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Objective: This study was undertaken to determine reasons for adults with drug-resistant focal epilepsy who undergo presurgical evaluation not proceeding with surgery, and to identify predictors of this course. // Methods: We retrospectively analyzed data on 617 consecutive individuals evaluated for epilepsy surgery at a tertiary referral center between January 2015 and December 2019. We compared the characteristics of those in whom a decision not to proceed with surgical treatment was made with those who underwent definitive surgery in the same period. Multivariate logistic regression was performed to identify predictors of not proceeding with surgery. // Results: A decision not to proceed with surgery was reached in 315 (51%) of 617 individuals evaluated. Common reasons for this were an inability to localize the epileptogenic zone (n = 104) and the presence of multifocal epilepsy (n = 74). An individual choice not to proceed with intracranial electroencephalography (icEEG; n = 50) or surgery (n = 39), risk of significant deficit (n = 33), declining noninvasive investigation (n = 12), and coexisting neurological comorbidity (n = 3) accounted for the remainder. Compared to 166 surgically treated patients, those who did not proceed to surgery were more likely to have a learning disability (odds ratio [OR] = 2.35, 95% confidence interval [CI] = 1.07‒5.16), normal magnetic resonance imaging (OR = 4.48, 95% CI = 1.68–11.94), extratemporal epilepsy (OR = 2.93, 95% CI = 1.82‒4.71), bilateral seizure onset zones (OR = 3.05, 95% CI = 1.41‒6.61) and to live in more deprived socioeconomic areas (median deprivation decile = 40%–50% vs. 50%–60%, p < .05). // Significance: Approximately half of those evaluated for surgical treatment of drug-resistant focal epilepsy do not proceed to surgery. Early consideration and discussion of the likelihood of surgical suitability or need for icEEG may help direct referral for presurgical evaluation.

Objective: Resective surgery for selected individuals with frontal lobe epilepsy can be effective, although multimodal outcomes are less established than in temporal lobe epilepsy. We describe long-term seizure remission and relapse patterns, psychiatric comorbidity, and socioeconomic outcomes following frontal lobe epilepsy surgery. Methods: We reviewed individual data on frontal lobe epilepsy procedures at our center between 1990 and 2020. This included the presurgical evaluation, operative details and annual postoperative seizure and psychiatric outcomes, prospectively recorded in an epilepsy surgery database. Outcome predictors were subjected to multivariable analysis, and rates of seizure freedom were analyzed using Kaplan-Meier methods. We used longitudinal assessment of the Index of Multiple Deprivation to assess change in socioeconomic status over time. Results: A total of 122 individuals with a median follow-up of seven years were included. Of these, 33 (27 %) had complete seizure freedom following surgery, with a further 13 (11 %) having only auras. Focal MRI abnormality, histopathology (focal cortical dysplasia, cavernoma or dysembryoplastic neuronal epithelial tumor) and fewer anti-seizure medications at the time of surgery were predictive of a favorable outcome; 67 % of those seizure-free for the first 12 months after surgery never experienced a seizure relapse. Thirty-one of 50 who had preoperative psychiatric pathology noticed improved psychiatric symptomatology by two years postoperatively. New psychiatric comorbidity was diagnosed in 15 (13 %). Persistent motor complications occurred in 5 % and dysphasia in 2 %. No significant change in socioeconomic deciles of deprivation was observed after surgery. Significance: Favorable long-term seizure, psychiatric and socioeconomic outcomes can be seen following frontal lobe epilepsy surgery. This is a safe and effective treatment that should be offered to suitable individuals early.

There has been a significant rise in robotic trajectory guidance devices that have been utilised for stereotactic neurosurgical procedures. These devices have significant costs and associated learning curves. Previous studies reporting devices usage have not undertaken prospective parallel-group comparisons before their introduction, so the comparative differences are unknown. We study the difference in stereoelectroencephalography electrode implantation time between a robotic trajectory guidance device (iSYS1) and manual frameless implantation (PAD) in patients with drug-refractory focal epilepsy through a single-blinded randomised control parallel-group investigation of SEEG electrode implantation, concordant with CONSORT statement. Thirty-two patients (18 male) completed the trial. The iSYS1 returned significantly shorter median operative time for intracranial bolt insertion, 6.36 min (95% CI 5.72–7.07) versus 9.06 min (95% CI 8.16–10.06), p = 0.0001. The PAD group had a better median target point accuracy 1.58 mm (95% CI 1.38–1.82) versus 1.16 mm (95% CI 1.01–1.33), p = 0.004. The mean electrode implantation angle error was 2.13° for the iSYS1 group and 1.71° for the PAD groups (p = 0.023). There was no statistically significant difference for any other outcome. Health policy and hospital commissioners should consider these differences in the context of the opportunity cost of introducing robotic devices.Trial registration: ISRCTN17209025 (https://doi.org/10.1186/ISRCTN17209025).

OBJECTIVEThe accuracy of stereoelectroencephalography (SEEG) electrode implantation is an important factor in maximizing its safety. The authors established a quality assurance (QA) process to aid advances in implantation accuracy.METHODSThe accuracy of three consecutive modifications of a frameless implantation technique was quantified in three cohorts comprising 22, 8, and 23 consecutive patients. The modifications of the technique aimed to increase accuracy of the bolt placement.RESULTSThe lateral shift of the axis of the implanted bolt at the level of the planned entry point was reduced from a mean of 3.0 ± 1.6 mm to 1.4 ± 0.8 mm. The lateral shift of the axis of the implanted bolt at the level of the planned target point was reduced from a mean of 3.8 ± 2.5 mm to 1.6 ± 0.9 mm.CONCLUSIONSThis QA framework helped to isolate and quantify the factors introducing inaccuracy in SEEG implantation, and to monitor ongoing accuracy and the effect of technique modifications.

Introduction Laser interstitial thermal therapy (LITT) is a novel minimally invasive alternative to open mesial temporal resection in drug-resistant mesial temporal lobe epilepsy (MTLE). The safety and efficacy of the procedure are dependent on the pre-planned trajectory and the extent of the ablation achieved. Ablation of the mesial hippocampal head has been suggested to be an independent predictor of seizure freedom, whilst sparing of collateral structures is thought to result in improved neuropsychological outcomes. We aim to validate an automated trajectory planning platform against manually planned trajectories to objectively standardize the process. Methods Using the EpiNav™ platform we compare automated trajectory planning parameters derived from expert opinion and machine learning to undertake a multicentre validation study against manually planned and implemented trajectories in 95 patients with MTLE. We estimate ablation volumes of regions of interest and quantify the size of the avascular corridor through the use of a risk score as a marker of safety. We also undertake blinded external expert feasibility ratings and preference rankings between the trajectories. Results Automated trajectory planning employs a complex algorithm to optimize planning parameters in order to maximize ablation of the mesial hippocampal head and amygdala, whilst sparing the parahippocampal gyrus. Automated trajectories resulted in significantly lower risk scores and greater amygdala ablation percentage, whilst overall hippocampal ablation percentage did not differ significantly. Blinded external expert raters were significantly more likely to give preference to automated compared to manually planned trajectories. Conclusion Retrospective studies of automated trajectory planning show much promise in optimizing safety parameters and ablation volumes during LITT for MTLE. Multi-center validation provides evidence that the algorithm is robust and blinded external expert ratings indicate that the trajectories are clinically feasible. Prospective validation studies are now required to determine if automated trajectories result in improved seizure freedom rates and reduced neuropsychological deficits.

