START NOW: a cognitive behavioral skills training for adolescent girls with conduct or oppositional defiant disorder - a randomized clinical trial.

BACKGROUND: Conduct disorder (CD) and oppositional defiant disorder (ODD) both convey a high risk for maladjustment later in life and are understudied in girls. Here, we aimed at confirming the efficacy of START NOW, a cognitive-behavioral, dialectical behavior therapy-oriented skills training program aiming to enhance emotion regulation skills, interpersonal and psychosocial adjustment, adapted for female adolescents with CD or ODD. METHODS: A total of 127 girls were included in this prospective, cluster randomized, multi-center, parallel group, quasi-randomized, controlled phase III trial, which tested the efficacy of START NOW (n = 72) compared with standard care (treatment as usual, TAU, n = 55). All female adolescents had a clinical diagnosis of CD or ODD, were 15.6 (±1.5) years on average (range: 12-20 years), and were institutionalized in youth welfare institutions. The two primary endpoints were the change in number of CD/ODD symptoms between (1) baseline (T1) and post-treatment (T3), and (2) between T1 and 12-week follow-up (T4). RESULTS: Both treatment groups showed reduced CD/ODD symptoms at T3 compared with T1 (95% CI: START NOW = -4.87, -2.49; TAU = -4.94, -2.30). There was no significant mean difference in CD/ODD symptom reduction from T1 to T3 between START NOW and TAU (-0.056; 95% CI = -1.860, 1.749; Hedge's g = -0.011). However, the START NOW group showed greater mean symptom reduction from T1 to T4 (-2.326; 95% CI = -4.274, -0.378; Hedge's g = -0.563). Additionally, secondary endpoint results revealed a reduction in staff reported aggression and parent-reported irritability at post assessment. CONCLUSIONS: Although START NOW did not result in greater symptom reduction from baseline to post-treatment compared with TAU, the START NOW group showed greater symptom reduction from baseline to follow-up with a medium effect size, which indicates a clinically meaningful delayed treatment effect.

ON-ICE trial: Investigation of the combined effects of oxytocin and naltrexone on stress-induced and alcohol cue-induced craving in alcohol use disorder-Study protocol of a phase II randomised double-blind placebo-controlled parallel-group trial.

INTRODUCTION: Although alcohol dependence (AD) is highly prevalent, only few medications are approved for its treatment. While currently approved medications, such as naltrexone (NTX), reduce craving and relapse risk to a certain extent, new approaches are needed to complement these pharmaca. One potential compound is oxytocin (OXY), which proved beneficial effects on alcohol craving and stress reactivity in preliminary clinical studies and synergism with NTX effects. METHODS AND ANALYSIS: This clinical phase II trial is a monocentre two-armed, placebo (PLC)-controlled, 1:1 randomised, double-blind, parallel-group study. 62 participants with AD will be randomised to receive either intranasal OXY spray (24 IU) or PLC spray plus oral NTX (50 mg) for 2 days, and alcohol craving will be assessed using a validated combined stress-exposure and cue-exposure experiments and MRI. The primary outcome will be the intensity of alcohol craving, assessed using the Alcohol Urge Questionnaire (AUQ), 60 min after OXY/PLC application, directly after the stress and cue exposures. Secondary outcomes include subjective stress, negative affect, cortisol and OXY plasma levels, and neural response to alcohol and emotional cues and natural rewards. Follow-up drinking data were collected over 90 days. The primary efficacy analysis will test the difference between the verum and the PLC group in the distribution of AUQ craving scores. Appropriate statistical analysis will be used for the evaluation of the secondary outcomes. ETHICS AND DISSEMINATION: This trial has been approved by the ethics committee of Heidelberg University and competent authority. All participants in the trial will provide written informed consent. The study will be conducted according to the principles of the Declaration of Helsinki and in accordance to the German Medicinal Products act. Results of this study will be disseminated in peer-reviewed scientific journals and deidentified data, and the statistical analysis plan will be made available via open-access online repositories. TRIAL REGISTRATION NUMBERS: EudraCT 2021-003610-40 and NCT05093296.

Cluster-randomised trial evaluating a complex intervention to improve mental health and well-being of employees working in hospital - a protocol for the SEEGEN trial.

