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Summary: Background: The World Health Organisation (WHO) has identified a range of symptomatic manifestations to aid in the clinical diagnosis of post-COVID conditions, herein referred to as post-acute COVID-19 symptoms. We conducted an international network cohort study to estimate the burden of these symptoms in North American, European, and Asian populations. Methods: A federated analysis was conducted including 10 databases from the United Kingdom, Netherlands, Norway, Estonia, Spain, France, South Korea, and the United States, between September 1st 2020 and latest data availability (which varied from December 31st 2021 to February 28th 2023), covering primary and secondary care, nationwide registries, and claims data, all mapped to the Observational Medical Outcomes Partnership Common Data Model (OMOP CDM). We defined two cohorts for the main analyses: a SARS-CoV-2 infection cohort [positive polymerase chain reaction (PCR) or rapid lateral flow test (LFT) result or clinical COVID-19 diagnosis] and a general population cohort. Individuals with less than 365 days of prior history or 120 days of follow-up were excluded. We estimated incidence rates (IRs) of the 25 WHO-proposed post-acute COVID-19 symptoms, considering symptoms that occurred ≥90 and ≤365 days after index date, excluding individuals with the respective symptoms 180 days prior to the index event. Stratified analyses were conducted by age and sex. Incidence rate ratios (IRRs) were calculated comparing rates in the infected cohort versus the general population. Results from the different databases were combined using random-effects meta-analyses. Findings: 3,019,408 individuals were included in the infection cohort. 1,585,160 of them were female and 1,434,248 of them male. 929,351,505 individuals were included in the general population group. 461,195,036 of them were female and 466,022,004 of them male. The 1-year IR of any post-acute COVID-19 symptom in the COVID-19 infection cohort varied significantly across databases, from 4.4 (95% CI 3.8–5.1) per 100 person-years to 103.9 (95% CI 103.2–104.7). The five most common symptoms were joint pain (from 1.6 (95% CI 1.3–1.9) to 14.3 (95% CI 14.1–14.6)), abdominal pain (from 0.3 (95% CI 0.1–0.5) to 9.9 (95% CI 9.7–10.1)), gastrointestinal issues (from 0.6 (95% CI 0.4–0.9) to 13.3 (95% CI 13.1–13.6)), cough (from 0.3 (95% CI 0.2–0.5) to 9.1 (95% CI 8.9–9.3)), and anxiety (from 0.8 (95% CI 0.6–1.2) to 11.4 (95% CI 11.2–11.6)); whereas muscle spasms (from 0.01 (95% CI 0.008–0.2) to 1.7 (95% CI 1.6–1.8)), pins and needles (from 0.05 (95% CI 0.03–0.0.9) to 1.5 (95% CI 1.4–1.6)), memory issues (from 0.03 (95% CI 0.02–0.06) to 0.8 (95% CI 0.7–0.8)), cognitive dysfunction (from 0.007 (95% CI 0.004–0.01) to 0.6 (95% CI 0.4–0.8)), and altered smell and/or taste (from 0.04 (95% CI 0.03–0.04) to 0.7 (95% CI 0.6–0.8)) were least common. Incidence rates of any post-acute COVID-19 symptoms generally increased with age, with certain symptoms peaking in middle-aged adults (anxiety, depressive disorders, headache, altered smell and taste) and others in pre-school children (gastrointestinal issues and cough). Females had higher incidence rates for most symptoms. Based on the random-effects model, the infected cohort had a higher incidence of any post-acute COVID-19 symptom than the general population, with a meta-analytic incidence rate ratio (meta-IRR) of 1.4 (1–2). A similar pattern was seen for all individual symptoms. The highest meta-IRRs were depressive disorder, 2.6 (1.7–3.9); anxiety, 2.3 (1.4–3.8); allergy, 2.1 (1.7–2.8) and sleep disorders, 2.1 (1.5–2.6). The meta-IRR for altered smell and/or taste was 1.9 (1.3–2.8). Interpretation: Post-acute COVID-19 symptoms, as listed by the WHO, were commonly observed following COVID-19 infection. However, even after standardising research methods, there was significant heterogeneity in the incidence rates from different healthcare settings and geographical locations. This is the first international study of the epidemiology of post-acute COVID-19 symptoms using the WHO-listed symptoms. Its findings contibute to understand the epidemiology of this condition from a multinational approach. Limitations of this study include the lack of consensus of the post-acute COVID-19 definition, as well as the difficulty to capture the impact on daily life of the post-acute COVID-19 symptoms in the available datasets. Funding: This work has been funded by the European Health Data Evidence Network (EHDEN) through an Evidence Generation Fund Grant and by the National Institute for Health and Care Research (NIHR) Oxford Biomedical Research Centre (BRC).

