Cost-effectiveness of therapist-assisted internet-delivered psychological therapies for PTSD differing in trauma focus in England: an economic evaluation based on the STOP-PTSD trial.

BACKGROUND: Although there are effective psychological treatments for post-traumatic stress disorder (PTSD), they remain inaccessible for many people. Digitally enabled therapy is a way to overcome this problem; however, there is little evidence on which forms of these therapies are most cost effective in PTSD. We aimed to assess the cost-effectiveness of the STOP-PTSD trial, which evaluated two therapist-assisted, internet-delivered cognitive behavioural therapies: cognitive therapy for PTSD (iCT-PTSD) and a programme focusing on stress management (iStress-PTSD). METHODS: In this health economic evaluation, we used data from the STOP-PTSD trial (n=217), a single-blind, randomised controlled trial, to compare iCT-PTSD and iStress-PTSD in terms of resource use and health outcomes. In the trial, participants (aged ≥18 years) who met DSM-5 criteria for PTSD were recruited from primary care therapy services in South East England. The interventions were delivered online with therapist support for the first 12 weeks, and three telephone calls over the next 3 months. Participants completed questionnaires on symptoms, wellbeing, quality of life, and resource use at baseline, 13 weeks, 26 weeks, and 39 weeks after randomisation. We used a cost-effectiveness analysis to assess cost per quality-adjusted life year (QALY) at 39 weeks post-randomisation, from the perspective of the English National Health Service (NHS) and personal social services and on the basis of intention-to-treat for complete cases. Treatment modules and the platform design were developed with extensive input from service users: service users also advised on the trial protocol and methods, including the health economic measures. This is a pre-planned analysis of the STOP-PTSD trial; the trial was registered prospectively on the ISRCTN Registry (ISRCTN16806208). FINDINGS: NHS costs were similar across treatment groups, but clinical outcomes were superior for iCT-PTSD compared with iStress-PTSD. The incremental cost-effectiveness ratio for NHS costs and personal social services was estimated as £1921 per QALY. iCT-PTSD had an estimated 91·6% chance of being cost effective at the £20 000 per QALY threshold. From the societal perspective, iCT-PTSD was cost saving compared with iStress-PTSD. INTERPRETATION: iCT-PTSD is a cost-effective form of therapist-assisted, internet-delivered psychological therapy relative to iStress-PTSD, and it could be considered for clinical implementation. FUNDING: Wellcome Trust and National Institute of Health Research Oxford Health Biomedical Research Centre.

VISGRADER: Automatic Grading of D3 Visualizations.

Manually grading D3 data visualizations is a challenging endeavor, and is especially difficult for large classes with hundreds of students. Grading an interactive visualization requires a combination of interactive, quantitative, and qualitative evaluation that are conventionally done manually and are difficult to scale up as the visualization complexity, data size, and number of students increase. We present VISGRADER, a first-of-its kind automatic grading method for D3 visualizations that scalably and precisely evaluates the data bindings, visual encodings, interactions, and design specifications used in a visualization. Our method enhances students' learning experience, enabling them to submit their code frequently and receive rapid feedback to better inform iteration and improvement to their code and visualization design. We have successfully deployed our method and auto-graded D3 submissions from more than 4000 students in a visualization course at Georgia Tech, and received positive feedback for expanding its adoption.

Therapist-assisted online psychological therapies differing in trauma focus for post-traumatic stress disorder (STOP-PTSD): a UK-based, single-blind, randomised controlled trial.

