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Sudden gains have been associated with better short- and long-term treatment outcomes in a number of psychiatric disorders. However, no studies to date have evaluated sudden gains in body dysmorphic disorder (BDD). We used data from a previous randomized controlled trial evaluating the efficacy of an Internet-based cognitive-behavior treatment (CBT) for BDD. The sample consisted of 47 adults diagnosed with BDD. We compared the treatment outcomes of sudden gainers vs. gradual gainers (i.e., treatment responders with no sudden gains) and non-sudden gainers (i.e., gradual gainers plus nonresponders) at posttreatment and 3, 12, and 24 months after the end of the treatment. Twelve (25.5%) participants experienced a sudden gain. Compared to non-sudden gainers and to gradual gainers, sudden gainers showed significantly larger improvements on the Yale-Brown Obsessive-Compulsive Scale modified for BDD at posttreatment (g = 1.23 and g = .91, respectively), and at 3-month (g = 1.23 and g = 1.00, respectively), 12-month (g = 1.12 and g = .91, respectively), and 24-month follow-up (g = 1.11 and g = .97, respectively). This translated into higher rates of treatment responders and remitters in the sudden gainers across all time points. The occurrence of sudden gains in Internet-based CBT for BDD is associated with favorable short- and long-term treatment outcomes. This suggests that a sudden improvement during the treatment could be a marker of good prognosis, while non-sudden-including gradual-gainers are more likely to need continued support or booster sessions. Early identification of patients who are not progressing as expected and subsequent tailoring of the delivered intervention has the potential to improve treatment outcomes in this group., Competing Interests: Conflict of Interest Statement Johan Bjureberg and Erik Andersson receive book royalties from Natur & Kultur. Christian Rück is a consultant for the Swedish Transport Agency and receives book royalties from Studentlitteratur. Lorena Fernández de la Cruz receives royalties for contributing articles to UpToDate, Wolters Kluwer Health. All other authors report no conflicts of interest., (Copyright © 2019. Published by Elsevier Ltd.)

Background: Problem gambling and gambling disorder are major public health concerns worldwide, and awareness of associated negative consequences is rising. In parallel, treatment demand has increased, and Internet interventions offer a promising alternative for providing evidence-based treatment at scale to a low cost., Method: We developed a novel Internet-delivered cognitive behavioral treatment for gambling, based on qualitative interviews with treatment-seeking gamblers, behavioral research on gambling behavior, and the pathway model for problem gambling. This research protocol describes a non-randomized pilot and feasibility trial conducted in routine addiction care with adult treatment-seeking patients (max N = 25) with problem gambling. The primary aim is to ensure acceptability and safety, measured by satisfaction, credibility, working alliance, and possible negative effects. Secondary aims are feasibility of study procedures in terms of recruitment and measurement procedures as well as potential effectiveness measured weekly by gambling symptoms as primary outcome and gambling behavior, quality of life, symptoms of depression and anxiety, alcohol, and drug use as secondary outcomes. Potential mediators measured weekly are loss of control, verbal rules, and well-being., Discussion: This study is innovative in several respects, regarding both treatment development and implementation. The results of the study will guide a future randomized controlled trial, as well as the development of the intervention and intervention implementation within ordinary addiction care., Trial Registration: Clinical trials.gov, NCT ID: NCT03946098. Registered 10 May 2019., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

Background: Population-based administrative registers are often used for research purposes. However, their potential usefulness depends on the validity of the registered information. This study assessed the validity of the recorded codes for social anxiety disorder (SAD), also known as social phobia, in the Swedish National Patient Register (NPR)., Methods: The personal identification numbers of 300 randomly selected individuals with a diagnosis of SAD recorded in the NPR were obtained from the Swedish National Board of Health and Welfare. The medical files of these individuals were then requested from clinics nationally. A total of 117 files were received and two independent raters reviewed each file to assess the presence or absence of SAD, according to the definition of the International Classification of Diseases, Tenth Edition (ICD-10) and the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). When disagreements between the two raters were found, a third rater reviewed the file to establish a best estimate diagnosis. Positive predictive values (PPV) and agreement between the two initial raters (using Cohen's kappa) were calculated. Additionally, raters completed the Clinical Global Impression - Severity (CGI-S) and the Global Assessment of Functioning (GAF) rating scales for each file. Inter-rater agreement for the CGI-S and the GAF was assessed using intraclass correlation coefficients (ICC)., Results: After exclusion of files not containing sufficient information, 95 files were included in the analyses. Of these, 77 files (81.05%) were considered to be 'true positive' cases (PPV = 0.81, 95% confidence interval = 0.72-0.88). Inter-rater agreement regarding the presence or absence of SAD was substantial (κ = 0.72). CGI-S and GAF scores indicated that patients were in the moderate range of severity and functional impairment. Inter-rater agreement for the CGI-S and the GAF was moderate to good (ICC = 0.72 and ICC = 0.82, respectively)., Conclusions: The ICD-10 codes for SAD in the Swedish NPR are generally valid and reliable, but we recommend sensitivity analyses in future register-based studies to minimise the impact of potential diagnostic misclassification. Most patients were moderately severe and impaired, suggesting that results from register-based studies of SAD may be generalizable.

