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Objectives: Approximately one in five adults experiences chronic pain, often in co-occurrence with depression, insomnia, anxiety, and lower self-rated health. Elevated levels of cytokines, e.g. tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), interleukin 8 (IL-8), and interleukin 10 (IL-10), have been identified in patients with chronic pain. Depression, insufficient sleep, poor self-rated health, and pain intensity have also been associated with inflammatory biomarkers. This study aimed to investigate the interrelationships between inflammatory biomarkers and depression, insomnia, anxiety, self-rated health, sickness behavior, and pain intensity in patients with chronic pain., Methods: Self-report questionnaires and blood samples analyzed for plasma levels of inflammatory biomarkers were collected from 80 adult patients with chronic pain. Associations between inflammatory biomarkers (TNF-α, IL-6, IL-8, IL-10, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)) and depression, insomnia, anxiety, self-rated health, sickness behavior, and pain intensity, were analyzed using bivariate Spearman rank correlation coefficients and regression analyses., Results: Participants were mainly women (72.5 %), with a mean age of 50.8 years, and a reported mean pain duration of 16.7 years. There were significant correlations between insomnia and CRP (r s =.26, p <.05); sex and ESR (r s =.29, p <.05); age and IL-6 (r s =.29, p <.05) and IL-8 (r s =.30, p <.05); BMI and IL-6 (r s =.50, p <.001), CRP (r s =.63, p <.001) and ESR (r s =.42, p <.001). Ratings of depression were positively and significantly related to ratings of sickness behavior and anxiety (β =.32 and β =.40, respectively), explaining 49 % of the total variance in depression ratings. Insomnia was positively and significantly related to sickness behavior (β =.37) explaining 31 % of the total variance in insomnia ratings. Inflammatory biomarkers, however, did not contribute significantly to the models., Conclusions: Participants reported high levels of symptoms, yet the associations between these ratings and the inflammatory biomarkers were either absent or weak. Also, despite high levels of self-reported sickness behavior, overall the inflammatory status remained within the normal range. Ratings of sickness behavior contributed more than inflammatory markers in explaining ratings of depression and insomnia. The present results point to the complexity of chronic pain, and the challenges of identifying biomarkers that explain symptomatology., Competing Interests: Declaration of Competing Interest No conflict., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Insomnia is common in adolescents. This study evaluated feasibility and preliminary efficacy of a six-week internet-delivered cognitive-behavioral therapy for insomnia (ICBT-I) in adolescents., Methods: In this uncontrolled pilot study, participants ( n = 27, 78% female) completed assessments pre- and post intervention. Data on recruitment, adherence to treatment, treatment activity, satisfaction and credibility was collected to assess feasibility. Self-reported insomnia symptoms, sleep parameters as well as depression, anxiety and daytime function were also assessed., Results: Participants showed good adherence to treatment and found the intervention overall credible and satisfactory. From pre- to post-assessment, statistically significant improvements were found for insomnia symptoms ( p < .001; d = 1.02), sleep onset latency ( p < .001; d = .39), wake after sleep onset ( p = .001; d = .34), sleep efficiency ( p < .001; d = .5) and depression ( p = .01, d = .37). Changes in scores of total sleep time, generalized anxiety, daytime sleepiness and functional disability were not significant., Conclusions: The present study indicates that ICBT-I is well accepted by adolescents, that insomnia symptoms and sleep parameters can improve following the intervention, and that co-morbid symptoms of depression can be reduced. Due to the limited sample size and the uncontrolled design, the suggested results need to be replicated in well-powered controlled clinical trials., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Social withdrawal is a well-established part of sickness behavior, but in some contexts sick animals might gain from keeping close instead of keeping away. For instance, sick individuals are more willing to be near known individuals who can provide care and safety (close others) compared to when healthy. Yet, interactions with some strangers might also be beneficial (i.e., healthcare professionals), but it is not known how sickness interplay with social behavior towards such individuals. Here, we assessed if sickness affects perception of caregivers, and developed a new task, the Caregiver Perception Task (CgPT). Twenty-six participants performed the CgPT, once after an injection of lipopolysaccharide (LPS, 0.8 ng/kg body weight, n = 24), and once after an injection of saline (n = 25), one hour and forty-five minutes post-injection. During the task, participants watched short video clips of three types of caregivers: a healthcare professional taking care of a sick individual, a healthcare professional not taking care of a sick individual, and a non-healthcare professional taking care of their sick adult child or partner. After each video clip, the likability, trustworthiness, professionalism, and willingness to interact with and receive care from the caregiver were rated on visual analogue scales. Results showed that participants injected with saline rated healthcare professionals who did not take care of a sick individual less positively on all aspects compared to healthcare professionals who took care of a sick individual. Moreover, compared to saline, LPS increased the participants' willingness to receive care from healthcare professionals and non-healthcare professionals providing care, but not from healthcare professionals not providing care. Thus, our results indicate that sick individuals may approach unknown individuals with potential to provide care and support., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Psychological constructs related to health outcomes and well-being, such as metacognitive beliefs, have been linked to executive functions in general, and cognitive flexibility more specifically. However, such effects have previously only been discussed on a theoretical level and behavioral flexibility has most often been measured through self-report, only approximating information processing capacities. Objectively measured executive functions may be a more potent predictor of health outcomes. We set out to test whether cognitive flexibility capacity was associated with sick leave in a medium sized company. We included 111 subjects of widely different occupations and assessed their executive functions using Delis-Kaplan Executive Function System test battery (D-KEFS). To assess cognitive flexibility capacity, we included Design Fluency (DF) and Verbal Fluency (VF) and computed these into an index of cognitive flexibility (DFVF). Detailed information on sick leave for the last 5 years was gathered from the company. Our results showed that there was a significant negative correlation between DFVF and sick leave [r s (109) = -0.23, p  = 0.015] in the full group as well as in the group that had at least 1 day of sick leave [r s (72) =  - 0.25, p  = 0.03]. The results withstood adjustment for sex, age, occupation, and several core executive functions as well as autistic and ADHD-traits. The results remained for separate analyses using DF or VF. Our main findings were conceptually replicated in a group of bipolar disorder patients. This study shows that objectively measured capacity of cognitive flexibility is associated with key health outcomes such as sick leave., Competing Interests: TV and PP have been involved as consultants in cognitive testing outside research. PP has shares in company that tests cognition. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Vestberg, Lebedev, Jacobsen, Lekander, Sparding, Landén, Maurex, Ingvar and Petrovic.)