BACKGROUND: Many patients are currently unable to access psychological treatments for post-traumatic stress disorder (PTSD), and it is unclear which types of therapist-assisted internet-based treatments work best. We aimed to investigate whether a novel internet-delivered cognitive therapy for PTSD (iCT-PTSD), which implements all procedures of a first-line, trauma-focused intervention recommended by the UK National Institute for Health and Care Excellence (NICE) for PTSD, is superior to internet-delivered stress management therapy for PTSD (iStress-PTSD), a comprehensive cognitive behavioural treatment programme focusing on a wide range of coping skills. METHODS: We did a single-blind, randomised controlled trial in three locations in the UK. Participants (≥18 years) were recruited from UK National Health Service (NHS) Improving Access to Psychological Therapies (IAPT) services or by self-referral and met DSM-5 criteria for PTSD to single or multiple events. Participants were randomly allocated by a computer programme (3:3:1) to iCT-PTSD, iStress-PTSD, or a 3-month waiting list with usual NHS care, after which patients who still met PTSD criteria were randomly allocated (1:1) to iCT-PTSD or iStress-PTSD. Randomisation was stratified by location, duration of PTSD (<18 months or ≥18 months), and severity of PTSD symptoms (high vs low). iCT-PTSD and iStress-PTSD were delivered online with therapist support by messages and short weekly phone calls over the first 12 weeks (weekly treatment phase), and three phone calls over the next 3 months (booster phase). The primary outcome was the severity of PTSD symptoms at 13 weeks after random assignment, measured by self-report on the PTSD Checklist for DSM-5 (PCL-5), and analysed by intention-to-treat. Safety was assessed in all participants who started treatment. Process analyses investigated acceptability and compliance with treatment, and candidate moderators and mediators of outcome. The trial was prospectively registered with the ISRCTN registry, ISRCTN16806208. FINDINGS: Of the 217 participants, 158 (73%) self-reported as female, 57 (26%) as male, and two (1%) as other; 170 (78%) were White British, 20 (9%) were other White, six (3%) were Asian, ten (5%) were Black, eight (4%) had a mixed ethnic background, and three (1%) had other ethnic backgrounds. Mean age was 36·36 years (SD 12·11; range 18-71 years). 52 (24%) participants met self-reported criteria for ICD-11 complex PTSD. Fewer than 10% of participants dropped out of each treatment group. iCT-PTSD was superior to iStress-PTSD in reducing PTSD symptoms, showing an adjusted difference on the PCL-5 of -4·92 (95% CI -8·92 to -0·92; p=0·016; standardised effect size d=0·38 [0·07 to 0·69]) for immediate allocations and -5·82 (-9·59 to -2·04; p=0·0027; d=0·44 [0·15 to 0·72]) for all treatment allocations. Both treatments were superior to the waiting list for PCL-5 at 13 weeks (d=1·67 [1·23 to 2·10] for iCT-PTSD and 1·29 [0·85 to 1·72] for iStress-PTSD). The advantages in outcome for iCT-PTSD were greater for participants with high dissociation or complex PTSD symptoms, and mediation analyses showed both treatments worked by changing negative meanings of the trauma, unhelpful coping, and flashback memories. No serious adverse events were reported. INTERPRETATION: Trauma-focused iCT-PTSD is effective and acceptable to patients with PTSD, and superior to a non-trauma-focused cognitive behavioural stress management therapy, suggesting that iCT-PTSD is an effective way of delivering the contents of CT-PTSD, one of the NICE-recommended first-line treatments for PTSD, while reducing therapist time compared with face-to-face therapy. FUNDING: Wellcome Trust, UK National Institute for Health and Care Research Oxford Health Biomedical Research Centre.

Imagery re-scripting for PTSD: session content and its relation to symptom improvement.

Imagery rescripting (ImRs) is a therapy technique that, unlike traditional re-living techniques, focuses less on exposure and verbal challenging of cognitions and instead encourages patients to directly transform the intrusive imagery to change the depicted course of events in a more desired direction. However, a comprehensive account of how and in what circumstances ImRs brings about therapeutic change is required if treatment is to be optimised, and this is yet to be developed. The present study reports on the development of a coding scheme of ImRs psychotherapy elements identified in the literature as potential ImRs mechanisms. The codes were assessed in relation to short-term outcomes of 27 individuals undergoing ImRs for post-traumatic stress disorder. The timing of the change in the image, degree of activation of the new image and associated cognitive, emotional and physiological processes, self-guided rescripting, rescript believability, narrative coherence and cognitive and emotional shift were identified as being related to symptom change and so are potentially important factors for the re-scripting process.

