Publications by authors named "Cyrus Cooper"

814 Publications

Maternal diet in pregnancy and child's respiratory outcomes: an individual participant data meta-analysis of 18 000 children.

Eur Respir J 2021 Sep 9. Epub 2021 Sep 9.

The Generation R Study Group, Erasmus MC, University Medical Center, Rotterdam, the Netherlands

Rationale: Severe fetal malnutrition has been related to an increased risk of respiratory diseases later in life, but evidence for the association of a suboptimal diet during pregnancy with respiratory outcomes in childhood is conflicting. We aimed to examine whether a pro-inflammatory or low-quality maternal diet during pregnancy was associated with child's respiratory health.

Methods: We performed an individual participant meta-analysis among 18 326 mother-child pairs from seven European birth cohorts. Maternal pro-inflammatory and low-quality diet were estimated by energy-adjusted Dietary Inflammatory Index (E-DII) and Dietary Approaches to Stop Hypertension (DASH) scores. Preschool wheezing and school-age asthma were measured by questionnaires and lung function by spirometry.

Results: After adjustment for lifestyle and sociodemographic factors, we observed that a higher maternal E-DII score (a more pro-inflammatory diet) during pregnancy was associated only with a lower FVC in children (Z-score difference (95% confidence interval (CI)): -0.05 (-0.08, -0.02), per IQR increase). No linear associations of the maternal E-DII or DASH score with child's wheezing or asthma were observed. When exploratively examining the extremes, a very low DASH score (<10th percentile) (a very low dietary quality) was associated with an increased risk of preschool wheezing and a low FEV/FVC (z-score <-1.64) (OR (95% CI) 1.20 (1.06, 1.36), 1.40 (1.06, 1.85), compared to ≥10th percentile), with corresponding population attributable risk fractions of 1.7% and 3.3%.

Conclusion: Main results from this individual participant data meta-analysis do not support the hypothesis that maternal pro-inflammatory or low-quality diet in pregnancy are related to respiratory diseases in childhood.
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http://dx.doi.org/10.1183/13993003.01315-2021DOI Listing
September 2021

Altering product placement to create a healthier layout in supermarkets: Outcomes on store sales, customer purchasing, and diet in a prospective matched controlled cluster study.

PLoS Med 2021 Sep 7;18(9):e1003729. Epub 2021 Sep 7.

Medical Research Council Lifecourse Epidemiology Unit, University of Southampton, Southampton General Hospital, Southampton, United Kingdom.

Background: Previous product placement trials in supermarkets are limited in scope and outcome data collected. This study assessed the effects on store-level sales, household-level purchasing, and dietary behaviours of a healthier supermarket layout.

Methods And Findings: This is a prospective matched controlled cluster trial with 2 intervention components: (i) new fresh fruit and vegetable sections near store entrances (replacing smaller displays at the back) and frozen vegetables repositioned to the entrance aisle, plus (ii) the removal of confectionery from checkouts and aisle ends opposite. In this pilot study, the intervention was implemented for 6 months in 3 discount supermarkets in England. Three control stores were matched on store sales and customer profiles and neighbourhood deprivation. Women customers aged 18 to 45 years, with loyalty cards, were assigned to the intervention (n = 62) or control group (n = 88) of their primary store. The trial registration number is NCT03518151. Interrupted time series analysis showed that increases in store-level sales of fruits and vegetables were greater in intervention stores than predicted at 3 (1.71 standard deviations (SDs) (95% CI 0.45, 2.96), P = 0.01) and 6 months follow-up (2.42 SDs (0.22, 4.62), P = 0.03), equivalent to approximately 6,170 and approximately 9,820 extra portions per store, per week, respectively. The proportion of purchasing fruits and vegetables per week rose among intervention participants at 3 and 6 months compared to control participants (0.2% versus -3.0%, P = 0.22; 1.7% versus -3.5%, P = 0.05, respectively). Store sales of confectionery were lower in intervention stores than predicted at 3 (-1.05 SDs (-1.98, -0.12), P = 0.03) and 6 months (-1.37 SDs (-2.95, 0.22), P = 0.09), equivalent to approximately 1,359 and approximately 1,575 fewer portions per store, per week, respectively; no differences were observed for confectionery purchasing. Changes in dietary variables were predominantly in the expected direction for health benefit. Intervention implementation was not within control of the research team, and stores could not be randomised. It is a pilot study, and, therefore, not powered to detect an effect.

Conclusions: Healthier supermarket layouts can improve the nutrition profile of store sales and likely improve household purchasing and dietary quality. Placing fruits and vegetables near store entrances should be considered alongside policies to limit prominent placement of unhealthy foods.

Trial Registration: ClinicalTrials.gov NCT03518151 (pre-results).
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http://dx.doi.org/10.1371/journal.pmed.1003729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423266PMC
September 2021

Human non-CpG methylation patterns display both tissue-specific and inter-individual differences suggestive of underlying function.

Epigenetics 2021 Aug 30:1-12. Epub 2021 Aug 30.

MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK.

DNA methylation (DNAm) in mammals is mostly examined within the context of CpG dinucleotides. Non-CpG DNAm is also widespread across the human genome, but the functional relevance, tissue-specific disposition, and inter-individual variability has not been widely studied. Our aim was to examine non-CpG DNAm in the wider methylome across multiple tissues from the same individuals to better understand non-CpG DNAm distribution within different tissues and individuals and in relation to known genomic regulatory features.DNA methylation in umbilical cord and cord blood at birth, and peripheral venous blood at age 12-13 y from 20 individuals from the Southampton Women's Survey cohort was assessed by Agilent SureSelect methyl-seq. Hierarchical cluster analysis (HCA) was performed on CpG and non-CpG sites and stratified by specific cytosine environment. Analysis of tissue and inter-individual variation was then conducted in a second dataset of 12 samples: eight muscle tissues, and four aliquots of cord blood pooled from two individuals.HCA using methylated non-CpG sites showed different clustering patterns specific to the three base-pair triplicate (CNN) sequence. Analysis of CAC sites with non-zero methylation showed that samples clustered first by tissue type, then by individual (as observed for CpG methylation), while analysis using non-zero methylation at CAT sites showed samples grouped predominantly by individual. These clustering patterns were validated in an independent dataset using cord blood and muscle tissue.This research suggests that CAC methylation can have tissue-specific patterns, and that individual effects, either genetic or unmeasured environmental factors, can influence CAT methylation.
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http://dx.doi.org/10.1080/15592294.2021.1950990DOI Listing
August 2021

Vitamin D supplementation and COVID-19 disease: safety but unproven efficacy-reply to Dr Helga Rhein.

Aging Clin Exp Res 2021 09 18;33(9):2635-2636. Epub 2021 Aug 18.

NIHR Barts Biomedical Research Centre, William Harvey Research Institute, Queen Mary University of London, London, UK.

