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Preclinical studies support a protective role for aspirin in early diabetic retinopathy (DR), but the findings from randomized trials are limited. We present randomized evidence for the efficacy and safety of aspirin on DR outcomes. A substudy of the A Study of Cardiovascular Events in Diabetes (ASCEND) double-masked, randomized, placebo-controlled trial of 100 mg aspirin daily for the primary prevention of serious cardiovascular events in people with diabetes. Fifteen thousand four hundred eighty United Kingdom adults at least 40 years of age with diabetes. Linkage to electronic National Health Service Diabetic Eye Screening Programme records in England and Wales and confirmation of participant-reported eye events via medical record review were carried out. Log-rank methods were used for intention-to-treat analyses of time until the first primary efficacy and safety outcomes. The primary efficacy end point was the first record of referable disease after randomization, a composite of referable retinopathy or referable maculopathy based on the grading criteria defined by the United Kingdom National Screening Committee. The primary safety outcome was the first sight-threatening eye bleed, defined as clinically significant bleeding in the eye that resulted in unresolved visual loss or required an urgent intervention such as laser photocoagulation, vitreoretinal surgery, intraocular injection, or a combination thereof. Linkage data were obtained for 7360 participants (48% of those randomized in ASCEND). During the mean follow-up of 6.5 years, 539 participants (14.6%) experienced a referable disease event in the aspirin group, compared with 522 participants (14.2%) in the placebo group (rate ratio, 1.03; 95% confidence interval [CI], 0.91–1.16; P = 0.64). No statistically significant between-group difference was found in the proportions of sight-threatening eye bleed events (57 participants [0.7%] and 64 participants [0.8%], respectively; rate ratio, 0.89; 95% CI, 0.62–1.27). These data exclude any clinically meaningful benefits of aspirin for DR, but give reassurance regarding the ophthalmologic safety of aspirin. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article. [ABSTRACT FROM AUTHOR]

To determine whether primary trabeculectomy or medical treatment produces better outcomes in terms of quality of life (QoL), clinical effectiveness, and safety in patients with advanced glaucoma. Multicenter randomized controlled trial. Between June 3, 2014, and May 31, 2017, 453 adults with newly diagnosed advanced open-angle glaucoma in at least 1 eye (Hodapp classification) were recruited from 27 secondary care glaucoma departments in the United Kingdom. Two hundred twenty-seven were allocated to trabeculectomy, and 226 were allocated medical management. Participants were randomized on a 1:1 basis to have either mitomycin C-augmented trabeculectomy or escalating medical management with intraocular pressure (IOP)-reducing drops as the primary intervention and were followed up for 5 years. The primary outcome was vision-specific QoL measured with the 25-item Visual Function Questionnaire (VFQ-25) at 5 years. Secondary outcomes were general health status, glaucoma-related QoL, clinical effectiveness (IOP, visual field, and visual acuity), and safety. At 5 years, the mean ± standard deviation VFQ-25 scores in the trabeculectomy and medication arms were 83.3 ± 15.5 and 81.3 ± 17.5, respectively, and the mean difference was 1.01 (95% confidence interval [CI], –1.99 to 4.00; P = 0.51). The mean IOPs were 12.07 ± 5.18 mmHg and 14.76 ± 4.14 mmHg, respectively, and the mean difference was –2.56 (95% CI, –3.80 to –1.32; P < 0.001). Glaucoma severity measured with visual field mean deviation were –14.30 ± 7.14 dB and –16.74 ± 6.78 dB, respectively, with a mean difference of 1.87 (95% CI, 0.87–2.87 dB; P < 0.001). Safety events occurred in 115 (52.2%) of patients in the trabeculectomy arm and 124 (57.9%) of patients in the medication arm (relative risk, 0.92; 95% CI, 0.72–1.19; P = 0.54). Serious adverse events were rare. At 5 years, the Treatment of Advanced Glaucoma Study demonstrated that primary trabeculectomy surgery is more effective in lowering IOP and preventing disease progression than primary medical treatment in patients with advanced disease and has a similar safety profile. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article. [ABSTRACT FROM AUTHOR]

