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ABSTRACTBackground: The COVID-19 pandemic caused multiple stressors that may lead to symptoms of adjustment disorder.Objective: We longitudinally examined relationships between risk and protective factors, pandemic-related stressors and symptoms of adjustment disorder during the COVID-19 pandemic, as well as whether these relationships differed by the time of assessment.Method: The European Society for Traumatic Stress Studies (ESTSS) ADJUST Study included N = 15,169 participants aged 18 years and above. Participants from 11 European countries were recruited and screened three times at 6-month intervals from June 2020 to January 2022. Associations between risk and protective factors (e.g. gender), stressors (e.g. fear of infection), and symptoms of adjustment disorder (AjD, ADNM-8) and their interaction with time of assessment were examined using mixed linear regression.Results: The following predictors were significantly associated with higher AjD symptom levels: female or diverse gender; older age; pandemic-related news consumption >30 min a day; a current or previous mental health disorder; trauma exposure before or during the pandemic; a good, satisfactory or poor health status (vs. very good); burden related to governmental crisis management and communication; fear of infection; restricted social contact; work-related problems; restricted activity; and difficult housing conditions. The following predictors were associated with lower AjD levels: self-employment or retirement; working in healthcare; and face-to-face contact ≥ once a week with loved ones or friends. The effects of the following predictors on AjD symptoms differed by the time of assessment in the course of the pandemic: a current or previous mental disorder; burden related to governmental crisis management; income reduction; and a current trauma exposure.Conclusions: We identified risk factors and stressors predicting AjD symptom levels at different stages of the pandemic. For some predictors, the effects on mental health may change at different stages of a pandemic.

Background The mental health burden among refugees in high-income countries (HICs) is high, whereas access to mental healthcare can be limited.Objective To examine the effectiveness of a peer-provided psychological intervention (Problem Management Plus; PM+) in reducing symptoms of common mental disorders (CMDs) among Syrian refugees in the Netherlands.Methods We conducted a single-blind, randomised controlled trial among adult Syrian refugees recruited in March 2019–December 2021 (No. NTR7552). Individuals with psychological distress (Kessler Psychological Distress Scale (K10) >15) and functional impairment (WHO Disability Assessment Schedule (WHODAS 2.0) >16) were allocated to PM+ in addition to care as usual (PM+/CAU) or CAU only. Participants were reassessed at 1-week and 3-month follow-up. Primary outcome was depression/anxiety combined (Hopkins Symptom Checklist; HSCL-25) at 3-month follow-up. Secondary outcomes included depression (HSCL-25), anxiety (HSCL-25), post-traumatic stress disorder (PTSD) symptoms (PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; PCL-5), impairment (WHODAS 2.0) and self-identified problems (PSYCHLOPS; Psychological Outcomes Profiles). Primary analysis was intention-to-treat.Findings Participants (n=206; mean age=37 years, 62% men) were randomised into PM+/CAU (n=103) or CAU (n=103). At 3-month follow-up, PM+/CAU had greater reductions on depression/anxiety relative to CAU (mean difference −0.25; 95% CI −0.385 to −0.122; p=0.0001, Cohen’s d=0.41). PM+/CAU also showed greater reductions on depression (p=0.0002, Cohen’s d=0.42), anxiety (p=0.001, Cohen’s d=0.27), PTSD symptoms (p=0.0005, Cohen’s d=0.39) and self-identified problems (p=0.03, Cohen’s d=0.26), but not on impairment (p=0.084, Cohen’s d=0.21).Conclusions PM+ effectively reduces symptoms of CMDs among Syrian refugees. A strength was high retention at follow-up. Generalisability is limited by predominantly including refugees with a resident permit.Clinical implications Peer-provided psychological interventions should be considered for scale-up in HICs.

