Measuring the impact of monoclonal antibody therapies.

Objective: Monoclonal antibody (Mab) treatments have significantly improved the quality and quantity of life, but they are some of the most expensive treatments, resulting in a degree of hesitancy to introduce new Mab agents. A system for estimating the effect of Mab drugs, in general, would optimally inform health strategy and fully realize how a single scientific discovery can deliver health benefits. We evaluated such a method with several well-established Mab regimens. Methods: We selected five different Mab regimens in oncology and rheumatology in England. We carried out two systematic literature reviews and meta-analyses to assess health outcomes (Health Assessment Questionnaire-Disability Index for rheumatoid arthritis; overall mortality for melanoma) from real-world data and compared them to the outcomes from randomized control trials (RCTs). We applied economic modeling to estimate the net monetary benefits for health outcomes for the estimated patient population size for each Mab regimen. Results: Meta-analyses of 27 eligible real-world data (RWD) sets and 26 randomized controlled trial (RCT) sets found close agreement between the observed and expected health outcomes. A Markov model showed the net positive monetary benefit in three Mab regimens and the negative benefit in two regimens. However, because of limited access to NHS data, the economic model made several assumptions about the number of treated patients and the cost of treatment to the NHS, the accuracy of which may affect the estimation of the net monetary benefit. Conclusion: RCT results reliably inform the real-world experience of Mab treatments. Calculation of the net monetary benefit by the algorithm described provides a valuable overall measure of the health impact, subject to the accuracy of data inputs. This study provides a compelling case for building a comprehensive, systematized, and accessible database and related analytics, on all Mab treatments within health services.

Nonadherence to systemic immune-modifying therapy in people with psoriasis during the COVID-19 pandemic: findings from a global cross-sectional survey.

BACKGROUND: Nonadherence to immune-modifying therapy is a complex behaviour which, before the COVID-19 pandemic, was shown to be associated with mental health disorders in people with immune-mediated diseases. The COVID-19 pandemic has led to a rise in the global prevalence of anxiety and depression, and limited data exist on the association between mental health and nonadherence to immune-modifying therapy during the pandemic. OBJECTIVES: To assess the extent of and reasons underlying nonadherence to systemic immune-modifying therapy during the COVID-19 pandemic in individuals with psoriasis, and the association between mental health and nonadherence. METHODS: Online self-report surveys (PsoProtectMe), including validated screens for anxiety and depression, were completed globally during the first year of the pandemic. We assessed the association between anxiety or depression and nonadherence to systemic immune-modifying therapy using binomial logistic regression, adjusting for potential cofounders (age, sex, ethnicity, comorbidity) and country of residence. RESULTS: Of 3980 participants from 77 countries, 1611 (40.5%) were prescribed a systemic immune-modifying therapy. Of these, 408 (25.3%) reported nonadherence during the pandemic, most commonly due to concerns about their immunity. In the unadjusted model, a positive anxiety screen was associated with nonadherence to systemic immune-modifying therapy [odds ratio (OR) 1.37, 95% confidence interval (CI) 1.07-1.76]. Specifically, anxiety was associated with nonadherence to targeted therapy (OR 1.41, 95% CI 1.01-1.96) but not standard systemic therapy (OR 1.16, 95% CI 0.81-1.67). In the adjusted model, although the directions of the effects remained, anxiety was not significantly associated with nonadherence to overall systemic (OR 1.20, 95% CI 0.92-1.56) or targeted (OR 1.33, 95% CI 0.94-1.89) immune-modifying therapy. A positive depression screen was not strongly associated with nonadherence to systemic immune-modifying therapy in the unadjusted (OR 1.22, 95% CI 0.94-1.57) or adjusted models (OR 1.14, 95% CI 0.87-1.49). CONCLUSIONS: These data indicate substantial nonadherence to immune-modifying therapy in people with psoriasis during the pandemic, with attenuation of the association with mental health after adjusting for confounders. Future research in larger populations should further explore pandemic-specific drivers of treatment nonadherence. Clear communication of the reassuring findings from population-based research regarding immune-modifying therapy-associated adverse COVID-19 risks to people with psoriasis is essential, to optimize adherence and disease outcomes.

Evaluation of the Growth Assessment Protocol (GAP) for antenatal detection of small for gestational age: The DESiGN cluster randomised trial.

