Persistent physical symptoms: definition, genesis, and management.

Persistent physical symptoms (synonymous with persistent somatic symptoms) is an umbrella term for distressing somatic complaints that last several months or more, regardless of their cause. These symptoms are associated with substantial disability and represent a major burden for patients, health-care professionals, and society. Persistent physical symptoms can follow infections, injuries, medical diseases, stressful life events, or arise de novo. As symptoms persist, their link to clearly identifiable pathophysiology often weakens, making diagnosis and treatment challenging. Multiple biological and psychosocial risk factors and mechanisms contribute to the persistence of somatic symptoms, including persistent inflammation; epigenetic profiles; immune, metabolic and microbiome dysregulation; early adverse life experiences; depression; illness-related anxiety; dysfunctional symptom expectations; symptom focusing; symptom learning; and avoidance behaviours, with many factors being common across symptoms and diagnoses. Basic care consists of addressing underlying pathophysiology and using person-centred communication techniques with validation, appropriate reassurance, and biopsychosocial explanation. If basic care is insufficient, targeted psychological and pharmacological interventions can be beneficial. A better understanding of the multifactorial persistence of somatic symptoms should lead to more specific, personalised, and mechanism-based treatment, and a reduction in the stigma patients commonly face.

Psychosocial factors, health behaviors and risk of cancer incidence: Testing interaction and effect modification in an individual participant data meta-analysis.

Depression, anxiety and other psychosocial factors are hypothesized to be involved in cancer development. We examined whether psychosocial factors interact with or modify the effects of health behaviors, such as smoking and alcohol use, in relation to cancer incidence. Two-stage individual participant data meta-analyses were performed based on 22 cohorts of the PSYchosocial factors and CAncer (PSY-CA) study. We examined nine psychosocial factors (depression diagnosis, depression symptoms, anxiety diagnosis, anxiety symptoms, perceived social support, loss events, general distress, neuroticism, relationship status), seven health behaviors/behavior-related factors (smoking, alcohol use, physical activity, body mass index, sedentary behavior, sleep quality, sleep duration) and seven cancer outcomes (overall cancer, smoking-related, alcohol-related, breast, lung, prostate, colorectal). Effects of the psychosocial factor, health behavior and their product term on cancer incidence were estimated using Cox regression. We pooled cohort-specific estimates using multivariate random-effects meta-analyses. Additive and multiplicative interaction/effect modification was examined. This study involved 437,827 participants, 36,961 incident cancer diagnoses, and 4,749,481 person years of follow-up. Out of 744 combinations of psychosocial factors, health behaviors, and cancer outcomes, we found no evidence of interaction. Effect modification was found for some combinations, but there were no clear patterns for any particular factors or outcomes involved. In this first large study to systematically examine potential interaction and effect modification, we found no evidence for psychosocial factors to interact with or modify health behaviors in relation to cancer incidence. The behavioral risk profile for cancer incidence is similar in people with and without psychosocial stress.

The mediating role of health behaviors in the association between depression, anxiety and cancer incidence: an individual participant data meta-analysis.

BACKGROUND: Although behavioral mechanisms in the association among depression, anxiety, and cancer are plausible, few studies have empirically studied mediation by health behaviors. We aimed to examine the mediating role of several health behaviors in the associations among depression, anxiety, and the incidence of various cancer types (overall, breast, prostate, lung, colorectal, smoking-related, and alcohol-related cancers). METHODS: Two-stage individual participant data meta-analyses were performed based on 18 cohorts within the Psychosocial Factors and Cancer Incidence consortium that had a measure of depression or anxiety (N = 319 613, cancer incidence = 25 803). Health behaviors included smoking, physical inactivity, alcohol use, body mass index (BMI), sedentary behavior, and sleep duration and quality. In stage one, path-specific regression estimates were obtained in each cohort. In stage two, cohort-specific estimates were pooled using random-effects multivariate meta-analysis, and natural indirect effects (i.e. mediating effects) were calculated as hazard ratios (HRs). RESULTS: Smoking (HRs range 1.04-1.10) and physical inactivity (HRs range 1.01-1.02) significantly mediated the associations among depression, anxiety, and lung cancer. Smoking was also a mediator for smoking-related cancers (HRs range 1.03-1.06). There was mediation by health behaviors, especially smoking, physical inactivity, alcohol use, and a higher BMI, in the associations among depression, anxiety, and overall cancer or other types of cancer, but effects were small (HRs generally below 1.01). CONCLUSIONS: Smoking constitutes a mediating pathway linking depression and anxiety to lung cancer and smoking-related cancers. Our findings underline the importance of smoking cessation interventions for persons with depression or anxiety.

