Observational methods for COVID-19 vaccine effectiveness research:an empirical evaluation and target trial emulation

Background:There are scarce data on best practices to control for confounding in observational studies assessing vaccine effectiveness to prevent COVID-19. We compared the performance of three well-established methods [overlap weighting, inverse probability treatment weighting and propensity score (PS) matching] to minimize confounding when comparing vaccinated and unvaccinated people. Subsequently, we conducted a target trial emulation to study the ability of these methods to replicate COVID-19 vaccine trials.Methods:We included all individuals aged ≥75 from primary care records from the UK [Clinical Practice Research Datalink (CPRD) AURUM], who were not infected with or vaccinated against SARS-CoV-2 as of 4 January 2021. Vaccination status was then defined based on first COVID-19 vaccine dose exposure between 4 January 2021 and 28 January 2021. Lasso regression was used to calculate PS. Location, age, prior observation time, regional vaccination rates, testing effort and COVID-19 incidence rates at index date were forced into the PS. Following PS weighting and matching, the three methods were compared for remaining covariate imbalance and residual confounding. Last, a target trial emulation comparing COVID-19 at 3 and 12 weeks after first vaccine dose vs unvaccinated was conducted.Results:Vaccinated and unvaccinated cohorts comprised 583 813 and 332 315 individuals for weighting, respectively, and 459 000 individuals in the matched cohorts. Overlap weighting performed best in terms of minimizing confounding and systematic error. Overlap weighting successfully replicated estimates from clinical trials for vaccine effectiveness for ChAdOx1 (57%) and BNT162b2 (75%) at 12 weeks.Conclusion:Overlap weighting performed best in our setting. Our results based on overlap weighting replicate previous pivotal trials for the two first COVID-19 vaccines approved in Europe

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

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

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

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

Geographic variation in secondary fracture prevention after a hip fracture during 1999-2013:a UK study

Purpose To describe the geographic variation in anti-osteoporosis drug therapy prescriptions before and after a hip fracture during 1999-2013 in the UK. Methods We used primary care data (Clinical Practice Research Datalink) to identify patients with a hip fracture and primary care prescriptions of any anti-osteoporosis drugs prior to the index hip fracture and up to five years after. Geographic variations in prescribing before and after availability of generic oral bisphosphonates were analysed. Multivariable logistic regression models were adjusted for gender, age and body mass index (BMI). Results 13,069 patients (76% female) diagnosed with a hip fracture during 1999-2013 were identified. 11% had any anti-osteoporosis drug prescription in the six months prior to the index hip fracture. In the 0-4 months following a hip fracture 5% of patients were prescribed anti-osteoporosis drugs in 1999, increasing to 51% in 2011 to then decrease to 39% in 2013. The independent predictors (OR (95%CI)) of treatment initiation included gender (male:0.42 (0.36-0.49)), BMI (0.98 per kg/m2 increase (0.97-1.00)) and geographic region (1.29 (0.89-1.87) North East vs. 0.56(0.43-0.73) South Central region). Geographic differences in prescribing persisted over the 5-year follow-up. If all patients were treated at the rate of the highest performing region, then nationally an additional 3,214 hip fracture patients would be initiated on therapy every year. Conclusions Significant geographic differences exist in prescribing of anti-osteoporosis drugs after hip fracture despite adjustment for potential confounders. Further work examining differences in health care provision may inform strategies to improve secondary fracture prevention after hip fracture. </p

Secular trends in the initiation of therapy in secondary fracture prevention in Europe : a multi-national cohort study including data from Denmark, Catalonia, and the United Kingdom

Altres ajuts: UCB funded this study. All analyses were conducted independently by the academic researchers involved. MKJ is supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC).This paper demonstrates a large post-fracture anti-osteoporosis treatment gap in the period 2005 to 2015. The gap was stable in Denmark at around 88-90%, increased in Catalonia from 80 to 88%, and started to increase in the UK towards the end of our study. Improved post-fracture care is needed. Patients experiencing a fragility fracture are at high risk of subsequent fractures, particularly within the first 2 years after the fracture. Previous studies have demonstrated that only a small proportion of fracture patients initiate therapy with an anti-osteoporotic medication (AOM), despite the proven fracture risk reduction of such therapies. The aim of this paper is to evaluate the changes in this post-fracture treatment gap across three different countries from 2005 to 2015. This analysis, which is part of a multinational cohort study, included men and women, aged 50 years or older, sustaining a first incident fragility fracture. Using routinely collected patient data from three administrative health databases covering Catalonia, Denmark, and the United Kingdom, we estimated the treatment gap as the proportion of patients not treated with AOM within 1 year of their first incident fracture. A total of 648,369 fracture patients were included. Mean age 70.2-78.9 years; 22.2-31.7% were men. In Denmark, the treatment gap was stable at approximately 88-90% throughout the 2005 to 2015 time period. In Catalonia, the treatment gap increased from 80 to 88%. In the UK, an initially decreasing treatment gap-though never smaller than 63%-was replaced by an increasing gap towards the end of our study. The gap was more pronounced in men than in women. Despite repeated calls for improved secondary fracture prevention, an unacceptably large treatment gap remains, with time trends indicating that the problem may be getting worse in recent years. The online version of this article (10.1007/s00198-020-05358-4) contains supplementary material, which is available to authorized users