Nicola L Barclay,1 Theresa Burkard,1 Edward Burn,1 Antonella Delmestri,1 Andrea Miquel Dominguez,2 Asieh Golozar,3 Carlos Guarner-Argente,4 Francesc Xavier Avilés-Jurado,5 Wai Yi Man,1 Àlvar Roselló Serrano,6 Andreas Weinberger Rosen,7 Eng Hooi Tan,1 Ilona Tietzova,8 Daniel Prieto Alhambra,1,9 Danielle Newby1 On behalf of the OPTIMA Consortium1Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom; 2Otorrinolaringology department, Hospital Joan XXIII de Tarragona, Tarragona, Spain; 3Odysseus Data Services, Cambridge, MA, USA; 4Gastroenterology Department, Hospital de la Santa Creu I Sant Pau, Universitat Autònoma de Barcelona, Sant Quintí, Barcelona, Spain; 5Head Neck Tumors Unit, Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona, Spain; 6Institut Català d’Oncologia, Hospital Universitari Dr Josep Trueta, Girona, Spain; 7Centre for Surgical Science, Department of Surgery, Zealand University Hospital, Koege, Denmark; 8First Department of Tuberculosis and Respiratory Diseases, First Faculty of Medicine, Charles University, Prague, Czech Republic; 9Department of Medical Informatics, Erasmus University Medical Centre, Rotterdam, the NetherlandsCorrespondence: Daniel Prieto Alhambra, Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, OX3 7LD, United Kingdom, Email daniel.prietoalhambra@ndorms.ox.ac.ukPurpose: The COVID-19 pandemic profoundly affected healthcare systems and patients. There is a need to comprehend the collateral effects of the pandemic on non-communicable diseases. We examined the impact of the pandemic on short-term survival for common solid tumours, including breast, colorectal, head and neck, liver, lung, oesophageal, pancreatic, prostate, and stomach cancer in the UK.Methods: This was a population-based cohort study of electronic health records from the UK primary care Clinical Practice Research Datalink GOLD database. In sum, 12,259,744 eligible patients aged ≥ 18 years with ≥ 1 year’s history identified from January 2000 to December 2022 were included. We estimated age-standardised incidence and short-term (one- and two-year) survival for several common cancers from 2000 to 2019 (in five-year strata) and compared these to 2020– 2022 using the Kaplan–Meier method.Results: Incidence decreased for most cancers in 2020 and recovered to different extents in 2021– 2022. Short-term survival improved for most cancers between 2000 and 2019, but then declined, albeit minimally, for those diagnosed in 2020– 2022. This was most pronounced for colorectal cancer, with one-year survival falling from 78.8% (95% CI 78%– 79.6%) in 2015– 2019 to 77% (95% CI 75.6– 78.3%) for those diagnosed in 2020– 2022.Conclusion: Short-term survival for many cancers was impacted, albeit minimally, by the pandemic in the UK, with reductions in survivorship from colorectal cancer equivalent to returning to the mortality seen in the first decade of the 2000s. While data on longer-term survival are needed to fully comprehend the impact of COVID-19 on cancer care, our findings illustrate the need for an urgent and substantial commitment from the UK National Health Service to address the existing backlog in cancer screening and diagnostic procedures to improve cancer care and mortality.Keywords: cancer, COVID-19, colorectal cancer, incidence, pandemic, survival

