Publications by authors named "Antonella Delmestri"

30 Publications

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

Rheumatology (Oxford) 2021 Apr 14. Epub 2021 Apr 14.

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

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

Characterizing the incidence of adverse events of special interest for COVID-19 vaccines across eight countries: a multinational network cohort study.

medRxiv 2021 Mar 28. Epub 2021 Mar 28.

Background: As large-scale immunization programs against COVID-19 proceed around the world, safety signals will emerge that need rapid evaluation. We report population-based, age- and sex- specific background incidence rates of potential adverse events of special interest (AESI) in eight countries using thirteen databases.

Methods: This multi-national network cohort study included eight electronic medical record and five administrative claims databases from Australia, France, Germany, Japan, Netherlands, Spain, the United Kingdom, and the United States, mapped to a common data model. People observed for at least 365 days before 1 January 2017, 2018, or 2019 were included. We based study outcomes on lists published by regulators: acute myocardial infarction, anaphylaxis, appendicitis, Bell's palsy, deep vein thrombosis, disseminated intravascular coagulation, encephalomyelitis, Guillain-Barre syndrome, hemorrhagic and non-hemorrhagic stroke, immune thrombocytopenia, myocarditis/pericarditis, narcolepsy, pulmonary embolism, and transverse myelitis. We calculated incidence rates stratified by age, sex, and database. We pooled rates across databases using random effects meta-analyses. We classified meta-analytic estimates into Council of International Organizations of Medical Sciences categories: very common, common, uncommon, rare, or very rare.

Findings: We analysed 126,661,070 people. Rates varied greatly between databases and by age and sex. Some AESI (e.g., myocardial infarction, Guillain-Barre syndrome) increased with age, while others (e.g., anaphylaxis, appendicitis) were more common in young people. As a result, AESI were classified differently according to age. For example, myocardial infarction was very rare in children, rare in women aged 35-54 years, uncommon in men and women aged 55-84 years, and common in those aged ≥85 years.

Interpretation: We report robust baseline rates of prioritised AESI across 13 databases. Age, sex, and variation between databases should be considered if background AESI rates are compared to event rates observed with COVID-19 vaccines.
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http://dx.doi.org/10.1101/2021.03.25.21254315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010764PMC
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

Safety of Oral Bisphosphonates in Moderate-to-Severe Chronic Kidney Disease: A Binational Cohort Analysis.

J Bone Miner Res 2020 Dec 29. Epub 2020 Dec 29.

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

Bisphosphonates are the first-line treatment for preventing fractures in osteoporosis patients. However, their use is contraindicated or to be used with caution in chronic kidney disease (CKD) patients, primarily because of a lack of information about their safety and effectiveness. We aimed to investigate the safety of oral bisphosphonates in patients with moderate to severe CKD, using primary-care electronic records from two cohorts, CPRD GOLD (1997-2016) and SIDIAP (2007-2015) in the UK and Catalonia, respectively. Both databases were linked to hospital records. SIDIAP was also linked to end-stage renal disease registry data. Patients with CKD stages 3b to 5, based on two or more estimated glomerular filtration rate measurements less than 45 mL/min/1.73 m , aged 40 years or older were identified. New bisphosphonate users were propensity score-matched with up to five non-users to minimize confounding within this population. Our primary outcome was CKD stage worsening (estimated glomerular filtration rate [eGFR] decline or renal replacement therapy). Secondary outcomes were acute kidney injury, gastrointestinal bleeding/ulcers, and severe hypocalcemia. Hazard ratios (HRs) were estimated using Cox regression and Fine and Gray sub-HRs were calculated for competing risks. We matched 2447 bisphosphonate users with 8931 non-users from CPRD and 1399 users with 6547 non-users from SIDIAP. Bisphosphonate use was associated with greater risk of CKD progression in CPRD (sub-HR [95% CI]: 1.14 [1.04, 1.26]) and SIDIAP (sub-HR: 1.15 [1.04, 1.27]). No risk differences were found for acute kidney injury, gastrointestinal bleeding/ulcers, or hypocalcemia. Hence, we can conclude a modest (15%) increased risk of CKD progression was identified in association with bisphosphonate use. No other safety concerns were identified. Our findings should be considered before prescribing bisphosphonates to patients with moderate to severe CKD. © 2020 American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4235DOI Listing
December 2020

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

Rheumatology (Oxford) 2020 Dec 17. Epub 2020 Dec 17.

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

Objectives: X-Linked hypophosphataemic rickets (XLH) is a rare multisystemic disease of mineral homeostasis that has a prominent skeletal phenotype. The aim of this study was to describe additional comorbidities in XLH patients compared with general population controls.

Methods: The Clinical Practice Research Datalink (CPRD) GOLD was used to identify a cohort of XLH patients (1995-2016), along with a non-XLH cohort matched (1:4) on age, sex and GP practice. Using the CALIBER portal, phenotyping algorithms were used to identify the first diagnosis (and associated age) of 273 comorbid conditions during patient follow-up. Fifteen major disease categories were used and the proportion of patients having ≥1 diagnosis was compared between cohorts for each category and condition. Main analyses were repeated according to Index of Multiple Deprivation (IMD).

Results: There were 64 and 256 patients in the XLH and non-XLH cohorts, respectively. There was increased prevalence of endocrine (OR 3.46 [95% CI: 1.44-8.31]) and neurological (OR 3.01 [95% CI: 1.41-6.44] disorders among XLH patients. Across all specific comorbidities, four were at least twice as likely to be present in XLH cases, but only depression met the Bonferroni threshold: OR 2.95 [95%CI: 1.47-5.92]. Distribution of IMD among XLH cases indicated greater deprivation than the general population.

Conclusion: We describe a higher risk of mental illness in XLH patients compared with matched controls, and greater than expected deprivation. These findings may have implications for clinical practice guidelines and decisions around health and social care provision for these patients.
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http://dx.doi.org/10.1093/rheumatology/keaa859DOI Listing
December 2020

Costs of joint replacement in osteoarthritis: a study using the National Joint Registry and Clinical Practice Research Datalink datasets.

Arthritis Care Res (Hoboken) 2020 Oct 1. Epub 2020 Oct 1.

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom of Great Britain and Northern Ireland.

Objectives: The aim of this study was to estimate the costs of primary hip and knee replacement in individuals with osteoarthritis up to 2 years post-surgery, compare costs before and after the surgery, and identify predictors of hospital costs.

