Efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate‐to‐severe plaque psoriasis over 52 weeks: a phase III, randomized controlled trial (ESTEEM 2)

SummaryBackground Apremilast, an oral phosphodiesterase 4 inhibitor, regulates immune responses associated with psoriasis. Objectives ESTEEM 2 evaluated the efficacy and safety of apremilast 30 mg twice daily for moderate-to-severe plaque psoriasis. Methods This phase III, double-blind, placebo-controlled trial randomized adults to apremilast or placebo (2 : 1). At week 16, placebo patients switched to apremilast. At week 32, apremilast patients achieving ≥ 50% reduction in Psoriasis Area and Severity Index (PASI 50) were rerandomized (1 : 1) to continue apremilast or receive placebo. Upon loss of 50% of PASI improvement obtained at week 32, patients rerandomized to placebo resumed apremilast. Results The modified intention-to-treat population (full analysis set) included 137 placebo and 274 apremilast patients. At week 16, significantly more apremilast patients achieved PASI 75 (28·8%), PASI 50 (55·5%) and static Physician's Global Assessment score of 0 or 1 (20·4%) vs. placebo (5·8%, 19·7%, 4·4%, respectively; P < 0·001). Most patients rerandomized to apremilast at week 32 had a PASI 50 response at week 52 (80%). Patients treated with apremilast showed significant improvements in quality of life (as assessed by the Dermatology Life Quality Index) and pruritus at week 16 compared with placebo (P < 0·001). The exposure-adjusted incidence of adverse events did not increase with continued apremilast treatment for up to 52 weeks. The most common adverse events were nausea, diarrhoea, nasopharyngitis and upper respiratory tract infection. Conclusions Apremilast was effective in the treatment of moderate-to-severe plaque psoriasis over 52 weeks

The NAVIGATE Program for First-Episode Psychosis: Rationale, Overview, and Description of Psychosocial Components

Comprehensive coordinated specialty care programs for first-episode psychosis have been widely implemented in other countries but not in the United States. The National Institute of Mental Health\u27s Recovery After an Initial Schizophrenia Episode (RAISE) initiative focused on the development and evaluation of first-episode treatment programs designed for the U.S. health care system. This article describes the background, rationale, and nature of the intervention developed by the RAISE Early Treatment Program project-known as the NAVIGATE program-with a particular focus on its psychosocial components. NAVIGATE is a team-based, multicomponent treatment program designed to be implemented in routine mental health treatment settings and aimed at guiding people with a first episode of psychosis (and their families) toward psychological and functional health. The core services provided in the NAVIGATE program include the family education program (FEP), individual resiliency training (IRT), supported employment and education (SEE), and individualized medication treatment. NAVIGATE embraces a shared decision-making approach with a focus on strengths and resiliency and on collaboration with clients and family members in treatment planning and reviews. The NAVIGATE program has the potential to fill an important gap in the U.S. health care system by providing a comprehensive intervention specially designed to meet the unique treatment needs of persons recovering from a first episode of psychosis. A cluster-randomized controlled trial comparing NAVIGATE with usual community care has recently been completed

Long-term safety and tolerability of apremilast in patients with psoriasis : Pooled safety analysis for ≥156 weeks from 2 phase 3, randomized, controlled trials (ESTEEM 1 and 2)

BACKGROUND: Randomized, controlled trials demonstrated efficacy and safety of apremilast for moderate-to-severe plaque psoriasis and psoriatic arthritis. OBJECTIVE: Assess long-term safety of oral apremilast in psoriasis patients. METHODS: Safety findings are reported for 0 to ≥156 weeks from the Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis (ESTEEM) 1 and 2. RESULTS: The 0 to ≥156-week apremilast-exposure period included 1184 patients treated twice daily with apremilast 30 mg (1902.2 patient-years). During 0 to ≤52 weeks, the adverse events (AEs) that occurred in ≥5% of patients included diarrhea, nausea, upper respiratory tract infection, nasopharyngitis, tension headache, and headache. From 0 to ≥156 weeks, no new AEs (affecting ≥5% of the population) were reported. AEs, serious AEs, and study drug discontinuations caused by AEs did not increase with long-term exposure. During the 0 to ≥156-week period, the rates of major cardiac events (exposure-adjusted incidence rate [EAIR] 0.5/100 patient-years), malignancies (EAIR 1.2/100 patient-years), depression (EAIR 1.8/100 patient-years), or suicide attempts (EAIR 0.1/100 patient-years) did not increase in comparison with the rates found during the 0 to ≤52-week period. No serious opportunistic infections, reactivation of tuberculosis, or clinically meaningful effects on laboratory measurements were reported. Limitations: This study had a high dropout rate (21% of patients ongoing [156 weeks); most were $1 56 weeks, no new AEs (affecting$5 % of the population) were reported. LIMITATIONS: This study had a high dropout rate (21% of patients ongoing >156 weeks); most were unrelated to safety concerns. CONCLUSIONS: Apremilast demonstrated an acceptable safety profile and was generally well tolerated for ≥156 weeks