Vincent Lo Re III,1,2,* Noelle M Cocoros,3,4,* Rebecca A Hubbard,2 Sarah K Dutcher,5 Craig W Newcomb,2 John G Connolly,3,4 Silvia Perez-Vilar,5 Dena M Carbonari,2 Maria E Kempner,3,4 José J Hernández-Muñoz,5 Andrew B Petrone,3,4 Allyson M Pishko,6 Meighan E Rogers Driscoll,3,4 James T Brash,7 Sean Burnett,8,9 Catherine Cohet,10 Matthew Dahl,8,11 Terese A DeFor,12 Antonella Delmestri,13 Djeneba Audrey Djibo,14 Talita Duarte-Salles,15,16 Laura B Harrington,17 Melissa Kampman,18 Jennifer L Kuntz,19 Xavier Kurz,10 Núria Mercadé-Besora,15 Pamala A Pawloski,12 Peter R Rijnbeek,16 Sarah Seager,7 Claudia A Steiner,20,21 Katia Verhamme,16 Fangyun Wu,8,22 Yunping Zhou,23 Edward Burn,13 J Michael Paterson,8,22,* Daniel Prieto-Alhambra13,16,* 1Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 2Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 3Department of Population Medicine, Harvard Medical School, Boston, MA, USA; 4Harvard Pilgrim Healthcare Institute, Boston, MA, USA; 5Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA; 6Division of Hematology and Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 7IQVIA, Real World Solutions, Brighton, UK; 8Canadian Network for Observational Drug Effect Studies (CNODES), Toronto, Ontario, Canada; 9Therapeutics Initiative, University of British Columbia, Vancouver, British Columbia, Canada; 10Data Analytics and Methods Task Force, European Medicines Agency, Amsterdam, Netherlands; 11Manitoba Centre for Health Policy, University of Manitoba, Winnipeg, Manitoba, Canada; 12HealthPartners Institute, Bloomington, MN, USA; 13Pharmaco- and Device Epidemiology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), University of Oxford, Oxford, UK; 14CVS Health, Blue Bell, PA, USA; 15Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Barcelona, Spain; 16Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, Netherlands; 17Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA; 18Health Canada, Ottawa, Ontario, Canada; 19Kaiser Permanente Northwest Center for Health Research, Portland, OR, USA; 20Kaiser Permanente Colorado Institute for Health Research, Aurora, CO, USA; 21Colorado Permanente Medical Group, Denver, CO, USA; 22ICES, Toronto, Ontario, Canada; 23Humana Healthcare Research, Inc., Louisville, KY, USA*These authors contributed equally to this workCorrespondence: Vincent Lo Re III, Division of Infectious Diseases, Department of Medicine, Division of Epidemiology, Department of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, 836 Blockley Hall, 423 Guardian Drive, Philadelphia, PA, 19104-6021, USA, Fax +1 215 573 5315, Email vincentl@pennmedicine.upenn.eduPurpose: Few studies have examined how the absolute risk of thromboembolism with COVID-19 has evolved over time across different countries. Researchers from the European Medicines Agency, Health Canada, and the United States (US) Food and Drug Administration established a collaboration to evaluate the absolute risk of arterial (ATE) and venous thromboembolism (VTE) in the 90 days after diagnosis of COVID-19 in the ambulatory (eg, outpatient, emergency department, nursing facility) setting from seven countries across North America (Canada, US) and Europe (England, Germany, Italy, Netherlands, and Spain) within periods before and during COVID-19 vaccine availability.Patients and Methods: We conducted cohort studies of patients initially diagnosed with COVID-19 in the ambulatory setting from the seven specified countries. Patients were followed for 90 days after COVID-19 diagnosis. The primary outcomes were ATE and VTE over 90 days from diagnosis date. We measured country-level estimates of 90-day absolute risk (with 95% confidence intervals) of ATE and VTE.Results: The seven cohorts included 1,061,565 patients initially diagnosed with COVID-19 in the ambulatory setting before COVID-19 vaccines were available (through November 2020). The 90-day absolute risk of ATE during this period ranged from 0.11% (0.09– 0.13%) in Canada to 1.01% (0.97– 1.05%) in the US, and the 90-day absolute risk of VTE ranged from 0.23% (0.21– 0.26%) in Canada to 0.84% (0.80– 0.89%) in England. The seven cohorts included 3,544,062 patients with COVID-19 during vaccine availability (beginning December 2020). The 90-day absolute risk of ATE during this period ranged from 0.06% (0.06– 0.07%) in England to 1.04% (1.01– 1.06%) in the US, and the 90-day absolute risk of VTE ranged from 0.25% (0.24– 0.26%) in England to 1.02% (0.99– 1.04%) in the US.Conclusion: There was heterogeneity by country in 90-day absolute risk of ATE and VTE after ambulatory COVID-19 diagnosis both before and during COVID-19 vaccine availability.Plain Language Summary: Cohort studies of patients diagnosed with COVID-19 in both the ambulatory and hospital settings have suggested that SARS-CoV-2 infection promotes hypercoagulability that could lead to arterial or venous thromboembolism. However, few studies have examined how the risk of thromboembolism with COVID-19 has evolved over time across different countries. A new collaboration was established among the regulatory authorities of Canada, Europe, and the US within the International Coalition of Medicines Regulatory Authorities to evaluate the 90-day risk of both arterial and venous thromboembolism after initial diagnosis of COVID-19 in the ambulatory or hospital setting from seven countries across North America (Canada, US) and Europe (England, Germany, Italy, Netherlands, and Spain) within periods before and during COVID-19 vaccine availability. The study found that there was variability in the risk of both arterial and venous thromboembolism by month across the countries among patients initially diagnosed with COVID-19 in the ambulatory or hospital setting. Differences in the healthcare systems, prevalence of comorbidities in the study cohorts, and approaches to the case definitions of thromboembolism likely contributed to the variability in estimates of thromboembolism risk across the countries.Keywords: COVID-19, ischemic stroke, myocardial infarction, thromboembolism, venous thromboembolism

