The role of plasma concentrations and drug characteristics of beta-blockers in fall risk of older persons

Beta-blocker usage is inconsistently associated with increased fall risk in the literature. However, due to age-related changes and interindividual heterogeneity in pharmacokinetics and dynamics, it is difficult to predict which older adults are more at risk for falls. Therefore, we wanted to explore whether elevated plasma concentrations of selective and nonselective beta-blockers are associated with an increased risk of falls in older beta-blocker users. To answer our research question, we analyzed samples of selective (metoprolol, n = 316) and nonselective beta-blockers (sotalol, timolol, propranolol, and carvedilol, n = 179) users from the B-PROOF cohort. The associations between the beta-blocker concentration and time to first fall were assessed using Cox proportional hazard models. Change of concentration over time in relation to fall risk was assessed with logistic regression models. Models were adjusted for potential confounders. Our results showed that above the median concentration of metoprolol was associated with an increased fall risk (HR 1.55 [1.11–2.16], p =.01). No association was found for nonselective beta-blocker concentrations. Also, changes in concentration over time were not associated with increased fall risk. To conclude, metoprolol plasma concentrations were associated with an increased risk of falls in metoprolol users while no associations were found for nonselective beta-blockers users. This might be caused by a decreased β1-selectivity in high plasma concentrations. In the future, beta-blocker concentrations could potentially help clinicians estimate fall risk in older beta-blockers users and personalize treatment.</p

Contemporary management of primary parapharyngeal space tumors

The parapharyngeal space is a complex anatomical area. Primary parapharyngeal tumors are rare tumors and 80% of them are benign. A variety of tumor types can develop in this location; most common are salivary gland neoplasm and neurogenic tumors. The management of these tumors has improved greatly owing to the developments in imaging techniques, surgery, and radiotherapy. Most tumors can be removed with a low rate of complications and recurrence. The transcervical approach is the most frequently used. In some cases, minimally invasive approaches may be used alone or in combination with a limited transcervical route, allowing large tumors to be removed by reducing morbidity of expanded approaches. An adequate knowledge of the anatomy and a careful surgical plan is essential to tailor management according to the patient and the tumor. The purpose of the present review was to update current aspects of knowledge related to this more challenging area of tumor occurrence.Peer reviewe

Genetically predicted circulating B vitamins in relation to digestive system cancers

Funder: United Kingdom Research and Innovation Future Leaders Fellowship (MR/T043202/1)Funder: EC‐Innovative Medicines Initiative (BigData@Heart)Funder: Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (204623/Z/16/Z)Abstract: Background: Folate, vitamin B6 and vitamin B12 have been associated with digestive system cancers. We conducted a two-sample Mendelian randomisation study to assess the causality of these associations. Methods: Two, one and 14 independent single nucleotide polymorphisms associated with serum folate, vitamin B6 and vitamin B12 at the genome-wide significance threshold were selected as genetic instruments. Summary-level data for the associations of the vitamin-associated genetic variants with cancer were obtained from the UK Biobank study including 367,561 individuals and FinnGen consortium comprising up to 176,899 participants. Results: Genetically predicted folate and vitamin B6 concentrations were not associated with overall cancer, overall digestive system cancer or oesophageal, gastric, colorectal or pancreatic cancer. Genetically predicted vitamin B12 concentrations were positively associated with overall digestive system cancer (ORSD, 1.12; 95% CI 1.04, 1.21, p = 0.003) and colorectal cancer (ORSD 1.16; 95% CI 1.06, 1.26, p = 0.001) in UK Biobank. Results for colorectal cancer were consistent in FinnGen and the combined ORSD was 1.16 (95% CI 1.08, 1.25, p < 0.001). There was no association of genetically predicted vitamin B12 with any other site-specific digestive system cancers or overall cancer. Conclusions: These results provide evidence to suggest that elevated serum vitamin B12 concentrations are associated with colorectal cancer

The impact of thiazide diuretics on bone mineral density and the trabecular bone score: the Rotterdam Study

The decreased risk of osteoporotic fractures in thiazide diuretics (TD) users is possibly not only caused by an increase in bone mineral density (BMD), but by an increase in other determinants of bone strength as well, such as the trabecular bone score (TBS). To test this hypothesis, we studied the association between TD use and both lumbar spine BMD (LS-BMD) and lumbar spine TBS (LS-TBS) cross-sectionally in 6096 participants from the Rotterdam Study, as well as the association between TD use and bone turnover estimated by serum osteocalcin levels. We found that past and current use of TD were associated with an increase of LS-BMD (β = 0.021 g/cm 2 (95% CI: 0.006;0.036) and β = 0.016 g/cm 2 (95% CI: 0.002;0.031), respectively). Use of ≥1 defined daily dose (DDD) (β = 0.028, 95% CI: 0.010;0.046; p for trend within DDD of use 365 days (β = 0.033, 95% CI: 0.014;0.052; p for trend within duration of use <0.001) were positively associated with LS-BMD. No significant association between TD use and LS-TBS was observed. Mean serum osteocalcin levels were significantly different between users and non-users of TD (20.2 ng/ml (SD 8.3) and 22.5 ng/ml (SD 17.0), respectively, p < 0.001). Furthermore, linear regression analysis showed that the use of TD was associated with a 3.2 ng/l (95% CI: −4.4.; −2.0) lower serum osteocalcin level compared to non-use of TD, when adjusted for Rotterdam Study cohort, age, and sex. Our results may implicate that the decreased fracture risk in TD users is explained by increased bone mass rather than by improved bone microarchitecture. Alternatively, changes in bone microarchitecture might not be detected through TBS and more sophisticated techniques are possibly needed to study a potential effect of TD on bone microarchitecture

The association between apathy, decline in physical performance, and falls in older persons

Background: Symptoms of apathy are common in older persons. Negative effects on physical performance and fall risk are plausible, considering the pathophysiology of apathy. However, literature is scarce. Aim: To longitudinally assess the association between apathy and (1) decline of physical performance and (2) the number of falls in older community-dwelling persons. Methods: The ‘B vitamins for the PRevention Of Osteoporotic Fractures’ study provided data on 2919 older persons over a period of 2 years. Apathy was assessed using the Geriatric Depression Scale 3. A physical performance score (PPS) was calculated using three performance tests. Falls were registered prospectively. We calculated adjusted odds ratios (ORs), Incidence Rate Ratios (IRRs), and their 95% confidence intervals. Effect modification by age and gender was investigated. We also investigated mediation by baseline PPS for the association between apathy and the number of falls. Results: Apathy and decline of PPS were independently associated. After stratification, the effect only remained in men. Age was an effect modifier; higher ORs for decreasing age. Apathy was also independently associated with the number of falls. After stratification, women had higher IRRs than men. Age modified the association in the opposite direction: higher IRRs for increasing age. Baseline PPS was a mediator in the association. Conclusion: The impact of apathy on physical performance and fall incidents varied with age and gender. Potentially, in older individuals with apathy, fall risk is preceded by a decline in physical performance. In clinical practice, identifying apathy in older persons might be useful to target mobility preserving interventions

B-vitamins and body composition: integrating observational and experimental evidence from the B-PROOF study

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. </p