Publications by authors named "Joshua A Bell"

34 Publications

Body muscle gain and markers of cardiovascular disease susceptibility in young adulthood: A cohort study.

PLoS Med 2021 Sep 9;18(9):e1003751. Epub 2021 Sep 9.

MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.

Background: The potential benefits of gaining body muscle for cardiovascular disease (CVD) susceptibility, and how these compare with the potential harms of gaining body fat, are unknown. We compared associations of early life changes in body lean mass and handgrip strength versus body fat mass with atherogenic traits measured in young adulthood.

Methods And Findings: Data were from 3,227 offspring of the Avon Longitudinal Study of Parents and Children (39% male; recruited in 1991-1992). Limb lean and total fat mass indices (kg/m2) were measured using dual-energy X-ray absorptiometry scans performed at age 10, 13, 18, and 25 y (across clinics occurring from 2001-2003 to 2015-2017). Handgrip strength was measured at 12 and 25 y, expressed as maximum grip (kg or lb/in2) and relative grip (maximum grip/weight in kilograms). Linear regression models were used to examine associations of change in standardised measures of these exposures across different stages of body development with 228 cardiometabolic traits measured at age 25 y including blood pressure, fasting insulin, and metabolomics-derived apolipoprotein B lipids. SD-unit gain in limb lean mass index from 10 to 25 y was positively associated with atherogenic traits including very-low-density lipoprotein (VLDL) triglycerides. This pattern was limited to lean gain in legs, whereas lean gain in arms was inversely associated with traits including VLDL triglycerides, insulin, and glycoprotein acetyls, and was also positively associated with creatinine (a muscle product and positive control). Furthermore, this pattern for arm lean mass index was specific to SD-unit gains occurring between 13 and 18 y, e.g., -0.13 SD (95% CI -0.22, -0.04) for VLDL triglycerides. Changes in maximum and relative grip from 12 to 25 y were both positively associated with creatinine, but only change in relative grip was also inversely associated with atherogenic traits, e.g., -0.12 SD (95% CI -0.18, -0.06) for VLDL triglycerides per SD-unit gain. Change in fat mass index from 10 to 25 y was more strongly associated with atherogenic traits including VLDL triglycerides, at 0.45 SD (95% CI 0.39, 0.52); these estimates were directionally consistent across sub-periods, with larger effect sizes with more recent gains. Associations of lean, grip, and fat measures with traits were more pronounced among males. Study limitations include potential residual confounding of observational estimates, including by ectopic fat within muscle, and the absence of grip measures in adolescence for estimates of grip change over sub-periods.

Conclusions: In this study, we found that muscle strengthening, as indicated by grip strength gain, was weakly associated with lower atherogenic trait levels in young adulthood, at a smaller magnitude than unfavourable associations of fat mass gain. Associations of muscle mass gain with such traits appear to be smaller and limited to gains occurring in adolescence. These results suggest that body muscle is less robustly associated with markers of CVD susceptibility than body fat and may therefore be a lower-priority intervention target.
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September 2021

Effects of adiposity on the human plasma proteome: observational and Mendelian randomisation estimates.

Int J Obes (Lond) 2021 Jul 5. Epub 2021 Jul 5.

Medical Research Council (MRC) Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.

Background: Variation in adiposity is associated with cardiometabolic disease outcomes, but mechanisms leading from this exposure to disease are unclear. This study aimed to estimate effects of body mass index (BMI) on an extensive set of circulating proteins.

Methods: We used SomaLogic proteomic data from up to 2737 healthy participants from the INTERVAL study. Associations between self-reported BMI and 3622 unique plasma proteins were explored using linear regression. These were complemented by Mendelian randomisation (MR) analyses using a genetic risk score (GRS) comprised of 654 BMI-associated polymorphisms from a recent genome-wide association study (GWAS) of adult BMI. A disease enrichment analysis was performed using DAVID Bioinformatics 6.8 for proteins which were altered by BMI.

Results: Observationally, BMI was associated with 1576 proteins (P < 1.4 × 10), with particularly strong evidence for a positive association with leptin and fatty acid-binding protein-4 (FABP4), and a negative association with sex hormone-binding globulin (SHBG). Observational estimates were likely confounded, but the GRS for BMI did not associate with measured confounders. MR analyses provided evidence for a causal relationship between BMI and eight proteins including leptin (0.63 standard deviation (SD) per SD BMI, 95% CI 0.48-0.79, P = 1.6 × 10), FABP4 (0.64 SD per SD BMI, 95% CI 0.46-0.83, P = 6.7 × 10) and SHBG (-0.45 SD per SD BMI, 95% CI -0.65 to -0.25, P = 1.4 × 10). There was agreement in the magnitude of observational and MR estimates (R = 0.33) and evidence that proteins most strongly altered by BMI were enriched for genes involved in cardiovascular disease.

Conclusions: This study provides evidence for a broad impact of adiposity on the human proteome. Proteins strongly altered by BMI include those involved in regulating appetite, sex hormones and inflammation; such proteins are also enriched for cardiovascular disease-related genes. Altogether, results help focus attention onto new proteomic signatures of obesity-related disease.
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July 2021

Evaluating the direct effects of childhood adiposity on adult systemic metabolism: a multivariable Mendelian randomization analysis.

Int J Epidemiol 2021 Mar 30. Epub 2021 Mar 30.

MRC Integrative Epidemiology Unit (IEU), Population Health Sciences, Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK.

Background: Individuals who are obese in childhood have an elevated risk of disease in adulthood. However, whether childhood adiposity directly impacts intermediate markers of this risk, independently of adult adiposity, is unclear. In this study, we have simultaneously evaluated the effects of childhood and adulthood body size on 123 systemic molecular biomarkers representing multiple metabolic pathways.

Methods: Two-sample Mendelian randomization (MR) was conducted to estimate the causal effect of childhood body size on a total of 123 nuclear magnetic resonance-based metabolic markers using summary genome-wide association study (GWAS) data from up to 24 925 adults. Multivariable MR was then applied to evaluate the direct effects of childhood body size on these metabolic markers whilst accounting for adult body size. Further MR analyses were undertaken to estimate the potential mediating effects of these circulating metabolites on the risk of coronary artery disease (CAD) in adulthood using a sample of 60 801 cases and 123 504 controls.

Results: Univariable analyses provided evidence that childhood body size has an effect on 42 of the 123 metabolic markers assessed (based on P < 4.07 × 10-4). However, the majority of these effects (35/42) substantially attenuated when accounting for adult body size using multivariable MR. We found little evidence that the biomarkers that were potentially influenced directly by childhood body size (leucine, isoleucine and tyrosine) mediate this effect onto adult disease risk. Very-low-density lipoprotein markers provided the strongest evidence of mediating the long-term effect of adiposity on CAD risk.

Conclusions: Our findings suggest that childhood adiposity predominantly exerts its detrimental effect on adult systemic metabolism along a pathway that involves adulthood body size.
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March 2021

Sex differences in systemic metabolites at four life stages: cohort study with repeated metabolomics.

BMC Med 2021 Feb 24;19(1):58. Epub 2021 Feb 24.

MRC Integrative Epidemiology Unit at the University of Bristol, Oakfield House, Bristol, BS8 2BN, UK.

Background: Males experience higher rates of coronary heart disease (CHD) than females, but the circulating traits underpinning this difference are poorly understood. We examined sex differences in systemic metabolites measured at four life stages, spanning childhood to middle adulthood.

