Abstract
Context
Total 25-hydroxyvitamin D 25(OH)D is mainly bound to vitamin d-binding protein (DBP). Bioavailable 25(OH)D consists of albumin-bound and free 25(OH)D and is available for metabolic ...processes. As sex steroids influence DBP, hormonal treatment (HT) in transgender people might affect DBP and consequently the available 25(OH)D. Total 25(OH)D might therefore not well represent bioavailable and free 25(OH)D.
Objective
To investigate the effects of HT on DBP, and total, bioavailable, and free 25(OH)D, and to assess whether total 25(OH)D well represents bioavailable and free 25(OH)D.
Design
A prospective study.
Setting
A university hospital.
Participants
Twenty-nine transwomen and 30 transmen.
Intervention
Estradiol and cyproterone acetate in transwomen, and testosterone in transmen.
Main Outcome Measures
DBP, total 25(OH)D, free 25(OH)D, and albumin were measured at baseline and after 3 months of HT, and deseasonalized total 25(OH)D and bioavailable 25(OH)D were calculated.
Results
DBP changed with +5% (95% CI, −0% to 10%; P = 0.06) in transwomen and with −3% (95% CI: −9% to 3%; P = 0.34) in transmen. No significant changes were found in total 25(OH)D, free, and bioavailable 25(OH)D concentrations. Total 25(OH)D was well correlated with bioavailable (R2, 0.75) and free (R2, 0.76) 25(OH)D.
Conclusions
DBP tended to increase in transwomen, but did not change in transmen. HT did not influence free 25(OH)D, total 25(OH)D, and bioavailable 25(OH)D concentrations in transwomen and transmen. As total 25(OH)D represents bioavailable and free 25(OH)D well, HT in transgender people does not interfere with the assessment of vitamin D status.
DBP tended to increase in transwomen, but not in transmen. Total, bioavailable, and free 25(OH)D did not change. Total 25(OH)D was well correlated with bioavailable and free 25(OH)D.
Aims
To investigate the association between use of β‐blockers and β‐blocker characteristics – selectivity, lipid solubility, intrinsic sympathetic activity (ISA) and CYP2D6 enzyme metabolism – and ...fall risk.
Methods
Data from two prospective studies were used, including community‐dwelling individuals, n = 7662 (the Rotterdam Study) and 2407 (B‐PROOF), all aged ≥55 years. Fall incidents were recorded prospectively. Time‐varying β‐blocker use was determined using pharmacy dispensing records. Cox proportional hazard models adjusted for age and sex were applied to determine the association between β‐blocker use, their characteristics – selectivity, lipid solubility, ISA and CYP2D6 enzyme metabolism – and fall risk. The results of the studies were combined using meta‐analyses.
Results
In total 2917 participants encountered a fall during a total follow‐up time of 89 529 years. Meta‐analysis indicated no association between use of any β‐blocker, compared to nonuse, and fall risk, hazard ratio (HR) = 0.97 95% confidence interval (CI) 0.88–1.06. Use of a selective β‐blocker was also not associated with fall risk, HR = 0.92 (95%CI 0.83–1.01). Use of a nonselective β‐blocker was associated with an increased fall risk, HR = 1.22 (95%CI 1.01–1.48). Other β‐blocker characteristics including lipid solubility and CYP2D6 enzyme metabolism were not associated with fall risk.
Conclusion
Our study suggests that use of a nonselective β‐blocker, contrary to selective β‐blockers, is associated with an increased fall risk in an older population. In clinical practice, β‐blockers have been shown effective for a variety of cardiovascular indications. However, fall risk should be considered when prescribing a β‐blocker in this age group, and the pros and cons for β‐blocker classes should be taken into consideration.
Objective
To investigate factors that together with hand or hip/knee osteoarthritis (OA) could contribute to functional decline over a year’s time in elderly individuals.