BACKGROUND: Antenatal detection and management of small for gestational age (SGA) is a strategy to reduce stillbirth. Large observational studies provide conflicting results on the effect of the Growth Assessment Protocol (GAP) in relation to detection of SGA and reduction of stillbirth; to the best of our knowledge, there are no reported randomised control trials. Our aim was to determine if GAP improves antenatal detection of SGA compared to standard care. METHODS AND FINDINGS: This was a pragmatic, superiority, 2-arm, parallel group, open, cluster randomised control trial. Maternity units in England were eligible to participate in the study, except if they had already implemented GAP. All women who gave birth in participating clusters (maternity units) during the year prior to randomisation and during the trial (November 2016 to February 2019) were included. Multiple pregnancies, fetal abnormalities or births before 24+1 weeks were excluded. Clusters were randomised to immediate implementation of GAP, an antenatal care package aimed at improving detection of SGA as a means to reduce the rate of stillbirth, or to standard care. Randomisation by random permutation was stratified by time of study inclusion and cluster size. Data were obtained from hospital electronic records for 12 months prerandomisation, the washout period (interval between randomisation and data collection of outcomes), and the outcome period (last 6 months of the study). The primary outcome was ultrasound detection of SGA (estimated fetal weight <10th centile using customised centiles (intervention) or Hadlock centiles (standard care)) confirmed at birth (birthweight <10th centile by both customised and population centiles). Secondary outcomes were maternal and neonatal outcomes, including induction of labour, gestational age at delivery, mode of birth, neonatal morbidity, and stillbirth/perinatal mortality. A 2-stage cluster-summary statistical approach calculated the absolute difference (intervention minus standard care arm) adjusted using the prerandomisation estimate, maternal age, ethnicity, parity, and randomisation strata. Intervention arm clusters that made no attempt to implement GAP were excluded in modified intention to treat (mITT) analysis; full ITT was also reported. Process evaluation assessed implementation fidelity, reach, dose, acceptability, and feasibility. Seven clusters were randomised to GAP and 6 to standard care. Following exclusions, there were 11,096 births exposed to the intervention (5 clusters) and 13,810 exposed to standard care (6 clusters) during the outcome period (mITT analysis). Age, height, and weight were broadly similar between arms, but there were fewer women: of white ethnicity (56.2% versus 62.7%), and in the least deprived quintile of the Index of Multiple Deprivation (7.5% versus 16.5%) in the intervention arm during the outcome period. Antenatal detection of SGA was 25.9% in the intervention and 27.7% in the standard care arm (adjusted difference 2.2%, 95% confidence interval (CI) -6.4% to 10.7%; p = 0.62). Findings were consistent in full ITT analysis. Fidelity and dose of GAP implementation were variable, while a high proportion (88.7%) of women were reached. Use of routinely collected data is both a strength (cost-efficient) and a limitation (occurrence of missing data); the modest number of clusters limits our ability to study small effect sizes. CONCLUSIONS: In this study, we observed no effect of GAP on antenatal detection of SGA compared to standard care. Given variable implementation observed, future studies should incorporate standardised implementation outcomes such as those reported here to determine generalisability of our findings. TRIAL REGISTRATION: This trial is registered with the ISRCTN registry, ISRCTN67698474.

Using electronic patient records to assess the effect of a complex antenatal intervention in a cluster randomised controlled trial-data management experience from the DESiGN Trial team.

BACKGROUND: The use of electronic patient records for assessing outcomes in clinical trials is a methodological strategy intended to drive faster and more cost-efficient acquisition of results. The aim of this manuscript was to outline the data collection and management considerations of a maternity and perinatal clinical trial using data from electronic patient records, exemplifying the DESiGN Trial as a case study. METHODS: The DESiGN Trial is a cluster randomised control trial assessing the effect of a complex intervention versus standard care for identifying small for gestational age foetuses. Data on maternal/perinatal characteristics and outcomes including infants admitted to neonatal care, parameters from foetal ultrasound and details of hospital activity for health-economic evaluation were collected at two time points from four types of electronic patient records held in 22 different electronic record systems at the 13 research clusters. Data were pseudonymised on site using a bespoke Microsoft Excel macro and securely transferred to the central data store. Data quality checks were undertaken. Rules for data harmonisation of the raw data were developed and a data dictionary produced, along with rules and assumptions for data linkage of the datasets. The dictionary included descriptions of the rationale and assumptions for data harmonisation and quality checks. RESULTS: Data were collected on 182,052 babies from 178,350 pregnancies in 165,397 unique women. Data availability and completeness varied across research sites; each of eight variables which were key to calculation of the primary outcome were completely missing in median 3 (range 1-4) clusters at the time of the first data download. This improved by the second data download following clarification of instructions to the research sites (each of the eight key variables were completely missing in median 1 (range 0-1) cluster at the second time point). Common data management challenges were harmonising a single variable from multiple sources and categorising free-text data, solutions were developed for this trial. CONCLUSIONS: Conduct of clinical trials which use electronic patient records for the assessment of outcomes can be time and cost-effective but still requires appropriate time and resources to maximise data quality. A difficulty for pregnancy and perinatal research in the UK is the wide variety of different systems used to collect patient data across maternity units. In this manuscript, we describe how we managed this and provide a detailed data dictionary covering the harmonisation of variable names and values that will be helpful for other researchers working with these data. TRIAL REGISTRATION: Primary registry and trial identifying number: ISRCTN 67698474 . Registered on 02/11/16.

