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1.  Predicting adherence to acupuncture appointments for low back pain: a prospective observational study 
Background
Acupuncture is a popular form of complementary and alternative medicine (CAM), but it is not clear why patients do (or do not) follow acupuncturists’ treatment recommendations. This study aimed to investigate theoretically-derived predictors of adherence to acupuncture.
Methods
In a prospective study, adults receiving acupuncture for low back pain completed validated questionnaires at baseline, 2 weeks, 3 months, and 6 months. Patients and acupuncturists reported attendance. Logistic regression tested whether illness perceptions, treatment beliefs, and treatment appraisals measured at 2 weeks predicted attendance at all recommended acupuncture appointments.
Results
Three hundred twenty-four people participated (aged 18–89 years, M = 55.9, SD = 14.4; 70% female). 165 (51%) attended all recommended acupuncture appointments. Adherence was predicted by appraising acupuncture as credible, appraising the acupuncturist positively, appraising practicalities of treatment positively, and holding pro-acupuncture treatment beliefs. A multivariable logistic regression model including demographic, clinical, and psychological predictors, fit the data well (χ 2 (21) = 52.723, p < .001), explained 20% of the variance, and correctly classified 65.4% of participants as adherent/non-adherent.
Conclusions
The results partially support the dynamic extended common-sense model for CAM use. As hypothesised, attending all recommended acupuncture appointments was predicted by illness perceptions, treatment beliefs, and treatment appraisals. However, experiencing early changes in symptoms did not predict attendance. Acupuncturists could make small changes to consultations and service organisation to encourage attendance at recommended appointments and thus potentially improve patient outcomes.
doi:10.1186/s12906-016-1499-9
PMCID: PMC5209924  PMID: 28049527
Acupuncture; Adherence; Back pain; Health knowledge, Attitudes, Practice; Illness perceptions; Treatment beliefs
2.  Epidemiology of Fractures in the United Kingdom 1988-2012: Variation with age, sex, geography, ethnicity and socioeconomic status 
Bone  2016;87:19-26.
Summary
Rates of fracture worldwide are changing. Using the Clinical Practice Research Datalink (CPRD), age, and gender, geographical, ethnic and socioeconomic trends in fracture rates across the United Kingdom were studied over a 24 year period 1988-2012. Previously observed patterns in fracture incidence by age and fracture site were evident. New data on the influence of geographic location, ethnic group and socioeconomic status were obtained.
Introduction
With secular changes in age- and sex-specific fracture incidence observed in many populations, and global shifts towards an elderly demography, it is vital for health care planners to have an accurate understanding of fracture incidence nationally. We aimed to present up to date fracture incidence data in the UK, stratified by age, sex, geographic location, ethnicity and socioeconomic status.
Methods
The Clinical Practice Research Datalink (CPRD) contains anonymised electronic health records for approximately 6.9% of the UK population. Information comes from General Practitioners, and covers 11.3 million people from 674 practices across the UK, demonstrated to be representative of the national population. The study population consisted of all permanently registered individuals aged >=18 years. Validated data on fracture incidence were obtained from their medical records, as was information on socioeconomic deprivation, ethnicity and geographic location. Age and sex-specific fracture incidence rates were calculated.
Results
Fracture incidence rates by age and sex were comparable to those documented in previous studies and demonstrated a bimodal distribution. Substantial geographic heterogeneity in age and sex adjusted fracture incidence was observed, with rates in Scotland almost 50% greater than those in London and South East England. Lowest rates of fracture were observed in black individuals of both sexes; rates of fragility fracture in white women were 4.7 times greater than in black women. Strong associations between deprivation and fracture risk were observed in hip fracture in men, with a relative risk of 1.3 (95% CI 1.21-1.41) in Index of Multiple Deprivation category 5 (representing the most deprived) compared to category 1.
Conclusions
This study presents robust estimates of fracture incidence across the UK, which will aid decisions regarding allocation of healthcare provision to populations of greatest need. It will also assist the implementation and design of strategies to reduce fracture incidence and its personal and financial impact on individuals and health services.
doi:10.1016/j.bone.2016.03.006
PMCID: PMC4890652  PMID: 26968752
3.  Health-related quality of life and a cost-utility simulation of adults in the UK with osteogenesis imperfecta, X-linked hypophosphatemia and fibrous dysplasia 
Background
Health-related quality of life of adults with osteogenesis imperfecta (OI), fibrous dysplasia (FD) and X-linked hypophosphatemia (XLH) remains poorly described. The aim of this study was to describe the HRQoL of adults with osteogenesis imperfecta, fibrous dysplasia and X-linked hypophophataemia and perform a cost-utility simulation to calculate the maximum cost that a health care system would be willing to pay for a hypothetical treatment of a rare bone disease.
Results
Participants completed the EQ-5D-5 L questionnaire between September 2014 and March 2016. For the economic simulation, we considered a hypothetical treatment that would be applied to OI participants in the lower tertile of the health utility score.
A total of 109 study participants fully completed the EQ-5D-5 L questionnaire (response rate 63%). Pain/discomfort was the most problematic domain for participants with all three diseases (FD 31%, XLH 25%, OI 16%).
The economic simulation identified an expected treatment impact of +2.5 QALYs gained per person during the 10-year period, which led to a willing to pay of £14,355 annually for a health care system willing to pay up to £50,000 for each additional QALY gained by an intervention.
Conclusions
This is the first study to quantitatively measure and compare the HRQoL of adults with OI, FD and XLH and the first to use such data to conduct an economic simulation leading to healthcare system willingness-to-pay estimates for treatment of musculoskeletal rare diseases at various cost-effectiveness thresholds.