Background & Aims: Scalable and effective treatments are needed for children with functional abdominal pain disorders (FAPDs). We performed a randomized controlled trial of the efficacy and cost effectiveness of cognitive behavioral therapy delivered online (Internet-CBT) compared with usual therapy., Methods: We studied children (age, 8-12 y) diagnosed with FAPDs, based on the Rome IV criteria, in Sweden from September 2016 through April 2017. The patients were assigned randomly to groups that received 10 weeks of therapist-guided, internet-delivered cognitive behavioral therapy (Internet-CBT, n = 46) or treatment as usual (treatments within the health care and school systems, including medications and visits to doctors and other health care professionals; n = 44). The primary outcome was global child-rated gastrointestinal symptom severity assessed using the Pediatric Quality of Life Gastrointestinal Symptom scale. All outcomes were collected from September 2016 through January 2018. Secondary outcomes included quality of life, gastrointestinal-specific anxiety, avoidance behaviors, and parental responses to children's symptoms. Societal costs and costs for health care consumption were collected during the treatment., Results: Children who received Internet-CBT had a significantly larger improvement in gastrointestinal symptom severity with a medium effect size (Cohen's d = 0.46; 95% CI, 0.05-0.88; number needed to treat, 3.8) compared with children who received the treatment as usual. The children's quality of life, gastrointestinal-specific anxiety, avoidance behaviors, and parental responses to children's symptoms also improved significantly in the Internet-CBT group compared with the treatment as usual group. The effects of Internet-CBT persisted through 36 weeks of follow-up evaluation. Children who received Internet-CBT had significantly less health care use than children who received treatment as usual, with an average cost difference of US $137 (P = .011). We calculated a cost savings of US $1050 for every child treated with Internet-CBT compared with treatment as usual., Conclusions: In a randomized trial of pediatric patients with FAPDs, we found Internet-CBT to be clinically cost effective compared with treatment as usual. Internet-CBT has the potential to increase the availability of treatment for a number of patients and reduce health care costs. ClinicalTrials.gov: NCT02873078., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Patient adherence is defined as the extent to which a patient complies with medical or health advice. At present, there is a lack of reliable and valid measures specifically designed to measure adherence to internet-delivered behavioral interventions., Objective: The objective of this study was to develop and psychometrically evaluate a novel measure of adherence to guided internet-delivered behavioral interventions., Methods: In collaboration with experienced clinicians and researchers in the field, a 5-item, clinician-rated internet intervention Patient Adherence Scale (iiPAS) was developed. The initial scale was tested in a sample of children and adolescents (N=50) participating in internet-delivered cognitive behavioral therapy (ICBT) studies. A revised version of the iiPAS was then administered to a larger sample of children and adolescents (N=148) with various behavioral problems participating in ICBT trials. The scale was evaluated according to a classical test theory framework., Results: The iiPAS demonstrated excellent internal consistency. Factor analyses revealed one underlying factor, explaining about 80% of the variance, suggesting that the scale captures a homogeneous adherence construct. The iiPAS was strongly associated with objective measures of patient activity in ICBT (number of logins, number of written characters, and completed modules). Furthermore, mid- and posttreatment ratings of the iiPAS were significantly correlated with treatment outcomes. By contrast, objective measures of patient activity in the Web-based platform did not correlate with treatment outcomes., Conclusions: The iiPAS could be a useful tool to measure adherence in a broad range of internet-delivered behavioral interventions., (©Fabian Lenhard, Kajsa Mitsell, Maral Jolstedt, Sarah Vigerland, Tove Wahlund, Martina Nord, Johan Bjureberg, Hanna Sahlin, Per Andrén, Kristina Aspvall, Karin Melin, David Mataix-Cols, Eva Serlachius, Jens Högström. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 01.10.2019.)

