More than doubling the clinical benefit of each hour of therapist time: a randomised controlled trial of internet cognitive therapy for social anxiety disorder.

BACKGROUND: Cognitive therapy for social anxiety disorder (CT-SAD) is recommended by NICE (2013) as a first-line intervention. Take up in routine services is limited by the need for up to 14 ninety-min face-to-face sessions, some of which are out of the office. An internet-based version of the treatment (iCT-SAD) with remote therapist support may achieve similar outcomes with less therapist time. METHODS: 102 patients with social anxiety disorder were randomised to iCT-SAD, CT-SAD, or waitlist (WAIT) control, each for 14 weeks. WAIT patients were randomised to the treatments after wait. Assessments were at pre-treatment/wait, midtreatment/wait, posttreatment/wait, and follow-ups 3 & 12 months after treatment. The pre-registered (ISRCTN 95 458 747) primary outcome was the social anxiety disorder composite, which combines 6 independent assessor and patient self-report scales of social anxiety. Secondary outcomes included disability, general anxiety, depression and a behaviour test. RESULTS: CT-SAD and iCT-SAD were both superior to WAIT on all measures. iCT-SAD did not differ from CT-SAD on the primary outcome at post-treatment or follow-up. Total therapist time in iCT-SAD was 6.45 h. CT-SAD required 15.8 h for the same reduction in social anxiety. Mediation analysis indicated that change in process variables specified in cognitive models accounted for 60% of the improvements associated with either treatment. Unlike the primary outcome, there was a significant but small difference in favour of CT-SAD on the behaviour test. CONCLUSIONS: When compared to conventional face-to-face therapy, iCT-SAD can more than double the amount of symptom change associated with each therapist hour.

Mechanisms of nuclear reprogramming by eggs and oocytes: a deterministic process?

Differentiated cells can be experimentally reprogrammed back to pluripotency by nuclear transfer, cell fusion or induced pluripotent stem cell technology. Nuclear transfer and cell fusion can lead to efficient reprogramming of gene expression. The egg and oocyte reprogramming process includes the exchange of somatic proteins for oocyte proteins, the post-translational modification of histones and the demethylation of DNA. These events occur in an ordered manner and on a defined timescale, indicating that reprogramming by nuclear transfer and by cell fusion rely on deterministic processes.

Hierarchical molecular events driven by oocyte-specific factors lead to rapid and extensive reprogramming.

Nuclear transfer to oocytes is an efficient way to transcriptionally reprogram somatic nuclei, but its mechanisms remain unclear. Here, we identify a sequence of molecular events that leads to rapid transcriptional reprogramming of somatic nuclei after transplantation to Xenopus oocytes. RNA-seq analyses reveal that reprogramming by oocytes results in a selective switch in transcription toward an oocyte rather than pluripotent type, without requiring new protein synthesis. Time-course analyses at the single-nucleus level show that transcriptional reprogramming is induced in most transplanted nuclei in a highly hierarchical manner. We demonstrate that an extensive exchange of somatic- for oocyte-specific factors mediates reprogramming and leads to robust oocyte RNA polymerase II binding and phosphorylation on transplanted chromatin. Moreover, genome-wide binding of oocyte-specific linker histone B4 supports its role in transcriptional reprogramming. Thus, our study reveals the rapid, abundant, and stepwise loading of oocyte-specific factors onto somatic chromatin as important determinants for successful reprogramming.

Long-term benefits of digital cognitive behavioural therapy for insomnia: Follow-up report from a randomized clinical trial.

Digital cognitive behavioural therapy (dCBT) is an effective treatment for chronic insomnia and also improves well-being and quality of life (QoL). We assessed whether these benefits are sustained and if the effects of dCBT extend to the use of sleep medication and healthcare. In total 1,711 adults (48.0 ± 13.8 years, 77.6% female) with complaints of chronic insomnia participated in a previously published randomized controlled trial (ISRCTN 60530898) comparing dCBT (n = 853) with sleep hygiene education (SHE, n = 858). At weeks 0, 4, 8, 24, 36 and 48, we assessed functional health (Patient-Reported Outcomes Measurement Information System: Global Health Scale); psychological well-being (Warwick-Edinburgh Mental Well-being Scale) and sleep-related QoL (Glasgow Sleep Impact Index), prescribed and non-prescribed sleep medication use, and healthcare utilization. At week 25, those who received SHE at baseline were offered dCBT. dCBT improved functional health (difference: 2.45, 95% confidence interval [CI]: 2.03; 2.88, Cohen's d: 0.50, p < .001), psychological well-being (difference: 4.34, 95% CI: 3.70; 4.98, Cohen's d: 0.55, p < .001) and sleep-related QoL (difference: -44.61, 95%CI: -47.17; -42.05, Cohen's d: -1.44, p < .001) at week 48 compared to baseline. At week 24 dCBT, compared to SHE, also reduced use of prescription and non-prescription sleep medication up to week 24 (adjusted rate ratio [RR]: 0.64, 95% CI: 0.42; 0.97, p = .037 and adjusted RR: 0.52, 95% CI: 0.37; 0.74, p < .0001, respectively), but not healthcare utilization. Uncontrolled follow-up suggests that these effects were sustained for non-prescribed sleep medication (RR: 0.52, 95% CI: 0.40; 0.67, p < .001). In conclusion, this study suggests that dCBT results in sustained benefits to insomnia and its daytime outcomes.