Methods: Data were from the Avon Longitudinal Study of Parents and Children (7727 offspring, 49% male; and 6500 parents, 29% male). Proton nuclear magnetic resonance (H-NMR) spectroscopy from a targeted metabolomics platform was performed on EDTA-plasma or serum samples to quantify 229 systemic metabolites (including lipoprotein-subclass-specific lipids, pre-glycaemic factors, and inflammatory glycoprotein acetyls). Metabolites were measured in the same offspring once in childhood (mean age 8 years), twice in adolescence (16 years and 18 years) and once in early adulthood (25 years), and in their parents once in middle adulthood (50 years). Linear regression models estimated differences in metabolites for males versus females on each occasion (serial cross-sectional associations).

Results: At 8 years, total lipids in very-low-density lipoproteins (VLDL) were lower in males; levels were higher in males at 16 years and higher still by 18 years and 50 years (among parents) for medium-or-larger subclasses. Larger sex differences at older ages were most pronounced for VLDL triglycerides-males had 0.19 standard deviations (SD) (95% CI = 0.12, 0.26) higher at 18 years, 0.50 SD (95% CI = 0.42, 0.57) higher at 25 years, and 0.62 SD (95% CI = 0.55, 0.68) higher at 50 years. Low-density lipoprotein (LDL) cholesterol, apolipoprotein-B, and glycoprotein acetyls were generally lower in males across ages. The direction and magnitude of effects were largely unchanged when adjusting for body mass index measured at the time of metabolite assessment on each occasion.

Conclusions: Our results suggest that males begin to have higher VLDL triglyceride levels in adolescence, with larger sex differences at older ages. Sex differences in other CHD-relevant metabolites, including LDL cholesterol, show the opposite pattern with age, with higher levels among females. Such life course trends may inform causal analyses with clinical endpoints in specifying traits which underpin higher age-adjusted CHD rates commonly seen among males.
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February 2021

Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study.

BMC Med 2020 12 17;18(1):396. Epub 2020 Dec 17.

Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background: Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood.

Methods: We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models.

Results: In sex-specific MR analyses, higher BMI (per 4.2 kg/m) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P ≤ 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles.

Conclusions: Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.
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December 2020

Puberty timing and adiposity change across childhood and adolescence: disentangling cause and consequence.

Hum Reprod 2020 12;35(12):2784-2792

School of Public Health, University College Cork, Cork, Ireland.

Study Question: Is earlier puberty more likely a result of adiposity gain in childhood than a cause of adiposity gain in adulthood?

Summary Answer: Pre-pubertal fat mass is associated with earlier puberty timing but puberty timing is not associated with post-pubertal fat mass change.

What Is Known Already: Age at puberty onset has decreased substantially in the last several decades. Whether reducing childhood adiposity prevents earlier puberty and if early puberty prevention itself also has additional independent benefits for prevention of adult adiposity is not well understood.

Study Design, Size, Duration: Prospective birth cohort study of 4176 participants born in 1991/1992 with 18 232 repeated measures of fat mass from age 9 to 18 years.

Participants/materials, Setting, Methods: We used repeated measures of height from 5 to 20 years to identify puberty timing (age at peak height velocity, aPHV) and repeated measures of directly measured fat mass from age 9 to 18 years, from a contemporary UK birth cohort study to model fat mass trajectories by chronological age and by time before and after puberty onset. We then examined associations of these trajectories with puberty timing separately in females and males.

Main Results And The Role Of Chance: In models by chronological age, a 1-year later aPHV was associated with 20.5% (95% confidence interval (CI): 18.6-22.4%) and 23.4% (95% (CI): 21.3-25.5%) lower fat mass in females and males, respectively, at 9 years. These differences were smaller at age 18 years: 7.8% (95% (CI): 5.9-9.6%) and 12.4% (95% (CI): 9.6-15.2%) lower fat mass in females and males per year later aPHV. Trajectories of fat mass by time before and after puberty provided strong evidence for an association of pre-pubertal fat mass with puberty timing, and little evidence of an association of puberty timing with post-pubertal fat mass change. The role of chance is likely to be small in this study given the large sample sizes available.

Limitations, Reasons For Caution: Participants included in our analyses were more socially advantaged than those excluded. The findings of this work may not apply to non-White populations and further work examining associations of puberty timing and fat mass in other ethnicities is required.

Wider Implications Of The Findings: Previous research has relied on self-reported measures of puberty timing such as age of voice breaking in males, has lacked data on pre-and post-pubertal adiposity together and relied predominantly on indirect measures of adiposity such as BMI. This has led to conflicting results on the nature and direction of the association between puberty timing and adiposity in females and males. Our work provides important clarity on this, suggesting that prevention of adiposity in childhood is key for prevention of early puberty, adult adiposity and associated cardiovascular risk. In contrast, our findings suggest that prevention of early puberty without prevention of childhood adiposity would have little impact on prevention of adult adiposity.

Study Funding/competing Interest(s): The UK Medical Research Council and Wellcome (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for Avon Longitudinal Study of Parents and Children (ALSPAC). L.M.O.K. is supported by a UK Medical Research Council Population Health Scientist fellowship (MR/M014509/1) and a Health Research Board (HRB) of Ireland Emerging Investigator Award (EIA-FA-2019-007 SCaRLeT). J.A.B. is supported by the Elizabeth Blackwell Institute for Health Research, University of Bristol and the Wellcome Trust Institutional Strategic Support Fund (204813/Z/16/Z). L.D.H. and A.F. are supported by Career Development Awards from the UK Medical Research Council (grants MR/M020894/1 and MR/M009351/1, respectively). All authors work in a unit that receives funds from the UK Medical Research Council (grant MC_UU_00011/3, MC_UU_00011/6). No competing interests to declare.

Trial Registration Number: N/A.
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December 2020

Impact of sex hormone-binding globulin on the human phenome.

Hum Mol Genet 2020 07;29(11):1824-1832

Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.

Background: Sex hormone-binding globulin (SHBG) is a circulating glycoprotein and a regulator of sex hormone levels, which has been shown to influence various traits and diseases. The molecular nature of SHBG makes it a feasible target for preventative or therapeutic interventions. A systematic study of its effects across the human phenome may uncover novel associations.

Methods: We used a Mendelian randomization phenome-wide association study (MR-pheWAS) approach to systematically appraise the potential functions of SHBG while reducing potential biases such as confounding and reverse causation common to the literature. We searched for potential causal effects of SHBG in UK Biobank (N = 334 977) and followed-up our top findings using two-sample MR analyses to evaluate whether estimates may be biased due to horizontal pleiotropy.

Results: Results of the MR-pheWAS across over 21 000 outcome phenotypes identified 12 phenotypes associated with genetically elevated SHBG after Bonferroni correction for multiple testing. Follow-up analysis using two-sample MR indicated the associations of increased natural log SHBG with higher impedance of the arms and whole body, lower pulse rate, lower bone density, higher odds of hip replacement, lower odds of high cholesterol or cholesterol medication use and higher odds of gallbladder removal.

Conclusions: Our systematic MR-pheWAS of SHBG, which was comprehensive to the range of phenotypes available in UK Biobank, suggested that higher circulating SHBG affects the body impedance, bone density and cholesterol levels, among others. These phenotypes should be prioritized in future studies aiming to investigate the biological effects of SHBG or develop targets for therapeutic intervention.
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July 2020

Early Metabolic Features of Genetic Liability to Type 2 Diabetes: Cohort Study With Repeated Metabolomics Across Early Life.

Diabetes Care 2020 07 28;43(7):1537-1545. Epub 2020 Apr 28.

Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Bristol, U.K.