Objective To determine reasons for adult patients with drug-resistant focal epilepsy who undergo presurgical evaluation not proceeding with surgery and identify factors that influence this decision. Methods We analyzed demographic, imaging and electroclinical data on 617 consecutive patients brought to the Queen Square presurgical epilepsy MDT between January 2015 and December 2019. Multivariable logistic regression was performed to identify predictors of not proceeding with surgery, using comparative data from a prospectively-followed cohort of individuals who had epilepsy surgery at the same centre over an identical 5-year period. Results A definitive decision not to proceed with surgery was made in 315 (51%) cases. Common reasons behind this were an inability to localise the epileptogenic zone (n=104), multifocal epilepsy (n=74) and patients’ decisions not to proceed with intracranial EEG (n=50) or surgery (n=39). Learning disability (OR: 2.35; 95% CI 1.07-5.16), normal MRI (OR: 6.68; 95% CI 3.71-12.05), extratemporal epilepsy (OR: 2.93; 95% CI 1.82-4.71) and bilateral seizure onset zones (OR 3.05; 95% CI 1.41-6.61) were independent predictors of not having surgery. Probability of having surgery in those with normal MRI and extratemporal epilepsy was Conclusions Although underutilized, epilepsy surgery is only appropriate for selected individuals with drug-resistant focal epilepsy. A predictive model based on demographic, imaging and electroclinical data can help determine those unlikely to be suitable for surgery and aid the decision to refer for more extensive or invasive evaluation.

Background We aimed to estimate the clinical effectiveness of Community Occupational Therapy for people with dementia and family carers–UK version (Community Occupational Therapy in Dementia–UK version [COTiD-UK]) relative to treatment as usual (TAU). We hypothesised that COTiD-UK would improve the ability of people with dementia to perform activities of daily living (ADL), and family carers’ sense of competence, compared with TAU. Methods and findings The study design was a multicentre, 2-arm, parallel-group, assessor-masked, individually randomised controlled trial (RCT) with internal pilot. It was conducted in 15 sites across England from September 2014 to January 2018. People with a diagnosis of mild to moderate dementia living in their own home were recruited in pairs with a family carer who provided domestic or personal support for at least 4 hours per week. Pairs were randomised to either receive COTiD-UK, which comprised 10 hours of occupational therapy delivered over 10 weeks in the person with dementia’s home or TAU, which comprised the usual local service provision that may or may not include standard occupational therapy. The primary outcome was the Bristol Activities of Daily Living Scale (BADLS) score at 26 weeks. Secondary outcomes for the person with dementia included the following: the BADLS scores at 52 and 78 weeks, cognition, quality of life, and mood; and for the family carer: sense of competence and mood; plus the number of social contacts and leisure activities for both partners. Participants were analysed by treatment allocated. A total of 468 pairs were recruited: people with dementia ranged from 55 to 97 years with a mean age of 78.6 and family carers ranged from 29 to 94 with a mean of 69.1 years. Of the people with dementia, 74.8% were married and 19.2% lived alone. Of the family carers, 72.6% were spouses, and 22.2% were adult children. On randomisation, 249 pairs were assigned to COTiD-UK (62% people with dementia and 23% carers were male) and 219 to TAU (52% people with dementia and 32% carers were male). At the 26 weeks follow-up, data were available for 364 pairs (77.8%). The BADLS score at 26 weeks did not differ significantly between groups (adjusted mean difference estimate 0.35, 95% CI −0.81 to 1.51; p = 0.55). Secondary outcomes did not differ between the groups. In total, 91% of the activity-based goals set by the pairs taking part in the COTiD-UK intervention were fully or partially achieved by the final COTiD-UK session. Study limitations include the following: Intervention fidelity was moderate but varied across and within sites, and the reliance on primarily proxy data focused on measuring the level of functional or cognitive impairment which may not truly reflect the actual performance and views of the person living with dementia. Conclusions Providing community occupational therapy as delivered in this study did not improve ADL performance, cognition, quality of life, or mood in people with dementia nor sense of competence or mood in family carers. Future research should consider measuring person-centred outcomes that are more meaningful and closely aligned to participants’ priorities, such as goal achievement or the quantity and quality of activity engagement and participation. Trial Registration Current Controlled Trials ISRCTN10748953., Jennifer Wenborn and colleagues investigate the effectiveness of community occupational therapy program in improving activities of daily living, cognition, and mood for people with dementia., Author summary Why was this study done? Maintaining everyday and pleasurable activities can be difficult for a person with dementia, as well as their family carer who often feels increasingly stressed as they need to give more and more support. Occupational therapists assist people to improve their health and well-being through carrying on with the activities they need and want to do. It is therefore important to develop effective strategies to deliver occupational therapy to people with dementia and their family carers who support them. What did the researchers do and find? We tested the effectiveness of the Community Occupational Therapy in Dementia–UK version (COTiD-UK) programme compared to the care that people with mild to moderate dementia and their family carers usually receive, through a clinical trial. We recruited 468 pairs comprising a person with dementia and a family carer across England who were randomly allocated to either take part in the COTiD-UK programme or to continue with their usual care. We found no statistical evidence that COTiD-UK gave more benefit to people with dementia or their carers than the usual care provided in terms of the people with dementia being able to carry out activities or their mood or quality of life nor their family carers’ sense of competence or mood. The pairs who took part in the COTiD-UK intervention set an average of 4.09 goals each, of which 91% were fully or partially achieved by the final COTiD-UK session. What do these findings mean? We did not find evidence to support commissioning the COTiD-UK intervention for people with mild to moderate dementia and their family carers. Future studies need to develop more realistic methods of measuring the effectiveness of programmes such as this, particularly to focus on the outcomes that most matter to the individuals taking part and to truly reflect the actual performance, experience, and views of the person living with dementia.

To estimate the cost and time taken to evaluate adults with drug-resistant focal epilepsy for potentially curative surgery.We reviewed data on 100 consecutive individuals at a tertiary referral center evaluated for epilepsy surgery in 2017. The time elapsed between referral and either surgery or a definitive decision not to progress was measured. National Health Service tariffs applicable to our setting were used to estimate the total cost of evaluation for individuals following different routes through the pre-surgical pathway. After surgery, self-reported seizure freedom rates were obtained from each individual to assess the approximate cost of pre-surgical evaluation per additional person seizure-free.Of 100 individuals evaluated, 27 had surgery, 63 had a definitive decision not to have surgery, and ten were awaiting further investigations. The median duration of the pre-surgical evaluation was 29.7 months (IQR 18.6-44.1 months), with a median cost per person of £9138 (IQR £6984-£14,868). Those who proceeded to Stage Two investigations (including fluorodeoxyglucose positron emission tomography, ictal single-photon emission computerized tomography and intracranial electroencephalography) had a higher cost and extended evaluation length. After a median of 3.1 (IQR 2.3-3.7) years, 15/27 people who had surgery were seizure-free. This equated to an approximate cost of £123,500 spent per additional person seizure-free.Pre-surgical evaluation is long and costly, particularly for those who require icEEG. For those with drug-resistant focal epilepsy, surgery is, however, associated with a greater chance of seizure freedom. The suitability and risk-benefit ratio of surgery should be considered at each step of the pre-surgical pathway.