Efficacy of digital cognitive behavioral therapy for moderate-to-severe symptoms of generalized anxiety disorder: A randomized controlled trial.

BACKGROUND: Cognitive behavioral therapy (CBT) is an efficacious intervention for generalized anxiety disorder (GAD). Digital CBT may provide a scalable means of delivering CBT at a population level. We investigated the efficacy of a novel digital CBT program in those with GAD for outcomes of anxiety, worry, depressive symptoms, sleep difficulty, wellbeing, and participant-specific quality of life. METHODS: This online, two-arm parallel-group superiority randomized controlled trial compared digital CBT with waitlist control in 256 participants with moderate-to-severe symptoms of GAD. Digital CBT (Daylight), was delivered using participants' own smartphones. Online assessments took place at baseline (Week 0; immediately preceding randomization), mid-intervention (Week 3; from randomization), post-intervention (Week 6; primary endpoint), and follow-up (Week 10). RESULTS: Overall, 256 participants were randomized and intention-to-treat analysis found Daylight reduced symptoms of anxiety compared with waitlist control at post-intervention, reflecting a large effect size (adjusted difference [95% CI]: 3.22 [2.14, 4.31], d = 1.08). Significant improvements were found for measures of worry; depressive symptoms, sleep difficulty, wellbeing, and participant-specific quality of life. CONCLUSION: Digital CBT (Daylight) appears to be safe and efficacious for symptoms of anxiety, worry, and further measures of mental health compared with waitlist control in individuals with GAD.

Citrullination regulates pluripotency and histone H1 binding to chromatin.

Citrullination is the post-translational conversion of an arginine residue within a protein to the non-coded amino acid citrulline. This modification leads to the loss of a positive charge and reduction in hydrogen-bonding ability. It is carried out by a small family of tissue-specific vertebrate enzymes called peptidylarginine deiminases (PADIs) and is associated with the development of diverse pathological states such as autoimmunity, cancer, neurodegenerative disorders, prion diseases and thrombosis. Nevertheless, the physiological functions of citrullination remain ill-defined, although citrullination of core histones has been linked to transcriptional regulation and the DNA damage response. PADI4 (also called PAD4 or PADV), the only PADI with a nuclear localization signal, was previously shown to act in myeloid cells where it mediates profound chromatin decondensation during the innate immune response to infection. Here we show that the expression and enzymatic activity of Padi4 are also induced under conditions of ground-state pluripotency and during reprogramming in mouse. Padi4 is part of the pluripotency transcriptional network, binding to regulatory elements of key stem-cell genes and activating their expression. Its inhibition lowers the percentage of pluripotent cells in the early mouse embryo and significantly reduces reprogramming efficiency. Using an unbiased proteomic approach we identify linker histone H1 variants, which are involved in the generation of compact chromatin, as novel PADI4 substrates. Citrullination of a single arginine residue within the DNA-binding site of H1 results in its displacement from chromatin and global chromatin decondensation. Together, these results uncover a role for citrullination in the regulation of pluripotency and provide new mechanistic insights into how citrullination regulates chromatin compaction.

Mitosis gives a brief window of opportunity for a change in gene transcription.

Cell differentiation is remarkably stable but can be reversed by somatic cell nuclear transfer, cell fusion, and iPS. Nuclear transfer to amphibian oocytes provides a special opportunity to test transcriptional reprogramming without cell division. We show here that, after nuclear transfer to amphibian oocytes, mitotic chromatin is reprogrammed up to 100 times faster than interphase nuclei. We find that, as cells traverse mitosis, their genes pass through a temporary phase of unusually high responsiveness to oocyte reprogramming factors (mitotic advantage). Mitotic advantage is not explained by nuclear penetration, DNA modifications, histone acetylation, phosphorylation, methylation, nor by salt soluble chromosomal proteins. Our results suggest that histone H2A deubiquitination may account, at least in part, for the acquisition of mitotic advantage. They support the general principle that a temporary access of cytoplasmic factors to genes during mitosis may facilitate somatic cell nuclear reprogramming and the acquisition of new cell fates in normal development.

