First-line venetoclax combinations versus chemoimmunotherapy in fit patients with chronic lymphocytic leukaemia (GAIA/CLL13): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: In the primary analysis report of the GAIA/CLL13 trial, we found that venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib improved undetectable measurable residual disease (MRD) rates and progression-free survival compared with chemoimmunotherapy in patients with previously untreated chronic lymphocytic leukaemia. However, to our knowledge, no data on direct comparisons of different venetoclax-based combinations are available. METHODS: GAIA/CLL13 is an open-label, randomised, phase 3 study conducted at 159 sites in ten countries in Europe and the Middle East. Eligible patients were aged 18 years or older, with a life expectancy of at least 6 months, an Eastern Cooperative Oncology group performance status of 0-2, a cumulative illness rating scale score of 6 or lower or a single score of 4 or lower, and no TP53 aberrations. Patients were randomly assigned (1:1:1:1), with a computer-generated list stratified by age, Binet stage, and regional study group, to either chemoimmunotherapy, venetoclax-rituximab, venetoclax-obinutuzumab, or venetoclax-obinutuzumab-ibrutinib. All treatments were administered in 28-day cycles. Patients in the chemoimmunotherapy group received six cycles of treatment, with patients older than 65 years receiving intravenous bendamustine (90 mg/m2, days 1-2), whereas patients aged 65 years or younger received intravenous fludarabine (25 mg/m2, days 1-3) and intravenous cyclophosphamide (250 mg/m2, days 1-3). Intravenous rituximab (375 mg/m2, day 1 of cycle 1; 500 mg/m2, day 1 of cycles 2-6) was added to chemotherapy. In the experimental groups, patients received daily venetoclax (400 mg orally) for ten cycles after a 5-week ramp-up phase starting on day 22 of cycle 1. In the venetoclax-rituximab group, intravenous rituximab (375 mg/m2, day 1 of cycle 1; 500 mg/m2, day 1 of cycles 2-6) was added. In the obinutuzumab-containing groups, obinutuzumab was added (cycle 1: 100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8 and 15; cycles 2-6: 1000 mg on day 1). In the venetoclax-obinutuzumab-ibrutinib group, daily ibrutinib (420 mg orally, from day 1 of cycle 1) was added until undetectable MRD was reached in two consecutive measurements (3 months apart) or until cycle 36. The planned treatment duration was six cycles in the chemoimmunotherapy group, 12 cycles in the venetoclax-rituximab and the venetoclax-obinutuzumab group and between 12 and 36 cycles in the venetoclax-obinutuzumab-ibrutinib group. Coprimary endpoints were the undetectable MRD rate in peripheral blood at month 15 for the comparison of venetoclax-obinutuzumab versus standard chemoimmunotherapy and investigator-assessed progression-free survival for the comparison of venetoclax-obinutuzumab-ibrutinib versus standard chemoimmunotherapy, both analysed in the intention-to-treat population (ie, all patients randomly assigned to treatment) with a split α of 0·025 for each coprimary endpoint. Both coprimary endpoints have been reported elsewhere. Here we report a post-hoc exploratory analysis of updated progression-free survival results after a 4-year follow-up of our study population. Safety analyses included all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT02950051, recruitment is complete, and all patients are off study treatment. FINDINGS: Between Dec 13, 2016, and Oct 13, 2019, 1080 patients were screened and 926 were randomly assigned to treatment (chemoimmunotherapy group n=229; venetoclax-rituximab group n=237; venetoclax-obinutuzumab group n=229; and venetoclax-obinutuzumab-ibrutinib group n=231); mean age 60·8 years (SD 10·2), 259 (28%) of 926 patients were female, and 667 (72%) were male (data on race and ethnicity are not reported). At data cutoff for this exploratory follow-up analysis (Jan 31, 2023; median follow-up 50·7 months [IQR 44·6-57·9]), patients in the venetoclax-obinutuzumab group had significantly longer progression-free survival than those in the chemoimmunotherapy group (hazard ratio [HR] 0·47 [97·5% CI 0·32-0·69], p<0·0001) and the venetoclax-rituximab group (0·57 [0·38-0·84], p=0·0011). The venetoclax-obinutuzumab-ibrutinib group also had a significantly longer progression-free survival than the chemoimmunotherapy group (0·30 [0·19-0·47]; p<0·0001) and the venetoclax-rituximab group (0·38 [0·24-0·59]; p<0·0001). There was no difference in progression-free survival between the venetoclax-obinutuzumab-ibrutinib and venetoclax-obinutuzumab groups (0·63 [0·39-1·02]; p=0·031), and the proportional hazards assumption was not met for the comparison between the venetoclax-rituximab group versus the chemoimmunotherapy group (log-rank p=0·10). The estimated 4-year progression-free survival rate was 85·5% (97·5% CI 79·9-91·1; 37 [16%] events) in the venetoclax-obinutuzumab-ibrutinib group, 81·8% (75·8-87·8; 55 [24%] events) in the venetoclax-obinutuzumab group, 70·1% (63·0-77·3; 84 [35%] events) in the venetoclax-rituximab group, and 62·0% (54·4-69·7; 90 [39%] events) in the chemoimmunotherapy group. The most common grade 3 or worse treatment-related adverse event was neutropenia (114 [53%] of 216 patients in the chemoimmunotherapy group, 109 [46%] of 237 in the venetoclax-rituximab group, 127 [56%] of 228 in the venetoclax-obinutuzumab group, and 112 [48%] of 231 in the venetoclax-obinutuzumab-ibrutinib group). Deaths determined to be associated with study treatment by the investigator occurred in three (1%) patients in the chemoimmunotherapy group (n=1 due to each of sepsis, metastatic squamous cell carcinoma, and Richter's syndrome), none in the venetoclax-rituximab and venetoclax-obinutuzumab groups, and four (2%) in the venetoclax-obinutuzumab-ibrutinib group (n=1 due to each of acute myeloid leukaemia, fungal encephalitis, small-cell lung cancer, and toxic leukoencephalopathy). INTERPRETATION: With more than 4 years of follow-up, venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib significantly extended progression-free survival compared with both chemoimmunotherapy and venetoclax-rituximab in previously untreated, fit patients with chronic lymphocytic leukaemia, thereby supporting their use and further evaluation in this patient group, while still considering the higher toxicities observed with the triple combination. FUNDING: AbbVie, Janssen, and F Hoffmann-La Roche.

