Interventions for promoting habitual exercise in people living with and beyond cancer

Background: This is an updated version of the original Cochrane Review published in the Cochrane Liibrary 2013, Issue 9. Despite good evidence for the health benefits of regular exercise for people living with or beyond cancer, understanding how to promote sustainable exercise behaviour change in sedentary cancer survivors, particularly over the long term, is not as well understood. A large majority of people living with or recovering from cancer do not meet current exercise recommendations. Hence, reviewing the evidence on how to promote and sustain exercise behaviour is important for understanding the most effective strategies to ensure benefit in the patient population and identify research gaps. Objectives: To assess the effects of interventions designed to promote exercise behaviour in sedentary people living with and beyond cancer and to address the following secondary questions: Which interventions are most effective in improving aerobic fitness and skeletal muscle strength and endurance? Which interventions are most effective in improving exercise behaviour amongst patients with different cancers? Which interventions are most likely to promote long-term (12 months or longer) exercise behaviour? What frequency of contact with exercise professionals and/or healthcare professionals is associated with increased exercise behaviour? What theoretical basis is most often associated with better behavioural outcomes? What behaviour change techniques (BCTs) are most often associated with increased exercise behaviour? What adverse effects are attributed to different exercise interventions? Search methods: We used standard methodological procedures expected by Cochrane. We updated our 2013 Cochrane systematic review by updating the searches of the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, Embase, AMED, CINAHL, PsycLIT/PsycINFO, SportDiscus and PEDro up to May 2018. We also searched the grey literature, trial registries, wrote to leading experts in the field and searched reference lists of included studies and other related recent systematic reviews. Selection criteria: We included only randomised controlled trials (RCTs) that compared an exercise intervention with usual care or 'waiting list' control in sedentary people over the age of 18 with a homogenous primary cancer diagnosis. Data collection and analysis: In the update, review authors independently screened all titles and abstracts to identify studies that might meet the inclusion criteria, or that could not be safely excluded without assessment of the full text (e.g. when no abstract is available). We extracted data from all eligible papers with at least two members of the author team working independently (RT, LS and RG). We coded BCTs according to the CALO-RE taxonomy. Risk of bias was assessed using the Cochrane's tool for assessing risk of bias. When possible, and if appropriate, we performed a fixed-effect meta-analysis of study outcomes. If statistical heterogeneity was noted, a meta-analysis was performed using a random-effects model. For continuous outcomes (e.g. cardiorespiratory fitness), we extracted the final value, the standard deviation (SD) of the outcome of interest and the number of participants assessed at follow-up in each treatment arm, to estimate the standardised mean difference (SMD) between treatment arms. SMD was used, as investigators used heterogeneous methods to assess individual outcomes. If a meta-analysis was not possible or was not appropriate, we narratively synthesised studies. The quality of the evidence was assessed using the GRADE approach with the GRADE profiler. Main results: We included 23 studies in this review, involving a total of 1372 participants (an addition of 10 studies, 724 participants from the original review); 227 full texts were screened in the update and 377 full texts were screened in the original review leaving 35 publications from a total of 23 unique studies included in the review. We planned to include all cancers, but only studies involving breast, prostate, colorectal and lung cancer met the inclusion criteria. Thirteen studies incorporated a target level of exercise that could meet current recommendations for moderate-intensity aerobic exercise (i.e.150 minutes per week); or resistance exercise (i.e. strength training exercises at least two days per week). Adherence to exercise interventions, which is crucial for understanding treatment dose, is still reported inconsistently. Eight studies reported intervention adherence of 75% or greater to an exercise prescription that met current guidelines. These studies all included a component of supervision: in our analysis of BCTs we designated these studies as 'Tier 1 trials'. Six studies reported intervention adherence of 75% or greater to an aerobic exercise goal that was less than the current guideline recommendations: in our analysis of BCTs we designated these studies as 'Tier 2 trials.' A hierarchy of BCTs was developed for Tier 1 and Tier 2 trials, with programme goal setting, setting of graded tasks and instruction of how to perform behaviour being amongst the most frequent BCTs. Despite the uncertainty surrounding adherence in some of the included studies, interventions resulted in improvements in aerobic exercise tolerance at eight to 12 weeks (SMD 0.54, 95% CI 0.37 to 0.70; 604 participants, 10 studies; low-quality evidence) versus usual care. At six months, aerobic exercise tolerance was also improved (SMD 0.56, 95% CI 0.39 to 0.72; 591 participants; 7 studies; low-quality evidence). Authors' conclusions: Since the last version of this review, none of the new relevant studies have provided additional information to change the conclusions. We have found some improved understanding of how to encourage previously inactive cancer survivors to achieve international physical activity guidelines. Goal setting, setting of graded tasks and instruction of how to perform behaviour, feature in interventions that meet recommendations targets and report adherence of 75% or more. However, long-term follow-up data are still limited, and the majority of studies are in white women with breast cancer. There are still a considerable number of published studies with numerous and varied issues related to high risk of bias and poor reporting standards. Additionally, the meta-analyses were often graded as consisting of low- to very low-certainty evidence. A very small number of serious adverse effects were reported amongst the studies, providing reassurance exercise is safe for this population. © 2018 The Cochrane Collaboration