Development of Gender Non-Contentedness During Adolescence and Early Adulthood.

Adolescence is an important period for the development of gender identity. We studied the development of gender non-contentedness, i.e., unhappiness with being the gender aligned with one's sex, from early adolescence to young adulthood, and its association with self-concept, behavioral and emotional problems, and adult sexual orientation. Participants were 2772 adolescents (53% male) from the Tracking Adolescents' Individual Lives Survey population and clinical cohort. Data from six waves were included (ages 11-26). Gender non-contentedness was assessed with the item "I wish to be of the opposite sex" from the Youth and Adult Self-Report at all six waves. Behavioral and emotional problems were measured by total scores of these scales at all six waves. Self-concept was assessed at age 11 using the Global Self-Worth and Physical Appearance subscales of the Self-Perception Profile for Children. Sexual orientation was assessed at age 22 by self-report. In early adolescence, 11% of participants reported gender non-contentedness. The prevalence decreased with age and was 4% at the last follow-up (around age 26). Three developmental trajectories of gender non-contentedness were identified: no gender non-contentedness (78%), decreasing gender non-contentedness (19%), and increasing gender non-contentedness (2%). Individuals with an increasing gender non-contentedness more often were female and both an increasing and decreasing trajectory were associated with a lower global self-worth, more behavioral and emotional problems, and a non-heterosexual sexual orientation. Gender non-contentedness, while being relatively common during early adolescence, in general decreases with age and appears to be associated with a poorer self-concept and mental health throughout development.

Quality indicators for collaborative care networks in persistent somatic symptoms and functional disorders: a modified delphi study.

BACKGROUND: Care for persistent somatic symptoms and functional disorders (PSS/FD) is often fragmented. Collaborative care networks (CCNs) may improve care quality for PSS/FD. Effectiveness likely depends on their functioning, but we lack a straightforward quality evaluation system. We therefore aimed to develop quality indicators to evaluate CCNs for PSS/FD. METHOD: Using an online three-round modified Delphi process, an expert panel provided, selected and ranked quality indicators for CCNs in PSS/FD. Recruited experts were diverse healthcare professionals with relevant experience in PSS/FD care in the Netherlands. RESULTS: The expert panel consisted of 86 professionals representing 15 disciplines, most commonly physiotherapists, psychologists and medical specialists. 58% had more than 10 years experience in PSS/FD care. Round one resulted in 994 quotations, which resulted in 46 unique quality indicators. These were prioritised in round two and ranked in round three by the panel, resulting in a final top ten. The top three indicators were: "shared vision of care for PSS/FD", "pathways tailored to the individual patient", and "sufficiently-experienced caregivers for PSS/FD". CONCLUSIONS: The identified quality indicators to evaluate CCNs in the field of PSS/FD can be implemented in clinical practice and may be useful in improving services and when assessing effectiveness.

Depression, anxiety, and the risk of cancer: An individual participant data meta-analysis.