OBJECTIVEOne-third of cases of focal epilepsy are drug refractory, and surgery might provide a cure. Seizure-free outcome after surgery depends on the correct identification and resection of the epileptogenic zone. In patients with no visible abnormality on MRI, or in cases in which presurgical evaluation yields discordant data, invasive stereoelectroencephalography (SEEG) recordings might be necessary. SEEG is a procedure in which multiple electrodes are placed stereotactically in key targets within the brain to record interictal and ictal electrophysiological activity. Correlating this activity with seizure semiology enables identification of the seizure-onset zone and key structures within the ictal network. The main risk related to electrode placement is hemorrhage, which occurs in 1% of patients who undergo the procedure. Planning safe electrode placement for SEEG requires meticulous adherence to the following: 1) maximize the distance from cerebral vasculature, 2) avoid crossing sulcal pial boundaries (sulci), 3) maximize gray matter sampling, 4) minimize electrode length, 5) drill at an angle orthogonal to the skull, and 6) avoid critical neurological structures. The authors provide a validation of surgical strategizing and planning with EpiNav, a multimodal platform that enables automated computer-assisted planning (CAP) for electrode placement with user-defined regions of interest.METHODSThirteen consecutive patients who underwent implantation of a total 116 electrodes over a 15-month period were studied retrospectively. Models of the cortex, gray matter, and sulci were generated from patient-specific whole-brain parcellation, and vascular segmentation was performed on the basis of preoperative MR venography. Then, the multidisciplinary implantation strategy and precise trajectory planning were reconstructed using CAP and compared with the implemented manually determined plans. Paired results for safety metric comparisons were available for 104 electrodes. External validity of the suitability and safety of electrode entry points, trajectories, and target-point feasibility was sought from 5 independent, blinded experts from outside institutions.RESULTSCAP-generated electrode trajectories resulted in a statistically significant improvement in electrode length, drilling angle, gray matter–sampling ratio, minimum distance from segmented vasculature, and risk (p < 0.05). The blinded external raters had various opinions of trajectory feasibility that were not statistically significant, and they considered a mean of 69.4% of manually determined trajectories and 62.2% of CAP-generated trajectories feasible; 19.4% of the CAP-generated electrode-placement plans were deemed feasible when the manually determined plans were not, whereas 26.5% of the manually determined electrode-placement plans were rated feasible when CAP-determined plans were not (no significant difference).CONCLUSIONSCAP generates clinically feasible electrode-placement plans and results in statistically improved safety metrics. CAP is a useful tool for automating the placement of electrodes for SEEG; however, it requires the operating surgeon to review the results before implantation, because only 62% of electrode-placement plans were rated feasible, compared with 69% of the manually determined placement plans, mainly because of proximity of the electrodes to unsegmented vasculature. Improved vascular segmentation and sulcal modeling could lead to further improvements in the feasibility of CAP-generated trajectories.

OBJECTIVE To ascertain seizure outcomes in people with drug-resistant focal epilepsy considered for epilepsy surgery but who did not proceed. METHODS We identified people discussed at a weekly presurgical epilepsy multi-disciplinary (MDT) meeting from January 2015 to December 2019 and in whom a decision not to proceed to surgery was made. Seizure outcomes were obtained from individuals, primary care physicians and attending neurologists at a minimum of 12 months following the not to proceed decision. RESULTS We considered 315 people who did not proceed to surgery after evaluation. Nine died, and 25 were lost to follow-up. We included 281 people with a median follow-up of 2.4 (IQR 1.5-4) years. In total, 83 (30%) people reported that seizures had improved or resolved since the MDT meeting. Thirteen (5%) were seizure-free over the last 12 months of follow-up, 70 (25%) had experienced more than 50% reduction in seizure frequency, 180 (64%) had no meaningful change, and 18 (6%) reported a doubling of seizure frequency. Of the 53 (16%) who had vagal nerve stimulation, 19/53 (37%) reported more than 50% reduction in frequency, including one seizure-free. SIGNIFICANCE The chances of seizure freedom with further medications and neurostimulation are low for people with drug-resistant focal epilepsy who have been evaluated for surgery and do not proceed, but improvement may still occur. Up to a quarter have a > 50% reduction in seizures, and one in twenty become seizure-free eventually. Trying additional anti-seizure medication and neurostimulation is worthwhile in this population.

OBJECTIVEThe aim of this study was to implement cumulative summation (CUSUM) analysis as an early-warning detection and quality assurance system for preclinical testing of the iSYS1 novel robotic trajectory guidance system.METHODSAnatomically accurate 3D-printed skull phantoms were created for 3 patients who underwent implantation of 21 stereoelectroencephalography electrodes by surgeons using the current standard of care (frameless technique). Implantation schema were recreated using the iSYS1 system, and paired accuracy measures were compared with the previous frameless implantations. Entry point, target point, and implantation angle accuracy were measured on postimplantation CT scans. CUSUM analysis was undertaken prospectively.RESULTSThe iSYS1 trajectory guidance system significantly improved electrode entry point accuracies from 1.90 ± 0.96 mm (mean ± SD) to 0.76 ± 0.57 mm (mean ± SD) without increasing implantation risk. CUSUM analysis was successful as a continuous measure of surgical performance and acted as an early-warning detection system. The surgical learning curve, although minimal, showed improvement after insertion of the eighth electrode.CONCLUSIONSThe iSYS1 trajectory guidance system did not show any increased risk during phantom preclinical testing when used by neurosurgeons who had no experience with its use. CUSUM analysis is a simple technique that can be applied to all stages of the IDEAL (idea, development, exploration, assessment) framework as an extra patient safety mechanism. Further clinical trials are required to prove the efficacy of the device.

Highlights • Automatic computation of SEEG accuracy metrics agree with those done manually. • The choice of image to generate a scalp model has an effect on entry point metrics. • Metrics have the lowest mean and variability when using an electrode bolt axis. • Lateral shift deviation should include a measure of insertion depth error., Background Implantation accuracy of electrodes during neurosurgical interventions is necessary to ensure safety and efficacy. Typically, metrics are computed by visual inspection which is tedious, prone to inter-/intra-observer variation, and difficult to replicate across sites. New Method We propose an automated approach for computing implantation metrics and investigate potential sources of error. We focus on accuracy metrics commonly reported in the literature to validate our approach against metrics computed manually including entry point (EP) and target point (TP) localisation errors and angle differences between planned and implanted trajectories in 15 patients with a total of 158 stereoelectroencephalography (SEEG) electrodes. We evaluate the effect of line-of-best-fit approaches, EP definition and lateral versus Euclidean distance on metrics to provide recommendations for reporting implantation accuracy metrics. Results We found no bias between manual and automated approaches for calculating accuracy metrics with limits of agreement of ±1 mm and ±1°. Automated metrics are robust to sources of errors including registration and electrode bending. We observe the highest error in EP deviations of μ = 0.25 mm when the post-implantation CT is used to define the point of entry. Comparison with Existing Method(s) We found no reports of automated approaches for quality assessment of SEEG electrode implantation. Neither the choice of metrics nor the possible errors that could occur have been investigated previously. Conclusions Our automated approach is useful to avoid human errors, unintentional bias and variation that may be introduced when manually computing metrics. Our work is relevant and timely to facilitate comparisons of studies reporting implantation accuracy.