IntroductionUnaccompanied refugee minors (URMs) are at increased risk of developing mental health problems, such as symptoms of posttraumatic stress disorder (PTSD) and depression. In addition, URMs face several barriers to mental health care. Few studies have evaluated trauma-focused interventions for URMs that target these issues. The current study evaluated a multimodal trauma-focused treatment approach for URMs. It aimed to provide an initial indication of the effectiveness of this treatment approach and to provide a qualitative evaluation assessing treatment satisfaction of the participating URMs.MethodsA mixed-methods study was conducted among ten URMs, combining quantitative data with qualitative data through triangulation. Quantitative data were collected using a non-concurrent multiple baseline design in which repeated, weekly assessments were carried out during a randomized baseline period, during treatment, and during a 4-week follow-up period. Questionnaires assessing PTSD (Children’s Revised Impact of Event Scale) and symptoms of depression (The Patient Health Questionnaire-9, modified for adolescents) were used. In addition, treatment satisfaction was measured post-treatment using a semi-structured interview.ResultsDuring the qualitative evaluation, all but one URM noted they found the trauma-focused treatment approach useful and felt the treatment had positively impacted their wellbeing. However, the results of the quantitative evaluation did not show clinically reliable symptom reductions at posttest or follow-up. Implications for clinical practice and research are discussed.DiscussionThe current study presents our search in developing a treatment approach for URMs. It adds to the current knowledge about methodological considerations in evaluating treatments for URMs, the potential effects of trauma-focused treatments on URMs, and the implementation of treatments for URMs.Clinical trial registration: The study was registered in the Netherlands Trial Register (NL8519), 10 April 2020.

There is growing evidence that parental trauma is associated with psychosocial disorders, externalizing and internalizing problems, and higher sensitivity to posttraumatic stress disorder (PTSD) in children. Recent research findings suggest multidimensional relational, psychological, and neurobiological interrelated pathways of intergenerational influence. Moreover, the intergenerational effects of parental trauma need to be understood within a broader systemic context, as a part of family adaptation. This article explores research findings and clinical practice to enhance our understanding of intergenerational processes and presents directions for therapeutic interventions. A trauma-focused multi-family therapy, aiming to restrict the relational consequences of parental trauma and strengthen family resilience, is described. The proposition is that to facilitate and improve the quality of parent–child interaction in response to psychotrauma, fostering emotion regulation capacities and mentalization is crucial. These efforts offered through family group interventions may benefit various families coping with adversity in culturally diverse societies.

Mental health issues are widespread among children and adolescents worldwide. Although mental health difficulties may manifest themselves in many different diagnoses, there is growing support for a limited number of underlying transdiagnostic processes. Attachment encompasses a key transdiagnostic mechanism, namely emotional regulation. This study protocol aims to evaluate the feasibility and potential effectiveness of structured emotionally focused family therapy (EFFT), the goal of which is to develop secure attachment between parents and their children to reduce children's vulnerability to mental health problems. A within-subjects design with three waves, a waiting period, treatment, and follow-up, will be conducted. Families will serve as their own controls. Approximately 15 to 20 families with adolescents (aged 12-18 years) as the 'identified patients' will be included. They will participate in 16-21 sessions of EFFT. The study will use a multi-method approach. Self-report questionnaires will be administered repeatedly (i.e., pre-waiting period, pre-treatment, halfway treatment, post-treatment, and follow-up), measuring parent-adolescent attachment, partner-partner attachment, negative interactions, and adolescent psychological complaints. Multi-level analyses will be conducted. Semi-structured interviews will be administered at follow-up to evaluate feasibility and acceptability of EFFT. Treatment integrity will be assessed. The present study is the first to evaluate feasibility of structured EFFT and obtain a first impression of its effectiveness. This information will help us to improve EFFT. Limitations are discussed. Trial registration: Recruitment commenced in June 2022. The approximate trial duration is 36 months. The trial was registered at ClinicalTrials.gov (NCT05657067) on December 9, 2022, and Open Science Framework (https://osf.io/39dt2/) on June 14, 2022.

