A nationally representative survey of ICD-11 PTSD among Danish adolescents and young adults aged 15-29.

Posttraumatic stress disorder (PTSD) is recognized as a debilitating psychiatric disorder affecting populations worldwide. This has inspired many countries to estimate the national prevalence rates of PTSD in Europe and beyond. At present, there are no published representative studies that have assessed the occurrence of trauma exposure and PTSD in Denmark using a valid measurement based on ICD-11 criteria. A national sample of the general population of young Danish residents, ranging in age between 15 to 29 years (n = 2,434), was surveyed cross-sectionally from April to October 2022. Data weights were applied to ensure representativity of the sample. Multiple regression was used to study the relationship between trauma exposure, sex, age, and PTSD. Accidents and violence were the most common types of trauma exposure with females being more likely to experience sexual violence. A total of 7.7% endorsed probable PTSD with women reporting higher rates of clinical and subclinical PTSD (12.3% and 12.7%, respectively) than men (3.5% and 7.3%, respectively). Findings from the multiple regression showed that female gender was associated with higher PTSD-severity, although the strongest predictor was trauma-type with other types of traumas, and sexual violence displaying the strongest relationship to PTSD-severity overall. A dose-response relationship between the number of trauma types and PTSD symptomatology was found. This is the first study of PTSD in a nationally representative Danish sample using a valid measure of ICD-11 PTSD. The identified PTSD rates were higher than Danish official estimates in a representative sample of the Danish adolescent and young adult population (7.7% weighted compared to 1%). The study replicated international findings of sex differences in probable PTSD endorsement.

Attachment Anxiety and Dissociation Mediate Associations Between Polytrauma and Somatization in Kenyan Adolescents.

The experience of several potentially traumatic events (PTE) is a risk factor for higher somatization symptoms severity among adolescents. Attachment orientations and dissociation may influence the link between exposure to PTE and somatization symptoms severity. We analyzed the associations between direct exposure to PTE and somatization symptoms in Kenyan adolescents and explored the mediating role of attachment orientations and dissociation symptoms in the associations between direct exposure to PTE with somatization symptoms severity. A sample of 475 Kenyan adolescents completed validated self-report questionnaires. Serial multiple mediation models were tested by conducting a structural equation modeling employing Preacher and Hayes' procedures (2008). Attachment anxiety and dissociation symptoms mediate the association between direct exposure to traumatic events and somatization symptoms. Higher exposure to traumatic events was significantly associated with higher attachment anxiety levels, which was associated with higher levels of dissociation symptoms, which was then associated with higher somatization symptoms severity. High levels of attachment anxiety and dissociation might aggravate somatization symptoms differently according to sex, which might be seen as a psychological distress mechanism subsequent to exposure to multiple PTE in African adolescents.

Time course of symptoms in posttraumatic stress disorder with delayed expression: A systematic review.

OBJECTIVE: To examine the hypothesis that PTSD with delayed expression in some cases occurs without subthreshold PTSD symptoms above background levels bridging the gap between the traumatic exposure(s) and the clinical diagnosis. METHODS: We performed systematic searches of peer-reviewed papers in English referenced in Pubmed, Embase, or PsycINFO and ascertained 34 prospective studies of PTSD symptom trajectories identified by latent class growth statistical modeling. Studies with delayed and low-stable trajectories provided appropriate data for this study. We computed the difference between the delayed trajectory PTSD symptom sumscore and the low-stable PTSD sumscore at the observed points in time after the traumatic event(s). RESULTS: In 29 study populations, the latent class growth analyses displayed delayed trajectories, and in these, we identified 110 data points (% PTSD sumscore difference/months since traumatic exposure). The median PTSD symptom sumscore was 25% higher during the initial 6 months among individuals in the delayed trajectory compared to those in low-stable trajectory. From this level, the difference widened and reached a plateau of 40-50% higher. The variation was large, and the baseline participation rate and loss to follow-up were exceeding 25% in the majority of the studies. Heterogeneity of populations, measures, and analyses precluded formal meta-analysis. CONCLUSION: Delayed PTSD is preceded by PTSD symptoms during the first year in most cases. Still, few individuals may experience an asymptomatic delay. The results underpin the rationale for monitoring PTSD symptoms and may inform forensic assessments in that delayed PTSD without symptoms bridging the traumatic event is rare.