Background Older people are vulnerable to sustained high levels of psychosocial distress following a crime. A cognitive behavioural therapy (CBT)-informed psychological therapy, the Victim Improvement Package (VIP) may aid recovery. The VIP trial aims to test the clinical and cost-effectiveness of the VIP for alleviating depressive and anxiety symptoms in older victims of crime. Methods/design People aged 65 years or more who report being a victim of crime will be screened by Metropolitan Police Service Safer Neighbourhood Teams within a month of the crime for distress using the Patient Health Questionnaire-2 and the Generalised Anxiety Disorder-2. Those who screen positive will be signposted to their GP for assistance, and re-screened at 3 months. Participants who screen positive for depression and/or anxiety at re-screening are randomised to a CBT informed VIP added to treatment as usual (TAU) compared to TAU alone. The intervention consists of 10 individual 1-h sessions, delivered weekly by therapists from the mental health charity Mind. The primary outcome measure is the Beck Depression Inventory-II (BDI-II) and the Beck Anxiety Inventory (BAI), used as a composite measure, assessed at 6 months after the crime (post therapy) with a 9-month post-crime follow-up. Secondary outcome measures include the EQ-5D, and a modified Client Service Receipt Inventory. A total of 226 participants will be randomised VIP:TAU with a ratio 1:1, in order to detect a standardised difference of at least 0.5 between groups, using a mixed-effects linear-regression model with 90% power and a 5% significance level (adjusting for therapist clustering and potential drop-out). A cost-effectiveness analysis will incorporate intervention costs to compare overall health care costs and quality of life years between treatment arms. An embedded study will examine the impact of past trauma and engagement in safety behaviours and distress on the main outcomes. Discussion This trial should provide data on the clinical and cost-effectiveness of a CBT-informed psychological therapy for older victims of crime with anxiety and/or depressive symptoms and should demonstrate a model of integrated cross-agency working. Our findings should provide evidence for policy-makers, commissioners and clinicians responding to the needs of older victims of crime. Trial registration International Standard Randomised Controlled Trials Number, ID: ISRCTN16929670. Registered on 3 August 2016.

Stereoelectroencephalography (SEEG) is a diagnostic procedure in which multiple electrodes are stereotactically implanted within predefined areas of the brain to identify the seizure onset zone, which needs to be removed to achieve remission of focal epilepsy. Computer-assisted planning (CAP) has been shown to improve trajectory safety metrics and generate clinically feasible trajectories in a fraction of the time needed for manual planning. We report a prospective validation study of the use of EpiNav (UCL, London, UK) as a clinical decision support software for SEEG. Thirteen consecutive patients (125 electrodes) undergoing SEEG were prospectively recruited. EpiNav was used to generate 3D models of critical structures (including vasculature) and other important regions of interest. Manual planning utilizing the same 3D models was performed in advance of CAP. CAP was subsequently employed to automatically generate a plan for each patient. The treating neurosurgeon was able to modify CAP generated plans based on their preference. The plan with the lowest risk score metric was stereotactically implanted. In all cases (13/13), the final CAP generated plan returned a lower mean risk score and was stereotactically implanted. No complication or adverse event occurred. CAP trajectories were generated in 30% of the time with significantly lower risk scores compared to manually generated. EpiNav has successfully been integrated as a clinical decision support software (CDSS) into the clinical pathway for SEEG implantations at our institution. To our knowledge, this is the first prospective study of a complex CDSS in stereotactic neurosurgery and provides the highest level of evidence to date. Electronic supplementary material The online version of this article (10.1007/s13311-019-00774-9) contains supplementary material, which is available to authorized users.

BackgroundThe START (STrAtegies for RelaTives) intervention reduced depressive and anxiety symptoms of family carers of relatives with dementia at home over 2 years and was cost-effective.AimsTo assess the clinical effectiveness over 6 years and the impact on costs and care home admission.MethodWe conducted a randomised, parallel group, superiority trial recruiting from 4 November 2009 to 8 June 2011 with 6-year follow-up (trial registration: ISCTRN 70017938). A total of 260 self-identified family carers of people with dementia were randomised 2:1 to START, an eight-session manual-based coping intervention delivered by supervised psychology graduates, or to treatment as usual (TAU). The primary outcome was affective symptoms (Hospital Anxiety and Depression Scale, total score (HADS-T)). Secondary outcomes included patient and carer service costs and care home admission.ResultsIn total, 222 (85.4%) of 173 carers randomised to START and 87 to TAU were included in the 6-year clinical efficacy analysis. Over 72 months, compared with TAU, the intervention group had improved scores on HADS-T (adjusted mean difference −2.00 points, 95% CI −3.38 to −0.63). Patient-related costs (START versus TAU, respectively: median £5759 v. £16 964 in the final year; P = 0.07) and carer-related costs (median £377 v. £274 in the final year) were not significantly different between groups nor were group differences in time until care home (intensity ratio START:TAU was 0.88, 95% CI 0.58–1.35).ConclusionsSTART is clinically effective and this effect lasts for 6 years without increasing costs. This is the first intervention with such a long-term clinical and possible economic benefit and has potential to make a difference to individual carers.Declarations of interestG.L., Z.W. and C.C. are supported by the UCLH National Institute for Health Research (NIHR) Biomedical Research Centre. G.L. and P.R. were in part supported by the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) North Thames at Bart's Health NHS Trust. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Z.W. reports during the conduct of the study; personal fees from GE Healthcare, grants from GE Healthcare, grants from Lundbeck, other from GE Healthcare, outside the submitted work.

In many studies, interest lies in determining whether members of the study population will undergo a particular event of interest. Such scenarios are often termed 'mover-stayer' scenarios, and interest lies in modelling two sub-populations of 'movers' (those who have a propensity to undergo the event of interest) and 'stayers' (those who do not). In general, mover-stayer scenarios within data sets are accounted for through the use of mixture distributions, and in this paper, we investigate the use of various random effects distributions for this purpose. Using data from the University of Toronto psoriatic arthritis clinic, we present a multi-state model to describe the progression of clinical damage in hand joints of patients with psoriatic arthritis. We consider the use of mover-stayer gamma, inverse Gaussian and compound Poisson distributions to account for both the correlation amongst joint locations and the possible mover-stayer situation with regard to clinical hand joint damage. We compare the fits obtained from these models and discuss the extent to which a mover-stayer scenario exists in these data. Furthermore, we fit a mover-stayer model that allows a dependence of the probability of a patient being a stayer on a patient-level explanatory variable.