Treating intrusive memories after trauma in healthcare workers: a Bayesian adaptive randomised trial developing an imagery-competing task intervention.

Intensive care unit (ICU) staff continue to face recurrent work-related traumatic events throughout the COVID-19 pandemic. Intrusive memories (IMs) of such traumatic events comprise sensory image-based memories. Harnessing research on preventing IMs with a novel behavioural intervention on the day of trauma, here we take critical next steps in developing this approach as a treatment for ICU staff who are already experiencing IMs days, weeks, or months post-trauma. To address the urgent need to develop novel mental health interventions, we used Bayesian statistical approaches to optimise a brief imagery-competing task intervention to reduce the number of IMs. We evaluated a digitised version of the intervention for remote, scalable delivery. We conducted a two-arm, parallel-group, randomised, adaptive Bayesian optimisation trial. Eligible participants worked clinically in a UK NHS ICU during the pandemic, experienced at least one work-related traumatic event, and at least three IMs in the week prior to recruitment. Participants were randomised to receive immediate or delayed (after 4 weeks) access to the intervention. Primary outcome was the number of IMs of trauma during week 4, controlling for baseline week. Analyses were conducted on an intention-to-treat basis as a between-group comparison. Prior to final analysis, sequential Bayesian analyses were conducted (n = 20, 23, 29, 37, 41, 45) to inform early stopping of the trial prior to the planned maximum recruitment (n = 150). Final analysis (n = 75) showed strong evidence for a positive treatment effect (Bayes factor, BF = 1.25 × 106): the immediate arm reported fewer IMs (median = 1, IQR = 0-3) than the delayed arm (median = 10, IQR = 6-16.5). With further digital enhancements, the intervention (n = 28) also showed a positive treatment effect (BF = 7.31). Sequential Bayesian analyses provided evidence for reducing IMs of work-related trauma for healthcare workers. This methodology also allowed us to rule out negative effects early, reduced the planned maximum sample size, and allowed evaluation of enhancements. Trial Registration NCT04992390 ( www.clinicaltrials.gov ).

Single-session visuospatial task procedure to prevent childbirth-related posttraumatic stress disorder: a multicentre double-blind randomised controlled trial.