Emotion regulation group therapy (ERGT) is a novel treatment specifically targeting deliberate non-suicidal self-harm (DSH) in individuals with borderline personality disorder (BPD). Identifying robust predictors of positive response to ERGT could aid clinicians in treatment selection; however, to date, only one such study has been conducted. Thus, we aimed to replicate previously identified predictors of treatment response to ERGT by investigating demographic, clinical, and diagnostic predictors in 95 women with BPD or subclinical BPD who had participated in an open-trial evaluation of ERGT. Outcomes evaluated were frequency of DSH and emotion dysregulation. Assessments were conducted at pretreatment, post-treatment, and 6-month follow-up. Multilevel mixed linear models and multilevel negative binomial generalized estimated equations were used to identify significant interactions between the predictors and outcomes. We found that greater pretreatment DSH frequency was associated with greater improvements in DSH during treatment ( b  = 0.998, SE = 0.00, p  = 0.03) and follow-up ( b  = 0.997, SE = 0.00, p  < 0.01) and that greater BPD severity was associated with greater improvements in DSH during treatment ( b  = 0.84, SE = 0.06, p  = 0.02) and in emotion dysregulation at follow-up ( b  = -3.05, SE = 1.47, p  = 0.04). Co-occurring disorders were associated with poorer treatment response during follow-up. Results were generally consistent with a previous study of the predictors of response to ERGT. The findings provide further support for the utility of this treatment across a range of BPD patients, including patients with severe DSH and BPD.

Background: Self-harm is common and there is a need for studies that investigate the relevance of this behavior in clinical samples to inform risk assessment and treatment. The objectives in the current studies were to compare clinical and psychosocial correlates and subsequent adverse outcomes in youth who present to child and adolescent mental health services (CAMHS) with self-harm only (SH), self-harm with suicidality (SH+SU), with those without any indication of SH or SH+SU., Methods: We conducted a case-control study and a longitudinal cohort study using data from a regional clinical care register, and Swedish national registers. The case-control study included all patients (5-17 years) between 2011 and 2015 (N = 25,161). SH and SH+SU cases were compared with controls (patients without SH) regarding a range of correlates. The longitudinal study included former CAMHS patients (N = 6,120) who were followed for a median time of 2.8 years after termination of CAMHS contact regarding outcomes such as clinical care consumption, social welfare recipiency, and crime conviction., Results: In the case-control study, both the SH and SH+SU groups received more clinical care, had lower global functioning, and higher odds of having mental disorders compared to controls. In most comparisons, the SH+SU group had more problems than the SH group. In the longitudinal study, the same pattern emerged for most outcomes; for example, the adjusted hazard ratio for recurrent care due to self-harm was 23.1 (95% confidence interval [CI], 17.0-31.4) in the SH+SU group compared to 3.9 (95% CI, 2.3-6.7) in the SH group., Conclusions: Adolescent patients presenting with self-harm have higher risks for adverse outcomes than patients without self-harm. Suicidality in addition to self-harm is associated with more severe outcomes, importantly recurrent episodes of care for self-harm., (© 2018 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Background: Nonsuicidal self-injury (NSSI) is common among adolescents and associated with negative outcomes. However, treatments developed specifically for NSSI and the proposed NSSI disorder (NSSID) are scarce, and access to empirically supported treatments for NSSI in many areas is limited. Online treatments carry the potential to increase the availability of evidence-based treatments. Emotion regulation individual therapy for adolescents (ERITA) has shown promise in the treatment of adolescents with NSSID., Method: The present study examined the feasibility, acceptability, and utility of an online version of ERITA. Twenty-five adolescents (aged 13-17) with NSSID and their parents were included in an uncontrolled open trial. Self-report and clinician-rated assessments of outcomes such as NSSI, self-destructive behaviors, emotion dysregulation, and global functioning were administered at pre-treatment, post-treatment, 3- and 6- month follow-up. Measures of NSSI, self-destructive behaviors, and emotion dysregulation were also assessed weekly during treatment., Results: Ratings of treatment credibility, expectancy, and satisfaction were acceptable, and the therapeutic