.8; CI: 0.7-0.9) and respondents >60 years (OR: 0.7; 0.6-0.8) were the least inclined to consider LT4 for this indication. Conversely, respondents managing many thyroid patients ("weekly" [OR: 1.4; CI: 1.0-1.9], "daily" [OR: 1.8; CI: 1.3-2.4]) and practicing in Eastern Europe (OR: 1.5; CI: 1.3-1.9) were most likely to consider LT4. CONCLUSIONS: A remarkably high number of respondents surveyed between 2019 and 2021, would consider LT4 treatment in TPOAb positive euthyroid women with infertility. This view varied widely across countries and correlated with sex, age and workload, potentially influencing patient management. These results raise concerns about potential risks of overtreatment.

Patients' Persistent Symptoms, Clinician Demographics, and Geo-Economic Factors Are Associated with Choice of Therapy for Hypothyroidism by European Thyroid Specialists: The "THESIS" Collaboration.

Background: Hypothyroidism is common, however, aspects of its treatment remain controversial. Our survey aimed at documenting treatment choices of European thyroid specialists and exploring how patients' persistent symptoms, clinician demographics, and geo-economic factors relate to treatment choices. Methods: Seventeen thousand two hundred forty-seven thyroid specialists from 28 countries were invited to participate in an online questionnaire survey. The survey included respondent demographic data and treatment choices for hypothyroid patients with persistent symptoms. Geo-economic data for each country were included in the analyses. Results: The response rate was 32.9% (6058 respondents out of 17,247 invitees). Levothyroxine (LT4) was the initial treatment preferred by the majority (98.3%). Persistent symptoms despite normal serum thyrotropin (TSH) while receiving LT4 treatment were reported to affect up to 10.0% of patients by 75.4% of respondents, while 28.4% reported an increasing such trend in the past 5 years. The principal explanations offered for patients' persistent symptoms were psychosocial factors (77.1%), comorbidities (69.2%), and unrealistic patient expectations (61.0%). Combination treatment with LT4+liothyronine (LT3) was chosen by 40.0% of respondents for patients who complained of persistent symptoms despite a normal TSH. This option was selected more frequently by female thyroid specialists, with high-volume practice, working in countries with high gross national income per capita. Conclusions: The perception of patients' dissatisfaction reported by physicians seems lower than that described by hypothyroid patients in previous surveys. LT4+LT3 treatment is used frequently by thyroid specialists in Europe for persistent hypothyroid-like symptoms even if they generally attribute such symptoms to nonendocrine causes and despite the evidence of nonsuperiority of the combined over the LT4 therapy. Pressure by dissatisfied patients on their physicians for LT3-containing treatments is a likely explanation. The association of the therapeutic choices with the clinician demographic characteristics and geo-economic factors in Europe is a novel information and requires further investigation.

Characteristics of specialists treating hypothyroid patients: the "THESIS" collaborative.

Introduction: Thyroid specialists influence how hypothyroid patients are treated, including patients managed in primary care. Given that physician characteristics influence patient care, this study aimed to explore thyroid specialist profiles and associations with geo-economic factors. Methods: Thyroid specialists from 28 countries were invited to respond to a questionnaire, Treatment of Hypothyroidism in Europe by Specialists: an International Survey (THESIS). Geographic regions were defined according to the United Nations Statistics Division. The national economic status was estimated using World Bank data on the gross national income per capita (GNI per capita). Results: 5,695 valid responses were received (response rate 33·0%). The mean age was 49 years, and 65·0% were female. The proportion of female respondents was lowest in Northern (45·6%) and highest in Eastern Europe (77·2%) (p <0·001). Respondent work volume, university affiliation and private practice differed significantly between countries (p<0·001). Age and GNI per capita were correlated inversely with the proportion of female respondents (p<0·01). GNI per capita was inversely related to the proportion of respondents working exclusively in private practice (p<0·011) and the proportion of respondents who treated >100 patients annually (p<0·01). Discussion: THESIS has demonstrated differences in characteristics of thyroid specialists at national and regional levels, strongly associated with GNI per capita. Hypothyroid patients in middle-income countries are more likely to encounter female thyroid specialists working in private practice, with a high workload, compared to high-income countries. Whether these differences influence the quality of care and patient satisfaction is unknown, but merits further study.