Preventive evidence-based interventions for childbirth-related posttraumatic stress disorder (CB-PTSD) are lacking. Yet, 18.5% of women develop CB-PTSD symptoms following an unplanned caesarean section (UCS). This two-arm, multicentre, double-blind superiority trial tested the efficacy of an early single-session intervention including a visuospatial task on the prevention of maternal CB-PTSD symptoms. The intervention was delivered by trained maternity clinicians. Shortly after UCS, women were included if they gave birth to a live baby, provided consent, and perceived their childbirth as traumatic. Participants were randomly assigned to the intervention or attention-placebo group (allocation ratio 1:1). Assessments were done at birth, six weeks, and six months postpartum. Group differences in maternal CB-PTSD symptoms at six weeks (primary outcomes) and six months postpartum (secondary outcomes) were assessed with the self-report PTSD Checklist for DSM-5 (PCL-5) and by blinded research assessors with the Clinician-administered PTSD scale for DSM-5 (CAPS-5). Analysis was by intention-to-treat. The trial was prospectively registered (ClinicalTrials.gov, NCT03576586). Of the 2068 women assessed for eligibility, 166 were eligible and 146 were randomly assigned to the intervention (n = 74) or attention-placebo control group (n = 72). For the PCL-5, at six weeks, a marginally significant intervention effect was found on the total PCL-5 PTSD symptom count (ß = -0.43, S.E. = 0.23, z = -1.88, p < 0.06), and on the intrusions (ß = -0.73, S.E. = 0.38, z = -1.94, p < 0.0525) and arousal (ß = -0.55, S.E. = 0.29, z = -1.92, p < 0.0552) clusters. At six months, a significant intervention effect on the total PCL-5 PTSD symptom count (ß = -0.65, S.E. = 0.32, z = -2.04, p = 0.041, 95%CI[-1.27, -0.03]), on alterations in cognition and mood (ß = -0.85, S.E. = 0.27, z = -3.15, p = 0.0016) and arousal (ß = -0.56, S.E. = 0.26, z = -2.19, p < 0.0289, 95%CI[-1.07, -0.06]) clusters appeared. No group differences on the CAPS-5 emerged. Results provide evidence that this brief, single-session intervention carried out by trained clinicians can prevent the development of CB-PTSD symptoms up to six months postpartum.

Neuromodulation of Visual Cortex Reduces the Intensity of Intrusive Memories.

Aversive events can be reexperienced as involuntary and spontaneous mental images of the event. Given that the vividness of retrieved mental images is coupled with elevated visual activation, we tested whether neuromodulation of the visual cortex would reduce the frequency and negative emotional intensity of intrusive memories. Intrusive memories of a viewed trauma film and their accompanied emotional intensity were recorded throughout 5 days. Functional connectivity, measured with resting-state functional magnetic resonance imaging prior to film viewing, was used as predictive marker for intrusions-related negative emotional intensity. Results indicated that an interaction between the visual network and emotion processing areas predicted intrusions' emotional intensity. To test the causal influence of early visual cortex activity on intrusions' emotional intensity, participants' memory of the film was reactivated by brief reminders 1 day following film viewing, followed by inhibitory 1 Hz repetitive transcranial magnetic stimulation (rTMS) over early visual cortex. Results showed that visual cortex inhibitory stimulation reduced the emotional intensity of later intrusions, while leaving intrusion frequency and explicit visual memory intact. Current findings suggest that early visual areas constitute a central node influencing the emotional intensity of intrusive memories for negative events. Potential neuroscience-driven intervention targets designed to downregulate the emotional intensity of intrusive memories are discussed.

Exploring preferences of older adults for dental services: A pilot multi-national discrete choice experiment.

