State of the Art Review: Aortic Valve Repair in Infants and Children.

BACKGROUND: Congenital aortic and truncal valve disease is challenging in infants and children given the lack of available prostheses in very small sizes and the limited durability of homograft aortic valve replacement. METHODS: A comprehensive literature search was performed using the PubMed database. Studies were included either if the report included patients less than 1 year of age or if the technique was tailored to accommodate for somatic growth. RESULTS: Techniques for aortic and truncal valve repair addressing each aspect of the aortic valve complex - the aorta, aortic annulus, commissures, and cusps - were reviewed. The incidence of reoperation following aortic or truncal valve repair is significant at 10-years ranging from 30% to 70% depending on the underlying diagnosis and the repair technique utilized. A significant challenge in interpreting the published literature relates to the lack of anatomic data available in the publications limiting the ability to make direct comparisons between operative techniques and also limits the ability to draw conclusions regarding these techniques as applied to varied etiologies. CONCLUSIONS: A comprehensive understanding of the aortic valve complex is necessary to achieve adequate results in pediatric aortic valve repair given the high variability in these valves.

Exploring the internal forward model: action-effect prediction and attention in sensorimotor processing.

Action-effect predictions are believed to facilitate movement based on its association with sensory objectives and suppress the neurophysiological response to self- versus externally generated stimuli (i.e. sensory attenuation). However, research is needed to explore theorized differences in the use of action-effect prediction based on whether movement is uncued (i.e. volitional) or in response to external cues (i.e. stimulus-driven). While much of the sensory attenuation literature has examined effects involving the auditory N1, evidence is also conflicted regarding this component's sensitivity to action-effect prediction. In this study (n = 64), we explored the influence of action-effect contingency on event-related potentials associated with visually cued and uncued movement, as well as resultant stimuli. Our findings replicate recent evidence demonstrating reduced N1 amplitude for tones produced by stimulus-driven movement. Despite influencing motor preparation, action-effect contingency was not found to affect N1 amplitudes. Instead, we explore electrophysiological markers suggesting that attentional mechanisms may suppress the neurophysiological response to sound produced by stimulus-driven movement. Our findings demonstrate lateralized parieto-occipital activity that coincides with the auditory N1, corresponds to a reduction in its amplitude, and is topographically consistent with documented effects of attentional suppression. These results provide new insights into sensorimotor coordination and potential mechanisms underlying sensory attenuation.

A cognitive model of delusion propensity through dysregulated correlation detection.

BACKGROUND: We present a novel account of delusion propensity that integrates the roles of working memory (WM), decision criteria, and information gathering biases. This framework emphasises the role of aberrant correlation detection, which leads to the spurious perception of relationships between one's experiences. The frequency of such outcomes is moderated by the scaling of one's decision criteria which, for reasons discussed, must also account for WM capacity. The proposed dysregulated correlation detection account posits that propensity for delusional ideation is influenced by disturbances in this mechanism. METHODS: Hypotheses were tested using a novel task that required participants (N = 92) to identify correlation between binary manipulations of simple shapes, presented as sequential pairs. Decision criteria and correlation detection were assessed under a Signal Detection Theory framework, while WM capacity was assessed through the Automated Operation Span Task and delusion propensity was measured using the Peters Delusion Inventory. Structural equation modeling was conducted to evaluate the proposed model. RESULTS: Consistent with the central hypothesis, an interaction between decision criteria and WM was found to contribute significantly to delusion propensity through its effect on correlation detection accuracy. Greater delusion propensity was observed among participants with more liberal decision criteria, which was also in accordance with hypotheses. At the same time, the total effect of WM on delusion propensity was not found to be significant. CONCLUSIONS: These findings provide preliminary support for the proposed dysregulated correlation detection account of propensity for delusional ideation.

Sensory attenuation is modulated by the contrasting effects of predictability and control.