Biopsychosocial factors associated with chronic low back pain disability in rural Nigeria: a population-based cross-sectional study.

INTRODUCTION: Many people in Nigeria are living with disability due to chronic low back pain (CLBP), with the greatest burden accounted for by people living in rural Nigeria. However, factors associated with disability in rural Nigeria have not yet been established. We investigated the biomechanical and psychosocial predictors of CLBP disability in a rural Nigerian population. METHODS: A cross-sectional study of adults with non-specific CLBP recruited from rural communities in Enugu State, South-eastern Nigeria. Measures of self-reported and performance-based disability, pain intensity, anxiety and depression, coping strategies, social support, occupational biomechanical factors, illness perceptions and fear avoidance beliefs were collected by trained community health workers. We used univariate and multivariate analyses. RESULTS: 200 individuals were recruited. Psychosocial factors were the most important factors associated with CLBP disability, and accounted for 62.5% and 49.1% of the variance in self-reported and performance-based disability, respectively. The significant predictors of self-reported disability were: illness perceptions (ß=0.289; p<0.0005), pain intensity (ß=0.230; p<0.0005), catastrophising (ß=0.210; p=0.001), fear avoidance beliefs (ß=0.198; p=0.001) and anxiety (ß=0.154; p=0.023). The significant predictors of performance-based disability were: illness perceptions (ß=0.366; p<0.0005), social support (ß=0.290; p<0.0005), fear avoidance beliefs (ß=0.189; p<0.01) and female gender (ß=0.184; p<0.01). Illness concern was the most salient dimension of illness perceptions predicting self-reported and performance-based disability. CONCLUSIONS: These results provide evidence which can be used to inform the development of interventions to reduce CLBP disability in rural Nigeria, and may have relevance in other rural African contexts.

Multicentre prospective survey of SeHCAT provision and practice in the UK.

OBJECTIVE: A clinical diagnosis of bile acid malabsorption (BAM) can be confirmed using SeHCAT (tauroselcholic ((75)selenium) acid), a radiolabelled synthetic bile acid. However, while BAM can be the cause of chronic diarrhoea, it is often overlooked as a potential diagnosis. Therefore, we investigated the use of SeHCAT for diagnosis of BAM in UK hospitals. DESIGN: A multicentre survey was conducted capturing centre and patient-level information detailing patient care-pathways, clinical history, SeHCAT results, treatment with bile acid sequestrants (BAS), and follow-up in clinics. Eligible data from 38 centres and 1036 patients were entered into a validated management system. RESULTS: SeHCAT protocol varied between centres, with no standardised patient positioning, and differing referral systems. Surveyed patients had a mean age of 50 years and predominantly women (65%). The mean SeHCAT retention score for all patients was 19% (95% CI 17.8% to 20.3%). However, this differed with suspected BAM type: type 1: 9% (95% CI 6.3% to 11.4%), type 2: 21% (95% CI 19.2% to 23.0%) and type 3: 22% (95% CI 19.6% to 24.2%). Centre-defined 'abnormal' and 'borderline' results represented over 50% of the survey population. BAS treatment was prescribed to only 73% of patients with abnormal results. CONCLUSIONS: The study identified a lack of consistent cut-off/threshold values, with differing centre criteria for defining an 'abnormal' SeHCAT result. BAS prescription was not related in a simple way to the SeHCAT result, nor to the centre-defined result, highlighting a lack of clear patient care-pathways. There is a clear need for a future diagnostic accuracy study and a better understanding of optimal management pathways.

