Efficacy of D-cycloserine augmented brief intensive cognitive-behavioural therapy for paediatric obsessive-compulsive disorder: A randomised clinical trial.

OBJECTIVE: To examine the efficacy of weight-adjusted D-cycloserine (DCS) (35 or 70 mg) relative to placebo augmentation of intensive exposure therapy for youth with obsessive-compulsive disorder (OCD) in a double-blind, randomised controlled trial, and examine whether antidepressant medication or patient age moderated outcomes. METHODS: Youth (n = 100, 7-17 years) with OCD were randomised in a 1:1 ratio to either DCS + exposure (n = 49) or placebo + exposure (n = 51). Assessments occurred posttreatment, 1 month later, and at 3 and 6 months. Pills were ingested immediately before sessions. RESULTS: Significant improvements on all outcomes were observed at posttreatment, and to 6-month follow-up. Treatment arms did not differ across time, with no significant time-by-medication interactions on symptom severity (T1 to T2 estimate: 9.3, 95% confidence interval [CI]: -11.2 to -7.4, and estimate -10.7, 95% CI: -12.6 to -8.7), diagnostic severity (T1 to T2 estimate: -2.0, 95% CI: -2.4 to -1.5 and estimate -2.5, 95% CI: -3.0 to -2.0) or global functioning (T1 to T2 estimate: 13.8, 95% CI: 10.6 to 17.0, and estimate 16.6, 95% CI: 13.2 to 19.9). Neither antidepressants at baseline nor age moderated primary outcomes. There were significantly fewer responders/remitters at 1- and 6-month follow-up among youth in the DCS condition stabilised on SSRIs, relative to youth not taking SSRIs. CONCLUSIONS: DCS augmented intensive exposure therapy did not result in overall additional benefits relative to placebo. Intensive exposure proved effective in reducing symptoms for the overall sample.

The sensitivity of 38 heart rate variability measures to the addition of artifact in human and artificial 24-hr cardiac recordings.

BACKGROUND: Artifact is common in cardiac RR interval data derived from 24-hr recordings and has a significant impact on heart rate variability (HRV) measures. However, the relative impact of progressively added artifact on a large group of commonly used HRV measures has not been assessed. This study compared the relative sensitivity of 38 commonly used HRV measures to artifact to determine which measures show the most change with increasing increments of artifact. A secondary aim was to ascertain whether short-term and long-term HRV measures, as groups, share similarities in their sensitivity to artifact. METHODS: Up to 10% of artifact was added to 20 artificial RR (ARR) files and 20 human cardiac recordings, which had been assessed for artifact by a cardiac technician. The added artifact simulated deletion of RR intervals and insertion of individual short RR intervals. Thirty-eight HRV measures were calculated for each file. Regression analysis was used to rank the HRV measures according to their sensitivity to artifact as determined by the magnitude of slope. RESULTS: RMSSD, SDANN, SDNN, RR triangular index and TINN, normalized power and relative power linear measures, and most nonlinear methods examined are most robust to artifact. CONCLUSION: Short-term time domain HRV measures are more sensitive to added artifact than long-term measures. Absolute power frequency domain measures across all frequency bands are more sensitive than normalized and relative frequency domain measures. Most nonlinear HRV measures assessed were relatively robust to added artifact, with Poincare plot SD1 being most sensitive.

A randomised controlled trial of extended immersion in multi-method continuing simulation to prepare senior medical students for practice as junior doctors.

BACKGROUND: Many commencing junior doctors worldwide feel ill-prepared to deal with their new responsibilities, particularly prescribing. Simulation has been widely utilised in medical education, but the use of extended multi-method simulation to emulate the junior doctor experience has rarely been reported. METHODS: A randomised controlled trial compared students who underwent two, week-long, extended simulations, several months apart (Intervention), with students who attended related workshops and seminars alone (Control), for a range of outcome measures. RESULTS: Eighty-four third year students in a graduate-entry medical program were randomised, and 82 completed the study. At the end of the first week, Intervention students scored a mean of 75% on a prescribing test, compared with 70% for Control students (P = 0.02) and Intervention teams initiated cardiac compressions a mean of 29.1 seconds into a resuscitation test scenario, compared with 70.1 seconds for Control teams (P < 0.01). At the beginning of the second week, an average of nine months later, a significant difference was maintained in relation to the prescribing test only (78% vs 70%, P < 0.01).At the end of the second week, significant Intervention vs Control differences were seen on knowledge and reasoning tests, a further prescribing test (71% vs 63% [P < 0.01]) and a paediatric resuscitation scenario test (252 seconds to initiation of fluid resuscitation vs 339 seconds [P = 0.05]). CONCLUSIONS: The study demonstrated long-term retention of improved prescribing skills, and an immediate effect on knowledge acquisition, reasoning and resuscitation skills, from contextualising learning activities through extended multi-method simulation.