Electronic supplementary material
The online version of this article (doi:10.1186/s13023-016-0538-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s13023-016-0538-4
PMCID: PMC5126812  PMID: 27894323
Quality of life; Economic evaluation; Osteogenesis imperfecta; Fibrous dysplasia; McCune Albright syndrome; X-linked hypophosphatemia
4.  Prevalence and risk factors for falls in older men and women: The English Longitudinal Study of Ageing 
Age and Ageing  2016;45(6):789-794.
Background
falls are a major cause of disability and death in older people. Women are more likely to fall than men, but little is known about whether risk factors for falls differ between the sexes. We used data from the English Longitudinal Study of Ageing to investigate the prevalence of falls by sex and to examine cross-sectionally sex-specific associations between a range of potential risk factors and likelihood of falling.
Methods
participants were 4,301 men and women aged 60 and over who had taken part in the 2012–13 survey of the English Longitudinal Study of Ageing. They provided information about sociodemographic, lifestyle and behavioural and medical factors, had their physical and cognitive function assessed and responded to a question about whether they had fallen down in the last two years.
Results
in multivariable logistic regression models, severe pain and diagnosis of at least one chronic disease were independently associated with falls in both sexes. Sex-specific risk factors were incontinence (odds ratio (OR), 1.48; 95% CI, 1.19, 1.85) and frailty (OR 1.69, 95% CI 1.06, 2.69) in women, and older age (OR 1.02, 95% CI 1.04, 1.07), high levels of depressive symptoms (OR 1.33, 95% CI 1.05, 1.68), and being unable to perform a standing balance test (OR 3.32, 95% CI 2.09, 5.29) in men.
Conclusion
although we found some homogeneity between the sexes in the risk factors that were associated with falls, the existence of several sex-specific risk factors suggests that gender should be taken into account in designing fall-prevention strategies.
doi:10.1093/ageing/afw129
PMCID: PMC5105823  PMID: 27496938
older people; falls; prevalence; risk factors
5.  Maternal gestational vitamin D supplementation and offspring bone health: a multicentre randomised, double-blind, placebo-controlled trial (MAVIDOS) 
Background
Maternal vitamin D status has been associated with lower bone mass of the offspring in many, but not all, observational studies. However, proof that maternal vitamin D repletion during pregnancy improves offspring bone mass is lacking.
Methods
Between 06/10/2008 and 11/02/2014, we randomly assigned pregnant women with a serum 25-hydroxyvitamin D [25(OH)D] 25-100nmol/l at 12 weeks’ gestation to either 1000IU/day cholecalciferol or matched placebo from 14 weeks’ gestation until delivery. Serum 25(OH)D was measured at 14 and 34 weeks’ gestation. Neonatal whole body bone mineral, assessed within 2 weeks after birth (n=665) by dual-energy X-ray absorptiometry (DXA), was the primary outcome. Secondary pre-specified analyses explored interactions with study centre, maternal ethnicity, parity, compliance, protocol completion, baseline BMI, baseline 25(OH)D and change in 25(OH)D from 14 to 34 weeks; and offspring sex and season of birth.
Findings
We found no difference in neonatal whole body bone mineral content (BMC) of infants born to mothers randomised to 1000IU/day cholecalciferol compared with infants born to mothers randomised to placebo [61.6g (95%CI: 60.3, 62.8g) vs 60.5g (95%CI: 59.3, 61.7g) respectively, p=0.21].
Interpretation
Supplementation of mothers with 1000IU/day cholecalciferol during pregnancy did not lead to increased offspring whole body BMC compared with placebo.
doi:10.1016/S2213-8587(16)00044-9
PMCID: PMC4843969  PMID: 26944421
Vitamin D; cholecalciferol; supplementation; trial; osteoporosis; epidemiology; DXA; pregnancy; neonate
6.  Determinants of the Maternal 25-Hydroxyvitamin D Response to Vitamin D Supplementation During Pregnancy 
Context:
Current approaches to antenatal vitamin D supplementation do not account for interindividual differences in 25-hydroxyvitamin D (25(OH)D) response.
Objective:
We assessed which maternal and environmental characteristics were associated with 25(OH)D after supplementation with cholecalciferol.
Design:
Within-randomization-group analysis of participants in the Maternal Vitamin D Osteoporosis Study trial of vitamin D supplementation in pregnancy.
Setting:
Hospital antenatal clinics.
Participants:
A total of 829 pregnant women (422 placebo, 407 cholecalciferol). At 14 and 34 weeks of gestation, maternal anthropometry, health, and lifestyle were assessed and 25(OH)D measured. Compliance was determined using pill counts at 19 and 34 weeks.
Interventions:
1000 IU/d of cholecalciferol or matched placebo from 14 weeks of gestation until delivery.
Main Outcome Measure:
25(OH)D at 34 weeks, measured in a single batch (Diasorin Liaison).
Results:
25(OH)D at 34 weeks of gestation was higher in the women randomized to vitamin D (mean [SD], 67.7 [21.3] nmol/L) compared with placebo (43.1 [22.5] nmol/L; P < .001). In women randomized to cholecalciferol, higher pregnancy weight gain from 14 to 34 weeks of gestation (kg) (β = −0.81 [95% confidence interval −1.39, −0.22]), lower compliance with study medication (%) (β = −0.28 [−0.072, −0.48]), lower early pregnancy 25(OH)D (nmol/L) (β = 0.28 [0.16, 0.40]), and delivery in the winter vs the summer (β = −10.5 [−6.4, −14.6]) were independently associated with lower 25(OH)D at 34 weeks of gestation.