Self-generated stimuli have been found to elicit a reduced sensory response compared with externally-generated stimuli. However, much of the literature has not adequately controlled for differences in the temporal predictability and temporal control of stimuli. In two experiments, we compared the N1 (and P2) components of the auditory-evoked potential to self- and externally-generated tones that differed with respect to these two factors. In Experiment 1 (n = 42), we found that increasing temporal predictability reduced N1 amplitude in a manner that may often account for the observed reduction in sensory response to self-generated sounds. We also observed that reducing temporal control over the tones resulted in a reduction in N1 amplitude. The contrasting effects of temporal predictability and temporal control on N1 amplitude meant that sensory attenuation prevailed when controlling for each. Experiment 2 (n = 38) explored the potential effect of selective attention on the results of Experiment 1 by modifying task requirements such that similar levels of attention were allocated to the visual stimuli across conditions. The results of Experiment 2 replicated those of Experiment 1, and suggested that the observed effects of temporal control and sensory attenuation were not driven by differences in attention. Given that self- and externally-generated sensations commonly differ with respect to both temporal predictability and temporal control, findings of the present study may necessitate a re-evaluation of the experimental paradigms used to study sensory attenuation.

Which exercise and behavioural interventions show most promise for treating fatigue in multiple sclerosis? A network meta-analysis.

BACKGROUND: Fatigue is a common, debilitating symptom of multiple sclerosis (MS) without a current standardised treatment. OBJECTIVE: The aim of this systematic review with network meta-analyses was to estimate the relative effectiveness of both fatigue-targeted and non-targeted exercise, behavioural and combined (behavioural and exercise) interventions. METHODS: Nine electronic databases up to August 2018 were searched, and 113 trials (n = 6909) were included: 34 were fatigue-targeted and 79 non-fatigue-targeted trials. Intervention characteristics were extracted using the Template for Intervention Description and Replication guidelines. Certainty of evidence was assessed using GRADE. RESULTS: Pairwise meta-analyses showed that exercise interventions demonstrated moderate to large effects across subtypes regardless of treatment target, with the largest effect for balance exercise (SMD = 0.84). Cognitive behavioural therapies (CBTs) showed moderate to large effects (SMD = 0.60), with fatigue-targeted treatments showing larger effects than those targeting distress. Network meta-analysis showed that balance exercise performed significantly better compared to other exercise and behavioural intervention subtypes, except CBT. CBT was estimated to be superior to energy conservation and other behavioural interventions. Combined exercise also had a moderate to large effect. CONCLUSION: Treatment recommendations for balance and combined exercise are tentative as the certainty of the evidence was moderate. The certainty of the evidence for CBT was high.

Investigating the potentially important role of psychological flexibility in adherence to antiretroviral therapy in people living with HIV.

Antiretroviral therapy (ART) has significantly improved immune health and survival rates in HIV, but these outcomes rely on near perfect adherence. While many psychosocial factors are related to sub-optimal adherence, effectiveness of associated interventions are modest or inconsistent. The Psychological Flexibility (PF) model underlying Acceptance and Commitment Therapy (ACT) identifies a core set of broadly applicable transdiagnostic processes that may be useful to explain and improve non-adherence. However, PF has not previously been examined in relation to ART adherence. Therefore, this cross-sectional study (n = 275) explored relationships between PF and intentional/unintentional ART non-adherence in people with HIV. Adults with HIV prescribed ART were recruited online. Participants completed online questionnaires assessing self-reported PF, adherence and emotional and general functioning. Logistic regressions examined whether PF processes were associated with intentional/unintentional non-adherence. Fifty-eight percent of participants were classified as nonadherent according to the Medication Adherence Rating Scale, of which 41.0% reported intentional and 94.0% unintentional non-adherence. Correlations between PF and adherence were small. PF did not significantly explain intentional/unintentional non-adherence after controlling for demographic and disease factors. Further clarification of the utility of PF in understanding ART non-adherence is warranted using prospective or experimental designs in conjunction with more objective adherence measures.