BACKGROUND: Health care employees in Germany and worldwide are exposed to a variety of stressors. However, most of the hospitals in Germany lack a systematic workplace health management. Thus, this study aims at the evaluation of the effects of a behavioural as well as organisational (´complex´) intervention on the mental health and well-being of hospital staff. METHODS: Mental health in the hospital workplace (SEElische GEsundheit am Arbeitsplatz KrankeNhaus - SEEGEN) is an unblinded, multi-centred cluster-randomised open trial with two groups (intervention group (IG) and waitlist control group (CG)). Study participants in the intervention clusters will receive the complex intervention; study participants in the waitlist control clusters will receive the complex intervention after the last follow-up measurement. The intervention consists of five behavioural and organisational intervention modules that are specifically tailored to hospital employees at different hierarchical and functional levels. Hospital staff may select one specific module according to their position and specific needs or interests. Towards the end of the intervention roundtable discussions with representatives from all professional groups will be held to facilitate organisational change. Primary outcome is the change in emotional and cognitive strain in the working environment, from baseline (T0) to 6 month-follow up (T1), between IG and CG. In addition, employees who do not participate in the modules are included in the trial by answering shorter questionnaires (cluster participants). Furthermore, using mixed methods, a process evaluation will identify uptake of the intervention, and mediators and moderators of the effect. DISCUSSION: There seems to be growing psychological strain on people working in the health care sector worldwide. This study will examine whether investing directly in the hospital staff and their interpersonal relationship may lead to measurable benefits in subjective well-being at the workplace and improved economic performance indicators of the hospital. In case of a positive outcome, health promotion strategies looking at behavioural as well as organisational components within the hospital may gain additional importance, especially in regard of the growing financial pressure within the health sector. TRIAL REGISTRATION DRKS: The SEEGEN study is registered at the German Clinical Trial Register (DRKS) under the DRKS-ID DRKS00017249. Registered 08 October 2019, URL. https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00017249.

Relational Aggression in Adolescents with Conduct Disorder: Sex Differences and Behavioral Correlates.

As most research on conduct disorder (CD) has been conducted on male participants, it has been suggested that female-specific symptoms may be underestimated based on current DSM-5 criteria. In particular, relational aggression, i.e. the hurtful, often indirect, manipulation of relationships with the intention of damaging the other's social position, has been proposed as a characteristic of CD that is more common in females. In addition, sex-specific studies on correlates of relational aggressive behavior are lacking. Relational aggression may be strongly related to the correlates of proactive aggression, namely low affective empathy, and high levels of callous-unemotional (CU) traits and relational victimization. Thus, the present study investigated sex differences in relational aggression, and associations between relational aggression and correlates of proactive aggression in 662 adolescents with CD (403 females) and 849 typically-developing controls (568 females) aged 9-18 years (M = 14.74, SD = 2.34) from the European multi-site FemNAT-CD study. Females with CD showed significantly higher levels of relational aggression compared to males with CD, whereas no sex differences were seen in controls. Relational aggression was only partly related to correlates of proactive aggression in CD: Independent of sex, CU traits showed a positive association with relational aggression. In females only, cognitive, but not affective empathy, was negatively associated with relational aggression. Relational victimization was more strongly associated with relational aggression in males compared to females. Despite interesting sex specific correlates of relational aggression, effects are small and the potential clinical implications should be investigated in future studies.

Decompressive Hemicraniectomy in Elderly Patients With Space-Occupying Infarction (DECAP): A Prospective Observational Study.