OBJECTIVES: To pilot an exploration of older adults' future preferences using discrete choice experiments to understand who should provide dental examinations and treatment, where these services should be provided, and participants' willingness to pay and willingness to travel. BACKGROUND: The proportion of older adults in the general population is increasing and is recognised as a pressing public health challenge. MATERIALS AND METHODS: Older people aged 65 years and over were recruited into this study from the UK, Switzerland and Greece. Drawing on earlier stakeholder engagement, a set of choice experiments are developed to explore the future preferences of older people for dental examinations and dental treatment, as they anticipated losing their independence. These were presented to the participants using a range of platforms, because of the COVID pandemic. Data were analysed in STATA using a random-effects logit model. RESULTS: Two hundred and forty-six participants (median age 70 years) completed the pilot study. There was a strong preference across all countries for a dentist to undertake a dental examination (Greece: ß = 0.944, Switzerland: ß = 0.260, UK ß = 0.791), rather than a medical doctor (Greece: ß = -0.556, Switzerland: ß = -0.4690, UK: ß = -0.468). Participants in Switzerland and the UK preferred these examinations to be undertaken in a dental practice (Switzerland: ß = 0.220, UK: ß = 0.580) while participants in Greece preferred the dental examination to be undertaken in their homes (ß = 1.172). Greek participants preferred dental treatment to be undertaken by a specialist (ß = 0.365) in their home (ß = 0.862), while participants from the UK and Switzerland preferred to avoid any dental treatment at home (Switzerland: ß = -0.387; UK: ß = -0.444). Willingness to pay analyses highlighted that participants in Switzerland and the UK were willing to pay more to ensure the continuity of future service provision at a family dental practice (Switzerland: ß = 0.454, UK: ß = 0.695). CONCLUSION: Discrete choice experiments are valuable for exploring older people's preferences for dental service provision in different countries. Future larger studies should be conducted to further explore the potential of this approach, given the pressing need to design services that are fit for purpose for older people. Continuity of dental service provision is considered as important by most older people, as they anticipate losing their dependence.

Novel Approach to Integrating Mental Health Care into a Primary Care Setting: Development, Implementation, and Outcomes.

It is now widely accepted that there is a growing discrepancy between demand and access to adequate treatment for behavioral or mental health conditions in the United States. This results in immense personal, societal, and economic costs. One rapidly growing method of addressing this discrepancy is to integrate mental health services into the primary care setting, which has become the de facto service provider for these conditions. In this paper, we describe the development and implementation of a novel integrated care program in a large mid-western university-based healthcare system, drawn from the collaborative care model, and describe the benefits in terms of both health care utilization and depression outcomes. Limitations and proposed future directions are discussed.

Anxiety disorders.

Anxiety disorders form the most common group of mental disorders and generally start before or in early adulthood. Core features include excessive fear and anxiety or avoidance of perceived threats that are persistent and impairing. Anxiety disorders involve dysfunction in brain circuits that respond to danger. Risk for anxiety disorders is influenced by genetic factors, environmental factors, and their epigenetic relations. Anxiety disorders are often comorbid with one another and with other mental disorders, especially depression, as well as with somatic disorders. Such comorbidity generally signifies more severe symptoms, greater clinical burden, and greater treatment difficulty. Reducing the large burden of disease from anxiety disorders in individuals and worldwide can be best achieved by timely, accurate disease detection and adequate treatment administration, scaling up of treatments when needed. Evidence-based psychotherapy (particularly cognitive behavioural therapy) and psychoactive medications (particularly serotonergic compounds) are both effective, facilitating patients' choices in therapeutic decisions. Although promising, no enduring preventive measures are available, and, along with frequent therapy resistance, clinical needs remain unaddressed. Ongoing research efforts tackle these problems, and future efforts should seek individualised, more effective approaches for treatment with precision medicine.

Imagery-enhanced v. verbally-based group cognitive behavior therapy for social anxiety disorder: a randomized clinical trial.

BACKGROUND: Cognitive behavior therapy (CBT) is effective for most patients with a social anxiety disorder (SAD) but a substantial proportion fails to remit. Experimental and clinical research suggests that enhancing CBT using imagery-based techniques could improve outcomes. It was hypothesized that imagery-enhanced CBT (IE-CBT) would be superior to verbally-based CBT (VB-CBT) on pre-registered outcomes. METHODS: A randomized controlled trial of IE-CBT v. VB-CBT for social anxiety was completed in a community mental health clinic setting. Participants were randomized to IE (n = 53) or VB (n = 54) CBT, with 1-month (primary end point) and 6-month follow-up assessments. Participants completed 12, 2-hour, weekly sessions of IE-CBT or VB-CBT plus 1-month follow-up. RESULTS: Intention to treat analyses showed very large within-treatment effect sizes on the social interaction anxiety at all time points (ds = 2.09-2.62), with no between-treatment differences on this outcome or clinician-rated severity [1-month OR = 1.45 (0.45, 4.62), p = 0.53; 6-month OR = 1.31 (0.42, 4.08), p = 0.65], SAD remission (1-month: IE = 61.04%, VB = 55.09%, p = 0.59); 6-month: IE = 58.73%, VB = 61.89%, p = 0.77), or secondary outcomes. Three adverse events were noted (substance abuse, n = 1 in IE-CBT; temporary increase in suicide risk, n = 1 in each condition, with one being withdrawn at 1-month follow-up). CONCLUSIONS: Group IE-CBT and VB-CBT were safe and there were no significant differences in outcomes. Both treatments were associated with very large within-group effect sizes and the majority of patients remitted following treatment.