Conclusions:
Women who gained more weight during pregnancy had lower 25(OH)D in early pregnancy and delivered in winter achieved a lower 25(OH)D in late pregnancy when supplemented with 1000 IU/d cholecalciferol. Future studies should aim to determine appropriate doses to enable consistent repletion of 25(OH)D during pregnancy.
Within the treatment arm of the MAVIDOS RCT, poorer 25(OH)D response to 1000IU/d cholecalciferol was associated with lower initial 25(OH)D, greater pregnancy weight gain and delivery in winter.
doi:10.1210/jc.2016-2869
PMCID: PMC5155676  PMID: 27788053
7.  Placental Size Is Associated Differentially With Postnatal Bone Size and Density 
Journal of Bone and Mineral Research  2016;31(10):1855-1864.
ABSTRACT
We investigated relationships between placental size and offspring adolescent bone indices using a population‐based, mother–offspring cohort. The Avon Longitudinal Study of Parents and Children (ALSPAC) recruited pregnant women from the southwest of England between 1991 and 1993. There were 12,942 singleton babies born at term who survived at least the first 12 months. From these, 8933 placentas were preserved in formaldehyde, with maternal permission for their use in research studies. At the approximate age of 15.5 years, the children underwent a dual‐energy X‐ray absorptiometry (DXA) scan (measurements taken of the whole body minus head bone area [BA], bone mineral content [BMC], and areal bone mineral density [aBMD]). A peripheral quantitative computed tomography (pQCT) scan (Stratec XCT2000L; Stratec, Pforzheim, Germany) at the 50% tibial site was performed at this visit and at approximately age 17.7 years. In 2010 a sample of 1680 placentas were measured and photographed. To enable comparison of effect size across different variables, predictor and outcome variables were standardized to Z‐scores and therefore results may be interpreted as partial correlation coefficients. Complete placental, DXA, and pQCT data were available for 518 children at age 15.5 years. After adjustment for gender, gestational age at birth, and age at time of pQCT, the placental area was positively associated with endosteal circumference (β [95% CI]: 0.21 [0.13, 0.30], p < 0.001), periosteal circumference (β [95% CI]: 0.19 [0.10, 0.27], p < 0.001), and cortical area (β [95% CI]: 0.10 [0.01, 0.18], p = 0.03), and was negatively associated with cortical density (β [95% CI]: –0.11 [–0.20, –0.03], p = 0.01) at age 15.5 years. Similar relationships were observed for placental volume, and after adjustment for additional maternal and offspring covariates. These results suggest that previously observed associations between placental size and offspring bone development persist into older childhood, even during puberty, and that placental size is differentially related to bone size and volumetric density. © 2016 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).
doi:10.1002/jbmr.2840
PMCID: PMC5010780  PMID: 26999363
OSTEOPOROSIS; EPIDEMIOLOGY; PLACENTA; BONE MASS; DXA; pQCT; ASLPAC
8.  Southampton PRegnancy Intervention for the Next Generation (SPRING): protocol for a randomised controlled trial 
Trials  2016;17:493.
Background
The nutritional status and health of mothers influence the growth and development of infants during pregnancy and postnatal life. Interventions that focus on improving the nutritional status and lifestyle of mothers have the potential to optimise the development of the fetus as well as improve the health of mothers themselves. Improving the diets of women of childbearing age is likely to require complex interventions that are delivered in a socially and culturally appropriate context. In this study we aim to test the efficacy of two interventions: behaviour change (Healthy Conversation Skills) and vitamin D supplementation, and to explore the efficacy of an intervention that combines both, in improving the diet quality and nutritional status of pregnant women.
Methods/design
Women attending the maternity hospital in Southampton are recruited at between 8 and 12 weeks gestation. They are randomised to one of four groups following a factorial design: Healthy Conversation Skills support plus vitamin D supplementation (1000 IU cholecalciferol) (n = 150); Healthy Conversation Skills support plus placebo (n = 150); usual care plus vitamin D supplementation (n = 150); usual care plus placebo (n = 150). Questionnaire data include parity, sunlight exposure, diet assessment allowing assessment of diet quality, cigarette and alcohol consumption, well-being, self-efficacy and food involvement. At 19 and 34 weeks maternal anthropometry is assessed and blood samples taken to measure 25(OH) vitamin D. Maternal diet quality and 25(OH) vitamin D are the primary outcomes. Secondary outcomes are women’s level of self-efficacy at 34 weeks, pregnancy weight gain, women’s self-efficacy and breastfeeding status at one month after birth and neonatal bone mineral content, assessed by DXA within the first 14 days after birth.
Discussion
This trial is evaluating two approaches to improving maternal diet: a behaviour change intervention and vitamin D supplementation. The factorial design of this trial has the advantage of enabling each intervention to be tested separately as well as allowing exploration of the synergistic effect of both interventions on women’s diets and vitamin D levels.
Trial registration
ISRCTN07227232. Registered on 13 September 2013.
doi:10.1186/s13063-016-1603-y
PMCID: PMC5059927  PMID: 27729061
9.  Sarcopenia in daily practice: assessment and management 
BMC Geriatrics  2016;16:170.
Background
Sarcopenia is increasingly recognized as a correlate of ageing and is associated with increased likelihood of adverse outcomes including falls, fractures, frailty and mortality. Several tools have been recommended to assess muscle mass, muscle strength and physical performance in clinical trials. Whilst these tools have proven to be accurate and reliable in investigational settings, many are not easily applied to daily practice.
Methods
This paper is based on literature reviews performed by members of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) working group on frailty and sarcopenia. Face-to-face meetings were afterwards organized for the whole group to make amendments and discuss further recommendations.