Which behavioural and exercise interventions targeting fatigue show the most promise in multiple sclerosis? A systematic review with narrative synthesis and meta-analysis.

Fatigue is a common and highly debilitating symptom of multiple sclerosis (MS). This meta-analytic systematic review with detailed narrative synthesis examined randomised-controlled (RCTs) and controlled trials of behavioural and exercise interventions targeting fatigue in adults with MS to assess which treatments offer the most promise in reducing fatigue severity/impact. Medline, EMBASE and PsycInfo electronic databases, amongst others, were searched through to August 2018. Thirty-four trials (12 exercise, 16 behavioural and 6 combined; n = 2,434 participants) met inclusion criteria. Data from 31 studies (n = 1,991 participants) contributed to the meta-analysis. Risk of bias (using the Cochrane tool) and study quality (GRADE) were assessed. The pooled (SMD) end-of-treatment effects on self-reported fatigue were: exercise interventions (n = 13) -.84 (95% CI -1.20 to -.47); behavioural interventions (n = 16) -.37 (95% CI -.53 to -.22); combined interventions (n = 5) -.16 (95% CI: -.36 to .04). Heterogeneity was high overall. Study quality was very low for exercise interventions and moderate for behavioural and combined interventions. Considering health care professional time, subgroup results suggest web-based cognitive behavioural therapy for fatigue, balance and/or multicomponent exercise interventions may be the cost-efficient therapies. These need testing in large RCTs with long-term follow-up to help define an implementable fatigue management pathway in MS.

An Account of Interference in Associative Memory: Learning the Fan Effect.

Associative learning is an essential feature of human cognition, accounting for the influence of priming and interference effects on memory recall. Here, we extend our account of associative learning that learns asymmetric item-to-item associations over time via experience (Thomson, Pyke, Trafton, & Hiatt, 2015) by including link maturation to balance associations between longer-term stability while still accounting for short-term variability. This account, combined with an existing account of activation strengthening and decay, predicts both human response times and error rates for the fan effect (Anderson, 1974; Anderson & Reder, 1999) for both target and foil stimuli.

Are We Speaking the Same Language? Finding Theoretical Coherence and Precision in "Mindfulness-Based Mechanisms" in Chronic Pain.

OBJECTIVE: Over the past 50 years, the field of chronic pain has witnessed an evolution of psychological approaches with some notable success. Some of this evolution has included "mindfulness-based interventions" (MBIs), now regarded as having encouraging partial support for their effectiveness. However, several theoretical challenges remain that may inhibit the progress of MBIs. These challenges include a lack of clarity surrounding the mindfulness construct itself, the proliferation of purported underlying mechanisms arising from different theories, and limited evidence for the mechanisms through which MBIs work. The current conceptual review provides a critique of existing theoretical models of mindfulness that have been applied to understanding and treating chronic pain. DESIGN: A conceptual narrative review was conducted. SETTING: Treatment programs for people with chronic pain. PATIENTS: Individuals with any type of chronic pain. INTERVENTIONS: MBIs for chronic pain. OUTCOME MEASURES: Mindfulness-based mechanisms explored in relation to several domains of functioning. RESULTS AND CONCLUSIONS: Based on this assessment, a summary of available evidence for a particular contextual behavioral theory of "mindfulness"-psychological flexibility-is outlined. Findings show the need for further integration of existing mindfulness constructs to better guide development and evaluation of mindfulness-based treatment methods in the future.

Using mixed methods case-series evaluation in the development of a guided self-management hybrid CBT and ACT intervention for multiple sclerosis pain.