BACKGROUND: Depression and anxiety have long been hypothesized to be related to an increased cancer risk. Despite the great amount of research that has been conducted, findings are inconclusive. To provide a stronger basis for addressing the associations between depression, anxiety, and the incidence of various cancer types (overall, breast, lung, prostate, colorectal, alcohol-related, and smoking-related cancers), individual participant data (IPD) meta-analyses were performed within the Psychosocial Factors and Cancer Incidence (PSY-CA) consortium. METHODS: The PSY-CA consortium includes data from 18 cohorts with measures of depression or anxiety (up to N = 319,613; cancer incidences, 25,803; person-years of follow-up, 3,254,714). Both symptoms and a diagnosis of depression and anxiety were examined as predictors of future cancer risk. Two-stage IPD meta-analyses were run, first by using Cox regression models in each cohort (stage 1), and then by aggregating the results in random-effects meta-analyses (stage 2). RESULTS: No associations were found between depression or anxiety and overall, breast, prostate, colorectal, and alcohol-related cancers. Depression and anxiety (symptoms and diagnoses) were associated with the incidence of lung cancer and smoking-related cancers (hazard ratios [HRs], 1.06-1.60). However, these associations were substantially attenuated when additionally adjusting for known risk factors including smoking, alcohol use, and body mass index (HRs, 1.04-1.23). CONCLUSIONS: Depression and anxiety are not related to increased risk for most cancer outcomes, except for lung and smoking-related cancers. This study shows that key covariates are likely to explain the relationship between depression, anxiety, and lung and smoking-related cancers. PREREGISTRATION NUMBER: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=157677.

Persistence of somatic symptoms after COVID-19 in the Netherlands: an observational cohort study.

BACKGROUND: Patients often report various symptoms after recovery from acute COVID-19. Previous studies on post-COVID-19 condition have not corrected for the prevalence and severity of these common symptoms before COVID-19 and in populations without SARS-CoV-2 infection. We aimed to analyse the nature, prevalence, and severity of long-term symptoms related to COVID-19, while correcting for symptoms present before SARS-CoV-2 infection and controlling for the symptom dynamics in the population without infection. METHODS: This study is based on data collected within Lifelines, a multidisciplinary, prospective, population-based, observational cohort study examining the health and health-related behaviours of people living in the north of the Netherlands. All Lifelines participants aged 18 years or older received invitations to digital COVID-19 questionnaires. Longitudinal dynamics of 23 somatic symptoms surrounding COVID-19 diagnoses (due to SARS-CoV-2 alpha [B.1.1.7] variant or previous variants) were assessed using 24 repeated measurements between March 31, 2020, and Aug 2, 2021. Participants with COVID-19 (a positive SARS-CoV-2 test or a physician's diagnosis of COVID-19) were matched by age, sex, and time to COVID-19-negative controls. We recorded symptom severity before and after COVID-19 in participants with COVID-19 and compared that with matched controls. FINDINGS: 76 422 participants (mean age 53·7 years [SD 12·9], 46 329 [60·8%] were female) completed a total of 883 973 questionnaires. Of these, 4231 (5·5%) participants had COVID-19 and were matched to 8462 controls. Persistent symptoms in COVID-19-positive participants at 90-150 days after COVID-19 compared with before COVID-19 and compared with matched controls included chest pain, difficulties with breathing, pain when breathing, painful muscles, ageusia or anosmia, tingling extremities, lump in throat, feeling hot and cold alternately, heavy arms or legs, and general tiredness. In 12·7% of patients, these symptoms could be attributed to COVID-19, as 381 (21·4%) of 1782 COVID-19-positive participants versus 361 (8·7%) of 4130 COVID-19-negative controls had at least one of these core symptoms substantially increased to at least moderate severity at 90-150 days after COVID-19 diagnosis or matched timepoint. INTERPRETATION: To our knowledge, this is the first study to report the nature and prevalence of post-COVID-19 condition, while correcting for individual symptoms present before COVID-19 and the symptom dynamics in the population without SARS-CoV-2 infection during the pandemic. Further research that distinguishes potential mechanisms driving post-COVID-19-related symptomatology is required. FUNDING: ZonMw; Dutch Ministry of Health, Welfare, and Sport; Dutch Ministry of Economic Affairs; University Medical Center Groningen, University of Groningen; Provinces of Drenthe, Friesland, and Groningen.

Individual Heterogeneity in the Relations Between Sleep, Inflammation, and Somatic Symptoms.