alliance and treatment completion rate (96%) were high. Adolescent participation in the treatment was associated with a statistically significant increase in past-month NSSI abstinence (p = .007), large-sized improvements in past-month NSSI frequency (55% reduction, 95% confidence interval [CI]: 29, 72; Cohen's d = 0.88, 95% CI: 0.73, 1.06) and global functioning (d = 1.01, 95% CI: 0.77, 1.32), and medium-sized improvements in emotion dysregulation (d = 0.75, 95% CI: 0.59, 0.90) and NSSI versatility (d = 0.63, 95% CI: 0.54, 0.77) from pre- to post-treatment. These improvements were further strengthened at 3-month follow-up and maintained at 6-month follow-up. The online therapist-guided parent program was associated with small- to large-sized (ds = 0.47-1.22) improvements in adaptive parent behaviors, and these improvements were maintained or further improved upon at 6-month follow-up. Moreover, in line with the theoretical model underlying ERITA, change in emotion dysregulation mediated changes in both NSSI frequency and self-destructive behaviors over the course of treatment., Conclusions: Together, results suggest that online ERITA is an acceptable, feasible, and promising low-intensity treatment for adolescents with NSSID. The results of this open trial must be replicated in controlled studies., Trial Registration: ClinicalTrials.gov ( NCT02697019 ). Registered 2 March 2016.

Irritable bowel syndrome (IBS) is common in adolescents with a pronounced negative impact on quality of life. A pattern of avoidance behavior is commonly seen in the IBS population, which is associated with more gastrointestinal (GI) symptoms. Exposure-based cognitive behavior therapy (CBT) targets the avoidance behavior to reduce symptoms, but it is unknown whether reduced avoidance is a mediator of symptom improvement in adolescent IBS. Stress has been suggested to play a key role in worsening GI symptoms and is also a potential mediator of the treatment effect in IBS. This study was based on data from a randomized controlled trial (N = 101) that evaluated exposure-based internet-delivered CBT (Internet-CBT) compared with a wait-list for adolescents with IBS. We investigated whether avoidance behavior and perceived stress mediated the improvement in global GI symptoms due to treatment. We found that a change in avoidance behavior, but not perceived stress, mediated the effect of exposure-based Internet-CBT on GI symptoms. The decrease in avoidance behavior explained a large portion (67%) of the total treatment effect. Moreover, a unidirectional relationship over time was observed between avoidance behavior and GI symptoms. Our conclusion is that exposure-based CBT in adolescent IBS reduces avoidance and, consequently, reduces GI symptoms., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Nonsuicidal self-injury (NSSI) is a serious health risk behavior that forms the basis of a tentative diagnosis in DSM-5, NSSI Disorder (NSSID). To date, established treatments specific to NSSI or NSSID are scarce. As a first step in evaluating the feasibility, acceptability, and utility of a novel treatment for adolescents with NSSID, we conducted an open trial of emotion regulation individual therapy for adolescents (ERITA): a 12-week, behavioral treatment aimed at directly targeting both NSSI and its proposed underlying mechanism of emotion regulation difficulties., Methods: Seventeen girls (aged 13-17; mean = 15.31) with NSSID were enrolled in a study adopting an uncontrolled open trial design with self-report and clinician-rated assessments of NSSI and other self-destructive behaviors, emotion regulation difficulties, borderline personality features, and global functioning administered at pre-treatment, post-treatment, and 6-month follow-up. Measures of NSSI and emotion regulation difficulties were also administered weekly during treatment., Results: Ratings of treatment credibility and expectancy and the treatment completion rate (88%) were satisfactory, and both therapeutic alliance and treatment attendance were strong. Intent-to-treat analyses revealed significant improvements associated with large effect sizes in past-month NSSI frequency, emotion regulation difficulties, self-destructive behaviors, and global functioning, as well as a medium effect size in past-month NSSI versatility, from pre- to post-treatment. Further, all of these improvements were either maintained or further improved upon at 6-month follow-up. Finally, change in emotion regulation difficulties mediated improvements in NSSI over the course of treatment., Conclusions: Results suggest the acceptability, feasibility, and utility of this treatment for adolescents with NSSID., Trial Registration: ClinicalTrials.gov (NCT02326012, December 22, 2014, retrospectively registered).

