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The Harmonising Outcome Measures for Eczema (HOME) initiative established a core outcome set (COS) for atopic eczema (AE) clinical trials in 2019. This set encompasses four core outcome domains and corresponding measurement instruments: clinical signs (EASI), patient-reported symptoms (POEM and NRS 11 point for worst itch over the last 24 h), quality of life (DLQI/CDLQI/IDQoLI), and long-term control (Recap or ADCT). Following its roadmap, the HOME initiative is now focused on supporting implementation of the COS. To identify barriers and facilitators to implementation of the COS, and to guide the effort to promote COS uptake, a virtual consensus meeting was held over 2 days (September 25–26, 2021) attended by 55 participants (26 healthcare professionals, 16 methodologists, 5 patients, 4 industry representatives, and 4 students). Implementation themes were identified by a pre-meeting survey distributed to HOME members, presentations, and whole-group discussion. Participants were divided into five multi-professional small groups which ranked their top 3 most important themes, followed by whole-group discussion and anonymous consensus voting (consensus criteria: < 30% disagreement). Three most important implementation themes were identified and agreed upon: (1) awareness and stakeholder engagement, (2) universal applicability of the COS, and (3) ensuring minimum administrative burden. Working groups to address these issues are now a priority for the HOME initiative. The results from this meeting will inform the development of a HOME Implementation Roadmap in an effort to support other COS groups planning for effective implementation of their core sets.

The National Institute for Health and Care Excellence (NICE) invited Gilead, the company manufacturing ledipasvir-sofosbuvir (LDV/SOF), to submit evidence for the clinical effectiveness and cost effectiveness of LDV/SOF for treating chronic hepatitis C. The School of Health and Related Research (ScHARR) Technology Assessment Group was commissioned as the Evidence Review Group (ERG). This paper describes the company’s submission (CS), the ERG review and the subsequent decision of the NICE Appraisal Committee (AC). The ERG produced a critical review of the clinical effectiveness and cost-effectiveness evidence of LDV/SOF based upon the CS. The clinical effectiveness data for LDV/SOF were taken from ten trials: three phase III trials and seven phase II trials. Trials compared different durations of LDV/SOF, with and without ribavirin (RBV). There were no head-to-head trials comparing LDV/SOF with any comparator listed in the NICE scope. Data from the trials were mostly from populations with genotype 1 (GT1) disease, although some limited data were available for populations with genotypes 3 and 4. For GT1 treatment-naïve patients, sustained viral response for 12 weeks (SVR12) rates for LDV/SOF ranged from 93.1 to 99.4 % for subgroups of patients with non-cirrhotic disease, whilst SVR rates of 94.1 to 100 % were reported for subgroups of patients with compensated cirrhosis. For GT1 treatment-experienced patients, SVR12 rates ranging from 95.4 to 100 % were reported for subgroups of non-cirrhotic patients, and SVR rates ranging from 81.8 to 100 % were reported within subgroups of patients with compensated cirrhosis. Comparator data were not searched systematically as part of the submission, but were based on the company’s previous NICE submission of sofosbuvir, with additional targeted searches. The ERG’s critical appraisal of the company’s economic evaluation highlighted a number of concerns. The ERG’s base case analyses suggested that the incremental cost-effectiveness ratios (ICERs) for LDV/SOF (+RBV) are dependent on (a) treatment durations, (b) whether patients have been previously treated and (c) whether patients have liver cirrhosis or not. The AC concluded that it was appropriate to use the approach taken in the ERG’s exploratory analyses, in line with the marketing authorisation, which considered people with and without cirrhosis separately, and estimated the cost effectiveness for each recommended treatment duration of LDV/SOF.