What do others think? The why, when and how of using surveys in CBT.

Surveys are a powerful technique in cognitive behavioural therapy (CBT). A form of behavioural experiment, surveys can be used to test beliefs, normalise symptoms and experiences, and generate compassionate perspectives. In this article, we discuss why and when to use surveys in CBT interventions for a range of psychological disorders. We also present a step-by-step guide to collaboratively designing surveys with patients, selecting the appropriate recipients, sending out surveys, discussing responses and using key learning as a part of therapy. In doing so, we hope to demonstrate that surveys are a flexible, impactful, time-efficient, individualised technique which can be readily and effectively integrated into CBT interventions.

Ten misconceptions about trauma-focused CBT for PTSD.

Therapist cognitions about trauma-focused psychological therapies can affect our implementation of evidence-based therapies for posttraumatic stress disorder (PTSD), potentially reducing their effectiveness. Based on observations gleaned from teaching and supervising one of these treatments, cognitive therapy for PTSD (CT-PTSD), ten common 'misconceptions' were identified. These included misconceptions about the suitability of the treatment for some types of trauma and/or emotions, the need for stabilisation prior to memory work, the danger of 'retraumatising' patients with memory-focused work, the risks of using memory-focused techniques with patients who dissociate, the remote use of trauma-focused techniques, and the perception of trauma-focused CBT as inflexible. In this article, these misconceptions are analysed in light of existing evidence and guidance is provided on using trauma-focused CT-PTSD with a broad range of presentations.

Treating common mental disorder including psychotic experiences in the primary care improving access to psychological therapies programme (the TYPPEX study): protocol for a stepped wedge cluster randomised controlled trial with nested economic and process evaluation of a training package for therapists.

INTRODUCTION: At least one in four people treated by the primary care improving access to psychological therapies (IAPT) programme in England experiences distressing psychotic experiences (PE) in addition to common mental disorder (CMD). These individuals are less likely to achieve recovery. IAPT services do not routinely screen for nor offer specific treatments for CMD including PE. The Tailoring evidence-based psychological therapY for People with common mental disorder including Psychotic EXperiences study will evaluate the clinical and cost-effectiveness of an enhanced training for cognitive behavioural therapists that aims to address this clinical gap. METHODS AND ANALYSIS: This is a multisite, stepped-wedge cluster randomised controlled trial. The setting will be IAPT services within three mental health trusts. The participants will be (1) 56-80 qualified IAPT cognitive behavioural therapists and (2) 600 service users who are triaged as appropriate for cognitive behavioural therapy in an IAPT service and have PE according to the Community Assessment of Psychic Experiences-Positive 15-items Scale. IAPT therapists will be grouped into eight study clusters subsequently randomised to the control-intervention sequence. We will obtain pseudonymous clinical outcome data from IAPT clinical records for eligible service users. We will invite service users to complete health economic measures at baseline, 3, 6, 9 and 12-month follow-up. The primary outcome will be the proportion of patients with common mental disorder psychotic experiences who have recovered by the end of treatment as measured by the official IAPT measure for recovery. ETHICS AND DISSEMINATION: The study received the following approvals: South Central-Berkshire Research Ethics Committee on 28 April 2020 (REC reference 20/SC/0135) and Health Research Authority (HRA) on 23 June 2020. An amendment was approved by the Ethics Committee on 01 October 2020 and HRA on 27 October 2020. Results will be made available to patients and the public, the funders, stakeholders in the IAPT services and other researchers. TRIAL REGISTRATION NUMBER: ISRCTN93895792.

Survivor Guilt: A Cognitive Approach.