Background: The COVID-19 pandemic is a health emergency resulting in multiple stressors that may be related to posttraumatic stress disorder (PTSD). Objective: This study examined relationships between risk and protective factors, pandemic-related stressors, and PTSD during the COVID-19 pandemic. Methods: Data from the European Society of Traumatic Stress Studies (ESTSS) ADJUST Study were used. N = 4,607 trauma-exposed participants aged 18 years and above were recruited from the general populations of eleven countries (Austria, Croatia, Georgia, Germany, Greece, Italy, Lithuania, the Netherlands, Poland, Portugal, and Sweden) from June to November 2020. We assessed sociodemographic (e.g. gender), pandemic-related (e.g. news consumption), and health-related (e.g. general health condition) risk and protective factors, pandemic-related stressors (e.g. fear of infection), and probable PTSD (PC-PTSD-5). The relationships between these variables were examined using logistic regression on multiple imputed data sets. Results: The prevalence of probable PTSD was 17.7%. Factors associated with an increased risk for PTSD were younger age, female gender, more than 3 h of daily pandemic-related news consumption (vs. no consumption), a satisfactory, poor, or very poor health condition (vs. a very good condition), a current or previous diagnosis of a mental disorder, and trauma exposure during the COVID-19 pandemic. Factors associated with a reduced risk for PTSD included a medium and high income (vs. very low income), face-to-face contact less than once a week or 3–7 times a week (vs. no contact), and digital social contact less than once a week or 1–7 days a week (vs. no contact). Pandemic-related stressors associated with an increased risk for PTSD included governmental crisis management and communication, restricted resources, restricted social contact, and difficult housing conditions. Conclusion: We identified risk and protective factors as well as stressors that may help identify trauma-exposed individuals at risk for PTSD, enabling more efficient and rapid access to care. HIGHLIGHTS N = 4,607 trauma-exposed adult participants were recruited from the general population during the first year of the COVID-19 pandemic. The prevalence for probable posttraumatic stress disorder was 17.7%. We identified risk factors (e.g. poor health condition) and protective factors (e.g. social contact) associated with posttraumatic stress disorder.

Abstract Background This study evaluated the feasibility of a short-term, multimodal trauma-focused treatment approach adapted specifically for unaccompanied refugee minors (URMs) in the Netherlands. This approach aims to overcome barriers to mental health care and to reduce symptoms of posttraumatic stress disorder (PTSD) and depression. Methods An uncontrolled study was conducted, evaluating the main request for help, treatment integrity and feasibility, and the course of symptoms of PTSD (Children's Revised Impact of Event Scale-13) and depression (Patient Health Questionnaire modified for Adolescents). Results In total, 41 minors were included in the study. Most participants were male (n = 27), predominately from Eritrea (75.6%) with a mean age of 16.5 (SD = 1.5). Minors mostly reported psychological problems, such as problems sleeping, and psychosocial problems, including worries about family reunification. Deviations from the approach were made to meet the current needs of the minors. Factors limiting the feasibility of the approach were often related to continuous stressors, such as news concerning asylum status. Conclusions The results provide a first indication that this approach partly overcomes barriers to mental health care and emphasize the added value of collaborating with intercultural mediators and offering outreach care. Trial registration: The study was registered in the Netherlands Trial Register (NL8585), 10 April 2020, Retrospectively registered, https://www.trialregister.nl/trial/8585 .

Introduction The World Health Organization’s (WHO) scalable psychological interventions, such as Problem Management Plus (PM+) and Step-by-Step (SbS) are designed to be cost-effective non-specialist delivered interventions to reduce symptoms of common mental disorders, such as anxiety, depression and post-traumatic stress disorder (PTSD). The STRENGTHS consortium aims to evaluate the effectiveness, cost-effectiveness and implementation of the individual format of PM+ and its group version (gPM+), as well as of the digital SbS intervention among Syrian refugees in seven countries in Europe and the Middle East. This is a study protocol for a prospective individual participant data (IPD) meta-analysis to evaluate (1) overall effectiveness and cost-effectiveness and (2) treatment moderators of PM+, gPM+ and SbS with Syrian refugees.Methods and analysis Five pilot randomised controlled trials (RCTs) and seven fully powered RCTs conducted within STRENGTHS will be combined into one IPD meta-analytic dataset. The RCTs include Syrian refugees of 18 years and above with elevated psychological distress (Kessler Psychological Distress Scale (K10>15)) and impaired daily functioning (WHO Disability Assessment Schedule 2.0 (WHODAS 2.0>16)). Participants are randomised into the intervention or care as usual control group, and complete follow-up assessments at 1-week, 3-month and 12-month follow-up. Primary outcomes are symptoms of depression and anxiety (25-item Hopkins Symptom Checklist). Secondary outcomes include daily functioning (WHODAS 2.0), PTSD symptoms (PTSD Checklist for DSM-5) and self-identified problems (PSYCHLOPS). We will conduct a one-stage IPD meta-analysis using linear mixed models. Quality of evidence will be assessed using the GRADE approach, and the economic evaluation approach will be assessed using the CHEC-list.Ethics and dissemination Local ethical approval has been obtained for each RCT. This IPD meta-analysis does not require ethical approval. The results of this study will be published in international peer-reviewed journals.

