Publications by authors named "Kevin Wing"

107 Publications

Trends and clinical characteristics of 57.9 million COVID-19 vaccine recipients: a federated analysis of patients' primary care records using OpenSAFELY.

Br J Gen Pract 2021 Sep 24. Epub 2021 Sep 24.

London School of Hygiene and Tropical Medicine, London.

Background: On 8 December 2020 NHS England administered the first COVID-19 vaccination.

Aim: To describe trends and variation in vaccine coverage in different clinical and demographic groups in the first 100 days of the vaccine rollout.

Design And Setting: With the approval of NHS England, a cohort study was conducted of 57.9 million patient records in general practice in England, and within the infrastructure of the electronic health record software vendors EMIS and TPP using OpenSAFELY.

Method: Vaccine coverage across various subgroups of Joint Committee on Vaccination and Immunisation (JCVI) priority cohorts is described.

Results: A total of 20 852 692 patients (36.0%) received a vaccine between 8 December 2020 and 17 March 2021. Of patients aged ≥80 years not in a care home (JCVI group 2) 94.7% received a vaccine, but with substantial variation by ethnicity (White 96.2%, Black 68.3%) and deprivation (least deprived 96.6%, most deprived 90.7%). Patients with pre-existing medical conditions were more likely to be vaccinated with two exceptions: severe mental illness (89.5%) and learning disability (91.4%). There were 275 205 vaccine recipients who were identified as care home residents (JCVI group 1; 91.2% coverage). By 17 March, 1 257 914 (6.0%) recipients had a second dose.

Conclusion: The NHS rapidly delivered mass vaccination. In this study a data-monitoring framework was deployed using publicly auditable methods and a secure processing model, using linked but pseudonymised patient-level NHS data for 57.9 million patients. Targeted activity may be needed to address lower vaccination coverage observed among certain key groups.
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http://dx.doi.org/10.3399/BJGP.2021.0376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8589463PMC
September 2021

OpenSAFELY NHS Service Restoration Observatory 1: primary care clinical activity in England during the first wave of COVID-19.

Br J Gen Pract 2021 Sep 24. Epub 2021 Sep 24.

London School of Hygiene and Tropical Medicine, London.

Background: The COVID-19 pandemic has disrupted healthcare activity. The NHS stopped non-urgent work in March 2020, later recommending services be restored to near-normal levels before winter where possible.

Aim: To describe the volume and variation of coded clinical activity in general practice, taking respiratory disease and laboratory procedures as examples.

Design And Setting: Working on behalf of NHS England, a cohort study was conducted of 23.8 million patient records in general practice, using OpenSAFELY.

Method: Activity using Clinical Terms Version 3 codes and keyword searches from January 2019 to September 2020 are described.

Results: Activity recorded in general practice declined during the pandemic, but largely recovered by September. There was a large drop in coded activity for laboratory tests, with broad recovery to pre-pandemic levels by September. One exception was the international normalised ratio test, with a smaller reduction (median tests per 1000 patients in 2020: February 8.0; April 6.2; September 6.9). The pattern of recording for respiratory symptoms was less affected, following an expected seasonal pattern and classified as 'no change'. Respiratory infections exhibited a sustained drop, not returning to pre-pandemic levels by September. Asthma reviews experienced a small drop but recovered, whereas chronic obstructive pulmonary disease reviews remained below baseline.

Conclusion: An open-source software framework was delivered to describe trends and variation in clinical activity across an unprecedented scale of primary care data. The COVD-19 pandemic led to a substantial change in healthcare activity. Most laboratory tests showed substantial reduction, largely recovering to near-normal levels by September, with some important tests less affected and recording of respiratory disease codes was mixed.
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http://dx.doi.org/10.3399/BJGP.2021.0380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8589464PMC
September 2021

Association between warfarin and COVID-19-related outcomes compared with direct oral anticoagulants: population-based cohort study.

J Hematol Oncol 2021 10 19;14(1):172. Epub 2021 Oct 19.

The DataLab, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.

Background: Thromboembolism has been reported as a consequence of severe COVID-19. Although warfarin is a commonly used anticoagulant, it acts by antagonising vitamin K, which is low in patients with severe COVID-19. To date, the clinical evidence on the impact of regular use of warfarin on COVID-19-related thromboembolism is lacking.

Methods: On behalf of NHS England, we conducted a population-based cohort study investigating the association between warfarin and COVID-19 outcomes compared with direct oral anticoagulants (DOACs). We used the OpenSAFELY platform to analyse primary care data and pseudonymously linked SARS-CoV-2 antigen testing data, hospital admissions and death records from England. We used Cox regression to estimate hazard ratios (HRs) for COVID-19-related outcomes comparing warfarin with DOACs in people with non-valvular atrial fibrillation. We also conducted negative control outcome analyses (being tested for SARS-CoV-2 and non-COVID-19 death) to assess the potential impact of confounding.

Results: A total of 92,339 warfarin users and 280,407 DOAC users were included. We observed a lower risk of all outcomes associated with warfarin versus DOACs [testing positive for SARS-CoV-2, HR 0.73 (95% CI 0.68-0.79); COVID-19-related hospital admission, HR 0.75 (95% CI 0.68-0.83); COVID-19-related deaths, HR 0.74 (95% CI 0.66-0.83)]. A lower risk of negative control outcomes associated with warfarin versus DOACs was also observed [being tested for SARS-CoV-2, HR 0.80 (95% CI 0.79-0.81); non-COVID-19 deaths, HR 0.79 (95% CI 0.76-0.83)].

Conclusions: Overall, this study shows no evidence of harmful effects of warfarin on severe COVID-19 disease.
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http://dx.doi.org/10.1186/s13045-021-01185-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8525065PMC
October 2021

Anticoagulant prescribing for atrial fibrillation and risk of incident dementia.

Heart 2021 12 13;107(23):1898-1904. Epub 2021 Oct 13.

Department of Non-communicable Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK

Objective: The aim of this study was to investigate the association between oral anticoagulant type (direct oral anticoagulants (DOACs) vs vitamin K antagonists (VKAs)) and incident dementia or mild cognitive impairment (MCI) among patients with newly diagnosed atrial fibrillation (AF).

Methods: Using linked electronic health record (EHR) data from the Clinical Practice Research Datalink in the UK, we conducted a historical cohort study among first-time oral anticoagulant users with incident non-valvular AF diagnosed from 2012 to 2018. We compared the incidence of (1) clinically coded dementia and (2) MCI between patients prescribed VKAs and DOACs using Cox proportional hazards regression models, with age as the underlying timescale, accounting for calendar time and time on treatment, sociodemographic and lifestyle factors, clinical comorbidities and medications.

Results: Of 39 200 first-time oral anticoagulant users (44.6% female, median age 76 years, IQR 68-83), 20 687 (53%) were prescribed a VKA and 18 513 (47%) a DOAC at baseline. Overall, 1258 patients (3.2%) had GP-recorded incident dementia, incidence rate 16.5 per 1000 person-years. DOAC treatment for AF was associated with a 16% reduction in dementia diagnosis compared with VKA treatment in the whole cohort (adjusted HR 0.84, 95% CI: 0.73 to 0.98) and with a 26% reduction in incident MCI (adjusted HR 0.74, 95% CI: 0.65 to 0.84). Findings were similar across various sensitivity analyses.

Conclusions: Incident EHR-recorded dementia and MCI were less common among patients prescribed DOACs for new AF compared with those prescribed VKAs.
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http://dx.doi.org/10.1136/heartjnl-2021-319672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8600601PMC
December 2021

Severity of SARS-CoV-2 alpha variant (B.1.1.7) in England.

Clin Infect Dis 2021 Sep 6. Epub 2021 Sep 6.

TPP, TPP House, 129 Low Lane, Horsforth, Leeds, UK.

Background: The SARS-CoV-2 alpha variant (B.1.1.7) is associated with higher transmissibility than wild type virus, becoming the dominant variant in England by January 2021. We aimed to describe the severity of the alpha variant in terms of the pathway of disease from testing positive to hospital admission and death.