Neurobiology of social behavior abnormalities in autism and Williams syndrome

Social behavior is a basic behavior mediated by multiple brain regions and neural circuits, and is crucial for the survival and development of animals and humans. Two neuropsychiatric disorders that have prominent social behavior abnormalities are autism spectrum disorders (ASD), which is characterized mainly by hyposociability, and Williams syndrome (WS), whose subjects exhibit hypersociability. Here we review the unique properties of social behavior in ASD and WS, and discuss the major theories in social behavior in the context of these disorders. We conclude with a discussion of the research questions needing further exploration to enhance our understanding of social behavior abnormalities

Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection

BACKGROUND Clostridium difficile is the most common cause of infectious diarrhea in hospitalized patients. Recurrences are common after antibiotic therapy. Actoxumab and bezlotoxumab are human monoclonal antibodies against C. difficile toxins A and B, respectively. METHODS We conducted two double-blind, randomized, placebo-controlled, phase 3 trials, MODIFY I and MODIFY II, involving 2655 adults receiving oral standard-of-care antibiotics for primary or recurrent C. difficile infection. Participants received an infusion of bezlotoxumab (10 mg per kilogram of body weight), actoxumab plus bezlotoxumab (10 mg per kilogram each), or placebo; actoxumab alone (10 mg per kilogram) was given in MODIFY I but discontinued after a planned interim analysis. The primary end point was recurrent infection (new episode after initial clinical cure) within 12 weeks after infusion in the modified intention-to-treat population. RESULTS In both trials, the rate of recurrent C. difficile infection was significantly lower with bezlotoxumab alone than with placebo (MODIFY I: 17% [67 of 386] vs. 28% [109 of 395]; adjusted difference, −10.1 percentage points; 95% confidence interval [CI], −15.9 to −4.3; P<0.001; MODIFY II: 16% [62 of 395] vs. 26% [97 of 378]; adjusted difference, −9.9 percentage points; 95% CI, −15.5 to −4.3; P<0.001) and was significantly lower with actoxumab plus bezlotoxumab than with placebo (MODIFY I: 16% [61 of 383] vs. 28% [109 of 395]; adjusted difference, −11.6 percentage points; 95% CI, −17.4 to −5.9; P<0.001; MODIFY II: 15% [58 of 390] vs. 26% [97 of 378]; adjusted difference, −10.7 percentage points; 95% CI, −16.4 to −5.1; P<0.001). In prespecified subgroup analyses (combined data set), rates of recurrent infection were lower in both groups that received bezlotoxumab than in the placebo group in subpopulations at high risk for recurrent infection or for an adverse outcome. The rates of initial clinical cure were 80% with bezlotoxumab alone, 73% with actoxumab plus bezlotoxumab, and 80% with placebo; the rates of sustained cure (initial clinical cure without recurrent infection in 12 weeks) were 64%, 58%, and 54%, respectively. The rates of adverse events were similar among these groups; the most common events were diarrhea and nausea. CONCLUSIONS Among participants receiving antibiotic treatment for primary or recurrent C. difficile infection, bezlotoxumab was associated with a substantially lower rate of recurrent infection than placebo and had a safety profile similar to that of placebo. The addition of actoxumab did not improve efficacy. (Funded by Merck; MODIFY I and MODIFY II ClinicalTrials.gov numbers, NCT01241552 and NCT01513239.