Survivor guilt is a common experience following traumatic events in which others have died. However, little research has addressed the phenomenology of survivor guilt, nor has the issue been conceptualised using contemporary psychological models which would help guide clinicians in effective treatment approaches for this distressing problem. This paper summarises the current survivor guilt research literature and psychological models from related areas, such as posttraumatic stress disorder, moral injury and traumatic bereavement. Based on this literature, a preliminary cognitive approach to survivor guilt is proposed. A cognitive conceptualisation is described, and used as a basis to suggest potential treatment interventions for survivor guilt. Both the model and treatment strategies require further detailed study and empirical validation, but provide testable hypotheses to stimulate further research in this area.

Complement Factor B Mediates Ocular Angiogenesis through Regulating the VEGF Signaling Pathway.

Complement factor B (CFB), a 95-kDa protein, is a crucial catalytic element of the alternative pathway (AP) of complement. After binding of CFB to C3b, activation of the AP depends on the proteolytic cleavage of CFB by factor D to generate the C3 convertase (C3bBb). The C3 convertase contains the catalytic subunit of CFB (Bb), the enzymatic site for the cleavage of a new molecule of C3 into C3b. In addition to its role in activating the AP, CFB has been implicated in pathological ocular neovascularization, a common feature of several blinding eye diseases, however, with somewhat conflicting results. The focus of this study was to investigate the direct impact of CFB on ocular neovascularization in a tightly controlled environment. Using mouse models of laser-induced choroidal neovascularization (CNV) and oxygen-induced retinopathy (OIR), our study demonstrated an increase in CFB expression during pathological angiogenesis. Results from several in vitro and ex vivo functionality assays indicated a promoting effect of CFB in angiogenesis. Mechanistically, CFB exerts this pro-angiogenic effect by mediating the vascular endothelial growth factor (VEGF) signaling pathway. In summary, we demonstrate compelling evidence for the role of CFB in driving ocular angiogenesis in a VEGF-dependent manner. This work provides a framework for a more in-depth exploration of CFB-mediated effects in ocular angiogenesis in the future.

Behavioural Experiments in Cognitive Therapy for Posttraumatic Stress Disorder: Why, When, and How?

Behavioural experiments are an integral component of cognitive therapy (CT) for posttraumatic stress disorder (PTSD), but they can be overlooked due to practical constraints and therapist concerns. Here we describe why behavioural experiments are an important part of CT, where they fit into different elements of treatment for PTSD, how to design and implement effective experiments including coping with unexpected outcomes, and how to incorporate behavioural experiments when therapy is delivered remotely. Clinical case examples are used to illustrate a range of idiosyncratic and creative behavioural experiments.

Cognitive therapy for moral injury in post-traumatic stress disorder.

Moral injury is the profound psychological distress that can arise following participating in, or witnessing, events that transgress an individual's morals and include harming, betraying, or failure to help others, or being subjected to such events, e.g. being betrayed by leaders. It has been primarily researched in the military, but it also found in other professionals such as healthcare workers coping with the COVID-19 pandemic and civilians following a wide range of traumas. In this article, we describe how to use cognitive therapy for post-traumatic stress disorder (CT-PTSD) to treat patients presenting with moral injury-related PTSD. We outline the key techniques involved in CT-PTSD and describe their application to treating patients with moral injury-related PTSD. A case study of a healthcare worker is presented to illustrate the treatment interventions. KEY LEARNING AIMS: (1)To recognise moral injury where it arises alongside PTSD.(2)To understand how Ehlers and Clark's cognitive model of PTSD can be applied to moral injury.(3)To be able to apply cognitive therapy for PTSD to patients with moral injury-related PTSD.

The Relationship Between Working Alliance and Symptom Improvement in Cognitive Therapy for Posttraumatic Stress Disorder.