Methods
The data of 1,886 ...individuals between ages 65 and 85 years in a prospective, observational population‐based study with 12–18 months of follow‐up in the context of the European Project on Osteoarthritis were analyzed. The outcome measures were self‐reported hand and hip/knee functional decline, evaluated using a minimum clinically important difference of 4 on the Australian/Canadian Hand OA Index and of 2 on the Western Ontario and McMaster Universities Osteoarthritis Index hip/knee physical function subscales, both normalized to 0–100. Using regression models adjusted for sex, age, country, and education level, the baseline factors considered were clinical hand or hip/knee OA, pain, analgesic/antiinflammatory medications, comorbidities, social isolation, income, walking time, grip strength, physical activity time, and medical/social care.
Results
After a year, 453 participants were identified as having worse hand functionality and 1,389 as not worse. Hand OA, anxiety, walking time, and grip strength were risk factors for hand functional decline; pain was a confounder of the effect of hand OA.
Analgesic/antiinflammatory medications mediated the combined effect of hip/knee OA plus pain on functional decline in the 554 individuals classified as having worse hip/knee functionality and the 1,291 persons who were not worse. Peripheral artery disease, obesity, and cognitive impairment were other baseline risk factors.
Conclusion
Study findings showed that together with emotional status and chronic physical and cognitive conditions, OA affects hand and hip/knee functional decline.
Low vitamin D status has been associated with impaired glycemic control in patients with type 2 diabetes. The purpose of our study was to evaluate the effect of vitamin D supplementation on glycemic ...control in patients with type 2 diabetes.
This randomized, double-blind, placebo-controlled trial was conducted in 275 adult patients with type 2 diabetes without insulin treatment. Patients were randomly assigned to receive either vitamin D3 (50,000 IU/month) or placebo for 6 months. To assess the primary outcome of the study, change in HbA(1c), we performed a linear regression analysis.
Mean baseline serum 25-hydroxyvitamin D 25(OH)D increased from 60.6 ± 23.3 to 101.4 ± 27.6 nmol/L and 59.1 ± 23.2 to 59.8 ± 23.2 nmol/L in the vitamin D and placebo group, respectively. Mean baseline HbA(1c) was 6.8 ± 0.5% (51 ± 6 mmol/mol) in both groups. After 6 months, no effect was seen on HbA(1c) (mean difference: β = 0.4 95% CI -0.6 to 1.5; P = 0.42) and other indicators of glycemic control (HOMA of insulin resistance, fasting insulin, and glucose) in the entire study population. Subgroup analysis in patients with a serum 25(OH)D <50 nmol/L or an HbA(1c) level >7% (53 mmol/mol) did not differ the results.
In a well-controlled group of patients with type 2 diabetes, intermittent high-dose vitamin D supplementation did not improve glycemic control.
Abstract
Studying the genome of centenarians may give insights into the molecular mechanisms underlying extreme human longevity and the escape of age-related diseases. Here, we set out to construct ...polygenic risk scores (PRSs) for longevity and to investigate the functions of longevity-associated variants. Using a cohort of centenarians with maintained cognitive health (N = 343), a population-matched cohort of older adults from 5 cohorts (N = 2905), and summary statistics data from genome-wide association studies on parental longevity, we constructed a PRS including 330 variants that significantly discriminated between centenarians and older adults. This PRS was also associated with longer survival in an independent sample of younger individuals (p = .02), leading up to a 4-year difference in survival based on common genetic factors only. We show that this PRS was, in part, able to compensate for the deleterious effect of the APOE-ε4 allele. Using an integrative framework, we annotated the 330 variants included in this PRS by the genes they associate with. We find that they are enriched with genes associated with cellular differentiation, developmental processes, and cellular response to stress. Together, our results indicate that an extended human life span is, in part, the result of a constellation of variants each exerting small advantageous effects on aging-related biological mechanisms that maintain overall health and decrease the risk of age-related diseases.
Purpose
Higher folate and vitamin-B12 have been linked to lower risk of overweight. However, whether this is a causal effect of these B-vitamins on obesity risk remains unclear and evidence in older ...individuals is scarce. This study aimed to assess the role of B-vitamin supplementation and levels on body composition in older individuals.