Abstract Background Families applying for asylum have often experienced multiple potentially traumatic events and continue to face stressors during their resettlement. Studies have indicated that traumatic events can negatively impact parenting behaviour and child development. A secondary preventive multi-family intervention programme, called Family Empowerment, was developed. Family Empowerment aims to strengthen parenting skills and prevent exacerbation of emotional problems in asylum-seeker families. This study protocol aims to evaluate the feasibility, acceptability, and potential effectiveness of Family Empowerment to reduce parental mental health problems and improve family functioning. Methods An uncontrolled pre-test-post-test design will be conducted, using a mixed-methods approach. Approximately 60 families living at asylum centres and family locations with children aged 0–18 will be included. All participants will be invited to take part in seven sessions of Family Empowerment. Measurements take place at baseline, during implementation of Family Empowerment and 1 week post-Family Empowerment. Demographic data, the quality of the parent-child interaction, family functioning, parental symptoms of depression and anxiety, and participants’ feedback on progress and the therapeutic alliance will be assessed. A programme integrity list will be filled out during each session. Semi-structured interviews at baseline and post-Family Empowerment will be used to evaluate Family Empowerment. Discussion This is the first study to provide a pilot implementation and evaluation of Family Empowerment. The current study will inform us on how to improve programme elements and the implementation of Family Empowerment. Limitations are discussed. Trial registration Dutch Trial Register, TC = NTR6934. Registered on January 8 2018.

Background: Refugee youth experience hardships associated with exposure to trauma in their homelands and during and after displacement, which results in higher rates of common mental disorders. The World Health Organization (WHO) developed Problem Management Plus (PM+), a non-specialist-delivered brief psychological intervention, for individuals who have faced adversity. PM+ comprises problem-solving, stress management, behavioural activation and strengthening social support. However, it does not include an emotional processing component, which is indicated in trauma-exposed populations. Objective: This pilot randomized controlled trial (RCT) aims to evaluate the feasibility and acceptability of PM+, adapted to Syrian, Eritrean and Iraqi refugee youth residing in the Netherlands, with and without a newly developed Emotional Processing (EP) Module. Methods: Refugee youth (N = 90) between 16 and 25 years of age will be randomized into PM+ with care-as-usual (CAU), (n = 30), PM+ with Emotional Processing (PM+EP) with CAU (n = 30) or CAU only (n = 30). Inclusion criteria are self-reported psychological distress (Kessler Psychological Distress Scale; K10 > 15) and impaired daily functioning (WHO Disability Assessment Schedule; WHODAS 2.0 > 16). Participants will be assessed at baseline, one-week post-intervention and three-month follow-up. The main outcome is the feasibility and acceptability of the adapted PM+ and PM+EP. The secondary outcomes are self-reported psychological distress, functional impairment, post-traumatic stress disorder (PTSD) symptom severity and diagnosis, social support, and self-identified problems. The pilot RCT will be succeeded by a process evaluation including trial participants, participants’ significant others, helpers, and mental health professionals (n = 20) to evaluate their experiences with the PM+ and PM+EP programmes. Results and Conclusion: This is the first study that evaluates the feasibility of PM+ for this age range with an emotional processing module integrated. The results may inform larger RCTs and implementation of PM+ interventions among refugee youth. Trial Registration: Registered to Dutch Trial Registry, NL8750, on 3 July 2020. Medical Ethical Committee of the Amsterdam University Medical Centre, location Vrije Universiteit Medical Centre, Protocol ID: 2020.224, 1 July 2020.