Summary Bidirectional changes over time in the estimated glomerular filtration rate and in urine protein content are of interest for the treatment and management of patients with lupus nephritis. Although these processes may be modelled by separate multistate models, the processes are likely to be correlated within patients. Motivated by the lupus nephritis application, we develop a new multistate modelling framework where subject-specific random effects are introduced to account for the correlations both between the processes and within patients over time. Models are fitted by using bespoke code in standard statistical software. A variety of forms for the random effects are introduced and evaluated by using the data from the Systemic Lupus International Collaborating Clinics.

OBJECTIVE: To determine nephritis outcomes in a prospective multi-ethnic/racial SLE inception cohort.METHODS: Patients in the Systemic Lupus International Collaborating Clinics inception cohort (≤15 months of SLE diagnosis) were assessed annually for estimated glomerular filtration rate (eGFR), proteinuria and end-stage renal disease (ESRD). Health-related quality of life was measured by the Short Form (36 questions) health survey questionnaire (SF-36) subscales, mental and physical component summary scores.RESULTS: There were 1827 patients, 89% females, mean (s.d.) age 35.1 (13.3) years. The mean (s.d.) SLE duration at enrolment was 0.5 (0.3) years and follow-up 4.6 (3.4) years. LN occurred in 700 (38.3%) patients: 566/700 (80.9%) at enrolment and 134/700 (19.1%) during follow-up. Patients with nephritis were younger, more frequently men and of African, Asian and Hispanic race/ethnicity. The estimated overall 10-year incidence of ESRD was 4.3% (95% CI: 2.8%, 5.8%), and with nephritis was 10.1% (95% CI: 6.6%, 13.6%). Patients with nephritis had a higher risk of death (HR = 2.98, 95% CI: 1.48, 5.99; P = 0.002) and those with eGFR CONCLUSION: LN occurred in 38.3% of SLE patients, frequently as the initial presentation, in a large multi-ethnic inception cohort. Despite current standard of care, nephritis was associated with ESRD and death, and renal insufficiency was linked to lower health-related quality of life. Further advances are required for the optimal treatment of LN.

Summary Objective Surgical resection of the mesial temporal structures brings seizure remission in 65% of individuals with drug‐resistant mesial temporal lobe epilepsy (MTLE). Laser interstitial thermal therapy (LiTT) is a novel therapy that may provide a minimally invasive means of ablating the mesial temporal structures with similar outcomes, while minimizing damage to the neocortex. Systematic trajectory planning helps ensure safety and optimal seizure freedom through adequate ablation of the amygdalohippocampal complex (AHC). Previous studies have highlighted the relationship between the residual unablated mesial hippocampal head and failure to achieve seizure freedom. We aim to implement computer‐assisted planning (CAP) to improve the ablation volume and safety of LiTT trajectories. Methods Twenty‐five patients who had previously undergone LiTT for MTLE were studied retrospectively. The EpiNav platform was used to automatically generate an optimal ablation trajectory, which was compared with the previous manually planned and implemented trajectory. Expected ablation volumes and safety profiles of each trajectory were modeled. The implemented laser trajectory and achieved ablation of mesial temporal lobe structures were quantified and correlated with seizure outcome. Results CAP automatically generated feasible trajectories with reduced overall risk metrics (P < .001) and intracerebral length (P = .007). There was a significant correlation between the actual and retrospective CAP‐anticipated ablation volumes, supporting a 15 mm diameter ablation zone model (P < .001). CAP trajectories would have provided significantly greater ablation of the amygdala (P = .0004) and AHC (P = .008), resulting in less residual unablated mesial hippocampal head (P = .001), and reduced ablation of the parahippocampal gyrus (P = .02). Significance Compared to manually planned trajectories CAP provides a better safety profile, with potentially improved seizure‐free outcome and reduced neuropsychological deficits, following LiTT for MTLE.

Background: People with Parkinson's disease (PD) who develop visuo‐perceptual deficits are at higher risk of dementia, but we lack tests that detect subtle visuo‐perceptual deficits and can be performed by untrained personnel. Hallucinations are associated with cognitive impairment and typically involve perception of complex objects. Changes in object perception may therefore be a sensitive marker of visuo‐perceptual deficits in PD. Objective: We developed an online platform to test visuo‐perceptual function. We hypothesised that (1) visuo‐perceptual deficits in PD could be detected using online tests, (2) object perception would be preferentially affected, and (3) these deficits would be caused by changes in perception rather than response bias. Methods: We assessed 91 people with PD and 275 controls. Performance was compared using classical frequentist statistics. We then fitted a hierarchical Bayesian signal detection theory model to a subset of tasks. Results: People with PD were worse than controls at object recognition, showing no deficits in other visuo‐perceptual tests. Specifically, they were worse at identifying skewed images (P

ObjectiveTo calculate the chance of a seizure in the next year (COSY) for seizures with impaired awareness in those experiencing auras only, those with no seizures and those with continuing seizures. Epilepsy surgery is an effective treatment for refractory focal epilepsy. Driving is an important factor affecting quality of life. In the UK, driving is not permitted if focal seizures with no impairment of awareness (auras, simple partial seizures) continue, if there is a prior history of seizures with impaired awareness, as will invariably be the case in those having epilepsy surgery. Current UK driving regulations allow driving if COSY is less than 20%.MethodWe calculated COSY in 819 epilepsy surgery patients with up to 25 years follow-up. Each patient year was graded on the The International League against Epilepsy surgery outcome scale.ResultsPatients who were entirely seizure-free for 1, 2 and 3 years had COSY of 4.9%, 3.5% and 2.4% respectively. Patients with only auras within the last 1, 2 or 3 years had a COSY of 11.3%, 9.2% and 7.8% respectively.ConclusionsIndividuals with auras only after epilepsy surgery had a higher COSY than those who were seizure-free. If a COSY of below 20% is regarded as an acceptable risk, it may be suggested that those with auras only in a given year be allowed to drive. The relative risk of these patients causing accidents is lower than population groups such as those aged 75 years, who are permitted to drive.

SummaryObjective Stereoelectroencephalography (SEEG) is a procedure in which electrodes are inserted into the brain to help define the epileptogenic zone. This is performed prior to definitive epilepsy surgery in patients with drug-resistant focal epilepsy when noninvasive data are inconclusive. The main risk of the procedure is hemorrhage, which occurs in 1–2% of patients. This may result from inaccurate electrode placement or a planned electrode damaging a blood vessel that was not detected on the preoperative vascular imaging. Proposed techniques include the use of a stereotactic frame, frameless image guidance systems, robotic guidance systems, and customized patient-specific fixtures. Methods Using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, a structured search of the PubMed, Embase, and Cochrane databases identified studies that involve the following: (1) SEEG placement as part of the presurgical workup in patients with (2) drug-resistant focal epilepsy for which (3) accuracy data have been provided. Results Three hundred twenty-six publications were retrieved, of which 293 were screened following removal of duplicate and non–English-language studies. Following application of the inclusion and exclusion criteria, 15 studies were included in the qualitative and quantitative synthesis of the meta-analysis. Accuracies for SEEG electrode implantations have been combined using a random-effects analysis and stratified by technique. Significance The published literature regarding accuracy of SEEG implantation techniques is limited. There are no prospective controlled clinical trials comparing different SEEG implantation techniques. Significant systematic heterogeneity exists between the identified studies, preventing any meaningful comparison between techniques. The recent introduction of robotic trajectory guidance systems has been suggested to provide a more accurate method of implantation, but supporting evidence is limited to class 3 only. It is important that new techniques are compared to the previous “gold-standard” through well-designed and methodologically sound studies before they are introduced into widespread clinical practice.