Metabolomic differences between critically Ill women and men.

Metabolism differs in women and men at homeostasis. Critically ill patients have profound dysregulation of homeostasis and metabolism. It is not clear if the metabolic response to critical illness differs in women compared to men. Such sex-specific differences in illness response would have consequences for personalized medicine. Our aim was to determine the sex-specific metabolomic response to early critical illness. We performed a post-hoc metabolomics study of the VITdAL-ICU trial where subjects received high dose vitamin D3 or placebo. Using mixed-effects modeling, we studied sex-specific changes in metabolites over time adjusted for age, Simplified Acute Physiology Score II, admission diagnosis, day 0 25-hydroxyvitamin D level, and 25-hydroxyvitamin D response to intervention. In women, multiple members of the sphingomyelin and lysophospholipid metabolite classes had significantly positive Bonferroni corrected associations over time compared to men. Further, multiple representatives of the acylcarnitine, androgenic steroid, bile acid, nucleotide and amino acid metabolite classes had significantly negative Bonferroni corrected associations over time compared to men. Gaussian graphical model analyses revealed sex-specific functional modules. Our findings show that robust and coordinated sex-specific metabolite differences exist early in critical illness.

Metabolomic basis for response to high dose vitamin D in critical illness.

BACKGROUND & AIMS: It is unclear if intervention can mitigate the dramatic alterations of metabolic homeostasis present in critical illness. Our objective was to determine the associations between increased 25-hydroxyvitamin D levels following high dose vitamin D3 and more favorable metabolomic profiles in critical illness. METHODS: We performed a post-hoc metabolomics study of the VITdAL-ICU randomized double-blind, placebo-controlled trial. Trial patients from Medical and Surgical Intensive Care Units at a tertiary university hospital with 25-hydroxyvitamin D level ≤20 ng/mL received either high dose oral vitamin D3 (540,000 IU) or placebo. We performed an analysis of 578 metabolites from 1215 plasma samples from 428 subjects at randomization (day 0), day 3 and 7. Using mixed-effects modeling, we studied changes in metabolite profiles in subjects receiving intervention or placebo relative to absolute increases in 25-hydroxyvitamin D levels from day 0 to day 3. RESULTS: 55.2% of subjects randomized to high dose vitamin D3 demonstrated an absolute increase in 25-hydroxyvitamin D ≥ 15 ng/ml from day 0 to day 3. With an absolute increase in 25-hydroxyvitamin D ≥ 15 ng/ml, multiple members of the sphingomyelin, plasmalogen, lysoplasmalogen and lysophospholipid metabolite classes had significantly positive Bonferroni corrected associations over time. Further, multiple representatives of the acylcarnitine and phosphatidylethanolamine metabolite classes had significantly negative Bonferroni corrected associations over time with an absolute increase in 25-hydroxyvitamin D ≥ 15 ng/ml. Changes in these highlighted metabolite classes were associated with decreased 28-day mortality. CONCLUSIONS: Increases in 25-hydroxyvitamin D following vitamin D3 intervention are associated with favorable changes in metabolites involved in endothelial protection, enhanced innate immunity and improved mitochondrial function.

Radiofrequency ablation of thyroid nodules: "Good Clinical Practice Recommendations" for Austria : An interdisciplinary statement from the following professional associations: Austrian Thyroid Association (ÖSDG), Austrian Society for Nuclear Medicine and Molecular Imaging (OGNMB), Austrian Society for Endocrinology and Metabolism (ÖGES), Surgical Endocrinology Working Group (ACE) of the Austrian Surgical Society (OEGCH).