Preclinical studies support a protective role for omega-3 fatty acids (FAs) on diabetic retinopathy (DR), but these observations have not been confirmed in randomized trials. We present randomized evidence for the effects of omega-3 FAs on DR outcomes. A substudy of the A Study of Cardiovascular Events iN Diabetes (ASCEND) double-blind, randomized, placebo-controlled trial of 1 g omega-3 fatty acids (containing 460 mg eicosapentaenoic acid and 380 mg docosahexaenoic acid) daily for the primary prevention of serious cardiovascular events, in 15 480 UK adults at least 40 years of age, with diabetes. Fifteen thousand four hundred eighty adults at least 40 years of age from the United Kingdom with diabetes from the ASCEND cohort. Linkage to electronic National Health Service Diabetic Eye Screening Programme records in England and Wales and confirmation of participant-reported eye events via medical record review. Log-rank and stratified log-rank methods were used for intention-to-treat analyses of time until the main outcomes of interest. The primary efficacy endpoint was time to the first postrandomization recording of referable disease, a composite of referable retinopathy (R 2 or R 3a/s) or referable maculopathy (M 1) based on the grading criteria defined by the United Kingdom National Screening Committee. Secondary and tertiary outcomes included the referable disease outcome stratified by the severity of DR at baseline, any progression in retinopathy grade, and incident diabetic maculopathy. Linkage data were obtained for 7360 participants (48% of those who were randomized in ASCEND). During their mean follow-up of 6.5 years, 548 participants (14.8%) had a referable disease event in the omega-3 FAs group, compared with 513 participants (13.9%) in the placebo group (rate ratio, 1.07; 95% confidence interval, 0.95–1.20; P = 0.29). There were no statistically significant between-group differences in the proportion of events for either of the secondary or tertiary outcomes. Representing the largest prospective test of its kind to date, these data exclude any clinically meaningful benefits of 1 g daily omega-3 FAs on DR. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article. [ABSTRACT FROM AUTHOR]

This paper summarizes the results of the Improving Mood with Psychoanalytic and Cognitive Therapies (IMPACT) study and its implications for psychological treatment of adolescents with moderate to severe unipolar major depression. IMPACT was a pragmatic, superiority, randomized controlled trial conducted in the United Kingdom, which compared the clinical and cost-effectiveness of short-term psychoanalytic therapy (STPP), cognitive−behavioral therapy (CBT), and a brief psychosocial intervention (BPI) in reducing depression symptoms in 465 adolescents with unipolar major depression, aged 11 to 17 years. Although this was a clinically heterogeneous group of adolescents, some symptoms (eg, sleep and concentration difficulties, irritability/anger) were common and disabling. The trial reported no significant difference among the 3 treatments in reducing depression symptoms. One year after treatment, 84% of participants showed improvement in depressive symptoms (<50% of baseline symptoms) and improved psychosocial functioning, achieving this through different symptom reduction trajectories. Although participants attended fewer treatment sessions than planned, the 3 treatments were delivered with fidelity to their respective models. Ending treatment without therapist agreement occurred in 37% of cases. This was not associated with outcomes by treatment group. Adolescents emphasized the importance of the therapeutic relationship in all 3 treatments. Results suggest that although most adolescents respond to time-limited, structured psychological therapy, subgroups of depressed adolescents are likely to need additional treatment or support. These include adolescents who live in complex circumstances and/or who believe that their needs are not met in therapy, some who stop treatment early, and the 16% to 18% of adolescents who do not respond to treatment. Improving Mood and Preventing Relapse With Psychoanalytic Psychotherapy and Cognitive Behaviour Therapy; https://www.isrctn.com ; ISRCTN83033550. [ABSTRACT FROM AUTHOR]