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http://dx.doi.org/10.1007/s40520-021-01947-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371426PMC
September 2021

Vitamin D and COVID-19 disease: don't believe everything you read in the papers! Reply to Dr William B. Grant.

Aging Clin Exp Res 2021 09 13;33(9):2639-2641. Epub 2021 Aug 13.

William Harvey Research Institute, NIHR Barts Biomedical Research Centre, Queen Mary University of London, London, UK.

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http://dx.doi.org/10.1007/s40520-021-01957-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363087PMC
September 2021

Predicting Imminent Fractures in Patients With a Recent Fracture or Starting Oral Bisphosphonate Therapy: Development and International Validation of Prognostic Models.

J Bone Miner Res 2021 Aug 3. Epub 2021 Aug 3.

Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, Nuffield Orthopaedic Centre, University of Oxford, Oxford, UK.

The availability of anti-osteoporosis medications with rapid onset and high potency requires tools to identify patients at high imminent fracture risk (IFR). There are few tools that predict a patient's IFR. We aimed to develop and validate tools for patients with a recent fracture and for patients initiating oral bisphosphonate therapy. Models for two separate cohorts, those with incident fragility fracture (IFx) and with incident oral bisphosphonate prescription (OBP), were developed in primary care records from Spain (SIDIAP database), UK (Clinical Practice Research Datalink GOLD), and Denmark (Danish Health Registries). Separate models were developed for hip, major, and any fracture outcomes. Only variables present in all databases were included in Lasso regression models for the development and logistic regression models for external validation. Discrimination was tested using area under curve (AUC) and calibration was assessed using observed versus predicted risk plots stratified by age, sex, and previous fracture history. The development analyses included 35,526 individuals in the IFx and 41,401 in the OBP cohorts, with 671,094 in IFx and 330,256 in OBP for the validation analyses. Both the IFx and OBP models demonstrated similarly good performance for hip fracture at 1 year (with AUCs of 0.79 [95% CI 0.75 to 0.82] and 0.87 [0.83 to 0.91] in Spain, 0.71 [0.71 to 0.72] and 0.73 [0.72 to 0.74] in the UK, and 0.70 [0.70 to 0.70] and 0.69 [0.68 to 0.70] in Denmark), and lower discrimination for major osteoporotic and any fracture sites. Calibration was good across all three countries. Discrimination and calibration for the 2-year models was similar. The proposed IFR prediction models could be used to identify more precisely patients at high imminent risk of fracture and inform anti-osteoporosis treatment selection. The freely available model parameters permit local validation and implementation. © 2021 American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4414DOI Listing
August 2021

Resources in women's social networks for food shopping are more strongly associated with better dietary quality than people: A cross-sectional study.

Soc Sci Med 2021 09 13;284:114228. Epub 2021 Jul 13.

Medical Research Council Lifecourse Epidemiology Unit, University of Southampton, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK; National Institute for Health Research Southampton Biomedical Research, Centre, University of Southampton and University Hospital Southampton, NHS Foundation Trust, Southampton, SO16 6YD, UK; NIHR Applied Research Collaboration Wessex, Southampton Science Park, Innovation Centre, 2 Venture Road, Chilworth, Southampton, SO16 7NP, UK. Electronic address:

When healthy people are part of an individual's social network, those individuals will have better dietary quality. Little, however, is known about whether social networks for food shopping, including both people and resources (e.g. recipes, weight loss programmes and food advertisements) are associated with dietary quality. The aim of this study was to explore the relationship between social networks for food shopping and dietary quality, and whether this differs for people and resources, among women aged 18-45 years. A total of 129 participants completed a cross-sectional questionnaire including an ego-centric Social Network Exposure tool and short Food Frequency Questionnaire. Associations between dietary quality and type of network member, perceived healthiness and support for healthy shopping choices were explored using linear regression models. Analyses revealed that participants who nominated people in their food shopping social network that eat healthily or support healthy food shopping had better dietary quality (β = 0.16 SD per 1-point change on a 4-point scale, 95%CI -0.06, 0.39; β = 0.20, 95%CI -0.07, 0.46, respectively). Resources in participants' food shopping social networks which promote healthy eating or support healthy shopping were associated with better dietary quality. These associations remained robust after adjustment for confounding variables identified using a directed acyclic graph (β = 0.31 SD per 1-point change on a 4-point scale, 95%CI 0.03, 0.58; β = 0.44, 95%CI 0.09, 0.79 respectively). The results were strengthened when the outcome was multiplied by frequency of contact (β = 0.33, 95%CI 0.05, 0.61; β = 0.47, 95%CI 0.11, 0.83 respectively). This study suggests that resources which promote healthy eating and healthy food shopping have a stronger association with dietary quality than social support from people. Further research is required in a larger sample, including multiple time-points, to confirm these findings.
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http://dx.doi.org/10.1016/j.socscimed.2021.114228DOI Listing
September 2021

Body mass index, prudent diet score and social class across three generations: evidence from the Hertfordshire Intergenerational Study.

BMJ Nutr Prev Health 2021 6;4(1):36-41. Epub 2021 Jan 6.

Medical Research Council Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK.

Background: Studies describing body mass index (BMI) and prudent diet score have reported that they are associated between parents and children. The Hertfordshire Intergenerational Study, which contains BMI, diet and social class information across three generations, provides an opportunity to consider the influence of grandparental and parental BMI and prudent diet score across multiple generations, and the influence of grandparental and parental social class on child BMI.

Methods: Linear regressions examining the tracking of adult BMI and prudent diet score across three generations (grandparent (F0), parent (F1) and child (F2)) were run from parent to child and from grandparent to grandchild. Linear mixed models investigated the influence of F0 and F1 BMI or prudent diet score on F2 BMI and prudent diet score. Linear regressions were run to determine whether social class and prudent diet score of parents and grandparents influenced the BMI of children and grandchildren.

Results: BMI was significantly associated across each generational pair and from F0 to F1 in multilevel models. Prudent diet score was significantly positively associated between grandparents and grandchildren. Lower grandparental and parental social class had a significantly positive association with F2 BMI (F0 low social class: b=1.188 kg/m, 95% CI 0.060 to 2.315, p=0.039; F1 middle social class: b=2.477 kg/m, 95% CI 0.726 to 4.227, p=0.006).

Conclusion: Adult BMI tracks across generations of the Hertfordshire Intergenerational Study, and child BMI is associated with parental and grandparental social class. The results presented here add to literature supporting behavioural and social factors in the transmission of BMI across generations.
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http://dx.doi.org/10.1136/bmjnph-2020-000178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8258032PMC
January 2021

Influence of Maternal Lifestyle and Diet on Perinatal DNA Methylation Signatures Associated With Childhood Arterial Stiffness at 8 to 9 Years.

Hypertension 2021 Sep 19;78(3):787-800. Epub 2021 Jul 19.