Models of care for the delivery of secondary fracture prevention after hip fracture:a health service cost, clinical outcomes and cost-effectiveness study within a region of England.

Background Professional bodies have produced comprehensive guidance about the management of hip fracture. They recommend orthogeriatric services focusing on achieving optimal recovery, and fracture liaison services (FLSs) focusing on secondary fracture prevention. Despite such guidelines being in place, there is significant variation in how services are structured and organised between hospitals. Objectives To establish the clinical effectiveness and cost-effectiveness of changes to the delivery of secondary fracture prevention services, and to identify barriers and facilitators to changes. Design A service evaluation to identify each hospital’s current models of care and changes in service delivery. A qualitative study to identify barriers and facilitators to change. Health economics analysis to establish NHS costs and cost-effectiveness. A natural experimental study to determine clinical effectiveness of changes to a hospital’s model of care. Setting Eleven acute hospitals in a region of England. Participants Qualitative study – 43 health professionals working in fracture prevention services in secondary care. Interventions Changes made to secondary fracture prevention services at each hospital between 2003 and 2012. Main outcome measures The primary outcome is secondary hip fracture. Secondary outcomes include mortality, non-hip fragility fracture and the overall rate of hip fracture. Data sources Clinical effectiveness/cost-effectiveness analyses – primary hip fracture patients identified from (1) Hospital Episode Statistics (2003–13, n = 33,152); and (2) Clinical Practice Research Datalink (1999–2013, n = 11,243). Results Service evaluation – there was significant variation in the organisation of secondary fracture prevention services, including staffing levels, type of service model (consultant vs. nurse led) and underlying processes. Qualitative – fracture prevention co-ordinators gave multidisciplinary health professionals capacity to work together, but communication with general practitioners was challenging. The intervention was easily integrated into practice but some participants felt that implementation was undermined by under-resourced services. Making business cases for a service was particularly challenging. Natural experiment – the impact of introducing an orthogeriatrician on 30-day and 1-year mortality was hazard ratio (HR) 0.73 [95% confidence interval (CI) 0.65 to 0.82] and HR 0.81 (95% CI 0.75 to 0.87), respectively. Thirty-day and 1-year mortality were likewise reduced following the introduction or expansion of a FLS: HR 0.80 (95% CI 0.71 to 0.91) and HR 0.84 (95% CI 0.77 to 0.93), respectively. There was no significant impact on time to secondary hip fracture. Health economics – the annual cost in the year of hip fracture was estimated at £10,964 (95% CI £10,767 to £11,161) higher than the previous year. The annual cost associated with all incident hip fractures in the UK among those aged ≥ 50 years (n = 79,243) was estimated at £1215M. At a £30,000 per quality-adjusted life-year threshold, the most cost-effective model was introducing an orthogeriatrician. Conclusion In hip fracture patients, orthogeriatrician and nurse-led FLS models are associated with reductions in mortality rates and are cost-effective, the orthogeriatrician model being the most cost-effective. There was no evidence for a reduction in second hip fracture. Qualitative data suggest that weaknesses lie in treatment adherence/monitoring, a possible reason for the lack of effectiveness on second hip fracture outcome. The effectiveness on non-hip fracture outcomes remains unanswered. Future work Reliable estimates of health state utility values for patients with hip and non-hip fractures are required to reduce uncertainty in health economic models. A clinical trial is needed to assess the clinical effectiveness and cost-effectiveness of a FLS for non-hip fracture patients. Funding The National Institute for Health Research (NIHR) Health Services and Delivery Research programme and the NIHR Musculoskeletal Biomedical Research Unit, University of Oxford