The 'Oslo Chronic Fatigue Consortium' consists of researchers and clinicians who question the current narrative that chronic fatigue syndromes, including post-covid conditions, are incurable diseases. Instead, we propose an alternative view, based on research, which offers more hope to patients. Whilst we regard the symptoms of these conditions as real, we propose that they are more likely to reflect the brain's response to a range of biological, psychological, and social factors, rather than a specific disease process. Possible causes include persistent activation of the neurobiological stress response, accompanied by associated changes in immunological, hormonal, cognitive and behavioural domains. We further propose that the symptoms are more likely to persist if they are perceived as threatening, and all activities that are perceived to worsen them are avoided. We also question the idea that the best way to cope with the illness is by prolonged rest, social isolation, and sensory deprivation.Instead, we propose that recovery is often possible if patients are helped to adopt a less threatening understanding of their symptoms and are supported in a gradual return to normal activities. Finally, we call for a much more open and constructive dialogue about these conditions. This dialogue should include a wider range of views, including those of patients who have recovered from them.

The Sickness Questionnaire (SicknessQ) is a questionnaire developed to assess symptoms of sickness behavior, including somatic, behavioral, and affective dimensions. To promote cross-cultural assessments of sickness behavior, we aim to expand the use of this questionnaire to other populations and languages. The aim of the present study was to evaluate the French translation of SicknessQ in a French-speaking general population during the COVID-19 pandemic. One hundred and thirty-nine individuals completed the SicknessQ online, along with the construct criteria measures of self-rated health, state anxiety (STAI-S), and depressive symptoms (PHQ-9). The principal component analyses revealed two components: the first component included seven items concerning mood, motivation and experiences of fatigue and pain; the second component included three items concerning somatic sickness symptoms. Higher scores on the total scale and the two component subscales were associated with poorer self-rated health and higher STAI-S and PHQ-9 scores. Since the associations with construct criteria variables were relatively similar between the single- and the two-dimensional solutions, both the total scale and the subscales of the two components of the French SicknessQ can be used in future studies to measure sickness behavior in French-speaking populations., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Individuals may have a different body odor, when they are sick compared to healthy. In the non-human animal literature, olfactory cues have been shown to predict avoidance of sick individuals. We tested whether the mere experimental activation of the innate immune system in healthy human individuals can make an individuals' body odor be perceived as more aversive (intense, unpleasant, and disgusting). Following an endotoxin injection (lipopolysaccharide; 0.6 ng/kg) that creates a transient systemic inflammation, individuals smelled more unpleasant compared to a placebo group (saline injection). Behavioral and chemical analyses of the body odor samples suggest that the volatile components of samples from "sick" individuals changed qualitatively rather than quantitatively. Our findings support the hypothesis that odor cues of inflammation in axillary sweat are detectable just a few hours after experimental activation of the innate immune system. As such, they may trigger behavioral avoidance, hence constituting a first line of defense against pathogens of infected conspecifics., (© 2023. Springer Nature Limited.)

Fatigue is a common presenting problem in healthcare settings, often attributed to chronic psychosocial stress. Understanding of fatigue and development of evidence-based treatments is hampered by a lack of consensus regarding diagnostic definitions and outcomes to be measured in clinical trials. This study aimed to map outcome domains of importance to the Swedish diagnosis stress-induced exhaustion disorder (ED; ICD-10, code F43.8 A). An online survey was distributed nationwide in Sweden to individuals who reported to have been diagnosed with ED and to healthcare professionals working with ED patients. To identify outcome domains, participants replied anonymously to four open-ended questions about symptoms and expectations for ED-treatment. Qualitative content analysis was conducted of a randomized subsample of respondents, using a mathematical model to determine data saturation. Six hundred seventy participants (573 with reported ED, 97 healthcare professionals) completed the survey. Qualitative content analysis of answers supplied by 105 randomized participants identified 87 outcomes of importance to ED encompassing physical, cognitive, and emotional symptoms as well as functional disability. Self-rating scales indicated that many ED participants, beyond reporting fatigue, also reported symptoms of moderate to severe depression, anxiety, insomnia, poor self-rated health, and sickness behavior. This study presents a map of outcome domains of importance for ED. Results shed light on the panorama of issues that individuals with ED deal with and can be used as a step to further understand the condition and to reach consensus regarding outcome domains to measure in clinical trials of chronic stress and fatigue. Preregistration: Open Science Framework (osf.io) with DOI https://doi.org/10.17605/OSF.IO/4VUAG., (© 2023 The Authors. Stress and Health published by John Wiley & Sons Ltd.)