To determine whether early switch to oral antibiotic treatment in adults with neutropenic sepsis at low risk of complications is non-inferior to switching later. This non-inferiority, parallel-group, randomized, open-label clinical trial enrolled UK adults hospitalized with neutropenic sepsis. Participants were randomly assigned to either switch to oral ciprofloxacin plus co-amoxiclav within 12–24 hours or to continue intravenous treatment for at least 48 hours. The primary outcome was a composite measure of treatment failure, 14 days after randomization. The non-inferiority margin was 15%. There were 129 participants from 16 centres and 125 were assessed for the primary outcome. Of these, 113 patients completed protocolized treatment and comprised the per-protocol population. In total, 9 (14.1%) of 64 patients in the standard care arm met the primary end point, compared with 15 (24.6%) of 61 in the early switch arm, giving a risk difference of 10.5% (1-sided 95% CI, −∞% to 22%; p 0.14). In the per-protocol population, 8 (13.3%) of the 60 patients in the standard care arm met the primary end point, compared with 9 (17%) of 53 in the intervention arm giving a risk difference of 3.7% (one-sided 95% CI, −∞% to 14.8%; p 0.59). Duration of hospital stay was shorter in the intervention arm (median 2 [inter-quartile range (IQR) 2–3] vs. 3 days [IQR 2–4]; p 0.002). Although non-inferiority of early oral switch was found in the per-protocol population, the intervention was not non-inferior in the intent-to-treat population. [ABSTRACT FROM AUTHOR]

The UK neurosurgical community has a track record of delivering high-quality, practice-changing clinical research studies, facilitated by a robust clinical research infrastructure and close collaborations between neurosurgical centers. More recently, these large-scale studies have been conceived, developed, and delivered by neurosurgical trainees, working under the umbrella of the British Neurosurgical Trainee Research Collaborative (BNTRC). In this paper, we outline the current landscape of large-scale neurosurgical studies in the UK, focusing on the role of trainees in facilitating this research. Importantly, we focus on our experience of trainee-led studies, including the development of the network, current challenges, and future directions. We believe that a similar model can be applied in different settings and countries, which will drive up the quality of neurosurgical research, ultimately benefiting future neurosurgical patients. [ABSTRACT FROM AUTHOR]

Objectives: We applied principles for conducting economic evaluations of factorial trials to a trial-based economic evaluation of a cluster-randomized 2 × 2 × 2 factorial trial. We assessed the cost-effectiveness of atorvastatin, omega-3 fish oil, and an action-planning leaflet, alone and in combination, from a UK National Health Service perspective.Methods: The Atorvastatin in Factorial With Omega EE90 Risk Reduction in Diabetes (AFORRD) Trial randomized 800 patients with type 2 diabetes to atorvastatin, omega-3, or their respective placebos and randomized general practices to receive a leaflet-based action-planning intervention designed to improve compliance or standard care. The trial was conducted at 59 UK general practices. Sixteen-week outcomes for each trial participant were extrapolated for 70 years using the United Kingdom Prospective Diabetes Study Outcomes Model v2.01. We analyzed the trial as a 2 × 2 factorial trial (ignoring interactions between action-planning leaflet and medication), as a 2 × 2 × 2 factorial trial (considering all interactions), and ignoring all interactions.Results: We observed several qualitative interactions for costs and quality-adjusted life-years (QALYs) that changed treatment rankings. However, different approaches to analyzing the factorial design did not change the conclusions. There was a ≥99% chance that atorvastatin is cost-effective and omega-3 is not, at a £20 000/QALY threshold.Conclusions: Atorvastatin monotherapy was the most cost-effective combination of the 3 trial interventions at a £20 000/QALY threshold. Omega-3 fish oil was not cost-effective, while there was insufficient evidence to draw firm conclusions about action planning. Recently-developed methods for analyzing factorial trials and combining parameter and sampling uncertainty were extended to estimate cost-effectiveness acceptability curves within a 2x2x2 factorial design with model-based extrapolation. [ABSTRACT FROM AUTHOR]