Difficult-to-treat pediatric obsessive-compulsive disorder: feasibility and preliminary results of a randomized pilot trial of D-cycloserine-augmented behavior therapy.

BACKGROUND: This study examined the feasibility and preliminary effectiveness of d-cycloserine (DCS)-augmented cognitive behavioral therapy (CBT) for children and adolescents with difficult-to-treat Obsessive Compulsive Disorder, in a double-blind randomized controlled pilot trial (RCT). METHODS: Seventeen children and adolescents (aged 8-18 years) with a primary diagnosis of OCD, which was deemed difficult-to-treat, were randomly assigned to either nine sessions of CBT including five sessions of DCS-augmented exposure and response prevention (ERP) [ERP + DCS] or nine sessions of CBT including five sessions of placebo-augmented ERP [ERP + PBO]. Weight-dependent DCS or placebo doses (25 or 50 mg) were taken 1 hour before ERP sessions. RESULTS: At posttreatment, both groups showed significant improvements with 94% of the entire sample classified as responders. However, a greater improvement in the ERP + DCS relative to the ERP + PBO condition was observed at 1-month follow-up on clinician-rated obsessional severity and diagnostic severity, and parent ratings of OCD severity. There were no changes across time or condition from 1- to 3-month follow-up. CONCLUSIONS: In this preliminary study, DCS-augmented ERP produced significant improvements in OCD severity from posttreatment to 1-month follow-up, relative to a placebo control condition, in severe and difficult-to-treat pediatric OCD. The significant effect on obsessional severity suggests that DCS augmentation might be associated with enhanced modification of obsessional thoughts during ERP, and warrants further investigation.

Mind and heart: heart rate variability in major depressive disorder and coronary heart disease - a review and recommendations.

OBJECTIVE: There is a reciprocal association between major depressive disorder (MDD) and coronary heart disease (CHD). These conditions are linked by a causal network of mechanisms. This causal network should be quantitatively studied and it is hypothesised that the investigation of vagal function represents a promising starting point. Heart rate variability (HRV) has been used to investigate cardiac vagal control in the context of MDD and CHD. This review aims to examine the relationship of HRV to both MDD and CHD in the context of vagal function and to make recommendations for clinical practice and research. METHODS: The search terms 'heart rate variability', 'depression' and 'heart disease' were entered into an electronic multiple database search engine. Abstracts were screened for their relevance and articles were individually selected and collated. RESULTS: Decreased HRV is found in both MDD and CHD. Both diseases are theorized to disrupt autonomic control feedback loops on the heart and are linked to vagal function. Existing theories link vagal function to both mood and emotion as well as cardiac function. However, several factors can potentially confound HRV measures and would thus impact on a complete understanding of vagal mechanisms in the link between MDD and CHD. CONCLUSIONS: The quantitative investigation of vagal function using HRV represents a reasonable starting point in the study of the relationship between MDD and CHD. Many psychotropic and cardiac medications have effects on HRV, which may have clinical importance. Future studies of HRV in MDD and CHD should consider antidepressant medication, as well as anxiety, as potential confounders.

A topographical map of the causal network of mechanisms underlying the relationship between major depressive disorder and coronary heart disease.