The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer (The Medicines Company) of bivalirudin to submit evidence for its clinical and cost effectiveness within its licensed indication for the treatment of adults with ST-segment elevation myocardial infarction (STEMI) intended for primary percutaneous coronary intervention (PPCI), as part of NICE’s single technology appraisal (STA) process. The School of Health and Related Research (ScHARR) at the University of Sheffield was commissioned to act as the Evidence Review Group (ERG), which produced a review of the evidence within the manufacturer’s submission to NICE. This article describes the manufacturer’s submission, the ERG review and NICE’s subsequent decisions. The main evidence was derived from one randomized controlled trial (RCT) of STEMI patients intended for PPCI, comparing bivalirudin with unfractionated heparin plus glycoprotein IIb/IIIa inhibitors (GPIs). Bivalirudin was associated with a significant reduction in cardiac mortality at 30 days ( p  = 0.03) and at 1-year follow-up ( p  = 0.005), and a significant reduction in major bleeding at 30 days ( p  < 0.001) and 1 year ( p  < 0.0001), compared with heparin plus GPI. Stent thrombosis up to 24 hours following PPCI was significantly ( p  < 0.001) more common with bivalirudin. However, there was no significant treatment effect for stent thrombosis from 1 to 30 days ( p  = 0.28), or at 1-year follow-up ( p  = 0.53). There were no significant treatment group differences at 30 days and at 1 year in stroke ( p  = 0.68 and p  = 0.99, respectively), in myocardial infarction [MI] ( p  = 0.90 and p  = 0.22, respectively), or in the need for the revascularization of the target vessel for ischaemia ( p  = 0.18 and p  = 0.12, respectively). There were two decision-analytic models: the base-case scenario used 1-year follow-up data from the RCT; and a sensitivity analysis used 3-year follow-up data. Resource use was primarily drawn from this RCT. Health-related quality-of-life (HR-QOL) estimates were drawn from a UK cohort study. Both models evaluated the incremental costs and outcomes of bivalirudin compared with heparin plus GPI for patients with STEMI intended for PPCI. The analysis adopted a UK NHS perspective over a lifetime horizon. Unit costs were based on year 2009–2010 prices. The model adopted a decision-tree structure to reflect initial events for the initial period (stroke, repeat MI, minor/major bleeding events, repeat revascularization and death) and a two-state Markov component to simulate longer-term survival. The economic analysis suggested that bivalirudin is expected to dominate the heparin plus GPI strategy. This finding was consistent across the probabilistic sensitivity analysis and the vast majority of deterministic sensitivity analyses undertaken. Three exceptions to this finding were observed for the following sensitivity analyses: (1) the exclusive use of eptifibatide as the GPI (incremental cost-effectiveness ratio [ICER] = £1,764); (2) the combination of 100 % eptifibatide use, 100 % radial arterial access and no differential length between strategies for initial hospital stay (ICER = £4,106); and (3) a longer length of ward stay (increase of 0.33 days) for the initial hospitalization (ICER = £415). The Appraisal Committee (AC) gave a positive recommendation for bivalirudin for the treatment of adults with STEMI undergoing PPCI.

The Department of Health has emphasised the need for a patient-centred National Health Service (NHS), and the involvement of users and carers in mental health services is often a policy recommendation (Mental Health Task Force User Group, 1995; NHS Health Advisory Service, 1997; Department of Health, 1999a,b, 2001). The Patients' Forum and Consumers in NHS Research are established national bodies concerned with stakeholder involvement. The Commission for Patient and Public Involvement in Health was established in 2003.

Introduction Atopic dermatitis (AD) affects multiple areas of the body, some of which may be more refractory to treatment. We evaluated improvements in the Eczema Area and Severity Index (EASI) by body region and clinical signs for each body region in lebrikizumab-treated patients with moderate-to-severe AD. Methods ADvocate 1 and ADvocate 2 compared lebrikizumab 250 mg as monotherapy every 2 weeks versus placebo for 16 weeks. Efficacy measures included EASI, which rates the extent and severity of four clinical signs (erythema, edema/papulation, excoriation, lichenification) in four body regions (head/neck, upper extremities, trunk, lower extremities). Analyses are post hoc. Results Mean baseline EASI, body region EASI subscores, and the severity of clinical signs were consistent across both studies (EASI ranging from 16.0 to 72.0). At week 16 in both studies, patients treated with lebrikizumab showed significantly greater percent improvement in EASI across all body regions versus placebo ( p  ≤ 0.001), with improvements as early as week 2. In ADvocate 1, all clinical signs significantly improved across all body regions at week 16 with lebrikizumab (51.4–71.6% improvement) versus placebo (23.1–43.5%, p  ≤ 0.001), with significant improvements as early as week 2 for all signs. Significant improvements for all clinical signs at week 16 were also seen in ADvocate 2 for lebrikizumab (53.5–75.6%) versus placebo (28.5–41.2%, p  ≤ 0.001) and as early as week 2 for all body regions and signs except head/neck erythema and lower extremity erythema, edema/papulation, and lichenification, which showed significant improvement by week 4. Conclusions Lebrikizumab as monotherapy consistently and rapidly reduced the extent of involvement and severity of AD in all EASI clinical signs and body regions, including the head and neck region and clinical sign of lichenification, compared with placebo. Trial Registration ClinicalTrials.gov identifier: ADvocate 1 (NCT04146363) and ADvocate 2 (NCT04178967).

Abstract Objective: To compare the incidence of venous thromboembolism among women taking combined oral contraceptives before and after the October 1995 pill scare. Design: Analysis of General Practice Research Database. Setting: United Kingdom, January 1993 to December 1998. Subjects: Women aged 15–49 taking combined oral contraceptives. Main outcome measures: Incidence of venous thromboembolism. Results: Use of so called “third generation” combined oral contraceptives fell from 53% during January 1993 to October 1995 to 14% during November 1995 to December 1998. There was no significant change in the incidence of venous thromboembolism between the two periods after age was adjusted for (incidence ratio 1.04, 95% confidence interval 0.78 to 1.39). Conclusions: The findings are not compatible with the assertion that third generation oral contraceptives are associated with a twofold increase in risk of venous thromboembolism compared with older progestogens.