Background: The coronavirus pandemic appears to put psychiatric patients with pre-existing symptomatology at risk of symptom increase, but evidence is scarce. While the pandemic and stringent governmental measures have accelerated the use of clinical videoconferencing (VCT), patient satisfaction with VCT is unclear. Objective: Aim of the study was to assess the wellbeing of patients in psychotrauma treatment during the coronavirus pandemic and to evaluate their use of and satisfaction with VCT. Method: This study used data from a routine outcome monitoring assessment completed by patients in treatment at a specialized psychotrauma institute and administered before the easing of governmental measures in June 2020. Wellbeing (Brief Symptom Inventory, Cantril Ladder, perceived stress level, and symptom change), VCT use and VCT satisfaction, and their association with demographic variables (gender, age, education level, and refugee status) were analysed. Results: Of the 318 respondents (response rate 64.5%), 139 (43.7%) reported a symptom increase, which was associated with a higher coronavirus-related stress level and general psychopathology as well as lower life satisfaction. There were significant effects of age and education level on wellbeing. VCT was reported to have been used by 228 (71.7%) patients. VCT satisfaction ratings were higher among women and those with lower levels of stress (r = −.20, p

Background: The COVID-19 pandemic exposes individuals to multiple stressors, such as quarantine, physical distancing, job loss, risk of infection, and loss of loved ones. Such a complex array of stressors potentially lead to symptoms of adjustment disorder. Objective: This cross-sectional exploratory study examined relationships between risk and protective factors, stressors, and symptoms of adjustment disorder during the first year of the COVID-19 pandemic. Methods: Data from the first wave of the European Society of Traumatic Stress Studies (ESTSS) longitudinal ADJUST Study were used. N = 15,563 participants aged 18 years and above were recruited in eleven countries (Austria, Croatia, Georgia, Germany, Greece, Italy, Lithuania, the Netherlands, Poland, Portugal, and Sweden) from June to November 2020. Associations between risk and protective factors (e.g. gender, diagnosis of a mental health disorder), stressors (e.g. fear of infection, restricted face-to-face contact), and symptoms of adjustment disorder (ADNM-8) were examined using multivariate linear regression. Results: The prevalence of self-reported probable adjustment disorder was 18.2%. Risk factors associated with higher levels of symptoms of adjustment disorder were female gender, older age, being at risk for severe COVID-19 illness, poorer general health status, current or previous trauma exposure, a current or previous mental health disorder, and longer exposure to COVID-19 news. Protective factors related to lower levels of symptoms of adjustment disorder were higher income, being retired, and having more face-to-face contact with loved ones or friends. Pandemic-related stressors associated with higher levels of symptoms of adjustment disorder included fear of infection, governmental crisis management, restricted social contact, work-related problems, restricted activity, and difficult housing conditions. Conclusions: We identified stressors, risk, and protective factors that may help identify individuals at higher risk for adjustment disorder.

Background During the current COVID-19 pandemic, the people in Europe are exposed to self-isolation, quarantine, job loss, risk of contracting COVID-19, or grief of loved ones. Such a complex array of stressors may lead to symptoms of adjustment disorder or posttraumatic stress disorder. This research protocol describes a study launched by the European Society of Traumatic Stress Studies (ESTSS) to investigate the impact of the COVID-19 pandemic on symptoms of adjustment disorder across European countries. Objective The longitudinal online cohort study aims (1) to explore psychosocial reactions to the COVID-19 pandemic across ten European countries; (2) to examine the relationships between risk and resilience factors, stressors and symptoms of adjustment disorder during the pandemic; and (3) to investigate whether these relationships are moderated by coping behaviours. Method In ten countries (Austria, Croatia, Georgia, Germany, Italy, Lithuania, Netherlands, Poland, Portugal, and Sweden), between 1,000 and 2,000 participants will be recruited, depending on the size of the country. Participants will be assessed at two timepoints with a six-month interval. Following a conceptual framework based on the WHO’s social framework of health, an assessment of risk and resilience factors, COVID-19 related stressors and pandemic-specific coping behaviours will be measured to estimate their contribution to symptoms of adjustment disorder. The Adjustment Disorder New Module 8 (ADNM-8) will be used to assess symptoms of adjustment disorder. As a secondary measure, symptoms of posttraumatic stress disorder will be measure using the Primary Care PTSD Screen for DSM-5 (PC-PTSD-5). Data analysis The relative contribution of risk factors, resilience factors, and stressors on symptoms of adjustment disorder or symptoms of posttraumatic stress disorder will be estimated using multilevel analysis. To determine the moderating effects of different types of coping behaviours on these relationships, a multilevel mediation analysis will be carried out.