ObjectiveTo examine the frequency and characteristics of headaches and their association with global disease activity and health-related quality of life (HRQOL) in patients with systemic lupus erythematosus (SLE). MethodsA disease inception cohort was assessed annually for headache (5 types) and 18 other neuropsychiatric (NP) events. Global disease activity scores (SLE Disease Activity Index 2000 [SLEDAI-2K]), damage scores (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index [SDI]), and Short Form 36 (SF-36) mental and physical component summary scores were collected. Time to first headache and associations with SF-36 scores were analyzed using Cox proportional hazards and linear regression models with generalized estimating equations. ResultsAmong the 1,732 SLE patients enrolled, 89.3% were female and 48.3% were white. The mean SD age was 34.6 +/- 13.4 years, duration of disease was 5.6 +/- 5.2 months, and length of followup was 3.8 +/- 3.1 years. At enrollment, 17.8% of patients had headache (migraine [60.7%], tension [38.6%], intractable nonspecific [7.1%], cluster [2.6%], and intracranial hypertension [1.0%]). The prevalence of headache increased to 58% after 10 years. Only 1.5% of patients had lupus headache, as identified in the SLEDAI-2K. In addition, headache was associated with other NP events attributed to either SLE or non-SLE causes. There was no association of headache with SLEDAI-2K scores (without the lupus headache variable), SDI scores, use of corticosteroids, use of antimalarials, use of immunosuppressive medications, or specific autoantibodies. SF-36 mental component scores were lower in patients with headache compared with those without headache (mean +/- SD 42.5 +/- 12.2 versus 47.8 +/- 11.3; P < 0.001), and similar differences in physical component scores were seen (38.0 +/- 11.0 in those with headache versus 42.6 +/- 11.4 in those without headache; P < 0.001). In 56.1% of patients, the headaches resolved over followup. ConclusionHeadache is frequent in SLE, but overall, it is not associated with global disease activity or specific autoantibodies. Although headaches are associated with a lower HRQOL, the majority of headaches resolve over time, independent of lupus-specific therapies. (Less)

Imbalance of gamma aminobutyric acid (GABA) and related modulators has been implicated as an important factor in the pathogenesis of amyotrophic lateral sclerosis (ALS), which is also known as motor neuron disease (MND). In this context, the role and mechanism of action of gabapentin and baclofen have been extensively investigated, although with conflicting results. This is the first systematic review to assess clinical trials of GABA modulators for the treatment of ALS.To examine the efficacy of gabapentin, baclofen, or other GABA modulators in delaying the progression of ALS, and to evaluate adverse effects of these interventionsOn 16 August 2016, we searched the Cochrane Neuromuscular Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL Plus, AMED, and LILACS. In addition, we checked the bibliographies of the trials found in order to identify any other trials, and contacted trial authors to identify relevant unpublished results or additional clinical trials. On 30 August 2016, we searched two clinical trials registries.Types of studies: double-blind randomized controlled trials (RCTs) or quasi-RCTsTypes of participants: adults with a diagnosis of probable or definite ALSTypes of interventions: gabapentin, baclofen, or other GABA modulators compared with placebo, no treatment, or each otherPrimary outcome: survival at one year from study enrollmentSecondary outcomes: individual rate of decline of maximum voluntary isometric contraction (MVIC), expressed as arm megascore; rate of decline of per cent predicted forced vital capacity (FVC); rate of decline of ALS Functional Rating Scale (ALSFRS); health-related quality of life; survival evaluated by pooling hazards; and adverse events DATA COLLECTION AND ANALYSIS: At least two review authors independently checked titles and abstracts identified by the searches. The review authors obtained and independently analyzed original individual participant data from each included study; additional review authors and the Cochrane Neuromuscular Managing Editor checked the outcome data. Two authors independently assessed the risk of bias in included studies.At least two review authors independently checked titles and abstracts identified by the searches. The review authors obtained and independently analyzed original individual participant data from each included study; additional review authors and the Cochrane Neuromuscular Managing Editor checked the outcome data. Two authors independently assessed the risk of bias in included studies.We identified two double-blind RCTs of gabapentin treatment in ALS for inclusion in this review. We found no eligible RCTs of baclofen or other GABA modulators. The selected studies were phase II and phase III trials, which lasted six and nine months, respectively. They were highly comparable because both were comparisons of oral gabapentin and placebo, performed by the same investigators. The trials enrolled 355 participants with ALS: 80 in the gabapentin group and 72 in the placebo group in the first (phase II) trial and 101 in the gabapentin group and 102 in the placebo group in the second (phase III) trial. Neither trial was long enough to report survival at one year, which was our primary outcome. We found little or no difference in estimated one-year survival between the treated group and the placebo group (78% versus 77%, P = 0.63 by log-rank test; high-quality evidence). We also found little or no difference in the rate of decline of MVIC expressed as arm megascore, or rate of FVC decline (high-quality evidence). One trial investigated monthly decline in the ALSFRS and quality of life measured using the 12-Item Short Form Survey (SF-12) and found little or no difference between groups (moderate-quality evidence). The trials reported similar adverse events. Complaints that were clearly elevated in those taking gabapentin, based on analyses of the combined data, were light-headedness, drowsiness, and limb swelling (high-quality evidence). Fatigue and falls occurred more frequently with gabapentin than with placebo in one trial, but when we combined the data for fatigue from both trials, there was no clear difference between the groups. We assessed the overall risk of bias in the included trials as low.According to high-quality evidence, gabapentin is not effective in treating ALS. It does not extend survival, slow the rate of decline of muscle strength, respiratory function and, based on moderate-quality evidence, probably does not improve quality of life or slow monthly decline in the ALSFRS. Other GABA modulators have not been studied in randomized trials.

Background Statins are widely prescribed for the primary prevention of cardiovascular disease. Guidelines exist for statin prescriptions, but there is little recent analysis concerning prescription trends over time and how these vary with respect to demographic variables. Methods and results Using The Health Improvement Network primary care database, statin therapy initiation and statin prescription prevalence rates were calculated using data from 7,027,711 individuals across the UK for the years 1995 to 2013, overall and stratified by sex, age group, and socioeconomic deprivation level (Townsend score). Statin therapy initiation rates rose sharply from 1995 (0.51 per 1,000 person-years) up to 2006 (19.83 per 1,000 person-years) and thereafter declined (10.76 per 1,000 person-years in 2013). Males had higher initiation rates than females and individuals aged 60–85 years had higher initiation rates than younger or more elderly age groups. Initiation rates were slightly higher as social deprivation level increased, after accounting for age and sex. Prescription prevalence increased sharply from 1995 (2.36 per 1,000 person-years) to 2013 (128.03 per 1,000 person-years) with males generally having a higher prevalence rate, over time, than females. Prevalence rates over time were generally higher for older age groups but were similar with respect to social deprivation level. Conclusion The uptake of statins within UK primary care has increased greatly over time with statins being more commonly prescribed to older patients in general and, in recent years, males appear to have been prescribed statins at higher rates than females. After accounting for age and sex, the statin therapy initiation rate increases with the level of social deprivation.