Objective: Type 2 diabetes develops for many years before diagnosis. We aimed to reveal early metabolic features characterizing liability to adult disease by examining genetic liability to adult type 2 diabetes in relation to metabolomic traits across early life.

Research Design And Methods: Up to 4,761 offspring from the Avon Longitudinal Study of Parents and Children were studied. Linear models were used to examine effects of a genetic risk score (162 variants) for adult type 2 diabetes on 229 metabolomic traits (lipoprotein subclass-specific cholesterol and triglycerides, amino acids, glycoprotein acetyls, and others) measured at age 8 years, 16 years, 18 years, and 25 years. Two-sample Mendelian randomization (MR) was also conducted using genome-wide association study data on metabolomic traits in an independent sample of 24,925 adults.

Results: At age 8 years, associations were most evident for type 2 diabetes liability (per SD higher) with lower lipids in HDL subtypes (e.g., -0.03 SD [95% CI -0.06, -0.003] for total lipids in very large HDL). At 16 years, associations were stronger with preglycemic traits, including citrate and with glycoprotein acetyls (0.05 SD; 95% CI 0.01, 0.08), and at 18 years, associations were stronger with branched-chain amino acids. At 25 years, associations had strengthened with VLDL lipids and remained consistent with previously altered traits, including HDL lipids. Two-sample MR estimates among adults indicated persistent patterns of effect of disease liability.

Conclusions: Our results support perturbed HDL lipid metabolism as one of the earliest features of type 2 diabetes liability, alongside higher branched-chain amino acid and inflammatory levels. Several features are apparent in childhood as early as age 8 years, decades before the clinical onset of disease.
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July 2020

Does peritrochanteric fat thickness increase the risk of early reoperation for infection or wound complications following total hip arthroplasty?

J Orthop 2019 Sep-Oct;16(5):359-362. Epub 2019 Apr 8.

Rush University Medical Center, Department of Orthopaedic Surgery, Chicago, IL, USA.

Background: Radiographically measured subcutaneous peri-incisional tissue depth has been correlated with post-operative surgical site infection after cardiac, cervical spine, and total knee surgery. Its impact following primary total hip arthroplasty (THA) has not been studied. We compare the interobserver reliability of measuring peritrochanteric fat thickness on pre-operative radiographs and hypothesize that these measurements are a reproducible way to predict acute post-operative wound complications and infection in patients undergoing THA.

Methods: A retrospective case-control analysis was performed at a single institution. Patients taken to the operating room within 90 days of their primary THA for a wound complication or deep infection between 2008 and 2016 were identified. Patients <18 years old, those with history of open surgery on the affected hip, or with inadequate radiographs were excluded. Patients were matched 1:1 for gender, age, BMI, and ASA score to THA patients without early wound complications.

Results: All radiographic measurements performed were found to have excellent inter-rater reliabilities (range 0.96-0.98). There was no difference in peritrochanteric fat thickness measurements between the two groups including the sourcil to skin surface (89.5 mm vs. 91.9 mm, p = 0.5), tip of greater trochanter to skin surface (52.9 mm vs. 53.7 mm, p = 0.8), and lateral greater trochanter to skin surface (36.0 mm vs. 37.8 mm, p = 0.6) measurements.

Conclusion: Contrary to other previously reported surgical procedures, radiographic measurement of subcutaneous depth is not a valid tool for predicting a return to the OR for wound complications in the early post-operative period following primary total hip arthroplasty.
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April 2019

Gender Differences for Hip and Knee Arthroplasty: Complications and Healthcare Utilization.

J Arthroplasty 2019 Aug 1;34(8):1593-1597.e1. Epub 2019 Apr 1.

Department of Orthopaedic Surgery, Rush University Medical Center, Chicago, IL.

Introduction: The influence of patient gender on complications and healthcare utilization remains unexplored. The purpose of the present study was to determine if patient gender significantly affected outcomes following total hip arthroplasty (THA) and total knee arthroplasty (TKA).

Methods: Retrospective cohort study of THA and TKA patients was performed using the Nationwide Inpatient Sample from 2002 to 2011. Only patients who underwent elective procedures and those with complete perioperative data were included. Multivariate logistic regression was used to compare the rates of adverse events between male and female cohorts while controlling for baseline characteristics.

Results: A total of 6,123,637 patients were included in the study (31.2% THA and 68.8% TKA). The cohort was 61.1% female. While males had a lower rate of any adverse event (odds ratio [OR] = 0.8, P < .001), urinary tract infection (OR = 0.4, P < .001), deep vein thrombosis/pulmonary embolism (OR = 0.9, P < .001), and blood transfusion (OR = 0.5, P < .001), male gender was associated with statistically significant increases in the rates of death (OR = 1.6, P < .001), acute kidney injury (OR = 1.6, P < .001), cardiac arrest (OR = 1.7, P < .001), myocardial infarction (OR = 1.6, P < .001), pneumonia (OR = 1.1, P < .001), sepsis (OR = 1.6, P < .001), surgical site infection (OR = 1.4, P < .001), and wound dehiscence (OR = 1.4, P < .001).

Conclusion: Males had increased rates of many individual adverse events. Females had higher rates of urinary tract infection, which translated to an overall higher rate of adverse events in females because of the rarity of the other individual adverse events.
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August 2019

Associations of Body Mass and Fat Indexes With Cardiometabolic Traits.

J Am Coll Cardiol 2018 12;72(24):3142-3154

MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom.

Background: Body mass index (BMI) is criticized for not distinguishing fat from lean mass and ignoring fat distribution, leaving its ability to detect health effects unclear.

Objectives: The aim of this study was to compare BMI with total and regional fat indexes from dual-energy x-ray absorptiometry in their associations with cardiometabolic traits. Duration of exposure to and change in each index across adolescence were examined in relation to detailed traits in young adulthood.

Methods: BMI was examined alongside total, trunk, arm, and leg fat indexes (each in kilograms per square meter) from dual-energy x-ray absorptiometry at ages 10 and 18 years in relation to 230 traits from targeted metabolomics at age 18 years in 2,840 offspring from the Avon Longitudinal Study of Parents and Children.

Results: Higher total fat mass index and BMI at age 10 years were similarly associated with cardiometabolic traits at age 18 years, including higher systolic and diastolic blood pressure, higher very low-density lipoprotein and low-density lipoprotein cholesterol, lower high-density lipoprotein cholesterol, higher triglycerides, and higher insulin and glycoprotein acetyls. Associations were stronger for both indexes measured at age 18 years and for gains in each index from age 10 to 18 years (e.g., 0.45 SDs [95% confidence interval: 0.38 to 0.53] in glycoprotein acetyls per SD unit gain in fat mass index vs. 0.38 SDs [95% confidence interval: 0.27 to 0.48] per SD unit gain in BMI). Associations resembled those for trunk fat index. Higher lean mass index was weakly associated with traits and was not protective against higher fat mass index.

Conclusions: The results of this study support abdominal fatness as a primary driver of cardiometabolic dysfunction and BMI as a useful tool for detecting its effects.
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December 2018

Examining associations between physical activity and cardiovascular mortality using negative control outcomes.

Int J Epidemiol 2019 08;48(4):1161-1166

Charles Perkins Centre, University of Sydney, Sydney, Australia.

Background: The purpose of a negative control is to reproduce a condition that cannot involve the hypothesized causal mechanism, but does involve the same sources of bias and confounding that may distort the primary association of interest. Observational studies suggest physical inactivity is a major risk factor for cardiovascular disease (CVD), although potential sources of bias, including reverse causation and residual confounding, make it difficult to infer causality. The aim was to employ a negative control outcome to explore the extent to which the association between physical activity and CVD mortality is explained by confounding.