Antecedentes/Objetivo: El maltrato infantil (MI) se ha asociado con la revictimizaci n y con el trastorno de estr s postraum tico (TEPT). Sin embargo, esta relaci n es poco conocida en los pa ses del Sur de Europa y en muestras comunitarias. Estas asociaciones se analizaron en una muestra de conveniencia compuesta por 1.200 adultos portugueses. M todo: Los datos fueron obtenidos usando la Escala de Diagn stico Post Traum tico (PDS) y el Cuestionario de Trauma Infantil-Versi n corta (CTQ-SF), y analizados con odds ratios y regresiones log sticas y jer rquicas. Resultados: La exposici n a MI aument m s del doble el riesgo de percibir revictimizaci n y tres veces el diagn stico de TEPT. Los eventos traum ticos frecuentes, como accidentes, se asociaron con CM. M s del 30% de los adultos diagnosticados con TEPT indicaron haber sufrido abuso emocional. Tras ajustar por factores demogr ficos, el abuso emocional predijo significativamente la revictimizaci n y fue el predictor con mayor efecto en la gravedad del TEPT ( = 0,24). Conclusiones: Nuestros hallazgos confirman el potential nocivo del abuso emocional en la infancia para los adultos de la comunidad. Se necesita m s conocimiento sobre los mecanismos que relacional el MI con la exposici n traum tica y el TEPT para informar mejor sobre posibles acciones preventivas y terap uticas.

Objective: The aim of this study was to explore perceived posttraumatic growth (PTG) and its associations with potentially traumatic events (PTEs), dispositional optimism, perceived social support, posttraumatic stress disorder (PTSD) symptoms, and satisfaction with life (SWL) among adolescent refugees and asylum seekers. Method: A cross-sectional design was employed including 111 refugees, aged 12–17, that were recruited from asylum seeker centres throughout the Netherlands. Measurements included the revised Posttraumatic Growth Inventory for Children, Children's Impact of Event Scale, Multidimensional Scale of Perceived Social Support, The Life Orientation Test, and the Satisfaction with Life Scale. Results: Participants reported mean PTG scores (20.2) indicating an average response of some perceived change, while reporting high levels of PTSD symptoms (30.6). PTG and PTSD symptoms were not related with each other (r=0.07, p=0.50). PTG was positively associated with dispositional optimism (r=0.41, p

While studies on the consequences of trauma and forced migration on young refugees have focused mainly on their pathology, a focus on resilience in young refugees is needed to adequately represent their response to adversity and to help understand their needs. The aim of this article is to present a proposed study of resilience in young refugees which has been informed by an overview of achievements and challenges in the field of resilience. In order to advance the field of resilience, several topics need clarification: definition and assessment of resilience, the relation of resilience to other constructs and the underlying biological and external factors influencing resilience. With respect to young refugees, the cross-cultural applicability of resilience has to be examined. Qualitative research, mixed method designs, comparative studies, and longitudinal studies seem especially promising in furthering this goal. The proposed study compares refugee adolescents with Dutch adolescents. Data from qualitative evidence synthesis, interviews, questionnaires, experiments, and DNA analysis will be combined to provide a multifaceted picture of factors contributing to resilience, resulting in a better understanding and efficient use of “resilience” to meet the needs of traumatised youth.

Existing tools for evaluating psychosocial interventions (un-validated self-reporting questionnaires) are not ideal for use in non-Western conflict settings. We implement a generic method of treatment evaluation, using client and counsellor feedback, in 18 projects in non-Western humanitarian settings. We discuss our findings from the perspective of validity and suggestions for future research. A retrospective analysis is executed using data gathered from psychosocial projects. Clients (n = 7,058) complete two (complaints and functioning) rating scales each session and counsellors rate the client's status at exit. The client-completed pre- and post-intervention rating scales show substantial changes. Counsellor evaluation of the clients' status shows a similar trend in improvement. All three multivariable models for each separate scale have similar associations between the scales and the investigated variables despite different cultural settings. The validity is good. Limitations are: ratings give only a general impression and clinical risk factors are not measured. Potential ceiling effects may influence change of scales. The intra and inter-rater reliability of the counsellors' rating is not assessed. The focus on client and counsellor perspectives to evaluate treatment outcome seems a strong alternative for evaluation instruments frequently used in psychosocial programming. The session client rated scales helps client and counsellor to set mutual treatment objectives and reduce drop-out risk. Further research should test the scales against a cross-cultural valid gold standard to obtain insight into their clinical relevance.