Elevated CO2 degassing rates prevented the return of Snowball Earth during the Phanerozoic

The Cryogenian period (~720–635 Ma) is marked by extensive Snowball Earth glaciations. These have previously been linked to CO₂ draw-down, but the severe cold climates of the Cryogenian have never been replicated during the Phanerozoic despite similar, and sometimes more dramatic changes to carbon sinks. Here we quantify the total CO₂ input rate, both by measuring the global length of subduction zones in plate tectonic reconstructions, and by sea-level inversion. Our results indicate that degassing rates were anomalously low during the Late Neoproterozoic, roughly doubled by the Early Phanerozoic, and remained comparatively high until the Cenozoic. Our carbon cycle modelling identifies the Cryogenian as a unique period during which low surface temperature was more easily achieved, and shows that the shift towards greater CO₂ input rates after the Cryogenian helped prevent severe glaciation during the Phanerozoic. Such a shift appears essential for the development of complex animal life

Psychological therapies for auditory hallucinations (voices): current status and key directions for future research

This report from the International Consortium on Hallucinations Research considers the current status and future directions in research on psychological therapies targeting auditory hallucinations (hearing voices). Therapy approaches have evolved from behavioral and coping-focused interventions, through formulation-driven interventions using methods from cognitive therapy, to a number of contemporary developments. Recent developments include the application of acceptance- and mindfulness-based approaches, and consolidation of methods for working with connections between voices and views of self, others, relationships and personal history. In this article, we discuss the development of therapies for voices and review the empirical findings. This review shows that psychological therapies are broadly effective for people with positive symptoms, but that more research is required to understand the specific application of therapies to voices. Six key research directions are identified: (1) moving beyond the focus on overall efficacy to understand specific therapeutic processes targeting voices, (2) better targeting psychological processes associated with voices such as trauma, cognitive mechanisms, and personal recovery, (3) more focused measurement of the intended outcomes of therapy, (4) understanding individual differences among voice hearers, (5) extending beyond a focus on voices and schizophrenia into other populations and sensory modalities, and (6) shaping interventions for service implementation

‘Not a country at all’: landscape and Wuthering Heights

This article explores the issue of women’s representational genealogies through an analysis of Andrea Arnold’s 2011 Wuthering Heights. Beginning with 1970s feminist arguments for a specifically female literary tradition, it argues that running through both these early attempts to construct an alternative female literary tradition and later work in feminist philosophy, cultural geography and film history is a concern with questions of ‘alternative landscapes’: of how to represent, and how to encounter, space differently. Adopting Mary Jacobus’ notion of intertextual ‘correspondence’ between women’s texts, and taking Arnold’s film as its case study, it seeks to trace some of the intertextual movements – the reframings, deframings and spatial reorderings – that link Andrea Arnold’s film to Emily Brontë’s original novel. Focusing on two elements of her treatment of landscape – her use of ‘unframed’ landscape and her focus on visceral textural detail – it points to correspondences in other women’s writing, photography and film-making. It argues that these intensely tactile close-up sequences which puncture an apparently realist narrative constitute an insistent presence beneath, or within, the ordered framing which is our more usual mode of viewing landscape. As the novel Wuthering Heights is unmade in Arnold’s adaptation and its framings ruptured, it is through this disturbance of hierarchies of time, space and landscape that we can trace the correspondences of an alternative genealogy