OBJECTIVE: Major depressive disorder (MDD) and coronary heart disease (CHD) are both clinically important public health problems. Depression is linked with a higher incidence of ischaemic cardiac events and MDD is more prevalent in patients with CHD. No single comprehensive model has yet described the causal mechanisms linking MDD to CHD. Several key mechanisms have been put forward, comprising behavioural mechanisms, genetic mechanisms, dysregulation of immune mechanisms, coagulation abnormalities and vascular endothelial dysfunction, polyunsaturated omega-3 free fatty acid deficiency, and autonomic mechanisms. It has been suggested that these mechanisms form a network, which links MDD and CHD. The aim of this review is to examine the causal mechanisms underlying the relationship between MDD and CHD, with the aim of constructing a topological map of the causal network which describes the relationship between MDD and CHD. METHODS: The search term 'depression and heart disease' was entered into an electronic multiple database search engine. Abstracts were screened for relevance and individually selected articles were collated. RESULTS: This review introduces the first topological map of the causal network which describes the relationship between MDD and CHD. CONCLUSIONS: Viewing the causal pathways as an interdependent network presents a new paradigm in this field and provides fertile ground for further research. The causal network can be studied using the methodology of systems biology, which is briefly introduced. Future research should focus on the creation of a more comprehensive topological map of the causal network and the quantification of the activity between each node of the causal network.

Sleep-Related Problems in Pediatric Obsessive-Compulsive Disorder and Intensive Exposure Therapy.

Limited research has examined sleep-related problems (SRPs) among children and adolescents with obsessive-compulsive disorder (OCD). The present study addresses this gap by investigating preliminary associations between SRPs, demographic factors (gender and age), family variables (family accommodation and parental stress), and clinical factors (medication status, internalizing and externalizing symptoms, OCD severity, OCD-related impairment), and treatment outcomes in a sample of 103 youth (aged 7 to 17 years; 53% female) with a primary diagnosis of OCD. Clinician, parent, and child measures were used to assess demographic, family, and clinical predictors. SRPs were assessed using an 8-item measure comprising items of the Child Behaviour Checklist, Child Depression Inventory, and Multidimensional Anxiety Scale for Children as used in previous studies. Results showed that SRPs were highly prevalent among this sample and that more SRPs were associated with younger age, internalizing problems, and functional impairment. However, SRPs were not an independent predictor of OCD severity, impairment, or treatment response. Preliminary findings suggest that SRPs among youth with OCD may be more strongly associated with broader internalizing symptoms than with OCD itself. Future longitudinal research is warranted to further explore the complexity of SRPs when co-occurring with pediatric OCD.

Changes in Dosing and Dose Timing of D-Cycloserine Explain Its Apparent Declining Efficacy for Augmenting Exposure Therapy for Anxiety-related Disorders: An Individual Participant-data Meta-analysis.

The apparent efficacy of d-cycloserine (DCS) for enhancing exposure treatment for anxiety disorders appears to have declined over the past 14 years. We examined whether variations in how DCS has been administered can account for this "declining effect". We also investigated the association between DCS administration characteristics and treatment outcome to find optimal dosing parameters. We conducted a secondary analysis of individual participant data obtained from 1047 participants in 21 studies testing the efficacy of DCS-augmented exposure treatments. Different outcome measures in different studies were harmonized to a 0-100 scale. Intent-to-treat analyses showed that, in participants randomized to DCS augmentation (n = 523), fewer DCS doses, later timing of DCS dose, and lower baseline severity appear to account for this decline effect. More DCS doses were related to better outcomes, but this advantage leveled-off at nine doses. Administering DCS more than 60 minutes before exposures was also related to better outcomes. These predictors were not significant in the placebo arm (n = 521). Results suggested that optimal DCS administration could increase pre-to-follow-up DCS effect size by 50%. In conclusion, the apparent declining effectiveness of DCS over time may be accounted for by how it has been administered. Optimal DCS administration may substantially improve outcomes. Registration: The analysis plan for this manuscript was registered on Open Science Framework (https://osf.io/c39p8/).

Virtual patient simulation for prevention of medical error: beyond just technical upskilling.

Virtual patient simulation is a well established mode of medical education for many technically oriented clinical skills. Resuscitation Annie has been used for teaching cardiopulmonary resuscitation for many years and other similar simulation has been used extensively for teaching colonoscopy, delivering babies, suturing, and a variety of surgical techniques and procedures. There are very few medical schools that would not routinely use such simulation as a standard part of their curriculum. This is not because they are cost effective (although they are) but rather because they have been shown to reduce human error in performing these clinical skills and provide a safe environment for doctors to learn such procedures without endangering real patients. Simulation has taken many forms in Medicine including: (1) Computer-based simulations; (2) Standardised patients widely used in OSCE training and examination; (3) Virtual environments; (4) mannequins such as Resuscitation Annie, and (5) so-called "high fidelity" simulations resembling as much as possible the actual clinical situations. These forms of simulation have been used to teach the important skill of clinical decision-making as well as technical procedures (Owen, 2008).