PURPOSE: Two-thirds of the people with multiple sclerosis (pwMS) experience pain. Medications provide minimal relief, and current non-pharmacological interventions lack a clear conceptualization of MS pain. This study explored the potential efficacy of a telephone-supported hybrid cognitive behavior therapy and acceptance and commitment therapy self-management intervention for pwMS based on an empirically supported model of MS pain using a replicated single-case series design. METHODS: Seven pwMS with varied demographic and disease characteristics completed the 8-week home-based program alongside 3 hours of telephone support. Online questionnaires were completed every four days for 16 weeks (4-weeks baseline, 8-weeks treatment, 4-weeks follow-up). The primary outcomes were pain severity and pain interference. Psychological process variables drawn from the MS pain model were also completed, and post-treatment qualitative interviews conducted. RESULTS: Simulation modeling analysis (SMA) showed three patients had large improvements in pain outcomes, two showed no change and two worsened. Five participants showed significant change on various psychological process variables. Change in pain catastrophizing was the most consistent finding. CONCLUSIONS: The findings suggest a self-management program for MS pain with minimal therapy support may be effective for some pwMS, but not those with more complex comorbidities. The participants suggested web-based delivery may simplify the approach, and therapist telephone contact was highly valued. Implications for Rehabilitation This case series suggests a hybrid CBT/ACT self-management workbook program for MS pain improves severity and impact of pain in some pwMS. Pain-related catastrophizing reduced in most pwMS, whilst change in other ACT and CBT process variables varied across the individuals. PwMS feedback suggests a tailored web-based delivery of the program with therapist telephone support may be optimal. PwMS with serious co-morbid depression and very advanced disease may not respond well to this self-management approach.

Operationalising cognitive fatigability in multiple sclerosis: A Gordian knot that can be cut?

BACKGROUND: Researchers have attempted to operationalise objective measures of cognitive fatigability in multiple sclerosis (MS) to overcome the perceived subjectivity of patient-reported outcomes of fatigue (PROs). Measures of cognitive fatigability examine decrements in performance during sustained neurocognitive tasks. OBJECTIVE: This personal viewpoint briefly summarises available evidence for measures of cognitive fatigability in MS and considers their overall utility. RESULTS: Studies suggest there may be a construct that is distinct from self-reported fatigue, reflecting a new potential intervention target. However, assessments vary and findings across and within measures are inconsistent. Few measures have been guided by a coherent theory, and those identified are likely to be influenced by other confounds, such as cognitive impairment caused more directly by disease processes, depression and assessment biases. CONCLUSION: Future research may benefit from (a) developing a guiding theory of cognitive fatigability, (b) examining ecological and construct validity of existing assessments and (c) exploring whether the more promising cognitive fatigability measures are correlated with impaired functioning after accounting for possible confounds. Given the issues raised, we caution that our purposes as researchers may be better served by continuing our search for a more objective cognitive fatigability construct that runs in parallel with improving, rather than devaluing, current PROs.

Non-pharmacological interventions to reduce ICU-related psychological distress: a systematic review.

INTRODUCTION: Patients frequently suffer stress in intensive care units (ICUs) and many develop serious psychological morbidity after discharge. Little is known about the nature and efficacy of interventions to reduce ICU-related distress. There is growing evidence that administering sedative drugs can be harmful. Therefore we carried out a systematic review of non-pharmacological interventions to reduce ICU-related distress. EVIDENCE ACQUISITION: A systematic search was conducted using Medline, Embase, Psychinfo, Cinahl and the Web of Science. Included studies evaluated the effect of non-pharmacological interventions to reduce ICU stress. Study populations were adults in mixed or general ICUs. Outcomes were stress or psychological distress in or after the ICU, using self-report or physiological measures. No meta-analysis was possible due to heterogeneity, therefore studies were arranged according to intervention type, and outcomes examined together with risk of bias criteria. EVIDENCE SYNTHESIS: Twenty-three studies were eligible, including 15 randomized controlled trials. Non-pharmacological interventions included music therapy (11 studies), mind-body practices (5) and psychological interventions (7). 12 studies showed a beneficial effect. However only three of the 12 had a low risk of bias, and many studies in the review were under-powered to detect an effect. Only 5 studies measured a medium/long term psychological outcome such as PTSD or depression at 2-12 months. CONCLUSIONS: Evidence indicates that non-pharmacological approaches to reducing ICU distress, in particular psychological interventions, may be beneficial. The evidence base would be strengthened by the implementation of fully-powered studies using robust designs, that measure longer-term outcomes.