From the School of Human Development and Health, Institute of Developmental Sciences Building, Faculty of Medicine (R.M., N.K., E.A., G.C.B., K.M.G., M.A.H.), University of Southampton, United Kingdom.

[Figure: see text].
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.121.17396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357051PMC
September 2021

The relationship of nutritional risk with diet quality and health outcomes in community-dwelling older adults.

Aging Clin Exp Res 2021 Jul 13. Epub 2021 Jul 13.

MRC Lifecourse Epidemiology Unit, Southampton General Hospital, University of Southampton, Southampton, SO16 6YD, UK.

Objectives: To identify early nutritional risk in older populations, simple screening approaches are needed. This study aimed to compare nutrition risk scores, calculated from a short checklist, with diet quality and health outcomes, both at baseline and prospectively over a 2.5-year follow-up period; the association between baseline scores and risk of mortality over the follow-up period was assessed.

Methods: The study included 86 community-dwelling older adults in Southampton, UK, recruited from outpatient clinics. At both assessments, hand grip strength was measured using a Jamar dynamometer. Diet was assessed using a short validated food frequency questionnaire; derived 'prudent' diet scores described diet quality. Body mass index (BMI) was calculated and weight loss was self-reported. Nutrition risk scores were calculated from a checklist adapted from the DETERMINE (range 0-17).

Results: The mean age of participants at baseline (n = 86) was 78 (SD 8) years; half (53%) scored 'moderate' or 'high' nutritional risk, using the checklist adapted from DETERMINE. In cross-sectional analyses, after adjusting for age, sex and education, higher nutrition risk scores were associated with lower grip strength [difference in grip strength: - 0.09, 95% CI (- 0.17, - 0.02) SD per unit increase in nutrition risk score, p = 0.017] and poorer diet quality [prudent diet score: - 0.12, 95% CI (- 0.21, - 0.02) SD, p = 0.013]. The association with diet quality was robust to further adjustment for number of comorbidities, whereas the association with grip strength was attenuated. Nutrition risk scores were not related to reported weight loss or BMI at baseline. In longitudinal analyses there was an association between baseline nutrition risk score and lower grip strength at follow-up [fully-adjusted model: - 0.12, 95% CI (- 0.23, - 0.02) SD, p = 0.024]. Baseline nutrition risk score was also associated with greater risk of mortality [unadjusted hazard ratio per unit increase in score: 1.29 (1.01, 1.63), p = 0.039]; however, this association was attenuated after adjustment for sex and age.

Conclusions: Cross-sectional associations between higher nutrition risk scores, assessed from a short checklist, and poorer diet quality suggest that this approach may hold promise as a simple way of screening older populations. Further larger prospective studies are needed to explore the predictive ability of this screening approach and its potential to detect nutritional risk in older adults.
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http://dx.doi.org/10.1007/s40520-021-01824-zDOI Listing
July 2021

Pharmacogenomic Effects of β-Blocker Use on Femoral Neck Bone Mineral Density.

J Endocr Soc 2021 Aug 15;5(8):bvab092. Epub 2021 May 15.

Center for Outcomes Research and Evaluation, Maine Medical Center Research Institute, Portland, ME 04101, USA.

Context: Recent studies have shown that β-blocker (BB) users have a decreased risk of fracture and higher bone mineral density (BMD) compared to nonusers, likely due to the suppression of adrenergic signaling in osteoblasts, leading to increased BMD. There is also variability in the effect size of BB use on BMD in humans, which may be due to pharmacogenomic effects.

Objective: To investigate potential single-nucleotide variations (SNVs) associated with the effect of BB use on femoral neck BMD, we performed a cross-sectional analysis using clinical data, dual-energy x-ray absorptiometry, and genetic data from the Framingham Heart Study's (FHS) Offspring Cohort. We then sought to validate our top 4 genetic findings using data from the Rotterdam Study, the BPROOF Study, the Malta Osteoporosis Fracture Study (MOFS), and the Hertfordshire Cohort Study.

Methods: We used sex-stratified linear mixed models to determine SNVs that had a significant interaction effect with BB use on femoral neck (FN) BMD across 11 gene regions. We also evaluated the association of our top SNVs from the FHS with microRNA (miRNA) expression in blood and identified potential miRNA-mediated mechanisms by which these SNVs may affect FN BMD.

Results: One variation (rs11124190 in ) was validated in females using data from the Rotterdam Study, while another (rs12414657 in ) was validated in females using data from the MOFS. We performed an exploratory meta-analysis of all 5 studies for these variations, which further validated our findings.

Conclusion: This analysis provides a starting point for investigating the pharmacogenomic effects of BB use on BMD measures.
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http://dx.doi.org/10.1210/jendso/bvab092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237849PMC
August 2021

Bariatric surgery increases the rate of major fracture: self-controlled case series study in UK Clinical Practice Research Datalink.

J Bone Miner Res 2021 Jun 25. Epub 2021 Jun 25.

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.

Conflicting results exist about the relationship between bariatric surgery and fracture risk. Also, prediction of who is at increased risk of fracture after bariatric surgery is not currently available. Hence, we used a combination of a self-controlled case series (SCCS) study to establish the association between bariatric surgery and fracture, and develop a prediction model for postoperative fracture risk estimation using a cohort study. Patients from UK Primary care records from the Clinical Practice Research Datalink GOLD linked to Hospital Episode Statistics undergoing bariatric surgery with body mass index (BMI) ≥30 kg/m between 1997 and 2018 were included in the cohort. Those sustaining one or more fractures in the 5 years before or after surgery were included in the SCCS. Fractures were considered in three categories: (i) any except skull and digits (primary outcome); (ii) major (hip, vertebrae, wrist/forearm, and humerus); and (iii) peripheral (forearm and lower leg). Of 5487 participants, 252 (4.6%) experienced 272 fractures (of which 80 were major and 135 peripheral) and were included in the SCCS analyses. Major fracture risk increased after surgery, incidence rate ratios (IRRs) and 95% confidence intervals (CIs): 2.77 (95% CI, 1.34-5.75) and 3.78 (95% CI, 1.42-10.08) at ≤3 years and 3.1 to 5 years postsurgery when compared to 5 years prior to surgery, respectively. Any fracture risk was higher only in the 2.1 to 5 years following surgery (IRR 1.73; 95% CI, 1.08-2.77) when compared to 5 years prior to surgery. No excess risk of peripheral fracture after surgery was identified. A prediction tool for major fracture was developed using 5487 participants included in the cohort study. It was also internally validated (area under the receiver-operating characteristic curve [AUC ROC] 0.70) with use of anxiolytics/sedatives/hypnotics and female as major predictors. Hence, major fractures are nearly threefold more likely after bariatric surgery. A simple prediction tool with five variables identifies high risk patients for major fracture. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4405DOI Listing
June 2021

Vitamin D and coronavirus disease 2019 (COVID-19): rapid evidence review.