Methods: The sample comprised 104 851 participants (aged 47 ± 17 years; 45.4% male) followed up over mean (SD) 9.4 ± 4.5 years, recruited from the Health Survey for England and the Scottish Health Survey.

Results: There were 10 309 deaths, of which 3109 were attributed to CVD and 157 to accidents (negative control outcome). Accidental death was related to age, male sex, smoking, longstanding illness and psychological distress, with some evidence of social patterning. This confounding structure was similar to that seen with CVD mortality, suggesting that our negative control outcome was appropriate. Physical activity (per SD unit increase in MET-hr-wk) was inversely associated with CVD [hazard ratio (HR) = 0.75; 95% confidence interval (CI), 0.70, 0.80]; the point estimate between physical activity and accidental death was in the same direction but of lesser magnitude (HR = 0.86; 95% CI: 0.69, 1.07). A linear dose-response pattern was observed for physical activity and CVD but not with the negative control.

Conclusions: Inverse associations between physical activity and risk of CVD mortality are likely causal but of a smaller magnitude than commonly observed. Negative control studies have the potential to improve causal inference within the physical activity field.
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August 2019

Associations of device-measured physical activity across adolescence with metabolic traits: Prospective cohort study.

PLoS Med 2018 09 11;15(9):e1002649. Epub 2018 Sep 11.

MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom.

Background: Multiple occasions of device-measured physical activity have not been previously examined in relation to metabolic traits. We described associations of total activity, moderate-to-vigorous physical activity (MVPA), and sedentary time from three accelerometry measures taken across adolescence with detailed traits related to systemic metabolism.

Methods And Findings: There were 1,826 male and female participants recruited at birth in 1991-1992 via mothers into the Avon Longitudinal Study of Parents and Children offspring cohort who attended clinics in 2003-2005, 2005-2006, and 2006-2008 who were included in ≥1 analysis. Waist-worn uniaxial accelerometers measured total activity (counts/min), MVPA (min/d), and sedentary time (min/d) over ≥3 d at mean age 12y, 14y, and 15y. Current activity (at age 15y), mean activity across occasions, interaction by previous activity, and change in activity were examined in relation to systolic and diastolic blood pressure, insulin, C-reactive protein, and 230 traits from targeted metabolomics (nuclear magnetic resonance spectroscopy), including lipoprotein cholesterol and triglycerides, amino and fatty acids, glycoprotein acetyls, and others, at age 15y. Mean current total activity was 477.5 counts/min (SD = 164.0) while mean MVPA and sedentary time durations were 23.6 min/d (SD = 17.9) and 522.1 min/d (SD = 66.0), respectively. Mean body mass index at age 15y was 21.4 kg/m2 (SD = 3.5). Correlations between first and last activity measurement occasions were low (e.g., r = 0.40 for counts/min). Current activity was most strongly associated with cholesterol and triglycerides in high-density lipoprotein (HDL) and very low-density lipoprotein (VLDL) particles (e.g., -0.002 mmol/l or -0.18 SD units; 95% CI -0.24--0.11 for triglycerides in chylomicrons and extremely large very low-density lipoprotein [XL VLDL]) and with glycoprotein acetyls (-0.02 mmol/l or -0.16 SD units; 95% CI -0.22--0.10), among others. Associations were similar for mean activity across 3 occasions. Attenuations were modest with adjustment for fat mass index based on dual-energy X-ray absorptiometry (DXA). In mutually adjusted models, higher MVPA and sedentary time were oppositely associated with cholesterol and triglycerides in VLDL and HDL particles (MVPA more strongly with glycoprotein acetyls and sedentary time more strongly with amino acids). Associations appeared less consistent for sedentary time than for MVPA based on longer-term measures and were weak for change in all activity types from age 12y-15y. Evidence was also weak for interaction between activity types at age 15y and previous activity measures in relation to most traits (minimum P = 0.003; median P = 0.26 for counts/min) with interaction coefficients mostly positive. Study limitations include modest sample sizes and relatively short durations of accelerometry measurement on each occasion (3-7 d) and of time lengths between first and last accelerometry occasions (<4 years), which can obscure patterns from chance variation and limit description of activity trajectories. Activity was also recorded using uniaxial accelerometers which predated more sensitive triaxial devices.

Conclusions: Our results support associations of physical activity with metabolic traits that are small in magnitude and more robust for higher MVPA than lower sedentary time. Activity fluctuates over time, but associations of current activity with most metabolic traits do not differ by previous activity. This suggests that the metabolic effects of physical activity, if causal, depend on most recent engagement.
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September 2018

Obesity and loss of disease-free years owing to major non-communicable diseases: a multicohort study.

Lancet Public Health 2018 10 1;3(10):e490-e497. Epub 2018 Sep 1.

National Centre for Sport and Exercise Medicine, Loughborough University, Loughborough, UK.

Background: Obesity increases the risk of several chronic diseases, but the extent to which the obesity-related loss of disease-free years varies by lifestyle category and across socioeconomic groups is unclear. We estimated the number of years free from major non-communicable diseases in adults who are overweight and obese, compared with those who are normal weight.

Methods: We pooled individual-level data on body-mass index (BMI) and non-communicable diseases from men and women with no initial evidence of these diseases in European cohort studies from the Individual-Participant-Data Meta-Analysis in Working Populations consortium. BMI was assessed at baseline (1991-2008) and non-communicable diseases (incident type 2 diabetes, coronary heart disease, stroke, cancer, asthma, and chronic obstructive pulmonary disease) were ascertained via linkage to records from national health registries, repeated medical examinations, or self-report. Disease-free years from age 40 years to 75 years associated with underweight (BMI <18·5 kg/m), overweight (≥25 kg/m to <30 kg/m), and obesity (class I [mild] ≥30 kg/m to <35 kg/m; class II-III [severe] ≥35 kg/m) compared with normal weight (≥18·5 kg/m to <25 kg/m) were estimated.

Findings: Of 137 503 participants from ten studies, we excluded 6973 owing to missing data and 10 349 with prevalent disease at baseline, resulting in an analytic sample of 120 181 participants. Of 47 127 men, 211 (0·4%) were underweight, 21 468 (45·6%) normal weight, 20 738 (44·0%) overweight, 3982 (8·4%) class I obese, and 728 (1·5%) class II-III obese. The corresponding numbers among the 73 054 women were 1493 (2·0%), 44 760 (61·3%), 19 553 (26·8%), 5670 (7·8%), and 1578 (2·2%), respectively. During 1 328 873 person-years at risk (mean follow-up 11·5 years [range 6·3-18·6]), 8159 men and 8100 women developed at least one non-communicable disease. Between 40 years and 75 years, the estimated number of disease-free years was 29·3 (95% CI 28·8-29·8) in normal-weight men and 29·4 (28·7-30·0) in normal-weight women. Compared with normal weight, the loss of disease-free years in men was 1·8 (95% CI -1·3 to 4·9) for underweight, 1·1 (0·7 to 1·5) for overweight, 3·9 (2·9 to 4·9) for class I obese, and 8·5 (7·1 to 9·8) for class II-III obese. The corresponding estimates for women were 0·0 (-1·4 to 1·4) for underweight, 1·1 (0·6 to 1·5) for overweight, 2·7 (1·5 to 3·9) for class I obese, and 7·3 (6·1 to 8·6) for class II-III obese. The loss of disease-free years associated with class II-III obesity varied between 7·1 and 10·0 years in subgroups of participants of different socioeconomic level, physical activity level, and smoking habit.