Episodes, events, and models.

We describe a novel computational theory of how individuals segment perceptual information into representations of events. The theory is inspired by recent findings in the cognitive science and cognitive neuroscience of event segmentation. In line with recent theories, it holds that online event segmentation is automatic, and that event segmentation yields mental simulations of events. But it posits two novel principles as well: first, discrete episodic markers track perceptual and conceptual changes, and can be retrieved to construct event models. Second, the process of retrieving and reconstructing those episodic markers is constrained and prioritized. We describe a computational implementation of the theory, as well as a robotic extension of the theory that demonstrates the processes of online event segmentation and event model construction. The theory is the first unified computational account of event segmentation and temporal inference. We conclude by demonstrating now neuroimaging data can constrain and inspire the construction of process-level theories of human reasoning.

Pharmacology of basimglurant (RO4917523, RG7090), a unique metabotropic glutamate receptor 5 negative allosteric modulator in clinical development for depression.

Major depressive disorder (MDD) is a serious public health burden and a leading cause of disability. Its pharmacotherapy is currently limited to modulators of monoamine neurotransmitters and second-generation antipsychotics. Recently, glutamatergic approaches for the treatment of MDD have increasingly received attention, and preclinical research suggests that metabotropic glutamate receptor 5 (mGlu5) inhibitors have antidepressant-like properties. Basimglurant (2-chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine) is a novel mGlu5 negative allosteric modulator currently in phase 2 clinical development for MDD and fragile X syndrome. Here, the comprehensive preclinical pharmacological profile of basimglurant is presented with a focus on its therapeutic potential for MDD and drug-like properties. Basimglurant is a potent, selective, and safe mGlu5 inhibitor with good oral bioavailability and long half-life supportive of once-daily administration, good brain penetration, and high in vivo potency. It has antidepressant properties that are corroborated by its functional magnetic imaging profile as well as anxiolytic-like and antinociceptive features. In electroencephalography recordings, basimglurant shows wake-promoting effects followed by increased delta power during subsequent non-rapid eye movement sleep. In microdialysis studies, basimglurant had no effect on monoamine transmitter levels in the frontal cortex or nucleus accumbens except for a moderate increase of accumbal dopamine, which is in line with its lack of pharmacological activity on monoamine reuptake transporters. These data taken together, basimglurant has favorable drug-like properties, a differentiated molecular mechanism of action, and antidepressant-like features that suggest the possibility of also addressing important comorbidities of MDD including anxiety and pain as well as daytime sleepiness and apathy or lethargy.

Metabotropic glutamate receptor 5 negative allosteric modulators: discovery of 2-chloro-4-[1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]pyridine (basimglurant, RO4917523), a promising novel medicine for psychiatric diseases.

Negative allosteric modulators (NAMs) of metabotropic glutamate receptor 5 (mGlu5) have potential for the treatment of psychiatric diseases including depression, fragile X syndrome (FXS), anxiety, obsessive-compulsive disorders, and levodopa induced dyskinesia in Parkinson's disease. Herein we report the optimization of a weakly active screening hit 1 to the potent and selective compounds chloro-4-[1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]pyridine (basimglurant, 2) and 2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine (CTEP, 3). Compound 2 is active in a broad range of anxiety tests reaching the same efficacy but at a 10- to 100-fold lower dose compared to diazepam and is characterized by favorable DMPK properties in rat and monkey as well as an excellent preclinical safety profile and is currently in phase II clinical studies for the treatment of depression and fragile X syndrome. Analogue 3 is the first reported mGlu5 NAM with a long half-life in rodents and is therefore an ideal tool compound for chronic studies in mice and rats.