Results
This paper proposes some user-friendly and inexpensive methods that can be used to assess sarcopenia in real-life settings. Healthcare providers, particularly in primary care, should consider an assessment of sarcopenia in individuals at increased risk; suggested tools for assessing risk include the Red Flag Method, the SARC-F questionnaire, the SMI method or different prediction equations. Management of sarcopenia should primarily be patient centered and involve the combination of both resistance and endurance based activity programmes with or without dietary interventions. Development of a number of pharmacological interventions is also in progress.
Conclusions
Assessment of sarcopenia in individuals with risk factors, symptoms and/or conditions exposing them to the risk of disability will become particularly important in the near future.
doi:10.1186/s12877-016-0349-4
PMCID: PMC5052976  PMID: 27716195
Sarcopenia; Daily practice; Assessment; Management; Tools
10.  Ethnic and geographic variations in the epidemiology of childhood fractures in the United Kingdom 
Bone  2016;85:9-14.
Background
Fractures are common in childhood, and there is considerable variation in the reported incidence across European countries, but few data relating to ethnic and geographic differences within a single country. We therefore aimed to determine the incidence of childhood fractures in the United Kingdom (UK), and to describe age-, ethnicity- and region-specific variations.
Methods
The Clinical Practice Research Datalink (CPRD) contains anonymised electronic health records for approximately 7% of the UK population. The occurrence of a fracture between 1988-2012 was determined from the CPRD for all individuals <18 years of age, and used to calculate fracture incidence rates for age, sex and ethnicity. Regional fracture incidence rates were also calculated based on general practitioner location within 14 Strategic Health Authorities (SHA) within the UK.
Results
The overall fracture incidence rate was 137 per 10,000 person-years (py). This was higher in boys (169 per 10,000 py) than girls (103 per 10,000 py) and white children (150 per 10,000 py) compared to those of black (64 per 10,000 py) and South Asian (81 per 10,000 py) ethnicity. Marked geographic variation in incidence was observed. The highest fracture rates were observed in Wales, where boys and girls had 1.82 and 1.97 times greater incidence than those residing in Greater London, respectively.
Conclusion
In the period 1988-2012, there was marked geographic and ethnic variation in childhood fracture incidence across the UK. These findings also implicate lifestyle and socio-economic differences associated with location and ethnicity, and are relevant to policy makers in the UK and internationally.
doi:10.1016/j.bone.2016.01.015
PMCID: PMC4841386  PMID: 26802259
Fracture; children; epidemiology; osteoporosis; ethnicity; CPRD
11.  Maternal serum retinol and β-carotene concentrations and neonatal bone mineralization: results from the Southampton Women’s Survey cohort1 
Background: Studies in older adults and animals have suggested contrasting relations between bone health and different vitamin A compounds. To our knowledge, the associations between maternal vitamin A status and offspring bone development have not previously been elucidated.
Objective: We examined the associations between maternal serum retinol and β-carotene concentrations during late pregnancy and offspring bone mineralization assessed at birth with the use of dual-energy X-ray absorptiometry.
Design: In the Southampton Women’s Survey mother-offspring birth cohort, maternal health, lifestyle, and diet were assessed prepregnancy and at 11 and 34 wk of gestation. In late pregnancy, maternal serum retinol and β-carotene concentrations were measured. Offspring total body bone mineral density (BMD), bone mineral content (BMC), and bone area (BA) were measured within 2 wk after birth.
Results: In total, 520 and 446 mother-offspring pairs had measurements of maternal serum retinol and β-carotene, respectively. Higher maternal serum retinol in late pregnancy was associated with lower offspring total body BMC (β = −0.10 SD/SD; 95% CI: −0.19, −0.02; P = 0.020) and BA (β = −0.12 SD/SD; 95% CI: −0.20, −0.03; P = 0.009) but not BMD. Conversely, higher maternal serum β-carotene concentrations in late pregnancy were associated with greater total body BMC (β = 0.12 SD/SD; 95% CI: 0.02, 0.21; P = 0.016) and BA (β = 0.12 SD/SD; 95% CI: 0.03, 0.22; P = 0.010) but not BMD.
Conclusions: Maternal serum retinol and β-carotene concentrations had differing associations with offspring bone size and growth at birth: retinol was negatively associated with these measurements, whereas β-carotene was positively associated. These findings highlight the need for further investigation of the effects of maternal retinol and carotenoid status on offspring bone development.
doi:10.3945/ajcn.116.130146
PMCID: PMC5039809  PMID: 27629051
bone development; epidemiology; pregnancy; vitamin A; retinol; β-carotene
12.  DNA methylation at birth within the promoter of ANRIL predicts markers of cardiovascular risk at 9 years 
Clinical Epigenetics  2016;8(1):90.
Aims
Antisense non-coding RNA in the INK4 locus (ANRIL) fixed genetic variants have consistently been linked with coronary heart disease (CHD) risk. We investigated relationships between perinatal ANRIL promoter DNA methylation and CHD risk markers in children aged 9 years. Genetic variants in the non-coding RNA ANRIL identify it as an important CHD risk locus. Increasing evidence suggests that the early life environment may act through epigenetic processes to influence later CHD risk markers such as increased arterial pulse wave velocity (PWV, a measure of arterial stiffness) blood pressure or heart rate.
Methods and results
Using pyrosequencing, ANRIL DNA methylation at nine CpG sites was measured in the umbilical cord from 144 children in a UK mother-offspring cohort and related to the descending aorta PWV measured by velocity-encoded phase contrast MRI at age 9 years. Perinatal methylation was not associated with child’s later blood pressure, but higher methylation at CpG5 was associated with increased childhood PWV (β = 0.066 m/s/10 % methylation increase [95 % CI, 0.004 to 0.128], p = 0.037); 10 % decreases in methylation at CpG1 and CpG2 were associated with increased heart rate (CpG1 β = 1.93 [0.07 to 3.8] beats/min, p = 0.041; CpG2 β = 2.30 [0.18 to 4.41] beats/min, p = 0.033, accounting for potential confounding variables). The associations with perinatal ANRIL promoter methylation were independent of neighbouring fixed genetic variants.