The present "Good Clinical Practice Recommendations" relate to radiofrequency ablation (RFA) training, execution, and quality control, as well as to pre- and postinterventional standards of care. They are aimed at all physicians who intend to learn to perform, or who are already conducting RFA interventions as well as at thyroid specialists providing pre- and postoperative care to RFA patients in Austria. Adoption of these recommendations is strongly encouraged by the afore-listed professional associations.All RFA interventionists who adhere to these standards shall be listed on a homepage linked to these professional associations entitled "RFA centers in compliance with the GCP recommendations of the ÖSDG/OGNMB/ÖGES/OEGCH-ACE." This will ensure harmonization of RFA training and quality control in the performance of the treatment in Austria.

Value of monopolar and bipolar radiofrequency ablation for the treatment of benign thyroid nodules.

Only a few thyroid nodules are perceived as functional or optically disturbing. If there is a need for action, surgical intervention is the long-term standard by which thermoablative procedures (radiofrequency-, laser-, microwave ablation, high intensity focused ultrasound) must be measured against in terms of safety, effectiveness and patient satisfaction. Prior to intervention assessment of the dignity of the nodule by ultrasound-guided fine needle aspiration is essential for cold and warm nodules, as is the confirmation of an inconspicuous cervical lymph node status. The short-term treatment results of these newer interventions in terms of nodule volume reduction and symptomatic improvement are promising and the general complication rate of the procedures is low. Since functional thyroid parenchyma is preserved, maintaining normal thyroid status is the rule. The procedure is usually performed on an outpatient basis, under local anesthesia and monitoring. The subsequent convalescence is usually very short. Most studies are available on monopolar radiofrequency ablation. Several professional societies have defined indications for radiofrequency ablation (RFA), but these need to be further refined based on practical experience and literature. An acceptable long-term recurrence rate still has to be proven for practically all thermoablative methods, for monopolar RFA limited long-term data are encouraging so far. The recurrence rate as well as patient satisfaction will provide the basis for a meaningful overall cost-benefit analysis in the future.

Trying to identify who may benefit most from future vitamin D intervention trials: a post hoc analysis from the VITDAL-ICU study excluding the early deaths.

BACKGROUND: Vitamin D supplementation has shown promise for reducing mortality in the intensive care setting. As a steroid prohormone with pleiotropic effects, there may be a lag between administration and observing clinical benefit. This secondary analysis of the VITdAL-ICU study sought to explore whether the effect size of vitamin D on mortality was different when study participants who died or were discharged early were excluded. METHODS: The VITdAL-ICU study was a randomized, placebo-controlled trial in critically ill adults who received placebo or 540,000 IU cholecalciferol followed by monthly supplementation. The effect of vitamin D on 28-day mortality was evaluated after exclusion of participants who died or were discharged within 7 days from study drug administration, according to vitamin D concentrations on day 3, using a bivariate analysis adjusted for confounders and in a stepwise multiple analysis. RESULTS: Of 475 study participants, 65 died or were discharged within the first 7 days. In the remaining 410 patients, vitamin D supplementation was associated with a reduction in 28-day mortality [OR 0.58 (95% CI 0.35-0.97) p value = 0.035]. The effect on mortality was not significant after adjusting for age, severity scores, female gender, chronic liver and kidney disease, COPD, diagnosis of the tumor, mechanical ventilation, and vasopressors at enrollment (all p > 0.05). In a multiple model, the mortality reduction by vitamin D supplementation did not remain independently significant [OR 0.61 (95% CI 0.35-1.05) p = 0.075]. Vitamin D metabolite response, in the treatment group, demonstrated that survivors at 28 days, had higher levels of 25-hydroxyvitamin D (34.4 vs 25.4 ng/ml, p = 0.010) and 1,25-dihydroxyvitamin D (107.6 vs 70.3 pg/ml, p = 0.049) on day 3. The increase of plasma metabolites after vitamin D oral supplementation, independent of the baseline value, was associated with lower odds of death [OR 0.48 (95% CI 0.27-0.87) p value = 0.016]. CONCLUSIONS: High-dose vitamin D3 supplementation was associated with a reduction of 28-day mortality in a mixed population of critically ill adults with vitamin D deficiency when excluding patients who died or were discharged within 7 days after study inclusion. However, this survival benefit was not independently confirmed when adjusted for other factors strongly associated with mortality.

Monopolar Radiofrequency Ablation of Thyroid Nodules: A Prospective Austrian Single-Center Study.