Objective: Emotion regulation group therapy (ERGT) has shown promising results in several efficacy trials. However, it has not been evaluated outside a research setting. In order to increase the availability of empirically supported treatments for individuals with borderline personality disorder and deliberate self-harm, an evaluation of ERGT in routine clinical care was conducted with therapists of different professional backgrounds who had received brief intensive training in ERGT prior to trial onset., Design: Multi-site evaluation, using an uncontrolled open trial design with assessments at pretreatment, post-treatment and 6-month follow-up., Setting: 14 adult outpatient psychiatric clinics across Sweden., Participants: Ninety-five women (mean age=25.1 years) with borderline personality disorder (both threshold and subthreshold) and repeated self-harm were enrolled in the study. Ninety-three per cent of participants completed the post-treatment assessment and 88% completed the follow-up assessment., Primary and Secondary Outcome Measures: Primary outcome was self-harm frequency as measured with the Deliberate Self-Harm Inventory. Secondary outcomes included self-harm versatility, emotion dysregulation, other self-destructive behaviours, depression, anxiety, stress symptoms and interpersonal and vocational difficulties., Intervention: ERGT is an adjunctive, 14-week, acceptance-based behavioural group treatment that directly targets both self-harm and its proposed underlying mechanism of emotion dysregulation., Results: At post-treatment, intent-to-treat analyses revealed a significant improvement associated with a moderate effect size on the primary outcome of self-harm frequency (51%, reduction; Cohen's d=0.52, p<0.001) as well as significant improvements in the secondary outcomes of self-harm versatility, emotion dysregulation, other self-destructive behaviours and general psychiatric symptomatology. These results were either maintained or further improved on at 6-month follow-up., Conclusions: ERGT appears to be a feasible, transportable and useful treatment for deliberate self-harm and other self-destructive behaviours, emotion dysregulation and psychiatric symptoms when delivered by clinicians in the community., Trial Registration Number: NCT01986257; results., Competing Interests: Competing interests: HS, JBju, KLG, MTT, JBjä, L-GL, JJ and CH report no competing interests. EH and BL are shareholders of a company, Dahlia, specialised in psychiatric symptom assessment., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Importance: Individuals who self-harm may have an increased risk of aggression toward others, but this association has been insufficiently investigated. More conclusive evidence may affect assessment, treatment interventions, and clinical guidelines., Objective: To investigate the association between nonfatal self-harm and violent crime., Design, Setting, and Participants: This population-based longitudinal cohort study, conducted from January 1, 1997, through December 31, 2013, studied all Swedish citizens born between 1982 and 1998 who were 15 years and older (N = 1 850 252). Individuals who emigrated from Sweden before the age of 15 years (n = 104 051) or immigrated to Sweden after the age of 13 years (ie, <2 years before the beginning of the follow-up; n = 22 009) were excluded. Data analysis was performed from April 21, 2016, to June 4, 2016., Exposures: Receipt of self-harm-associated clinical care., Main Outcomes and Measures: Conviction of a violent crime according to the Swedish penal code., Results: The study cohort consisted of 1 850 525 individuals (950 382 males and 900 143 females), and the mean (SD) follow-up time was 8.1 (4.7) years (range, 0-17.0 years; minimum age, 15 years; maximum age, 32 years). During a mean follow-up period of 8.1 years, 55 185 individuals (3.0%) received clinical care for self-harm. The crude hazard ratio was 4.9 (95% CI, 4.8-5.0) for violent crime conviction in exposed individuals compared with the unexposed group. Women who self-harm were at particularly high risk for expressing violent behaviors. After adjustment for relevant psychiatric comorbidities and socioeconomic status, an almost doubled hazard of violent offense remained (hazard ratio, 1.8; 95% CI, 1.8-1.9)., Conclusions and Relevance: Self-harm is associated with an increased risk of conviction for a violent offense in both sexes. The risk of violence, as well as the risk of suicide and self-harm, should be assessed among offending and self-harming individuals.