Methods
A double-blind, randomized controlled trial in 2919 participants aged ≥ 65 years with elevated homocysteine levels. The intervention comprised a 2-year supplementation with a combination of folic acid (400 µg) and vitamin B12 (500 µg), or with placebo. Serum folate, vitamin-B12, active vitamin-B12 (HoloTC), methylmalonic acid (MMA), and anthropometrics were measured at baseline and after 2 years of follow-up. Dietary intake of folate and vitamin-B12 was measured at baseline in a subsample (
n
= 603) using a validated food-frequency questionnaire. Fat mass index (FMI) and fat-free mass index (FFMI) were assessed with Dual Energy X-ray absorptiometry (DXA).
Results
Cross-sectional analyses showed that a 1 nmol/L higher serum folate was associated with a 0.021 kg/m
2
lower BMI (95% CI − 0.039; − 0.004). Higher HoloTC (per pmol/L log-transformed) was associated with a 0.955 kg/m
2
higher FMI (95% CI 0.262; 1.647), and higher MMA (per μgmol/L) was associated with a 1.108 kg/m
2
lower FMI (95% CI − 1.899; − 0.316). However, random allocation of B-vitamins did not have a significant effect on changes in BMI, FMI or FFMI during 2 years of intervention.
Conclusions
Although observational data suggested that folate and vitamin B12 status are associated with body composition, random allocation of a supplement with both B-vitamins combined versus placebo did not confirm an effect on BMI or body composition.
To what extent endogenous subclinical thyroid disorders contribute to impaired physical and cognitive function, depression, and mortality in older individuals remains a matter of debate.
A ...population-based, prospective cohort of the Longitudinal Aging Study Amsterdam.
TSH and, if necessary, thyroxine and triiodothyronine levels were measured in individuals aged 65 years or older. Participants were classified according to clinical categories of thyroid function. Participants with overt thyroid disease or use of thyroid medication were excluded, leaving 1219 participants for analyses. Outcome measures were physical and cognitive function, depressive symptoms (cross-sectional), and mortality (longitudinal)
Sixty-four (5.3%) individuals had subclinical hypothyroidism and 34 (2.8%) individuals had subclinical hyperthyroidism. Compared with euthyroidism (n=1121), subclinical hypo-, and hyper-thyroidism were not significantly associated with impairment of physical or cognitive function, or depression. On the contrary, participants with subclinical hypothyroidism did less often report more than one activity limitation (odds ratio 0.44, 95% confidence interval (CI) 0.22-0.86). After a median follow-up of 10.7 years, 601 participants were deceased. Subclinical hypo- and hyper-thyroidism were not associated with increased overall mortality risk (hazard ratio 0.89, 95% CI 0.59-1.35 and 0.69, 95% CI 0.40-1.20 respectively).
This study does not support disadvantageous effects of subclinical thyroid disorders on physical or cognitive function, depression, or mortality in an older population.
Studies of vitamin D and calcium for fracture prevention have produced inconsistent results, as a result of different vitamin D status and calcium intake at baseline, different doses and poor to ...adequate compliance. This study tries to define the types of patients, both at risk of osteoporosis and with established disease, who may benefit from calcium and vitamin D supplementation. The importance of adequate compliance in these individuals is also discussed. Calcium and vitamin D therapy has been recommended for older persons, either frail and institutionalized or independent, with key risk factors including decreased bone mineral density (BMD), osteoporotic fractures, increased bone remodelling as a result of secondary hyperparathyroidism and increased propensity to falls. In addition, treatment of osteoporosis with a bisphosphonate was less effective in patients with vitamin D deficiency. Calcium and vitamin D supplementation is a key component of prevention and treatment of osteoporosis unless calcium intake and vitamin D status are optimal. For primary disease prevention, supplementation should be targeted to those with dietary insufficiencies. Several serum 25-hydroxyvitamin D (25(OH)D) cut-offs have been proposed to define vitamin D insufficiency (as opposed to adequate vitamin D status), ranging from 30 to 100 nmol/l. Based on the relationship between serum 25(OH)D, BMD, bone turnover, lower extremity function and falls, we suggest that 50 nmol/l is the appropriate serum 25(OH)D threshold to define vitamin D insufficiency. Supplementation should therefore generally aim to increase 25(OH)D levels within the 50-75 nmol/l range. This level can be achieved with a dose of 800 IU/day vitamin D, the dose that was used in successful fracture prevention studies to date; a randomized clinical trial assessing whether higher vitamin D doses achieve a greater reduction of fracture incidence would be of considerable interest. As calcium balance is not only affected by vitamin D status but also by calcium intake, recommendations for adequate calcium intake should also be met. The findings of community-based clinical trials with vitamin D and calcium supplementation in which compliance was moderate or less have often been negative, whereas studies in institutionalized patients in whom medication administration was supervised ensuring adequate compliance demonstrated significant benefits.