Right temporal lobe epilepsy surgery activates suppressed post-traumatic stress disorder 31 years after a robbery.

Hippocampus and amygdala play central roles in the development of post-traumatic stress disorder (PTSD). Changes in neurological structures due to surgery leading to PTSD have previously been reported. In this case, we present a patient that develops PTSD right after epilepsy surgery in the right temporal lobe. The case adds knowledge to the mechanisms of storage of PTSD memories. A 56-year-old male suffering from refractory temporal lobe epilepsy was treated with an anteromesial temporal lobe resection on the right side. A few weeks after the surgery, he developed strong PTSD symptoms. They included flashbacks from a robbery he was subjected to three decades ago when he was 25 years old. In addition, he suffered from hypervigilance, irritability, and avoidance behavior. Psychotherapy eventually eased his symptoms. No previous disorders were recorded. No psychiatry symptoms were present before surgery. This case is one of few reports on the sudden occurrence of PTSD after epilepsy-surgery in the form of right-sided anteromesial temporal lobe resection. The disorder may not have been detected if not included in the Danish Epilepsy-Surgery-Protocol, among them both the pre-surgery psychiatric management and in the post-operative monitoring.

A Longitudinal Course of ICD-11 Adjustment Disorder Symptom Profiles: A 12-Month Follow-Up Study.

INTRODUCTION: Adjustment disorder is frequently diagnosed in clinical practice; however, the course of adjustment disorder over time has not yet been studied extensively. METHODS: This longitudinal study was one of the first that aimed to analyze trajectories of adjustment disorder symptoms in a 12-month follow-up among a high-risk community sample (n = 205) exposed to various stressors. Adjustment disorder symptoms were measured at baseline and 12-month follow-up with the Brief Adjustment Disorder New Module based on the definition of adjustment disorder provided in the 11th Edition of International Classification of Diseases (ICD-11) released in 2018 by the World Health Organization (WHO). RESULTS: A latent transition analysis of adjustment symptoms identified four distinct trajectories: "high symptom," "recovery," "onset," and "low symptom." We found 46% of ICD-11 adjustment disorder at baseline, and 29% of the sample was classified as having a high-symptom adjustment symptom profile. The high-symptom profile was predicted by ongoing stressors, female gender, and higher education. CONCLUSION: Study findings indicate that adjustment disorder among high-risk samples, in particular, those exposed to ongoing stressors, could have a high-symptom course over 12 months.

Self-control and coping responses are mediating factors between child behavior difficulties and parental stress and family impact in caregivers of children with severe epilepsy.

OBJECTIVES: To gain a better understanding of parental support needs by assessing parental individual psychological factors as mediating factors between child behavior difficulties and parental perceived stress and family impact of severe childhood epilepsy. METHODS: One-hundred and sixty two parents of children with severe epilepsy were enrolled in the survey during the hospitalization of their child at the Danish Epilepsy Center. Questionnaires targeted the impact on the family, coping style responses, sense of control, and the level of parental perceived stress. RESULTS: Serial mediation models demonstrated a mediating effect of self-control and emotional coping (EMCOP) response between child behavioral difficulties and both parental stress (F(4, 127) = 56.371, p < 0.001, R2 = 0.64) and family impact (F(3, 134) = 32.202, p < 0.001, R2 = 0.42). Low level of control was associated with a higher level of EMCOP response, and a high EMCOP response was associated with greater perceived stress and family impact. Social support ceased to be a protective factor for parental stress in the presence of decreased self-control and higher levels of EMCOP response. CONCLUSION: Individual caregiver psychological factors influence the degree to which sequelae of epilepsy impact family life and perceived stress in parents. Coping interventions should direct awareness toward the life-control aspect, coping response styles, and illness-specific factors to ensure that appropriate support is provided. Maintaining parental resources is essential, and the parents' capacities to handle the child's behavioral difficulties should be considered.

Post-traumatic stress disorder (PTSD) symptoms in children with severe epilepsy.