Background: The COVID-19 pandemic affected cancer screening, diagnosis and treatments. Many surgeries were substituted with bridging therapies during the initial lockdown, yet consideration of treatment side effects and their management was not a priority. Objectives: To examine how the changing social restrictions imposed by the pandemic affected incidence and trends of endocrine treatment prescriptions in newly diagnosed (incident) breast and prostate cancer patients and, secondarily, endocrine treatment-related outcomes (including bisphosphonate prescriptions, osteopenia and osteoporosis), in UK clinical practice from March 2020 to June 2022. Design: Population-based cohort study using UK primary care Clinical Practice Research Datalink GOLD database. Methods: There were 13,701 newly diagnosed breast cancer patients and 12,221 prostate cancer patients with ⩾1-year data availability since diagnosis between January 2017 and June 2022. Incidence rates (IR) and incidence rate ratios (IRR) were calculated across multiple time periods before and after lockdown to examine the impact of changing social restrictions on endocrine treatments and treatment-related outcomes, including osteopenia, osteoporosis and bisphosphonate prescriptions. Results: In breast cancer patients, aromatase inhibitor (AI) prescriptions increased during lockdown versus pre-pandemic [IRR: 1.22 (95% confidence interval (CI): 1.11–1.34)], followed by a decrease post-first lockdown [IRR: 0.79 (95% CI: 0.69–0.89)]. In prostate cancer patients, first-generation antiandrogen prescriptions increased versus pre-pandemic [IRR: 1.23 (95% CI: 1.08–1.4)]. For breast cancer patients on AIs, diagnoses of osteopenia, osteoporosis and bisphosphonate prescriptions were reduced across all lockdown periods versus pre-pandemic (IRR range: 0.31–0.62). Conclusion: During the first 2 years of the pandemic, newly diagnosed breast and prostate cancer patients were prescribed more endocrine treatments compared to pre-pandemic due to restrictions on hospital procedures replacing surgeries with bridging therapies. But breast cancer patients had fewer diagnoses of osteopenia and osteoporosis and bisphosphonate prescriptions. These patients should be followed up in the coming years for signs of bone thinning. Evidence of poorer management of treatment-related side effects will help assess resource allocation for patients at high risk for bone-related complications.

Abstract Persistent symptoms following the acute phase of COVID-19 present a major burden to both the affected and the wider community. We conducted a cohort study including over 856,840 first COVID-19 cases, 72,422 re-infections and more than 3.1 million first negative-test controls from primary care electronic health records from Spain and the UK (Sept 2020 to Jan 2022 (UK)/March 2022 (Spain)). We characterised post-acute COVID-19 symptoms and identified key symptoms associated with persistent disease. We estimated incidence rates of persisting symptoms in the general population and among COVID-19 patients over time. Subsequently, we investigated which WHO-listed symptoms were particularly differential by comparing their frequency in COVID-19 cases vs. matched test-negative controls. Lastly, we compared persistent symptoms after first infections vs. reinfections.Our study shows that the proportion of COVID-19 cases affected by persistent post-acute COVID-19 symptoms declined over the study period. Risk for altered smell/taste was consistently higher in patients with COVID-19 vs test-negative controls. Persistent symptoms were more common after reinfection than following a first infection. More research is needed into the definition of long COVID, and the effect of interventions to minimise the risk and impact of persistent symptoms.

IntroductionThe COVID-19 pandemic had collateral effects on many health systems. Cancer screening and diagnostic tests were postponed, resulting in delays in diagnosis and treatment. This study assessed the impact of the pandemic on screening, diagnostics and incidence of breast, colorectal, lung, and prostate cancer; and whether rates returned to pre-pandemic levels by December, 2021.MethodsThis is a cohort study of electronic health records from the United Kingdom (UK) primary care Clinical Practice Research Datalink (CPRD) GOLD database. The study included individuals registered with CPRD GOLD between January, 2017 and December, 2021, with at least 365 days of clinical history. The study focused on screening, diagnostic tests, referrals and diagnoses of first-ever breast, colorectal, lung, and prostate cancer. Incidence rates (IR) were stratified by age, sex, and region, and incidence rate ratios (IRR) were calculated to compare rates during and after lockdown with rates before lockdown. Forecasted rates were estimated using negative binomial regression models.ResultsAmong 5,191,650 eligible participants, the first lockdown resulted in reduced screening and diagnostic tests for all cancers, which remained dramatically reduced across the whole observation period for almost all tests investigated. There were significant IRR reductions in breast (0.69 [95% CI: 0.63-0.74]), colorectal (0.74 [95% CI: 0.67-0.81]), and prostate (0.71 [95% CI: 0.66-0.78]) cancer diagnoses. IRR reductions for lung cancer were non-significant (0.92 [95% CI: 0.84-1.01]). Extrapolating to the entire UK population, an estimated 18,000 breast, 13,000 colorectal, 10,000 lung, and 21,000 prostate cancer diagnoses were missed from March, 2020 to December, 2021.DiscussionThe UK COVID-19 lockdown had a substantial impact on cancer screening, diagnostic tests, referrals, and diagnoses. Incidence rates remained significantly lower than pre-pandemic levels for breast and prostate cancers and associated tests by December, 2021. Delays in diagnosis are likely to have adverse consequences on cancer stage, treatment initiation, mortality rates, and years of life lost. Urgent strategies are needed to identify undiagnosed cases and address the long-term implications of delayed diagnoses.