Hotspots in the immediate aftermath of trauma - Mental imagery of worst moments highlighting time, space and motion.

Intrusive memories of trauma (memories that enter consciousness involuntarily) highjack cognitive processing, cause emotional distress, and represent a core symptom of posttraumatic stress disorder. Intrusive memories often contain the worst moment/s ('hotspots') of the trauma memory. Little is known about hotspots shortly after they are formed, i.e., in the first hours after trauma. We investigated the features of hotspots in trauma-exposed individuals (n = 21) within 72 h post-trauma, using linguistic analysis and qualitative coding. On average, participants reported three hotspots per traumatic event (M = 7.8 words/hotspot). Hotspots primarily contained words related to time, space, motion, and sensory processing. Most hotspots contained sensory features (97%) and motion (59%). Few cognitions and no emotion words were identified. Results indicate that hotspots collected shortly post-trauma are expressed as motion-rich sensory-perceptual experiences (mental imagery) with little detail about emotion/cognition. Findings are discussed in terms of the function of hotspots (e.g., preparedness for action) and clinical implications.

Emotional mental imagery generation during spontaneous future thinking: relationship with optimism and negative mood.

Optimism is known to buffer against negative mood. Thus, understanding the factors that contribute to individual variation in optimism may inform interventions for mood disorders. Preliminary evidence suggests that the generation of mental imagery-based representations of positive relative to negative future scenarios is related to optimism. This study investigated the hypothesis that an elevated tendency to generate positive relative to negative mental imagery during spontaneous future thinking would be associated with reduced negative mood via its relationship to higher optimism. Participants (N = 44) with varied levels of naturally occurring negative mood reported current levels of optimism and the real-time occurrence and characteristics of spontaneous thoughts during a sustained attention computer task. Consistent with hypotheses, higher optimism statistically mediated the relationship between a higher proportional frequency of positive relative to negative mental imagery during spontaneous future thinking and lower negative mood. Further, the relationship between emotional mental imagery and optimism was found for future, but not past, thinking, nor for verbal future or past thinking. Thus, a greater tendency to generate positive rather than negative imagery-based mental representations when spontaneously thinking about the future may influence how optimistic one feels, which in turn may influence one's experience of negative mood.

Current preparation status in AAC: perspectives of special education teachers in the United States.

Special education teachers are essential team members in the provision of services to students with complex communication needs. Professional competencies related to augmentative and alternative communication (AAC) practices have been outlined for special education teachers as part of their professional standards. Yet, it is unclear to what extent these professionals have knowledge and skills in this area. Given existing gaps in the literature, an anonymous, web-based survey was disseminated across the United States to gather information on special education teachers' self-reported knowledge and skills in AAC. A total of 1198 special education teachers from 46 states responded to the survey. Findings indicated that most special education teachers did not receive formal training in AAC during their teacher licensure preparation programs, resulting in low levels of self-reported knowledge and skills. Data also indicated that while influencing factors existed, special education teachers' knowledge and skills in AAC remained minimal. Implications and recommendations for stakeholders are discussed.

Future self-imagery of young people in Sweden during the COVID-19 pandemic: an exploratory mixed methods analysis.