OBJECTIVES: To assess symptoms of post-traumatic stress disorder (PTSD) in children with severe epilepsy and the associations of trauma symptoms across age, comorbid symptoms, epilepsy-specific factors, parental resources, and psychopathology. METHODS: Fifty children with severe epilepsy across three different age groups (0-5 yrs., 6-12 yrs., 13-18 yrs.) were assessed with developmental-sensitive and standardized PTSD assessment tools when hospitalized at the tertiary epilepsy center Filadelfia, Denmark. The Diagnostic Infant and Preschool Assessment (DIPA), the Darryl test, and the ITQ questionnaire were used to assess the three age groups, respectively. RESULTS: Twenty-two percent of the overall sample met the criteria for PTSD, with a prevalence of symptoms increasing with age (6%, 28%, and 40%). Comorbid psychiatric symptoms in preschoolers were present in 81% of the children witnessing a high level of distress in this group. Behavioral difficulties were elevated across all three age groups, and 40% of the children with trauma symptoms had a parent with concurrent psychopathology. CONCLUSION: To the authors' knowledge, this study is the first to assess trauma symptoms with standardized tests in children with more complicated epilepsies. Trauma symptoms in the group are high; however, there is a need for larger scale studies and research into trauma symptoms in children with more severe epilepsy than those assessable with the included assessment tools. The trauma perspective in severe childhood epilepsy might further clarify the complex associations of biological and contextual variables that affect the children's life quality and enable better preventative treatment options for this group.

Work-related violence and organizational commitment among health care workers: does supervisor's support make a difference?

INTRODUCTION: Work-related threats and violence are major occupational hazards, with potentially serious consequences for both victims and the organization that employs them. Only a few studies have prospectively examined the mitigating effect of social support from supervisors on organizational commitment following exposure to work-related violence and threats. OBJECTIVE: This study aimed at examining the effect of immediate supervisor's support on affective commitment within 1, 3, 6 and 12 months after exposure to violence and threats. METHODS: After exposure to work-related violence and threats, the employees received a questionnaire within the first month and after 3, 6 and 12 months. Right after the incident, 398 employees filled out the questionnaire, and 138 employees answered the questionnaire at all four time points. Prospective associations and mean differences between groups were calculated using linear mixed models. RESULTS: Employees receiving very high levels of social support from supervisors immediately after being exposed to work-related violence or threats had a significantly higher level of organizational commitment across all four time points when compared to the group experiencing middle/low levels of support. Furthermore, at 1- and 3-month follow-up employees receiving very high levels of social support from supervisors following work-related violence and threats reported significantly higher levels of commitment than did the group with high levels of social support from supervisors. CONCLUSION: Organizations should enhance the availability of social support from supervisors for employees experiencing work-related violence and threats. Training of supervisors to be very much concerned about employees exposed to work-related violence may be of critical importance to both the health and work outcomes of employees.

Does acute stress disorder predict posttraumatic stress disorder following workplace violence? A prospective study of psychiatric staff.

OBJECTIVES: Psychiatric staff is at risk of workplace violence (WV) and subsequent posttraumatic symptomatology. The current study assesses the prevalence of acute stress disorder (ASD) and posttraumatic stress disorder (PTSD) in psychiatric staff following WV. This also examines the prospective association between ASD and PTSD. METHODS: This is a prospective cohort study of staff from 18 psychiatric wards in Denmark (n = 250), that reported an incident of workplace violence. RESULTS: The prevalence of ASD was 10.8%, while 8% had PTSD 3 months post-assault. Generalized linear mixed models showed a significant predictive power of ASD on PTSD (OR 8.45, p < 0.001) in the fully adjusted model. CONCLUSIONS: ASD seems to be a predictor of future PTSD in an occupational context and should be considered a possible instrument in enactment of preventive strategies.

Fears of compassion magnify the harmful effects of threat of COVID-19 on mental health and social safeness across 21 countries.

BACKGROUND: The COVID-19 pandemic is a massive global health crisis with damaging consequences to mental health and social relationships. Exploring factors that may heighten or buffer the risk of mental health problems in this context is thus critical. Whilst compassion may be a protective factor, in contrast fears of compassion increase vulnerability to psychosocial distress and may amplify the impact of the pandemic on mental health. This study explores the magnifying effects of fears of compassion on the impact of perceived threat of COVID-19 on depression, anxiety and stress, and social safeness. METHODS: Adult participants from the general population (N = 4057) were recruited across 21 countries worldwide, and completed self-report measures of perceived threat of COVID-19, fears of compassion (for self, from others, for others), depression, anxiety, stress and social safeness. RESULTS: Perceived threat of COVID-19 predicted increased depression, anxiety and stress. The three flows of fears of compassion predicted higher levels of depression, anxiety and stress and lower social safeness. All fears of compassion moderated (heightened) the impact of perceived threat of COVID-19 on psychological distress. Only fears of compassion from others moderated the effects of likelihood of contracting COVID-19 on social safeness. These effects were consistent across all countries. CONCLUSIONS: Fears of compassion have a universal magnifying effect on the damaging impact of the COVID-19 pandemic on mental health and social safeness. Compassion focused interventions and communications could be implemented to reduce resistances to compassion and promote mental wellbeing during and following the pandemic.