Summary In psoriatic arthritis, permanent joint damage characterizes disease progression and represents a major debilitating aspect of the disease. Understanding the process of joint damage will assist in the treatment and disease management of patients. Multistate models provide a means to examine patterns of disease, such as symmetric joint damage. Additionally, the link between damage and the dynamic course of disease activity (represented by joint swelling and stress pain) at both the individual joint level and otherwise can be represented within a correlated multistate model framework. Correlation is reflected through the use of random effects for progressive models and robust variance estimation for non-progressive models. Such analyses, undertaken with data from a large psoriatic arthritis cohort, are discussed and the extent to which they permit causal reasoning is considered. For this, emphasis is given to the use of the Bradford Hill criteria for causation in observational studies and the concept of local (in)dependence to capture the dynamic nature of the relationships.

ObjectivesOne third of patients with focal epilepsy fail to achieve seizure freedom despite best medical therapy. Surgery may provide seizure freedom if the epileptogenic zone can be safely remove. We compare the outcomes following open surgery, laser interstitial thermal therapy (LITT), radiofrequency ablation (RFA) and radiosurgery (RS).DesignPRISMA systematic review and meta-analysis.SubjectsMTLEMethodsStructured searchs of PubMed, Embase and Cochrane databases. Random effects meta-analysis to calculate effects sizes and a pooled estimate of the probability of remaining seizure free at one year following intervention.ResultsFrom 1212 screened publications, 57 articles were included in the quantitative analysis. Open surgery included anterior temporal lobectomy as well as transcortical, subtemporal and transsylvian selective amygdalohippocampectomy. The probability of remaining seizure free at one year was 0.89 (95% CI 0.83–0.93) with open surgery based on Level 1 and 2 evidence. RS resulted in 0.88 (95% CI 0.84–0.90) probability and a single RCT revealed RS was less efficacious than open surgery. Follow up duration and study sizes were limited with LITT and RFA providing a probability of remaining seizure free at one year of 0.71 (95% CI 0.65–0.76) and 0.86 (95% CI 0.76–0.92) respectively.ConclusionsThere is no evidence supporting novel ‘minimally invasive’ approaches as being as efficacious as open surgery. Secondary outcome measures such as neuropsychological outcome and intervention morbidity are poorly reported.

IntroductionRoux-en-Y gastric bypass and sleeve gastrectomy are the two most common bariatric surgery performed in the UK that result in comparable weight loss and remission of obesity-associated comorbidities. However, there is a paucity of studies examining the impact of these procedures on body composition, physical activity levels, sedentary behaviour, physical function and strength, dietary intake, health-related quality of life and costs.Methods and analysisThe BARI-LIFESTYLE observational study is a 1-year prospective, longitudinal cohort study within a real-world routine clinical care setting aiming to recruit 100 patients with severe obesity undergoing either primary Roux-en-Y gastric bypass or sleeve gastrectomy from two bariatric centres in London, UK. Participants will be followed up four times during the study period; presurgery baseline (T0) and at 3 (T1), 6 (T2) and 12 months (T3) postsurgery. In addition to the standard follow-up investigations, assessments including dual-energy X-ray absorptiometry scan, bioelectric impedance analysis, 6 min walk test, sit-to-stand test and handgrip test will be undertaken together with completion of questionnaires. Physical activity levels and sedentary behaviour will be assessed using accelerometer, and dietary intake will be recorded using a 3-day food diary. Outcome measures will include body weight, body fat mass, lean muscle mass, bone mineral density, physical activity levels, sedentary behaviour, physical function and strength, dietary intake, health-related quality of life, remission of comorbidities, healthcare resource utilisation and costs.Ethics and disseminationThis study has been reviewed and given a favourable ethical opinion by London-Dulwich Research Ethics Committee (17/LO/0950). The results will be presented to stakeholder groups locally, nationally and internationally and published in peer-reviewed medical journals. The lay-person summary of the findings will be published on the Centre for Obesity Research, University College London website (http://www.ucl.ac.uk/obesity).

The Regression Discontinuity (RD) design is a quasi-experimental design which emulates a randomised study by exploiting situations where treatment is assigned according to a continuous variable as is common in many drug treatment guidelines. The RD design literature focuses principally on continuous outcomes. In this paper we exploit the link between the RD design and instrumental variables to obtain a causal effect estimator, the risk ratio for the treated (RRT), for the RD design when the outcome is binary. Occasionally the RRT estimator can give negative lower confindence bounds. In the Bayesian framework we impose prior constraints that prevent this from happening. This is novel and cannot be easily reproduced in a frequentist framework. We compare our estimators to those based on estimating equation and generalized methods of moments methods. Based on extensive simulations our methods compare favourably with both methods. We apply our method on a real example to estimate the effect of statins on the probability of Low-density Lipoprotein (LDL) cholesterol levels reaching recommended levels., Comment: 29 pages, 4 figures

In longitudinal randomised trials and observational studies within a medical context, a composite outcome-which is a function of several individual patient-specific outcomes-may be felt to best represent the outcome of interest. As in other contexts, missing data on patient outcome, due to patient drop-out or for other reasons, may pose a problem. Multiple imputation is a widely used method for handling missing data, but its use for composite outcomes has been seldom discussed. Whilst standard multiple imputation methodology can be used directly for the composite outcome, the distribution of a composite outcome may be of a complicated form and perhaps not amenable to statistical modelling. We compare direct multiple imputation of a composite outcome with separate imputation of the components of a composite outcome. We consider two imputation approaches. One approach involves modelling each component of a composite outcome using standard likelihood-based models. The other approach is to use linear increments methods. A linear increments approach can provide an appealing alternative as assumptions concerning both the missingness structure within the data and the imputation models are different from the standard likelihood-based approach. We compare both approaches using simulation studies and data from a randomised trial on early rheumatoid arthritis patients. Results suggest that both approaches are comparable and that for each, separate imputation offers some improvement on the direct imputation of a composite outcome.

Regression discontinuity designs use observational data to examine treatment efficacy. This article uses the example of statin prescription in primary care to explain the concept of the method and how it can be used

The regression discontinuity (RD) design is a quasi-experimental design that estimates the causal effects of a treatment by exploiting naturally occurring treatment rules. It can be applied in any context where a particular treatment or intervention is administered according to a pre-specified rule linked to a continuous variable. Such thresholds are common in primary care drug prescription where the RD design can be used to estimate the causal effect of medication in the general population. Such results can then be contrasted to those obtained from randomised controlled trials (RCTs) and inform prescription policy and guidelines based on a more realistic and less expensive context. In this paper we focus on statins, a class of cholesterol-lowering drugs, however, the methodology can be applied to many other drugs provided these are prescribed in accordance to pre-determined guidelines. NHS guidelines state that statins should be prescribed to patients with 10 year cardiovascular disease risk scores in excess of 20%. If we consider patients whose scores are close to this threshold we find that there is an element of random variation in both the risk score itself and its measurement. We can thus consider the threshold a randomising device assigning the prescription to units just above the threshold and withholds it from those just below. Thus we are effectively replicating the conditions of an RCT in the area around the threshold, removing or at least mitigating confounding. We frame the RD design in the language of conditional independence which clarifies the assumptions necessary to apply it to data, and which makes the links with instrumental variables clear. We also have context specific knowledge about the expected sizes of the effects of statin prescription and are thus able to incorporate this into Bayesian models by formulating informative priors on our causal parameters., Comment: 21 pages, 5 figures, 2 tables