Background: Sleep problems are common in adolescence and often related to psychopathology and impaired functioning. However, most studies have used summative scores, and little is known about how adolescents with disrupted sleep perceive their specific symptoms and dysfunctions. This study explored differences in levels of psychiatric symptoms and functional ability between Swedish adolescents with and without self-reported disturbed sleep in a school-based sample., Methods: Swedish adolescents ( n = 618, mean age 15.7+/-1.9yrs) answered the PROMIS pediatric measures for fatigue, anxiety, depression, pain interference, anger, physical activity and peer and family relationships. Logistic regression analyses were performed to assess differences between respondents with and without disturbed sleep., Results: Disturbed sleep was associated with higher levels of symptoms of fatigue, anxiety, depression, anger and pain interference, as well as lower functional abilities in terms of physical activity and peer- and family relationships. Adolescents reporting disturbed sleep generally displayed a pattern of impaired executive functioning, internal emotional distress and school- and sleep related worry and dysfunction, as compared to physical disability, aggressive behavior, stress and generalized worry., Conclusions: The present study adds to the understanding of how disturbed sleep and specific psychiatric symptoms and functional ability are interrelated, which may also have clinical implications.

Identification of sick conspecifics allows for avoidance of infectious threats, and is therefore an important behavioral defense against diseases. Here, we investigated if humans can identify sick individuals solely from biological motion and posture (using point-light displays). Additionally, we sought to determine which movements and sickness parameters would predict such detection. We collected video clips and derived point-light displays (one stride presented in a loop) of sick walkers (injected with lipopolysaccharide at 2.0 ng/kg body weight) and the same walkers when healthy (injected with saline). We then presented these displays to two groups, one group classified each walker as sick or healthy (study 1, n = 106), and the other group scored the walkers' health on a visual analogue scale (study 2, n = 106). The raters were able to identify sick individuals above chance, and rated sick walkers as having worse health, both from observing video clips and point-light displays. Furthermore, both sickness detection and worse apparent health were predicted by inflammation-induced increase in rigidity and slower walking, but not other cues. Altogether, these findings indicate that biological motion can serve as a sickness cue, possibly allowing humans to identify sick conspecifics from a distance, and thereby allowing for disease avoidance., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Objectives: It has been argued that sex and disease-related traits should influence how observers respond to sensory sickness cues. In fact, there is evidence that humans can detect sensory cues related to infection in others, but lack of power from earlier studies prevents any firm conclusion regarding whether perception of sickness cues is associated with sex and disease-related personality traits. Here, we tested whether women (relative to men), individuals with poorer self-reported health, and who are more sensitive to disgust, vulnerable to disease, and concerned about their health, overestimate the presence of, and/or are better at detecting sickness cues., Methodology: In a large online study, 343 women and 340 men were instructed to identify the sick faces from a series of sick and healthy photographs of volunteers with an induced acute experimental inflammation. Participants also completed several disease-related questionnaires., Results: While both men and women could discriminate between sick and healthy individuals above chance level, exploratory analyses revealed that women outperformed men in accuracy and speed of discrimination. Furthermore, we demonstrated that higher disgust sensitivity to body odors is associated with a more liberal decision criterion for categorizing faces as sick., Conclusion: Our findings give strong support for the human ability to discriminate between sick and healthy individuals based on early facial cues of sickness and suggest that women are significantly, although only slightly, better at this task. If this finding is replicated, future studies should determine whether women's better performance is related to increased avoidance of sick individuals., Competing Interests: The authors declare no conflict of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Foundation for Evolution, Medicine, and Public Health.)

Objectives: Compare mental health, stress, and well-being in the Swedish population as measured before and during the COVID-19 pandemic., Methods: Repeated cross-sectional design using data measured before (Jan-2019; n  = 2791) and during (Oct/Nov-2020; n  = 2926) COVID-19 pandemic in Swedish population-representative cohorts. Following constructs were measured: anxiety (Beck Anxiety Inventory), depression (Beck Depression Inventory-II), stress (Perceived Stress Scale-10 items), health-related quality of life (HRQOL[Functional Assessment of Cancer Therapy-General Population]) and self-rated health (SRH) was assessed with a single-item question., Results: When adjusting for age, sex, education, and income there were significantly higher levels of anxiety (M̂ = 9.15 vs. 8.48, p  < 0.01) and depression (M̂ = 3.64 vs. 3.30, p  = 0.03), lower levels of stress (M̂ = 14.06 vs. 14.91, p  < 0.001), but worsened HRQOL (M̂ = 76.40 vs. 77.92, p  < 0.01) and SRH (M̂ = 6.91 vs. 7.20, p  < 0.001), observed in 2020 compared to 2019. For the negative effects seen in anxiety, depression, HRQOL, and SRH, higher income and education had a protective effect. The decrease in stress was also correlated with higher income., Conclusions: The COVID-19 pandemic led to a small but significant worsening in mental health and well-being in the general Swedish population, where higher socioeconomic status seemed to have a protective effect.