Methods: With the approval of NHS England, we linked individual-level data from primary care with SARS-CoV-2 community testing, hospital admission, and ONS all-cause death data. We used testing data with S-gene target failure as a proxy for distinguishing alpha and wild-type cases, and stratified Cox proportional hazards regression to compare the relative severity of alpha cases compared to wild type diagnosed from 16th November 2020 to 11th January 2021.

Results: Using data from 185,234 people who tested positive for SARS-CoV-2 in the community (alpha=93,153; wild-type=92,081), in fully adjusted analysis accounting for individual-level demographics and comorbidities as well as regional variation in infection incidence, we found alpha associated with 73% higher hazards of all-cause death (aHR: 1.73 (95% CI 1.41 - 2.13; P<.0001)) and 62% higher hazards of hospital admission (aHR: 1.62 ((95% CI 1.48 - 1.78; P<.0001), compared to wild-type virus. Among patients already admitted to ICU, the association between alpha and increased all-cause mortality was smaller and the confidence interval included the null (aHR: 1.20 (95% CI 0.74 - 1.95; P=0.45)).

Conclusions: The SARS-CoV-2 alpha variant is associated with an increased risk of both hospitalisation and mortality than wild-type virus.
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http://dx.doi.org/10.1093/cid/ciab754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8522415PMC
September 2021

Identifying Care Home Residents in Electronic Health Records - An OpenSAFELY Short Data Report.

Wellcome Open Res 2021 27;6:90. Epub 2021 Apr 27.

1 Electronic Health Records Research Group, Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK.

Care home residents have been severely affected by the COVID-19 pandemic. Electronic Health Records (EHR) hold significant potential for studying the healthcare needs of this vulnerable population; however, identifying care home residents in EHR is not straightforward. We describe and compare three different methods for identifying care home residents in the newly created OpenSAFELY-TPP data analytics platform.  Working on behalf of NHS England, we identified individuals aged 65 years or older potentially living in a care home on the 1st of February 2020 using (1) a complex address linkage, in which cleaned GP registered addresses were matched to old age care home addresses using data from the Care and Quality Commission (CQC); (2) coded events in the EHR; (3) household identifiers, age and household size to identify households with more than 3 individuals aged 65 years or older as potential care home residents. Raw addresses were not available to the investigators. Of 4,437,286 individuals aged 65 years or older, 2.27% were identified as potential care home residents using the complex address linkage, 1.96% using coded events, 3.13% using household size and age and 3.74% using either of these methods. 53,210 individuals (32.0% of all potential care home residents) were classified as care home residents using all three methods. Address linkage had the largest overlap with the other methods; 93.3% of individuals identified as care home residents using the address linkage were also identified as such using either coded events or household age and size.  We have described the partial overlap between three methods for identifying care home residents in EHR, and provide detailed instructions for how to implement these in OpenSAFELY-TPP to support research into the impact of the COVID-19 pandemic on care home residents.
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http://dx.doi.org/10.12688/wellcomeopenres.16737.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8374378PMC
April 2021

Medications for chronic obstructive pulmonary disease: a historical non-interventional cohort study with validation against RCT results.

Health Technol Assess 2021 08;25(51):1-70

Department of Non-communicable Disease Epidemiology, Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, UK.

Background: Chronic obstructive pulmonary disease treatment is informed by randomised controlled trial results, but it is unclear if these findings apply to people excluded from these trials. We used data from the TORCH (TOwards a Revolution in COPD Health) randomised controlled trial to validate non-interventional methods for assessing the clinical effectiveness of chronic obstructive pulmonary disease treatment in the UK Clinical Practice Research Datalink, before applying these methods to the analysis of people who would have been excluded from TORCH.

Objectives: To validate the use of non-interventional Clinical Practice Research Datalink data and methods for estimating chronic obstructive pulmonary disease treatment effects against trial results, and, using validated methods, to determine treatment effects in people who would have been excluded from the TORCH trial.

Design: A historical non-interventional cohort design, including validation against randomised controlled trial results.

Setting: The UK Clinical Practice Research Datalink.

Participants: People aged ≥ 18 years with chronic obstructive pulmonary disease registered in Clinical Practice Research Datalink GOLD between January 2000 and January 2017. For objective 1, we prepared a cohort that was analogous to the TORCH trial cohort by applying TORCH trial inclusion/exclusion criteria followed by individual matching to TORCH trial participants. For objectives 2 and 3, we prepared cohorts that were analogous to the TORCH trial that, nevertheless, would not have been eligible for the TORCH trial because of age, asthma, comorbidity or mild disease.

Interventions: The long-acting beta-2 agonist and inhaled corticosteroid combination product Seretide (GlaxoSmithKline plc) [i.e. fluticasone propionate plus salmeterol (FP-SAL)] compared with (1) no FP-SAL exposure or (2) exposure to salmeterol (i.e. the long-acting beta-2 agonist) only.

Main Outcome Measures: Exacerbations, mortality, pneumonia and time to treatment change.

Results: For objective 1, the exacerbation rate ratio was comparable to that in the TORCH trial for FP-SAL compared with salmeterol (0.85, 95% confidence interval 0.74 to 0.97, vs. TORCH trial 0.88, 95% confidence interval 0.81 to 0.95), but not for FP-SAL compared with no FP-SAL (1.30, 95% confidence interval 1.19 to 1.42, vs. TORCH trial 0.75, 95% confidence interval 0.69 to 0.81). Active comparator results were also consistent with the TORCH trial for mortality (hazard ratio 0.93, 95% confidence interval 0.65 to 1.32, vs. TORCH trial hazard ratio 0.93, 95% confidence interval 0.77 to 1.13) and pneumonia (risk ratio 1.39, 95% confidence interval 1.04 to 1.87, vs. TORCH trial risk ratio 1.47, 95% confidence interval 1.25 to 1.73). For objectives 2 and 3, active comparator results were consistent with the TORCH trial for exacerbations, with the exception of people with milder chronic obstructive pulmonary disease, in whom we observed a stronger protective association (risk ratio 0.56, 95% confidence interval 0.46 to 0.70, vs. TORCH trial risk ratio 0.85, 95% confidence interval 0.74 to 0.97). For the analysis of mortality, we saw a lack of association with being prescribed FP-SAL (vs. being prescribed salmeterol), with the exception of those with prior asthma, for whom we observed an increase in mortality (hazard ratio 1.49, 95% confidence interval 1.21 to 1.85, vs. TORCH trial-analogous HR 0.93, 95% confidence interval 0.64 to 1.32).

Conclusions: Routinely collected electronic health record data can be used to successfully measure chronic obstructive pulmonary disease treatment effects when comparing two treatments, but not for comparisons between active treatment and no treatment. Analyses involving patients who would have been excluded from trials mostly suggests that treatment effects for FP-SAL are similar to trial effects, although further work is needed to characterise a small increased risk of death in those with concomitant asthma.

Limitations: Some of our analyses had small numbers.

Future Work: The differences in treatment effects that we found should be investigated further in other data sets. Currently recommended chronic obstructive pulmonary disease inhaled combination therapy (other than FP-SAL) should also be investigated using these methods.

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. 51. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta25510DOI Listing
August 2021

Clinical coding of long COVID in English primary care: a federated analysis of 58 million patient records using OpenSAFELY.

Br J Gen Pract 2021 11 28;71(712):e806-e814. Epub 2021 Oct 28.

TPP, Leeds.

Background: Long COVID describes new or persistent symptoms at least 4 weeks after onset of acute COVID-19. Clinical codes to describe this phenomenon were recently created.

Aim: To describe the use of long-COVID codes, and variation of use by general practice, demographic variables, and over time.

Design And Setting: Population-based cohort study in English primary care.

Method: Working on behalf of NHS England, OpenSAFELY data were used encompassing 96% of the English population between 1 February 2020 and 25 May 2021. The proportion of people with a recorded code for long COVID was measured overall and by demographic factors, electronic health record software system (EMIS or TPP), and week.

Results: Long COVID was recorded for 23 273 people. Coding was unevenly distributed among practices, with 26.7% of practices having never used the codes. Regional variation ranged between 20.3 per 100 000 people for East of England (95% confidence interval [CI] = 19.3 to 21.4) and 55.6 per 100 000 people in London (95% CI = 54.1 to 57.1). Coding was higher among females (52.1, 95% CI = 51.3 to 52.9) than males (28.1, 95% CI = 27.5 to 28.7), and higher among practices using EMIS (53.7, 95% CI = 52.9 to 54.4) than those using TPP (20.9, 95% CI = 20.3 to 21.4).