Aging Clin Exp Res 2021 Jul 12;33(7):2031-2041. Epub 2021 Jun 12.

MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton General Hospital, Southampton, SO16 6YD, UK.

Background: The rapid global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), has re-ignited interest in the possible role of vitamin D in modulation of host responses to respiratory pathogens. Indeed, vitamin D supplementation has been proposed as a potential preventative or therapeutic strategy. Recommendations for any intervention, particularly in the context of a potentially fatal pandemic infection, should be strictly based on clinically informed appraisal of the evidence base. In this narrative review, we examine current evidence relating to vitamin D and COVID-19 and consider the most appropriate practical recommendations.

Observations: Although there are a growing number of studies investigating the links between vitamin D and COVID-19, they are mostly small and observational with high risk of bias, residual confounding, and reverse causality. Extrapolation of molecular actions of 1,25(OH)-vitamin D to an effect of increased 25(OH)-vitamin D as a result of vitamin D supplementation is generally unfounded, as is the automatic conclusion of causal mechanisms from observational studies linking low 25(OH)-vitamin D to incident disease. Efficacy is ideally demonstrated in the context of adequately powered randomised intervention studies, although such approaches may not always be feasible.

Conclusions: At present, evidence to support vitamin D supplementation for the prevention or treatment of COVID-19 is inconclusive. In the absence of any further compelling data, adherence to existing national guidance on vitamin D supplementation to prevent vitamin D deficiency, predicated principally on maintaining musculoskeletal health, appears appropriate.
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http://dx.doi.org/10.1007/s40520-021-01894-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195723PMC
July 2021

Women's perceptions of factors influencing their food shopping choices and how supermarkets can support them to make healthier choices.

BMC Public Health 2021 06 5;21(1):1070. Epub 2021 Jun 5.

Medical Research Council Lifecourse Epidemiology Unit, University of Southampton, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK.

Objectives: To examine women's perceptions of factors that influence their food shopping choices, particularly in relation to store layout, and their views on ways that supermarkets could support healthier choices.

Design: This qualitative cross-sectional study used semi-structured telephone interviews to ask participants the reasons for their choice of supermarket and factors in-store that prompted their food selections. The actions supermarkets, governments and customers could take to encourage healthier food choices were explored with women. Thematic analysis was conducted to identify key themes.

Setting: Six supermarkets across England.

Participants: Twenty women customers aged 18-45 years.

Results: Participants had a median age of 39.5 years (IQR: 35.1, 42.3), a median weekly grocery spend of £70 (IQR: 50, 88), and 44% had left school aged 16 years. Women reported that achieving value for money, feeling hungry, tired, or stressed, and meeting family members' food preferences influenced their food shopping choices. The physical environment was important, including product quality and variety, plus ease of accessing the store or products in-store. Many participants described how they made unintended food selections as a result of prominent placement of unhealthy products in supermarkets, even if they adopted more conscious approaches to food shopping (i.e. written or mental lists). Participants described healthy eating as a personal responsibility, but some stated that governments and supermarkets could be more supportive.

Conclusions: This study highlighted that in-store environments can undermine intentions to purchase and consume healthy foods. Creating healthier supermarket environments could reduce the burden of personal responsibility for healthy eating, by making healthier choices easier. Future research could explore the interplay of personal, societal and commercial responsibility for food choices and health status.
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http://dx.doi.org/10.1186/s12889-021-11112-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178895PMC
June 2021

Placental polar lipid composition is associated with placental gene expression and neonatal body composition.

Biochim Biophys Acta Mol Cell Biol Lipids 2021 09 23;1866(9):158971. Epub 2021 May 23.

MRC Lifecourse Epidemiology Unit, University of Southampton, UK; NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK. Electronic address:

The polar-lipid composition of the placenta reflects its cellular heterogeneity and metabolism. This study explored relationships between placental polar-lipid composition, gene expression and neonatal body composition. Placental tissue and maternal and offspring data were collected in the Southampton Women's Survey. Lipid and RNA were extracted from placental tissue and polar lipids measured by mass spectrometry, while gene expression was assessed using the nCounter analysis platform. Principal component analysis was used to identify patterns within placental lipid composition and these were correlated with neonatal body composition and placental gene expression. In the analysis of placental lipids, the first three principal components explained 19.1%, 12.7% and 8.0% of variation in placental lipid composition, respectively. Principal component 2 was characterised by high principal component scores for acyl-alkyl-glycerophosphatidylcholines and lipid species containing DHA. Principal component 2 was associated with placental weight and neonatal lean mass; this component was associated with gene expression of APOE, PLIN2, FATP2, FABP4, LEP, G0S2, PNPLA2 and SRB1. Principal components 1 and 3 were not related to birth outcomes but they were associated with the gene expression of lipid related genes. Principal component 1 was associated with expression of LEP, APOE, FATP2 and ACAT2. Principal component 3 was associated with expression of PLIN2, PLIN3 and PNPLA2. This study demonstrates that placentas of different sizes have specific differences in polar-lipid composition and related gene expression. These differences in lipid composition were associated with birth weight and neonatal lean mass, suggesting that placental lipid composition may influence prenatal lean mass accretion.
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http://dx.doi.org/10.1016/j.bbalip.2021.158971DOI Listing
September 2021

The genomic loci of specific human tRNA genes exhibit ageing-related DNA hypermethylation.

Nat Commun 2021 05 11;12(1):2655. Epub 2021 May 11.

William Harvey Research Institute, Barts & The London School of Medicine and Dentistry, Charterhouse Square, Queen Mary University of London, London, UK.

The epigenome has been shown to deteriorate with age, potentially impacting on ageing-related disease. tRNA, while arising from only ˜46 kb (<0.002% genome), is the second most abundant cellular transcript. tRNAs also control metabolic processes known to affect ageing, through core translational and additional regulatory roles. Here, we interrogate the DNA methylation state of the genomic loci of human tRNA. We identify a genomic enrichment for age-related DNA hypermethylation at tRNA loci. Analysis in 4,350 MeDIP-seq peripheral-blood DNA methylomes (16-82 years), identifies 44 and 21 hypermethylating specific tRNAs at study-and genome-wide significance, respectively, contrasting with none hypomethylating. Validation and replication (450k array and independent targeted Bisuphite-sequencing) supported the hypermethylation of this functional unit. Tissue-specificity is a significant driver, although the strongest consistent signals, also independent of major cell-type change, occur in tRNA-iMet-CAT-1-4 and tRNA-Ser-AGA-2-6. This study presents a comprehensive evaluation of the genomic DNA methylation state of human tRNA genes and reveals a discreet hypermethylation with advancing age.
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http://dx.doi.org/10.1038/s41467-021-22639-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113476PMC
May 2021

The importance of maternal pregnancy vitamin D for offspring bone health: learnings from the MAVIDOS trial.

Ther Adv Musculoskelet Dis 2021 8;13:1759720X211006979. Epub 2021 Apr 8.

MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton General Hospital, Southampton, Hampshire, UK.

Optimisation of skeletal mineralisation in childhood is important to reduce childhood fracture and the long-term risk of osteoporosis and fracture in later life. One approach to achieving this is antenatal vitamin D supplementation. The Maternal Vitamin D Osteoporosis Study is a randomised placebo-controlled trial, the aim of which was to assess the effect of antenatal vitamin D supplementation (1000 IU/day cholecalciferol) on offspring bone mass at birth. The study has since extended the follow up into childhood and diversified to assess demographic, lifestyle and genetic factors that determine the biochemical response to antenatal vitamin D supplementation, and to understand the mechanisms underpinning the effects of vitamin D supplementation on offspring bone development, including epigenetics. The demonstration of positive effects of maternal pregnancy vitamin D supplementation on offspring bone development and the delineation of underlying biological mechanisms inform clinical care and future public-health policies.
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http://dx.doi.org/10.1177/1759720X211006979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040612PMC
April 2021

Corrigendum to: Higher prevalence of non-skeletal comorbidity related to X-linked hypophosphataemia: a UK parallel cohort study using CPRD.

Rheumatology (Oxford) 2021 Jun;60(6):3036

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.

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http://dx.doi.org/10.1093/rheumatology/keab321DOI Listing
June 2021

Childhood vascular phenotypes have differing associations with prenatal and postnatal growth.

J Hypertens 2021 Sep;39(9):1884-1892

NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton.

Objective: In children aged 8--9 years, we examined the associations of linear and abdominal circumference growth during critical stages of prenatal and postnatal development with six vascular measurements commonly used as early markers of atherosclerosis and later cardiovascular disease (CVD) risk.

Methods: In 724 children from the UK Southampton Women's Survey mother--offspring cohort, offspring length/height and abdominal circumference measurements were collected at 10 ages between 11 weeks' gestation and age 8--9 years. Using residual growth modelling and linear regression, we examined the independent associations between growth and detailed vascular measures made at 8--9 years.

Results: Postnatal linear and abdominal circumference growth were associated with higher childhood SBP and carotid--femoral pulse wave velocity, whereas prenatal growth was not. For example, 1SD faster abdominal circumference gain between ages 3 and 6 years was associated with 2.27 [95% confidence interval (CI): 1.56--2.98] mmHg higher SBP. In contrast, faster abdominal circumference gain before 19 weeks' gestation was associated with greater carotid intima--media thickness [0.009 mm (0.004--0.015) per 1SD larger 19-week abdominal circumference), whereas later growth was not. We found no strong associations between prenatal or postnatal growth and DBP or measures of endothelial function.

Conclusion: Higher postnatal linear growth and adiposity gain are related to higher SBP and carotid--femoral pulse wave velocity in childhood. In contrast, faster growth in early gestation is associated with greater childhood carotid intima--media thickness, perhaps resulting from subtle changes in vascular structure that reflect physiological adaptations rather than subclinical atherosclerosis.
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http://dx.doi.org/10.1097/HJH.0000000000002870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373454PMC
September 2021

Sarcopenia Definitions as Predictors of Fracture Risk Independent of FRAX , Falls, and BMD in the Osteoporotic Fractures in Men (MrOS) Study: A Meta-Analysis.

J Bone Miner Res 2021 07 8;36(7):1235-1244. Epub 2021 Apr 8.

Centre for Metabolic Bone Diseases, University of Sheffield, Sheffield, UK.

Dual-energy X-ray absorptiometry (DXA)-derived appendicular lean mass/height (ALM/ht ) is the most commonly used estimate of muscle mass in the assessment of sarcopenia, but its predictive value for fracture is substantially attenuated by femoral neck (fn) bone mineral density (BMD). We investigated predictive value of 11 sarcopenia definitions for incident fracture, independent of fnBMD, fracture risk assessment tool (FRAX ) probability, and prior falls, using an extension of Poisson regression in US, Sweden, and Hong Kong Osteoporois Fractures in Men Study (MrOS) cohorts. Definitions tested were those of Baumgartner and Delmonico (ALM/ht only), Morley, the International Working Group on Sarcopenia, European Working Group on Sarcopenia in Older People (EWGSOP1 and 2), Asian Working Group on Sarcopenia, Foundation for the National Institutes of Health (FNIH) 1 and 2 (using ALM/body mass index [BMI], incorporating muscle strength and/or physical performance measures plus ALM/ht ), and Sarcopenia Definitions and Outcomes Consortium (gait speed and grip strength). Associations were adjusted for age and time since baseline and reported as hazard ratio (HR) for first incident fracture, here major osteoporotic fracture (MOF; clinical vertebral, hip, distal forearm, proximal humerus). Further analyses adjusted additionally for FRAX-MOF probability (n = 7531; calculated ± fnBMD), prior falls (y/n), or fnBMD T-score. Results were synthesized by meta-analysis. In 5660 men in USA, 2764 Sweden and 1987 Hong Kong (mean ages 73.5, 75.4, and 72.4 years, respectively), sarcopenia prevalence ranged from 0.5% to 35%. Sarcopenia status, by all definitions except those of FNIH, was associated with incident MOF (HR = 1.39 to 2.07). Associations were robust to adjustment for prior falls or FRAX probability (without fnBMD); adjustment for fnBMD T-score attenuated associations. EWGSOP2 severe sarcopenia (incorporating chair stand time, gait speed, and grip strength plus ALM) was most predictive, albeit at low prevalence, and appeared only modestly influenced by inclusion of fnBMD. In conclusion, the predictive value for fracture of sarcopenia definitions based on ALM is reduced by adjustment for fnBMD but strengthened by additional inclusion of physical performance measures. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4293DOI Listing
July 2021

DNA methylation signatures in cord blood associated with birthweight are enriched for dmCpGs previously associated with maternal hypertension or pre-eclampsia, smoking and folic acid intake.

Epigenetics 2021 Apr 28:1-17. Epub 2021 Apr 28.

NIHR, NIHR Southampton BiomedGical Research Centre, Southampton.