OBJECTIVE: Poor sleep is associated with the experience of more somatic symptoms and a proinflammatory state, whereas a proinflammatory state may also result in the experience of more somatic symptoms. However, existing studies ignore individual differences in these associations. We aimed to study relations between sleep, inflammatory markers, and somatic symptoms at a within-individual level. METHODS: Time series of daily data on sleep, somatic symptoms, and inflammation markers in 10 healthy individuals (age, 19-58 years; three men) for 63 days were analyzed. Bidirectional lagged ( t - 1) and contemporaneous ( t ) relations between sleep duration, inflammatory markers (C-reactive protein, interferon-α, interleukin 1RA), and somatic symptoms were analyzed using 24-hour urine and diary data. Unified structural equation modeling was used to analyze the association between sleep duration, the three inflammatory markers, and the amount of somatic symptoms at the individual level. RESULTS: Associations were found between sleep and at least one of three inflammatory markers in four individuals, both positive (three associations) and negative (five associations) and contemporaneous (four associations) and lagged (four associations). Sleep was related to somatic symptoms in four individuals, both positive ( n = 2) and negative ( n = 2) and contemporaneous ( n = 3) and lagged ( n = 1). Inflammatory markers were associated with somatic symptoms in three individuals, both positive (three associations) and negative (one association) and contemporaneous (three associations) and lagged (one associations). Two individuals showed no associations between sleep, inflammatory markers, and somatic symptoms. CONCLUSIONS: We observed a large variability in presence, strength, and direction of associations between sleep, inflammatory markers, and somatic symptoms.

A distinctive profile of family genetic risk scores in a Swedish national sample of cases of fibromyalgia, irritable bowel syndrome, and chronic fatigue syndrome compared to rheumatoid arthritis and major depression.

BACKGROUND: Functional somatic disorders (FSD) feature medical symptoms of unclear etiology. Attempts to clarify their origin have been hampered by a lack of rigorous research designs. We sought to clarify the etiology of the FSD by examining the genetic risk patterns for FSD and other related disorders. METHODS: This study was performed in 5 829 186 individuals from Swedish national registers. We quantified familial genetic risk for FSD, internalizing disorders, and somatic disorders in cases of chronic fatigue syndrome (CFS), fibromyalgia (FM), and irritable bowel syndrome (IBS), using a novel method based on aggregate risk in first to fifth degree relatives, adjusting for cohabitation. We compared these profiles with those of a prototypic internalizing psychiatric - major depression (MD) - and a somatic/autoimmune disorder: rheumatoid arthritis (RA). RESULTS: Patients with FM carry substantial genetic risks not only for FM, but also for pain syndromes and internalizing, autoimmune and sleep disorders. The genetic risk profiles for IBS and CFS are also widely distributed although with lower average risks. By contrast, genetic risk profiles of MD and RA are much more restricted to related conditions. CONCLUSION: Patients with FM have a relatively unique family genetic risk score profile with elevated genetic risk across a range of disorders that differs markedly from the profiles of a classic autoimmune disorder (RA) and internalizing disorder (MD). A similar less marked pattern of genetic risks was seen for IBS and CFS. FSD arise from a distinctive pattern of genetic liability for a diversity of psychiatric, autoimmune, pain, sleep, and functional somatic disorders.

How to Ensure Inclusivity in Large-Scale General Population Cohort Studies? Lessons Learned with Regard to Including and Assessing Sex, Gender, and Sexual Orientation.

Despite recent advances in the measurement of sex, gender, and sexual orientation in large-scale cohort studies, the three concepts are still gaining relatively little attention, may be mistakenly equated, or non-informatively operationalized. The resulting imprecise or lacking information hereon in studies is problematic, as sex, gender, and sexual orientation are important health-related factors. Omission of these concepts from general population cohort studies might dismiss participants' identity and experiences and pushes research on sexual or gender minority populations toward purposive sampling, potentially introducing selection bias. It also reinforces the unintentional notion of irrelevance of these concepts to health research, ultimately disadvantaging sexual and gender minority populations. Similarly, a lack of uniform measures on sex, gender, and sexual orientation hampers multi-cohort studies in which data from multiple studies are combined, facilitating increased statistical power. This paper discusses the encountered pitfalls and lessons learned on including and assessing sex, gender, and sexual orientation in large-scale general population cohort studies, exemplified by the Dutch Lifelines Cohort Study. Additionally, we propose hands-on strategies on how to operationalize these concepts in an inclusive manner that is useful for large-scale general population cohort studies.