Conclusion: Current recording of long COVID in primary care is very low, and variable between practices. This may reflect patients not presenting; clinicians and patients holding different diagnostic thresholds; or challenges with the design and communication of diagnostic codes. Increased awareness of diagnostic codes is recommended to facilitate research and planning of services, and also surveys with qualitative work to better evaluate clinicians' understanding of the diagnosis.
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http://dx.doi.org/10.3399/BJGP.2021.0301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8340730PMC
November 2021

Risks of covid-19 hospital admission and death for people with learning disability: population based cohort study using the OpenSAFELY platform.

BMJ 2021 07 14;374:n1592. Epub 2021 Jul 14.

TPP, TPP House, Horsforth, Leeds, UK.

Objective: To assess the association between learning disability and risk of hospital admission and death from covid-19 in England among adults and children.

Design: Population based cohort study on behalf of NHS England using the OpenSAFELY platform.

Setting: Patient level data were obtained for more than 17 million people registered with a general practice in England that uses TPP software. Electronic health records were linked with death data from the Office for National Statistics and hospital admission data from NHS Secondary Uses Service.

Participants: Adults (aged 16-105 years) and children (<16 years) from two cohorts: wave 1 (registered with a TPP practice as of 1 March 2020 and followed until 31 August 2020); and wave 2 (registered 1 September 2020 and followed until 8 February 2021). The main exposure group consisted of people on a general practice learning disability register; a subgroup was defined as those having profound or severe learning disability. People with Down's syndrome and cerebral palsy were identified (whether or not they were on the learning disability register).

Main Outcome Measure: Covid-19 related hospital admission and covid-19 related death. Non-covid-19 deaths were also explored.

Results: For wave 1, 14 312 023 adults aged ≥16 years were included, and 90 307 (0.63%) were on the learning disability register. Among adults on the register, 538 (0.6%) had a covid-19 related hospital admission; there were 222 (0.25%) covid-19 related deaths and 602 (0.7%) non-covid deaths. Among adults not on the register, 29 781 (0.2%) had a covid-19 related hospital admission; there were 13 737 (0.1%) covid-19 related deaths and 69 837 (0.5%) non-covid deaths. Wave 1 hazard ratios for adults on the learning disability register (adjusted for age, sex, ethnicity, and geographical location) were 5.3 (95% confidence interval 4.9 to 5.8) for covid-19 related hospital admission and 8.2 (7.2 to 9.4) for covid-19 related death. Wave 2 produced similar estimates. Associations were stronger among those classified as having severe to profound learning disability, and among those in residential care. For both waves, Down's syndrome and cerebral palsy were associated with increased hazards for both events; Down's syndrome to a greater extent. Hazard ratios for non-covid deaths followed similar patterns with weaker associations. Similar patterns of increased relative risk were seen for children, but covid-19 related deaths and hospital admissions were rare, reflecting low event rates among children.

Conclusions: People with learning disability have markedly increased risks of hospital admission and death from covid-19, over and above the risks observed for non-covid causes of death. Prompt access to covid-19 testing and healthcare is warranted for this vulnerable group, and prioritisation for covid-19 vaccination and other targeted preventive measures should be considered.
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http://dx.doi.org/10.1136/bmj.n1592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278652PMC
July 2021

Ethnic differences in SARS-CoV-2 infection and COVID-19-related hospitalisation, intensive care unit admission, and death in 17 million adults in England: an observational cohort study using the OpenSAFELY platform.

Lancet 2021 05 30;397(10286):1711-1724. Epub 2021 Apr 30.

Department of Medical Statistics, London School of Hygiene & Tropical Medicine, London, UK.

Background: COVID-19 has disproportionately affected minority ethnic populations in the UK. Our aim was to quantify ethnic differences in SARS-CoV-2 infection and COVID-19 outcomes during the first and second waves of the COVID-19 pandemic in England.

Methods: We conducted an observational cohort study of adults (aged ≥18 years) registered with primary care practices in England for whom electronic health records were available through the OpenSAFELY platform, and who had at least 1 year of continuous registration at the start of each study period (Feb 1 to Aug 3, 2020 [wave 1], and Sept 1 to Dec 31, 2020 [wave 2]). Individual-level primary care data were linked to data from other sources on the outcomes of interest: SARS-CoV-2 testing and positive test results and COVID-19-related hospital admissions, intensive care unit (ICU) admissions, and death. The exposure was self-reported ethnicity as captured on the primary care record, grouped into five high-level census categories (White, South Asian, Black, other, and mixed) and 16 subcategories across these five categories, as well as an unknown ethnicity category. We used multivariable Cox regression to examine ethnic differences in the outcomes of interest. Models were adjusted for age, sex, deprivation, clinical factors and comorbidities, and household size, with stratification by geographical region.

Findings: Of 17 288 532 adults included in the study (excluding care home residents), 10 877 978 (62·9%) were White, 1 025 319 (5·9%) were South Asian, 340 912 (2·0%) were Black, 170 484 (1·0%) were of mixed ethnicity, 320 788 (1·9%) were of other ethnicity, and 4 553 051 (26·3%) were of unknown ethnicity. In wave 1, the likelihood of being tested for SARS-CoV-2 infection was slightly higher in the South Asian group (adjusted hazard ratio 1·08 [95% CI 1·07-1·09]), Black group (1·08 [1·06-1·09]), and mixed ethnicity group (1·04 [1·02-1·05]) and was decreased in the other ethnicity group (0·77 [0·76-0·78]) relative to the White group. The risk of testing positive for SARS-CoV-2 infection was higher in the South Asian group (1·99 [1·94-2·04]), Black group (1·69 [1·62-1·77]), mixed ethnicity group (1·49 [1·39-1·59]), and other ethnicity group (1·20 [1·14-1·28]). Compared with the White group, the four remaining high-level ethnic groups had an increased risk of COVID-19-related hospitalisation (South Asian group 1·48 [1·41-1·55], Black group 1·78 [1·67-1·90], mixed ethnicity group 1·63 [1·45-1·83], other ethnicity group 1·54 [1·41-1·69]), COVID-19-related ICU admission (2·18 [1·92-2·48], 3·12 [2·65-3·67], 2·96 [2·26-3·87], 3·18 [2·58-3·93]), and death (1·26 [1·15-1·37], 1·51 [1·31-1·71], 1·41 [1·11-1·81], 1·22 [1·00-1·48]). In wave 2, the risks of hospitalisation, ICU admission, and death relative to the White group were increased in the South Asian group but attenuated for the Black group compared with these risks in wave 1. Disaggregation into 16 ethnicity groups showed important heterogeneity within the five broader categories.

Interpretation: Some minority ethnic populations in England have excess risks of testing positive for SARS-CoV-2 and of adverse COVID-19 outcomes compared with the White population, even after accounting for differences in sociodemographic, clinical, and household characteristics. Causes are likely to be multifactorial, and delineating the exact mechanisms is crucial. Tackling ethnic inequalities will require action across many fronts, including reducing structural inequalities, addressing barriers to equitable care, and improving uptake of testing and vaccination.

Funding: Medical Research Council.
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http://dx.doi.org/10.1016/S0140-6736(21)00634-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087292PMC
May 2021

Real-world effects of medications for stroke prevention in atrial fibrillation: protocol for a UK population-based non-interventional cohort study with validation against randomised trial results.

BMJ Open 2021 04 15;11(4):e042947. Epub 2021 Apr 15.

Department of Non-communicable Disease Epidemiology, Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK.

Introduction: Patients with atrial fibrillation experience an irregular heart rate and have an increased risk of stroke; prophylactic treatment with anticoagulation medication reduces this risk. Direct-acting oral anticoagulants (DOACs) have been approved providing an alternative to vitamin K antagonists such as warfarin. There is interest from regulatory bodies on the effectiveness of medications in routine clinical practice; however, uncertainty remains regarding the suitability of non-interventional data for answering questions on drug effectiveness and on the most suitable methods to be used. In this study, we will use data from Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE)-the pivotal trial for the DOAC apixaban-to validate non-interventional methods for assessing treatment effectiveness of anticoagulants. These methods could then be applied to analyse treatment effectiveness in people excluded from or under-represented in ARISTOTLE.