Psychiatric and Physical Health Outcomes Associated with Interpersonal Violence: A Propensity Score Matching Approach.

This study examined the association between interpersonal violence and a range of psychiatric and physical health outcomes and assessed whether these associations changed when controlling for a stress-related diagnosis. An observational case-control study was conducted on a sample of 4,059 victims of violence. Using propensity score matching a number of risk factors (assessed five years prior assault) were used. Controls were matched 10:1 using the Danish Central Registry System. Outcomes were ICD-10 diagnoses of a range of psychiatric and physical health outcomes in the 15 years post-injury. Statistically significant associations were found for all psychiatric conditions and a diagnosis of a drug or substance misuse disorder. These findings remained even after controlling for a diagnosis of a stress-related disorder. Large scale case-control studies using the Danish nationwide registers enables a powerful way of assessing the relative impact of exposure to interpersonal violence on the development of psychiatric and physical health problems.

The impact of severe pediatric epilepsy on experienced stress and psychopathology in parents.

OBJECTIVES: To assess the prevalence of psychopathology and the level of stress in parents of children with severe epilepsy to gain a better understanding of parental support needs. METHODS: Questionnaires were completed by parents of children with severe epilepsy during the hospitalization of their child at the Danish Epilepsy Center. The questions targeted symptoms of post-traumatic stress disorder (PTSD), complex PTSD (CPTSD), depression, and anxiety, and the level of perceived stress. RESULTS: A total of 162 caregivers of 140 children with epilepsy participated in the survey. Mothers were more often unemployed than fathers (38% vs. 11%, p < 0.01), and nearly half of the children (47%) attended special needs classes. Psychopathology symptoms were found in 43.5% of parents, fulfilling criteria for one or more diagnoses, and an additional 11% showed symptoms of sub-clinical PTSD. Parent-rated child difficulties were significantly associated with PTSD (Mdiff = 5.51, p = 0.001), depression (Mdiff = 4.50, p < 0.000), and anxiety (Mdiff = 4.61, p = 0.01), and with higher levels of perceived stress (p < 0.001). CONCLUSION: Caring for a child with severe epilepsy has a significant psychopathological impact on caregivers. Caregivers' resources and the degree of behavioral difficulties in the child, rather than epilepsy-related factors, are highly correlated with distress and psychopathological symptoms in caregivers.

Network Analysis of Posttraumatic Stress Experiences of Adults Seeking Psychological Treatment for Childhood Sexual Abuse.

Network analysis proposes that mental disorders may best be construed as causal systems embodied in networks of functionally interconnected symptoms. We employed network analysis to test how adult survivors of childhood sexual abuse (CSA) experienced symptoms of posttraumatic stress, using alternative conceptualizations of posttraumatic stress disorder (PTSD). Given the characteristics of the sample (i.e., the nature of and time since trauma), we hypothesized that (a) symptoms related to arousal would not be prominent in the networks and (b) symptoms related to negative alternations in cognition and mood (NACM) would be core components in the network. Danish adults seeking psychological treatment for CSA (n = 473) completed the Harvard Trauma Questionnaire and Trauma Symptom Checklist. Three alternative models (DSM-5, DSM-5 with dissociation, and ICD-11 complex PTSD [CPTSD]) were estimated using regularized partial correlation models. In the DSM-5 network, strong associations emerged for experiences of NACM (blame and guilt) and intrusions (thoughts and flashbacks). The addition of "depersonalization" and "derealization" to the DSM-5 model produced a strong association, but these experiences were largely unrelated to other PTSD clusters. In the CPTSD network, interpersonal problems and negative self-concept were central to the survivors' experiences. For this highly-specific survivor group who experienced traumatic CSA many years ago, experiences related to NACM appeared to be more central to the posttrauma experience than those of arousal. If replicated, these findings could help inform treatment plans for specific groups of survivors. Methodological implications as to the usefulness of network models in the psychopathological research literature are discussed.