Conclusions
Our findings suggest developmental epigenetic regulation of ANRIL promoter methylation as a factor in later CHD risk in children.
Electronic supplementary material
The online version of this article (doi:10.1186/s13148-016-0259-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s13148-016-0259-5
PMCID: PMC5010744  PMID: 27594927
Pregnancy; Non-coding RNA; Pulse wave velocity
13.  Greater access to fast food outlets is associated with poorer bone health in young children 
Purpose
Identifying factors that contribute to optimal childhood bone development could help pinpoint strategies to improve long term bone health. A healthy diet positively influences bone health from before birth and during childhood. This study addressed a gap in the literature by examining the relationship between residential neighbourhood food environment and bone mass in infants and children.
Methods
1107 children participating in the Southampton Women’s Survey, United Kingdom, underwent measurement of bone mineral density (BMD) and bone mineral content (BMC) at birth and four and/or six years by Dual-energy X-ray Absorptiometry (DXA). Cross-sectional observational data describing food outlets within the boundary of each participant’s neighbourhood were used to derive three measures of the food environment: the counts of fast food outlets, healthy speciality stores and supermarkets.
Results
Neighbourhood exposure to fast food outlets was associated with lower BMD in infancy (β=−0.23(z-score): 95% CI −0.38, −0.08), and lower BMC after adjustment for bone area and confounding variables (β=−0.17(z-score): 95% CI −0.32, −0.02). Increasing neighbourhood exposure to healthy speciality stores was associated with higher BMD at four and six years (β=0.16(z-score): 95% CI 0.00, 0.32 and β=0.13(z-score): 95% CI −0.01, 0.26 respectively). The relationship with BMC after adjustment for bone area and confounding variables was statistically significant at four years but not at six years.
Conclusions
The neighbourhood food environment pregnant mothers and young children are exposed to may effect bone development during early childhood. If confirmed in future studies, action to reduce access to fast food outlets could have benefits for childhood development and long term bone health.
doi:10.1007/s00198-015-3340-6
PMCID: PMC4841385  PMID: 26458387
general population studies; DXA; nutrition; developmental modelling; epidemiology
14.  The neighbourhood environment and use of neighbourhood resources in older adults with and without lower limb osteoarthritis: results from the Hertfordshire Cohort Study 
Clinical Rheumatology  2016;35(11):2797-2805.
This study aimed to examine the associations of perceptions of neighbourhood cohesion and neighbourhood problems and objectively measured neighbourhood deprivation with the use of neighbourhood resources by older adults with and without lower limb osteoarthritis (LLOA), and to assess whether these relationships are stronger in older persons with LLOA than in those without the condition. Data from the Hertfordshire Cohort Study were used. American College of Rheumatology classification criteria were used to diagnose clinical LLOA (knee and/or hip osteoarthritis). Use of neighbourhood resources was assessed using the Home and Community Environment instrument. Participants were asked about their perceptions of neighbourhood cohesion and neighbourhood problems. Objective neighbourhood deprivation was assessed using the Index of Multiple Deprivation score based on 2010 census data. Of the 401 participants (71–80 years), 74 (18.5 %) had LLOA. The neighbourhood measures were not significantly associated with use of resources in the full sample. A trend for a negative association between use of public transport and perceived neighbourhood problems was observed in participants with LLOA (OR = 0.77, 99 % CI = 0.53–1.12), whereas a trend for a positive association between perceived neighbourhood problems and use of public transport was found in participants without LLOA (OR = 1.18, 99 % CI = 1.00–1.39). The perception of more neighbourhood problems seems only to hinder older adults with LLOA to make use of public transport. Older adults with LLOA may be less able to deal with neighbourhood problems and more challenging environments than those without the condition.
doi:10.1007/s10067-016-3388-5
PMCID: PMC5063902  PMID: 27567628
Neighbourhood environment; Older population; Osteoarthritis
15.  Metabolomic identification of a novel pathway of blood pressure regulation involving hexadecanedioate 
Hypertension  2015;66(2):422-429.
High blood pressure is a major contributor to the global burden of disease and discovering novel causal pathways of blood pressure regulation has been challenging. We tested blood pressure associations with 280 fasting blood metabolites in 3980 TwinsUK females. Survival analysis for all-cause mortality was performed on significant independent metabolites (P<8.9×10−5). Replication was conducted in two independent cohorts KORA (n=1494) and Hertfordshire (n=1515). Three independent animal experiments were performed to establish causality: (1) blood pressure change after increasing circulating metabolite levels in Wistar-Kyoto rats; (2) circulating metabolite change following salt-induced blood pressure elevation in Spontaneously Hypertensive Stroke-Prone rats; (3) mesenteric artery response to noradrenaline and carbachol in metabolite treated and control rats. Of the15 metabolites that showed an independent significant association with blood pressure, only hexadecanedioate, a dicarboxylic acid, showed concordant association with blood pressure (systolic: Beta[95%C.I.]:1.31[0.83;1.78], P=6.81×10−8; diastolic: 0.81[0.5;1.11], P=2.96×10−7) and mortality (H.R.[95%C.I.]:1.49[1.08;2.05], P=0.02) in TwinsUK. The blood pressure association was replicated in KORA and Hertfordshire. In the animal experiments, we show that oral hexadecanedioate increased both circulating hexadecanedioate and blood pressure in Wistar-Kyoto rats, while blood pressure elevation with oral sodium chloride in hypertensive rats did not affect hexadecanedioate levels. Vascular reactivity to noradrenaline was significantly increased in mesenteric resistance arteries from hexadecanedioate treated rats compared to controls, indicated by the shift to the left of the concentration-response curve (P=0.013). Relaxation to carbachol did not show any difference. Our findings indicate that hexadecanedioate is causally associated with blood pressure regulation through a novel pathway that merits further investigation.