Methods And Analysis: Patient characteristics from ARISTOTLE will be used to select a cohort of patients with similar baseline characteristics from two UK electronic health record (EHR) databases, Clinical Practice Research Datalink Gold and Aurum (between 1 January 2013 and 31 July 2019). Methods such as propensity score matching and coarsened exact matching will be explored in matching between EHR treatment groups to determine the optimal method of obtaining a balanced cohort.Absolute and relative risk of outcomes in the EHR trial-analogous cohort will be calculated and compared with the ARISTOTLE results; if results are deemed compatible the methods used for matching EHR treatment groups can then be used to examine drug effectiveness over a longer duration of exposure and in special patient groups of interest not studied in the trial.

Ethics And Dissemination: The study has been approved by the Independent Scientific Advisory Committee of the UK Medicines and Healthcare Products Regulatory Agency. Results will be disseminated in scientific publications and at relevant conferences.
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http://dx.doi.org/10.1136/bmjopen-2020-042947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055153PMC
April 2021

Level of Evidence for the Treatment of Chronic Noninsertional Achilles Tendinopathy.

Foot Ankle Spec 2021 Mar 22:19386400211001261. Epub 2021 Mar 22.

University of British Columbia, Vancouver, BC, Canada.

Background: Noninsertional Achilles tendinopathy affects both athletes and sedentary individuals, and its incidence is rising. Conservative management is the mainstay of treatment, but a variety of operative techniques have been described to treat recalcitrant cases. We seek to outline the current available evidence for surgical management of noninsertional Achilles tendinopathy.

Study Design And Methods: A systematic review was performed using the MEDLINE and EMBASE databases, and all articles were reviewed by at least 2 authors. Each article was assigned a level of evidence in accordance with the standards of . The available data were reviewed and a level of evidence was assigned to each intervention of interest, based on the revised classifications of Wright.

Results And Conclusion: A total of 46 articles met inclusion and exclusion criteria. There is fair evidence (grade B) in support of open debridement with 1 level II study, 1 level III study, and 8 level IV studies. There is fair evidence (grade B) in support of arthroscopic or minimally invasive surgical techniques. There is poor evidence (grade C) in support of flexor hallucis longus transfer, longitudinal tenotomy, peritenolysis, gastrocnemius recession, and plantaris excision. There is insufficient evidence (grade I) to provide a recommendation about other surgical treatment methods for noninsertional Achilles tendinopathy. .
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http://dx.doi.org/10.1177/19386400211001261DOI Listing
March 2021

Total Ankle Arthroplasty Radiographic Alignment Comparison Between Patient-Specific Instrumentation and Standard Instrumentation.

Foot Ankle Int 2021 Jul 22;42(7):851-858. Epub 2021 Mar 22.

Department of Orthopaedics, University of British Columbia, Vancouver, British Columbia, Canada.

Background: Several benefits are published supporting patient-specific instrumentation (PSI) in total ankle arthroplasty (TAA). This study seeks to determine if TAA with PSI yields different radiographic outcomes vs standard instrumentation (SI).

Methods: Sixty-seven primary TAA patients having surgery using PSI or SI between 2013 and 2015 were retrospectively reviewed using weightbearing radiographs at 6-12 weeks postsurgery. Radiographic parameters analyzed were the medial distal tibia angle (MDTA), talar-tilt angle (TTA), anatomic sagittal distal tibia angle (aSDTA), lateral talar station (LTS), and talar component inclination angle (TCI). A comparison of the 2 groups for each radiologic parameter's distribution was performed using a nonparametric median test and Fisher exact test. Furthermore, TAAs with all radiographic measurements within acceptable limits were classified as "perfectly aligned." The rate of "perfectly aligned" TAAs between groups was compared using a Fisher exact test with a significance of .05.

Results: Of the 67 TAAs, 51 were done with PSI and 16 with SI. There were no differences between groups in MDTA ( = .174), TTA ( = .145), aSDTA ( = .98), LTS ( = .922), or TCI angle ( = .98). When the rate of "perfectly aligned TAA" between the 2 groups were compared, there was no significant difference ( = .35).

Conclusion: No significant radiographic alignment differences were found between PSI and SI implants. This study showed that both techniques achieve reproducible TAA radiographic coronal and sagittal alignment for the tibial component when performed by experienced surgeons. The talar component's sagittal alignment is similar whether or not PSI was used but is noticeably different from normal anatomic alignment by design.

Level Of Evidence: Level III, retrospective cohort study using prospectively collected data.
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http://dx.doi.org/10.1177/1071100721996379DOI Listing
July 2021

Case fatality risk of the SARS-CoV-2 variant of concern B.1.1.7 in England, 16 November to 5 February.

Euro Surveill 2021 03;26(11)

The Phoenix Partnership (TPP), TPP House, Leeds, United Kingdom.

The SARS-CoV-2 B.1.1.7 variant of concern (VOC) is increasing in prevalence across Europe. Accurate estimation of disease severity associated with this VOC is critical for pandemic planning. We found increased risk of death for VOC compared with non-VOC cases in England (hazard ratio: 1.67; 95% confidence interval: 1.34-2.09; p < 0.0001). Absolute risk of death by 28 days increased with age and comorbidities. This VOC has potential to spread faster with higher mortality than the pandemic to date.
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http://dx.doi.org/10.2807/1560-7917.ES.2021.26.11.2100256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7976383PMC
March 2021

Association between living with children and outcomes from covid-19: OpenSAFELY cohort study of 12 million adults in England.

BMJ 2021 03 18;372:n628. Epub 2021 Mar 18.

Electronic Health Records Research Group, Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK.

Objective: To investigate whether risk of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and outcomes of coronavirus disease 2019 (covid-19) differed between adults living with and without children during the first two waves of the UK pandemic.

Design: Population based cohort study, on behalf of NHS England.

Setting: Primary care data and pseudonymously linked hospital and intensive care admissions and death records from England, during wave 1 (1 February to 31 August 2020) and wave 2 (1 September to 18 December 2020).

Participants: Two cohorts of adults (18 years and over) registered at a general practice on 1 February 2020 and 1 September 2020.

Main Outcome Measures: Adjusted hazard ratios for SARS-CoV-2 infection, covid-19 related admission to hospital or intensive care, or death from covid-19, by presence of children in the household.

Results: Among 9 334 392adults aged 65 years and under, during wave 1, living with children was not associated with materially increased risks of recorded SARS-CoV-2 infection, covid-19 related hospital or intensive care admission, or death from covid-19. In wave 2, among adults aged 65 years and under, living with children of any age was associated with an increased risk of recorded SARS-CoV-2 infection (hazard ratio 1.06 (95% confidence interval 1.05 to 1.08) for living with children aged 0-11 years; 1.22 (1.20 to 1.24) for living with children aged 12-18 years) and covid-19 related hospital admission (1.18 (1.06 to 1.31) for living with children aged 0-11; 1.26 (1.12 to 1.40) for living with children aged 12-18). Living with children aged 0-11 was associated with reduced risk of death from both covid-19 and non-covid-19 causes in both waves; living with children of any age was also associated with lower risk of dying from non-covid-19 causes. For adults 65 years and under during wave 2, living with children aged 0-11 years was associated with an increased absolute risk of having SARS-CoV-2 infection recorded of 40-60 per 10 000 people, from 810 to between 850 and 870, and an increase in the number of hospital admissions of 1-5 per 10 000 people, from 160 to between 161 and 165. Living with children aged 12-18 years was associated with an increase of 160-190 per 10 000 in the number of SARS-CoV-2 infections and an increase of 2-6 per 10 000 in the number of hospital admissions.

Conclusions: In contrast to wave 1, evidence existed of increased risk of reported SARS-CoV-2 infection and covid-19 outcomes among adults living with children during wave 2. However, this did not translate into a materially increased risk of covid-19 mortality, and absolute increases in risk were small.
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http://dx.doi.org/10.1136/bmj.n628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970340PMC
March 2021

Indirect acute effects of the COVID-19 pandemic on physical and mental health in the UK: a population-based study.

