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Additional file 2. Study specific instruments of the P.E.L.I.O.N. trial.

Additional file 1. List of study sites.

IMPORTANCE: Many patients with severe stroke have impaired airway protective reflexes, resulting in prolonged invasive mechanical ventilation. OBJECTIVE: To test whether early vs standard tracheostomy improved functional outcome among patients with stroke receiving mechanical ventilation. DESIGN, SETTING, AND PARTICIPANTS: In this randomized clinical trial, 382 patients with severe acute ischemic or hemorrhagic stroke receiving invasive ventilation were randomly assigned (1:1) to early tracheostomy (≤5 days of intubation) or ongoing ventilator weaning with standard tracheostomy if needed from day 10. Patients were randomized between July 28, 2015, and January 24, 2020, at 26 US and German neurocritical care centers. The final date of follow-up was August 9, 2020. INTERVENTIONS: Patients were assigned to an early tracheostomy strategy (n = 188) or to a standard tracheostomy (control group) strategy (n = 194). MAIN OUTCOMES AND MEASURES: The primary outcome was functional outcome at 6 months, based on the modified Rankin Scale score (range, 0 [best] to 6 [worst]) dichotomized to a score of 0 (no disability) to 4 (moderately severe disability) vs 5 (severe disability) or 6 (death). RESULTS: Among 382 patients randomized (median age, 59 years; 49.8% women), 366 (95.8%) completed the trial with available follow-up data on the primary outcome (177 patients [94.1%] in the early group; 189 patients [97.4%] in the standard group). A tracheostomy (predominantly percutaneously) was performed in 95.2% of the early tracheostomy group in a median of 4 days after intubation (IQR, 3-4 days) and in 67% of the control group in a median of 11 days after intubation (IQR, 10-12 days). The proportion without severe disability (modified Rankin Scale score, 0-4) at 6 months was not significantly different in the early tracheostomy vs the control group (43.5% vs 47.1%; difference, −3.6% [95% CI, −14.3% to 7.2%]; adjusted odds ratio, 0.93 [95% CI, 0.60-1.42]; P = .73). Of the serious adverse events, 5.0% (6 of 121 reported events) in the early tracheostomy group vs 3.4% (4 of 118 reported events) were related to tracheostomy. CONCLUSIONS AND RELEVANCE: Among patients with severe stroke receiving mechanical ventilation, a strategy of early tracheostomy, compared with a standard approach to tracheostomy, did not significantly improve the rate of survival without severe disability at 6 months. However, the wide confidence intervals around the effect estimate may include a clinically important difference, so a clinically relevant benefit or harm from a strategy of early tracheostomy cannot be excluded. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02377167

Additional file 1. Additional information on Methods (list of parameters listed in the eCRF, list of categories of disorders and underlying diseases, definitions and statistics. Supplement Table 1: Neurologic past medical history according to disease categories (multiple answers possible). Supplement Table 2: PANDEMIC inclusion criteria and COVID state of disease according to disease categories (multiple answers possible). Supplement Table 3: Neurologic symptoms according to disease categories in 392 patients (multiple answers possible). Supplement Table 4: Diagnostic findings in 392 patients (multiple answers possible). Supplement Table 5: Factors influencing the occurrence of a disease category. Supplement Table 6: Factors influencing the occurrence of most common diseases. Supplement Table 7: Factors influencing the decision to therapy limitation.

Additional file 1. Study questionnaire for sociodemographic variables and days of sickness absence.

Additional file 2. SPIRIT 2013 checklist.

Objectives: Mental disorders are frequent, associated with disability-adjusted life years, societal, and economic costs. Children of parents with a mental illness (COPMI) are at an increased risk to develop disorders themselves. The transgenerational transmission of mental disorders has been conceptualized in a model that takes parental and family factors, the social environment (i.e., school, work, and social support), parent-child-interaction and possible child outcomes into account. The goal of the “Children of Mentally Ill Parents At Risk Evaluation” (COMPARE) study will thus be twofold: (1) to establish the efficacy and cost-effectiveness of a high-quality randomized controlled trial (RCT) with the aim of interrupting the intergenerational transmission of mental disorders in COPMI, (2) to test the components of the trans-generational transmission model of mental disorders. Methods: To implement a randomized controlled trial (RCT: comparison of parental cognitive behavioral therapy/CBT with CBT + Positive Parenting Program) that is flanked by four add-on projects that apply behavioral, psychophysiological, and neuro-imaging methods to examine potential moderators and mediators of risk transmission (projects COMPARE-emotion/-interaction/-work/-school). COMPARE-emotion targets emotion processing and regulation and its impact on the transgenerational disorder transmission; COMPARE-interaction focuses especially on the impact of maternal comorbid diagnoses of depression and anxiety disorders and will concentrate on different pathways of the impact of maternal disorders on socio-emotional and cognitive infant development, such as parent-infant interaction and the infant's stress regulation skills. COMPARE-work analyzes the transmission of strains a person experiences in one area of life to another (i.e., from family to work; spill-over), and how stress and strain are transmitted between individuals (i.e., from parent to child; cross-over). COMPARE-school focuses on the psychosocial adjustment, school performance, and subjective well-being in COPMI compared to an adequate control group of healthy children. Results: This study protocol reports on the interdisciplinary approach of COMPARE testing the model of the transgenerational transmission of mental disorders. Conclusion: The combination of applied basic with clinical research will facilitate the examination of specific risk transmission mechanisms, promotion, dissemination and implementation of results into a highly important but largely neglected field. Clinical Trial Registration: DRKS-ID: DRKS00013516 (German Clinical Trials Register, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00013516).