Symptom profiles and their risk factors in patients with post-COVID-19 condition: a Dutch longitudinal cohort study.

BACKGROUND: To improve research and care for patients with post-COVID-19 condition more insight into different subtypes of post-COVID-19 condition and their risk factors is urgently needed. We aimed to identify risk factors of post-COVID-19 condition in general and for specific symptom profiles. METHODS: This study is based on data collected within the Lifelines Coronavirus disease 2019 (COVID-19) cohort (N = 76 503). Mean pre- and post-SARS-CoV-2 infection symptom scores were compared to classify post-COVID-19 condition. Latent Profile Analysis was used to identify symptom profiles. Logistic and multinomial regression analyses were used to examine the association between demographic, lifestyle and health-related risk factors and post-COVID-19 condition, and symptom profiles, respectively. RESULTS: Of the 3465 participants having had COVID-19, 18.5% (n = 642) classified for post-COVID-19 condition. Four symptom profiles were identified: muscle pain, fatigue, cardiorespiratory and ageusia/anosmia. Female sex was a risk factor for the muscle pain and fatigue profiles. Being overweight or obese increased risk for all profiles, except the fatigue profile. Having a chronic disease increased the risk for all profiles except the ageusia/anosmia profile, with the cardiorespiratory profile being only significant in case of multimorbidity. Being unvaccinated increased risk of the ageusia/anosmia profile. CONCLUSIONS: Findings from this study suggest that Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may trigger different pathophysiological mechanisms that may result in different subtypes of post-COVID-19 condition. These subtypes have shared and unique risk factors. Further characterization of symptom profiles and quantification of the individual and societal impact of specific symptom profiles are pressing challenges for future research.

Sex and gender differences in primary care help-seeking for common somatic symptoms: a longitudinal study.

OBJECTIVE: Women are reported to consult general practitioners (GPs) more frequently than men. However, previous studies on sex differences in help-seeking behavior for somatic symptoms do not distinguish between sex and gender, do not account for sex differences in presented symptoms, and are frequently conducted in clinical settings, automatically excluding non-help seekers. Therefore, we aim to assess the independent associations of sex and gender with primary care help-seeking for somatic symptoms in the general population. DESIGN AND SETTING: Records from the longitudinal population-based Lifelines Cohort Study were linked to routine electronic health records from GPs. SUBJECTS: Participants reporting new-onset common somatic symptoms. MAIN OUTCOME MEASURES: Associations between sex and gender, operationalized via a novel gender-index, with primary care help-seeking for somatic symptoms and differences in the strength of the association between gender and help-seeking for somatic symptoms between women and men. RESULTS: Of 20,187 individuals with linked data, 8325 participants (67.5% female; mean age = 44.5 years [SD = 12.9]) reported at least one new-onset somatic symptom. Hereof, 255 (3.1%) consulted the GP within 6 weeks of symptom onset. Female sex was positively associated with consulting the GP (OR = 1.78; 95%CI = 1.13-2.80), whereas feminine gender was not (OR = 0.67; 95%CI = 0.39-1.16). The latter association did not differ in strength between men and women. More paid working days are negatively associated with help-seeking (OR = 0.95; 95%CI = 0.91-0.98). CONCLUSIONS: The results suggest that female sex rather than feminine gender is associated with primary care help-seeking behavior for somatic symptoms. Nevertheless, clinicians should be aware that gender-related variables, such as mean paid working days, may be associated with help-seeking behavior.

Discordance between Adolescents and Parents in Functional Somatic Symptom Reports: Sex Differences and Future Symptom Prevalence.