BACKGROUND: Monopolar radiofrequency ablation is currently deemed an exotic treatment option for benign thyroid nodules in many central European countries. The aim of this study was to evaluate prospectively the safety and efficacy of this method in a large patient cohort following its introduction in Austria. METHODS: Peri- and post-interventional complications were analyzed for 277 patients. Efficacy was determined for 300 and 154 nodules at 3 and 12 months post treatment, respectively. All treatments were performed with an internally cooled 18G radiofrequency electrode using a free-hand, "moving-shot" technique following subcutaneous and local perithyroidal anesthesia. RESULTS: Mean patient age (SD) was 52 ± 12.9 years (75% female), and overall mean baseline nodule volume (SD) was 13.8 ± 15.9 mL. Nodules were visible in 62.8% of patients, 40% had a symptom score ≥4 on a 10-point visual analogue scale, and 14.4% had hyperthyroidism. Mean overall nodule volume reduction rates (VRR) at 3 and 12 months were 68 ± 16% and 82 ± 13%, respectively (p < 0.001). At 12 months, 81% of nodules exhibited a VRR of ≥70%, with 10%, 6%, and 2% of nodules showing VRRs of 60-70%, 50-60%, and ≤50%, respectively. Subgroup analysis according to baseline nodule size (≤10 mL to >30 mL) or baseline nodule composition (solid, mixed, cystic) revealed significantly higher VRRs for smaller and cystic nodules. Moreover, nodule shrinkage was accompanied by significantly improved symptom and cosmetic scores after 3 and 12 months (p < 0.001). Of 32 hyperthyroid patients, 27 (84%) were euthyroid, four had subclinical hyperthyroidism, and one had subclinical hypothyroidism at last follow-up. Post-procedural complications were absent in 83% of patients, minimal in 12.9%, moderate and reversible in 3.2% (1.8% voice change, 0.7% hyperthyroidism, 0.3% wound infection treated with antibiotics, 0.3% epifascial hematoma), and irreversible in 0.7% (one case with hypothyroidism and one with a wound infection treated by surgery). CONCLUSIONS: It is concluded that a single treatment course with monopolar radiofrequency ablation is both safe and highly effective in terms of nodule volume reduction, relief of local symptoms, and (in patients with hyperthyroidism) restoration of euthyroid function. In no case was a prescription of thyroid medication required among those patients who were euthyroid at baseline.

Improvement of cancellous bone microstructure in patients on teriparatide following alendronate pretreatment.

An increase in procollagen type I amino-terminal propeptide (PINP) early after teriparatide initiation was shown to correlate with increased lumbar spine areal BMD and is a good predictor of the anabolic response to teriparatide. Few data exist correlating PINP and bone microstructure, and no data exist in patients on teriparatide following prior potent antiresorptive treatment. This exploratory analysis aimed to investigate the effects of teriparatide on cancellous bone microstructure and correlations of bone markers with microstructure in alendronate-pretreated patients. This was a post hoc analysis of changes in bone markers and three-dimensional indices of bone microstructure in paired iliac crest biopsies from a prospective teriparatide treatment study in postmenopausal women with osteoporosis who were either treatment-naïve (TN, n=16) or alendronate-pretreated (ALN, n=29) at teriparatide initiation. Teriparatide (20µg/day) was given for 24months; biopsies were taken at baseline and endpoint, and serum concentrations of PINP and type 1 collagen cross-linked C-telopeptide (ßCTX) were measured at intervals up to 24months. In the TN and ALN groups, respectively, mean (SD) increases in three-dimensional bone volume/tissue volume were 105 (356)% (P=0.039) and 55 (139)% (P<0.005) and trabecular thickness 30.4 (30)% (P<0.001) and 30.8 (53)% (P<0.001). No significant changes were observed in trabecular number or separation. In the ALN patients, 3-month change of neither PINP nor ßCTX correlated with indices of cancellous bone microstructure. However, 12-month changes in biochemical bone markers correlated significantly with improvements in bone volume/tissue volume, r=0.502 (P<0.01) and r=0.378 (P<0.05), trabecular number, r=0.559 (P<0.01) and r=0.515 (P<0.01), and reduction of trabecular separation, r=-0.432 (P<0.05) and r=-0.530 (P<0.01), for PINP and ßCTX, respectively. We conclude that cancellous bone microstructure improved with teriparatide therapy irrespective of prior antiresorptive use.