doi:10.1161/HYPERTENSIONAHA.115.05544
PMCID: PMC4490909  PMID: 26034203
hypertension; blood pressure; metabolomics; fatty acid; mortality
16.  Validity of parental recall of children’s fracture: implications for investigation of childhood osteoporosis 
Purpose
The diagnosis of osteoporosis in children requires either a vertebral compression fracture, or a significant fracture history (defined as ≥2 long bone fractures <10 years or ≥3 long bone fractures <19 years, excluding high impact fractures) and low bone mineral density. As children with frequent fractures might benefit from further evaluation, we determined whether parental reports of lifetime fracture were accurate compared to radiological reports, and if they appropriately selected children for further consideration of osteoporosis.
Methods
Parents of children (<18 years) with a musculoskeletal injury completed a questionnaire on their child’s fracture history, including age, site and mechanism of previous fracture(s). Radiological reports were reviewed to confirm the fracture.
Results
660 parents completed the questionnaire, and reported 276 previous fractures in 207 children. An injury treated at our hospital was recorded in 214 of the 276 parentally reported fractures. 34 of 214 (16%) had not resulted in a confirmed fracture. An injury was recorded for all parentally reported fractures in 150 children, but for 21% children there were inaccurate details (no evidence of fracture, incorrect site or forgotten fractures) on parent report. 18/150 children had a significant fracture history on parental report alone, but following review of radiology reports, 2 of 18 (11%) did not have clinically significant fracture histories.
Conclusions
Approximately 1 in 6 fractures reported by parents to have occurred in their child’s lifetime had not resulted in a fracture. 1 in 9 children with a significant fracture history could have been investigated unnecessarily.
doi:10.1007/s00198-015-3287-7
PMCID: PMC4778270  PMID: 26286627
Osteoporosis; fracture; mental recall; parent; paediatric
17.  Influence of maternal vitamin D status on obstetric outcomes and the foetal skeleton 
Vitamin D status is increasingly associated with wide ranging clinical outcomes. There is now a wealth of observational studies reporting on its associations with obstetric complications, including preeclampsia, gestational diabetes and mode and timing of delivery. The findings are inconsistent and currently there is a lack of data from high quality intervention studies to confirm a causal role for vitamin D in these outcomes. This is similarly true with regards to fetal development, including measures of fetal size and skeletal mineralisation. The available data justify the instatement of high-quality randomised placebo controlled trials in a range of populations and health care settings to establish potential efficacy and safety of vitamin D supplementation to improve particular outcomes.
doi:10.1530/EJE-14-0826
PMCID: PMC4968635  PMID: 25862787
Vitamin D; pregnancy; pre-eclampsia; gestational diabetes; osteoporosis; epidemiology
18.  ‘Making every contact count’: evaluation of the impact of an intervention to train health and social care practitioners in skills to support health behaviour change 
Journal of health psychology  2014;21(2):138-151.
A total of 148 health and social care practitioners were trained in skills to support behaviour change: creating opportunities to discuss health behaviours, using open discovery questions, listening, reflecting and goal-setting. At three time points post-training, use of the skills was evaluated and compared with use of skills by untrained practitioners. Trained practitioners demonstrated significantly greater use of these client-centred skills to support behaviour change compared to their untrained peers up to one year post-training. Because it uses existing services to deliver support for behaviour change, this training intervention has the potential to improve public health at relatively low cost.
doi:10.1177/1359105314523304
PMCID: PMC4678584  PMID: 24713156
Behaviour change; Evaluation; Health and social care practitioners; Healthy Conversation Skills; Intervention; Public health; Training
19.  Increase in Fracture Risk Following Unintentional Weight Loss in Postmenopausal Women: The Global Longitudinal Study of Osteoporosis in Women† 
Increased fracture risk has been associated with weight loss in postmenopausal women but the time course over which this occurs has not been established. The aim of this study was to examine the effects of unintentional weight loss of ≥10 lb (4.5 kg) in postmenopausal women on fracture risk at multiple sites up to 5 years following weight loss. Using data from the Global Longitudinal Study of Osteoporosis in Women (GLOW) we analyzed the relationships between self-reported unintentional weight loss of ≥10 lb at baseline, year 2, or year 3 and incident clinical fracture in the years following weight loss. Complete data were available in 40,179 women (mean age ± SD 68 ± 8.3 years). Five-year cumulative fracture rate was estimated using the Kaplan-Meier method, and adjusted hazard ratios for weight loss as a time-varying covariate were calculated from Cox multiple regression models. Unintentional weight loss at baseline was associated with a significantly increased risk of fracture of the clavicle, wrist, spine, rib, hip, and pelvis for up to 5 years following weight loss. Adjusted hazard ratios showed a significant association between unintentional weight loss and fracture of the hip, spine, and clavicle within 1 year of weight loss, and these associations were still present at 5 years. These findings demonstrate increased fracture risk at several sites after unintentional weight loss in postmenopausal women. This increase is seen as early as 1 year following weight loss, emphasizing the need for prompt fracture risk assessment and appropriate management to reduce fracture risk in this population.
doi:10.1002/jbmr.2810
PMCID: PMC4935593  PMID: 26861139
WEIGHT LOSS; FRACTURE; POSTMENOPAUSAL WOMEN
20.  Clustering of lifestyle risk factors and poor physical function in older adults: The Hertfordshire Cohort Study 
OBJECTIVES
To examine the relationship between number of lifestyle risk factors (out of: low physical activity, poor diet, obesity and smoking) and physical function in older community-dwelling men and women.