Methods: Patients aged 18 years or over with primary planned hip or knee replacements and osteoarthritis in England between 2008 and 2016 were identified from the National Joint Registry and linked with Hospital Episode Statistics data containing inpatient episodes. Primary care data linked with hospital outpatient records were also used to identify patients aged 18 years or over with primary hip or knee replacements between 2008 and 2016. All healthcare resource use was valued using 2016/17 costs and non-parametric censoring methods were used to estimate total 1-year and 2-year costs.

Results: We identified 854,866 individuals undergoing hip or knee replacement. The mean censor-adjusted 1-year hospitalisation costs for hip and knee replacement were £7,827 (95% CI £7,813 to £7,842) and £7,805 (95% CI £7,790 to £7,818), respectively. Complications and revisions were associated with up to a three-fold increase in 1-year hospitalisation costs. The censor-adjusted 2-year costs were £9,258 (95 % CI £9,233 to £9,280) and £9,452 (95%CI £9,430 to £9,475) for hip and knee replacement. Adding primary and outpatient care, the mean total hip and knee replacement 2-year costs were £11,987 and £12,578, respectively.

Conclusions: There are significant costs following joint replacement. Revisions and complications accounted for considerable costs and there is a significant incentive to identify best approaches to reduce these.
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http://dx.doi.org/10.1002/acr.24470DOI Listing
October 2020

CPRD GOLD and linked ONS mortality records: Reconciling guidelines.

Int J Med Inform 2020 04 30;136:104038. Epub 2019 Nov 30.

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

Background: The Clinical Practice Research Datalink (CPRD) GOLD is an extremely influential U.K. primary care dataset for epidemiological research having a number of published papers based on its data much bigger than any other U.K. primary care dataset. The Office for National Statistics (ONS) death data for England can be linked to GOLD at the patient level and are considered the gold standard on mortality. GOLD, which also holds death data, has been recently assessed against ONS linked dataset and the accuracy of its dates of death has been deemed sufficient for the majority of observational studies. However, there is a lack of guidance on how to manage the challenges existing when ONS mortality and GOLD datasets are linked, including linkage coverage period, linkage correctness likelihood, linkage regional limitations and data discrepancy.

Objectives: Provide reconciling guidelines on how to make maximum and at the same time trustworthy use of mortality information coming from both GOLD and ONS linked datasets with the aim of improving the quality, reproducibility, transparency and comparison of clinical research.

Method And Results: We have developed recommendations on how to manage mortality data coming from both GOLD and linked ONS, taking into account linkage coverage period, linkage correctness likelihood, linkage regional limitations and data discrepancies between these two datasets. We have also implemented these guidelines in an SQL algorithm for researchers to use.

Conclusion: We have provided detailed guidelines on the reconciliation of mortality data between GOLD and ONS linked death datasets, taking into account both their strengths and limitations. The consistent application of these guidelines made practical by an SQL algorithm, has the potential to improve clinical research quality, reproducibility, transparency and comparison.
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http://dx.doi.org/10.1016/j.ijmedinf.2019.104038DOI Listing
April 2020

Atopic eczema and fracture risk in adults: A population-based cohort study.

J Allergy Clin Immunol 2020 02 19;145(2):563-571.e8. Epub 2019 Nov 19.

Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom; Health Data Research UK, London, United Kingdom.

Background: Limited evidence suggests increased fracture risk in people with atopic eczema. Any link could have substantial effect; atopic eczema is common, and fractures have associated morbidity and mortality.

Objective: We sought to examine whether atopic eczema is associated with fracture and whether fracture risk varies with eczema severity.

Methods: We performed a matched cohort study set in primary care (Clinical Practice Research Datalink GOLD 1998-2016) and linked hospital admissions data (Hospital Episode Statistics), including adults (≥18 years old) with atopic eczema matched (by age, sex, general practice, and cohort entry date) with up to 5 individuals without eczema. We estimated hazard ratios (HRs) from stratified Cox regression comparing risk of major osteoporotic (hip, pelvis, spine, wrist, and proximal humerus) fractures individually and any fracture in those with and without atopic eczema.

Results: We identified 526,808 people with atopic eczema and 2,569,030 people without atopic eczema. Those with eczema had increased risk of hip (HR, 1.10; 99% CI, 1.06-1.14), pelvic (HR, 1.10; 99% CI, 1.02-1.19), spinal (HR, 1.18; 99% CI, 1.10-1.27), and wrist (HR, 1.07; 99% CI, 1.03,-1.11) fractures. We found no evidence of increased proximal humeral (HR, 1.06; 99% CI, 0.97-1.15) fracture risk. Fracture risk increased with increasing eczema severity, with the strongest associations in people with severe eczema (compared with those without) for spinal (HR, 2.09; 99% CI, 1.66-2.65), pelvic (HR, 1.66; 99% CI, 1.26-2.20), and hip (HR, 1.50; 99% CI, 1.30-1.74) fractures. Associations persisted after oral glucocorticoid adjustment.

Conclusions: People with atopic eczema have increased fracture risk, particularly major osteoporotic fractures.
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http://dx.doi.org/10.1016/j.jaci.2019.09.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014587PMC
February 2020

Prevalence and Mortality of Individuals With X-Linked Hypophosphatemia: A United Kingdom Real-World Data Analysis.

J Clin Endocrinol Metab 2020 03;105(3)

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

Background: X-linked hypophosphatemia (XLH) is a rare multisystemic disease with a prominent musculoskeletal phenotype. We aim here to improve understanding of the prevalence of XLH across the life course and of overall survival among people with XLH.

Methods: This was a population-based cohort study using a large primary care database in the United Kingdom (UK) from 1995 to 2016. XLH cases were matched by age, gender, and practice to up to 4 controls. Trends in prevalence over the study period were estimated (stratified by age) and survival among cases was compared with that of controls.

Findings: From 522 potential cases, 122 (23.4%) were scored as at least possible XLH, while 62 (11.9%) were classified as highly likely or likely (conservative definition). In main analyses, prevalence (95% CI) increased from 3.1 (1.5-6.7) per million in 1995-1999 to 14.0 (10.8-18.1) per million in 2012-2016. Corresponding estimates using the conservative definition were 3.0 (1.4-6.5) to 8.1 (5.8-11.4). Nine (7.4%) of the possible cases died during follow-up, at median age of 64 years. Fourteen (2.9%) of the controls died at median age of 72.5 years. Mortality was significantly increased in those with possible XLH compared with controls (hazard ratio [HR] 2.93; 95% CI, 1.24-6.91). Likewise, among those with likely or highly likely XLH (HR 6.65; 1.44-30.72).