Education, self-management, and upper extremity exercise training in people with rheumatoid arthritis: a randomized controlled trial.

OBJECTIVE: To evaluate the effectiveness of a brief supervised education, self-management, and global upper extremity exercise training program, supplementing a home exercise regimen, for people with rheumatoid arthritis (RA; the Education, Self-Management, and Upper Extremity Exercise Training in People with Rheumatoid Arthritis [EXTRA] program). METHODS: Adults with RA of ≤5 years' duration were randomized to receive either usual care or the EXTRA program comprising 4 (1-hour) group education, self-management, and global upper extremity exercise training sessions supplementing the first 2 weeks of a 12-week individualized, functional home exercise regimen in addition to usual care. Outcome measures were assessed at baseline, 12 weeks (primary end point), and 36 weeks and included the Disabilities of the Arm, Shoulder, and Hand questionnaire (primary outcome measure), the Grip Ability Test, handgrip strength (N), the Arthritis Self-Efficacy Scale (pain, function, and symptoms subscales), and the 28-joint Disease Activity Score. RESULTS: One hundred eight participants (26 men, mean ± SD age 55 ± 15 years, mean ± SD disease duration 20 ± 19 months) were randomized to receive either usual care (n = 56) or the EXTRA program (n = 52). At 12 weeks, there was a significant between-group difference in the mean change in disability (-6.8 [95% confidence interval (95% CI) -12.6, -1.0]; P = 0.022), function (-3.0 [95% CI -5.0, -0.5]; P = 0.011), nondominant handgrip strength (31.3N [95% CI 9.8, 52.8]; P = 0.009), self-efficacy (10.5 [95% CI 1.6, 19.5]; P = 0.021 for pain and 9.3 [95% CI 0.5, 18.2]; P = 0.039 for symptoms), and disease activity (-0.7 [95% CI -1.4, 0.0]; P = 0.047), all favoring the EXTRA program. CONCLUSION: The EXTRA program improves upper extremity disability, function, handgrip strength, and self-efficacy in people with RA, with no adverse effects on disease activity.

Variations in acute stroke care and the impact of organised care on survival from a European perspective: the European Registers of Stroke (EROS) investigators.

BACKGROUND: The need for stroke care is escalating with an ageing population, yet methods to estimate the delivery of effective care across countries are not standardised or robust. Associations between quality and intensity of care and stroke outcomes are often assumed but have not been clearly demonstrated. OBJECTIVE: To examine variations in acute care processes across six European populations and investigate associations between the delivery of care and survival. METHODS: Data were obtained from population-based stroke registers of six centres in France, Lithuania, UK, Spain, Poland and Italy between 2004 and 2006 with follow-up for 1 year. Variations in the delivery of care (stroke unit, multidisciplinary team and acute drug treatments) were analysed adjusting for case mix and sociodemographic factors using logistic regression methods. Unadjusted and adjusted survival probabilities were estimated and stratified by levels of Organised Care Index. RESULTS: Of 1918 patients with a first-ever stroke registered, 30.7% spent more than 50% of their hospital stay in a stroke unit (13.9-65.4%) among centres with a stroke unit available. The percentage of patients assessed by a stroke physician varied between 7.1% and 96.6%. There were significant variations after adjustment for confounders, in the organisation of care across populations. Significantly higher probabilities of survival (p<0.01) were associated with increased organisational care. CONCLUSIONS: This European study demonstrated associations between delivery of care and stroke outcomes. The implementation of evidence-based interventions is suboptimal and understanding better ways to implement these interventions in different healthcare settings should be a priority for health systems.

Predicting independent survival after stroke: a European study for the development and validation of standardised stroke scales and prediction models of outcome.