OBJECTIVE: MTX is widely used to treat synovitis in PsA without supporting trial evidence. The aim of our study was to test the value of MTX in the first large randomized placebo-controlled trial (RCT) in PsA. METHODS: A 6-month double-blind RCT compared MTX (15 mg/week) with placebo in active PsA. The primary outcome was PsA response criteria (PsARC). Other outcomes included ACR20, DAS-28 and their individual components. Missing data were imputed using multiple imputation methods. Treatments were compared using logistic regression analysis (adjusted for age, sex, disease duration and, where appropriate, individual baseline scores). RESULTS: Four hundred and sixty-two patients were screened and 221 recruited. One hundred and nine patients received MTX and 112 received placebo. Forty-four patients were lost to follow-up (21 MTX, 23 placebo). Twenty-six patients discontinued treatment (14 MTX, 12 placebo). Comparing MTX with placebo in all randomized patients at 6 months showed no significant effect on PsARC [odds ratio (OR) 1.77, 95% CI 0.97, 3.23], ACR20 (OR 2.00, 95% CI 0.65, 6.22) or DAS-28 (OR 1.70, 95% CI 0.90, 3.17). There were also no significant treatment effects on tender and swollen joint counts, ESR, CRP, HAQ and pain. The only benefits of MTX were reductions in patient and assessor global scores and skin scores at 6 months (P = 0.03, P < 0.001 and P = 0.02, respectively). There were no unexpected adverse events. CONCLUSIONS: This trial of active PsA found no evidence for MTX improving synovitis and consequently raises questions about its classification as a disease-modifying drug in PsA. Trial registration. Current Controlled Trials, www.controlled-trials.com, ISRCTN:54376151.

Background Health Related Quality of Life (HRQoL) is important in systemic lupus erythematosus (SLE) for both global and organ specific disease. Objectives To examine the association between lupus nephritis at inception and patient self-report HRQoL in a large, multi-ethnic/racial, cohort of SLE patients. Methods An observational cohort study of new onset SLE (ACR classification criteria 60 ml/min); state 2 (eGFR: 30 – 60 mL/min); and state 3 (eGFR: 3.0 gr/day). HRQoL was determined by patient self-report SF-36 subscale scores, mental (MCS) and physical (PCS) component summary scores. Statistical analyses were based on analysis of variance or equivalent t-tests. Results There were 1,827 patients, 89% females, predominantly Caucasian (49.2%) with a mean ± SD age of 35.1±13.3 years. The mean ± SD disease duration was 0.5±0.3 years and the mean duration of follow-up was 4.6±3.4 years. The cumulative occurrence of lupus nephritis was 38.4% and the majority of patients (71.2%) were diagnosed at enrollment. SF-36 subscale and summary scores were not significantly lower in patients with lupus nephritis compared to those without nephritis at enrollment. However, for patients with lupus nephritis at enrollment or follow-up, those in state 3 GFR had clinically and statistically significant lower scores in three subscales (Physical function, Physical role and Bodily pain) and in the Physical component summary score of the SF-36 (p Conclusions The presence of lupus nephritis in a large multi-ethnic cohort was not associated with a reduction in HRQoL. However, severe impairment in renal function and to a lesser extent heavy proteinuria, were associated with lower subscale and physical component summary scores of the SF-36. Patient self-report HRQoL is reduced in severe lupus nephritis and may be an important outcome variable in clinical trials of renal disease in SLE. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.1114

Background The outcome of lupus nephritis has evolved over the past decade due to improved immunosuppressive therapies and close attention to co-morbidities. Objectives To study a large, prospective, multi-ethnic/racial, inception cohort of patients with systemic lupus erythematosus (SLE) to determine the outcome of lupus nephritis with current standard of care. Methods An international research network of 37 investigators in 32 academic centers from 11 countries participated in this study. Patients who fulfilled the American College of Rheumatology (ACR) classification criteria for SLE were evaluated within 15 months of diagnosis of SLE and annually thereafter, using a standardized protocol. Data collection included patient demographics, ACR classification criteria, medications, International Society of Nephrology (ISN) classification of chronic kidney disease (CKD) and of renal biopsies (when performed), estimated glomerular filtration rate (eGFR) and proteinuria (ePrU), end stage renal disease (ESRD), SLE disease activity index-2000 (SLEDAI-2K) and Systemic Lupus International Collaborating Clinics (SLICC)/ACR damage index (SDI). Chi-squared test and t-tests were used for group comparisons and Kaplan-Meier curves were produced for time to event analyses. Results There were 1,827 SLE patients, 89% females with a mean ±SD age of 35.1±13.3 years. The ethnic/racial distribution was 49.2% Caucasian, 16.6% African, 15.4% Hispanic, 14.9% Asian and 3.9% other. At enrollment, SLE duration was 0.5±0.3 years, SLEDAI-2K was 5.4±5.4, SDI was 0.31±0.74. The duration of follow-up was 4.6±3.4 years. Lupus nephritis, as defined in the ACR classification criteria, occurred in 499 (27.3%) patients at enrollment and in an additional 202 (11.1%) during follow-up for a cumulative prevalence of 38.4%. The frequency of nephritis was more common in Africans (46%), Hispanics (55%) and Asians (44%) compared to Caucasians (26%) (p Conclusions Lupus nephritis occurred in 38% of SLE patients in a large multi-ethnic/racial inception cohort. Nephritis presented most frequently around the time of diagnosis of SLE and was associated with individual patient9s racial/ethnic background. Although the outcome with standard of care was generally favourable, the results indicate the need for further therapeutic advances in the care of patients with lupus nephritis. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.1113

In randomized trials, it is typical that a number of outcome variables are collected at each follow-up time. Sometimes, a composite outcome may be of scientific interest. A composite outcome is composed as a function of several patient-specific outcomes and could measure, for example, improvement or deterioration in the condition of a patient. Multiple imputation is one method for handling patient drop-out in randomized trials, and usually involves a maximum likelihood-based model fitted to complete cases, which is then used to draw imputations for the missing data. In principle, imputation could be used to impute composite outcomes. However, composite outcomes may be complicated combinations of many outcome variables and, as a result, it can be difficult to impute composite outcomes, since they may not possess a distribution amenable to statistical modelling. Using trial data on early rheumatoid arthritis patients, we examine the use of linear increments models, introduced by Diggle, Farewell and Henderson [1] as a basis for the multiple imputation of missing outcome information. These imputations are used to create random draws of the composite outcome ACR20, a binary indicator of disease improvement defined by the American College of Rheumatology. We compare the multiple imputation of ACR20 using linear increments methodology to that using more established maximum likelihood methods. We observe some evidence to suggest that the use of linear increment models may result in a more accurate imputation of missing ACR20 values. The methodology presented has broad applicability in randomized trials.