Conclusions: We provide conservative estimates of the prevalence of XLH in children and adults within the UK. There was an unexpected increase in mortality in later life, which may have implications for other fibroblast growth factor 23-related disorders.
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http://dx.doi.org/10.1210/clinem/dgz203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7025948PMC
March 2020

Descriptive epidemiology of hip and knee replacement in rheumatoid arthritis: An analysis of UK electronic medical records.

Semin Arthritis Rheum 2020 04 26;50(2):237-244. Epub 2019 Aug 26.

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom; MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, United Kingdom; GREMPAL Research Group, Idiap Jordi Gol and CIBERFes, Unviersitat Autonoma de Barcelona and Insituto de Salud Carlos III, Barcelona, Spain.

Objective: To provide descriptive data on rates of total hip replacement (THR) and total knee replacement (TKR) within a large RA cohort and describe variation in risk.

Methods: Incident RA patients (1995 to 2014) were identified from the Clinical Practice Research Datalink (CPRD). First subsequent occurrence of THR and TKR were identified (analysed separately) and incidence rates calculated, stratified by sex, age, BMI, geographic region, and quintiles of the index of multiple deprivation (IMD) score.

Results: There were 27,607 RA patients included, with a total of 1,028 THRs (mean age at surgery: 68.4 years) and 1,366 TKRs (mean age at surgery: 67.6 years), at an overall incidence rate per 1,000 person-years (PYs) [95% CI] of 6.38 [6.00-6.78] and 8.57 [8.12-9.04], respectively. TKR incidence was similar by gender but THR rates were higher in females than males. Rates of TKR but not THR rose according to BMI. An increasing trend was observed in rates of both outcomes according to age (although not ≥75) but of decreasing rates according to socio-economic deprivation. There was some evidence for regional variation in TKR. The 10-year cumulative incidence was 5.2% [4.9, 5.6] and 7.0% [6.6, 7.4] for THR and TKR, respectively.

Conclusion: We provide generalizable estimates of THR and TKR incidence in the UK RA patient population and note variation across several key variables. Increased BMI was associated with a large increase in TKR but not THR incidence. Increased deprivation was associated with a downward trend in rates of THR and TKR.
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http://dx.doi.org/10.1016/j.semarthrit.2019.08.008DOI Listing
April 2020

Increased Risk of Musculoskeletal Disorders and Mental Health Problems in Retired Professional Jockeys: A Cross-Sectional Study.

Int J Sports Med 2019 Sep 3. Epub 2019 Sep 3.

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Arthritis Research UK Centre for Sport, Exercise and Osteoarthritis, Oxford, United Kingdom of Great Britain and Northern Ireland.

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http://dx.doi.org/10.1055/a-1004-5495DOI Listing
September 2019

Increased Risk of Musculoskeletal Disorders and Mental Health Problems in Retired Professional Jockeys: A Cross-Sectional Study.

Int J Sports Med 2019 Oct 7;40(11):732-738. Epub 2019 Aug 7.

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Arthritis Research UK Centre for Sport, Exercise and Osteoarthritis, Oxford, United Kingdom of Great Britain and Northern Ireland.

To examine the prevalence of chronic disease and mental health problems in retired professional, male jockeys compared to an age-matched reference population. A cross-sectional study comparing data from a cohort of retired professional jockeys with an age-matched general population sample. Male participants (age range: 50-89 years old) were used to compare health outcomes of self-reported physician-diagnosed conditions: heart disease, stroke, diabetes, hypertension, osteoporosis, osteoarthritis, depression and anxiety between study populations. Conditional logistic regression models were used to estimate associations between study groups and health outcome. In total, 810 participants (135 retired professional male jockeys and 675 participants from the reference population) were included, with an average age of 64.7±9.9 years old. Increased odds of having osteoporosis (OR=6.5, 95%CI 2.1-20.5), osteoarthritis (OR=7.5, 95%CI 4.6-12.2), anxiety (OR=2.8, 95%CI 1.3-5.9) and depression (OR=2.6, 95%CI 1.3-5.7) were seen in the retired professional jockeys. No differences were found for the remaining health outcomes. Retired professional jockeys had increased odds of musculoskeletal disease and mental health problems compared to the general population. Understanding the prevalence of chronic disease and mental health problems in retired professional jockeys will help inform screening and intervention strategies for jockeys.
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http://dx.doi.org/10.1055/a-0902-8601DOI Listing
October 2019

The effect of smoking on outcomes following primary total hip and knee arthroplasty: a population-based cohort study of 117,024 patients.

Acta Orthop 2019 12 2;90(6):559-567. Epub 2019 Aug 2.

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

Background and purpose - Smoking is a modifiable risk factor that may adversely affect postoperative outcomes. Healthcare providers are increasingly denying smokers access to total hip and knee arthroplasty (THA and TKA) until they stop smoking. Evidence supporting this is unclear. We assessed the effect of smoking on outcomes following arthroplasty.Patients and methods - We identified THAs and TKAs from the Clinical Practice Research Datalink, which were linked with datasets from Hospital Episode Statistics and the Office for National Statistics to identify outcomes. The effect of smoking on postoperative outcomes (complications, medications, revision, mortality, patient-reported outcome measures [PROMs]) was assessed using adjusted regression models.Results - We studied 60,812 THAs and 56,212 TKAs (11% smokers, 33% ex-smokers, 57% non-smokers). Following THA, smokers had an increased risk of lower respiratory tract infection (LRTI) and myocardial infarction compared with non-smokers and ex-smokers. Following TKA, smokers had an increased risk of LRTI compared with non-smokers. Compared with non-smokers (THA relative risk ratio [RRR] = 0.65; 95% CI = 0.61-0.69; TKA RRR = 0.82; CI = 0.78-0.86) and ex-smokers (THR RRR = 0.90; CI = 0.84-0.95), smokers had increased opioid usage 1-year postoperatively. Similar patterns were observed for weak opioids, paracetamol, and gabapentinoids. 1-year mortality rates were higher in smokers compared with non-smokers (THA hazard ratio [HR] = 0.37, CI = 0.29-0.49; TKA HR = 0.52, CI = 0.34-0.81) and ex-smokers (THA HR = 0.53, CI = 0.40-0.70). Long-term revision rates were not increased in smokers. Smokers had improvement in PROMs compared with preoperatively, with no clinically important difference in postoperative PROMs between smokers, non-smokers, and ex-smokers.Interpretation - Smoking is associated with more medical complications, higher analgesia usage, and increased mortality following arthroplasty. Most adverse outcomes were reduced in ex-smokers, therefore smoking cessation should be encouraged before arthroplasty.
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http://dx.doi.org/10.1080/17453674.2019.1649510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6844375PMC
December 2019

Natural History of Radiographic First Metatarsophalangeal Joint Osteoarthritis: A Nineteen-Year Population-Based Cohort Study.