Effect of high-dose vitamin D3 on hospital length of stay in critically ill patients with vitamin D deficiency: the VITdAL-ICU randomized clinical trial.

IMPORTANCE: Low vitamin D status is linked to increased mortality and morbidity in patients who are critically ill. It is unknown if this association is causal. OBJECTIVE: To investigate whether a vitamin D3 treatment regimen intended to restore and maintain normal vitamin D status over 6 months is of health benefit for patients in ICUs. DESIGN, SETTING, AND PARTICIPANTS: A randomized double-blind, placebo-controlled, single-center trial, conducted from May 2010 through September 2012 at 5 ICUs that included a medical and surgical population of 492 critically ill adult white patients with vitamin D deficiency (≤20 ng/mL) assigned to receive either vitamin D3 (n = 249) or a placebo (n = 243). INTERVENTIONS: Vitamin D3 or placebo was given orally or via nasogastric tube once at a dose of 540,000 IU followed by monthly maintenance doses of 90,000 IU for 5 months. MAIN OUTCOMES AND MEASURES: The primary outcome was hospital length of stay. Secondary outcomes included, among others, length of ICU stay, the percentage of patients with 25-hydroxyvitamin D levels higher than 30 ng/mL at day 7, hospital mortality, and 6-month mortality. A predefined severe vitamin D deficiency (≤12 ng/mL) subgroup analysis was specified before data unblinding and analysis. RESULTS: A total of 475 patients were included in the final analysis (237 in the vitamin D3 group and 238 in the placebo group). The median (IQR) length of hospital stay was not significantly different between groups (20.1 days [IQR, 11.1-33.3] for vitamin D3 vs 19.3 days [IQR, 11.1-34.9] for placebo; P = .98). Hospital mortality and 6-month mortality were also not significantly different (hospital mortality: 28.3% [95% CI, 22.6%-34.5%] for vitamin D3 vs 35.3% [95% CI, 29.2%-41.7%] for placebo; hazard ratio [HR], 0.81 [95% CI, 0.58-1.11]; P = .18; 6-month mortality: 35.0% [95% CI, 29.0%-41.5%] for vitamin D3 vs 42.9% [95% CI, 36.5%-49.4%] for placebo; HR, 0.78 [95% CI, 0.58-1.04]; P = .09). For the severe vitamin D deficiency subgroup analysis (n = 200), length of hospital stay was not significantly different between the 2 study groups: 20.1 days (IQR, 12.9-39.1) for vitamin D3 vs 19.0 days (IQR, 11.6-33.8) for placebo. Hospital mortality was significantly lower with 28 deaths among 98 patients (28.6% [95% CI, 19.9%-38.6%]) for vitamin D3 compared with 47 deaths among 102 patients (46.1% [95% CI, 36.2%-56.2%]) for placebo (HR, 0.56 [95% CI, 0.35-0.90], P for interaction = .04), but not 6-month mortality (34.7% [95% CI, 25.4%-45.0%] for vitamin D3 vs 50.0% [95% CI, 39.9%-60.1%] for placebo; HR, 0.60 [95% CI, 0.39-0.93], P for interaction = .12). CONCLUSIONS AND RELEVANCE: Among critically ill patients with vitamin D deficiency, administration of high-dose vitamin D3 compared with placebo did not reduce hospital length of stay, hospital mortality, or 6-month mortality. Lower hospital mortality was observed in the severe vitamin D deficiency subgroup, but this finding should be considered hypothesis generating and requires further study. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01130181.

Sclerostin in institutionalized elderly women: associations with quantitative bone ultrasound, bone turnover, fractures, and mortality.