Interpretation: Mild obesity was associated with the loss of one in ten, and severe obesity the loss of one in four potential disease-free years during middle and later adulthood. This increasing loss of disease-free years as obesity becomes more severe occurred in both sexes, among smokers and non-smokers, the physically active and inactive, and across the socioeconomic hierarchy.

Funding: NordForsk, UK Medical Research Council, US National Institute on Aging, Academy of Finland, Helsinki Institute of Life Science, and Cancer Research UK.
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October 2018

Influence of puberty timing on adiposity and cardiometabolic traits: A Mendelian randomisation study.

PLoS Med 2018 08 28;15(8):e1002641. Epub 2018 Aug 28.

Medical Research Council Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom.

Background: Earlier puberty is widely linked with future obesity and cardiometabolic disease. We examined whether age at puberty onset likely influences adiposity and cardiometabolic traits independent of childhood adiposity.

Methods And Findings: One-sample Mendelian randomisation (MR) analyses were conducted on up to 3,611 white-European female and male offspring from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort recruited at birth via mothers between 1 April 1991 and 31 December 1992. Time-sensitive exposures were age at menarche and age at voice breaking. Outcomes measured at age 18 y were body mass index (BMI), dual-energy X-ray absorptiometry-based fat and lean mass indices, blood pressure, and 230 cardiometabolic traits derived from targeted metabolomics (150 concentrations plus 80 ratios from nuclear magnetic resonance [NMR] spectroscopy covering lipoprotein subclasses of cholesterol and triglycerides, amino acids, inflammatory glycoproteins, and others). Adjustment was made for pre-pubertal BMI measured at age 8 y. For negative control MR analyses, BMI and cardiometabolic trait measures taken at age 8 y (before puberty, and which therefore cannot be an outcome of puberty itself) were used. For replication analyses, 2-sample MR was conducted using summary genome-wide association study data on up to 322,154 adults for post-pubertal BMI, 24,925 adults for post-pubertal NMR cardiometabolic traits, and 13,848 children for pre-pubertal obesity (negative control). Like observational estimates, 1-sample MR estimates in ALSPAC using 351 polymorphisms for age at menarche (explaining 10.6% of variance) among 2,053 females suggested that later age at menarche (per year) was associated with -1.38 kg/m2 of BMI at age 18 y (or -0.34 SD units, 95% CI -0.46, -0.23; P = 9.77 × 10-09). This coefficient attenuated 10-fold upon adjustment for BMI at age 8 y, to -0.12 kg/m2 (or -0.03 SDs, 95% CI -0.13, 0.07; P = 0.55). Associations with blood pressure were similar, but associations across other traits were small and inconsistent. In negative control MR analyses, later age at menarche was associated with -0.77 kg/m2 of pre-pubertal BMI measured at age 8 y (or -0.39 SDs, 95% CI -0.50, -0.29; P = 6.28 × 10-13), indicating that variants influencing menarche also influence BMI before menarche. Cardiometabolic trait associations were weaker and less consistent among males and both sexes combined. Higher BMI at age 8 y (per 1 kg/m2 using 95 polymorphisms for BMI explaining 3.4% of variance) was associated with earlier menarche among 2,648 females (by -0.26 y, 95% CI -0.37, -0.16; P = 1.16 × 10-06), likewise among males and both sexes combined. In 2-sample MR analyses using 234 polymorphisms and inverse variance weighted (IVW) regression, each year later age at menarche was associated with -0.81 kg/m2 of adult BMI (or -0.17 SD units, 95% CI -0.21, -0.12; P = 4.00 × 10-15). Associations were weaker with cardiometabolic traits. Using 202 polymorphisms, later menarche was associated with lower odds of childhood obesity (IVW-based odds ratio = 0.52 per year later, 95% CI 0.48, 0.57; P = 6.64 × 10-15). Study limitations include modest sample sizes for 1-sample MR, lack of inference to non-white-European populations, potential selection bias through modest completion rates of puberty questionnaires, and likely disproportionate measurement error of exposures by sex. The cardiometabolic traits examined were heavily lipid-focused and did not include hormone-related traits such as insulin and insulin-like growth factors.

Conclusions: Our results suggest that puberty timing has a small influence on adiposity and cardiometabolic traits and that preventive interventions should instead focus on reducing childhood adiposity.
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August 2018

Do worse baseline risk factors explain the association of healthy obesity with increased mortality risk? Whitehall II Study.

Int J Obes (Lond) 2019 08 14;43(8):1578-1589. Epub 2018 Aug 14.

School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK.

Objective: To describe 20-year risk factor trajectories according to initial weight/health status and investigate the extent to which baseline differences explain greater mortality among metabolically healthy obese (MHO) individuals than healthy non-obese individuals.

Methods: The sample comprised 6529 participants in the Whitehall II study who were measured serially between 1991-1994 and 2012-2013. Baseline weight (non-obese or obese; body mass index (BMI) ≥30 kg/m) and health status (healthy or unhealthy; two or more of hypertension, low high-density lipoprotein cholesterol (HDL-C), high triglycerides, high glucose, and high homeostatic model assessment of insulin resistance (HOMA-IR)) were defined. The relationships of baseline weight/health status with 20-year trajectories summarizing ~25,000 observations of systolic and diastolic blood pressures, HDL-C, triglycerides, glucose, and HOMA-IR were investigated using multilevel models. Relationships of baseline weight/health status with all-cause mortality up until July 2015 were investigated using Cox proportional hazards regression.

Results: Trajectories tended to be consistently worse for the MHO group compared to the healthy non-obese group (e.g., glucose by 0.21 (95% CI 0.09, 0.33; p < 0.001) mmol/L at 20-years of follow-up). Consequently, the MHO group had a greater risk of mortality (hazard ratio 2.11 (1.24, 3.58; p = 0.006)) when the referent group comprised a random sample of healthy non-obese individuals. This estimate, however, attenuated (1.34 (0.85, 2.13; p = 0.209)) when the referent group was matched to the MHO group on baseline risk factors.

Conclusions: Worse baseline risk factors may explain any difference in mortality risk between obese and non-obese groups both labelled as healthy, further challenging the concept of MHO.
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August 2019

The Influence of Patient Gender on Morbidity Following Total Hip or Total Knee Arthroplasty.

J Arthroplasty 2018 02 19;33(2):345-349. Epub 2017 Sep 19.

Department of Orthopaedic Surgery, Rush University Medical Center, Chicago, Illinois.

Background: Little research has focused on the influence of gender on postoperative morbidity following total hip arthroplasty (THA) and total knee arthroplasty (TKA). This study aimed to compare operative time, length of stay, 30-day complications, and readmissions based on patient gender.

Methods: The prospectively collected National Surgical Quality Improvement Program registry from 2005 to 2014 was queried to identify primary elective THA and TKA patients. Multivariate regression was used to compare the rates of 30-day adverse events, rates of readmission, operative time, and postoperative length of stay between men and women. Multivariate analyses were controlled for baseline patient characteristics and procedure type.

Results: A total of 173,777 patients were included (63.5% TKA and 36.5% THA). Male gender increased the risk of multiple adverse events, including death (relative risk [RR] 1.1, P < .001), surgical site infection (RR 1.2, P < .001), sepsis (RR 1.4, P < .001), cardiac arrest (RR 1.8, P < .001), and return to the operating room (RR 1.3, P < .001). Men had decreased overall adverse events (RR 0.8, P < .001) secondary to a lower risk of urinary tract infection (RR 0.5, P < .001) and blood transfusion (RR 0.7, P < .001), which were prevalent adverse events. Men had an increased risk of 30-day readmission (RR 1.2, P < .001), slightly increased operative time (+6 minutes, P < .001), and slightly decreased length of stay (-0.2 days, P < .001).