Arthritis Care Res (Hoboken) 2020 09;72(9):1224-1230

University of Oxford, Oxford, UK, and University of Southampton, Southampton, UK.

Objective: To assess the long-term prevalence, natural history, progression, and incidence of radiographic first metatarsophalangeal (MTP) joint osteoarthritis (OA).

Methods: A longitudinal cohort design was used in which radiographic OA at the first MTP joint was investigated in participants from the Chingford 1,000 Women Study at year 6 (1995) and year 23 (2013-2015). Radiographic features of osteophytes (OPs) and/or joint space narrowing (JSN) at the first MTP joint were scored according to a validated foot atlas. Natural history was determined by the change in prevalence, incidence, progression, and worsening of OA in the first MTP joint.

Results: Complete case-matched foot radiographic data were available for 193 of the women currently enrolled in the study (mean ± SD age 75.7 ± 5.2 years [range 69-90 years]). At the level of the first MTP joint, prevalence of OA at year 6 was 21.76% in the left and 24.35% in the right; at year 23, it was 23.83% in the left and 32.64% in the right. Over the 19-year period, 13.5% of the women developed incident OA in the right first MTP joint and 8.3% in the left. Both progression and worsening of OA were more evident for OPs and in the right first MTP joints.

Conclusion: In this study of the natural history of radiographic first MTP joint OA, which to our knowledge is the longest study to date, the prevalence and incidence of first MTP joint OA increased over a 19-year period. Progression and/or worsening of OA at the first MTP joint over time appears to be driven by OP development rather than JSN, which suggests a biomechanical cause.
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http://dx.doi.org/10.1002/acr.24015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496760PMC
September 2020

Antibiotic treatment and flares of rheumatoid arthritis: a self-controlled case series study analysis using CPRD GOLD.

Sci Rep 2019 06 20;9(1):8941. Epub 2019 Jun 20.

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), University of Oxford, Botnar Research Centre, Old Road, Oxford, UK.

There is emerging evidence of the impact of infections on rheumatoid arthritis pathogenesis and flares. We aimed to study the association between antibiotic use (and timing of use), and the occurrence of flares in patients with RA. We nested a self-controlled case series (SCCS) of patients who have RA flares within a newly diagnosed RA cohort (n = 31,992) from the UK Clinical Practice Research Datalink (CPRD) GOLD dataset. We determined associations between exposure to antibiotics (beta-lactam, imidazole, macrolide, nitrofurantoin, quinolone, sulphonamide and trimethoprim, and tetracycline) and the occurrence of RA flares. Conditional fixed-effects Poisson regression models were used to determine incidence rate ratios (IRR), offset by the natural logarithm of risk periods. A total of 1,192 (3.7%) of RA subjects had one or more flare/s during the study period, and were therefore included. Use of sulphonamide and trimethoprim was associated with an increased risk of RA flare at 29-90 days (IRR 1.71, CI 1.12-2.59, p = 0.012); 91-183 days (IRR 1.57, CI 1.06-2.33, p = 0.025); and 184-365 days (IRR 1.44, CI 1.03-2.02, p = 0.033) after commencement of antibiotic treatment. No other antibiotic group/s appear associated with RA flare/s risk. Usage of sulphonamide and trimethoprim antibiotics, is associated with a 70% increased risk of RA flare at 1-3 months, which decreases but remains significant up to 12 months after treatment. We hypothesise that the delayed onset of RA flares after specific antibiotics is mediated through the gut or urinary microbiomes. Further epidemiological and mechanistic research is needed to determine the role of infections in RA.
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http://dx.doi.org/10.1038/s41598-019-45435-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586671PMC
June 2019

Coding algorithms for defining Charlson and Elixhauser co-morbidities in Read-coded databases.

BMC Med Res Methodol 2019 06 6;19(1):115. Epub 2019 Jun 6.

Oxford Trauma, Kadoorie Centre for Critical Care Research and Education, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), John Radcliffe Hospital, Headley Way, Oxford, OX3 9BU, UK.

Background: Comorbidity measures, such as the Charlson Comorbidity Index (CCI) and Elixhauser Method (EM), are frequently used for risk-adjustment by healthcare researchers. This study sought to create CCI and EM lists of Read codes, which are standard terminology used in some large primary care databases. It also aimed to describe and compare the predictive properties of the CCI and EM amongst patients with hip fracture (and matched controls) in a large primary care administrative dataset.

Methods: Two researchers independently screened 111,929 individual Read codes to populate the 17 CCI and 31 EM comorbidity categories. Patients with hip fractures were identified (together with age- and sex-matched controls) from UK primary care practices participating in the Clinical Practice Research Datalink (CPRD). The predictive properties of both comorbidity measures were explored in hip fracture and control populations using logistic regression models fitted with 30- and 365-day mortality as the dependent variables together with tests of equality for Receiver Operating Characteristic (ROC) curves.

Results: There were 5832 CCI and 7156 EM comorbidity codes. The EM improved the ability of a logistic regression model (using age and sex as covariables) to predict 30-day mortality (AUROC 0.744 versus 0.686). The EM alone also outperformed the CCI (0.696 versus 0.601). Capturing comorbidities over a prolonged period only modestly improved the predictive value of either index: EM 1-year look-back 0.645 versus 5-year 0.676 versus complete record 0.695 and CCI 0.574 versus 0.591 versus 0.605.

Conclusions: The comorbidity code lists may be used by future researchers to calculate CCI and EM using records from Read coded databases. The EM is preferable to the CCI but only marginal gains should be expected from incorporating comorbidities over a period longer than 1 year.
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http://dx.doi.org/10.1186/s12874-019-0753-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6554904PMC
June 2019

Encounters for foot and ankle pain in UK primary care: a population-based cohort study of CPRD data.

Br J Gen Pract 2019 Jun 20;69(683):e422-e429. Epub 2019 May 20.