Towards a better understanding of MS pain: a systematic review of potentially modifiable psychosocial factors.

OBJECTIVE: Pain is a common symptom of Multiple Sclerosis (MS). Biomedical treatments achieve only modest reductions in pain severity suggesting that this approach may be too narrow. The aim of this systematic review was to assess evidence for associations between modifiable psychosocial factors and MS pain severity and pain interference and use this evidence to develop a preliminary biopsychosocial model of MS pain. METHODS: Empirical studies of pain in MS utilising standardised pain severity and pain interference measures were included. Online databases (Cochrane, PsychInfo, EMBASE, CINAHL, Medline, Web of Science and World Cat) and reference sections of included articles were searched, and corresponding authors contacted to identify unpublished studies. Information about design, sample size, MS type, time since diagnosis, psychosocial and pain measures and key findings were extracted. Thirty-one studies were assessed for quality and a narrative synthesis was conducted. RESULTS: Similar to primary chronic pain, most studies reported small to medium associations between several psychosocial factors and pain severity and interference. Pain catastrophizing showed consistently strong associations with pain interference. Preliminary findings revealed a strong correlation between pain acceptance and pain interference. However, fear-avoidance appeared less important in MS, and other forms of behavioural avoidance were not explored. CONCLUSIONS: A preliminary model of MS pain outlining specific psychosocial factors is presented with a conceptual formulation from both traditional, and contextual, cognitive-behavioural perspectives. Pain catastrophizing, acceptance, and endurance, as opposed to fear avoidance, responses are highlighted as potentially important treatment targets in MS, and directions for future research are outlined.

'It feels like someone is hammering my feet': understanding pain and its management from the perspective of people with multiple sclerosis.

BACKGROUND: Pain affects around 63% of people with multiple sclerosis (pwMS). Biomedical treatments demonstrate limited efficacy. More research is needed to understand pain from the individual's perspective in order to better inform a patient-centred approach that improves engagement, self-management and outcome. OBJECTIVE: The objective of this paper is to explore pwMS' experience and responses to pain, and their perspectives on pain management. METHODS: Twenty-five in-depth, semi-structured telephone interviews were conducted. Interviews were audiotaped, transcribed and analysed using an inductive thematic analysis approach with elements of grounded theory. RESULTS: Key themes included vivid descriptions of pain and beliefs that pain is unpredictable, a sign of damage and may worsen. Anger was a common emotional response. Two dominant pain management themes emerged: one related to pain reduction and another to acceptance. Those focusing on pain reduction appeared to engage in cycles in which they struggled with symptoms and experienced continued distress. CONCLUSION: Findings identify pain-related beliefs, emotional reactions and disparate pain-management attitudes. All may influence pwMS' responses to pain and what they ask of their clinicians. Uncovering pwMS' personal beliefs about pain, and introducing a broader biopsychosocial understanding of pain in the clinical context, may provide opportunities to rectify potentially unhelpful management choices and enhance pain acceptance.

Psych-related iPhone apps.

iPhone apps are a widely utilised technology that have recently been identified as a useful medium for health research, clinical interventions and education. While some researchers have discussed advances in app technology, others promote specific apps that are not free to access. To our knowledge, no study has conducted a review of current, free iPhone apps related to psychology, psychiatry and mental health. Therefore, we conducted a pilot, web-based review exploring free iPhone apps using a replicable search strategy within the iTunes Store search function. A selection of apps were selected and subjectively assessed in terms of their usability, utility, graphics, and associated costs for the consumer. We concluded that the apps reviewed, though novel, are limited in their scope and utility. We also note a significant gap in more scientific, evidence-based app technology, and pose some pertinent ethical questions when developing future psych-related apps.