Association Between Dating Violence and Behavioral and Health Outcomes Among Early Adolescents From Denmark: The Role of Exposure to Childhood Maltreatment.

AIM: To examine the unique contribution of child maltreatment victimization on the association between adolescent dating violence (ADV) and four negative behavioral and health-related factors. METHOD: In total, 2,934 7th grade students (M = 13.5, SD = .5) filled out questionnaires at school. Binominal logistic regression was performed to assess the impact of child maltreatment on the relationship between ADV and behavioral and health-related factors. RESULTS: After child maltreatment was taken into account, associations between ADV and the negative behavioral and health-related factors became weaker. CONCLUSIONS: The findings from the present study suggest that focusing on one victimization type (such as ADV) when examining psychological outcomes, can be problematic as the causal relationship may be misrepresented when an adolescent's broader victimization profile and context is not considered.

The Role of Traumatic Experiences and Posttraumatic Stress on Social Anxiety in a Youth Sample in Lithuania.

Emerging adulthood is a developmental stage with an increased vulnerability to mental disorders. Social anxiety disorder (SAD) is highly prevalent anxiety disorder especially among adolescents and young adults. Furthermore, SAD is highly comorbid with posttraumatic stress disorder (PTSD). The aim of this study was to evaluate the prevalence of SAD, life-time traumatic experiences and PTSD among Lithuanian young adults studying at the Universities. We also aimed to search for associations between social anxiety, traumatic experiences, and posttraumatic stress in our sample. In total 590 young adults (67.7% female), aged 20 years on average and studying at the Universities in Lithuania were recruited for this study. Self-report measures were used to measure SAD and PTSD. SAD was measured using the Social Phobia Inventory (SPIN), and PTSD was measured using the Impact of Event Scale - Revised (IES-R). SAD prevalence based on SPIN cut-off >26 in our sample was 15.3%, life-time trauma exposure was 67.5%. No association between accumulative trauma exposure and SAD was found. SAD symptoms were highly correlated with PTSD symptoms. Comorbidity between SAD and PTSD was high, with 32.2% cases of PTSD in SAD group. We found high comorbidity between SAD and PTSD in our study among young adults. Further studies are needed to explore development of SAD and PTSD in longitudinal studies.

Attachment and social support mediate associations between Polyvictimization and psychological distress in early adolescence.

The current study assesses associations between multiple experience of traumatic events (polyvictimization), PTSD symptoms (PTSS) and psychiatric symptoms in early adolescence, and explores the mediating roles of attachment orientations and perceived social support in the associations between polyvictimization, PTSS and psychiatric symptoms. In 2001, a representative national sample of 390 Danish eighth-graders (M = 13.95, SD = .37) completed validated self-report questionnaires. Polyvictimization was related to higher PTSS and psychiatric symptoms. Importantly, polyvictimization was significantly linked to high attachment anxiety, which was linked with low perceived social support, which in turn was linked with high PTSS levels and psychiatric symptoms. Polyvictimization might have dire consequences in early adolescence. An individual's high attachment anxiety might be connected with lack of perceived social support, which should be seen as a possible psychological distress mechanism subsequent to exposure to a number of potentially traumatic events.

Work-related threats and violence and post-traumatic symptoms in four high-risk occupations: short- and long-term symptoms.

OBJECTIVES: To examine the associations between exposure to work-related violence and threats and subsequent PTSD among males and females in four high-risk occupations in human service work. Furthermore, we examined the modifying effect of coping style and self-efficacy. METHODS: Questionnaire data were collected in 2011 and in 2015 from 2678 employees working in psychiatric wards, in the elder sector, in special schools and in the Prison and Probation Service (PPS). Exposure to work-related violence and threats was measured in 2011, while PTSD was measured in 2011 and 2015 by the Impact of Event Scale-Revised. To assess the associations, logistic regression was conducted, adjusted for bullying, sexual harassment, negative acts, conflicts at work, other private traumas and baseline PTSD. RESULTS: There was an association between work-related threats and PTSD in 2011 and 2015. Furthermore, there was an association between work-related violence and PTSD in 2011. The associations were strongest in the PPS. Male staff had a higher risk for PTSD. Neither coping style nor self-efficacy did modify the associations between exposure to work-related violence and threats and subsequent PTSD. CONCLUSION: The prevention of PTSD following work-related violence and threats should first of all be based on reducing the risk of work-related violence. In addition, supervisors should be trained to detect symptoms of PTSD after exposure to traumatic events.