BACKGROUND: Accurate prediction of stroke outcome is desirable for clinical management and provision of appropriate care, and potentially for stratification of patients into studies. OBJECTIVES: To investigate the predictive properties of validated scales and severity measures, and their constituent variables, and to compare their prediction in six European populations. METHODS: We studied 2033 first-ever stroke patients in population-based stroke registers in France, Italy, Lithuania, the UK, Spain and Poland. Logistic models were used to predict independent survival at 3 and 12 months after stroke using a range of measures including the Six Simple Variable (SSV), Barthel index (BI) and the National Institute of Heath Stroke Scale (NIHSS). Predictions were compared within and between populations using receiver operating characteristic curves. A five-variable scale was developed and validated. RESULTS: Comparisons of BI with BI+age, and NIHSS with NIHSS+age, across populations showed that inclusion of age significantly improved prediction. Fairly equal predictions were obtained by three models: five variables, BI+age, and NIHSS+age. Better agreement between predicted and actual outcomes, and more precise estimates were obtained by the five variables model (age, verbal component of the Glasgow Coma Scale, arm power, ability to walk, and pre-stroke dependency). CONCLUSIONS: Living alone before the stroke was not significantly associated with independent survival after the stroke. Five variables (excluding living alone, from the SSV) provided good prediction for all populations and subgroups. Further external validation for our estimates is recommended before utilisation of the model in practice and research.

Mild traumatic brain injury in UK military personnel returning from Afghanistan and Iraq: cohort and cross-sectional analyses.

OBJECTIVES: : To assess (a) the prevalence of mild traumatic brain injury (mTBI) in UK military personnel deployed to Iraq and/or Afghanistan, (b) the risk factors associated with mTBI, and (c) the association between mTBI and subsequent postconcussion symptoms (PCS). PARTICIPANTS: : A total of 4620 personnel deployed to Iraq and/or Afghanistan who completed a questionnaire between 2007 and 2009, of whom 2333 were also studied in 2005, participated in the study. MAIN OUTCOME MEASURES: : Mild traumatic brain injury during deployment, as identified using a modified version of the Brief Traumatic Brain Injury Screen questionnaire; symptoms associated with PCS in the month before questionnaire completion. RESULTS: : The prevalence of mTBI was 4.4%, and the prevalence in those with a combat role was 9.5%. Having an mTBI was associated with current symptoms of posttraumatic stress disorder (adjusted odds ratio (AOR), 5.2; 95% confidence interval [CI], 2.3-11.4), alcohol misuse (AOR, 2.3; 95% CI, 1.4-3.7), and multiple physical symptoms (AOR, 2.6; 95% CI, 1.3-5.2). Only 3 of 9 symptoms remained associated with mTBI after adjustment. Psychological distress and alcohol misuse recorded before deployment were associated with subsequent mTBI. CONCLUSIONS: : The prevalence of mTBI in UK military is lower than that in the US military. Symptoms of current posttraumatic stress disorder and alcohol misuse are associated with mTBI. Symptoms of mental disorder predated occurrence of mTBI. The majority PCS were not associated with mTBI.

What are the consequences of deployment to Iraq and Afghanistan on the mental health of the UK armed forces? A cohort study.

BACKGROUND: Concerns have been raised about the psychological effect of continued combat exposure and of repeated deployments. We examined the consequences of deployment to Iraq and Afghanistan on the mental health of UK armed forces from 2003 to 2009, the effect of multiple deployments, and time since return from deployment. METHODS: We reassessed the prevalence of probable mental disorders in participants of our previous study (2003-05). We also studied two new randomly chosen samples: those with recent deployment to Afghanistan, and those who had joined the UK armed forces since April, 2003, to ensure that the final sample continued to be representative of the UK armed forces. Between November, 2007, and September, 2009, participants completed a questionnaire about their deployment experiences and health outcomes. FINDINGS: 9990 (56%) participants completed the study questionnaire (8278 regulars, 1712 reservists). The prevalence of probable post-traumatic stress disorder was 4.0% (95% CI 3.5-4.5; n=376), 19.7% (18.7-20.6; n=1908) for symptoms of common mental disorders, and 13.0% (12.2-13.8; n=1323) for alcohol misuse. Deployment to Iraq or Afghanistan was significantly associated with alcohol misuse for regulars (odds ratio 1.22, 95% CI 1.02-1.46) and with probable post-traumatic stress disorder for reservists (2.83, 1.23-6.51). Regular personnel in combat roles were more likely than were those in support roles to report probable post-traumatic stress disorder (1.87, 1.26-2.78). There was no association with number of deployments for any outcome. There was some evidence for a small increase in the reporting of probable post-traumatic stress disorder with time since return from deployment in regulars (1.13, 1.03-1.24). INTERPRETATION: Symptoms of common mental disorders and alcohol misuse remain the most frequently reported mental disorders in UK armed forces personnel, whereas the prevalence of probable post-traumatic stress disorder was low. These findings show the importance of continued health surveillance of UK military personnel. FUNDING: UK Ministry of Defence.