Global restrictions imposed during the COVID-19 pandemic significantly limited the capacity to plan for the future. Little is known about young people's future self-images and the impact the COVID-19 pandemic may have had upon them. Given evidence that the ability to imagine a positive future can be protective for mental health, research into the impact of the pandemic on future self-imagery is needed. In two studies, we therefore explored the consequences of the COVID-19 pandemic for future self-imagery in an unselected sample of young people in Sweden, specifically: (a) how content and characteristics of future self-images changed from before to during the pandemic, and (b) how such change was related to trauma history, intrusive memories of COVID-19 media footage, past time perspective and optimism (assessed with questionnaires/intrusive memory diary). Future self-images before and during the pandemic were assessed using the 'I Will Be' task (N Study1=74; N Study2=99). A mixed methods design, combining quantitative analysis, qualitative content coding and thematic analysis was used. Exploratory results of Study 1 indicated that future images were rated as less positive during than before the pandemic and that this reduction was less pronounced in people with higher optimism. Results were replicated in an independent sample (Study 2, collected later during the pandemic). In conclusion, whilst the findings are preliminary and emerged from an unselected sample, they prompt the suggestion that brief, novel interventions which aim to bolster positive future imagery may hold promise as a scalable means by which to enhance mental health for young people in the context of the COVID-19 pandemic. Supplementary information: The online version contains supplementary material available at 10.1007/s12144-022-04100-z.

WASh multicentre randomised controlled trial: water-assisted sigmoidoscopy in English NHS bowel scope screening.

OBJECTIVES: The English Bowel Cancer Screening Programme invites 55 year olds for a sigmoidoscopy (Bowel Scope Screening (BSS)), aiming to resect premalignant polyps, thus reducing cancer incidence. A national patient survey indicated higher procedural pain than anticipated, potentially impacting on screening compliance and effectiveness. We aimed to assess whether water-assisted sigmoidoscopy (WAS), as opposed to standard CO2 technique, improved procedural pain and detection of adenomatous polyps. DESIGN: The WASh (Water-Assisted Sigmoidoscopy) trial was a multicentre, single-blind, randomised control trial for people undergoing BSS. Participants were randomised to either receive WAS or CO2 from five sites across England. The primary outcome measure was patient-reported moderate/severe pain, as assessed by patients on a standard Likert scale post procedure prior to discharge. The key secondary outcome was adenoma detection rate (ADR). The costs of each technique were also measured. RESULTS: 1123 participants (50% women, mean age 55) were randomised (561 WAS, 562 CO2). We found no difference in patient-reported moderate/severe pain between WAS and CO2 (14% in WAS, 15% in CO2; p=0.47). ADR was 15% in the CO2 arm and 11% in the WAS arm (p=0.03); however, it remained above the minimum national performance standard in both arms. There was no statistical difference in mean number of adenomas nor overall polyp detection rate. There was negligible cost difference between the two techniques. CONCLUSION: In the context of enema-prepared unsedated screening sigmoidoscopies performed by screening-accredited endoscopists, no difference in patient-reported pain was seen when using either a CO2 or WAS intubation technique. TRIAL REGISTRATION NUMBER: ISRCTN81466870.

Mechanistically informed non-invasive peripheral nerve stimulation for peripheral neuropathic pain: a randomised double-blind sham-controlled trial.

BACKGROUND: Induction of long-term synaptic depression (LTD) is proposed as a treatment mechanism for chronic pain but remains untested in clinical populations. Two interlinked studies; (1) A patient-assessor blinded, randomised, sham-controlled clinical trial and (2) an open-label mechanistic study, sought to examine therapeutic LTD for persons with chronic peripheral nerve injury pain. METHODS: (1) Patients were randomised using a concealed, computer-generated schedule to either active or sham non-invasive low-frequency nerve stimulation (LFS), for 3 months (minimum 10 min/day). The primary outcome was average pain intensity (0-10 Likert scale) recorded over 1 week, at 3 months, compared between study groups. (2) On trial completion, consenting subjects entered a mechanistic study assessing somatosensory changes in response to LFS. RESULTS: (1) 76 patients were randomised (38 per group), with 65 (31 active, 34 sham) included in the intention to treat analysis. The primary outcome was not significant, pain scores were 0.3 units lower in active group (95% CI - 1.0, 0.3; p = 0.30) giving an effect size of 0.19 (Cohen's D). Two non-device related serious adverse events were reported. (2) In the mechanistic study (n = 19) primary outcomes of mechanical pain sensitivity (p = 0.006) and dynamic mechanical allodynia (p = 0.043) significantly improved indicating reduced mechanical hyperalgesia. CONCLUSIONS: Results from the RCT failed to reach significance. Results from the mechanistic study provide new evidence for effective induction of LTD in a clinical population. Taken together results add to mechanistic understanding of LTD and help inform future study design and approaches to treatment. Trial registration ISRCTN53432663.

