A comprehensive assessment of risk factors for falls in middle-aged adults: co-ordinated analyses of cohort studies in four countries

© 2019, International Osteoporosis Foundation and National Osteoporosis Foundation. Summary: We identified demographic, health and lifestyle factors associated with falls in adults aged 50–64 years from Australia, The Netherlands, Great Britain and Ireland. Nearly all factors were associated with falls, but there were differences between countries and between men and women. Existing falls prevention programs may also benefit middle-aged adults. Introduction: Between ages 40–44 and 60–64 years, the annual prevalence of falls triples suggesting that middle age may be a critical life stage for preventive interventions. We aimed to identify demographic, health and lifestyle factors associated with falls in adults aged 50–64 years. Methods: Harmonised data were used from four population-based cohort studies based in Australia (Australian Longitudinal Study on Women’s Health, n = 10,641, 51–58 years in 2004), Ireland (The Irish Longitudinal Study on Ageing, n = 4663, 40–64 years in 2010), the Netherlands (Longitudinal Ageing Study Amsterdam, n = 862, 55–64 years in 2012–13) and Great Britain (MRC National Survey of Health and Development, n = 2987, 53 years in 1999). Cross-sectional and prospective associations of 42 potential risk factors with self-reported falls in the past year were examined separately by cohort and gender using logistic regression. In the absence of differences between cohorts, estimates were pooled using meta-analysis. Results: In cross-sectional models, nearly all risk factors were associated with fall risk in at least one cohort. Poor mobility (pooled OR = 1.71, CI = 1.34–2.07) and urinary incontinence (OR range = 1.53–2.09) were consistently associated with falls in all cohorts. Findings from prospective models were consistent. Statistically significant interactions with cohort and sex were found for some of the risk factors. Conclusion: Risk factors known to be associated with falls in older adults were also associated with falls in middle age. Compared with findings from previous studies of older adults, there is a suggestion that specific risk factors, for example musculoskeletal conditions, may be more important in middle age. These findings suggest that available preventive interventions for falls in older adults may also benefit middle-aged adults, but tailoring by age, sex and country is required

Should prevention of falls start earlier? Co-ordinated analyses of harmonised data on falls in middle-aged adults across four population-based cohort studies

© 2018 Peeters et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The prevalence of risk factors for falls increases during middle-age, but the prevalence of falls in this age-range is often overlooked and understudied. The aim was to calculate the prevalence of falls in middle-aged adults (aged 40–64 years) from four countries. Data were from four population-based cohort studies from Australia (Australian Longitudinal Study on Women’s Health, n = 10556, 100% women, 51–58 years in 2004), Ireland (The Irish Longitudinal Study on Ageing, n = 4968, 57.5% women, 40–64 years in 2010), the Netherlands (Longitudinal Aging Study Amsterdam, n = 862, 51.6% women, 55–64 years in 2012–13) and Great Britain (MRC National Survey of Health and Development, n = 2821, 50.9% women, 53 years in 1999). In each study, falls assessment was based on recall of any falls in the past year. The prevalence of falls was calculated for the total group, for each country, for men and women separately, and for 5-year age-bands. The prevalence was higher in Australia (27.8%, women only) and the Netherlands (25.1%) than in Ireland (17.6%) and Great Britain (17.8%, p<0.001). Women (27.0%) had higher prevalences than men (15.2%, p<0.001). The prevalence increased from 8.7% in 40–44 year olds to 29.9% in 60–64 year olds in women, and from 14.7% in 45–49 year olds to 15.7% in 60–64 year olds in men. Even within 5-year age-bands, there was substantial variation in prevalence between the four cohorts. Weighting for age, sex and education changed the prevalence estimates by less than 2 percentage points. The sharp increase in prevalence of falls in middle-age, particularly among women supports the notion that falls are not just a problem of old age, and that middle-age may be a critical life stage for preventive interventions

Comparison of mannitol and methacholine to predict exercise-induced bronchoconstriction and a clinical diagnosis of asthma