Background: Patients with stress-related mental disorders often report cognitive impairment, but studies investigating objective cognitive impairment in patients with stress-related disorders have produced inconsistent findings., Aim: The primary aim of this study was to investigate objective cognitive functioning in patients diagnosed with the stress-related disorders adjustment disorder or exhaustion disorder, compared to a healthy normative group. Secondary aims were to conduct subgroup analyses of cognitive functioning between the diagnostic groups and explore associations between self-reported symptoms and cognitive functioning., Methods: Cognitive test results on a digitally self-administered cognitive test battery from 266 patients (adjustment disorder, n = 131; exhaustion disorder, n = 135) were cross-sectionally compared with results from a healthy normative group (N = 184 to 692) using one-tailed t-tests. ANOVAs were conducted for subgroup analyses, and regression analyses for associations between self-reported symptoms and cognitive functioning. Effect sizes were calculated., Results: Patients performed significantly worse than the normative group on all measures with small to moderate effect sizes ranging from d = -.13 to -.57. Those diagnosed with exhaustion disorder performed worse than norms on more measures than did patients with adjustment disorder, but no significant differences between diagnostic groups were found on any measure. Self-reported memory impairment was weakly associated with one of two memory measures. No clear associations between self-reported burnout symptoms and objective cognitive functioning were found., Conclusions: This study adds to the literature indicative of small to moderate objective cognitive impairments in patients diagnosed with stress-related mental disorders. Further exploration into mechanisms of cognitive functioning in different populations is needed for development of theoretical models that may explain the weak correlation between self-reported symptoms and objective measures., Trial Registration: ClinicalTrial.gov: NCT04797273. Trial registration date 15 March 2021. This study was also pre-registered on Open Science Framework (osf.io) with https://doi.org/10.17605/OSF.IO/TQXZV ., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Metabolites of the kynurenine pathway are hypothesized to be implicated in inflammation-associated depression, but there is a lack of experimental studies in humans assessing the kinetics of kynurenine metabolites in relation to experimentally-induced sickness. The aim of the present study was to assess changes in the kynurenine pathway and to explore its relation to symptoms of sickness behavior during an acute experimental immune challenge. This double-blind placebo-controlled randomized cross-over study included 22 healthy human participants (n = 21 both sessions, M age = 23.4, SD = 3.6, nine women) who received an intravenous injection of 2.0 ng/kg lipopolysaccharide (LPS) and saline (placebo) on two different occasions in a randomized order. Blood samples (0 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 5 h, 7 h post-injection) were analyzed for kynurenine metabolites and inflammatory cytokines. The intensity of symptoms of sickness behavior was assessed using the 10-item Sickness Questionnaire at 0 h, 1.5 h, 3 h, 5 h, and 7 h post-injection. LPS induced significantly lower concentrations of plasma tryptophan (at 2 h, 4 h, 5 h, and 7 h post-injection), kynurenine (at 2 h, 3 h, 4 h, and 5 h post-injection), nicotinamide (at 4 h, 5 h, and 7 h post-injection), and higher levels for quinolinic acid at 5 h post-injection as compared to placebo. LPS did not affect kynurenic acid, 3-hydroxykynurenine, and picolinic acid. The development of the sickness symptoms was largely similar across items, with the highest levels around 1.5-3 h post-injection. Changes in plasma levels of kynurenine metabolites seem to coincide rather than precede or follow changes in subjective sickness. Exploratory analyses indicate that higher Sickness Questionnaire total scores at 1.5-5 h post-injection were correlated with lower kynurenic acid and nicotinamide levels. These results lend further support for LPS-induced changes in the kynurenine pathway, but may not, as interpreted from blood levels, causally link to LPS-induced acute symptoms of sickness behavior. Future research may consider a larger sample to further scrutinize the role of the kynurenine pathway in the sickness response., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aims: Psychological distress is a global public health concern with individual and societal implications causing work-related disability and loss of productivity. It is less known how much work ability contributes to the development of psychological distress. This study aimed to assess the association between self-perceived physical and mental work ability in relation to job demands, and the incidence of psychological distress in a Swedish working population., Methods: Data were obtained from three subsamples of the Stockholm Public Health Cohort with baseline in 2010 and follow-up in 2014, based on a working population in Stockholm County aged 18-60 years, with no or mild psychological distress at baseline ( n =29,882). Self-perceived physical and mental work ability in relation to job demands were assessed at baseline with a subscale from the Work Ability Index. Study participants scoring 4 or more on the General Health Questionnaire 12 at follow-up were classified as having developed psychological distress during the study period. Poisson log linear regression was used to calculate crude and adjusted rate ratios with 95% confidence intervals., Results: At follow-up, 2543 participants (12%) had developed psychological distress. Reporting poor physical and/or poor mental work ability in relation to job demands at baseline was associated with an almost doubled rate ratio of psychological distress at follow-up, compared to reporting good work ability (rate ratio 1.8; 95% confidence interval 1.6-2.0)., Conclusions: Poor work ability is associated with a higher incidence of future psychological distress compared to good work ability.

Background and Objectives: Body odor conveys information about health status to conspecifics and influences approach-avoidance behaviors in animals. Experiments that induce sickness in otherwise healthy individuals suggest that humans too can detect sensory cues to infection in others. Here, we investigated whether individuals could detect through smell a naturally occurring acute respiratory infection in others and whether sickness severity, measured via body temperature and sickness symptoms, was associated with the accuracy of detection., Methodology: Body odor samples were collected from 20 donors, once while healthy and once while sick with an acute respiratory infection. Using a double-blind, two-alternative forced-choice method, 80 raters were instructed to identify the sick body odor from paired sick and healthy samples (i.e. 20 pairs)., Results: Sickness detection was significantly above chance, although the magnitude of the effect was low (56.7%). Raters' sex and disgust sensitivity were not associated with the accuracy of sickness detection. However, we find some indication that greater change in donor body temperature, but not sickness symptoms, between sick and healthy conditions improved sickness detection accuracy., Conclusion and Implications: Our findings suggest that humans can detect individuals with an acute respiratory infection through smell, albeit only slightly better than chance. Humans, similar to other animals, are likely able to use sickness odor cues to guide adaptive behaviors that decrease the risk of contagion, such as social avoidance. Further studies should determine how well humans can detect specific infections through body odor, such as Covid-19, and how multisensory cues to infection are used simultaneously., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Foundation for Evolution, Medicine, and Public Health.)