Lancet Digit Health 2021 04 18;3(4):e217-e230. Epub 2021 Feb 18.

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

Background: There are concerns that the response to the COVID-19 pandemic in the UK might have worsened physical and mental health, and reduced use of health services. However, the scale of the problem is unquantified, impeding development of effective mitigations. We aimed to ascertain what has happened to general practice contacts for acute physical and mental health outcomes during the pandemic.

Methods: Using de-identified electronic health records from the Clinical Research Practice Datalink (CPRD) Aurum (covering 13% of the UK population), between 2017 and 2020, we calculated weekly primary care contacts for selected acute physical and mental health conditions: anxiety, depression, self-harm (fatal and non-fatal), severe mental illness, eating disorder, obsessive-compulsive disorder, acute alcohol-related events, asthma exacerbation, chronic obstructive pulmonary disease exacerbation, acute cardiovascular events (cerebrovascular accident, heart failure, myocardial infarction, transient ischaemic attacks, unstable angina, and venous thromboembolism), and diabetic emergency. Primary care contacts included remote and face-to-face consultations, diagnoses from hospital discharge letters, and secondary care referrals, and conditions were identified through primary care records for diagnoses, symptoms, and prescribing. Our overall study population included individuals aged 11 years or older who had at least 1 year of registration with practices contributing to CPRD Aurum in the specified period, but denominator populations varied depending on the condition being analysed. We used an interrupted time-series analysis to formally quantify changes in conditions after the introduction of population-wide restrictions (defined as March 29, 2020) compared with the period before their introduction (defined as Jan 1, 2017 to March 7, 2020), with data excluded for an adjustment-to-restrictions period (March 8-28).

Findings: The overall population included 9 863 903 individuals on Jan 1, 2017, and increased to 10 226 939 by Jan 1, 2020. Primary care contacts for almost all conditions dropped considerably after the introduction of population-wide restrictions. The largest reductions were observed for contacts for diabetic emergencies (odds ratio 0·35 [95% CI 0·25-0·50]), depression (0·53 [0·52-0·53]), and self-harm (0·56 [0·54-0·58]). In the interrupted time-series analysis, with the exception of acute alcohol-related events (0·98 [0·89-1·10]), there was evidence of a reduction in contacts for all conditions (anxiety 0·67 [0·66-0·67], eating disorders 0·62 [0·59-0·66], obsessive-compulsive disorder [0·69 [0·64-0·74]], self-harm 0·56 [0·54-0·58], severe mental illness 0·80 [0·78-0·83], stroke 0·59 [0·56-0·62], transient ischaemic attack 0·63 [0·58-0·67], heart failure 0·62 [0·60-0·64], myocardial infarction 0·72 [0·68-0·77], unstable angina 0·72 [0·60-0·87], venous thromboembolism 0·94 [0·90-0·99], and asthma exacerbation 0·88 [0·86-0·90]). By July, 2020, except for unstable angina and acute alcohol-related events, contacts for all conditions had not recovered to pre-lockdown levels.

Interpretation: There were substantial reductions in primary care contacts for acute physical and mental conditions following the introduction of restrictions, with limited recovery by July, 2020. Further research is needed to ascertain whether these reductions reflect changes in disease frequency or missed opportunities for care. Maintaining health-care access should be a key priority in future public health planning, including further restrictions. The conditions we studied are sufficiently severe that any unmet need will have substantial ramifications for the people with the conditions as well as health-care provision.

Funding: Wellcome Trust Senior Fellowship, Health Data Research UK.
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http://dx.doi.org/10.1016/S2589-7500(21)00017-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985613PMC
April 2021

Effect of Patient Demographics on Minimally Important Difference of Ankle Osteoarthritis Scale Among End-Stage Ankle Arthritis Patients.

Foot Ankle Int 2021 May 27;42(5):624-632. Epub 2021 Jan 27.

Department of Orthopaedics, University of British Columbia, Vancouver, British Columbia, Canada.

Background: Ankle replacement and ankle arthrodesis are standard treatments for treating end-stage ankle arthritis when conservative treatment fails. Comparing patient-reported outcome scores to the instrument's minimal important difference (MID) helps physicians and researchers infer whether a meaningful change in health from the patient's perspective has occurred following treatment. The objective of this study was to estimate the MID of the Ankle Osteoarthritis Scale among a cohort of operatively treated end-stage ankle arthritis patients undergoing ankle replacement or arthrodesis.

Methods: A survey package including the Ankle Osteoarthritis Scale was completed by participants preoperatively and 2 years postoperatively. Distribution and anchor-based approaches to calculating the MID were used to estimate the MID of the Ankle Osteoarthritis Scale and its 2 domains. The distribution-based approaches used were the small and medium effect size methods, while the mean absolute change method and linear regression method were the anchor-based approaches. Bootstrap sampling was used to obtain the variance of MID estimates. The MID was estimated for sex, age, operative, and baseline health subgroups. The cohort comprised 283 participants, totaling 298 ankles.

Results: The MID did not vary with sex or operative procedure. Age-based differences in MID values may exist for the Ankle Osteoarthritis Scale total score, and MID values were generally smallest among the oldest patients. Patients with the best and worst ankle-related health preoperatively had higher MID values than patients reporting mid-range Ankle Osteoarthritis Scale values preoperatively.

Conclusion: The best estimate of the MID of the Ankle Osteoarthritis Scale total score is 5.81. Our findings indicate that the MID of the Ankle Osteoarthritis Scale may not vary by sex or operative subgroups but likely varies by age and preoperative Ankle Osteoarthritis Scale score.

Level Of Evidence: Level II, prospective comparative study.
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http://dx.doi.org/10.1177/1071100720977842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127667PMC
May 2021

Use of non-steroidal anti-inflammatory drugs and risk of death from COVID-19: an OpenSAFELY cohort analysis based on two cohorts.

Ann Rheum Dis 2021 07 21;80(7):943-951. Epub 2021 Jan 21.

Department of Non-Communicable Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK.

Objectives: To assess the association between routinely prescribed non-steroidal anti-inflammatory drugs (NSAIDs) and deaths from COVID-19 using OpenSAFELY, a secure analytical platform.

Methods: We conducted two cohort studies from 1 March to 14 June 2020. Working on behalf of National Health Service England, we used routine clinical data in England linked to death data. In study 1, we identified people with an NSAID prescription in the last 3 years from the general population. In study 2, we identified people with rheumatoid arthritis/osteoarthritis. We defined exposure as current NSAID prescription within the 4 months before 1 March 2020. We used Cox regression to estimate HRs for COVID-19 related death in people currently prescribed NSAIDs, compared with those not currently prescribed NSAIDs, accounting for age, sex, comorbidities, other medications and geographical region.

Results: In study 1, we included 536 423 current NSAID users and 1 927 284 non-users in the general population. We observed no evidence of difference in risk of COVID-19 related death associated with current use (HR 0.96, 95% CI 0.80 to 1.14) in the multivariable-adjusted model. In study 2, we included 1 708 781 people with rheumatoid arthritis/osteoarthritis, of whom 175 495 (10%) were current NSAID users. In the multivariable-adjusted model, we observed a lower risk of COVID-19 related death (HR 0.78, 95% CI 0.64 to 0.94) associated with current use of NSAID versus non-use.

Conclusions: We found no evidence of a harmful effect of routinely prescribed NSAIDs on COVID-19 related deaths. Risks of COVID-19 do not need to influence decisions about the routine therapeutic use of NSAIDs.
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http://dx.doi.org/10.1136/annrheumdis-2020-219517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823433PMC
July 2021

Proton pump inhibitors and risk of all-cause and cause-specific mortality: A cohort study.

Br J Clin Pharmacol 2021 08 4;87(8):3150-3161. Epub 2021 Feb 4.

Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.

Aim: To investigate the association between proton pump inhibitors (PPIs) and both all-cause and cause-specific mortality.

Methods: We conducted a cohort study using the UK Clinical Practice Research Datalink GOLD database. We compared 733 885 new users of PPIs to 124 410 new users of H2 receptor antagonists (H2Ras). In a secondary analysis we compared 689 602 PPI new users to 1 361 245 nonusers of acid suppression therapy matched on age, sex and calendar year. Hazard ratios for all-cause and cause-specific mortality were estimated using propensity score (PS) weighted Cox models.