D-cycloserine-augmented one-session treatment of specific phobias in children and adolescents.

BACKGROUND: D-Cycloserine has potential to enhance exposure therapy outcomes. The current study presents a preliminary randomized, placebo-controlled double-blind pilot trial of DCS-augmented one-session treatment (OST) for youth (7-14 years) with specific phobia. A secondary aim of this pilot study was to explore the effects of youth age and within-session fear reduction as potential moderators of DCS outcomes in order to generate hypotheses for a larger trial. It was hypothesized that DCS would be associated with greater improvements than placebo, that children (7-10 years) would have greater benefits than adolescents (11-14 years), and that DCS effects would be stronger for participants with the greater within-session fear reduction during the OST. METHODS: Thirty-five children and adolescents were randomized to either OST combined with DCS (n = 17), or OST combined with placebo (PBO; n = 18) and assessed at 1 week, 1 month, and 3 month following treatment. RESULTS: There were no significant pre- to post-treatment or follow-up benefits of DCS relative to placebo. Secondary analyses of age indicated that relative to PBO, DCS was associated with greater improvements for children (but not adolescents) on measures of severity at 1-month follow-up. Children in the DCS condition also showed significantly greater improvement to 1 month on global functioning relative to other groups. Conversely, adolescents had significant post-treatment benefits in the PBO condition on symptom severity measures relative to DCS, and adolescents in the DCS condition had significantly poorer functioning at 3 months relative to all other groups. Finally, there was a trend for within-session fear reduction to be associated with moderating effects of DCS, whereby greater reduction in fear was associated with greater functioning at one-month follow-up for children who received DCS, relative to PBO. LIMITATIONS: The study sample was small and therefore conclusions are tentative and require replication. CONCLUSIONS: Age and within-session fear reduction may be important moderators of DCS-augmented one-session exposure therapy, which requires testing in a fully powered randomized controlled trial.

D-Cycloserine Augmentation of Exposure-Based Cognitive Behavior Therapy for Anxiety, Obsessive-Compulsive, and Posttraumatic Stress Disorders: A Systematic Review and Meta-analysis of Individual Participant Data.

Importance: Whether and under which conditions D-cycloserine (DCS) augments the effects of exposure-based cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders is unclear. Objective: To clarify whether DCS is superior to placebo in augmenting the effects of cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders and to evaluate whether antidepressants interact with DCS and the effect of potential moderating variables. Data Sources: PubMed, EMBASE, and PsycINFO were searched from inception to February 10, 2016. Reference lists of previous reviews and meta-analyses and reports of randomized clinical trials were also checked. Study Selection: Studies were eligible for inclusion if they were (1) double-blind randomized clinical trials of DCS as an augmentation strategy for exposure-based cognitive behavior therapy and (2) conducted in humans diagnosed as having specific phobia, social anxiety disorder, panic disorder with or without agoraphobia, obsessive-compulsive disorder, or posttraumatic stress disorder. Data Extraction and Synthesis: Raw data were obtained from the authors and quality controlled. Data were ranked to ensure a consistent metric across studies (score range, 0-100). We used a 3-level multilevel model nesting repeated measures of outcomes within participants, who were nested within studies. Results: Individual participant data were obtained for 21 of 22 eligible trials, representing 1047 of 1073 eligible participants. When controlling for antidepressant use, participants receiving DCS showed greater improvement from pretreatment to posttreatment (mean difference, -3.62; 95% CI, -0.81 to -6.43; P = .01; d = -0.25) but not from pretreatment to midtreatment (mean difference, -1.66; 95% CI, -4.92 to 1.60; P = .32; d = -0.14) or from pretreatment to follow-up (mean difference, -2.98, 95% CI, -5.99 to 0.03; P = .05; d = -0.19). Additional analyses showed that participants assigned to DCS were associated with lower symptom severity than those assigned to placebo at posttreatment and at follow-up. Antidepressants did not moderate the effects of DCS. None of the prespecified patient-level or study-level moderators was associated with outcomes. Conclusions and Relevance: D-cycloserine is associated with a small augmentation effect on exposure-based therapy. This effect is not moderated by the concurrent use of antidepressants. Further research is needed to identify patient and/or therapy characteristics associated with DCS response.