Chronic pain is characterized by high psychological comorbidity, and diagnoses are symptom-based due to a lack of clear pathophysiological factors and valid biomarkers. We investigate if inflammatory blood biomarker signatures are associated with pain intensity and psychological comorbidity in a mixed chronic pain population. Eighty-one patients (72% women) with chronic pain (>6 months) were included. Patient reported outcomes were collected, and blood was analyzed with the Proseek Multiplex Olink Inflammation Panel (Bioscience Uppsala, Uppsala, Sweden), resulting in 77 inflammatory markers included for multivariate data analysis. Three subgroups of chronic pain patients were identified using an unsupervised principal component analysis. No difference between the subgroups was seen in pain intensity, but differences were seen in mental health and inflammatory profiles. Ten inflammatory proteins were significantly associated with anxiety and depression (using the Generalized Anxiety Disorder 7-item scale (GAD-7) and the Patient Health Questionnaire (PHQ-9): STAMBP, SIRT2, AXIN1, CASP-8, ADA, IL-7, CD40, CXCL1, CXCL5, and CD244. No markers were related to pain intensity. Fifteen proteins could differentiate between patients with moderate/high (GAD-7/PHQ-9 > 10) or mild/no (GAD-7/PHQ-9 < 10) psychological comorbidity. This study further contributes to the increasing knowledge of the importance of inflammation in chronic pain conditions and indicates that specific inflammatory proteins may be related to psychological comorbidity.

Introduction: In an attempt to avoid contact with infectious individuals, humans likely respond to generalized rather than specific markers of disease. Humans may thus perceive a noninfectious individual as socially less attractive if they look (e.g., have facial discolouration), move (e.g., have a slower walking pace), or sound (e.g., sneeze) sick. This pilot study tested whether humans are averse to the body odour of noninfectious individuals with a low-grade systemic inflammation., Methods: We collected the axillary body odour of individuals with severe seasonal allergy (N = 14) and healthy controls (N = 10) during and outside the allergy season and measured serum levels of two inflammatory cytokines (tumour necrosis factor-α and interleukin-5). Independent participants (N = 67) then sampled and rated these odours on intensity and pleasantness., Results: While individuals with seasonal allergy had nominally more unpleasant and intense body odours during the allergy season, relative to outside the allergy season and to healthy controls, these effects were not significant. When examining immune markers, the change in perceived pleasantness of an individual's body odour (from out-to-inside pollen season) was significantly related to the change in their interleukin-5 levels but not to tumour necrosis factor-α., Discussion: Our findings tentatively suggest that the human olfactory system could be sensitive to inflammation as present in a noncommunicable condition. Larger replications are required to determine the role of olfaction in the perception of infectious and noninfectious (e.g., chronic diseases) conditions., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Recent research has characterized the behavioral defense against disease. In particular the detection of sickness cues, the adaptive reactions (e.g. avoidance) to these cues and the mediating role of disgust have been the focus. A presumably important but less investigated part of a behavioral defense is the immune system response of the observer of sickness cues. Odors are intimately connected to disease and disgust, and research has shown how olfaction conveys sickness cues in both animals and humans. This study aims to test whether odorous sickness cues (i.e. disgusting odors) can trigger a preparatory immune response in humans. We show that subjective and objective disgust measures, as well as TNFα levels in saliva increased immediately after exposure to disgusting odors in a sample of 36 individuals. Altogether, these results suggest a collaboration between behavioral mechanisms of pathogen avoidance in olfaction, mediated by the emotion of disgust, and mechanisms of pathogen elimination facilitated by inflammatory mediators. Disgusting stimuli are associated with an increased risk of infection. We here test whether disgusting odors, can trigger an immune response in the oral cavity. The results indicate an increase level of TNFα in the saliva. This supports that disease cues can trigger a preparatory response in the oral cavity., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Foundation for Evolution, Medicine, and Public Health.)

Background: Symptoms related to chronic stress are prevalent and entail high societal costs, yet there is a lack of international consensus regarding diagnostics and treatment. A new stress-related diagnosis, exhaustion disorder, was introduced into the Swedish version of ICD-10 in 2005. Since then, use of the diagnosis has increased rapidly., Aims: To create the first comprehensive synthesis of research on exhaustion disorder to report on the current state of knowledge. Preregistration: Open Science Framework (http://www.w3.org/1999/xlink">osf.io), doi 10.17605/OSF.IO/VFDKW., Method: A PRISMA-guided scoping review of all empirical studies of exhaustion disorder was conducted. Searches were run in the MEDLINE, PsycInfo and Web of Science databases. Data were systematically charted and thematically categorised based on primary area of investigation., Results: Eighty-nine included studies were sorted into six themes relating to lived experience of exhaustion disorder ( n = 9), symptom presentation and course ( n = 13), cognitive functioning ( n = 10), biological measures ( n = 24), symptom measurement scales ( n = 4) and treatment ( n = 29). Several studies indicated that individuals with exhaustion disorder experience a range of psychiatric and somatic symptoms beyond fatigue, but robust findings within most thematic categories were scarce. The limited number of studies, lack of replication of findings and methodological limitations (e.g. small samples and scarcity of specified primary outcomes) preclude firm conclusions about the diagnostic construct., Conclusions: More research is needed to build a solid knowledge base for exhaustion disorder. International collaboration regarding the conceptualisation of chronic stress and fatigue is warranted to accelerate the growth of evidence.