Results: PPI prescription was associated with increased risk of all-cause mortality, with hazard ratios decreasing considerably by increasing adjustment (unadjusted hazard ratio [HR] 1.65, 95% confidence interval [CI] 1.62-1.69; PS-weighted HR 1.38, 95% CI 1.33-1.44; high-dimensional PS-weighted HR 1.31, 95% CI 1.26-1.37). Short-term associations were observed with mortality from causes where a causal short-term association is unexpected (eg, lung cancer mortality: PS-weighted HR at 6 months 1.77, 95% CI 1.39-2.25). Adjusted hazard ratios were substantially higher when compared to nonusers (PS-weighted HR all-cause mortality 1.96, 95% CI 1.94-1.99) rather than H2RA users.

Conclusions: PPI prescription was strongly associated with all-cause and cause-specific mortality. However, the change in hazard ratios (a) by increasing adjustment and (b) between comparator groups indicates that residual confounding is likely to explain the association between poor health outcomes and PPI use, and fully accounting for this using observational data may not be possible.
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http://dx.doi.org/10.1111/bcp.14728DOI Listing
August 2021

Effect of pre-exposure use of hydroxychloroquine on COVID-19 mortality: a population-based cohort study in patients with rheumatoid arthritis or systemic lupus erythematosus using the OpenSAFELY platform.

Lancet Rheumatol 2021 Jan 5;3(1):e19-e27. Epub 2020 Nov 5.

Centre for Epidemiology Versus Arthritis, The University of Manchester, Manchester, UK.

Background: Hydroxychloroquine has been shown to inhibit entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into epithelial cells in vitro, but clinical studies found no evidence of reduced mortality when treating patients with COVID-19. We aimed to evaluate the effectiveness of hydroxychloroquine for prevention of COVID-19 mortality, as opposed to treatment for the disease.

Methods: We did a prespecified observational, population-based cohort study using national primary care data and linked death registrations in the OpenSAFELY platform, which covers approximately 40% of the general population in England, UK. We included all adults aged 18 years and older registered with a general practice for 1 year or more on March 1, 2020. We used Cox regression to estimate the association between ongoing routine hydroxychloroquine use before the COVID-19 outbreak in England (considered as March 1, 2020) compared with non-users of hydroxychloroquine and risk of COVID-19 mortality among people with rheumatoid arthritis or systemic lupus erythematosus. Model adjustment was informed by a directed acyclic graph.

Findings: Between Sept 1, 2019, and March 1, 2020, of 194 637 people with rheumatoid arthritis or systemic lupus erythematosus, 30 569 (15·7%) received two or more prescriptions of hydroxychloroquine. Between March 1 and July 13, 2020, there were 547 COVID-19 deaths, 70 among hydroxychloroquine users. Estimated standardised cumulative COVID-19 mortality was 0·23% (95% CI 0·18 to 0·29) among users and 0·22% (0·20 to 0·25) among non-users; an absolute difference of 0·008% (-0·051 to 0·066). After accounting for age, sex, ethnicity, use of other immunosuppressive drugs, and geographical region, no association with COVID-19 mortality was observed (HR 1·03, 95% CI 0·80 to 1·33). We found no evidence of interactions with age or other immunosuppressive drugs. Quantitative bias analyses indicated that our observed associations were robust to missing information for additional biologic treatments for rheumatological disease. We observed similar associations with the negative control outcome of non-COVID-19 mortality.

Interpretation: We found no evidence of a difference in COVID-19 mortality among people who received hydroxychloroquine for treatment of rheumatological disease before the COVID-19 outbreak in England. Therefore, completion of randomised trials investigating pre-exposure prophylactic use of hydroxychloroquine for prevention of severe outcomes from COVID-19 are warranted.

Funding: Medical Research Council.
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http://dx.doi.org/10.1016/S2665-9913(20)30378-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745258PMC
January 2021

The Impact of Concomitant LOW Back Pain (LBP) on Functional Outcomes in Total Ankle Arthroplasty (TAA).

J Foot Ankle Surg 2021 Jan-Feb;60(1):80-84. Epub 2020 Sep 18.

Associate Clinical Professor, Department of Orthopaedics, University of British Columbia, Footbridge Centre for Integrated Orthopaedic Care, Vancouver, British Columbia, Canada.

Although numerous studies have demonstrated that concomitant low back pain (LBP) is associated with worse functional outcomes in patients undergoing total hip and knee arthroplasty, no study has analyzed its impact on patients undergoing total ankle arthroplasty (TAA). The aim of this study was to determine the prevalence of LBP in people undergoing TAA and analyze its impact on patient reported functional outcome measures (PROMs). A retrospective review was performed on data from the Vancouver End Stage Ankle Arthritis Database. In total, 87 patients undergoing TAA were studied, with patient demographics collected preoperatively, including the absence or presence of LBP. Postoperative follow-up was performed at 5 years, primarily analyzing disease-specific PROMs including the Ankle Osteoarthritis Score and Ankle Arthritis Score. The Short Form-36 was used as a secondary outcome measure to assess global function. Multivariable linear mixed-effects regression models were conducted to compare the PROM between patients with LBP with those without LBP. In total, 30 patients (35%) presented with concomitant LBP. There were no significant differences at baseline between the LBP group and no LBP group in terms of demographics or baseline primary disease-specific PROMs. At 5 years, the patients with LBP had significantly worse Ankle Arthritis Score (32 ± 23 vs 22 ± 17, p = .03), Ankle Osteoarthritis Score Total (34 ± 23 vs 22 ± 16, p = .01), and Short Form-36 physical (PCS) components summaries (33 ± 12 vs 44 ± 9, p = .001) compared to the no-LBP group. Both groups improved significantly from baseline across all outcome measures. Our study demonstrated that the prevalence of concomitant LBP in end stage ankle arthritis undergoing TAA is similar to that described in arthritic knees and hips. If present, it can be associated with worse functional outcomes in the intermediate term. However it is not a contraindication to surgery, with patients still experiencing significant improvements from baseline. Further studies are needed to evaluate if LBP influences complications, implant failure rates and survival.
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http://dx.doi.org/10.1053/j.jfas.2020.08.031DOI Listing
June 2021

Real world effects of COPD medications: a cohort study with validation against results from randomised controlled trials.

Eur Respir J 2021 03 25;57(3). Epub 2021 Mar 25.

Dept of Non-communicable Disease Epidemiology, Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK.

Real-world data provide the potential for generating evidence on drug treatment effects in groups excluded from trials, but rigorous, validated methodology for doing so is lacking. We investigated whether non-interventional methods applied to real-world data could reproduce results from the landmark TORCH COPD trial.We performed a historical cohort study (2000-2017) of COPD drug treatment effects in the UK Clinical Practice Research Datalink (CPRD). Two control groups were selected from CPRD by applying TORCH inclusion/exclusion criteria and 1:1 matching to TORCH participants, as follows. Control group 1: people with COPD not prescribed fluticasone propionate (FP)-salmeterol (SAL); control group 2: people with COPD prescribed SAL only. FP-SAL exposed groups were then selected from CPRD by propensity score matching to each control group. Outcomes studied were COPD exacerbations, death from any cause and pneumonia.2652 FP-SAL exposed people were propensity score matched to 2652 FP-SAL unexposed people while 991 FP-SAL exposed people were propensity score matched to 991 SAL exposed people. Exacerbation rate ratio was comparable to TORCH for FP-SAL SAL (0.85, 95% CI 0.74-0.97 0.88, 0.81-0.95) but not for FP-SAL no FP-SAL (1.30, 1.19-1.42 0.75, 0.69-0.81). In addition, active comparator results were consistent with TORCH for mortality (hazard ratio 0.93, 0.65-1.32 0.93, 0.77-1.13) and pneumonia (risk ratio 1.39, 1.04-1.87 1.47, 1.25-1.73).We obtained very similar results to the TORCH trial for active comparator analyses, but were unable to reproduce placebo-controlled results. Application of these validated methods for active comparator analyses to groups excluded from randomised controlled trials provides a practical way for contributing to the evidence base and supporting COPD treatment decisions.
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http://dx.doi.org/10.1183/13993003.01586-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176192PMC
March 2021

Risk of COVID-19-related death among patients with chronic obstructive pulmonary disease or asthma prescribed inhaled corticosteroids: an observational cohort study using the OpenSAFELY platform.