Seeing Is Believing: Using Video Feedback in Cognitive Therapy for Social Anxiety Disorder.

Distorted negative self-images and impressions appear to play a key role in maintaining Social Anxiety Disorder (SAD). In previous research, McManus et al. (2009) found that video feedback can help people undergoing cognitive therapy for SAD (CT-SAD) to develop a more realistic impression of how they appear to others, and this was associated with significant improvement in their social anxiety. In this paper we first present new data from 47 patients that confirms the value of video feedback. Ninety-eighty percent of the patients indicated that they came across more favorably than they had predicted after viewing a video of their social interactions. Significant reductions in social anxiety were observed during the following week and these reductions were larger than those observed after control periods. Comparison with our earlier data (McManus et al., 2009) suggests we may have improved the effectiveness of video feedback by refining and developing our procedures over time. The second part of the paper outlines our current strategies for maximizing the impact of video feedback. The strategies have evolved in order to help patients with SAD overcome a range of processing biases that could otherwise make it difficult for them to spot discrepancies between their negative self-imagery and the way they appear on video.

Nuclear reprogramming.

There is currently particular interest in the field of nuclear reprogramming, a process by which the identity of specialised cells may be changed, typically to an embryonic-like state. Reprogramming procedures provide insight into many mechanisms of fundamental cell biology and have several promising applications, most notably in healthcare through the development of human disease models and patient-specific tissue-replacement therapies. Here, we introduce the field of nuclear reprogramming and briefly discuss six of the procedures by which reprogramming may be experimentally performed: nuclear transfer to eggs or oocytes, cell fusion, extract treatment, direct reprogramming to pluripotency and transdifferentiation.

SLEEP AND TREATMENT OUTCOME IN POSTTRAUMATIC STRESS DISORDER: RESULTS FROM AN EFFECTIVENESS STUDY.

BACKGROUND: Most patients with posttraumatic stress disorder (PTSD) suffer from sleep problems. Concerns have been raised about possible detrimental effects of sleep problems on the efficacy of psychological treatments for PTSD. In this study, we investigated the relation of session-to-session changes in PTSD symptoms and sleep, and tested whether sleep problems predicted poorer short- and long-term treatment outcome. METHODS: Self-reported sleep quality, sleep duration, and PTSD symptoms were assessed weekly in a consecutive sample of 246 patients who received cognitive therapy for PTSD (CT-PTSD; Ehlers & Clark, 2000), and at follow-up (mean = 247 days posttreatment). Additionally, moderating effects of medication use and comorbid depression were assessed. RESULTS: Sleep and PTSD symptoms improved in parallel. The relation was moderated by depression: Sleep problems at the start of therapy did not predict improvement in PTSD symptoms during treatment for patients without comorbid depression. Patients with comorbid depression, however, showed less rapid decreases in PTSD symptoms, but comparable overall outcome, if their sleep quality was poor. Residual sleep problems at the end of treatment did not predict PTSD symptoms at follow-up once residual PTSD symptoms were taken into account. CONCLUSIONS: CT-PTSD leads to simultaneous improvement in sleep and PTSD symptoms. Sleep problems may reduce the speed of recovery in PTSD patients with comorbid depression. For these patients, additional treatment sessions are indicated to achieve comparable outcomes, and additional interventions targeting sleep may be beneficial. For those without comorbid depression, self-reported sleep problems did not interfere with response to trauma-focused psychological treatment.

Epigenetic factors influencing resistance to nuclear reprogramming.

Patient-specific somatic cell reprogramming is likely to have a large impact on medicine by providing a source of cells for disease modelling and regenerative medicine. Several strategies can be used to reprogram cells, yet they are generally characterised by a low reprogramming efficiency, reflecting the remarkable stability of the differentiated state. Transcription factors, chromatin modifications, and noncoding RNAs can increase the efficiency of reprogramming. However, the success of nuclear reprogramming is limited by epigenetic mechanisms that stabilise the state of gene expression in somatic cells and thereby resist efficient reprogramming. We review here the factors that influence reprogramming efficiency, especially those that restrict the natural reprogramming mechanisms of eggs and oocytes. We see this as a step towards understanding the mechanisms by which nuclear reprogramming takes place.

Histone variant macroH2A marks embryonic differentiation in vivo and acts as an epigenetic barrier to induced pluripotency.