Many epidemiological studies have linked low birthweight to an increased risk of non-communicable diseases (NCDs) in later life, with epigenetic proceseses suggested as an underlying mechanism. Here, we sought to identify neonatal methylation changes associated with birthweight, at the individual CpG and genomic regional level, and whether the birthweight-associated methylation signatures were associated with specific maternal factors. Using the Illumina Human Methylation EPIC array, we assessed DNA methylation in the cord blood of 557 and 483 infants from the UK Pregnancies Better Eating and Activity Trial and Southampton Women's Survey, respectively. Adjusting for gestational age and other covariates, an epigenome-wide association study identified 2911 (FDR≤0.05) and 236 (Bonferroni corrected p ≤ 6.45×10-8) differentially methylated CpGs (dmCpGs), and 1230 differentially methylated regions (DMRs) (Stouffer ≤0.05) associated with birthweight. The top birthweight-associated dmCpG was located within the Homeobox Telomere-Binding Protein 1 (HMBOX1) gene with a 195 g (95%CI: -241, -149 g) decrease in birthweight per 10% increase in methylation, while the top DMR was located within the promoter of corticotropin-releasing hormone-binding protein (CRHBP). Furthermore, the birthweight-related dmCpGs were enriched for dmCpGs previously associated with gestational hypertension/pre-eclampsia (14.51%, p = 1.37×10-255), maternal smoking (7.71%, p = 1.50 x 10-57) and maternal plasma folate levels during pregnancy (0.33%, p = 0.029). The identification of birthweight-associated methylation markers, particularly those connected to specific pregnancy complications and exposures, may provide insights into the developmental pathways that affect birthweight and suggest surrogate markers to identify adverse prenatal exposures for stratifying for individuals at risk of later NCDs.
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http://dx.doi.org/10.1080/15592294.2021.1908706DOI Listing
April 2021

Level and change in bone microarchitectural parameters and their relationship with previous fracture and established bone mineral density loci.

Bone 2021 06 22;147:115937. Epub 2021 Mar 22.

MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK. Electronic address:

Background: Osteoporosis is characterised by a reduction of bone mineral density (BMD) and predisposition to fracture. Bone microarchitecture, measured by high resolution peripheral quantitative computed tomography (HR-pQCT), has been related to fragility fractures and BMD and has been the subject of large-scale genome-wide analysis. We investigated whether fracture was related to baseline values and longitudinal changes in bone microarchitecture and whether bone microarchitecture was associated with established BMD loci.

Methods: 115 males and 99 females (aged 72-81 at baseline) from the Hertfordshire Cohort Study (HCS) were analysed. Fracture history was determined in 2011-2012 by self-report and vertebral fracture assessment. Participants underwent HR-pQCT scans of the distal radius and tibia in 2011-2012 and 2017. Previous fracture in relation to baseline values and changes in tibial HR-pQCT parameters was examined using sex-adjusted logistic regression with and without adjustment for age, sociodemographic, lifestyle and clinical characteristics; baseline values and changes in parameters associated with previous fracture were then examined in relation to four established BMD loci after adjustment for sex and age.

Results: Previous fracture was related to: higher trabecular area (fully-adjusted odds ratio [95% CI] per SD greater baseline value: 2.18 [1.27,3.73], p = 0.005); lower total volumetric BMD (0.53 [0.34,0.84], p = 0.007), cortical area (0.53 [0.30,0.95], p = 0.032), cortical BMD (0.56 [0.36,0.88], p = 0.011) and cortical thickness (0.45 [0.27,0.77], p = 0.004); and greater declines in trabecular BMD (p = 0.001). Associations were robust in sex- and fully-adjusted analysis. Relationships between BMD loci and these HR-pQCT parameters were weak: rs3801387 (WNT16) was related to decline in trabecular BMD (p = 0.011) but no other associations were significant (p > 0.05).

Conclusion: Baseline values of HR-pQCT parameters and greater decline in trabecular BMD were associated with fracture. Change in trabecular BMD was associated with WNT16 which has been demonstrated to influence bone health in murine models and human genome-wide association studies (GWAS).
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http://dx.doi.org/10.1016/j.bone.2021.115937DOI Listing
June 2021

Older working adults in the HEAF study are more likely to report loneliness after two years of follow-up if they have negative perceptions of their work quality.

BMC Public Health 2021 03 23;21(1):574. Epub 2021 Mar 23.

MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton General Hospital, Southampton, SO16 6YD, UK.

Background: Loneliness is an important public health issue associated with mortality and morbidity. Often researched amongst older people, less is known about risk factors for loneliness among adults aged 50-64 years who are in work. We investigated (a) if exit from the workforce increases the odds of loneliness; (b) whether adverse psychosocial work factors are associated with increased odds of loneliness over 2 years of follow-up; and (c) whether the association is stronger among subjects still working compared with those who have exited the workforce.

Methods: Data came from the Health and Employment After Fifty (HEAF) study, a large population cohort who provided questionnaire information about work and health at baseline and 2 annual follow-ups. Logistic regression was used to explore the association between psychosocial risk factors and loneliness at follow-up 2, with adjustment for loneliness at baseline, sex, age, self-rated health, living alone, and mental health diagnosis.

Results: Of the initial 8134 participants, 4521 were working at baseline and provided data for this analysis. Of those, 507 (11.2%) were defined as lonely at 2 years' follow-up. Exiting the workforce was not significantly associated with loneliness (OR = 1.1, 95%CI: 0.7-1.7). However, negative psychosocial work factors predicted loneliness at follow-up. After mutual adjustment, lack of choice at work (OR: 1.5, 95%CI: 1.1-1.9), often lying awake worrying about work (OR: 1.4, 95%CI: 1.0-1.9) and perceived not coping with physical demands of the job (OR: 1.3, 95%CI: 1.0-1.7) were independent predictors, with associations robust to adjustment for demographic factors and health. Associations were only slightly altered when we restricted the sample to those who remained in work until the end of follow-up.

Conclusions: Loneliness amongst middle-aged working adults is not predicted by permanent work exit but is predicted by individuals' perceptions about their work. Provision of good-quality work, matched to the capacity of the older worker, could prevent loneliness.
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http://dx.doi.org/10.1186/s12889-021-10610-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988922PMC
March 2021

Bisphosphonates to reduce bone fractures in stage 3B+ chronic kidney disease: a propensity score-matched cohort study.

Health Technol Assess 2021 Mar;25(17):1-106

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, National Institute for Health Research (NIHR) Biomedical Research Centre, University of Oxford, Oxford, UK.

Background: Bisphosphonates are contraindicated in patients with stage 4+ chronic kidney disease. However, they are widely used to prevent fragility fractures in stage 3 chronic kidney disease, despite a lack of good-quality data on their effects.

Objectives: The aims of each work package were as follows. Work package 1: to study the relationship between bisphosphonate use and chronic kidney disease progression. Work package 2: to study the association between using bisphosphonates and fracture risk. Work package 3: to determine the risks of hypocalcaemia, hypophosphataemia, acute kidney injury and upper gastrointestinal events associated with using bisphosphonates. Work package 4: to investigate the association between using bisphosphonates and changes in bone mineral density over time.

Design: This was a new-user cohort study design with propensity score matching.

Setting And Data Sources: Data were obtained from UK NHS primary care (Clinical Practice Research Datalink GOLD database) and linked hospital inpatient records (Hospital Episode Statistics) for work packages 1-3 and from the Danish Odense University Hospital Databases for work package 4.