Lancet Respir Med 2020 11 24;8(11):1106-1120. Epub 2020 Sep 24.

London School of Hygiene & Tropical Medicine, London, UK; NIHR Health Protection Research Unit in Immunisation, London, UK.

Background: Early descriptions of patients admitted to hospital during the COVID-19 pandemic showed a lower prevalence of asthma and chronic obstructive pulmonary disease (COPD) than would be expected for an acute respiratory disease like COVID-19, leading to speculation that inhaled corticosteroids (ICSs) might protect against infection with severe acute respiratory syndrome coronavirus 2 or the development of serious sequelae. We assessed the association between ICS and COVID-19-related death among people with COPD or asthma using linked electronic health records (EHRs) in England, UK.

Methods: In this observational study, we analysed patient-level data for people with COPD or asthma from primary care EHRs linked with death data from the Office of National Statistics using the OpenSAFELY platform. The index date (start of follow-up) for both cohorts was March 1, 2020; follow-up lasted until May 6, 2020. For the COPD cohort, individuals were eligible if they were aged 35 years or older, had COPD, were a current or former smoker, and were prescribed an ICS or long-acting β agonist plus long-acting muscarinic antagonist (LABA-LAMA) as combination therapy within the 4 months before the index date. For the asthma cohort, individuals were eligible if they were aged 18 years or older, had been diagnosed with asthma within 3 years of the index date, and were prescribed an ICS or short-acting β agonist (SABA) only within the 4 months before the index date. We compared the outcome of COVID-19-related death between people prescribed an ICS and those prescribed alternative respiratory medications: ICSs versus LABA-LAMA for the COPD cohort, and low-dose or medium-dose and high-dose ICSs versus SABAs only in the asthma cohort. We used Cox regression models to estimate hazard ratios (HRs) and 95% CIs for the association between exposure categories and the outcome in each population, adjusted for age, sex, and all other prespecified covariates. We calculated e-values to quantify the effect of unmeasured confounding on our results.

Findings: We identified 148 557 people with COPD and 818 490 people with asthma who were given relevant respiratory medications in the 4 months before the index date. People with COPD who were prescribed ICSs were at increased risk of COVID-19-related death compared with those prescribed LABA-LAMA combinations (adjusted HR 1·39 [95% CI 1·10-1·76]). Compared with those prescribed SABAs only, people with asthma who were prescribed high-dose ICS were at an increased risk of death (1·55 [1·10-2·18]), whereas those given a low or medium dose were not (1·14 [0·85-1·54]). Sensitivity analyses showed that the apparent harmful association we observed could be explained by relatively small health differences between people prescribed ICS and those not prescribed ICS that were not recorded in the database (e value lower 95% CI 1·43).

Interpretation: Our results do not support a major role for regular ICS use in protecting against COVID-19-related death among people with asthma or COPD. Observed increased risks of COVID-19-related death can be plausibly explained by unmeasured confounding due to disease severity.

Funding: UK Medical Research Council.
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http://dx.doi.org/10.1016/S2213-2600(20)30415-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515601PMC
November 2020

Effect of Dexamethasone in Peripheral Nerve Blocks on Recovery of Nerve Function.

Foot Ankle Int 2021 Jan 23;42(1):23-30. Epub 2020 Sep 23.

Department of Orthopedics, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.

Background: Peripheral nerve blocks (PNBs) have revolutionized distal extremity surgery reducing pain and improving hospital efficiency. Perineural dexamethasone has been administered with PNBs to prolong their effects, although the safety of dexamethasone has not been established in the literature. This study aimed to determine if the addition of dexamethasone affected the postoperative neurological sensory status for foot and ankle surgeries and the recovery of nerve injuries. We hypothesized that the rate of persistent nerve injury would be higher in the dexamethasone group.

Methods: This is a retrospective observational cohort study of prospectively collected data of all patients from a single foot and ankle surgeon's practice. Perineural dexamethasone was routinely used as an adjunct by the regional anesthesia group until a clinical trend of increased paresthesia was found on short-term follow-up, which led to the discontinuation of its use. In this study, the cohort that received dexamethasone with ropivacaine was compared with the cohort that received ropivacaine alone. The primary outcome was a separate sensory nerve status sheet that was completed for every distal nerve territory for every patient at their follow-up visits at 2 weeks, 6 weeks, 3 months, and 6 months. Univariate analysis and a logistic regression model were used to determine the association between dexamethasone and delayed nerve recovery. A total of 250 patients were included in the study, with 117 patients in the dexamethasone group and 133 in the ropivacaine-only group.

Results: The rates of nerve injuries were not different between the groups (72 [62%] in the dexamethasone group vs 79 [59%] in the ropivacaine-only group). However, nerve injury symptoms were more likely to persist and not fully recover in the dexamethasone group ( = 47, 65%) compared with the ropivacaine-only group ( = 32, 41%) (OR, 2.12; = .006).

Conclusion: Perineural dexamethasone added to PNBs may be associated with delayed nerve recovery after foot and ankle surgery. It may be prudent to avoid its use until its full safety profile is established in larger prospective trials.

Level Of Evidence: Level III, retrospective comparative study.
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http://dx.doi.org/10.1177/1071100720952075DOI Listing
January 2021

The Impact of Concomitant Ipsilateral Knee Pain on Functional Outcomes in Total Ankle Arthroplasty.

Foot Ankle Spec 2020 Aug 25:1938640020950893. Epub 2020 Aug 25.

Department of Orthopaedics, University of British Columbia Faculty of Medicine, Vancouver, British Columbia, Canada (MJS, AY, MJP, KW, AV).

In end-stage ankle arthritis, little is known about the impact of concomitant knee pathology, including the impact of ipsilateral knee pain on total ankle arthroplasty (TAA) outcomes. The aim of this study was to determine the prevalence of ipsilateral preoperative knee pain in patients undergoing TAA and analyze its impact on patient-reported functional outcome measures (PROMs). A retrospective review was performed on the Vancouver End Stage Ankle Arthritis Database at a single institution. In total, 114 patients were studied, with patient demographics collected preoperatively, including the presence or absence of knee pain. Postoperative follow-up was performed at 5 years, primarily analyzing disease-specific PROMs, including the Ankle Osteoarthritis Score (AOS) and Ankle Arthritis Score (AAS). Multivariate mixed-effects linear regression models compared the scores between the groups. In total, 31 patients (27.2%) presented with concomitant ipsilateral knee pain. Despite more females in the knee pain group (64.5% vs 36.1%) there were no other significant differences at baseline between the knee pain and no knee pain groups in terms of demographics or baseline primary disease specific PROMs. At 5 years, the patients with knee pain had significantly worse AAS (37.9 ± 23.8 vs 21.2 ± 16.3, = .004) and AOS total scores (38.1 ± 24.1 vs 21.9 ± 15.5, = .005) compared with the no-knee pain group. Both groups improved significantly from baseline across all outcome measures; however, the magnitude of improvement was less in the knee pain group. Our study demonstrated that over one-quarter of patients with end-stage ankle arthritis undergoing TAA present with ipsilateral concomitant knee pain. If present, it is associated with worse functional outcomes at the 5-year mark. Further studies are needed to evaluate if knee pain influences complications, implant failure rates, and survival. Level III.
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http://dx.doi.org/10.1177/1938640020950893DOI Listing
August 2020

Reoperation Profile of Lateral vs Anterior Approach Ankle Arthroplasty.

Foot Ankle Int 2020 07 22;41(7):834-838. Epub 2020 May 22.

Department of Orthopaedics, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.

Background: The operative procedure for a total ankle replacement (TAR) is intimately associated with the prosthetic design. The anterior and lateral approaches both have pros and cons regarding their respective soft tissue complications, osteotomy requirements, orientation of the bone cut, and gutter visualization. Although both have been studied independently, few reports have compared both in the same setting. The purpose of this retrospective study was to investigate the difference in reoperation rate after lateral or anterior approach ankle arthroplasty. We hypothesized that the anterior approach had a higher rate of wound complications.