Background: Mental health problems are highly frequent, as well as being associated with enormous societal and economic costs and significant disability-adjusted life years. Children of parents with a mental illness (COPMI) are at a tremendously increased risk to develop disorders themselves. According to the literature, parental mental disorders launch a wave of risk factors that in turn predict the emergence of psychological problems in the offspring, and effective treatment of the parental disorder has been associated with reduced child psychopathology (launch and grow assumption). Furthermore, studies focusing on parent-child interaction demonstrate generally poorer parenting skills in parents with mental disorders, and the enhancement of such skills has been a significant mediator in improving child outcomes (parenting assumption). Objective: To implement a preventive intervention for COPMI with the aim of interrupting the transmission of mental disorders in children of a parent with mental disorders. An RCT will compare state-of-the-art cognitive behavioral therapy (CBT) for a parent with mental disorders to CBT plus the Positive Parenting Program (Triple-P), a well-established and evidence-based program that enhances parenting skills. Methods: A total of 634 patients seeking treatment in 8 outpatient clinics in Germany and their children will be included between January 2018 and April 2021 in the study. We use (clinical) interviews and self- as well as other-report questionnaires to assess the families at four main measurement points [T1: beginning of waiting period for psychotherapy treatment (duration of waiting period depends on usual waiting period in the study center: multiple baselines), T2: begin of parental psychotherapy, T3: post-assessment, T4: 6 months follow-up]. The total observation period will be 39 months. The patients will be randomly assigned to either the control condition (25 to 45 CBT sessions) or the experimental condition (25 to 45 CBT sessions + 10 Triple-P sessions). For evaluating the treatment process, the patients and clinicians will also be assessed after each treatment session. Furthermore, there will be a continuous assessment and report of adverse events during treatment. Discussion: This trial will be the first ever to address the launch and grow as well as the parenting assumption in one study and to establish effects of the two different interventions on children's health. Our study will also likely be the first one to provide data on the comparative cost-effectiveness and will therefore provide essential information relevant for the potential implementation of such programs. The structure of the RCT will allow us to establish effects of the parental disorder(s) with/without comorbidities on children's health, to test assumptions of the trans-generational transmission model of mental disorders and bi-directional influences of different treatments on the model and to analyze specific transmission mechanisms. A deeper understanding of risk mechanisms will reveal specific transmission profiles that will result in the early detection of and effective reduction in risk factors and thus improve the health of the children at risk. Ethics: The study is carried out according to the Good Clinical Practice (GCP) guidelines, the Declaration of Helsinki and its later supplements and local legal requirements. The lead ethics committee at the department of psychology at Philipps-University Marburg approved the study procedure and all study documents. A positive ethics committee vote is required at a study site, before the inclusion of a first patient at the respective site. Dissemination: Via peer-reviewed publications in scientific journals, the results of this study will be made available to the scientific community. Using PsychData all primary data will be made available for re- and meta-analyses. Politicians, public health services, and stakeholders will be informed throughout the study and beyond, thus, improving public policy and health care decisions concerning preventive interventions and treatments for COPMI. Trial Registration: DRKS-ID: DRKS00013516 (German Clinical Trials Register, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00013516)

Artemisinin resistance is threatening global efforts for malaria control and elimination. Primaquine (PQ) and methylene blue (MB) are gametocytocidal drugs that can be combined with artemisinin-based combination therapy (ACT) to reduce malaria transmission, including resistant strains. Children (6-59 months) with uncomplicated falciparum malaria in Burkina Faso were treated with artesunate-amodiaquine (AS-AQ) and randomized to MB (15 mg/kg/day for 3 days) or PQ (0.25 mg/kg at day 2) with the aim to show non-inferiority of the MB regimen with regard to haematological recovery at day 7 (primary endpoint). MB-AS-AQ could not be shown to be non-inferior to PQ-AS-AQ (mean Hb difference between treatment groups on day 7 was -0.352, 95% CI -0.832-0.128, p = 0.0767), however, haemoglobin recovery following treatment was alike in the two study arms (day 7: mean 0.2±1.4 g/dl vs. 0.5±0.9 g/dl, p = 0.446). Occurrence of adverse events was similar in both groups, except for vomiting, which was more frequent in the MB than in the PQ arm (20/50 vs 7/50, p = 0.003). Adequate clinical and parasitological response was above 95% in both groups, but significantly more asexual parasites were cleared in the MB arm compared to the PQ arm already on day 1 (48/50, 96%, vs 40/50, 80%, p = 0.014). Moreover, P. falciparum gametocyte prevalence and density were lower in the MB arm than in the PQ arm, which reached statistical significance on day 2 (prevalence: 2/50, 4%, vs 15/49, 31%, p

Additional file 1. SPIRIT 2013 checklist: recommended items to address in a clinical trial protocol and related documents.

SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents. (DOCX 62 kb)

SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents*. (PDF 205 kb)