DESIGN
Cross-sectional study, Hertfordshire, UK
PARTICIPANTS
1682 men and 1540 women aged 59-73 years
MEASUREMENTS
Physical activity was assessed by administered questionnaire and a score derived (0-100); low activity was defined as a score ≤50. Diet was assessed by food frequency questionnaire; diet quality was assessed according to a score for a principal component analysis-defined ‘healthy’ dietary pattern. Poor diet was categorised as a dietary pattern score in the lowest quarter of the distribution. Obesity was defined as BMI ≥30kg/m2. Physical function was assessed by self-report (SF-36 PF); poor function was defined as a score in lowest quarter of the distribution. A sub-group of participants had objective assessments of physical function (timed up-and-go, timed 3-m walk, chair rises, one-legged standing balance).
RESULTS
There were graded positive increases in prevalence of poor self-reported physical function in both men and women, in parallel with increasing number of risk factors (men: adjusted odds ratio for 3 or 4 risk factors in comparison with none: 3.79 (95% CI 2.31 to 6.21); women: adjusted odds ratio 5.37 (95% CI 2.66 to10.84). With the exception of balance, the objective assessments also showed graded relationships with increasing number of risk factors, such that a greater number of risk factors was associated with poorer physical function.
CONCLUSION
These modifiable lifestyle risk factors are linked to marked differences in risk of poorer physical function in older adults. Efforts to encourage healthy lifestyles have the potential to improve physical function and to promote healthier ageing.
doi:10.1111/jgs.12457
PMCID: PMC4930137  PMID: 24083502
older adults; SF-36; physical function; lifestyle; risk factor
21.  Contribution of common non-synonymous variants in PCSK1 to body mass index variation and risk of obesity: a systematic review and meta-analysis with evidence from up to 331 175 individuals 
Human Molecular Genetics  2015;24(12):3582-3594.
Polymorphisms rs6232 and rs6234/rs6235 in PCSK1 have been associated with extreme obesity [e.g. body mass index (BMI) ≥ 40 kg/m2], but their contribution to common obesity (BMI ≥ 30 kg/m2) and BMI variation in a multi-ethnic context is unclear. To fill this gap, we collected phenotypic and genetic data in up to 331 175 individuals from diverse ethnic groups. This process involved a systematic review of the literature in PubMed, Web of Science, Embase and the NIH GWAS catalog complemented by data extraction from pre-existing GWAS or custom-arrays in consortia and single studies. We employed recently developed global meta-analytic random-effects methods to calculate summary odds ratios (OR) and 95% confidence intervals (CIs) or beta estimates and standard errors (SE) for the obesity status and BMI analyses, respectively. Significant associations were found with binary obesity status for rs6232 (OR = 1.15, 95% CI 1.06–1.24, P = 6.08 × 10−6) and rs6234/rs6235 (OR = 1.07, 95% CI 1.04–1.10, P = 3.00 × 10−7). Similarly, significant associations were found with continuous BMI for rs6232 (β = 0.03, 95% CI 0.00–0.07; P = 0.047) and rs6234/rs6235 (β = 0.02, 95% CI 0.00–0.03; P = 5.57 × 10−4). Ethnicity, age and study ascertainment significantly modulated the association of PCSK1 polymorphisms with obesity. In summary, we demonstrate evidence that common gene variation in PCSK1 contributes to BMI variation and susceptibility to common obesity in the largest known meta-analysis published to date in genetic epidemiology.
doi:10.1093/hmg/ddv097
PMCID: PMC4498155  PMID: 25784503
22.  Structural and functional changes of the iNKT clonal repertoire in early Rheumatoid Arthritis 
Invariant Natural Killer T cells (iNKT) are potent immunoregulatory T cells which recognise CD1d via a semi-invariant TCR (iNKT-TCR). Despite the knowledge of a defective iNKT pool in several autoimmune conditions including Rheumatoid Arthritis (RA), a clear understanding of the intrinsic mechanisms including qualitative and structural changes of the human iNKT repertoire at the earlier stages of autoimmune disease is lacking. Here, we compared the structure and function of the iNKT repertoire in early RA patients with age- and gender-matched controls. We analysed the phenotype and function of the ex vivo iNKT repertoire as well as CD1d antigen presentation, combined with analyses of a large panel of ex vivo sorted iNKT clones. We show that circulating iNKTs were reduced in early RA and their frequency was inversely correlated to Disease Activity Score (DAS28). Proliferative iNKT responses were defective in early RA, independent of CD1d function. Functional iNKT alterations were associated with a skewed iNKT-TCR repertoire with a selective reduction of high-affinity iNKT clones in early RA. Furthermore, High-affinity iNKTs in early RA exhibited an altered functional T-helper profile with Th1 or Th2-like phenotype, in treatment-naive and treated patients respectively, compared to Th0-like T-helper profiles exhibited by high-affinity iNKTs in controls. To our knowledge, this is the first study to provide a mechanism for the intrinsic qualitative defects of the circulating iNKT clonal repertoire in early RA, demonstrating defects of iNKTs bearing high-affinity TCRs. These defects may contribute to immune dysregulation and our findings could be exploited for future therapeutic intervention.
doi:10.4049/jimmunol.1501092
PMCID: PMC4671310  PMID: 26553073
23.  Regional differences in treatment for osteoporosis. The Global Longitudinal Study of Osteoporosis in Women (GLOW) 
Bone  2011;49(3):493-498.