Functional somatic symptoms, i.e., physical complaints that cannot be sufficiently explained by an objectifiable biomedical abnormality, become increasingly more prevalent in girls than in boys during adolescence. Both parents and adolescents report more functional somatic symptoms in girls, but their reports correspond only limitedly. It remains unknown whether parent-adolescent discordance contributes to the higher symptom prevalence in girls. This study investigated parent-adolescent discordance in reported functional somatic symptoms throughout adolescence, examined the longitudinal association of parent-adolescent discordance with symptom prevalence in early adulthood and focused on sex differences in these processes. Participants included 2229 adolescents (50.7% female) from four assessments (age 11 to 22 years) of the TRAILS population cohort. Parents and adolescents reported significantly more symptoms in girls than in boys during adolescence. Variance analyses showed that throughout adolescence, parents reported fewer symptoms than girls self-reported and more than boys self-reported. Regression analyses using standardized difference scores showed that lower parent-report than self-report was positively associated with symptom prevalence in early adulthood. Polynomial regression analyses revealed no significant interaction between parent-reported and adolescent self-reported symptoms. Associations did not differ between boys and girls. The findings show that lower parent-reported than self-reported symptoms predict future symptom prevalence in both sexes, but this discordance was more observed in girls. The higher functional somatic symptom prevalence in girls might be partly explained by parental underestimation of symptoms.

Cognitive Task Performance and Subjective Cognitive Symptoms in Individuals With Chronic Fatigue Syndrome or Fibromyalgia: A Cross-Sectional Analysis of the Lifelines Cohort Study.

OBJECTIVE: This study examined cognitive task performance and self-reported cognitive functioning in individuals with chronic fatigue syndrome (CFS) and fibromyalgia (FM) in a population-based sample and investigated the role of mood and anxiety disorders as well as severity of the physical symptoms. METHODS: This study was performed in 79,966 participants (mean [standard deviation] age = 52.9 [12.6] years, 59.2% women) from the Lifelines general population. Symptoms consistent with the diagnostic criteria for CFS and FM were assessed using questionnaires. Two comparison groups were used: participants with self-reported medical disorders with well-defined pathophysiology (i.e., multiple sclerosis and rheumatic arthritis) and controls without these diseases. Objective task performance was based on the computerized CogState cognitive battery and subjective cognitive symptoms using the concentration subscale of the Checklist Individual Strength. RESULTS: Cognitive task performance was poorer in individuals with CFS versus controls without disease and controls with a medical disorder, although the severity of cognitive dysfunction was mild. Participants meeting the criteria for CFS ( n = 2461) or FM ( n = 4295) reported more subjective cognitive symptoms compared with controls without a medical disorder ( d = 1.53, 95% confidence interval [CI] = 1.49-1.57 for CFS; d = 1.25, 95% CI = 1.22-1.29 for FM) and participants with a medical disease ( d = 0.62, 95% CI = 0.46-0.79 for CFS; d = 0.75, 95% CI = 0.70-0.80 for FM). These differences remained essentially the same when excluding participants with comorbid mood or anxiety disorders or adjusting for physical symptom severity. CONCLUSIONS: Subjective cognitive symptoms and, to a lesser extent, suboptimal cognitive task performance are more prevalent in individuals with CFS or FM compared with controls without these conditions.

Predictors of new onsets of irritable bowel syndrome, chronic fatigue syndrome and fibromyalgia: the lifelines study.

BACKGROUND: It has been claimed that functional somatic syndromes share a common etiology. This prospective population-based study assessed whether the same variables predict new onsets of irritable bowel syndrome (IBS), chronic fatigue syndrome (CFS) and fibromyalgia (FM). METHODS: The study included 152 180 adults in the Dutch Lifelines study who reported the presence/absence of relevant syndromes at baseline and follow-up. They were screened at baseline for physical and psychological disorders, socio-demographic, psycho-social and behavioral variables. At follow-up (mean 2.4 years) new onsets of each syndrome were identified by self-report. We performed separate analyses for the three syndromes including participants free of the relevant syndrome or its key symptom at baseline. LASSO logistic regressions were applied to identify which of the 102 baseline variables predicted new onsets of each syndrome. RESULTS: There were 1595 (1.2%), 296 (0.2%) and 692 (0.5%) new onsets of IBS, CFS, and FM, respectively. LASSO logistic regression selected 26, 7 and 19 predictors for IBS, CFS and FM, respectively. Four predictors were shared by all three syndromes, four predicted IBS and FM and two predicted IBS and CFS but 28 predictors were specific to a single syndrome. CFS was more distinct from IBS and FM, which predicted each other. CONCLUSIONS: Syndrome-specific predictors were more common than shared ones and these predictors might form a better starting point to unravel the heterogeneous etiologies of these syndromes than the current approach based on symptom patterns. The close relationship between IBS and FM is striking and requires further research.