OBJECTIVES: To evaluate the association between levels of circulating sclerostin (an emerging biomarker and important regulator of bone formation) and laboratory parameters of bone and mineral metabolism, bone mineral density and quality measured using quantitative ultrasound (QUS), fracture risk, and mortality. DESIGN: Prospective cohort study. SETTING: Austrian nursing homes (N = 95). PARTICIPANTS: Female nursing home residents aged 70 and older (mean 84 ± 6; N = 539). MEASUREMENTS: Serum sclerostin, bone turnover markers, and bone mineral density and quality were measured at baseline. Participants were followed for clinical fractures and all-cause mortality. RESULTS: Partial correlation analysis adjusted for age, weight, and renal function revealed a significant positive correlation between sclerostin levels and calcaneal stiffness and radial and phalangeal speed of sound (all P < .01) and a significant negative correlation between sclerostin levels and osteocalcin, serum C-terminal telopeptide of type I collagen, and parathyroid hormone (PTH; P < .05). After a mean follow-up of 27 ± 8 months, 139 participants (26%) had died and 64 had a hip or other nonvertebral fracture (12%). Sclerostin was not predictive of mortality. In women with a negative fracture history, it was significantly but not linearly associated with fracture risk. CONCLUSION: In institutionalized elderly women, there is a significant relationship between serum sclerostin levels and QUS indices, bone turnover, and PTH, but sclerostin was not strongly associated with important clinical outcomes. Thus, it remains unclear whether sclerostin is a clinically useful predictor of fractures or mortality, at least in this setting.

Vitamin D status and its association with season, hospital and sepsis mortality in critical illness.

INTRODUCTION: Vitamin D plays a key role in immune function. Deficiency may aggravate the incidence and outcome of infectious complications in critically ill patients. We aimed to evaluate the prevalence of vitamin D deficiency and the correlation between serum 25-hydroxyvitamin D (25(OH) D) and hospital mortality, sepsis mortality and blood culture positivity. METHODS: In a single-center retrospective observational study at a tertiary care center in Graz, Austria, 655 surgical and nonsurgical critically ill patients with available 25(OH) D levels hospitalized between September 2008 and May 2010 were included. Cox regression analysis adjusted for age, gender, severity of illness, renal function and inflammatory status was performed. Vitamin D levels were categorized by month-specific tertiles (high, intermediate, low) to reflect seasonal variation of serum 25(OH) D levels. RESULTS: Overall, the majority of patients were vitamin D deficient (<20 ng/ml; 60.2%) or insufficient (≥20 and <30 ng/dl; 26.3%), with normal 25(OH) D levels (>30 ng/ml) present in only 13.6%. The prevalence of vitamin D deficiency and mean 25(OH) D levels was significantly different in winter compared to summer months (P <0.001). Hospital mortality was 20.6% (135 of 655 patients). Adjusted hospital mortality was significantly higher in patients in the low (hazard ratio (HR) 2.05, 95% confidence interval (CI) 1.31 to 3.22) and intermediate (HR 1.92, 95% CI 1.21 to 3.06) compared to the high tertile. Sepsis was identified as cause of death in 20 of 135 deceased patients (14.8%). There was no significant association between 25(OH) D and C-reactive protein (CRP), leukocyte count or procalcitonin levels. In a subgroup analysis (n = 244), blood culture positivity rates did not differ between tertiles (23.1% versus 28.2% versus 17.1%, P = 0.361). CONCLUSIONS: Low 25(OH) D status is significantly associated with mortality in the critically ill. Intervention studies are needed to investigate the effect of vitamin D substitution on mortality and sepsis rates in this population.

Effects of teriparatide on cortical histomorphometric variables in postmenopausal women with or without prior alendronate treatment.