Workplace violence and development of burnout symptoms: a prospective cohort study on 1823 social educators.

PURPOSE: Burnout and workplace violence (WPV) have been associated in cross-sectional studies, but longitudinal studies with solid methods and adequate sample sizes are lacking. This study investigates whether WPV increases burnout symptoms during a 12-month period. METHODS: Questionnaire data were collected on 1823 social educators at baseline and 12-month follow-up, coupled with additionally 12 monthly text-message surveys on exposure to WPV. Using general linear modelling for repeated measures, we estimated change over time in burnout symptoms in three WPV exposure groups (none, low, high). RESULTS: A time by exposure to WPV interaction existed for development of burnout; F(2) = 7.2, p = 0.001 η2 = 0.011. Burnout increased significantly within the group of low exposure; F(1) = 6.8, p = 0.01 and high exposure; F(1) = 6.7 p = 0.001, but not within the non-exposed F(1) = 2.1 p = 0.15. At follow-up, both the low exposed and high exposed had significantly higher levels of burnout compared to the non-exposed. CONCLUSION: Exposure to WPV increases level of burnout within a 12-month period. We propose that assessment of burnout in future studies should utilize instruments capable of detecting small changes. We further propose that prevention against employee burnout could be improved using monitoring targeted at employees exposed to WPV.

Youth Responses to School Shootings: a Review.

PURPOSE OF REVIEW: This paper aims to synthesize research relating to youth responses to school shootings between 2014 and 2017. The main questions it addresses are how such events impact young people psychologically, and what risk or protective factors may contribute to different trajectories of recovery? RECENT FINDINGS: Recent research suggests that most young people exposed to school shootings demonstrate resilience, exhibiting no long-term dysfunction. However, a minority will experience severe and chronic symptoms. The likelihood of experiencing clinically significant reactions is influenced by pre-trauma functioning as well as peri-traumatic and post-traumatic factors. These include proximity to the trauma, peri-traumatic dissociation, post-traumatic emotional regulation difficulties, social support, and flexibility of coping styles. Research that separates the distinguishing features of young people with differing recovery styles is vital to tailor intervention. But methodological and design issues associated with such research necessitates caution in drawing conclusions. Variation in definitions and measures and the self-report nature of many of the studies are potential sources of bias. Greater uniformity across designs would enhance confidence and allow for improved evidence-based intervention.

Variation in post-traumatic response: the role of trauma type in predicting ICD-11 PTSD and CPTSD symptoms.

PURPOSE: The World Health Organization's 11th revision to the International Classification of Diseases manual (ICD-11) will differentiate between two stress-related disorders: PTSD and Complex PTSD (CPTSD). ICD-11 proposals suggest that trauma exposure which is prolonged and/or repeated, or consists of multiple forms, that also occurs under circumstances where escape from the trauma is difficult or impossible (e.g., childhood abuse) will confer greater risk for CPTSD as compared to PTSD. The primary objective of the current study was to provide an empirical assessment of this proposal. METHODS: A stratified, random probability sample of a Danish birth cohort (aged 24) was interviewed by the Danish National Centre for Social Research (N = 2980) in 2008-2009. Data from this interview were used to generate an ICD-11 symptom-based classification of PTSD and CPTSD. RESULTS: The majority of the sample (87.1%) experienced at least one of eight traumatic events spanning childhood and early adulthood. There was some indication that being female increased the risk for both PTSD and CPTSD classification. Multinomial logistic regression results found that childhood sexual abuse (OR = 4.98) and unemployment status (OR = 4.20) significantly increased risk of CPTSD classification as compared to PTSD. A dose-response relationship was observed between exposure to multiple forms of childhood interpersonal trauma and risk of CPTSD classification, as compared to PTSD. CONCLUSIONS: Results provide empirical support for the ICD-11 proposals that childhood interpersonal traumatic exposure increases risk of CPTSD symptom development.