BackgroundPatients with symptomatic knee osteoarthritis may undergo non-surgical interventions such as intra-articular steroid injections and knee arthroscopy. This study aimed to investigate their association with the timing and outcomes of subsequent primary knee replacement.Methods and findingsObservational retrospective analysis of linked Clinical Practice Research Datalink, Hospital Episode Statistics, Patient Reported Outcome Measures (CPRD GOLD-HES-PROMS) data of 38,494 patients undergoing primary knee replacements in England. Prior use of intra-articular steroid injections and knee arthroscopy were identified. Hazard ratios (HRs) with 95% CIs were estimated for primary outcomes of revision and reoperation using Cox regression. Secondary outcomes included time from first diagnosis of ipsilateral knee osteoarthritis to knee replacement, 6-month post-operative Oxford Knee Scores (OKS), mortality (90-days and 3-months), and post-operative surgical site infection (SSI) (3-months) using linear and logistic regression. Prior steroid injections were associated with an increased risk of revision (HR = 1.25 95%CI (1.06 to 1.49)), re-operation (HR = 1.18 95%CI (1.05 to 1.32)), and SSI (HR = 3.10 95%CI (1.14 to 8.46). Timing from diagnosis of knee osteoarthritis to knee replacement was 6 months longer in patients receiving steroid injections. Knee arthroscopy was associated with an increased risk of revision (HR = 3.14 95%CI (2.64 to 3.73)), re-operation (HR = 3.25 95%CI (2.89 to 3.66)), lower post-operative OKS -1.63 95%CI (-2.31 to -0.95). Both interventions were associated with a lower risk of mortality.ConclusionsSteroid injection and knee arthroscopy prior to primary knee replacement are each associated with worse outcomes. The observed association of lower mortality risk is suggestive of confounding by indication. The observed associations in this study could be used to inform shared decision making with patients on the treatment pathway for knee osteoarthritis.

ObjectiveTo quantify the background incidence rates of 15 prespecified adverse events of special interest (AESIs) associated with covid-19 vaccines.DesignMultinational network cohort study.SettingElectronic health records and health claims data from eight countries: Australia, France, Germany, Japan, the Netherlands, Spain, the United Kingdom, and the United States, mapped to a common data model.Participants126 661 070 people observed for at least 365 days before 1 January 2017, 2018, or 2019 from 13 databases.Main outcome measuresEvents of interests were 15 prespecified AESIs (non-haemorrhagic and haemorrhagic stroke, acute myocardial infarction, deep vein thrombosis, pulmonary embolism, anaphylaxis, Bell's palsy, myocarditis or pericarditis, narcolepsy, appendicitis, immune thrombocytopenia, disseminated intravascular coagulation, encephalomyelitis (including acute disseminated encephalomyelitis), Guillain-Barré syndrome, and transverse myelitis). Incidence rates of AESIs were stratified by age, sex, and database. Rates were pooled across databases using random effects meta-analyses and classified according to the frequency categories of the Council for International Organizations of Medical Sciences.ResultsBackground rates varied greatly between databases. Deep vein thrombosis ranged from 387 (95% confidence interval 370 to 404) per 100 000 person years in UK CPRD GOLD data to 1443 (1416 to 1470) per 100 000 person years in US IBM MarketScan Multi-State Medicaid data among women aged 65 to 74 years. Some AESIs increased with age. For example, myocardial infarction rates in men increased from 28 (27 to 29) per 100 000 person years among those aged 18-34 years to 1400 (1374 to 1427) per 100 000 person years in those older than 85 years in US Optum electronic health record data. Other AESIs were more common in young people. For example, rates of anaphylaxis among boys and men were 78 (75 to 80) per 100 000 person years in those aged 6-17 years and 8 (6 to 10) per 100 000 person years in those older than 85 years in Optum electronic health record data. Meta-analytic estimates of AESI rates were classified according to age and sex.ConclusionThis study found large variations in the observed rates of AESIs by age group and sex, showing the need for stratification or standardisation before using background rates for safety surveillance. Considerable population level heterogeneity in AESI rates was found between databases.

Population-based studies can provide information on the safety of COVID-19 vaccines. Here the authors report the rates thrombosis and thrombocytopenia after vaccination against and infection with SARS-CoV-2 in the United Kingdom and compare them with the background (expected) rates in the general population.