Objectives Apathy is common, impactful, and difficult to manage in people with dementia. We evaluated the efficacy of nonpharmacological interventions, exercise, and social interaction, in combination with antipsychotic review, to reduce apathy in people with dementia living in nursing homes in a cluster randomized controlled trial (RCT). Methods Well-being and health for people with dementia (WHELD) program included a 2 × 2 × 2 factorial cluster RCT involving people with dementia living in 16 nursing homes in the United Kingdom. All homes received training in person-centered care, and were randomized to receive antipsychotic review, social interaction, and exercise, either alone or in combinations. Apathy was one of the secondary outcomes of the WHELD trial, and it was measured by the Neuropsychiatric Inventory–nursing home version at baseline and 9 months (n = 273). We used multilevel mixed effects linear regression models to assess the impact of the interventions on apathy. Results Prevalence of apathy was 44.0% (n = 120; 95% confidence interval [CI] 38.1%–49.9%) at baseline. Severity of apathy had significant positive correlations with dementia severity, neuropsychiatric symptoms, depressive symptoms, agitation, and the needs of the people with dementia ( P < .001). Antipsychotic review reduced antipsychotic use, but it significantly increased apathy (β = 5.37; SE = 0.91; P < . 001). However, antipsychotic review in combination with either social interaction (β = −5.84; SE = 1.15; P < . 001) or exercise (β = −7.54; SE = 0.93; P < . 001) significantly reduced apathy. Conclusions Antipsychotic review can play a significant role in improving apathy in people with dementia living in nursing homes, when combined with psychosocial interventions such as social interaction and exercise. Guidance must be adapted to reflect this subtlety in care. [ABSTRACT FROM AUTHOR]

• The intervention was not more effective than services as usual at improving outcomes. • This may relate, in part, to implementation issues; fidelity could be improved. • It may also reflect the relative lack of behavioral components in the program. The aim of the study was to evaluate the implementation and effectiveness of a therapeutic parenting program that targets parents of children aged 6 to 11 years identified as having behavioral and emotional difficulties. The intervention comprises two parts, delivered sequentially: a 10–12-week group-based program for all parents, and one-to-one sessions for up to 12 weeks with selected parents from the group-based element. In a randomized controlled trial, 264 participants were allocated to the Inspiring Futures program (intervention) or services as usual (control) arms with follow-up assessments at 16 (post-group program) and 32 (post-one-to-one sessions) weeks. The primary outcome was the parent-rated Strengths and Difficulties Questionnaire (SDQ) Total Difficulties score at 32 weeks. Secondary outcomes included parent-rated SDQ subscales, parent coping strategies, empathy in parenting and parenting skills. All 264 participants were included in outcome analyses. There was no statistically significant effect on SDQ Total Difficulties (standardized mean difference: −0.07; 95% CI: −0.30 to 0.16; p = 0.54). There were no sub-group effects. Only 1 of 40 comparisons between the trial arms for secondary outcomes across both follow-ups was statistically significant at the 5% level. The mean number of group sessions attended by intervention arm participants was 6.1 (out of 10 to 12) and only 1 in 20 intervention arm participants received one-to-one support. Independent observation indicated scope to improve fidelity in terms of adherence, quality and participant responsiveness. The intervention is not more effective than services as usual at improving targeted outcomes. This may be related, in part, to implementation issues but arguably more to the inability of a non-behavioral intervention to improve caregiving adequately, particularly when it is not targeted at new parents who have experienced trauma or deprivation early in life or subsequently. [ABSTRACT FROM AUTHOR]

Context: Chronic or refractory breathlessness is common and distressing. To evaluate new treatments, outcome measures that capture change in patients' experience are needed.Objectives: To explore the extent to which the numerical rating scale (NRS) worst and average, and the Chronic Respiratory Questionnaire capture change in patients' experience during a trial of mirtazapine for refractory breathlessness.Methods: Convergent mixed-methods design embedded within a randomized trial comprising 1) semi-structured qualitative interviews (considered to be the gold standard) and 2) outcome measure data collected pre- and post-intervention. Data were integrated, exploring examples where findings agreed and disagreed. Adults with advanced cancer, chronic obstructive pulmonary disease, interstitial lung disease, or chronic heart failure, with a modified Medical Research Council dyspnea scale grade 3 or 4 were recruited from three U.K. sites.Results: Data were collected for 22 participants. Eleven had a diagnosis of chronic obstructive pulmonary disease, eight interstitial lung disease, two chronic heart failure, and one cancer. Median age was 71 (56-84) years. Sixteen participants were men. Changes in the qualitative data were commonly captured in the NRS (worst and average) and the Chronic Respiratory Questionnaire. The NRS worst captured change most frequently. Improvement in the emotional domain was associated with physical changes, improved confidence, and control.Conclusion: This study found that the NRS using the question "How bad has your breathlessness felt at its worst over the past 24 hours?" captured change across multiple domains, and therefore may be an appropriate primary outcome measure in trials in this population. Future work should confirm the construct validity of this question. [ABSTRACT FROM AUTHOR]