Background: Working alliance has been shown to predict outcome of psychological treatments in multiple studies. Conversely, changes in outcome scores have also been found to predict working alliance ratings. Objective: To assess the temporal relationships between working alliance and outcome in 230 patients receiving trauma-focused cognitive behavioral treatment for posttraumatic stress disorder (PTSD). Methods: Ratings of working alliance were made by both the patient and therapist after sessions 1, 3, and 5 of a course of Cognitive Therapy for PTSD (CT-PTSD). Autoregressive, cross-lagged panel models were used to examine whether working alliance predicted PTSD symptom severity at the next assessment point and vice versa. Linear regressions tested the relationship between alliance and treatment outcome. Results: Both patients' and therapists' working alliance ratings after session 1 predicted PTSD symptom scores at the end of treatment, controlling for baseline scores. At each assessment point, higher therapist working alliance was associated with lower PTSD symptoms. Crossed-lagged associations were found for therapist-rated alliance, but not for patient-rated alliance: higher therapists' alliance ratings predicted lower PTSD symptom scores at the next assessment point. Similarly, lower PTSD symptoms predicted higher therapist working alliance ratings at the next assessment point. Ruminative thinking was negatively related to therapists' alliance ratings. Conclusions: Working alliance at the start of treatment predicted treatment outcome in patients receiving CT-PTSD and may be an important factor in setting the necessary conditions for effective treatment. For therapists, there was a reciprocal relationship between working alliance and PTSD symptom change in their patients during treatment, suggesting that their alliance ratings predicted symptom change, but were also influenced by patients' symptom change.

Treatment of survivor guilt after trauma using imagery rescripting: a proof-of-concept study.

Survivor guilt can arise after surviving a trauma in which others die. No studies have systematically investigated psychological treatment for survivor guilt. The present study was a proof-of-concept investigation of treatment of survivor guilt using imagery rescripting. Thirteen participants with post-traumatic stress disorder and self-reported survivor guilt attended two consecutive imagery therapy sessions, to first elaborate and then rescript related imagery. Significant improvements were observed on idiographic process measures of cognitons, emotions and distress related to survivor guilt following the rescripting session. The study provides preliminary evidence that imagery rescripting can be used as an experiential technique to treat survivor guilt.

Treating posttraumatic stress disorder remotely with cognitive therapy for PTSD.

Delivering trauma-focused cognitive behavioural therapy to patients with PTSD during the COVID-19 pandemic poses challenges. The therapist cannot meet with the patient in person to guide them through trauma-focused work and other treatment components, and patients are restricted in carrying out treatment-related activities and behavioural experiments that involve contact with other people. Whilst online trauma-focused CBT treatments for PTSD have been developed, which overcome some of these barriers in that they can be delivered remotely, they are not yet routinely available in clinical services in countries, such as the UK. Cognitive therapy for PTSD (CT-PTSD) is a trauma-focused cognitive behavioural therapy that is acceptable to patients, leads to high rates of recovery and is recommended as a first-line treatment for the disorder by international clinical practice guidelines. Here we describe how to deliver CT-PTSD remotely so that patients presenting with PTSD during the COVID-19 pandemic can still benefit from this evidence-based treatment.

Brindar terapia cognitivo conductual (TCC) centrada en el trauma a pacientes con Trastorno de Estrés Postraumático (TEPT) durante la pandemia de COVID-19 plantea desafíos. El terapeuta no puede reunirse con el paciente en persona para guiarlo a través del trabajo centrado en el trauma y apoyarlo con otros componentes del tratamiento; y por otra parte, los pacientes tienen restricciones para llevar a cabo las actividades relacionadas con el tratamiento y los experimentos de comportamiento que impliquen contacto con otras personas. Si bien se han desarrollado tratamientos de TCC centrados en el trauma en línea para el TEPT, que superan algunas de estas barreras en el sentido de que pueden administrarse de forma remota, todavía no están disponibles de forma rutinaria en los servicios clínicos de los países, como en el Reino Unido. La terapia cognitiva para el TEPT (TC-TEPT) es una terapia cognitiva conductual centrada en el trauma que es aceptable para los pacientes, conduce a altas tasas de recuperación y se recomienda como tratamiento de primera línea para el trastorno según las pautas internacionales de práctica clínica (APA, 2017; International Society of Traumatic Stress Studies, 2019; National Institute of Health and Clinical Excellence, 2018). Aquí describimos cómo administrar TC-TEPT de forma remota para que los pacientes que se presentan con TEPT durante la pandemia de COVID-19 aún puedan beneficiarse de este tratamiento basado en la evidencia.