Abstract Background Approximately 20% of patients experience chronic pain after total knee replacement (TKR). The impact of chronic pain after TKR on primary care services in the UK is currently unknown. The aim of this study was to compare primary care consultations and pain medicine prescriptions between patients with and without chronic pain after TKR. Methods Data from 5,055 patients who received TKR between 2009 and 2016 with anonymised linked data from the Clinical Practice Research Datalink Gold (CPRD) and English Hospital Episode Statistics (HES) Patient Reported Outcome Measures (PROMs) programme were analysed. The exposure time was from 10 years pre-operative to eight years post-operative. Patients with a score ≤ 14 on the Oxford Knee Score pain component scale at 6 months post-operative were classified as having chronic pain after TKR. Primary care consultations and prescribed pain medicines were quantified, and costs calculated based on national cost data. Results 721 patients (14%) had chronic pain after TKR. The prevalence and costs of primary care consultations and pain medicine prescriptions per year were consistently higher for patients with chronic pain after TKR compared with those without chronic pain after TKR; these differences were observed both before and after surgery. There was a substantial and sustained increase in the cost of opioid prescriptions after surgery for patients with chronic pain after TKR, peaking at seven years post-operative. Conclusions Increased primary care consultations and pain medicine prescriptions associated with chronic pain after TKR represent a considerable financial cost to primary care services. Evaluation of interventions to reduce the risk of developing this pain condition and improve the early management of pain after TKR are needed to improve outcomes for patients and reduce costs to healthcare services.

Background: Patients with symptomatic knee osteoarthritis may undergo non-surgical interventions such as intra-articular steroid injections and knee arthroscopy. This study aimed to investigate their association with the timing and outcomes of subsequent primary knee replacement. Methods and findings: Observational retrospective analysis of linked Clinical Practice Research Datalink, Hospital Episode Statistics, Patient Reported Outcome Measures (CPRD GOLD-HES-PROMS) data of 38,494 patients undergoing primary knee replacements in England. Prior use of intra-articular steroid injections and knee arthroscopy were identified. Hazard ratios (HRs) with 95% CIs were estimated for primary outcomes of revision and reoperation using Cox regression. Secondary outcomes included time from first diagnosis of ipsilateral knee osteoarthritis to knee replacement, 6-month post-operative Oxford Knee Scores (OKS), mortality (90-days and 3-months), and post-operative surgical site infection (SSI) (3-months) using linear and logistic regression. Prior steroid injections were associated with an increased risk of revision (HR = 1.25 95%CI (1.06 to 1.49)), re-operation (HR = 1.18 95%CI (1.05 to 1.32)), and SSI (HR = 3.10 95%CI (1.14 to 8.46). Timing from diagnosis of knee osteoarthritis to knee replacement was 6 months longer in patients receiving steroid injections. Knee arthroscopy was associated with an increased risk of revision (HR = 3.14 95%CI (2.64 to 3.73)), re-operation (HR = 3.25 95%CI (2.89 to 3.66)), lower post-operative OKS -1.63 95%CI (-2.31 to -0.95). Both interventions were associated with a lower risk of mortality. Conclusions: Steroid injection and knee arthroscopy prior to primary knee replacement are each associated with worse outcomes. The observed association of lower mortality risk is suggestive of confounding by indication. The observed associations in this study could be used to inform shared decision making with patients on the treatment pathway for knee osteoarthritis. [ABSTRACT FROM AUTHOR]

Background: Thrombosis with thrombocytopenia syndrome (TTS) has been identified as a rare adverse event following some COVID-19 vaccines. Various guidelines have been issued on the treatment of TTS. We aimed to characterize the treatment of TTS and other thromboembolic events (venous thromboembolism (VTE), and arterial thromboembolism (ATE) after COVID-19 vaccination and compared to historical (pre-vaccination) data in Europe and the US.Methods: We conducted an international network cohort study using 8 primary care, outpatient, and inpatient databases from France, Germany, Netherlands, Spain, The United Kingdom, and The United States. We investigated treatment pathways after the diagnosis of TTS, VTE, or ATE for a pre-vaccination (background) cohort (01/2017—11/2020), and a vaccinated cohort of people followed for 28 days after a dose of any COVID-19 vaccine recorded from 12/2020 onwards).Results: Great variability was observed in the proportion of people treated (with any recommended therapy) across databases, both before and after vaccination. Most patients with TTS received heparins, platelet aggregation inhibitors, or direct Xa inhibitors. The majority of VTE patients (before and after vaccination) were first treated with heparins in inpatient settings and direct Xa inhibitors in outpatient settings. In ATE patients, treatments were also similar before and after vaccinations, with platelet aggregation inhibitors prescribed most frequently. Inpatient and claims data also showed substantial heparin use.Conclusion: TTS, VTE, and ATE after COVID-19 vaccination were treated similarly to background events. Heparin use post-vaccine TTS suggests most events were not identified as vaccine-induced thrombosis with thrombocytopenia by the treating clinicians.