Purpose
To determine if important geographic differences exist in treatment rates for osteoporosis and whether this variation can be explained by regional variation in risk factors.
Methods
The Global Longitudinal Study of Osteoporosis in Women is an observational study of women ≥55 years sampled from primary care practices in 10 countries. Self-administered questionnaires were used to collect data on patient characteristics, risk factors for fracture, previous fractures, anti-osteoporosis medication, and health status.
Results
Among 58,009 women, current anti-osteoporosis medication use was lowest in Northern Europe (16%) and highest in USA and Australia (32%). Between 48% (USA, Southern Europe) and 68% (Northern Europe) of women aged ≥65 years with a history of spine or hip fracture since age 45 were untreated. Among women with osteoporosis, the percentage of treated cases was lowest in Europe (45– 52% versus 62–65% elsewhere). Women with osteopenia and no other risk factors were treated with anti-osteoporosis medication most frequently in USA (31%) and Canada (31%), and least frequently in Southern Europe (12%), Northern Europe (13%), and Australia (16%). After adjusting for risk factors, US women were threefold as likely to be treated with anti-osteoporosis medication as Northern European women (odds ratio 2.8; 95% confidence interval 2.5–3.1) and 1.5 times as likely to be treated as Southern European women (1.5, 1.4–1.6). Up to half of women reporting previous hip or spine fracture did not receive treatment.
Conclusions
The likelihood of being treated for osteoporosis differed between regions, and cannot be explained by variation in risk factors. Many women at risk of fracture do not receive prophylaxis.
doi:10.1016/j.bone.2011.05.007
PMCID: PMC4897770  PMID: 21605715
Fracture; Regional variation; Women; Risk factor; Preventive treatment
24.  Obesity is Not Protective Against Fracture in Postmenopausal Women: GLOW 
The American journal of medicine  2011;124(11):1043-1050.
OBJECTIVE
To investigate the prevalence and incidence of clinical fractures in obese, postmenopausal women enrolled in the Global Longitudinal study of Osteoporosis in Women (GLOW).
METHODS
This was a multinational, prospective, observational, population-based study carried out by 723 physician practices at 17 sites in 10 countries. A total of 60,393 women aged ≥55 years were included. Data were collected using self-administered questionnaires that covered domains that included patient characteristics, fracture history, risk factors for fracture, and anti-osteoporosis medications.
RESULTS
Body mass index (BMI) and fracture history were available at baseline, 1 and 2 years in 44,534 women, 23.4% of whom were obese (BMI ≥30 kg/m2). Fracture prevalence in obese women at baseline was 222 per 1,000 and incidence at 2 years was 61.7 per 1,000, similar to rates in non-obese women (227 and 66.0 per 1,000, respectively). Fractures in obese women accounted for 23% and 22% of all previous and incident fractures, respectively. The risk of incident ankle and upper leg fractures was significantly higher in obese than in non-obese women whilst the risk of wrist fracture was significantly lower. Obese women with fracture were more likely to have experienced early menopause and to report two or more falls in the past year. Self-reported asthma, emphysema, and type 1 diabetes were all significantly more common in obese than non-obese women with incident fracture. At 2 years, 27% of obese women with incident fracture were receiving bone-protective therapy, compared with 41% of non-obese and 57% of underweight women.
CONCLUSIONS
Our results demonstrate that obesity is not protective against fracture in postmenopausal women and is associated with increased risk of ankle and upper leg fractures. These findings have major public health implications in view of the rapidly rising incidence of obesity. Further studies are required to establish the pathogenesis of fractures in the obese population and to develop effective preventive strategies.
doi:10.1016/j.amjmed.2011.06.013
PMCID: PMC4897773  PMID: 22017783
Fractures; Obesity; Postmenopausal; Osteoporosis
25.  Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12 
Thorax  2016;71(6):501-509.
Background
Several regions of the genome have shown to be associated with COPD in genome-wide association studies of common variants.
Objective
To determine rare and potentially functional single nucleotide polymorphisms (SNPs) associated with the risk of COPD and severity of airflow limitation.
Methods
3226 current or former smokers of European ancestry with lung function measures indicative of Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2 COPD or worse were genotyped using an exome array. An analysis of risk of COPD was carried out using ever smoking controls (n=4784). Associations with %predicted FEV1 were tested in cases. We followed-up signals of interest (p<10−5) in independent samples from a subset of the UK Biobank population and also undertook a more powerful discovery study by meta-analysing the exome array data and UK Biobank data for variants represented on both arrays.
Results
Among the associated variants were two in regions previously unreported for COPD; a low frequency non-synonymous SNP in MOCS3 (rs7269297, pdiscovery=3.08×10−6, preplication=0.019) and a rare SNP in IFIT3, which emerged in the meta-analysis (rs140549288, pmeta=8.56×10−6). In the meta-analysis of % predicted FEV1 in cases, the strongest association was shown for a splice variant in a previously unreported region, SERPINA12 (rs140198372, pmeta=5.72×10−6). We also confirmed previously reported associations with COPD risk at MMP12, HHIP, GPR126 and CHRNA5. No associations in novel regions reached a stringent exome-wide significance threshold (p<3.7×10−7).
Conclusions
This study identified several associations with the risk of COPD and severity of airflow limitation, including novel regions MOCS3, IFIT3 and SERPINA12, which warrant further study.
doi:10.1136/thoraxjnl-2015-207876
PMCID: PMC4893124  PMID: 26917578
COPD epidemiology; Tobacco and the lung

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