Brief intensive CBT for pediatric OCD with E-therapy maintenance.

Cognitive behaviour therapy (CBT), incorporating exposure and response prevention (ERP), has received strong empirical support for the treatment of paediatric OCD, and moreover, is considered the first line treatment of choice (Geller & March, 2012). However, despite the availability of effective treatments for this chronic and debilitating disorder, only a small proportion of youth receive these evidence-based approaches. The present study aimed to examine the effectiveness of an intensive ERP-based treatment for youth OCD, using a multiple baseline controlled design. Children and youth (N=10; aged 11-16 years) with a primary diagnosis of OCD were randomly assigned to a 1- or 2-week baseline monitoring condition followed by the intervention. The efficacy of the intensive treatment, involving 1 session psychoeducation, 2-sessions ERP plus e-therapy maintenance was examined across parent- child- and clinician-rated measures at post-treatment and 6-month follow-up. Overall, there were significant reductions across time on almost all measures (except self-report anxiety), and moreover, the majority of the sample (80%) were considered reliably improved, and meeting clinically significant change. At post-treatment, 60% were in remission of symptoms, and at 6-month follow-up this increased to 70%. These findings provide strong support for intensive, time-limited approaches to ERP-based CBT for children and youth with OCD.

A preprocessing tool for removing artifact from cardiac RR interval recordings using three-dimensional spatial distribution mapping.

Artifact is common in cardiac RR interval data that is recorded for heart rate variability (HRV) analysis. A novel algorithm for artifact detection and interpolation in RR interval data is described. It is based on spatial distribution mapping of RR interval magnitude and relationships to adjacent values in three dimensions. The characteristics of normal physiological RR intervals and artifact intervals were established using 24-h recordings from 20 technician-assessed human cardiac recordings. The algorithm was incorporated into a preprocessing tool and validated using 30 artificial RR (ARR) interval data files, to which known quantities of artifact (0.5%, 1%, 2%, 3%, 5%, 7%, 10%) were added. The impact of preprocessing ARR files with 1% added artifact was also assessed using 10 time domain and frequency domain HRV metrics. The preprocessing tool was also used to preprocess 69 24-h human cardiac recordings. The tool was able to remove artifact from technician-assessed human cardiac recordings (sensitivity 0.84, SD = 0.09, specificity of 1.00, SD = 0.01) and artificial data files. The removal of artifact had a low impact on time domain and frequency domain HRV metrics (ranging from 0% to 2.5% change in values). This novel preprocessing tool can be used with human 24-h cardiac recordings to remove artifact while minimally affecting physiological data and therefore having a low impact on HRV measures of that data.

Using distance-based technologies for emergency medicine training and education.

Cost-effective and sustainable ways of continuing to improve emergency medical services and education worldwide must be pursued if the field is to continue to expand globally. Distance-based learning and the use of telecommunications advances present us with an ideal opportunity to improve international medical education. Such technologies can overcome the financial and logistic constraints of travel and can complement existing exchanges.

International efforts in implementing national health information infrastructure and electronic health records.

Many countries are developing national strategies using information and communication technologies (ICTs) to implement health information infrastructure and electronic health records (EHR), into their medical systems. Efficiency, quality of care and medical error along with new opportunities presented by the technologies themselves have driven this process internationally. Many countries have had spectacular failures costing billions of dollars alongside some amazing successes. There has been very little dialogue internationally about what works and what doesn't work despite the fact that many government and international agencies have placed this key priority on their agendas. The nature of the technologies used promotes cooperation and these innovations in healthcare lend themselves particularly to working together for collaboration and for communication in order to learn best practice from each other. In this paper, I look at some of the national initiatives for developing an information infrastructure for healthcare as well as some of the challenges presented by these very different approaches around the world. We also review briefly the many organizations looking at international standards relating to eHealth and to implementation of electronic health records.

The World Health Channel: an innovation for health and development.