Purpose: To illustrate the interest in using interrupted time series (ITS) methods, this study evaluated the impact of the UK MHRA's March 2019 Risk Minimisation Measures (RMM) on fluoroquinolone usage. Methods: Monthly and quarterly fluoroquinolone use incidence rates from 2012 to 2022 were analysed across hospital care (Barts Health NHS Trust), primary care (Clinical Practice Research Datalink (CPRD) Aurum and CPRD GOLD), and linked records from both settings (East Scotland). Rates were stratified by age (19–59 and ≥ 60 years old). Seasonality‐adjusted segmented regression and ARIMA models were employed to model quarterly and monthly rates, respectively. Results: Post‐RMM, with segmented regression, both age groups in Barts Health experienced nearly complete reductions (> 99%); CPRD Aurum saw 20.19% (19–59) and 19.29% (≥$$ \ge $$ 60) reductions; no significant changes in CPRD GOLD; East Scotland had 45.43% (19–59) and 41.47% (≥$$ \ge $$ 60) decreases. Slope analysis indicated increases for East Scotland (19–59) and both CPRD Aurum groups, but a decrease for CPRD GOLD's ≥$$ \ge $$ 60; ARIMA detected significant step changes in CPRD GOLD not identified by segmented regression and noted a significant slope increase in Barts Health's 19–59 group. Both models showed no post‐modelling autocorrelations across databases, yet Barts Health's residuals were non‐normally distributed with non‐constant variance. Conclusions: Both segmented regression and ARIMA confirmed the reduction of fluoroquinolones use after RMM across four different UK primary care and hospital databases. Model diagnostics showed good performance in eliminating residual autocorrelation for both methods. However, diagnostics for hospital databases with low incident use revealed the presence of heteroscedasticity and non‐normal white noise using both methods. [ABSTRACT FROM AUTHOR]

Objective: To characterize the trend of opioid use (number of users, dispensations and oral morphine milligram equivalents) in Catalonia (Spain).Design, setting, and participants: This population-based cohort study included all individuals aged 18 years or older, registered in the Information System for Research in Primary Care (SIDIAP), which covers >75% of the population in Catalonia, Spain, from 1 January 2007, to 31 December 2019.Main exposure and outcomes: The exposures were all commercialized opioids and their combinations (ATC-codes): codeine, tramadol, oxycodone, tapentadol, fentanyl, morphine, and other opioids (dihydrocodeine, hydromorphone, dextropropoxyphene, buprenorphine, pethidine, pentazocine). The main outcomes were the annual figures per 1,000 individuals of 1) opioid users, 2) dispensations, and 3) oral morphine milligram equivalents (MME). Results were stratified separately by opioid types, age (5-year age groups), sex (male or female), living area (rural or urban), and socioeconomic status (from least, U1, to most deprived, U5). The overall trends were quantified using the percentage change (PC) between 2007 and 2019.Results: Among 4,656,197 and 4,798,114 residents from 2007 to 2019, the number of opioid users, dispensations and morphine milligram equivalents per 1,000 individuals increased 12% (percentage change: 95% confidence interval (CI) 11.9–12.3%), 105% (95% confidence interval 83%–126%) and 339% (95% CI 289%–390%) respectively. Tramadol represented the majority of opioid use in 2019 (61, 59, and 54% of opioid users, dispensations, and total MME, respectively). Individuals aged 80 years or over reported the sharpest increase regarding opioid users (PC: 162%), dispensations (PC: 424%), and MME (PC: 830%). Strong opioids were increasingly prescribed for non-cancer pains over the years.Conclusion: Despite the modest increase of opioid users, opioid dispensations and MME increased substantially, particularly in the older population. In addition, strong opioids were incrementally indicated for non-cancer pains over the years. These findings suggest a transition of opioid prescriptions from intermittent to chronic and weak to strong and call for more rigorous opioid stewardship.

Objective As part of the STAR Programme, a comprehensive study exploring long-term pain after surgery, we investigated how pain and function, health-related quality of life (HRQL), and healthcare resource use evolved over 5 years after total knee replacement (TKR) for those with and without chronic pain 1 year after their primary surgery.Methods We used data from the Clinical Outcomes in Arthroplasty Study prospective cohort study, which followed patients undergoing TKR from two English hospitals for 5 years. Chronic pain was defined using the Oxford Knee Score Pain Subscale (OKS-PS) where participants reporting a score of 14 or lower were classified as having chronic pain 1-year postsurgery. Pain and function were measured with the OKS, HRQL using the EuroQoL-5 Dimension, resource use from yearly questionnaires, and costs estimated from a healthcare system perspective. We analysed the changes in OKS-PS, HRQL and resource use over a 5-year follow-up period. Multiple imputation accounted for missing data.Results Chronic pain was reported in 70/552 operated knees (12.7%) 1 year after surgery. The chronic pain group had worse pain, function and HRQL presurgery and postsurgery than the non-chronic pain group. Those without chronic pain markedly improved right after surgery, then plateaued. Those with chronic pain improved slowly but steadily. Participants with chronic pain reported greater healthcare resource use and costs than those without, especially 1 year after surgery, and mostly from hospital readmissions. 64.7% of those in chronic pain recovered during the following 4 years, while 30.9% fluctuated in and out of chronic pain.Conclusion Although TKR is often highly beneficial, some patients experienced chronic pain postsurgery. Although many fluctuated in their pain levels and most recovered over time, identifying people most likely to have chronic pain and supporting their recovery would benefit patients and healthcare systems.