Conclusion: Men had increased risk of multiple individual adverse events including death, surgical site infection, cardiac arrest, return to the operating room, and readmission. Conversely, women had increased risk of urinary tract infection and blood transfusion.
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February 2018

Overweight, obesity, and risk of cardiometabolic multimorbidity: pooled analysis of individual-level data for 120 813 adults from 16 cohort studies from the USA and Europe.

Lancet Public Health 2017 Jun 19;2(6):e277-e285. Epub 2017 May 19.

Institute of Behavioral Sciences, University of Helsinki, Helsinki, Finland.

Background: Although overweight and obesity have been studied in relation to individual cardiometabolic diseases, their association with risk of cardiometabolic multimorbidity is poorly understood. Here we aimed to establish the risk of incident cardiometabolic multimorbidity (ie, at least two from: type 2 diabetes, coronary heart disease, and stroke) in adults who are overweight and obese compared with those who are a healthy weight.

Methods: We pooled individual-participant data for BMI and incident cardiometabolic multimorbidity from 16 prospective cohort studies from the USA and Europe. Participants included in the analyses were 35 years or older and had data available for BMI at baseline and for type 2 diabetes, coronary heart disease, and stroke at baseline and follow-up. We excluded participants with a diagnosis of diabetes, coronary heart disease, or stroke at or before study baseline. According to WHO recommendations, we classified BMI into categories of healthy (20·0-24·9 kg/m), overweight (25·0-29·9 kg/m), class I (mild) obesity (30·0-34·9 kg/m), and class II and III (severe) obesity (≥35·0 kg/m). We used an inclusive definition of underweight (<20 kg/m) to achieve sufficient case numbers for analysis. The main outcome was cardiometabolic multimorbidity (ie, developing at least two from: type 2 diabetes, coronary heart disease, and stroke). Incident cardiometabolic multimorbidity was ascertained via resurvey or linkage to electronic medical records (including hospital admissions and death). We analysed data from each cohort separately using logistic regression and then pooled cohort-specific estimates using random-effects meta-analysis.

Findings: Participants were 120  813 adults (mean age 51·4 years, range 35-103; 71 445 women) who did not have diabetes, coronary heart disease, or stroke at study baseline (1973-2012). During a mean follow-up of 10·7 years (1995-2014), we identified 1627 cases of multimorbidity. After adjustment for sociodemographic and lifestyle factors, compared with individuals with a healthy weight, the risk of developing cardiometabolic multimorbidity in overweight individuals was twice as high (odds ratio [OR] 2·0, 95% CI 1·7-2·4; p<0·0001), almost five times higher for individuals with class I obesity (4·5, 3·5-5·8; p<0·0001), and almost 15 times higher for individuals with classes II and III obesity combined (14·5, 10·1-21·0; p<0·0001). This association was noted in men and women, young and old, and white and non-white participants, and was not dependent on the method of exposure assessment or outcome ascertainment. In analyses of different combinations of cardiometabolic conditions, odds ratios associated with classes II and III obesity were 2·2 (95% CI 1·9-2·6) for vascular disease only (coronary heart disease or stroke), 12·0 (8·1-17·9) for vascular disease followed by diabetes, 18·6 (16·6-20·9) for diabetes only, and 29·8 (21·7-40·8) for diabetes followed by vascular disease.

Interpretation: The risk of cardiometabolic multimorbidity increases as BMI increases; from double in overweight people to more than ten times in severely obese people compared with individuals with a healthy BMI. Our findings highlight the need for clinicians to actively screen for diabetes in overweight and obese patients with vascular disease, and pay increased attention to prevention of vascular disease in obese individuals with diabetes.

Funding: NordForsk, Medical Research Council, Cancer Research UK, Finnish Work Environment Fund, and Academy of Finland.
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June 2017

Improving risk estimates for metabolically healthy obesity and mortality using a refined healthy reference group.

Eur J Endocrinol 2017 Aug 31;177(2):169-174. Epub 2017 May 31.

MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.

Objective: We aimed to re-examine mortality risk estimates for metabolically healthy obesity by using a 'stable' healthy non-obese referent group.

Design: Prospective cohort study.

Methods: Participants were 5427 men and women (aged 65.9 ± 9.4 years, 45.9% men) from the English Longitudinal Study of Ageing. Obesity was defined as body mass index ≥30 kg/m (vs non-obese as below this threshold). Based on blood pressure, HDL cholesterol, triglycerides, glycated hemoglobin and C-reactive protein, participants were classified as 'healthy' (0 or 1 metabolic abnormality) or 'unhealthy' (≥2 metabolic abnormalities).

Results: Totally, 671 deaths were observed over an average follow-up of 8 years. When defining the referent group based on 1 clinical assessment, the unhealthy non-obese (hazard ratio (HR) = 1.22; 95% CI: 1.01, 1.45) and unhealthy obese (HR = 1.29; CI: 1.05, 1.60) were at greater risk of all-cause mortality compared to the healthy non-obese, yet no excess risk was seen in the healthy obese (HR = 1.14; CI: 0.83, 1.52). When we re-defined the referent group based on 2 clinical assessments, effect estimates were accentuated and healthy obesity was at increased risk of mortality (HR = 2.67; CI: 1.64, 4.34).

Conclusion: An unstable healthy referent group may make 'healthy obesity' appear less harmful by obscuring the benefits of remaining never obese without metabolic dysfunction.
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August 2017

Stability-preserving decompression in degenerative versus congenital spinal stenosis: demographic patterns and patient outcomes.

Spine J 2017 10 26;17(10):1420-1425. Epub 2017 Apr 26.

Rush University Medical Center, Department of Orthopaedic Surgery, Chicago, IL.

Background Context: Although lumbar spinal stenosis often presents as a degenerative condition (degenerative stenosis [DS]), some patients present with symptoms from lifelong narrowing of the spinal canal. These patients have congenital stenosis (CS) and present with symptoms of stenosis at a younger age. Patients with CS often have a distinct pathophysiology with fewer degenerative changes but present with multilevel involvement. In the setting of neurologic symptoms, decompression alone while preserving stability has been proposed for both patient populations.

Purpose: The purpose of this study is to evaluate if the different etiology for narrowing in CS and DS results in a different natural history of pain progression, different locations requiring decompression, and different outcomes following a stability-preserving decompression procedure.

Study Design/setting: This study used a retrospective cohort study patient sample: We retrospectively reviewed consecutive patients of a single surgeon with DS or CS who underwent surgical decompression without fusion between 2008 and 2014. Patients were excluded if they had undergone a previous lumbar surgical procedure (decompression or fusion) or follow-up less than 12 months.

Outcome Measures: Pre- and postoperative clinical outcome scores including visual analogue scale (VAS) and Oswestry Disability Index (ODI) were recorded. Postoperatively, data were collected regarding complications, the presence of new radicular or myelopathic symptoms, and necessity of reoperation in the lumbar spine.

Methods: Demographic information included age, sex, body mass index, smoking status, and Charleston Comorbidity Index (CCI). Preoperative clinical symptoms as well as the presence of lower extremity radiculopathy and claudication were evaluated. Patients were determined to have a diagnosis of CS by the treating surgeon if primary radiographs revealed shortened pedicles and decreased cross-sectional area of the spinal canal as detailed by previous studies. Binary outcomes were compared between congenital and degenerative cohorts using bivariate and multivariate logistic regression. Multivariate regressions controlled for baseline patient and operative characteristics.