Age-related cognitive decline has large-scale functional and economic consequences and understanding its' pathophysiological mechanisms is therefore essential. Previous research has suggested ...associations between hormones adiponectin, ghrelin and leptin and neurodegenerative disease. However, their association with age-related cognitive decline has not been fully described. We examine the association between serum high-molecular-weight (HMW) adiponectin, ghrelin and leptin and age-related cognitive decline in older adults.
The associations between HMW adiponectin, ghrelin and leptin and the Mini-Mental-State-Examination, Coding task (Coding), 15 Words Test (15WT) and composite Z-score (general cognitive function) were analyzed by means of a sex-stratified multivariable linear regression analysis in a population-based cohort of 898 older adults at baseline and after 3 years of follow-up.
In women, we found a positive association between HMW adiponectin and general cognitive function at baseline (fully adjusted model composite Z-score standardized regression co-efficient beta β = .089, p = .025). After 3 years of follow-up, HMW adiponectin was associated with more decline in general cognitive function and information processing speed (fully adjusted model composite Z-score β = -.123, p = .018; Coding β = -.116, p = .027). Ghrelin and leptin were significantly associated with memory in a baseline subgroup analysis of older women. For men, we found no significant associations at baseline or follow-up.
Our results show variable associations between hormones HMW adiponectin, ghrelin and leptin and age-related cognitive decline in women but not in men. As there was no clear trend, all our results should be interpreted with caution.
Fibrodysplasia Ossificans Progressiva (FOP) is a genetic, progressive and devastating disease characterized by severe heterotopic ossification (HO), loss of mobility and early death. There are no FDA ...approved medications. The STOPFOP team identified AZD0530 (saracatinib) as a potent inhibitor of the ALK2/ACVR1-kinase which is the causative gene for this rare bone disease. AZD0530 was proven to prevent HO formation in FOP mouse models. The STOPFOP trial investigates the repositioning of AZD0530, originally developed for ovarian cancer treatment, to treat patients with FOP.
The STOPFOP trial is a phase 2a study. It is designed as a European, multicentre, 6-month double blind randomized controlled trial of AZD0530 versus placebo, followed by a 12-month trial comparing open-label extended AZD0530 treatment with natural history data as a control. Enrollment will include 20 FOP patients, aged 18-65 years, with the classic FOP mutation (ALK2 R206H). The primary endpoint is objective change in heterotopic bone volume measured by low-dose whole-body computer tomography (CT) in the RCT phase. Secondary endpoints include
F NaF PET activity and patient reported outcome measures.
Clinical trials in rare diseases with limited study populations pose unique challenges. An ideal solution for limiting risks in early clinical studies is drug repositioning - using existing clinical molecules for new disease indications. Using existing assets may also allow a more fluid transition into clinical practice. With positive study outcome, AZD0530 may provide a therapy for FOP that can be rapidly progressed due to the availability of existing safety data from 28 registered clinical trials with AZD0530 involving over 600 patients.
EudraCT, 2019-003324-20. Registered 16 October 2019, https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-003324-20/NL .
gov , NCT04307953 . Registered 13 March 2020.
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