Suicide attempt and suicide in refugees in Sweden - a nationwide population-based cohort study.

BACKGROUND: Despite a reported high rate of mental disorders in refugees, scientific knowledge on their risk of suicide attempt and suicide is scarce. We aimed to investigate (1) the risk of suicide attempt and suicide in refugees in Sweden, according to their country of birth, compared with Swedish-born individuals and (2) to what extent time period effects, socio-demographics, labour market marginalisation (LMM) and morbidity explain these associations. METHODS: Three cohorts comprising the entire population of Sweden, 16-64 years at 31 December 1999, 2004 and 2009 (around 5 million each, of which 3.3-5.0% refugees), were followed for 4 years each through register linkage. Additionally, the 2004 cohort was followed for 9 years, to allow analyses by refugees' country of birth. Crude and multivariate hazard ratios (HRs) with 95% confidence intervals (CIs) were computed. The multivariate models were adjusted for socio-demographic, LMM and morbidity factors. RESULTS: In multivariate analyses, HRs regarding suicide attempt and suicide in refugees, compared with Swedish-born, ranged from 0.38-1.25 and 0.16-1.20 according to country of birth, respectively. Results were either non-significant or showed lower risks for refugees. Exceptions were refugees from Iran (HR 1.25; 95% CI 1.14-1.41) for suicide attempt. The risk for suicide attempt in refugees compared with the Swedish-born diminished slightly across time periods. CONCLUSIONS: Refugees seem to be protected from suicide attempt and suicide relative to Swedish-born, which calls for more studies to disentangle underlying risk and protective factors.

Emotional recognition training modifies neural response to emotional faces but does not improve mood in healthy volunteers with high levels of depressive symptoms.

BACKGROUND: There is demand for new, effective and scalable treatments for depression, and development of new forms of cognitive bias modification (CBM) of negative emotional processing biases has been suggested as possible interventions to meet this need. METHODS: We report two double blind RCTs, in which volunteers with high levels of depressive symptoms (Beck Depression Inventory ii (BDI-ii) > 14) completed a brief course of emotion recognition training (a novel form of CBM using faces) or sham training. In Study 1 (N = 36), participants completed a post-training emotion recognition task whilst undergoing functional magnetic resonance imaging to investigate neural correlates of CBM. In Study 2 (N = 190), measures of mood were assessed post-training, and at 2-week and 6-week follow-up. RESULTS: In both studies, CBM resulted in an initial change in emotion recognition bias, which (in Study 2) persisted for 6 weeks after the end of training. In Study 1, CBM resulted in increases neural activation to happy faces, with this effect driven by an increase in neural activity in the medial prefrontal cortex and bilateral amygdala. In Study 2, CBM did not lead to a reduction in depressive symptoms on the BDI-ii, or on related measures of mood, motivation and persistence, or depressive interpretation bias at either 2 or 6-week follow-ups. CONCLUSIONS: CBM of emotion recognition has effects on neural activity that are similar in some respects to those induced by Selective Serotonin Reuptake Inhibitors (SSRI) administration (Study 1), but we find no evidence that this had any later effect on self-reported mood in an analogue sample of non-clinical volunteers with low mood (Study 2).

The Effects of Modifying Dysfunctional Appraisals in Posttraumatic Stress Disorder Using a Form of Cognitive Bias Modification: Results of a Randomized Controlled Trial in an Inpatient Setting.