Results: The average age of the DS cohort was 66.7±10.7 years, whereas for the CS group, it was 47.1±9.2 years. Average follow-up was 27.6 months. The patients with DS had significantly more comorbidities as shown by the CCI score (2.8±1.6 vs. 0.5±0.6); p<.001) and the American Society of Anesthesiologists (ASA) score ≥3 (52.8% vs. 11.1%; p<.001). Patients with CS presented with higher VAS back (8.0 vs. 5.1; p=.008) and leg (7.9 vs. 4.5; p<.001) scores. Patients with DS presented with significantly greater duration of preoperative back pain and leg pain (42.7 vs. 30.5 months; p=.042). Postoperatively, there were no significant differences in VAS back, leg, or ODI scores. However, a trend toward a lower VAS leg score was present in the patients with CS when compared with patients with DS (2.6±3.0 vs. 4.2±3.2; p<.117). Both patient groups experienced similar levels of symptomatic relief and improvement in VAS and ODI scores. There were no significant differences in new-onset radicular symptoms requiring conservative treatment or reoperation. In both groups combined, 81.9% of patients reported resolution of lower extremity symptoms at final follow-up. Overall, 20.6% of patients experienced new lower-extremity radicular symptoms after a period of resolution of symptoms postoperatively. There were significantly more reoperations following surgical decompression in patients with DS (13.9% vs. 2.8%; p=.02).

Conclusions: Patients with CS and patients with DS respond well to decompression alone, without a supplemental fusion, despite differences in pain experience and presentation. The localization of pathology requiring decompression is similar. The patients with DS were more susceptible to require another operation resulting in a fusion, which confirms the theory that initial microinstability can progress in DS, but is likely not part of the disease process in CS. At just over 2 years after decompression, patients with CS may not need to be treated by a fusion in the setting of lower back pain; however, longer-term follow up is necessary to further assess these outcomes.
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October 2017

Involvement of Residents Does Not Increase Postoperative Complications After Open Reduction Internal Fixation of Ankle Fractures: An Analysis of 3251 Cases.

J Foot Ankle Surg 2017 May - Jun;56(3):492-496. Epub 2017 Feb 27.

Orthopedist, Department of Orthopaedic Surgery, Rush University Medical Center, Chicago, IL.

Ankle fractures are common injuries frequently treated by foot and ankle surgeons. Therefore, it has become a core competency for orthopedic residency training. Surgical educators must balance the task of training residents with optimizing patient outcomes and minimizing morbidity and mortality. The present study aimed to determine the effect of resident involvement on the 30-day postoperative complication rates after open reduction and internal fixation of ankle fractures. A second objective of the present study was to determine the independent risk factors for complications after this procedure. We identified patients in the American College of Surgeons National Surgical Quality Improvement Program database who had undergone open reduction internal fixation for ankle fractures from 2005 to 2012. Propensity score matching was used to help account for a potential selection bias. We performed univariate and multivariate analyses to identify the independent risk factors associated with short-term postoperative complications. A total of 3251 open reduction internal fixation procedures for ankle fractures were identified, of which 959 (29.4%) had resident involvement. Univariate (2.82% versus 4.54%; p = .024) and multivariate (odds ratio 0.71; p = .75) analyses demonstrated that resident involvement did not increase short-term complication rates. The independent risk factors for complications after open reduction internal fixation of ankle fractures included insulin-dependent diabetes, increasing age, higher American Society of Anesthesiologists score, and longer operative times.
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March 2018

Association between inflammatory biomarkers and all-cause, cardiovascular and cancer-related mortality.

CMAJ 2017 Mar 28;189(10):E384-E390. Epub 2016 Nov 28.

INSERM U1018 Centre de recherche en Epidémiologie et Santé des Populations (Singh-Manoux, Canonico, Elbaz), Hôpital universitaire Paul-Brousse, Villejuif, France; Department of Epidemiology and Public Health (Shipley, Bell, Kivimäki), University College London, London, UK.

Background: The inflammatory biomarker α-acid glycoprotein (AGP) was found to have the strongest association with 5-year mortality in a recent study of 106 biomarkers. We examined whether AGP is a better biomarker of mortality risk than the more widely used inflammatory biomarkers interleukin-6 (IL-6) and C-reactive protein (CRP).

Methods: We analyzed data for 6545 men and women aged 45-69 (mean 55.7) years from the Whitehall II cohort study. We assayed AGP, IL-6 and CRP levels from fasting serum samples collected in 1997-1999. Mortality followup was until June 2015. Cox regression analysis was used to model associations of inflammatory biomarkers with all-cause, cardiovascular and cancer-related mortality.

Results: Over the mean follow-up of 16.7 years, 736 deaths occurred, of which 181 were from cardiovascular disease and 347 from cancer. In the model adjusted for all covariates (age, sex, socioeconomic status, body mass index, health behaviours and chronic disease), AGP did not predict mortality beyond the first 5 years of follow-up; over this period, IL-6 and CRP had stronger associations with mortality. When we considered all covariates and biomarkers simultaneously, AGP no longer predicted all-cause mortality over the entire follow-up period (adjusted hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.90-1.08). Only IL-6 predicted all-cause mortality (adjusted HR 1.22, 95% CI 1.12-1.33) and cancer-related mortality (adjusted HR 1.13, 95% CI 1.00-1.29) over the entire follow-up period, whereas CRP predicted only cardiovascular mortality (adjusted HR 1.30, 95% CI 1.06-1.61).

Interpretation: Our findings suggest that AGP is not a better marker of short-or long-term mortality risk than the more commonly used biomarkers IL-6 and CRP.
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March 2017

Ecce Homo: Science and Society Need Anthropological Collections.

Trends Ecol Evol 2016 08 21;31(8):580-583. Epub 2016 May 21.

Department of Anthropology, National Museum of Natural History, Smithsonian Institution, Washington, DC 20013-7012, USA.

Scientific collections are crucial to understanding the biological and cultural diversity of the Earth. Anthropological collections document the human experience and the interactions between people, ecosystems, and organisms. Unfortunately, anthropological collections are often poorly known by the public and face a variety of threats to their permanent care and conservation.
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August 2016

Stability of metabolically healthy obesity over 8 years: the English Longitudinal Study of Ageing.

Eur J Endocrinol 2015 Nov 18;173(5):703-8. Epub 2015 Aug 18.

National Centre for Sport and Exercise MedicineSchool of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, LE11 3TU, UKDepartment of Epidemiology and Public HealthUniversity College London, London, UK.

Objective: Metabolically healthy obesity possibly reflects a transitional stage before the onset of metabolic dysfunction, but few studies have characterised this transition. We examined the behavioural and biological characteristics of healthy obese adults that progressed to an unhealthy state over 8 years follow-up.

Methods: Participants were 2422 men and women (aged 63.3±7.7 years, 44.2% men) from the English Longitudinal Study of Ageing. Obesity was defined as BMI ≥30 kg/m(2). Based on blood pressure (BP), HDL-cholesterol, triglycerides, HbA1c and C-reactive protein (CRP) participants were classified as 'healthy' (0 or 1 metabolic abnormality) or 'unhealthy' (≥2 metabolic abnormalities).