Patterns of Coupled Theta Activity in Amygdala-Hippocampal-Prefrontal Cortical Circuits during Fear Extinction

Signals related to fear memory and extinction are processed within brain pathways involving the lateral amygdala (LA) for formation of aversive stimulus associations, the CA1 area of the hippocampus for context-dependent modulation of these associations, and the infralimbic region of the medial prefrontal cortex (mPFC) for extinction processes. While many studies have addressed the contribution of each of these modules individually, little is known about their interactions and how they function as an integrated system. Here we show, by combining multiple site local field potential (LFP) and unit recordings in freely behaving mice in a fear conditioning paradigm, that theta oscillations may provide a means for temporally and functionally connecting these modules. Theta oscillations occurred with high specificity in the CA1-LA-mPFC network. Theta coupling increased between all areas during retrieval of conditioned fear, and declined during extinction learning. During extinction recall, theta coupling partly rebounded in LA-mPFC and CA1-mPFC, and remained at a low level in CA1-LA. Interfering with theta coupling through local electrical microstimulation in CA1-LA affected conditioned fear and extinction recall depending on theta phase. These results support the hypothesis that theta coupling provides a means for inter-areal coordination in conditioned behavioral responsiveness. More specifically, theta oscillations seem to contribute to a population code indicating conditioned stimuli during recall of fear memory before and after extinction

Developing an emotional coping skills workbook for inpatient psychiatric settings: a focus group investigation

Background: Evidence suggests an unmet need for provision of psychological interventions in inpatient psychiatric settings. However, inpatient wards can present a challenging environment in which to implement interventions. The authors developed the Emotional Coping Skills workbook, a psychosocial intervention designed to overcome these challenges and provide inpatients with an opportunity for psychologically-informed therapeutic engagement. The workbook includes information and exercises to empower inpatients to understand their emotions and learn to cope with their distress. Methods: A qualitative study using thematic analysis was undertaken in two UK inpatient psychiatric hospitals to explore staff’s views about whether and how the workbook could be implemented, and on barriers to its use. Thirty-five nursing and occupational therapy staff members participated in four focus groups, and a further two psychologists in semi-structured interviews. Results: Staff identified key barriers to successful implementation of the workbook. These were firstly, the difficulty in finding time and space for therapeutic work in the stressful ward environment. Secondly, staff identified a culture of emotional neglect whereby neither staff nor inpatients felt able to talk about emotions, and patients’ physical needs and medication were prioritised. Thirdly, staff discussed how psychotic symptoms and emotional distress could limit patients’ ability to engage with the workbook material. Staff suggested ways in which the feasibility of using the workbook could be enhanced. Firstly, they discussed the importance of encouraging staff to value psychological approaches and to view the workbook as a resource to help them manage their existing tasks. Secondly, they emphasised the value of staff drawing on their expertise to deliver the workbook flexibly in different formats and settings, depending on each patient’s particular presentation. Thirdly, they advocated empowering staff to decide the timing of intervention delivery in the context of each inpatient’s fluctuations in distress and progress towards recovery. Conclusions: The study has highlighted key principles for flexible and well-integrated intervention delivery; these principles will be helpful for enhancing the feasibility of any nurse-delivered psychological intervention in inpatient settings