Faculty of Health Sciences and Arthritis Research UK Sport, Exercise and Osteoarthritis Centre, University of Southampton, Southampton, UK.

Background: Older patients who have foot pain report variation in access to services to manage their foot health. To plan services it is essential to understand the scale and burden of foot pain that exists for GPs.

Aim: To provide UK-wide population-level data of the frequency of foot and/or ankle pain encounters recorded in general practice.

Design And Setting: Population-based cohort design study using data drawn from the UK Clinical Practice Research Datalink (CPRD) from January 2010 to December 2013.

Method: All CPRD data were collected prospectively by participating GPs. The primary outcome was prevalence of GP encounters for foot and/or ankle pain, stratified by age, sex, and different subgroups of causes.

Results: A foot and/or ankle pain encounter was recorded for 346 067 patients, and there was a total of 567 095 recorded encounters (mean per person 1.6, standard deviation [SD] 1.3). The prevalence of recorded encounters of foot and/or ankle pain was 2980 per 100 000 (3%). The number of patients with a recorded encounter of foot and/or ankle pain was 1820 per 100 000 (1.8%). Foot and/or ankle pain encounters were reported across all age groups (54.4% females), with those aged 71-80 years placing the greatest burden on GPs. The most common specified referrals were to orthopaedics ( = 36 881) and physiotherapy ( = 33 987), followed by podiatry ( = 25 980).

Conclusion: The burden of foot and/or ankle pain encounters recorded by GPs is not insubstantial, and spans all ages, with a high proportion of referrals to orthopaedics. The authors recommend further exploration of 'first-contact practitioners' for foot and/or ankle pain in general practice to alleviate the burden on GPs.
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http://dx.doi.org/10.3399/bjgp19X703817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6532799PMC
June 2019

Treatment of first-time traumatic anterior shoulder dislocation: the UK TASH-D cohort study.

Health Technol Assess 2019 04;23(18):1-104

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

Background: Shoulder dislocations are the most common joint dislocations seen in emergency departments. Most traumatic cases are anterior and cause recurrent dislocations. Management options include surgical and conservative treatments. There is a lack of evidence about which method is most effective after the first traumatic anterior shoulder dislocation (TASD).

Objectives: To produce UK age- and sex-specific incidence rates for TASD. To assess whether or not surgery within 6 months of a first-time TASD decreases re-dislocation rates compared with no surgery. To identify clinical predictors of recurrent dislocation.

Design: A population-based cohort study of first-time TASD patients in the UK. An initial validation study and subsequent propensity-score-matched analysis to compare re-dislocation rates between surgery and no surgery after a first-time TASD. Prediction modelling was used to identify potential predictors of recurrent dislocation.

Setting: UK primary and secondary care data.

Participants: Patients with a first-time TASD between 1997 and 2015.

Interventions: Stabilisation surgery within 6 months of a first-time TASD (compared with no surgery). Stabilisation surgery within 12 months of a first-time TASD was also carried out as a sensitivity analysis.

Main Outcome Measure: Re-dislocation rate up to 2 years after the first TASD.

Methods: Eligible patients were identified from the Clinical Practice Research Datalink (CPRD) (1997-2015). Accuracy of shoulder dislocation coding was internally validated using the CPRD General Practitioner questionnaire service. UK age- and sex-specific incidence rates for TASD were externally validated against rates from the USA and Canada. A propensity-score-matched analysis using linked CPRD and Hospital Episode Statistics (HES) data compared re-dislocation rates for patients aged 16-35 years, comparing surgery with no surgery. Multivariable Cox regression models for predicting re-dislocation were developed for the surgical and non-surgical cohorts.

Results: Shoulder dislocation was coded correctly for 89% of cases in the CPRD [95% confidence interval (CI) 83% to 95%], with a 'primary' dislocation confirmed for 76% of cases (95% CI 67% to 85%). Far fewer patients than expected received stabilisation surgery within 6 months of a first TASD, leading to an underpowered study. Around 20% of re-dislocation rates were observed for both surgical and non-surgical patients. The sensitivity analysis at 12 months also showed little difference in re-dislocation rates. Missing data on risk factors limited the value of the prediction modelling; however, younger age, epilepsy and sex (male) were identified as statistically significant predictors of re-dislocation.

Limitations: Far fewer than the expected number of patients had surgery after a first-time TASD, resulting in an underpowered study. This and residual confounding from missing risk factors mean that it is not possible to draw valid conclusions.

Conclusions: This study provides, for the first time, UK data on the age- and sex-specific incidence rates for TASD. Most TASD occurs in men, but an unexpected increased incidence was observed in women aged > 50 years. Surgery after a first-time TASD is uncommon in the NHS. Re-dislocation rates for patients receiving surgery after their first TASD are higher than previously expected; however, important residual confounding risk factors were not recorded in NHS primary and secondary care databases, thus preventing useful recommendations.

Future Work: The high incidence of TASD justifies investigation into preventative measures for young men participating in contact sports, as well as investigating the risk factors in women aged > 50 years. A randomised controlled trial would account for key confounders missing from CPRD and HES data. A national TASD registry would allow for a more relevant data capture for this patient group.

Study Registration: Independent Scientific Advisory Committee (ISAC) for the Medicines and Healthcare Products Regulatory Agency (ISAC protocol 15_0260).

Funding: The National Institute for Health Research Health Technology Assessment programme.
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http://dx.doi.org/10.3310/hta23180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511890PMC
April 2019

Evaluating Patients' Expectations From a Novel Patient-Centered Perspective Predicts Knee Arthroplasty Outcome.

J Arthroplasty 2018 07 15;33(7):2146-2152.e4. Epub 2018 Feb 15.

Arthritis Research UK Centre for Sport, Exercise and Osteoarthritis, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Botnar Research Centre, Oxford UK.

Background: One-in-five patients are dissatisfied following knee arthroplasty and <50% have fulfilled expectations. The relationship between knee-arthroplasty expectations and surgical outcome remains unclear.

Purpose: Are expectations regarding the impact of pain on postoperative life predictive of one-year outcome? Does the impact of pain on preoperative quality of life (QOL) influence this relationship?