Female sex and femininity independently associate with common somatic symptom trajectories.

BACKGROUND: Multiple predictors have been associated with persistent somatic symptoms. However, previous studies problematically defined the persistence of symptoms, conflated participants' sex and gender, and focused on patient populations. Therefore, we studied associations between predictors, especially sex and gender, and longitudinal patterns of somatic symptoms in the general adult population. We also assessed whether predictors for persisting symptoms differ between sexes. METHOD: To identify developmental trajectories of somatic symptoms, assessed by the SCL-90 SOM, we used latent class trajectory modeling in the Dutch Lifelines Cohort Study [N = 150 494; 58.6% female; median time to follow-up: 46.0 (min-max: 22.0-123.0) months]. To identify predictors of trajectories, we applied multiple logistic regression analyses. Predictors were measured by surveys at baseline and a composite gender index was previously developed. RESULTS: A five-class linear LCGA model fitted the data best: 93.7% of the population had a stable symptom trajectory, whereas 1.5% and 4.8% of the population had a consistently increasing or decreasing symptom trajectory, respectively. Female sex predicted severe, stable symptom severity (OR 1.74, 95% CI 1.36-2.22), but not increasing symptom severity (OR 1.15, 95% CI 0.99-1.40). Femininity was protective hereof (OR 0.60, 95% CI 0.44-0.82 and OR 0.66, 95% CI 0.51-0.85, respectively). Merely a few predictors of symptom severity, for instance hours of paid employment and physical functioning, differed in strength between sexes. Yet, effect sizes were small. CONCLUSION: Female sex and femininity predict symptom trajectories. No large sex differences in the strength of additional predictors were found, thus it may not be clinically useful to distinguish between predictors specific to male or female patients of persistent somatic symptoms.

"One time I fell, but I didn't have to cry." A qualitative study on everyday physical complaints in children.

OBJECTIVE: Young children experience physical complaints, like abdominal pain or minor injuries from playing, almost every day. These experiences may shape how they deal with health issues later in life. While models exist to explain illness perception in adults, information is lacking on the perspective of young children. This qualitative study aimed to explore important themes in the experience of everyday physical complaints in four- and five-year-old children, using children as informants. STUDY DESIGN: 30 semi-structured interviews were performed in which four- and five-year-old children were questioned about their experiences with everyday physical complaints. The interviews were double coded using Atlas.ti and subsequently qualitative content analysis was used to define themes. RESULTS: All participating children were able to elaborate on their experiences with physical complaints. Three themes emerged from the interviews: causes of complaints, appraisal of complaints, and implications of complaints. In their appraisal of complaints, four- and five-year-old children made a distinction between visible and invisible complaints and real or pretended complaints. CONCLUSION: Four- and five-year-old children can already give details about their experiences with everyday physical complaints. They have developed ideas about the causes and implications of complaints and try to make an appraisal.

Methodology of the DCCSS later fatigue study: a model to investigate chronic fatigue in long-term survivors of childhood cancer.

BACKGROUND: A debilitating late effect for childhood cancer survivors (CCS) is cancer-related fatigue (CRF). Little is known about the prevalence and risk factors of fatigue in this population. Here we describe the methodology of the Dutch Childhood Cancer Survivor Late Effect Study on fatigue (DCCSS LATER fatigue study). The aim of the DCCSS LATER fatigue study is to examine the prevalence of and factors associated with CRF, proposing a model which discerns predisposing, triggering, maintaining and moderating factors. Triggering factors are related to the cancer diagnosis and treatment during childhood and are thought to trigger fatigue symptoms. Maintaining factors are daily life- and psychosocial factors which may perpetuate fatigue once triggered. Moderating factors might influence the way fatigue symptoms express in individuals. Predisposing factors already existed before the diagnosis, such as genetic factors, and are thought to increase the vulnerability to develop fatigue. Methodology of the participant inclusion, data collection and planned analyses of the DCCSS LATER fatigue study are presented. RESULTS: Data of 1955 CCS and 455 siblings was collected. Analysis of the data is planned and we aim to start reporting the first results in 2022. CONCLUSION: The DCCSS LATER fatigue study will provide information on the epidemiology of CRF and investigate the role of a broad range of associated factors in CCS. Insight in associated factors for fatigue in survivors experiencing severe and persistent fatigue may help identify individuals at risk for developing CRF and may aid in the development of interventions.