Background: The medical and scientific communities struggle to understand chronic pain and find effective treatments. Multimodal approaches are encouraging but show significant individual differences. Methods: Seventy-eight persons (56 women) with chronic pain received Acceptance and Commitment Therapy and provided blood samples before and after treatment. The participants completed surveys with the blood sampling. Blood plasma was analyzed for IL-6 and TNF-α levels with the Olink Inflammation Panel (Olink Bioscience Uppsala, Sweden). The treatment effects and moderating effects of low-grade inflammation on changes in outcomes were analyzed using linear mixed models. Results: Pain interference (p < 0.001) and psychological inflexibility (p < 0.001) improved significantly during treatment, but pain intensity did not (p = 0.078). Cytokine levels did not change over the course of the treatment (IL-6/TNF-α p = 0.086/0.672). Mean baseline levels of IL-6 and TNF-α moderated improvement in psychological inflexibility during the course of treatment (p = 0.044), but cytokine levels did not moderate changes in pain interference (p = 0.205) or pain intensity (p = 0.536). Conclusions: Higher baseline inflammation levels were related to less improvement in psychological inflexibility. Low-grade inflammation may be one factor underlying the variability in behavioral treatment in chronic pain.

Objectives: Long-duration activity-limiting neck/back pain is common, but the knowledge of what work and lifestyle factors that influence the prognosis is sparse. The objective was therefore to evaluate if two factors, good self-perceived work ability and no daily smoking, are associated with a favourable prognosis of long-duration activity-limiting neck/back pain in a working population, and if these exposures have a synergistic prognostic effect., Design: A prospective cohort study based on three subsamples from the Stockholm Public Health Cohort., Settings: A working population in Stockholm County, Sweden., Participants: Individuals, 18-61 years old, reporting long-duration activity-limiting neck/back pain the previous 6 months at baseline in 2010 (n=5177)., Measures: The exposures were: self-perceived work ability (categorised into good, moderate and poor) and daily smoking (no/yes). The outcome in 2014 was 'absence of long-duration activity-limiting neck/back pain' the previous 6 months representing a favourable prognosis of reported problems at baseline in 2010. Risk ratios (RRs) and risk differences (RDs) with 95% CI was estimated by general linear regressions, and the synergistic effect was estimated by the synergy index (SI) with 95% CI., Results: Participants with moderate or good work ability, respectively, had an adjusted RR for a favourable prognosis of 1.37 (95% CI 1.11 to 1.69), and 1.80 (1.49 to 2.17) in comparison with participants with poor work ability. The corresponding adjusted RD were 0.07 (0.02 to 0.11) and 0.17 (0.12 to 0.22). Participants not smoking on daily basis had an adjusted RR of 1.21 (1.02 to 1.42), and an adjusted RD of 0.05 (0.01 to 0.10) for a favourable outcome compared with daily smokers. The adjusted SI was 0.92 (0.60 to 1.43)., Conclusion: For participants with long-duration activity-limiting neck/back pain, moderate or good self-perceived work ability and not being a daily smoker were associated with a favourable prognosis but having both exposures seemed to have no synergistic prognostic effect., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The COVID Stress Scales (CSS) assess health- and contamination-related distress in the face of a medical outbreak like the ongoing COVID-19 pandemic. Though the CSS is translated into 21 languages, it has not been validated in a Swedish national sample., Aim: Our general objective is to provide a translation, replication, and validation of the CSS and test its convergent- and discriminant validity in relation to anxiety, health anxiety, depression, and stress in the general Swedish population. We also present latent psychometric properties by modelling based on item response theory., Methods: Participants consisted of 3044 Swedish adults (> 18 years) from a pre-stratified (gender, age, and education) sample from The Swedish Citizen Panel. Mental health status was assessed by validated instruments, including the CSS, PHQ-4, SHAI-14, and PSS-10., Results: Results indicate that our Swedish translation of CSS has good psychometric properties and consists of 5 correlated factors., Discussion: The CSS is useful either as a unidimensional or multidimensional construct using the CSS scales to measure key facets of pandemic-related stress., Conclusions: The findings support the cross-cultural validity of the CSS and its potential utility in understanding many of the emotional challenges posed by the current and future pandemics., Competing Interests: Co-author ROB has received institutional research grants from Bristol-Myers Squibb (BMS) and SkyLineDx, speaker honorarium from Roche and Pfizer and has served on advisory boards for Amgen, BD/BARD, Bristol-Myers Squibb (BMS), Merck Sharp & Dohme(MSD), Novartis, Roche and Sanofi Genzyme. None of the work is linked in any way to the current manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Introduction: The role of inflammation in common psychiatric diseases is now well acknowledged. However, the factors and mechanisms underlying inter-individual variability in the vulnerability to develop psychopathology-related symptoms in response to inflammation are not well characterized. Herein, we aimed at investigating morphological brain regions central for interoception and emotion regulation, and if these are associated with acute inflammation-induced sickness and anxiety responses., Methods: Systemic inflammation was induced using an intravenous injection of lipopolysaccharide (LPS) at a dose of 0.6 ng/kg body weight in 28 healthy individuals, while 21 individuals received an injection of saline (placebo). Individuals' gray matter volume was investigated by automated voxel-based morphometry technique on T1-weighted anatomical images derived from magnetic resonance imaging (MRI). Plasma concentrations of TNF-α and IL-6, sickness symptoms (SicknessQ), and state anxiety (STAI-S) were measured before and after the injection., Results: A stronger sickness response to LPS was significantly associated with a larger anterior insula gray matter volume, independently from increases in cytokine concentrations, age, sex and body mass index (R 2  = 65.6%). Similarly, a greater LPS-induced state anxiety response was related to a larger anterior insula gray matter volume, and also by a stronger increase in plasma TNF-α concentrations (R 2  = 40.4%)., Discussion: Anterior insula morphology appears central in the sensitivity to develop symptoms of sickness and anxiety in response to inflammation, and could thus be one risk factor in inflammation-related psychopathologies. Because of the limited sample size, the current results need to be replicated., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Previous research indicates elevated levels of clinically significant traits and symptoms of autism spectrum disorder and attention-deficit hyperactivity disorder (ADHD) in children with chronic pain, but associations with functioning and depression are yet unclear. The current study examined the relationships of autistic traits and ADHD symptoms with pain interference, depression, and health-related quality of life, as well as the mediating roles of insomnia and psychological inflexibility, in children with chronic pain ( n = 146, 8-17 years, 102 girls) presenting at a tertiary pain clinic. Children completed measures of pain intensity, depression, pain interference, health-related quality of life, insomnia, and psychological inflexibility. Parents ( n = 146, 111 mothers) completed measures to assess autistic traits and ADHD symptoms in their children. Children with clinically significant autistic traits and ADHD symptoms presented with significantly higher levels of depressive symptoms and pain interference, and significantly lower health-related quality of life, than did the other children. Autistic traits and ADHD symptoms contributed significantly to the prediction of pain interference and depressive symptoms, as well as health-related quality of life. Psychological inflexibility mediated the relationships between ADHD symptoms and autistic traits on the one hand and depression, pain interference, and health-related quality of life on the other, while insomnia mediated the relationships between ADHD symptoms and depression, pain interference, and health-related quality of life. All analyses were adjusted for demographics and pain intensity. Results suggest the utility of screening for neurodevelopmental disorders in children with chronic pain. Furthermore, the findings may indicate insomnia and skills related to psychological flexibility as potential treatment targets in interventions aiming at improving functioning and health-related quality of life in children with chronic pain and co-occurring symptoms of neurodevelopmental disorders., Competing Interests: SB has in the last 3 years acted as author, consultant, or lecturer for Medicine and Roche. He receives royalties for text books and diagnostic/intervention tools from Hogrefe publishers. TH receives royalties for text books from Hogrefe. RW receives royalties from Natur & Kultur. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wiwe Lipsker, Hirvikoski, Balter, Bölte, Lekander, Holmström and Wicksell.)