Methods: Longitudinal cohort of 1044 uni-compartmental (43%) or total knee-arthroplasty (57%) (UKA or TKA) patients, aged mean 69 ± 9 years. Preoperatively, patients reported the impact of pain on QOL and expected impact of pain on life one-year post-arthroplasty. One-year postoperative outcomes: non-return to desired activity, surgical dissatisfaction, not achieving Oxford Knee Score minimal important change (OKS
Results: Expecting moderate-to-extreme pain (vs no pain) predicted non-return to activity (odds ratio [95% confidence interval], 2.3 [1.3, 4.1]), dissatisfaction (4.0 [1.7, 9.3]), OKS
Conclusions: Expecting a worse outcome predicted surgical dissatisfaction, less clinical improvement and non-return to desired activity. Patients expecting a more optimistic outcome relative to preoperative status achieved better surgical outcomes.
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http://dx.doi.org/10.1016/j.arth.2018.02.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005343PMC
July 2018

Oral bisphosphonate use and age-related macular degeneration: retrospective cohort and nested case-control study.

Ann N Y Acad Sci 2018 03 24;1415(1):34-46. Epub 2018 Jan 24.

Oxford NIHR Biomedical Research Centre, Musculoskeletal Theme, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Nuffield Orthopaedic Centre, University of Oxford, Oxford, UK.

Our objective here was to determine whether oral bisphosphonate (BP) use is associated with the incidence of age-related macular degeneration (AMD). We performed a population-based study using electronic health records from UK primary care (Clinical Practice Research Datalink). A cohort of 13,974 hip fracture patients (1999-2013) was used to conduct (1) a propensity score-matched cohort analysis and (2) a nested case-control analysis. Hip fracture patients were aged ≥50 years without AMD diagnosis before hip fracture date or in the first year of follow-up. Among 6208 matched patients and during 22,142 person-years of follow-up, 57 (1.8%) and 42 (1.4%) AMD cases occurred in BP users and non-BP users, respectively. The survival analysis model did not provide significant evidence of a higher risk of AMD in BP users (subhazard ratio: 1.60; 95% confidence interval (CI): 0.95-2.72; P = 0.08), although there was a significant increased risk among BP users with high medication possession ratio (MPR) (top quartile) relative to non-BP users (odds ratio: 5.08, 95% CI: 3.11-8.30; P < 0.001, respectively). Overall, oral BP use was not associated with an increased risk of AMD in this cohort of hip fracture patients, although the risk increased significantly with higher MPR. More data are needed to confirm these findings.
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http://dx.doi.org/10.1111/nyas.13589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886355PMC
March 2018

Incidence of shoulder dislocations in the UK, 1995-2015: a population-based cohort study.

BMJ Open 2017 Nov 14;7(11):e016112. Epub 2017 Nov 14.

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

Objective: This cohort study evaluates the unknown age-specific and gender-specific incidence of primary shoulder dislocations in the UK.

Setting: UK primary care data from the Clinical Practice Research Datalink (CPRD) were used to identify patients aged 16-70 years with a shoulder dislocation during 1995-2015. Coding of primary shoulder dislocations was validated using the CPRD general practitioner questionnaire service.

Participants: A cohort of 16 763 patients with shoulder dislocation aged 16-70 years during 1995-2015 were identified.

Primary Outcome Measure: Incidence rates per 100 000 person-years and 95% CIs were calculated.

Results: Correct coding of shoulder dislocation within CPRD was 89% (95% CI 83% to 95%), and confirmation that the dislocation was a 'primary' was 76% (95% CI 67% to 85%). Seventy-two percent of shoulder dislocations occurred in men. The overall incidence rate in men was 40.4 per 100 000 person-years (95% CI 40.4 to 40.4), and in women was 15.5 per 100 000 person-years (95% CI 15.5 to 15.5). The highest incidence was observed in men aged 16-20 years (80.5 per 100 000 person-years; 95% CI 80.5 to 80.6). Incidence in women increased with age to a peak of 28.6 per 100 000 person-years among those aged 61-70 years.

Conclusions: This is the first time the incidence of shoulder dislocations has been studied using primary care data from a national database, and the first time the results for the UK have been produced. While most primary dislocations occurred in young men, an unexpected finding was that the incidence increased in women aged over 50 years, but not in men. The reasons for this are unknown. Further work is commissioned by the National Institute for Health Research to examine treatments and predictors for recurrent shoulder dislocation.

Study Registration: The design of this study was approved by the Independent Scientific Advisory Committee (15_260) for the Medicines & Healthcare products Regulatory Agency.
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http://dx.doi.org/10.1136/bmjopen-2017-016112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5695490PMC
November 2017

Osteoarthritis and other long-term health conditions in former elite cricketers.

J Sci Med Sport 2018 Jun 18;21(6):558-563. Epub 2017 Oct 18.

University of Oxford, Botnar Research Centre, UK; Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, UK.

Objectives: This study aimed to describe the prevalence and risk of chronic conditions in former elite cricketers compared to a normal population, and describe wellbeing in former elite cricketers.

Design: Cross-sectional study.

Methods: Former elite cricketers, recruited from the Professional Cricketers' Association, completed a self-report cross-sectional questionnaire. The English Longitudinal Study of Ageing (ELSA) served as the normal population. The prevalence of self-reported, GP-diagnosed conditions (heart problems, hypertension, stroke, diabetes, asthma, dementia, osteoarthritis (OA), total hip replacement (THR), total knee replacement (TKR), anxiety, depression) were reported for both population samples. Standardised morbidity ratios (SMRs) compared chronic conditions in sex-, age- and BMI-matched former cricketers (n=113) and normal population (n=4496).

Results: Heart problems were reported by 13.3% of former cricketers, significantly lower than the normal population, SMR 0.55 (0.33-0.91). Former cricketers reported 31.9% hypertension, 1.8% stroke, 6.2% diabetes, 15.0% asthma, and no dementia, none significantly different to the normal population. OA, THR, and TKR were reported by 51.3%, 14.7% and 10.7% of former cricketers, respectively, significantly higher than the normal population, SMRs 3.64 (2.81-4.71), 3.99 (2.21-7.20) and 3.84 (1.92-7.68). Anxiety and depression were reported by 12.4% and 8.8% of former cricketers, respectively, SMRs 3.95 (2.34-6.67) and 2.22 (1.20-4.14). 97% of former cricketers reflected they would undertake their cricket career again, 98% agreed that cricket enriched their lives.

Conclusions: Heart problems were significantly lower, while OA, THR, TKR, anxiety, and depression were significantly higher in the former cricketers compared to the normal population (ELSA). Most former cricketers reflected positively on their career.
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http://dx.doi.org/10.1016/j.jsams.2017.10.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5964309PMC
June 2018

Association between NICE guidance on biologic therapies with rates of hip and knee replacement among rheumatoid arthritis patients in England and Wales: An interrupted time-series analysis.