<p>Abstract</p> <p>Background</p> <p>Asthma can be difficult to diagnose, but bronchial provocation with methacholine, exercise or mannitol is helpful when used to identify bronchial hyperresponsiveness (BHR), a key feature of the disease. The utility of these tests in subjects with signs and symptoms of asthma but without a clear diagnosis has not been investigated. We investigated the sensitivity and specificity of mannitol to identify exercise-induced bronchoconstriction (EIB) as a manifestation of BHR; compared this with methacholine; and compared the sensitivity and specificity of mannitol and methacholine for a clinician diagnosis of asthma.</p> <p>Methods</p> <p>509 people (6–50 yr) were enrolled, 78% were atopic, median FEV₁92.5% predicted, and a low NAEPPII asthma score of 1.2. Subjects with symptoms of seasonal allergy were excluded. BHR to exercise was defined as a ≥ 10% fall in FEV₁on at least one of two tests, to methacholine a PC₂₀≤ 16 mg/ml and to mannitol a 15% fall in FEV₁at ≤ 635 mg or a 10% fall between doses. The clinician diagnosis of asthma was made on examination, history, skin tests, questionnaire and response to exercise but they were blind to the mannitol and methacholine results.</p> <p>Results</p> <p>Mannitol and methacholine were therapeutically equivalent to identify EIB, a clinician diagnosis of asthma, and prevalence of BHR. The sensitivity/specificity of mannitol to identify EIB was 59%/65% and for methacholine it was 56%/69%. The BHR was mild. Mean EIB % fall in FEV₁in subjects positive to exercise was 19%, (SD 9.2), mannitol PD₁₅158 (CI:129,193) mg, and methacholine PC₂₀2.1(CI:1.7, 2.6)mg/ml. The prevalence of BHR was the same: for exercise (43.5%), mannitol (44.8%), and methacholine (41.6%) with a test agreement between 62 & 69%. The sensitivity and specificity for a clinician diagnosis of asthma was 56%/73% for mannitol and 51%/75% for methacholine. The sensitivity increased to 73% and 72% for mannitol and methacholine when two exercise tests were positive.</p> <p>Conclusion</p> <p>In this group with normal FEV₁, mild symptoms, and mild BHR, the sensitivity and specificity for both mannitol and methacholine to identify EIB and a clinician diagnosis of asthma were equivalent, but lower than previously documented in well-defined populations.</p> <p>Trial registration</p> <p>This was a multi-center trial comprising 25 sites across the United States of America. (NCT0025229).</p

Investigation of Variation in Gene Expression Profiling of Human Blood by Extended Principle Component Analysis

BACKGROUND: Human peripheral blood is a promising material for biomedical research. However, various kinds of biological and technological factors result in a large degree of variation in blood gene expression profiles. METHODOLOGY/PRINCIPAL FINDINGS: Human peripheral blood samples were drawn from healthy volunteers and analysed using the Human Genome U133Plus2 Microarray. We applied a novel approach using the Principle Component Analysis and Eigen-R(2) methods to dissect the overall variation of blood gene expression profiles with respect to the interested biological and technological factors. The results indicated that the predominating sources of the variation could be traced to the individual heterogeneity of the relative proportions of different blood cell types (leukocyte subsets and erythrocytes). The physiological factors like age, gender and BMI were demonstrated to be associated with 5.3% to 9.2% of the total variation in the blood gene expression profiles. We investigated the gene expression profiles of samples from the same donors but with different levels of RNA quality. Although the proportion of variation associated to the RNA Integrity Number was mild (2.1%), the significant impact of RNA quality on the expression of individual genes was observed. CONCLUSIONS: By characterizing the major sources of variation in blood gene expression profiles, such variability can be minimized by modifications to study designs. Increasing sample size, balancing confounding factors between study groups, using rigorous selection criteria for sample quality, and well controlled experimental processes will significantly improve the accuracy and reproducibility of blood transcriptome study

Dissecting Early Differentially Expressed Genes in a Mixture of Differentiating Embryonic Stem Cells

The differentiation of embryonic stem cells is initiated by a gradual loss of pluripotency-associated transcripts and induction of differentiation genes. Accordingly, the detection of differentially expressed genes at the early stages of differentiation could assist the identification of the causal genes that either promote or inhibit differentiation. The previous methods of identifying differentially expressed genes by comparing different cell types would inevitably include a large portion of genes that respond to, rather than regulate, the differentiation process. We demonstrate through the use of biological replicates and a novel statistical approach that the gene expression data obtained without prior separation of cell types are informative for detecting differentially expressed genes at the early stages of differentiation. Applying the proposed method to analyze the differentiation of murine embryonic stem cells, we identified and then experimentally verified Smarcad1 as a novel regulator of pluripotency and self-renewal. We formalized this statistical approach as a statistical test that is generally applicable to analyze other differentiation processes

Acquisition of biologically relevant gene expression data by Affymetrix microarray analysis of archival formalin-fixed paraffin-embedded tumours

Robust protocols for microarray gene expression profiling of archival formalin-fixed paraffin-embedded tissue (FFPET) are needed to facilitate research when availability of fresh-frozen tissue is limited. Recent reports attest to the feasibility of this approach, but the clinical value of these data is poorly understood. We employed state-of-the-art RNA extraction and Affymetrix microarray technology to examine 34 archival FFPET primary extremity soft tissue sarcomas. Nineteen arrays met stringent QC criteria and were used to model prognostic signatures for metastatic recurrence. Arrays from two paired frozen and FFPET samples were compared: although FFPET sensitivity was low (∼50%), high specificity (95%) and positive predictive value (92%) suggest that transcript detection is reliable. Good agreement between arrays and real time (RT)–PCR was confirmed, especially for abundant transcripts, and RT–PCR validated the regulation pattern for 19 of 24 candidate genes (overall R(2)=0.4662). RT–PCR and immunohistochemistry on independent cases validated prognostic significance for several genes including RECQL4, FRRS1, CFH and MET – whose combined expression carried greater prognostic value than tumour grade – and cmet and TRKB proteins. These molecules warrant further evaluation in larger series. Reliable clinically relevant data can be obtained from archival FFPET, but protocol amendments are needed to improve the sensitivity and broad application of this approach