INTRODUCTION: Dysfunctional appraisals about traumatic events and their sequelae are a key mechanism in posttraumatic stress disorder (PTSD). Experimental studies have shown that a computerized cognitive training, cognitive bias modification for appraisals (CBM-APP), can modify dysfunctional appraisals and reduce analogue trauma symptoms amongst healthy and subclinical volunteers. OBJECTIVE: We aimed to test whether CBM-APP could reduce dysfunctional appraisals related to trauma reactions in PTSD patients, and whether this would lead to improvements in PTSD symptoms. METHODS: We compared CBM-APP to sham training in a parallel-arm proof-of-principle double-blind randomized controlled trial amongst 80 PTSD patients admitted to an inpatient clinic. Both arms comprised a training schedule of 8 sessions over a 2-week period and were completed as an adjunct to the standard treatment programme. RESULTS: In intention-to-treat analyses, participants receiving CBM-APP showed a greater reduction in dysfunctional appraisals on a scenario task from pre- to posttraining (primary outcome) assessments, compared to those receiving sham training (d = 1.30, 95% CI 0.82-1.80), with between-group differences also found on the Posttraumatic Cognitions Inventory (PTCI; d = 0.85, 95% CI 0.39-1.32) and the PTSD Checklist for DSM-5 (PCL-5; d = 0.68, 95% CI 0.23-1.14), but not for long-term cortisol concentrations (d = 0.25, 95% CI -0.28 to 0.78). Reductions in dysfunctional appraisals assessed via the scenario task correlated with reductions on the PTCI, PCL-5, and hair cortisol concentrations from pre- to posttraining time points. CONCLUSIONS: Results support dysfunctional appraisals as a modifiable cognitive mechanism, and that their proximal modification transfers to downstream PTSD symptoms. These findings could open new avenues for improving present therapeutic approaches.

Healthcare use before and after suicide attempt in refugees and Swedish-born individuals.

PURPOSE: There is a lack of research on whether healthcare use before and after a suicide attempt differs between refugees and the host population. We aimed to investigate if the patterns of specialised (inpatient and specialised outpatient) psychiatric and somatic healthcare use, 3 years before and after a suicide attempt, differ between refugees and the Swedish-born individuals in Sweden. Additionally, we aimed to explore if specialised healthcare use differed among refugee suicide attempters according to their sex, age, education or receipt of disability pension. METHODS: All refugees and Swedish-born individuals, 20-64 years of age, treated for suicide attempt in specialised healthcare during 2004-2013 (n = 85,771 suicide attempters, of which 4.5% refugees) were followed 3 years before and after (Y - 3 to Y + 3) the index suicide attempt (t0) regarding their specialised healthcare use. Annual adjusted prevalence with 95% confidence intervals (CIs) of specialised healthcare use were assessed by generalized estimating equations (GEE). Additionally, in analyses among the refugees, GEE models were stratified by sex, age, educational level and disability pension. RESULTS: Compared to Swedish-born, refugees had lower prevalence rates of psychiatric and somatic healthcare use during the observation period. During Y + 1, 25% (95% CI 23-28%) refugees and 30% (95% CI 29-30%) Swedish-born used inpatient psychiatric healthcare. Among refugees, a higher specialised healthcare use was observed in disability pension recipients than non-recipients. CONCLUSION: Refugees used less specialised healthcare, before and after a suicide attempt, relative to the Swedish-born. Strengthened cultural competence among healthcare professionals and better health literacy among the refugees may improve healthcare access in refugees.

A single case series using visuospatial task interference to reduce the number of visual intrusive memories of trauma with refugees.

The current worldwide so-called "refugee crisis" has led to an unprecedented increase in migration globally. Because of stigma and language barriers, mental health care for refugees is limited. There is a need for novel, scalable psychological interventions. We investigated whether a brief behavioural intervention involving a memory reminder cue and Tetris gameplay on a smartphone reduces intrusive memories in refugees using a single case (N = 4) ABAB withdrawal design. The baseline phase (A) included a no-intervention week; the intervention phase (B) included an in-person session with the researchers, comprised of the behavioural intervention followed by self-guided use in daily life the following week. All participants reported a decrease in intrusive memories after the intervention, as well as functional improvements (e.g., in concentration). Importantly, participants rated the intervention as feasible and acceptable. As one in-person session was effective in persistent intrusion reduction, ABAB proved not to be the optimal design as intrusions did not rebound in the withdrawal phase. Findings are promising and highlight the need for further evaluation of novel interventions for mental health problems in refugees.

"Sow, Grow, Know, and Show": The Impact of School Gardens on Student Self-Perception in the Mississippi Delta.

This research evaluates the impact of participation in school garden programs on fifth grade student garden knowledge, self-perception, and standardized test scores in the Mississippi Delta. We collected pre and posttest participant data for two years, compared garden participants' standardized test scores with non-participants, and conducted participant observation and interviews in three school gardens for eight months during the 2017-2018 school year. While no effect on standardized test scores could be determined, students increased garden knowledge and reported feeling positive about their future, teamwork, and leadership ability. These results were supported by observations of student joy, confidence, leadership, and teamwork.