Participants: Patients registered in the data sources who had at least one measurement of estimated glomerular filtration rate of < 45 ml/minute/1.73 m were eligible. A second estimated glomerular filtration rate value of < 45 ml/minute/1.73 m within 1 year after the first was requested for work packages 1 and 3. Patients with no Hospital Episode Statistics linkage were excluded from work packages 1-3. Patients with < 1 year of run-in data before index estimated glomerular filtration rate and previous users of anti-osteoporosis medications were excluded from work packages 1-4.

Interventions/exposure: Bisphosphonate use, identified from primary care prescriptions (for work packages 1-3) or pharmacy dispensations (for work package 4), was the main exposure.

Main Outcome Measures: Work package 1: chronic kidney disease progression, defined as stage worsening or starting renal replacement. Work package 2: hip fracture. Work package 3: acute kidney injury, hypocalcaemia and hypophosphataemia identified from Hospital Episode Statistics, and gastrointestinal events identified from Clinical Practice Research Datalink or Hospital Episode Statistics. Work package 4: annualised femoral neck bone mineral density percentage change.

Results: Bisphosphonate use was associated with an excess risk of chronic kidney disease progression (subdistribution hazard ratio 1.12, 95% confidence interval 1.02 to 1.24) in work package 1, but did not increase the probability of other safety outcomes in work package 3. The results from work package 2 suggested that bisphosphonate use increased fracture risk (hazard ratio 1.25, 95% confidence interval 1.13 to 1.39) for hip fractures, but sensitivity analyses suggested that this was related to unresolved confounding. Conversely, work package 4 suggested that bisphosphonates improved bone mineral density, with an average 2.65% (95% confidence interval 1.32% to 3.99%) greater gain in femoral neck bone mineral density per year in bisphosphonate users than in matched non-users.

Limitations: Confounding by indication was a concern for the clinical effectiveness (i.e. work package 2) data. Bias analyses suggested that these findings were due to inappropriate adjustment for pre-treatment risk. work packages 3 and 4 were based on small numbers of events and participants, respectively.

Conclusions: Bisphosphonates were associated with a 12% excess risk of chronic kidney disease progression in participants with stage 3B+ chronic kidney disease. No other safety concerns were identified. Bisphosphonate therapy increased bone mineral density, but the research team failed to demonstrate antifracture effectiveness.

Future Work: Randomised controlled trial data are needed to demonstrate antifracture efficacy in patients with stage 3B+ chronic kidney disease. More safety analyses are needed to characterise the renal toxicity of bisphosphonates in stage 3A chronic kidney disease, possibly using observational data.

Study Registration: This study is registered as EUPAS10029.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 25, No. 17. See the NIHR Journals Library website for further project information. The project was also supported by the National Institute for Health Research Biomedical Research Centre, Oxford.
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http://dx.doi.org/10.3310/hta25170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020200PMC
March 2021

Maternal dietary quality, inflammatory potential and childhood adiposity: an individual participant data pooled analysis of seven European cohorts in the ALPHABET consortium.

BMC Med 2021 02 22;19(1):33. Epub 2021 Feb 22.

HRB Centre for Health and Diet Research, School of Public Health, Physiotherapy, and Sports Science, University College Dublin, Dublin, Republic of Ireland.

Background: Mounting evidence suggests that maternal diet influences pregnancy and birth outcomes, but its contribution to the global epidemic of childhood obesity has not as yet been definitively characterized. We investigated whether maternal whole diet quality and inflammatory potential influence childhood adiposity.

Methods: We harmonized and pooled individual participant data from 16,295 mother-child pairs in seven European birth cohorts. Maternal pre-, early-, late-, and whole-pregnancy (any time during pregnancy) dietary quality and inflammatory potential assessed with the Dietary Approaches to Stop Hypertension (DASH) score and the energy-adjusted Dietary Inflammatory Index (E-DII™) score, respectively. Primary outcome was childhood overweight and obesity (OWOB) (age-and-sex-specific BMI z-score > 85th percentile). Secondary outcomes were sum of skinfold thickness (SST), fat mass index (FMI) and fat-free mass index (FFMI). We used multivariable regression analyses (adjusting for maternal lifestyle and sociodemographic factors) to assess the associations of maternal DASH and E-DII scores with offspring adiposity outcomes in cohort-specific analyses, with subsequent random-effect meta-analyses.

Results: The study mothers had a mean (SD) age of 30.2 (4.6) years and a mean BMI of 23.4 (4.2) kg/m. Higher early-pregnancy E-DII scores (more pro-inflammatory diet) tended to be associated with a higher odds of late-childhood [10.6 (1.2) years] OWOB [OR (95% CI) 1.09 (1.00, 1.19) per 1-SD E-DII score increase], whereas an inverse association was observed for late-pregnancy E-DII score and early-childhood [2.8 (0.3) years] OWOB [0.91 (0.83, 1.00)]. Higher maternal whole pregnancy DASH score (higher dietary quality) was associated with a lower odds of late-childhood OWOB [OR (95% CI) 0.92 (0.87, 0.98) per 1-SD DASH score increase]; associations were of similar magnitude for early and late-pregnancy [0.86 (0.72, 1.04) and 0.91 (0.85, 0.98), respectively]. These associations were robust in several sensitivity analyses and further adjustment for birth weight and childhood diet did not meaningfully alter the associations and conclusions. In two cohorts with available data, a higher whole pregnancy E-DII and lower DASH scores were associated with a lower late-childhood FFMI in males and a higher mid-childhood FMI in females (P interactions < 0.10).

Conclusions: A pro-inflammatory, low-quality maternal antenatal diet may adversely influence offspring body composition and OWOB risk, especially during late-childhood. Promoting an overall healthy and anti-inflammatory maternal dietary pattern may contribute to the prevention of childhood obesity, a complex health issue requiring multifaceted strategy.
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http://dx.doi.org/10.1186/s12916-021-01908-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898733PMC
February 2021

The association between social isolation and musculoskeletal health in older community-dwelling adults: findings from the Hertfordshire Cohort Study.

Qual Life Res 2021 Jul 17;30(7):1913-1924. Epub 2021 Feb 17.

MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton General Hospital, Southampton, UK.

Purpose: Social isolation has been associated with both physical and psychological adverse outcomes and is prevalent in older adults. We investigated the impact of social isolation on bone mineral density (BMD) and physical capability in community-dwelling older adults.

Methods: Data were collected in 2011 and 2017 from the Hertfordshire Cohort Study. In 2011, we assessed social isolation using the six-item Lubben Social Network Scale (LSNS-6) and the Maastricht Social Participation Profile (MSSP) and depressive and anxiety symptoms using the Hospital Anxiety and Depression Scale (HADS). Physical capability was assessed by performing tests of gait speed, chair stands, timed up and go and balance at both time points. BMD was assessed using dual X-ray absorptiometry (DXA) at both time points.

Results: Data were available from 369 participants in 2011 and 184 in 2017. Forty percent of men and 42.4% of women were socially isolated. Isolated participants had higher odds of depressive disorder (OR 3.01, 95% CI 1.27-7.11, p < 0.02). Social isolation at baseline was associated with poor physical capability scores at follow-up (OR 5.53, 95% CI 1.09-27.99, p < 0.04). No associations were found between social isolation and BMD at either time point.