Reduction of claustrophobia during magnetic resonance imaging: methods and design of the "CLAUSTRO" randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Magnetic resonance (MR) imaging has been described as the most important medical innovation in the last 25 years. Over 80 million MR procedures are now performed each year and on average 2.3% (95% confidence interval: 2.0 to 2.5%) of all patients scheduled for MR imaging suffer from claustrophobia. Thus, prevention of MR imaging by claustrophobia is a common problem and approximately 2,000,000 MR procedures worldwide cannot be completed due to this situation. Patients with claustrophobic anxiety are more likely to be frightened and experience a feeling of confinement or being closed in during MR imaging. In these patients, conscious sedation and additional sequences (after sedation) may be necessary to complete the examinations. Further improvements in MR design appear to be essential to alleviate this situation and broaden the applicability of MR imaging. A more open scanner configuration might help reduce claustrophobic reactions while maintaining image quality and diagnostic accuracy.</p> <p>Methods/Design</p> <p>We propose to analyze the rate of claustrophobic reactions, clinical utility, image quality, patient acceptance, and cost-effectiveness of an open MR scanner in a randomized comparison with a recently designed short-bore but closed scanner with 97% noise reduction. The primary aim of this study is thus to determine whether an open MR scanner can reduce claustrophobic reactions, thereby enabling more examinations of claustrophobic patients without incurring the safety issues associated with conscious sedation. In this manuscript we detail the methods and design of the prospective "CLAUSTRO" trial.</p> <p>Discussion</p> <p>This randomized controlled trial will be the first direct comparison of open vertical and closed short-bore MR systems in regards to claustrophobia and image quality as well as diagnostic utility.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00715806">NCT00715806</a></p

Medial prefrontal cortex serotonin 1A and 2A receptor binding interacts to predict threat-related amygdala reactivity

Background\ud The amygdala and medial prefrontal cortex (mPFC) comprise a key corticolimbic circuit that helps shape individual differences in sensitivity to threat and the related risk for psychopathology. Although serotonin (5-HT) is known to be a key modulator of this circuit, the specific receptors mediating this modulation are unclear. The colocalization of 5-HT1A and 5-HT2A receptors on mPFC glutamatergic neurons suggests that their functional interactions may mediate 5-HT effects on this circuit through top-down regulation of amygdala reactivity. Using a multimodal neuroimaging strategy in 39 healthy volunteers, we determined whether threat-related amygdala reactivity, assessed with blood oxygen level-dependent functional magnetic resonance imaging, was significantly predicted by the interaction between mPFC 5-HT1A and 5-HT2A receptor levels, assessed by positron emission tomography.\ud \ud Results\ud 5-HT1A binding in the mPFC significantly moderated an inverse correlation between mPFC 5-HT2A binding and threat-related amygdala reactivity. Specifically, mPFC 5-HT2A binding was significantly inversely correlated with amygdala reactivity only when mPFC 5-HT1A binding was relatively low.\ud \ud Conclusions\ud Our findings provide evidence that 5-HT1A and 5-HT2A receptors interact to shape serotonergic modulation of a functional circuit between the amygdala and mPFC. The effect of the interaction between mPFC 5-HT1A and 5-HT2A binding and amygdala reactivity is consistent with the colocalization of these receptors on glutamatergic neurons in the mPFC

D-Cycloserine as an augmentation strategy for cognitive behavioral therapy of anxiety disorders

The goal of this review is to examine the clinical studies on d-cycloserine, a partial glutamatergic N-methyl-D-aspartate agonist, as an augmentation strategy for exposure procedures during cognitive behavioral therapy for anxiety disorders. Although cognitive behavioral therapy and anxiolytic medications are more effective than placebo for treating anxiety disorders, there is still considerable room for further improvement. Traditional combination strategies typically yield disappointing results. However, recent studies based on translational research have shown promise to augment the neural circuitry underlying fear extinction with pharmacological means. We discuss the current state of the literature, including inconsistencies of findings and issues concerning the drug mechanism, dosing, and dose timing. D-cycloserine is a promising combination strategy for cognitive behavioral therapy of anxiety disorders by augmenting extinction learning. However, there is also evidence to suggest that d-cycloserine can facilitate reconsolidation of fear memory when exposure procedures are unsuccessful