Association of Recognized and Unrecognized Myocardial Infarction With Depressive and Anxiety Disorders in 125,988 Individuals: A Report of the Lifelines Cohort Study.

OBJECTIVE: No previous study has focused on recognition of myocardial infarction (MI) and the presence of both depressive and anxiety disorders in a large population-based sample. The aim of this study was to investigate the association of recognized MI (RMI) and unrecognized MI (UMI) with depressive and anxiety disorders. METHODS: Analyses included 125,988 individuals enrolled in the Lifelines study. Current mental disorders according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) were assessed with the Mini-International Neuropsychiatric Interview. UMI was detected using electrocardiogram in participants who did not report a history of MI. The classification of RMI was based on self-reported MI history together with the use of either antithrombotic medications or electrocardiogram signs of MI. Analyses were adjusted for age, sex, smoking, somatic comorbidities, and physical health-related quality of life as measured by the RAND 36-Item Health Survey in different models. RESULTS: Participants with RMI had significantly higher odds of having any depressive and any anxiety disorder as compared with participants without MI (depressive disorder: odds ratio [OR] = 1.86, 95% confidence interval [CI] = 1.38-2.52; anxiety disorder: OR = 1.60, 95% CI = 1.32-1.94) after adjustment for age and sex. Participants with UMI did not differ from participants without MI (depressive disorder: OR = 1.60, 95% CI = 0.96-2.64; anxiety disorder: OR = 0.73, 95% CI = 0.48-1.11). After additional adjustment for somatic comorbidities and low physical health-related quality of life, the association between RMI with any depressive disorder was no longer statistically significant (OR = 1.18; 95% CI =0.84-1.65), but the association with any anxiety disorder remained (OR = 1.27, 95% CI = 1.03-1.57). CONCLUSIONS: Recognition of MI seems to play a major role in the occurrence of anxiety, but not depressive, disorders.

Systemic and Local Corticosteroid Use Is Associated with Reduced Executive Cognition, and Mood and Anxiety Disorders.

BACKGROUND: Use of local corticosteroids, especially the inhaled types, has increasingly been associated with systemic uptake and consequent adverse effects. In this study, we assessed the associations between the use of different corticosteroid types with cognitive and neuropsychiatric adverse effects related to high glucocorticoid exposure. METHODS: In 83,592 adults (mean age 44 years, 59% women) of the general population (Lifelines Cohort Study), we analyzed the relationship between corticosteroid use with executive cognitive functioning (Ruff Figural Fluency Test), and presence of mood and anxiety disorders (Mini-International Neuropsychiatric Interview survey). We performed additional exploration for effects of physical quality of life (QoL; RAND-36), and inflammation (high-sensitive C-reactive protein [CRP]). RESULTS: Cognitive scores were lower among corticosteroid users, in particular of systemic and inhaled types, when compared to nonusers. Users of inhaled types showed lower cognitive scores irrespective of physical QoL, psychiatric disorders, and high-sensitive CRP. Overall corticosteroid use was also associated with higher likelihood for mood and anxiety disorders. Users of inhaled corticosteroids were more likely to have mood disorders (OR 1.40 [95% CI 1.19-1.65], p < 0.001) and anxiety disorders (OR 1.19 [95% CI 1.06-1.33], p = 0.002). These findings were independent of physical QoL. A higher likelihood for mood disorders was also found for systemic users whereas nasal and dermal corticosteroid users were more likely to have anxiety disorders. CONCLUSIONS: Commonly used local corticosteroids, in particular inhaled types, and systemic corticosteroids are associated with reduced executive cognitive functioning and a higher likelihood of mood and anxiety disorders in the general adult population.