The issues of the digital divide and of accessing health information in areas of greatest need has been addressed by many. It has been a key component of the discussion of the World Summit for the Information Society and also the focus of an important new initiative, the Global Review for Health Information. Only approximately 1 in 700 people in Africa have internet access compared to a rate worldwide of approximately 10%. Access to essential health information and knowledge management for health care has been deemed a priority for the development of health systems and for the care of patients in areas with limited resources, prompting recent efforts by international organisations and by both governmental and non-governmental agencies (see Godlee et al, 2004 and McConnell, 2004). Health care in developing countries can be limited by many different resources: lack of health care workers with sufficient training, lack of diagnostic equipment, lack of treatment facilities or essential pharmaceuticals; and lack of education or expertise in many relevant areas. Much of the health care done in developing countries is by local lay persons or practitioners or by volunteers working with a variety of NGOs. These volunteers are often very dedicated young people with a vision of health-for-all that is often frustrated in the limited time they are able to spend in these areas and further constrained by meager resources (including availability of appropriate information). The availability of medical expertise and consultation depends largely on the geographical location of the health practitioner and of the patient as well as the level of integration with local practitioners and extent of outside agency involvement. Futhermore, there are often many NGOs working simultaneously on similar projects in the same region without knowledge of each other's activities. Often this occurs simply because a lack of communication exists between organisations, resulting in unnecessary duplication of effort. The availability of medical expertise and consultation depends largely on the geographical location of the health practitioner and of the patient as well as the level of integration with local practitioners and extent of outside agency involvement. The health care worker in developing countries is frequently faced with a paucity of information appropriate to the clinical situations on hand as well as a lack of locally available expertise. The lack of access to health care and other vital resources is one factor in the much lower (by approximately 1/3) life expectancy in the least developed countries campared to industrialised nations. In many developing countries there is only one doctor for 5-10,00 people, compared to a ratio of 1:200 in many developed countries. Textbooks, if they exist, may be 10-20 years out of date and are often directed more at the needs of developed countries. There is thus a growing need for wider availability of training and information on health care in developing countries and support for health care workers. There is also a need for increased communication and collaboration between governmental and non-governmental organisations working in international health to share education, resources and to coordinate efforts in areas supporting improved health care delivery. In recognition of this, the Institute for Sustainable Health Education and Development (www.ished.org) is launching the World Health Channel (WHC) in the spring of 2005 in collaboration with WorldSpace. This will allow access to critical health information in developing countries and place the emphasis on issues important for clinical care for front line health workers in these areas.

Augmenting one-session treatment of children's specific phobias with attention training to positive stimuli.

This study examined the efficacy of combining two promising approaches to treating children's specific phobias, namely attention training and one 3-h session of exposure therapy ('one-session treatment', OST). Attention training towards positive stimuli (ATP) and OST (ATP+OST) was expected to have more positive effects on implicit and explicit cognitive mechanisms and clinical outcome measures than an attention training control (ATC) condition plus OST (ATC+OST). Thirty-seven children (6-17 years) with a specific phobia were randomly assigned to ATP+OST or ATC+OST. In ATP+OST, children completed 160 trials of attention training responding to a probe that always followed the happy face in happy-angry face pairs. In ATC+OST, the probe appeared equally often after angry and happy faces. In the same session, children completed OST targeting their phobic situation/object. Clinical outcomes included clinician, parent and child report measures. Cognitive outcomes were assessed in terms of change in attention bias to happy and angry faces and in danger and coping expectancies. Assessments were completed before and after treatment and three-months later. Compared to ATC+OST, the ATP+OST condition produced (a) significantly greater reductions in children's danger expectancies about their feared situations/object during the OST and at three-month follow-up, and (b) significantly improved attention bias towards positive stimuli at post-treatment, which in turn, predicted a lower level of clinician-rated phobia diagnostic severity three-months after treatment. There were no significant differences between ATP+OST and ATC+OST conditions in clinician, parent, or child-rated clinical outcomes. Training children with phobias to focus on positive stimuli is effective in increasing attention towards positive stimuli and reducing danger expectancy biases. Studies with larger sample sizes and a stronger 'dose' of ATP prior to the OST may reveal promising outcomes on clinical measures for training attention towards positive stimuli.