BACKGROUND: Decompressive hemicraniectomy improves survival rates and functional outcome in patients with space-occupying middle cerebral artery (MCA) infarction. We sought to determine clinical outcomes in elderly patients with MCA infarction treated with hemicraniectomy and to identify factors associated with functional outcome. METHODS: We performed a prospective, single-center observational study aiming to include patients aged ≥ 61 years with large MCA infarction treated with hemicraniectomy. The primary endpoint was the functional outcome according to modified Rankin Scale (mRS) score at 6 months after hemicraniectomy. Secondary endpoints included outcome measures at 12 months. A pooled analysis of individual patient data from the single-center cohort and a DESTINY 2 trial subgroup was performed to identify factors associated with functional status at 12 months. RESULTS: We included 40 MCA infarction patients who underwent hemicraniectomy between 2012 and 2017 at our university hospital (median [IQR] patient age 64 [62-67] years, National Institutes of Health Stroke Scale score 17 [16-21]). The dominant hemisphere was affected in 22/40 patients. Hemicraniectomy was performed within 31 [23-53] h of symptom onset. At 6 months after hemicraniectomy, 6/40 patients (15%) were moderately or moderately severely disabled (mRS score 3 or 4), 19 (47.5%) severely disabled (mRS score 5), and 15 (37.5%) had died. Compared to surgically treated DESTINY 2 patients, the single-center patients less likely exhibited favorable functional outcome at 6 months (mRS scores 0-4; odds ratio 0.239 [95% CI 0.082-0.696]). Case-fatality rate at 12 months was 43%. In a pooled analysis including 79 patients from DECAP and DESTINY 2, no significant associations of baseline and treatment factors with the clinical status at 12 months were observed. CONCLUSIONS: In this single-center cohort of elderly patients with space-occupying MCA infarction and decompressive hemicraniectomy, the probability for survival without severe disability was low. Lethality at 6 and 12 months was comparable to previously reported data from a randomized trial.

Imatinib induces sustained progression arrest in RECIST progressive desmoid tumours: Final results of a phase II study of the German Interdisciplinary Sarcoma Group (GISG).

BACKGROUND: Desmoid tumours describe a rare monoclonal, fibroblastic proliferation characterised by an often unpredictable clinical course. Surgery is one therapeutic option for progressing patients, except if mutilating and associated with considerable function loss. Different systemic treatment approaches have been investigated and promising results could be demonstrated using imatinib. PATIENTS AND METHODS: We initiated a phase II trial within the German Interdisciplinary Sarcoma Group (GISG) evaluating imatinib to induce progression arrest in desmoid tumour patients being Response Evaluation Criteria in Solid Tumours (RECIST) progressive, not amenable to surgical resection with R0 intent or accompanied by unacceptable function loss (NCT01137916). Thirty-eight patients (median age 44 years [range: 19-80]; 68% female; 90% Eastern Cooperative Oncology Group (ECOG) performance status 0) were treated with a daily dose of 800 mg imatinib planned over 2 years. The progression arrest rate after 6 months of imatinib treatment (PAR6mo) was the primary end-point. Patients showing disease progression under imatinib could be treated with nilotinib 800 mg daily. Accrual started in July 2010 in four GISG centres and finalised in September 2013. RESULTS: The final analysis for the primary end-point in the evaluable patients of the full analysis set revealed a PAR6mo of 65%. Subsequent progression arrest rates at 9, 12, 15, 18, 21 and 24 months were 65%, 59%, 53%, 53%, 50% and 45%, respectively. None of the patients died within the study observational period. Best reported response was seven partial responses at 21 months revealing an overall response rate of 19%. Eight patients treated with nilotinib demonstrated a PAR at 3 months of 88% (7/8); no more disease progressions occurred until end of study. In general imatinib adverse events were mild to moderate. CONCLUSIONS: Imatinib induces sustained progression arrest in RECIST progressive desmoid tumour patients. In addition, nilotinib had the potential to stabilise desmoid tumour growth after treatment failure with imatinib.

Hemicraniectomy in older patients with extensive middle-cerebral-artery stroke.

BACKGROUND: Early decompressive hemicraniectomy reduces mortality without increasing the risk of very severe disability among patients 60 years of age or younger with complete or subtotal space-occupying middle-cerebral-artery infarction. Its benefit in older patients is uncertain. METHODS: We randomly assigned 112 patients 61 years of age or older (median, 70 years; range, 61 to 82) with malignant middle-cerebral-artery infarction to either conservative treatment in the intensive care unit (the control group) or hemicraniectomy (the hemicraniectomy group); assignments were made within 48 hours after the onset of symptoms. The primary end point was survival without severe disability (defined by a score of 0 to 4 on the modified Rankin scale, which ranges from 0 [no symptoms] to 6 [death]) 6 months after randomization. RESULTS: Hemicraniectomy improved the primary outcome; the proportion of patients who survived without severe disability was 38% in the hemicraniectomy group, as compared with 18% in the control group (odds ratio, 2.91; 95% confidence interval, 1.06 to 7.49; P=0.04). This difference resulted from lower mortality in the surgery group (33% vs. 70%). No patients had a modified Rankin scale score of 0 to 2 (survival with no disability or slight disability); 7% of patients in the surgery group and 3% of patients in the control group had a score of 3 (moderate disability); 32% and 15%, respectively, had a score of 4 (moderately severe disability [requirement for assistance with most bodily needs]); and 28% and 13%, respectively, had a score of 5 (severe disability). Infections were more frequent in the hemicraniectomy group, and herniation was more frequent in the control group. CONCLUSIONS: Hemicraniectomy increased survival without severe disability among patients 61 years of age or older with a malignant middle-cerebral-artery infarction. The majority of survivors required assistance with most bodily needs. (Funded by the Deutsche Forschungsgemeinschaft; DESTINY II Current Controlled Trials number, ISRCTN21702227.).