Small-Animal PET Imaging of Amyloid-Beta Plaques with [11C]PiB and Its Multi-Modal Validation in an APP/PS1 Mouse Model of Alzheimer's Disease

In vivo imaging and quantification of amyloid-β plaque (Aβ) burden in small-animal models of Alzheimer's disease (AD) is a valuable tool for translational research such as developing specific imaging markers and monitoring new therapy approaches. Methodological constraints such as image resolution of positron emission tomography (PET) and lack of suitable AD models have limited the feasibility of PET in mice. In this study, we evaluated a feasible protocol for PET imaging of Aβ in mouse brain with [11C]PiB and specific activities commonly used in human studies. In vivo mouse brain MRI for anatomical reference was acquired with a clinical 1.5 T system. A recently characterized APP/PS1 mouse was employed to measure Aβ at different disease stages in homozygous and hemizygous animals. We performed multi-modal cross-validations for the PET results with ex vivo and in vitro methodologies, including regional brain biodistribution, multi-label digital autoradiography, protein quantification with ELISA, fluorescence microscopy, semi-automated histological quantification and radioligand binding assays. Specific [11C]PiB uptake in individual brain regions with Aβ deposition was demonstrated and validated in all animals of the study cohort including homozygous AD animals as young as nine months. Corresponding to the extent of Aβ pathology, old homozygous AD animals (21 months) showed the highest uptake followed by old hemizygous (23 months) and young homozygous mice (9 months). In all AD age groups the cerebellum was shown to be suitable as an intracerebral reference region. PET results were cross-validated and consistent with all applied ex vivo and in vitro methodologies. The results confirm that the experimental setup for non-invasive [11C]PiB imaging of Aβ in the APP/PS1 mice provides a feasible, reproducible and robust protocol for small-animal Aβ imaging. It allows longitudinal imaging studies with follow-up periods of approximately one and a half years and provides a foundation for translational Alzheimer neuroimaging in transgenic mice

Non-pharmacological management of osteoporosis: a consensus of the Belgian Bone Club

This consensus article reviews the various aspects of the non-pharmacological management of osteoporosis, including the effects of nutriments, physical exercise, lifestyle, fall prevention, and hip protectors. Vertebroplasty is also briefly reviewed. Non-pharmacological management of osteoporosis is a broad concept. It must be viewed as an essential part of the prevention of fractures from childhood through adulthood and the old age. The topic also includes surgical procedures for the treatment of peripheral and vertebral fractures and the post-fracture rehabilitation. The present document is the result of a consensus, based on a systematic review and a critical appraisal of the literature. Diets deficient in calcium, proteins or vitamin D impair skeletal integrity. The effect of other nutriments is less clear, although an excessive consumption of sodium, caffeine, or fibres exerts negative effects on calcium balance. The deleterious effects of tobacco, excessive alcohol consumption and a low BMI are well accepted. Physical activity is of primary importance to reach optimal peak bone mass but, if numerous studies have shown the beneficial effects of various types of exercise on bone mass, fracture data as an endpoint are scanty. Fall prevention strategies are especially efficient in the community setting, but less evidence is available about their effectiveness in preventing fall-related injuries and fractures. The efficacy of hip protectors remains controversial. This is also true for vertebroplasty and kyphoplasty. Several randomized controlled studies had reported a short-term advantage of vertebroplasty over medical treatment for pain relief, but these findings have been questioned by recent sham-controlled randomized clinical studies

Rationale and design of the B-PROOF study, a randomized controlled trial on the effect of supplemental intake of vitamin B12 and folic acid on fracture incidence

Background: Osteoporosis is a major health problem, and the economic burden is expected to rise due to an increase in life expectancy throughout the world. Current observational evidence suggests that an elevated homocysteine concentration and poor vitamin B12and folate status are associated with an increased fracture risk. As vitamin B12and folate intake and status play a large role in homocysteine metabolism, it is hypothesized that supplementation with these B-vitamins will reduce fracture incidence in elderly people with an elevated homocysteine concentration. Methods/Design. The B-PROOF (B-Vitamins for the PRevention Of Osteoporotic Fractures) study is a randomized double-blind placebo-controlled trial. The intervention comprises a period of two years, and includes 2919 subjects, aged 65 years and older, independently living or institutionalized, with an elevated homocysteine concentration ( 12 mol/L). One group receives daily a tablet with 500 g vitamin B12and 400 g folic acid and the other group receives a placebo tablet. In both tablets 15 g (600 IU) vitamin D is included. The primary outcome of the study is osteoporotic fractures. Measurements are performed at baseline and after two years and cover bone health