How cell fate becomes restricted during somatic cell differentiation is a long-lasting question in biology. Epigenetic mechanisms not present in pluripotent cells and acquired during embryonic development are expected to stabilize the differentiated state of somatic cells and thereby restrict their ability to convert to another fate. The histone variant macroH2A acts as a component of an epigenetic multilayer that heritably maintains the silent X chromosome and has been shown to restrict tumor development. Here we show that macroH2A marks the differentiated cell state during mouse embryogenesis. MacroH2A.1 was found to be present at low levels upon the establishment of pluripotency in the inner cell mass and epiblast, but it was highly enriched in the trophectoderm and differentiated somatic cells later in mouse development. Chromatin immunoprecipitation revealed that macroH2A.1 is incorporated in the chromatin of regulatory regions of pluripotency genes in somatic cells such as mouse embryonic fibroblasts and adult neural stem cells, but not in embryonic stem cells. Removal of macroH2A.1, macroH2A.2 or both increased the efficiency of induced pluripotency up to 25-fold. The obtained induced pluripotent stem cells reactivated pluripotency genes, silenced retroviral transgenes and contributed to chimeras. In addition, overexpression of macroH2A isoforms prevented efficient reprogramming of epiblast stem cells to naïve pluripotency. In summary, our study identifies for the first time a link between an epigenetic mark and cell fate restriction during somatic cell differentiation, which helps to maintain cell identity and antagonizes induction of a pluripotent stem cell state.

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.

Characterization of somatic cell nuclear reprogramming by oocytes in which a linker histone is required for pluripotency gene reactivation.

When transplanted into Xenopus oocytes, the nuclei of mammalian somatic cells are reprogrammed to express stem cell genes such as Oct4, Nanog, and Sox2. We now describe an experimental system in which the pluripotency genes Sox2 and Oct4 are repressed in retinoic acid-treated ES cells but are reprogrammed up to 100% within 24 h by injection of nuclei into the germinal vesicle (GV) of growing Xenopus oocytes. The isolation of GVs in nonaqueous medium allows the reprogramming of individual injected nuclei to be seen in real time. Analysis using fluorescence recovery after photobleaching shows that nuclear transfer is associated with an increase in linker histone mobility. A simultaneous loss of somatic H1 linker histone and incorporation of the oocyte-specific linker histone B4 precede transcriptional reprogramming. The loss of H1 is not required for gene reprogramming. We demonstrate both by antibody injection experiments and by dominant negative interference that the incorporation of B4 linker histone is required for pluripotency gene reactivation during nuclear reprogramming. We suggest that the binding of oocyte-specific B4 linker histone to chromatin is a key primary event in the reprogramming of somatic nuclei transplanted to amphibian oocytes.

Worry and rumination in anorexia nervosa.

BACKGROUND: Difficulties with comprehending and managing emotions are core features of the pathology of anorexia nervosa (AN). Advancements in understanding aetiology and treatment have been made within other clinical domains by targeting worry and rumination. However, worry and rumination have been given minimal consideration in AN. AIMS: This study is the largest to date of worry and rumination in AN. METHOD: Sixty-two outpatients with a diagnosis of AN took part. Measures of worry, rumination, core AN pathology and neuropsychological correlates were administered. RESULTS: Findings suggest that worry and rumination are elevated in AN patients compared with both healthy controls and anxiety disorder comparison groups. Regression analyses indicated that worry and rumination were significant predictors of eating disorder symptomatology, over and above the effects of anxiety and depression. Worry and rumination were not associated with neuropsychological measures of set-shifting and focus on detail. CONCLUSIONS: The data suggest that worry and rumination are major concerns for this group and warrant further study.

Internet-delivered cognitive therapy for social anxiety disorder: a development pilot series.

BACKGROUND: Randomized controlled trials have established that individual cognitive therapy based on the Clark and Wells (1995) model is an effective treatment for social anxiety disorder that is superior to a range of alternative psychological and pharmacological interventions. Normally the treatment involves up to 14 weekly face-to-face therapy sessions. AIM: To develop an internet based version of the treatment that requires less therapist time. METHOD: An internet-delivered version of cognitive therapy (iCT) for social anxiety disorder is described. The internet-version implements all key features of the face-to-face treatment; including video feedback, attention training, behavioural experiments, and memory focused techniques. Therapist support is via a built-in secure messaging system and by brief telephone calls. A cohort of 11 patients meeting DSM-IV criteria for social anxiety disorder worked through the programme and were assessed at pretreatment and posttreatment. RESULTS: No patients dropped out. Improvements in social anxiety and related process variables were within the range of those observed in randomized controlled trials of face-to-face CT. Nine patients (82%) were classified as treatment responders and seven (64%) achieved remission status. Therapist time per patient was only 20% of that in face-to-face CT. CONCLUSIONS: iCT shows promise as a way of reducing therapist time without compromising efficacy. Further evaluation of iCT is ongoing.