Cortical bone, the dominant component of the human skeleton by volume, plays a key role in protecting bones from fracture. We analyzed the cortical bone effects of teriparatide treatment in postmenopausal women with osteoporosis who had previously received long-term alendronate (ALN) therapy or were treatment naïve (TN). Tetracycline-labeled paired iliac crest biopsies obtained from 29 ALN-pretreated and 16 TN women were evaluated for dynamic histomorphometric parameters of bone formation at the periosteal, endocortical and intracortical bone compartments, before and after 24months of teriparatide treatment. At baseline, the frequency of specimens without any endocortical and periosteal tetracycline labeling, and the percentage of quiescent osteons, was higher in the ALN than the TN group. Endocortical and periosteal mineralizing surface (MS/BS%), periosteal bone formation rate (BFR/BS), mineral apposition rate (MAR) and the number of intracortical forming osteons were significantly lower in the ALN-pretreated patients than in the TN group. Following teriparatide treatment, the frequency of endocortical and periosteal unlabeled biopsies decreased; in the ALN-pretreated group the percentage of quiescent osteons decreased and, in contrast, forming and resorbing osteons were increased. Teriparatide treatment resulted in significant increases of MAR in the endocortical, and MS/BS% in the periosteal compartment in the ALN-pretreated group. Most indices of bone formation remained lower in the ALN-pretreated group compared with the TN group at study end. Endocortical wall width was increased in both ALN-pretreated and TN groups. Cortical porosity and cortical thickness were significantly increased in the ALN-pretreated group after teriparatide treatment. Our results suggest that 24months of teriparatide treatment increases cortical bone formation and cortical turnover in patients who were either TN or had previous ALN therapy.

Cystatin C is independently associated with total and cardiovascular mortality in individuals undergoing coronary angiography. The Ludwigshafen Risk and Cardiovascular Health (LURIC) study.

AIMS: Cystatin C is a well established marker of kidney function. There is evidence that cystatin C concentrations are also associated with mortality. The present analysis prospectively evaluated the associations of cystatin C with all-cause and cardiovascular (CV) mortality in a well-characterized cohort of persons undergoing angiography, but without overt renal insufficiency. METHODS: Cystatin C was available in 2998 persons (mean age: 62.7 ± 10.5 years; 30.3% women). Of those 2346 suffered from coronary artery disease (CAD) and 652 (controls) did not. Creatinine (mean ± SD: 83.1 ± 47.8 vs. 74.1 ± 24.7 µmol/L, p = 0.036) but not Cystatin C (mean ± SD: 1.02 ± 0.44 vs. 0.92 ± 0.26 mg/L, p = 0.065) was significantly higher in patients with CAD. After a median follow-up of 9.9 years, in total 898 (30%) deaths occurred, 554 (18.5%) due to CV disease and 326 (10.9%) due to non-CV causes. Multivariable-adjusted Cox analysis (adjusting for eGFR and established cardiovascular risk factors, lipid lowering therapy, angiographic coronary artery disease, and C-reactive protein) revealed that patients in the highest cystatin C quartile were at an increased risk for all-cause (hazard ratio (HR) 1.93, 95% CI 1.50-2.48) and CV mortality (HR 2.05 95% CI 1.48-2.84) compared to those in the lowest quartile. The addition of cystatin C to a model consisting of established cardiovascular risk factors increased the area under the receiver-operating characteristic curve for CV and all-cause mortality, but the difference was statistically not significant. However, reclassification analysis revealed significant improvement by addition of cystatin C for CV and all-cause mortality (p < 0.001), respectively. CONCLUSION: The concentration of cystatin C is strongly associated with long-term all-cause and cardiovascular mortality in patients referred to coronary angiography, irrespective of creatinine-based renal function.

Circulating aldosterone and mortality in female nursing home residents.

OBJECTIVES: To date studies evaluating the relation between circulating aldosterone levels and mortality in elderly female individuals are lacking. We therefore aimed to assess the relationship between circulating aldosterone levels and mortality in a population-based cohort study of female nursing home residents. METHODS: Individuals aged 70years and older were recruited from 95 nursing homes in Austria. Participants were enrolled and followed up by mobile study teams. All participants underwent an extensive health examination and were followed until death or end of the study. Serum aldosterone concentration (SAC) was measured at baseline after exclusion of twenty seven patients taking mineralocorticoid-receptor (MR) blockers. RESULTS: Median SAC was 171.1 (IQR: 103.2-303.4) pg/mL (normal range: 30-400) in 471 female individuals (mean age: 83.7±6.2years). After a median follow-up of 27±8months, a total of 121 (25.7%) participants died. In multivariable Cox proportional hazard analysis, SAC levels stratified in quartiles were significantly associated with all-cause mortality. Compared with the reference (first) SAC quartile, the Cox proportional hazard ratio (confidence interval 95%) for the fourth SAC quartiles was 1.94, 95% CI=1.08-3.46, p=0.026. We found statistically significant interaction terms between SAC-related mortality and the presence of advanced heart failure (NYHA functional class III; p=0.038), HbA1c (p=0.043) and eGFR levels (p=0.030). CONCLUSIONS: Higher circulating aldosterone levels are related to an increased mortality risk in elderly female nursing home residents. Interventional studies are needed to assess the potential influence of MR blockade on "hard" clinical outcomes in individuals aged 70years and older.