Depression is one of the global leading causes of disability, but treatments remain limited and classical antidepressants were found to be ineffective in a substantial proportion of patients. Thus, novel effective therapies for the treatment of depression are urgently needed. Given the emerging role of inflammation in the etiology and pathophysiology of affective disorders, we herein illustrate how experimental endotoxemia, a translational model of systemic inflammation, could be used as a tool to develop and test new therapeutic options against depression. Our concept is based on the striking overlap of inflammatory, neural, and affective characteristics in patients with inflammation-associated depression and in endotoxin-challenged healthy subjects. Experimental administration of endotoxin in healthy volunteers is safe, well-tolerated, and without known long-term health risks. It offers a highly standardized translational approach to characterize potential targets of therapies against inflammation-associated depression, as well as to identify characteristics of patients that would benefit from these interventions, and, therefore, could contribute to improve personalization of treatment and to increase the overall rate of responders., (© 2020. The Author(s).)

Animals across phyla can detect early cues of infection in conspecifics, thereby reducing the risk of contamination. It is unknown, however, if humans can detect cues of sickness in people belonging to communities with whom they have limited or no experience. To test this, we presented Western faces photographed 2 h after the experimental induction of an acute immune response to one Western and five non-Western communities, including small-scale hunter-gatherer and large urban-dwelling communities. All communities could detect sick individuals. There were group differences in performance but Western participants, who observed faces from their own community, were not systematically better than all non-Western participants. At odds with the common belief that sickness detection of an out-group member should be biased to err on the side of caution, the majority of non-Western communities were unbiased. Our results show that subtle cues of a general immune response are recognized across cultures and may aid in detecting infectious threats.

Understanding the association between autonomic nervous system [ANS] function and brain morphology across the lifespan provides important insights into neurovisceral mechanisms underlying health and disease. Resting-state ANS activity, indexed by measures of heart rate [HR] and its variability [HRV] has been associated with brain morphology, particularly cortical thickness [CT]. While findings have been mixed regarding the anatomical distribution and direction of the associations, these inconsistencies may be due to sex and age differences in HR/HRV and CT. Previous studies have been limited by small sample sizes, which impede the assessment of sex differences and aging effects on the association between ANS function and CT. To overcome these limitations, 20 groups worldwide contributed data collected under similar protocols of CT assessment and HR/HRV recording to be pooled in a mega-analysis (N = 1,218 (50.5% female), mean age 36.7 years (range: 12-87)). Findings suggest a decline in HRV as well as CT with increasing age. CT, particularly in the orbitofrontal cortex, explained additional variance in HRV, beyond the effects of aging. This pattern of results may suggest that the decline in HRV with increasing age is related to a decline in orbitofrontal CT. These effects were independent of sex and specific to HRV; with no significant association between CT and HR. Greater CT across the adult lifespan may be vital for the maintenance of healthy cardiac regulation via the ANS-or greater cardiac vagal activity as indirectly reflected in HRV may slow brain atrophy. Findings reveal an important association between CT and cardiac parasympathetic activity with implications for healthy aging and longevity that should be studied further in longitudinal research., (© 2020 The Authors. Psychophysiology published by Wiley Periodicals LLC on behalf of Society for Psychophysiological Research.)