Changes in cognitive processes and coping strategies precede changes in symptoms during cognitive therapy for posttraumatic stress disorder.

Theories of posttraumatic stress disorder (PTSD) highlight the role of cognitive and behavioral factors in its development, maintenance, and treatment. This study investigated the relationship between changes in factors specified in Ehlers and Clark's (2000) model of PTSD and PTSD symptom change in 217 patients with PTSD who were treated with cognitive therapy for PTSD (CT-PTSD) in routine clinical care. Bivariate latent change score models (LCSM) of session-by-session changes in self-report measures showed that changes in PTSD symptoms were preceded by changes in negative appraisals, flashback characteristics of unwanted memories, safety behaviours, and unhelpful responses to intrusions, but not vice versa. For changes in trauma memory disorganization and PTSD symptoms we found a bidirectional association. This study provides evidence that cognitive and behavioral processes proposed in theoretical models of PTSD play a key role in driving symptom improvement during CT-PTSD.

Video feedback to update negative self-perceptions in social anxiety disorder: A comparison of internet-delivered vs face-to-face cognitive therapy formats.

BACKGROUND: Video feedback is a technique used in cognitive therapy for social anxiety disorder (CT-SAD) to update patients' negative self-perceptions of how they appear to others. Clients are supported to watch video of themselves engaging in social interactions. While typically undertaken in session with a therapist, this study aimed to investigate the effectiveness of remotely delivered video feedback embedded within an Internet-based cognitive therapy program (iCT-SAD). METHODS: We examined patients' self-perceptions and social anxiety symptoms before and after video feedback in two randomised controlled trials. Study 1 compared 49 iCT-SAD participants with 47 from face-to-face CT-SAD. Study 2 was a replication using data from 38 iCT-SAD participants from Hong Kong. RESULTS: In Study 1, ratings of self-perceptions and social anxiety showed significant reductions following video feedback, in both treatment formats. 92 % of participants in iCT-SAD, and 96 % in CT-SAD thought they looked less anxious compared to their predictions after viewing the videos. The change in self-perception ratings was larger in CT-SAD compared to iCT-SAD, but there was no evidence that the impact of video feedback on social anxiety symptoms around a week later differed between the two treatments. Study 2 replicated the iCT-SAD findings of Study 1. LIMITATIONS: The level of therapist support in iCT-SAD videofeedback varied with clinical need and was not measured. CONCLUSIONS: The findings indicate that video feedback can be delivered effectively online, and that its impact on social anxiety is not significantly different from in-person treatment delivery.

Quality-adjusted life years for digital cognitive behavioural therapy for insomnia (Sleepio): a secondary analysis.

BACKGROUND: Insomnia is common, and difficulty with daytime functioning is a core symptom. Studies show cognitive behavioural therapy (CBT) improves functioning, but evidence is needed on its value for money. Quality-adjusted life years (QALYs), capturing length and quality of life, provide a standard metric by which to judge whether a treatment is worth its cost. Studies have found QALY gains with therapist-delivered and therapist-guided CBT, but most have not reached statistical significance. Estimates of QALY gains with fully automated digital CBT (dCBT) for insomnia are lacking. AIM: To assess whether dCBT (Sleepio) for insomnia is associated with gains in QALYs compared with a sleep hygiene education control. DESIGN & SETTING: A secondary analysis of a large effectiveness trial of 1711 participants from the UK, US, and Australia. METHOD: EQ-5D scores, the National Institute for Health and Care Excellence's (NICE's) preferred measure of health-related quality of life (HRQoL), were predicted (mapped) from the 10-item Patient-Reported Outcomes Measurement Information System (PROMIS-10) Global Health scores and used to determine QALYs from baseline to 24 weeks (controlled), and to 48 weeks (uncontrolled). RESULTS: At week 24, QALYs were significantly higher for the dCBT group, with mean QALYs 0.375 and 0.362 in the dCBT and control groups, respectively. The mean difference was 0.014 (95% confidence interval [CI] = 0.008 to 0.019), and this difference was maintained over the 48-week study period (0.026, 95% CI = 0.016 to 0.036). The difference of 0.026 QALYs is equivalent to 9.5 days in perfect health. CONCLUSION: Sleepio is associated with statistically significant gains in QALYs over time compared with control. Findings may be used to power future studies and inform cost-effectiveness analyses of automated dCBT for insomnia scaled to a population level.