Correction of vitamin D deficiency in critically ill patients - VITdAL@ICU study protocol of a double-blind, placebo-controlled randomized clinical trial.

BACKGROUND: Vitamin D deficiency is associated with multiple adverse health outcomes including increased morbidity and mortality in the general population and in critically ill patients. However, no randomized controlled trial has evaluated so far whether treatment with sufficiently large doses of vitamin D can improve clinical outcome of patients in an intensive care setting. METHODS/DESIGN: The VITdAL@ICU trial is an investigator-initiated, non-commercial, double-blind, placebo-controlled randomized clinical trial. This study compares high-dose oral cholecalciferol (vitamin D3) versus placebo treatment in a mixed population of 480 critically ill patients with low 25-hydroxyvitamin-D levels at study enrollment (≤ 20ng/ml). Following an initial loading dose of 540,000 IU of vitamin D3, patients receive 90,000 IU of vitamin D3 on a monthly basis for 5 months. The study is designed to compare clinical outcome in the two study arms with the primary endpoint being length of hospital stay. Secondary endpoints include among others length of ICU stay, the percentage of patients with 25(OH)D levels > 30 ng/ml at day 7, ICU and hospital mortality and duration of mechanical ventilation. We describe here the VITdAL@ICU study protocol for the primary report. DISCUSSION: This trial is designed to evaluate whether high-dose vitamin D3 is able to improve morbidity and mortality in a mixed population of adult critically ill patients and correct vitamin D deficiency safely. TRIAL REGISTRATION: ClinicalTrials: NCT01130181.

Allelic determinants of vitamin d insufficiency, bone mineral density, and bone fractures.

CONTEXT: Low 25-hydroxycholecalciferol [25(OH) vitamin D] status is known to play an important role in many diseases with focus on bone health. OBJECTIVE: Based on recently reported genetic determinants of vitamin D insufficiency, we aimed to analyze genetic variants of group-specific component (GC), 7-dehydrocholesterol reductase (DHCR7), and cytochrome P450IIR-1 (CYP2R1) for association with vitamin D levels, bone mineral density (BMD), and bone fractures. DESIGN: We conducted a cross-sectional BMD and fracture study and a prospective cohort study. SETTING: The cross-sectional study comprised participants of a BMD screening study, and the prospective cohort study comprised nursing home subjects. PATIENTS: The cross-sectional study included 342 subjects (mean age, 55.3 ± 12.0 yr), and the prospective study included 1093 subjects (mean age, 84.0 ± 6.0 yr). INTERVENTIONS: Patients were stratified by GC, DHCR7, and CYP2R1 genotypes. For each gene, the allele associated with lower 25(OH) vitamin D levels was designated as "risk allele." The potential role of these risk alleles in fracture risk was analyzed by logistic regression analysis including age and sex as confounders. MAIN OUTCOME MEASURES: We measured BMD and fractures. RESULTS: GC genotypes were significantly associated with lower mean 25(OH) vitamin D levels in both cohorts (P = 0.001 and P = 0.048, respectively). There was no significant association of BMD with any of the genotypes. None of the alleles was associated with past fractures, whereas the DHCR7 G-allele was significantly associated with prospective fractures (odds ratio, 0.68; 95% confidence interval, 0.51-0.92; P = 0.011). CONCLUSIONS: The DHCR7 gene polymorphism may be a predictor for fracture risk.