Results: Over 8 years follow-up, 44.5% of healthy obese subjects had transitioned into an unhealthy state, compared to only 16.6 and 26.2% of healthy normal-weight and overweight adults respectively. Compared with healthy obese adults who remained stable, those who progressed to an unhealthy state were more likely to have high BP (75.0% vs 37.0%, age- and sex-adjusted odds ratio (OR) 8.9, 95% CI 4.7-17.0), high CRP (53.7% vs 17.0%, OR=8.6, 95% CI 4.1-18.0), high HbA1c (46.3% vs 5.9%, OR=13.8, 95% CI 6.1-31.2) and high triglycerides (45.4% vs 11.9%, OR=5.9, 95% CI 2.9-12.0) at follow-up, with excess risk remaining independent of lifestyle factors including self-reported physical activity. Progression to an unhealthy state was also linked with significant gains in waist circumference (B=2.7, 95% CI, 0.5-4.9 cm).

Conclusion: These data show that a healthy obesity phenotype is relatively unstable. Transition to an unhealthy state is characterised by multiple biological changes that are not fully explained by lifestyle risk factors.
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November 2015

Underweight as a risk factor for respiratory death in the Whitehall cohort study: exploring reverse causality using a 45-year follow-up.

Thorax 2016 Jan 7;71(1):84-5. Epub 2015 Aug 7.

Department of Epidemiology and Public Health, University College London, London, UK Centre for Research in Epidemiology and Population Health, INSERM, Villejuif, France.

Underweight adults have higher rates of respiratory death than the normal weight but it is unclear whether this association is causal or reflects illness-induced weight loss (reverse causality). Evidence from a 45-year follow-up of underweight participants for respiratory mortality in the Whitehall study (N=18 823; 2139 respiratory deaths) suggests that excess risk among the underweight is attributable to reverse causality. The age-adjusted and smoking-adjusted risk was 1.55-fold (95% CI 1.32 to 1.83) higher among underweight compared with normal weight participants, but attenuated in a stepwise manner to 1.14 (95% CI 0.76 to 1.71) after serial exclusions of deaths during the first 5-35 years of follow-up (P(trend)<0.001).
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January 2016

Healthy obesity and objective physical activity.

Am J Clin Nutr 2015 Aug 8;102(2):268-75. Epub 2015 Jul 8.

Department of Epidemiology & Public Health, University College London, London, United Kingdom; University Versailles St-Quentin, Boulogne-Billancourt, France.

Background: Disease risk is lower in metabolically healthy obese adults than in their unhealthy obese counterparts. Studies considering physical activity as a modifiable determinant of healthy obesity have relied on self-reported measures, which are prone to inaccuracies and do not capture all movements that contribute to health.

Objective: We aimed to examine differences in total and moderate-to-vigorous physical activity between healthy and unhealthy obese groups by using both self-report and wrist-worn accelerometer assessments.

Design: Cross-sectional analyses were based on 3457 adults aged 60-82 y (77% male) participating in the British Whitehall II cohort study in 2012-2013. Normal-weight, overweight, and obese adults were considered "healthy" if they had <2 of the following risk factors: low HDL cholesterol, hypertension, high blood glucose, high triacylglycerol, and insulin resistance. Differences across groups in total physical activity, based on questionnaire and wrist-worn triaxial accelerometer assessments (GENEActiv), were examined by using linear regression. The likelihood of meeting 2010 World Health Organization recommendations for moderate-to-vigorous activity (≥2.5 h/wk) was compared by using prevalence ratios.

Results: Of 3457 adults, 616 were obese [body mass index (in kg/m²) ≥30]; 161 (26%) of those were healthy obese. Obese adults were less physically active than were normal-weight adults, regardless of metabolic health status or method of physical activity assessment. Healthy obese adults had higher total physical activity than did unhealthy obese adults only when assessed by accelerometer (P = 0.002). Healthy obese adults were less likely to meet recommendations for moderate-to-vigorous physical activity than were healthy normal-weight adults based on accelerometer assessment (prevalence ratio: 0.59; 95% CI: 0.43, 0.79) but were not more likely to meet these recommendations than were unhealthy obese adults (prevalence ratio: 1.26; 95% CI: 0.89, 1.80).

Conclusions: Higher total physical activity in healthy than in unhealthy obese adults is evident only when measured objectively, which suggests that physical activity has a greater role in promoting health among obese populations than previously thought.
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August 2015

The Use of Trabecular Metal Cones in Complex Primary and Revision Total Knee Arthroplasty.

J Arthroplasty 2015 Sep 3;30(9 Suppl):90-3. Epub 2015 Jun 3.

Orthopaedic Surgery, Midwest Orthopaedics at Rush, Chicago, Illinois.

Trabecular metal cones are one option for treating osseous defects during TKA. A total of 83 consecutive TKAs utilizing cones with an average of 40 months follow-up were reviewed. There were 24 males and 59 females, with an average age of 69 years old. Four were complex primary and 79 were revision procedures. Of 83 patients, 10 (12%) required repeat revision surgery (8 infections, one periprosthetic fracture, one aseptic loosening) and overall, 37 of 83 patients (45%) experienced at least one complication. Of 73 unrevised knees, 72 (99%) demonstrated radiographic evidence of osseointegration. Despite a high complication rate in this population, trabecular metal cones represent an attractive option for managing bone loss in complex primary and revision TKA with a high rate of osseointegration.
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September 2015

Physical activity and adiposity markers at older ages: accelerometer vs questionnaire data.

J Am Med Dir Assoc 2015 May 6;16(5):438.e7-13. Epub 2015 Mar 6.

Department of Epidemiology and Public Health, University College London, London, United Kingdom; University Versailles St-Quentin, Boulogne-Billancourt, France; INSERM, U1018, Center for Research in Epidemiology and Population Health, Villejuif, France; University Paris 11, Villejuif, France; Centre de Gérontologie, Hôpital Ste Périne, AP-HP, France.

Objective: Physical activity is critically important for successful aging, but its effect on adiposity markers at older ages is unclear as much of the evidence comes from self-reported data on physical activity. We assessed the associations of questionnaire-assessed and accelerometer-assessed physical activity with adiposity markers in older adults.

Design/setting/participants: This was a cross-sectional study on 3940 participants (age range 60-83 years) of the Whitehall II study who completed a 20-item physical activity questionnaire and wore a wrist-mounted accelerometer for 9 days in 2012 and 2013.

Measurements: Total physical activity was estimated using metabolic equivalent hours/week for the questionnaire and mean acceleration for the accelerometer. Time spent in moderate-and-vigorous physical activity (MVPA) was also assessed by questionnaire and accelerometer. Adiposity assessment included body mass index, waist circumference, and fat mass index. Fat mass index was calculated as fat mass/height² (kg/m²), with fat mass estimated using bioimpedance.

Results: Greater total physical activity was associated with lower adiposity for all adiposity markers in a dose-response manner. In men, the strength of this association was 2.4 to 2.8 times stronger with the accelerometer than with questionnaire data. In women, it was 1.9 to 2.3 times stronger. For MVPA, questionnaire data in men suggested no further benefit for adiposity markers past 1 hour/week of activity. This was not the case for accelerometer-assessed MVPA where, for example, compared with men undertaking <1 hour/week of accelerometer-assessed MVPA, waist circumference was 3.06 (95% confidence interval 2.06-4.06) cm lower in those performing MVPA 1-2.5 hours/week, 4.69 (3.47-5.91) cm lower in those undertaking 2.5-4 hours/week, and 7.11 (5.93-8.29) cm lower in those performing ≥4 hours/week.

Conclusions: The association of physical activity with adiposity markers in older adults was stronger when physical activity was assessed by accelerometer compared with questionnaire, suggesting that physical activity might be more important for adiposity than previously estimated.
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May 2015