Conclusions: Social isolation was associated with higher odds of having depressive symptoms and predicted the development of poor physical capability 6 years later. Further longitudinal studies that include loneliness as a covariate are warranted.
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http://dx.doi.org/10.1007/s11136-021-02784-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233263PMC
July 2021

Knee osteoarthritis and time-to all-cause mortality in six community-based cohorts: an international meta-analysis of individual participant-level data.

Aging Clin Exp Res 2021 Mar 15;33(3):529-545. Epub 2021 Feb 15.

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.

Background: Osteoarthritis (OA) is a chronic joint disease, with increasing global burden of disability and healthcare utilisation. Recent meta-analyses have shown a range of effects of OA on mortality, reflecting different OA definitions and study methods. We seek to overcome limitations introduced when using aggregate results by gathering individual participant-level data (IPD) from international observational studies and standardising methods to determine the association of knee OA with mortality in the general population.

Methods: Seven community-based cohorts were identified containing knee OA-related pain, radiographs, and time-to-mortality, six of which were available for analysis. A two-stage IPD meta-analysis framework was applied: (1) Cox proportional hazard models assessed time-to-mortality of participants with radiographic OA (ROA), OA-related pain (POA), and a combination of pain and ROA (PROA) against pain and ROA-free participants; (2) hazard ratios (HR) were then pooled using the Hartung-Knapp modification for random-effects meta-analysis.

Findings: 10,723 participants in six cohorts from four countries were included in the analyses. Multivariable models (adjusting for age, sex, race, BMI, smoking, alcohol consumption, cardiovascular disease, and diabetes) showed a pooled HR, compared to pain and ROA-free participants, of 1.03 (0.83, 1.28) for ROA, 1.35 (1.12, 1.63) for POA, and 1.37 (1.22, 1.54) for PROA.

Discussion: Participants with POA or PROA had a 35-37% increased association with reduced time-to-mortality, independent of confounders. ROA showed no association with mortality, suggesting that OA-related knee pain may be driving the association with time-to-mortality.

Funding: Versus Arthritis Centre for Sport, Exercise and Osteoarthritis and Osteoarthritis Research Society International.
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http://dx.doi.org/10.1007/s40520-020-01762-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943431PMC
March 2021

Cardiovascular safety of calcium, magnesium and strontium: what does the evidence say?

Aging Clin Exp Res 2021 Mar 9;33(3):479-494. Epub 2021 Feb 9.

MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton General Hospital, Southampton, SO16 6YD, UK.

Calcium, magnesium and strontium have all been implicated in both musculoskeletal and cardiovascular health and disease. However, despite these three elements being closely chemically related, there is marked heterogeneity of their characteristics in relation to cardiovascular outcomes. In this narrative review, we describe the relevant evidential landscape, focusing on clinical trials where possible and incorporating findings from observational and causal analyses, to discern the relative roles of these elements in musculoskeletal and cardiovascular health. We conclude that calcium supplementation (for bone health) is most appropriately used in combination with vitamin D supplementation and targeted to those who are deficient in these nutrients, or in combination with antiosteoporosis medications. Whilst calcium supplementation is associated with gastrointestinal side effects and a small increased risk of renal stones, purported links with cardiovascular outcomes remain unconvincing. In normal physiology, no mechanism for an association has been elucidated and other considerations such as dose response and temporal relationships do not support a causal relationship. There is little evidence to support routine magnesium supplementation for musculoskeletal outcomes; greater dietary intake and serum concentrations appear protective against cardiovascular events. Strontium ranelate, which is now available again as a generic medication, has clear anti-fracture efficacy but is associated with an increased risk of thromboembolic disease. Whilst a signal for increased risk of myocardial infarction has been detected in some studies, this is not supported by wider analyses. Strontium ranelate, under its current licence, thus provides a useful therapeutic option for severe osteoporosis in those who do not have cardiovascular risk factors.
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http://dx.doi.org/10.1007/s40520-021-01799-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943433PMC
March 2021

Individualised placement and support programme for people unemployed because of chronic pain: a feasibility study and the InSTEP pilot RCT.

Health Technol Assess 2021 Jan;25(5):1-72

MRC Versus Arthritis Centre for Musculoskeletal Health and Work, University of Southampton, Southampton General Hospital, Southampton, UK.

Background: Chronic pain is a common cause of health-related incapacity for work among people in the UK. Individualised placement and support is a systematic approach to rehabilitation, with emphasis on early supported work placement. It is effective in helping people with severe mental illness to gain employment, but has not been tested for chronic pain.

Objective: To inform the design of a definitive randomised controlled trial to assess the clinical effectiveness of individualised placement and support for people unemployed because of chronic pain.

Methods: A mixed-methods feasibility study comprising qualitative interviews and focus groups with key stakeholders, alongside a pilot trial.

Study Participants: Primary care-based health-care professionals, employment support workers, employers, clients who participated in an individualised placement and support programme, and individuals aged 18-64 years with chronic pain who were unemployed for at least 3 months.

Intervention: An individualised placement and support programme integrated with a personalised, responsive pain management plan, backed up by communication with a general practitioner and rapid access to community-based pain services.

Outcomes: Outcomes included stakeholder views about a trial and methods of recruitment; the feasibility and acceptability of the individualised placement and support intervention; study processes (including methods to recruit participants from primary care, training and support needs of the employment support workers to integrate with pain services, acceptability of randomisation and the treatment-as-usual comparator); and scoping of outcome measures for a definitive trial.

Results: All stakeholders viewed a trial as feasible and important, and saw the relevance of employment interventions in this group. Using all suggested methods, recruitment was feasible through primary care, but it was slow and resource intensive. Recruitment through pain services was more efficient. Fifty people with chronic pain were recruited (37 from primary care and 13 from pain services). Randomisation was acceptable, and 22 participants were allocated to individualised placement and support, and 28 participants were allocated to treatment as usual. Treatment as usual was found acceptable. Retention of treatment-as-usual participants was acceptable throughout the 12 months. However, follow-up of individualised placement and support recipients using postal questionnaires proved challenging, especially when the participant started paid work, and new approaches would be needed for a trial. Clients, employment support workers, primary care-based health-care professionals and employers contributed to manualisation of the intervention. No adverse events were reported.

Conclusion: Unless accurate and up-to-date employment status information can be collected in primary care health records, or linkage can be established with employment records, research such as this relating to employment will be impracticable in primary care. The trial may be possible through pain services; however, clients may differ. Retention of participants proved challenging and methods for achieving this would need to be developed. The intervention has been manualised.

Trial Registration: Current Controlled Trials ISRCTN30094062.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 25, No. 5. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta25050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869008PMC
January 2021
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