Semin Arthritis Rheum 2018 04 23;47(5):605-610. Epub 2017 Sep 23.

Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Windmill Road, Oxford, OX3 7LD; GREMPAL Research Group, Idiap Jordi Gol Primary Care Research Institute and CIBERFes, Universitat Autònoma de Barcelona and Instituto de Salud Carlos III, Barcelona, Spain. Electronic address:

Objective: To estimate the impact of NICE approval of tumor necrosis factor inhibitor (TNFi) therapies on the incidence of total hip replacement (THR) and total knee replacement (TKR) among rheumatoid arthritis (RA) patients in England and Wales.

Methods: Primary care data [Clinical Practice Research Datalink (CPRD)] for the study period (1995-2014) were used to identify incident adult RA patients. The age and sex-standardised 5-year incidence of THR and TKR was calculated separately for RA patients diagnosed in each six-months between 1995-2009. We took a natural experimental approach, using segmented linear regression to estimate changes in level and trend following the publication of NICE TA 36 in March 2002, incorporating a 1-year lag. Regression coefficients were used to calculate average change in rates, adjusted for prior level and trend.

Results: We identified 17,505 incident RA patients of whom 465 and 650 underwent THR and TKR surgery, respectively. The modeled average incidence of THR and TKR over the biologic-era was 6.57/1000 person years (PYs) and 8.51/1000 PYs, respectively, with projected (had pre-NICE TA 36 level and trend continued uninterrupted) figures of 5.63/1000 PYs and 12.92 PYs, respectively. NICE guidance was associated with a significant average decrease in TKR incidence of -4.41/1000 PYs (95% C.I. -6.88 to -1.94), equating to a relative 34% reduction. Overall, no effect was seen on THR rates.

Conclusions: Among incident RA patients in England and Wales, NICE guidance on TNFi therapies for RA management was temporally associated with reduced rates of TKR but not THR.
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http://dx.doi.org/10.1016/j.semarthrit.2017.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866918PMC
April 2018

Health amongst former rugby union players: A cross-sectional study of morbidity and health-related quality of life.

Sci Rep 2017 09 28;7(1):11786. Epub 2017 Sep 28.

Arthritis Research UK Centre for Sport, Exercise and Osteoarthritis, University of Oxford, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, Oxford, UK.

In the general population, physical activity is associated with improved health outcomes. However, long-term sports participation may be associated with adverse outcomes, particularly at the elite level. The aims of this study were to assess morbidity and health-related quality of life (HrQoL) amongst former rugby players, compared to an age-standardised general population sample. A cross-sectional study of former elite, male, rugby players (n = 259) was undertaken, and standardised morbidity ratios (SMR) calculated, assessing morbidity prevalence relative to English Longitudinal Study of Aging participants (ELSA, n = 5186). HrQoL, measured using the EQ-5D, was compared to a Health Survey for England (HSE, n = 2981) sample. In SMR analyses of participants aged 50+, diabetes was significantly lower amongst former players, (0.28, 95% CI 0.11-0.66), whereas osteoarthritis (4.00, 95% CI 3.32-4.81), joint replacement (6.02, 95% CI 4.66-7.77), osteoporosis (2.69, 95% CI 1.35-5.38), and anxiety (2.00, 95% CI 1.11-3.61) were significantly higher. More problems in HrQoL were reported amongst former players within the domains of mobility (p < 0.001), self-care (p = 0.041), usual activities (p < 0.001) and pain/discomfort (p < 0.001). Morbidity and HrQoL differ between players and the general population, with higher musculoskeletal morbidity and lower diabetes amongst former players. The magnitude of musculoskeletal morbidity may warrant proactive osteoarthritis management within this population.
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http://dx.doi.org/10.1038/s41598-017-12130-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5620077PMC
September 2017

Cost-Effectiveness of Orthogeriatric and Fracture Liaison Service Models of Care for Hip Fracture Patients: A Population-Based Study.

J Bone Miner Res 2017 Feb 1;32(2):203-211. Epub 2016 Nov 1.

Oxford NIHR Musculoskeletal Biomedical Research Unit, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, UK.

Fracture liaison services are recommended as a model of best practice for organizing patient care and secondary fracture prevention for hip fracture patients, although variation exists in how such services are structured. There is considerable uncertainty as to which model is most cost-effective and should therefore be mandated. This study evaluated the cost- effectiveness of orthogeriatric (OG)- and nurse-led fracture liaison service (FLS) models of post-hip fracture care compared with usual care. Analyses were conducted from a health care and personal social services payer perspective, using a Markov model to estimate the lifetime impact of the models of care. The base-case population consisted of men and women aged 83 years with a hip fracture. The risk and costs of hip and non-hip fractures were derived from large primary and hospital care data sets in the UK. Utilities were informed by a meta-regression of 32 studies. In the base-case analysis, the orthogeriatric-led service was the most effective and cost-effective model of care at a threshold of £30,000 per quality-adjusted life years gained (QALY). For women aged 83 years, the OG-led service was the most cost-effective at £22,709/QALY. If only health care costs are considered, OG-led service was cost-effective at £12,860/QALY and £14,525/QALY for women and men aged 83 years, respectively. Irrespective of how patients were stratified in terms of their age, sex, and Charlson comorbidity score at index hip fracture, our results suggest that introducing an orthogeriatrician-led or a nurse-led FLS is cost-effective when compared with usual care. Although considerable uncertainty remains concerning which of the models of care should be preferred, introducing an orthogeriatrician-led service seems to be the most cost-effective service to pursue. © 2016 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.2995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5321497PMC
February 2017

Anti-Osteoporosis Medication Prescriptions and Incidence of Subsequent Fracture Among Primary Hip Fracture Patients in England and Wales: An Interrupted Time-Series Analysis.

J Bone Miner Res 2016 11 4;31(11):2008-2015. Epub 2016 Jul 4.