Possibly the most extensive and best-preserved Archaean halite casts yet discovered occur in the c. 2.58 Ga upper Black Reef and basal Oaktree formations, Transvaal Supergroup, in Mpumalanga Province, South Africa. Halite casts are isolated on bedding planes, range in size from c. 1 mm to 20 mm, and have cubic, dumbbell and triangular shapes, as well as hopper-like pyramidal hollows on cube faces. Some of the casts display distinct hopper shapes characteristic of halite crystals. The halite cast-bearing pavements are developed within silicified mudstone interbedded with siltstone or stromatolitic dolomite. Associated sedimentary structures pointing to subaerial exposure include adhesion ripples and warts, desiccation and prism cracks, rill marks and tepee structures. Halite cast-bearing beds are interpreted as supratidal flat or sabkha deposits. The presence of isolated casts and hopper-shaped crystals suggests that halite resulted from displacive growth within the sediment from supersaturated residual brines after mudstone deposition. Absence of any indication of the former presence of gypsum or anhydrite supports previous contentions that the Neoarchaean ocean was deficient in sulphate or contained a high bicarbonate to calcium ratio such that with progressive evaporation, most calcium was consumed before the gypsum stability field was reached. The association of halite and carbonate in the upper Black Reef and basal Oaktree formations constrains the palaeolatitude of the Transvaal Basin at 2.58 Ga to subequatorial (10-30°).

Abstract Objectives: To identify evidence from comparative studies on the effects of involving users in the delivery and evaluation of mental health services. Data sources: English language articles published between January 1966 and October 2001 found by searching electronic databases. Study selection: Systematic review of randomised controlled trials and other comparative studies of involving users in the delivery or evaluation of mental health services. Data extraction:Patterns of delivery of services by employees who use or who used to use the service and professional employees and the effects on trainees, research, or clients of mental health services. Results: Five randomised controlled trials and seven other comparative studies were identified. Half of the studies considered involving users in managing cases. Involving users as employees of mental health services led to clients having greater satisfaction with personal circumstances and less hospitalisation. Providers of services who had been trained by users had more positive attitudes toward users. Clients reported being less satisfied with services when interviewed by users. Conclusions: Users can be involved as employees, trainers, or researchers without detrimental effect. Involving users with severe mental disorders in the delivery and evaluation of services is feasible.

In two 16-week, placebo-controlled trials enrolling adults with moderate-to-severe atopic dermatitis, dupilumab, a human monoclonal antibody against interleukin-4 receptor alpha, was effective in controlling the signs and symptoms of atopic dermatitis. Atopic dermatitis is a chronic, relapsing inflammatory skin disease that is characterized by the up-regulation of type 2 immune responses (including those involving type 2 helper T cells), 1 , 2 an impaired skin barrier, and increased Staphylococcus aureus colonization. 3 , 4 In patients with moderate-to-severe atopic dermatitis, skin lesions can encompass a large body-surface area and are frequently accompanied by intense, persistent pruritus, which leads to sleep deprivation, symptoms of anxiety or depression, and a poor quality of life. 5 – 7 For patients with moderate-to-severe atopic dermatitis, topical therapies have limited efficacy, and systemic treatments are associated with substantial toxic effects. Thus, there . . .

The standard model of particle physics 1 – 4 describes the known fundamental particles and forces that make up our Universe, with the exception of gravity. One of the central features of the standard model is a field that permeates all of space and interacts with fundamental particles 5 – 9 . The quantum excitation of this field, known as the Higgs field, manifests itself as the Higgs boson, the only fundamental particle with no spin. In 2012, a particle with properties consistent with the Higgs boson of the standard model was observed by the ATLAS and CMS experiments at the Large Hadron Collider at CERN 10 , 11 . Since then, more than 30 times as many Higgs bosons have been recorded by the ATLAS experiment, enabling much more precise measurements and new tests of the theory. Here, on the basis of this larger dataset, we combine an unprecedented number of production and decay processes of the Higgs boson to scrutinize its interactions with elementary particles. Interactions with gluons, photons, and W and Z bosons—the carriers of the strong, electromagnetic and weak forces—are studied in detail. Interactions with three third-generation matter particles (bottom ( b ) and top ( t ) quarks, and tau leptons ( τ )) are well measured and indications of interactions with a second-generation particle (muons, μ ) are emerging. These tests reveal that the Higgs boson discovered ten years ago is remarkably consistent with the predictions of the theory and provide stringent constraints on many models of new phenomena beyond the standard model. Ten years after the discovery of the Higgs boson, the ATLAS  experiment at CERN probes its kinematic properties with a significantly larger dataset from 2015–2018 and provides further insights on its interaction with other known particles.