Pancreatogastrostomy versus pancreatojejunostomy for RECOnstruction after partial PANCreatoduodenectomy (RECOPANC): study protocol of a randomized controlled trial UTN U1111-1117-9588.

BACKGROUND: Pancreatoduodenectomy is one of the most complex abdominal operations, usually performed for tumors of the periampullary region and chronic pancreatitis. Leakage of pancreatic juice from the pancreatoenteric anastomosis, called postoperative pancreatic fistula, is the most prominent postoperative complication. Retrospective studies show a significant reduction of fistula rates with pancreatogastrostomy as compared to pancreatojejunostomy, the most frequently employed method of pancreatoenterostomy. Most single-center prospective trials, however, have not validated this finding. A large multicenter trial is needed for clarification. METHODS/DESIGN: RECOPANC is a prospective, randomized, controlled multicenter trial with two treatment arms, pancreatogastrostomy versus pancreatojejunostomy. The trial hypothesis is that postoperative pancreatic fistula rate is lower after pancreatogastrostomy when compared to pancreatojejunostomy. Fourteen academic centers for pancreatic surgery will participate to allocate 360 patients to the trial. The duration of the entire trial is four years including prearrangement and analyses. DISCUSSION: Postoperative pancreatic fistula is the main reason for clinically important postoperative morbidity after pancreatoduodenectomy. The primary goal of the chosen reconstruction technique for pancreatoenteric anastomosis is to minimize postoperative fistula rate. A randomized trial performed at multiple high-volume centers for pancreatic surgery is the best opportunity to investigate one of the most crucial issues in pancreatic surgery. TRIAL REGISTRATION: German Clinical Trials Register DRKS00000767 (2011/03/23), FSI 2011/05/31. Universal Trial Number U1111-1117-9588.

DESTINY II: DEcompressive Surgery for the Treatment of malignant INfarction of the middle cerebral arterY II.

BACKGROUND: Patients with severe space-occupying--so-called malignant--middle cerebral artery infarcts have a poor prognosis even under maximum intensive care treatment. Randomised trials demonstrated that early hemicraniectomy reduces mortality from about 70% to 20% without increasing the risk of being very severely disabled. Hemicraniectomy increases the chance to survive completely independent more than fivefold and doubles the chance to survive at least partly independent. Only patients up to 60-years have been included in these trials. However, patients older than 60-years represent about 50% of all patients with malignant middle cerebral artery infarcts. Data from observational studies, suggesting that older patients may not profit from hemicraniectomy, are inconclusive, because these patients have generally been treated later and less aggressively. This leads to great uncertainty in everyday clinical practice. AIMS: To investigate the efficacy of early hemicraniectomy in patients older than 60-years with malignant MCA infarcts. MATERIALS & METHODS: DEcompressive Surgery for the Treatment of malignant INfarction of the middle cerebral arterY II is a randomised controlled trial including patients 61-years and older with malignant middle cerebral artery infarcts. Patients are randomised to either maximum conservative treatment alone or in addition to early hemicraniectomy within 48 h after symptom onset. The trial uses a sequential design with a maximum number of 160 patients to be enrolled (ISRCTN 21702227). DISCUSSION: In the face of an ageing population, the potential benefit of hemicraniectomy in older patients is of major clinical relevance, but remains controversial. CONCLUSION: The results of this trial are expected to directly influence decision making in these patients.