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

In January 2005, the National Institute for Health and Care Excellence (NICE) in England and Wales provided new guidance on the use of antiosteoporosis therapies for the secondary prevention of osteoporotic fractures. This was shortly followed in the same year by market authorization of a generic form of alendronic acid within the UK. We here set out to estimate the actual practice impact of these events among hip fracture patients in terms of antiosteoporosis medication prescribing and subsequent fracture incidence using primary care data (Clinical Practice Research Datalink) from 1999 to 2013. Changes in level and trend of prescribing and subsequent fracture following publication of NICE guidance and availability of generic alendronic acid were estimated using an interrupted time series analysis. Both events were considered in combination within a 1-year "intervention period." We identified 10,873 primary hip fracture patients between April 1999 and Sept 2012. Taking into account prior trend, the intervention period was associated with an immediate absolute increase of 14.9% (95% CI, 10.9 to 18.9) for incident antiosteoporosis prescriptions and a significant and clinically important reduction in subsequent major and subsequent hip fracture: -0.19% (95% CI, -0.28 to -0.09) and -0.17% (95% CI, -0.26 to -0.09) per 6 months, respectively. This equated to an approximate 14% (major) and 22% (hip) reduction at 3 years postintervention relative to expected values based solely on preintervention level and trend. We conclude that among hip fracture patients, publication of NICE guidance and availability of generic alendronic acid was temporally associated with increased prescribing and a significant decline in subsequent fractures. © 2016 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.2882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5122450PMC
November 2016

Status update and interim results from the asymptomatic carotid surgery trial-2 (ACST-2).

Eur J Vasc Endovasc Surg 2013 Nov 17;46(5):510-8. Epub 2013 Sep 17.

Objectives: ACST-2 is currently the largest trial ever conducted to compare carotid artery stenting (CAS) with carotid endarterectomy (CEA) in patients with severe asymptomatic carotid stenosis requiring revascularization.

Methods: Patients are entered into ACST-2 when revascularization is felt to be clearly indicated, when CEA and CAS are both possible, but where there is substantial uncertainty as to which is most appropriate. Trial surgeons and interventionalists are expected to use their usual techniques and CE-approved devices. We report baseline characteristics and blinded combined interim results for 30-day mortality and major morbidity for 986 patients in the ongoing trial up to September 2012.

Results: A total of 986 patients (687 men, 299 women), mean age 68.7 years (SD ± 8.1) were randomized equally to CEA or CAS. Most (96%) had ipsilateral stenosis of 70-99% (median 80%) with contralateral stenoses of 50-99% in 30% and contralateral occlusion in 8%. Patients were on appropriate medical treatment. For 691 patients undergoing intervention with at least 1-month follow-up and Rankin scoring at 6 months for any stroke, the overall serious cardiovascular event rate of periprocedural (within 30 days) disabling stroke, fatal myocardial infarction, and death at 30 days was 1.0%.

Conclusions: Early ACST-2 results suggest contemporary carotid intervention for asymptomatic stenosis has a low risk of serious morbidity and mortality, on par with other recent trials. The trial continues to recruit, to monitor periprocedural events and all types of stroke, aiming to randomize up to 5,000 patients to determine any differential outcomes between interventions.

Clinical Trial: ISRCTN21144362.
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http://dx.doi.org/10.1016/j.ejvs.2013.07.020DOI Listing
November 2013

Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial.

Lancet 2013 Mar;381(9869):805-16

Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, UK.

Background: For women with oestrogen receptor (ER)-positive early breast cancer, treatment with tamoxifen for 5 years substantially reduces the breast cancer mortality rate throughout the first 15 years after diagnosis. We aimed to assess the further effects of continuing tamoxifen to 10 years instead of stopping at 5 years.

Methods: In the worldwide Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial, 12,894 women with early breast cancer who had completed 5 years of treatment with tamoxifen were randomly allocated to continue tamoxifen to 10 years or stop at 5 years (open control). Allocation (1:1) was by central computer, using minimisation. After entry (between 1996 and 2005), yearly follow-up forms recorded any recurrence, second cancer, hospital admission, or death. We report effects on breast cancer outcomes among the 6846 women with ER-positive disease, and side-effects among all women (with positive, negative, or unknown ER status). Long-term follow-up still continues. This study is registered, number ISRCTN19652633.

Findings: Among women with ER-positive disease, allocation to continue tamoxifen reduced the risk of breast cancer recurrence (617 recurrences in 3428 women allocated to continue vs 711 in 3418 controls, p=0·002), reduced breast cancer mortality (331 deaths vs 397 deaths, p=0·01), and reduced overall mortality (639 deaths vs 722 deaths, p=0·01). The reductions in adverse breast cancer outcomes appeared to be less extreme before than after year 10 (recurrence rate ratio [RR] 0·90 [95% CI 0·79–1·02] during years 5–9 and 0·75 [0·62–0·90] in later years; breast cancer mortality RR 0·97 [0·79–1·18] during years 5–9 and 0·71 [0·58–0·88] in later years). The cumulative risk of recurrence during years 5–14 was 21·4% for women allocated to continue versus 25·1% for controls; breast cancer mortality during years 5–14 was 12·2% for women allocated to continue versus 15·0% for controls (absolute mortality reduction 2·8%). Treatment allocation seemed to have no effect on breast cancer outcome among 1248 women with ER-negative disease, and an intermediate effect among 4800 women with unknown ER status. Among all 12,894 women, mortality without recurrence from causes other than breast cancer was little affected (691 deaths without recurrence in 6454 women allocated to continue versus 679 deaths in 6440 controls; RR 0·99 [0·89–1·10]; p=0·84). For the incidence (hospitalisation or death) rates of specific diseases, RRs were as follows: pulmonary embolus 1·87 (95% CI 1·13–3·07, p=0·01 [including 0·2% mortality in both treatment groups]), stroke 1·06 (0·83–1·36), ischaemic heart disease 0·76 (0·60–0·95, p=0·02), and endometrial cancer 1·74 (1·30–2·34, p=0·0002). The cumulative risk of endometrial cancer during years 5–14 was 3·1% (mortality 0·4%) for women allocated to continue versus 1·6% (mortality 0·2%) for controls (absolute mortality increase 0·2%).

Interpretation: For women with ER-positive disease, continuing tamoxifen to 10 years rather than stopping at 5 years produces a further reduction in recurrence and mortality, particularly after year 10. These results, taken together with results from previous trials of 5 years of tamoxifen treatment versus none, suggest that 10 years of tamoxifen treatment can approximately halve breast cancer mortality during the second decade after diagnosis.

Funding: Cancer Research UK, UK Medical Research Council, AstraZeneca UK, US Army, EU-Biomed.
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http://dx.doi.org/10.1016/S0140-6736(12)61963-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3596060PMC
March 2013