Methods: We evaluated data from a single center collected between 2014 and 2017, comprising a total of 115 total ankle replacements performed by 1 of 4 fellowship-trained foot and ankle surgeons. Reoperations were recorded as an operative report with classification by Canadian Orthopaedic Foot and Ankle Society (COFAS) Reoperations Coding System (CROCS). The index approach used was determined by the surgeon's practice preference. Patients were included when they had a primary TAR in the time frame noted and had a complete data set up to at least 2 years after surgery. The cohort comprised 67 anterior and 48 lateral operations with balanced demographics for age (95% CI: 63-67 years) and gender (47% F). The lateral group had more complex cases with higher COFAS type arthritis (more periarticular arthritis and surrounding deformity).

Results: Comparing the 2 groups, a total of 40 reoperations (7 anterior [A], 33 lateral [L]) occurred in 27 patients (5 A, 22 L). One patient had 4 related reoperations. The only revision was in the anterior group. The only soft tissue reconstruction was a split-thickness skin graft in the lateral group. Nine reoperations were irrigation debridement related to an infection or wound complication (3 A, 6 L). The majority (19/33) of reoperations in the lateral group were gutter debridement (8) or lateral hardware removal (11). Operative time was statistically different at 145 minutes (95% CI: 127-164 minutes) in anterior TAR and 178 minutes (95% CI: 154-202 minutes) for lateral TAR ( = .0058). The odds ratio of having any reoperation with a lateral approach TAR was 6.19 compared to the anterior group.

Conclusion: The results at the 2-year time point demonstrated that there were more reoperations after a lateral approach TAR than an anterior TAR, recognizing the significant case complexity imbalance between the groups and a corresponding relative increase in resource utilization of lateral TAR patients. The 2 implant designs were associated with different reoperation rates, favoring the anterior group. Change in the lateral fixation may have reduced the risk of repeat surgery.

Level Of Evidence: Level III, retrospective comparative series.
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http://dx.doi.org/10.1177/1071100720920276DOI Listing
July 2020

Agonizing and Expensive: A Review of Institutional Costs of Ankle Fusion Nonunions.

Orthopedics 2020 Jul 12;43(4):e219-e224. Epub 2020 Apr 12.

Nonunion after ankle arthrodesis requiring revision is a challenging operative complication, and bone graft substitutes are costly. This study sought to summarize all institutional expenditures related to the revision of an ankle fusion nonunion, presuming that cost and skin-to-skin time would exceed those of the index surgery. The electronic records from 2 foot and ankle centers were reviewed, leading to a list of patients with 2 or more entries for tibiotalar fusions being generated. A total of 24 cases were found to match the criteria. Demographic factors and skin-to-skin time of the remaining patients were compiled. This cohort included 24 patients (6 female and 18 male) with a mean age of 64 years and body mass index of 30.4 kg/m. Supplemental clinic visits and investigations were included either after computed tomography to assess union or 365 days after index surgery. Total cost of the revision was calculated from billing codes, length of operation, and period of hospitalization. Postrevision outpatient fees were included as well. The revisions were performed open in all cases, and 21 patients received autograft and/or bone substitute. Mean postoperative hospitalization was 3 days. The additional costs (in US dollars) associated with nonunion were $1061 for imaging, $627 for prerevision visits, $3026 for the revision, $3432 for the hospital stay, and $1754 for postrevision follow-up. The total mean amount was $9683, equivalent to 9 nights of acute inpatient stay. Mean index skin-to-skin time was 114 minutes, being 126 minutes for revisions (P=.26). Additional care related to ankle fusion nonunion represents a financial burden equivalent to 9 nights of acute inpatient stay. The use of an orthobiologic would need to be less than $436 to be cost saving. Revision surgery is not significantly longer intraoperatively than index surgery. [Orthopedics. 2020;43(4):e219-e224.].
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http://dx.doi.org/10.3928/01477447-20200404-01DOI Listing
July 2020

Arthroscopic Repair of Talar Osteochondral Defects With Umbilical Cord Allograft: A Prospective, Single-Center, Pilot Study.

Foot Ankle Spec 2021 Jun 14;14(3):193-200. Epub 2020 Mar 14.

Department of Orthopaedics (MP, AY, KW, AV).

Cryopreserved umbilical cord (UC) allografts have been shown to promote postoperative wound healing by suppressing inflammation and reducing scar formation. The purpose of this study was to determine whether adjunctive use of UC may improve clinical and functional outcomes following arthroscopic repair of talar osteochondral defects (OCDs). A total of 10 patients with talar OCDs that failed nonoperative treatment were enrolled in this single-center, prospective, pilot study. Clinical and functional outcomes were assessed using the Ankle Osteoarthritis Scale (AOS), Foot and Ankle Ability Measure, and Visual Analog Scale (VAS) pain scale at 6, 12, 24, and 52 weeks postoperatively. Results showed a consistent improvement in all outcome measures. VAS pain scores significantly improved from 4.2 ± 2.9 to 1.3 ± 2.2 at 52 weeks (P = .015). AOS difficulty and pain scores nonsignificantly improved from 27.0 ± 24.6 and 33.1 ± 28.3 at baseline to 15.3 ± 20.5 and 14.8 ± 18.7 at 52 weeks, respectively. The clinical outcome improvement was accompanied by significant reduction in OCD defect size and associated bone marrow lesion. This pilot study suggests that adjunctive use of UC during arthroscopic repair of talar OCD may lead to clinical and functional improvement. Level II: Prospective Cohort Study.
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http://dx.doi.org/10.1177/1938640020910953DOI Listing
June 2021

Relationship of Preoperative Patient-Reported Outcome Measures (PROMs) to Postoperative Success in End-Stage Ankle Arthritis.

Foot Ankle Int 2020 03 9;41(3):253-258. Epub 2019 Dec 9.

Department of Orthopedic Surgery, University of British Columbia, Vancouver, BC, Canada.

Background: Ankle osteoarthritis is a significant cause of pain and disability. Despite the effectiveness of treatments, a subset of patients remains with persistent pain and functional limitations. The purpose of this study was to use preoperative patient-reported outcome measures to predict which ankle osteoarthritis patients would be most likely to experience postoperative improvements in functional outcomes.

Methods: A retrospective analysis of prospectively collected data was used to evaluate 427 patients with end-stage ankle arthritis with 5-year follow-up. Demographics, comorbidities, Ankle Osteoarthritis Scale (AOS), Ankle Arthritis Score (AAS), and the physical and mental component scores of the Short Form-36 (SF-36 Physical Components Score [PCS] and Mental Components Score [MCS]) were collected. The minimal clinically important difference (MCID) was then calculated. Receiver operating characteristic (ROC) analysis was used to choose the optimal threshold values of preoperative patient-reported outcome measure and assess the prediction performance.

Results: Patients who scored worst at preoperative baseline made the greatest gains in function and pain relief, and they had a high chance of achieving MCID following surgical treatment. ROC curves demonstrated that preoperative AOS, AAS, and SF-36 PCS and MCS scores were predictive of postoperative improvements in physical and mental function. Patients with preoperative AOS score above 45.7 had an 83% probability of achieving an MCID (AUC = 0.67). Similarly, patients with a preoperative AAS score above 25.7 had a 78% probability of achieving an MCID (AUC = 0.63). Patients with a preoperative SF-36 PCS score below 31 had a 62% probability of achieving an MCID (AUC = 0.64). Patients with a preoperative SF-36 MCS below 52.7 had a 47% probability of achieving an MCID (AUC = 0.89). MCIDs for AOS, AAS, SF3-36 PCS, and SF-36 MCS score changes were 12.4, 10.0, 6.43, and 8.1, respectively.

Conclusion: Preoperative patient-reported outcomes measures could predict postoperative improvement in ankle arthritis patients. The results of this study may be used to facilitate discussion between physicians and patients regarding the expected benefit of surgery.

Level Of Evidence: Level III, prognostic comparative study.
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http://dx.doi.org/10.1177/1071100719893334DOI Listing
March 2020
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