Investigating the Role of PPARß/δ in Retinal Vascular Remodeling Using Pparß/δ-Deficient Mice.

Peroxisome proliferator-activated receptor (PPAR)ß/δ is a member of the nuclear receptor superfamily of transcription factors, which plays fundamental roles in cell proliferation and differentiation, inflammation, adipogenesis, and energy homeostasis. Previous studies demonstrated a reduced choroidal neovascularization (CNV) in Pparß/δ-deficient mice. However, PPARß/δ's role in physiological blood vessel formation and vessel remodeling in the retina has yet to be established. Our study showed that PPARß/δ is specifically required for disordered blood vessel formation in the retina. We further demonstrated an increased arteriovenous crossover and wider venous caliber in Pparß/δ-haplodeficient mice. In summary, these results indicated a critical role of PPARß/δ in pathological angiogenesis and blood vessel remodeling in the retina.

A randomised controlled trial of therapist-assisted online psychological therapies for posttraumatic stress disorder (STOP-PTSD): trial protocol.

BACKGROUND: Over the last few decades, effective psychological treatments for posttraumatic stress disorder (PTSD) have been developed, but many patients are currently unable to access these treatments. There is initial evidence that therapist-assisted internet-based psychological treatments are effective for PTSD and may help increase access, but it remains unclear which of these treatments work best and are most acceptable to patients. This randomised controlled trial will compare a trauma-focussed and a nontrauma-focussed therapist-assisted cognitive behavioural Internet treatment for PTSD: Internet-delivered cognitive therapy for PTSD (iCT-PTSD) and internet-delivered stress management therapy (iStress-PTSD). METHODS/DESIGN: The study is a single-blind, randomised controlled trial comparing iCT-PTSD, iStress-PTSD and a 13-week wait-list condition, with an embedded process study. Assessors of treatment outcome will be blinded to trial arm. Two hundred and seventeen participants who meet DSM-5 criteria for PTSD will be randomly allocated by a computer programme to iCT-PTSD, iStress-PTSD or wait-list at a 3:3:1 ratio. The primary assessment point is at 13 weeks, and further assessments are taken at 6, 26, 39 and 65 weeks. The primary outcome measure is the severity of PTSD symptoms as measured by the PTSD Checklist for DSM-5 (PCL-5). Secondary measures of PTSD symptoms are the Clinician Administered PTSD Scale for DSM-5 (CAPS-5) and the Impact of Event Scale-Revised (IES-R). Other symptoms and well-being will be assessed with the Patient Health Questionnaire (PHQ-9), Generalised Anxiety Disorder Scale (GAD-7), WHO (Five) Well-Being Index, Work and Social Adjustment Scale (WSAS), Endicott Quality of Life Scale (QoL), and Insomnia Sleep Index (ISI). Health economics analyses will consider quality of life, productivity, health resource utilisation, employment status and state benefits, and treatment delivery costs. Process analyses will investigate candidate mediators and moderators of outcome. Patient experience will be assessed by interview and questionnaire. DISCUSSION: This study will be the first to compare the efficacy of a trauma-focussed and nontrauma-focussed therapist-assisted online cognitive behavioural treatment for people with posttraumatic stress disorder. TRIAL REGISTRATION: ISRCTN16806208. Registered prospectively on 5 January 2018.

Cognitive therapy for post-traumatic stress disorder following critical illness and intensive care unit admission.

Around a quarter of patients treated in intensive care units (ICUs) will develop symptoms of post-traumatic stress disorder (PTSD). Given the dramatic increase in ICU admissions during the COVID-19 pandemic, clinicians are likely to see a rise in post-ICU PTSD cases in the coming months. Post-ICU PTSD can present various challenges to clinicians, and no clinical guidelines have been published for delivering trauma-focused cognitive behavioural therapy with this population. In this article, we describe how to use cognitive therapy for PTSD (CT-PTSD), a first line treatment for PTSD recommended by the National Institute for Health and Care Excellence. Using clinical case examples, we outline the key techniques involved in CT-PTSD, and describe their application to treating patients with PTSD following ICU. KEY LEARNING AIMS: To recognise PTSD following admissions to intensive care units (ICUs).To understand how the ICU experience can lead to PTSD development.To understand how Ehlers and Clark's (2000) cognitive model of PTSD can be applied to post-ICU PTSD.To be able to apply cognitive therapy for PTSD to patients with post-ICU PTSD.