Objective To identify patients at risk of mid-late term revision of hip replacement to inform targeted follow-up.Design Analysis of linked national data sets from primary and secondary care (Clinical Practice Research Datalink (CPRD-GOLD); National Joint Registry (NJR); English Hospital Episode Statistics (HES); Patient-Reported Outcome Measures (PROMs)).Participants Primary elective total hip replacement (THR) aged≥18.Event of interest Revision surgery≥5 years (mid-late term) after primary THR.Statistical methods Cox regression modelling to ascertain risk factors of mid-late term revision. HR and 95% CI assessed association of sociodemographic factors, comorbidities, medication, surgical variables and PROMs with mid-late term revision.Results NJR-HES-PROMs data were available from 2008 to 2011 on 142 275 THR; mean age 70.0 years and 61.9% female. CPRD GOLD-HES data covered 1995–2011 on 17 047 THR; mean age 68.4 years, 61.8% female. Patients had minimum 5 years postprimary surgery to end 2016. In NJR-HES-PROMS data, there were 3582 (2.5%) revisions, median time-to-revision after primary surgery 1.9 years (range 0.01–8.7), with 598 (0.4%) mid-late term revisions; in CPRD GOLD, 982 (5.8%) revisions, median time-to-revision 5.3 years (range 0–20), with 520 (3.1%) mid-late term revisions.Reduced risk of mid-late term revision was associated with older age at primary surgery (HR: 0.96; 95% CI: 0.95 to 0.96); better 6-month postoperative pain/function scores (HR: 0.35; 95% CI: 0.27 to 0.46); use of ceramic-on-ceramic (HR: 0.73; 95% CI: 0.56 to 0.95) or ceramic-on-polyethylene (HR: 0.76; 95% CI: 0.58 to 1.00) bearing surfaces.Increased risk of mid-late term revision was associated with the use of antidepressants (HR: 1.32; 95% CI: 1.09 to 1.59), glucocorticoid injections (HR: 1.33; 95% CI: 1.06 to 1.67) and femoral head size≥44 mm (HR: 2.56; 95% CI: 1.09 to 6.02)No association of gender, obesity or Index of Multiple Deprivation was observed.Conclusion The risk of mid-late term THR is associated with age at primary surgery, 6-month postoperative pain and function and implant factors. Further work is needed to explore the associations with prescription medications observed in our data.

Objective To identify patients at risk of mid-late term revision of knee replacement (KR) to inform targeted follow-up.Design Analysis of linked national datasets from primary and secondary care (Clinical Practice Research Datalink (CPRD GOLD), National Joint Registry (NJR), English Hospital Episode Statistics (HES) and Patient Reported Outcome Measures (PROMs)).Participants Primary elective KRs aged ≥18 years.Event of interest Revision surgery ≥5 years (mid–late term) postprimary KR.Statistical methods Cox regression modelling to ascertain risk factors of mid–late term revision. HRs and 95% CIs assessed association of sociodemographic factors, comorbidities, medication, surgical variables and PROMs with mid–late term revision.Results NJR-HES-PROMs data were available from 2008 to 2011 on 188 509 KR. CPRD GOLD-HES data covered 1995–2011 on 17 378 KR. Patients had minimum 5 years postprimary surgery to end 2016. Age and gender distribution were similar across datasets; mean age 70 years, 57% female. In NJR, there were 8607 (4.6%) revisions, median time-to-revision postprimary surgery 1.8 years (range 0–8.8), with 1055 (0.6%) mid–late term revisions; in CPRD GOLD, 877 (5.1%) revisions, median time-to-revision 4.2 years (range 0.02–18.3), with 352 (2.0%) mid–late term revisions.Reduced risk of revision after 5 years was associated with older age (HR: 0.95; 95% CI 0.95 to 0.96), obesity (0.70; 0.56 to 0.88), living in deprived areas (0.71; 0.58 to 0.87), non-white ethnicity (0.58; 0.43 to 0.78), better preoperative pain and functional limitation (0.42; 0.33 to 0.53), better 6-month postoperative pain and function (0.33; 0.26 to 0.41) or moderate anxiety/depression (0.73; 0.63 to 0.83) at primary surgery.Increased risk was associated with male gender (1.32; 1.04 to 1.67); when anticonvulsants (gabapentin and pregabalin) (1.58; 1.01 to 2.47) or opioids (1.36; 1.08 to 1.71) were required prior to primary surgery.No implant factors were identified.Conclusion The risk of mid–late term KR revision is very low. Increased risk of revision is associated with patient case-mix factors, and there is evidence of sociodemographic inequality.