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

In January 2005 the National Institute for Health and Care Excellence (NICE) in England and Wales provided new guidance on the use of anti-osteoporosis therapies for the secondary prevention of osteoporotic fractures. This was shortly followed in the same year by market authorisation of a generic form of alendronic acid. We here set out to estimate the actual practice impact of these events among hip fracture patients in terms of anti-osteoporosis medicationprescribing and subsequent fracture incidence using primary care data (Clinical Practice Research Datalink) from 1999-2013. Changes in level and trend of prescribing and subsequent fracture following publication of NICE guidance and availability of generic alendronic acid were estimated using an interrupted time series analysis. Both events were considered in combination within a 1-year ‘intervention period’. We identified 10,873 primary hip fracture patients between April 1999 and Sept 2012. Taking into account prior trend, the intervention period was associated with an immediate absolute increase of 14.9% (95% C.I. 10.9 – 18.9) for incident anti-osteoporosis prescriptions and a significant and clinically important reduction in subsequent major and subsequent hip fracture: -0.19% (95% C.I.-0.28 to -0.09) and -0.17% (95% C.I. -0.26 to -0.09) per six months, respectively. This equated to an approximate 14% (major) and 22% (hip) reduction at three years post-intervention relative to expected values based solely on pre-intervention level and trend. We conclude that among hip fracture patients, publication of NICE guidance and availability of generic alendronic acid was temporally associated with increased prescribing and a significant decline in subsequent fractures

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

Objective: To estimate the impact of NICE approval of tumour necrosis factor inhibitor (TNFi) therapies on the incidence of total hip replacement (THR) and total knee replacement (TKR) among rheumatoid arthritis (RA) patients in England and Wales.Methods: Primary care data (Clinical Practice Research Datalink (CPRD)) for the study period (1995-2014) were used to identify incident adult RA patients. The age and sex-standardised 5-year incidence of THR and TKR was calculated separately for RA patients diagnosed in each six-months between 1995-2009. We took a natural experimental approach, using segmented linear regression to estimate changes in level and trend following the publication of NICE TA 36 in March 2002, incorporating a 1-year lag. Regression coefficients were used to calculate average change in rates, adjusted for prior level and trend.Results: We identified 17,505 incident RA patients of whom 465 and 650 underwent THR and TKR surgery, respectively. The modeled average incidence of THR and TKR over the biologic-era was 6.57/1,000 person years (PYs) and 8.51/1,000 PYs, respectively, with projected (had pre-NICE TA 36 level and trend continued uninterrupted) figures of 5.63/1,000 PYs and 12.92 PYs, respectively. NICE guidance was associated with a significant average decrease in TKR incidence of -4.41/1,000 PYs (95% C.I. -6.88 to -1.94), equating to a relative 34% reduction. Overall, no effect was seen on THR rates.Conclusions: Among incident RA patients in England and Wales, NICE guidance on TNFi therapies for RA management was temporally associated with reduced rates of TKR but not THR</p

Does pre-existing morbidity influences risks and benefits of total hip replacement for osteoarthritis: a prospective study of 6682 patients from linked national datasets in England.

Total hip arthroplasty (THA) surgery for elderly people with multimorbidity increases the risk of serious health hazards including mortality. Whether such background morbidity reduces the clinical benefit is less clear. OBJECTIVE: To evaluate how pre-existing health status, using multiple approaches, influences risks of, and quality of life benefits from, THA. SETTING: Longitudinal record linkage study of a UK sample linking their primary care to their secondary care records. PARTICIPANTS: A total of 6682 patients were included, based on the recording of the diagnosis of hip osteoarthritis in a national primary care register and the recording of the receipt of THA in a national secondary care register.Data were extracted from the primary care register on background health and morbidity status using five different constructs: Charlson Comorbidity Index, Electronic Frailty Index (eFI) and counts of comorbidity disorders (from list of 17), prescribed medications and number of primary care visits prior to recording of THA. OUTCOME MEASURES: (1) Postoperative complications and mortality; (2) postoperative hip pain and function using the Oxford Hip Score (OHS) and health-related quality of life using the EuroQoL (EQ)-5D score. RESULTS: Perioperative complication rate was 3.2% and mortality was 0.9%, both increased with worse preoperative health status although this relationship varied depending on the morbidity construct: the eFI showing the strongest relationship but number of visits having no predictive value. By contrast, the benefits were not reduced in those with worse preoperative health, and improvement in both OHS and EQ-5D was observed in all the morbidity categories. CONCLUSIONS: Independent of preoperative morbidity, THA leads to similar substantial improvements in quality of life. These are offset by an increase in medical complications in some subgroups of patients with high morbidity, depending on the definition used. For most elderly people, their other health disorders should not be a barrier for THA

Machina ex Deus? From Distributed to Orchestrated Agency

In this chapter, the author draws on a historical case study of the Australian wine industry to explore variations in collective agency. The inductively derived process model illustrates the emergence of a new profession of scientific win- emaking, which unfolds in three phases. Each phase is characterized by a dis- tinct form of agency: distributed agency during the earliest phase, coordinated agency during later phases, and orchestrated agency during consolidation. In addition to exploring the temporal shifts in agency, the study includes a detailed analysis of the early stages of distributed agency, examining how col- lective agency is achieved in the absence of shared intentions