Apratoxin S4 Inspired by a Marine Natural Product, a New Treatment Option for Ocular Angiogenic Diseases.

Purpose: Abnormal blood vessel formation is a defining feature of many blinding eye diseases. Targeting abnormal angiogenesis by inhibiting VEGF has revolutionized the treatment of many ocular angiogenic diseases over the last decade. However, a substantial number of patients are refractory to anti-VEGF treatment or may develop resistance over time. The objective of this study was to determine the efficacy and the mechanism of action of Apratoxin S4 in ocular angiogenesis. Methods: Retinal vascular cell proliferation, migration, and the ability to form tube-like structure were studied in vitro. Ex vivo aortic ring, choroid, and metatarsal assays were used to study Apratoxin S4's impact on vessel outgrowth in a multicellular environment. Apratoxin S4 was also tested in mouse models of oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV), and in a rabbit model of persistent retinal neovascularization (PRNV). Western blot and ELISA were used to determine the expression of key angiogenic regulators after Apratoxin S4 treatment. Results: Apratoxin S4 strongly inhibits retinal vascular cell activation by suppressing multiple angiogenic pathways. VEGF-activated vascular cells and angiogenic vessels are more susceptible to Apratoxin S4 treatment than quiescent vascular cells and vessels. Both intraperitoneal and intravitreal delivery of Apratoxin S4 are able to impede ocular neovascularization in vivo. Apratoxin S4 specifically attenuates pathological ocular angiogenesis and exhibits a combinatorial inhibitory effect with standard-of-care VEGF inhibitor drug (aflibercept). Conclusions: Apratoxin S4 is a potent antiangiogenic drug that inhibits the activation of retinal endothelial cells and pericytes through mediating multiple angiogenic pathways.

Psychological interventions for people with psychotic experiences: protocol for a systematic review and meta-analysis.

BACKGROUND: Many people who have common mental disorders, such as depression and anxiety, also have some psychotic experiences. These experiences are associated with higher clinical complexity, poor treatment response, and negative clinical outcomes. Psychological interventions have the potential to improve outcomes for people with psychotic experiences. The aims of this systematic review are to (1) synthesise the evidence on the effectiveness and cost-effectiveness of psychological interventions to reduce psychotic experiences and their associated distress and (2) identify key components of effective interventions. METHODS: Our search strategy will combine terms for (1) psychological interventions, (2) psychotic experiences, and (3) symptoms associated with psychotic experiences. We will search the following online databases: MEDLINE, Embase, PsycINFO, all Cochrane databases, British Nursing Index (BNI), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Health Management Information Consortium (HMIC), Education Resources Information Center (ERIC), and EconLit. Our primary outcome is the proportion of people who recovered or remitted from psychotic experiences after the intervention. Our secondary outcomes are changes in positive psychotic symptoms, negative psychotic symptoms, depression, anxiety, functioning (including social, occupational, and academic), quality of life, and cost-effectiveness. Two independent reviewers will judge each study against pre-specified inclusion and exclusion criteria and will extract study characteristics, outcome data, and intervention components. Risk of bias and methodological quality will be assessed using the Effective Public Health Practice Project Quality Assessment Tool for Quantitative Studies and the Drummond Checklist. Results will be synthesised using random-effects meta-analysis and narrative synthesis. DISCUSSION: The identification of effective psychological interventions and of specific components associated with intervention effectiveness will augment existing evidence that can inform the development of a new, tailored intervention to improve outcomes related to psychotic symptoms, anxiety and depression, distress, functioning, and quality of life. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016033869.