Worry is a common phenotype in both psychiatric patients and the normal population. Worry can be seen as a covert behavior with primary function to avoid aversive emotional experiences. Our research group has developed a treatment protocol based on an operant model of worry, where we use exposure-based strategies to extinguish the catastrophic worry thoughts. The aim of this study was to test this treatment delivered via the Internet in a large-scale randomized controlled trial. We randomized 140 high-worriers (defined as > 56 on the Penn State Worry Questionnaire [PSWQ]) to either Internet-based extinction therapy (IbET) or to a waiting-list condition (WL). Results showed that IbET was superior to WL with an overall large between-group effect size of d = 1.39 (95% confidence interval [1.04,1.73]) on the PSWQ. In the IbET group, 58% were classified as responders. The corresponding figure for WL participants was 7%. IbET was also superior to the WL on secondary outcome measures of anxiety, depression, meta-cognitions, cognitive avoidance, and quality of life. Overall treatment results were maintained for the IbET group at 4- and 12-month follow-up. The results from this trial are encouraging as they indicate that worry can be targeted with an accessible and novel intervention for worry. Replication trials with active control group are needed., (Copyright © 2016. Published by Elsevier Ltd.)

The Difficulties in Emotion Regulation Scale (DERS) is a widely-used, theoretically-driven, and psychometrically-sound self-report measure of emotion regulation difficulties. However, at 36-items, the DERS may be challenging to administer in some situations or settings (e.g., in the course of patient care or large-scale epidemiological studies). Consequently, there is a need a briefer version of the DERS. The goal of the present studies was to develop and evaluate a 16-item version of the DERS - the DERS-16. The reliability and validity of the DERS-16 were examined in a clinical sample (N = 96) and two large community samples (Ns = 102 and 482). The validity of the DERS-16 was evaluated comparing the relative strength of the association of the two versions of the DERS with measures of emotion regulation and related constructs, psychopathology, and clinically-relevant behaviors theorized to stem from emotion regulation deficits. Results demonstrate that the DERS-16 has retained excellent internal consistency, good test-retest reliability, and good convergent and discriminant validity. Further, the DERS-16 showed minimal differences in its convergent and discriminant validity with relevant measures when compared to the original DERS. In conclusion, the DERS-16 offers a valid and brief method for the assessment of overall emotion regulation difficulties.

Body dysmorphic disorder (BDD) is an often severe, chronic, and disabling disorder, and although some controlled trials of cognitive behavior therapy (CBT) have shown efficacy, the body of evidence is still limited. The condition is generally considered difficult to treat, and further research to determine the effectiveness of psychological treatments for BDD is needed. The present study is the first to evaluate an acceptance-based therapy for BDD. In total, 21 patients received a 12-week group treatment consisting of weekly sessions of psychoeducation, acceptance and defusion practice, and exposure exercises to foster acceptance of internal discomfort and to strengthen the patients' committed purposeful actions. The primary outcome was BDD symptomatology (measured on the BDD-YBOCS) assessed by a psychiatrist before and after treatment and at 6months follow-up. The secondary outcomes were self-rated BDD symptoms, psychological flexibility, depressive symptoms, quality of life, and disability. Reductions in BDD symptomatology from pre- to posttreatment were significant and showed a large effect size, d=1.93 (95% CI 0.82-3.04). At posttreatment, 68% of the participants showed clinically significant improvement in the primary outcome variable. Treatment gains were maintained at 6months follow-up. The treatment also resulted in significant improvements in all secondary outcomes. The dropout rate was low; 90.5% of the participants completed treatment. This study suggests that acceptance-based exposure therapy may be an efficacious and acceptable treatment for BDD that warrants further investigation in larger controlled trials., (Copyright © 2015. Published by Elsevier Ltd.)