Introduction: Disturbed sleep in inflammatory disorders such as allergy and rheumatoid arthritis (RA) is common and may be directly or indirectly related to disease processes, but has not been well characterized in these patient groups, especially not with objective methods., Aim: The present study aimed to characterize objective and subjective sleep in patients with allergy or RA using sleep diaries, one-channel EEG and actigraphy. It also aimed to investigate if sleep measures were associated with central immune activation, assessed using translocator protein (TSPO) positron emission tomography, as well as cytokine markers of peripheral inflammation and disease-specific symptoms or general symptoms of sickness., Methods: In total, 18 patients with seasonal pollen allergy, 18 patients with RA and 26 healthy controls were included in the study. Allergy patients and matched controls were assessed twice, in and out of pollen season, and RA patients and controls were assessed once. Sleep was recorded for approximately 1 week at each occasion., Results: Patients with allergy had increased levels of slow-wave sleep during pollen season. In contrast, patients with RA had less SWS compared to healthy controls, while no differences were observed in sleep duration or subjective sleep quality. Across groups, neither proinflammatory cytokines, grey matter TSPO levels nor general sickness symptoms were associated with objective or subjective measures of sleep. Rhinitis, but not conjunctivitis, was correlated to worse subjective sleep and more slow wave sleep in allergy. Functional status, but not disease activity, predicted lower subjective sleep in RA., Conclusion: This study tentatively indicates that both patients with allergy and RA display sleep alterations but does not support inflammation as an independent predictor of the sleep disturbance across these patient groups., Competing Interests: Professor John Axelsson reports Financial disclosures: Funding from Swedish Research Council, Riksbankens Jubileumsfond and AFA Insurance. Served as a paid panel member for The Research Council of Norway. Consulting fees or speaker honorarium from Lifesum, Banqit, Game Intelligence, Norra Stockholm Psychiatry, Svensk Kiropraktik, Swedish Agency for Marine and Water Management, and the Swedish Professional Associations for Physical Activity. Dr Caroline Olgart Höglund reports grants from The Swedish Heart Lung Foundation, grants from Swedish Asthma and Allergy Association, grants from Center for Allergy Research, grants from Karolinska Institutet, grants from Stockholm Stress Center, grants from Osher Center for Integrative Medicine, grants from Hedlund Foundation, grants from Swedish Council for Working Life and Social Research, during the conduct of the study, grants from Swedish Social Insurance Agency, outside the submitted work. Dr Simon Cervenka reports grants from Otsuka, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2021 Tamm et al.)

Background: Studies of Internet-delivered acceptance and commitment therapy (ACT) for chronic pain have shown small to moderate positive effects for pain interference and pain acceptance. Effects on pain intensity, depression, anxiety and quality of life (QoL) have been less favourable, and improvements for values and sleep are lacking. In this randomized controlled trial iACT - a novel format of Internet-ACT using daily microlearning exercises - was examined for efficacy compared to a waitlist condition., Methods: Adult participants (mean age 49.5 years, pain duration 18.1 years) with diverse chronic pain conditions were recruited via self-referral, and randomized to iACT (n = 57) or waitlist (n = 56). The primary outcome was pain interference. The secondary outcomes were QoL, depression, anxiety, insomnia and pain intensity. The process variables included psychological inflexibility and values. Post-assessments were completed by 88% (n = 100) of participants. Twelve-month follow-up assessments were completed by 65% (iACT only, n = 37). Treatment efficacy was analysed using linear mixed models and an intention-to-treat-approach., Results: Significant improvements in favour of iACT were seen for pain interference, depression, anxiety, pain intensity and insomnia, as well as process variables psychological inflexibility and values. Between-group effect sizes were large for pain interference (d = 0.99) and pain intensity (d = 1.2), moderate for anxiety and depressive symptoms and small for QoL and insomnia. For the process variables, the between-group effect size was large for psychological inflexibility (d = 1.0) and moderate for values. All improvements were maintained at 1-year follow-up., Conclusions: Internet-ACT as microlearning may improve a broad range of outcomes in chronic pain., Significance: The study evaluates a novel behavioral treatment with positive results on pain interference, mood as well as pain intensity for longtime chronic pain sufferers. The innovative format of a digital ACT intervention delivered in short and experiential daily learnings may be a promising way forward., (© 2021 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC ®.)

Considerable heterogeneity among pediatric chronic pain patients may at least partially explain the variability seen in the response to behavioral therapies. The current study tested whether autistic traits and attention-deficit/hyperactivity disorder (ADHD) symptoms in a clinical sample of children and adolescents with chronic pain are associated with socioemotional and functional impairments and response to acceptance and commitment therapy (ACT) treatment, which has increased psychological flexibility as its core target for coping with pain and pain-related distress. Children and adolescents aged 8-18 years ( N = 47) were recruited. Patients and their parents completed questionnaires pre- and post-ACT of 17 sessions. Correlational analyses and mixed-effects models were used to assess the role of autistic traits and ADHD symptoms in pretreatment functioning and ACT-treatment response. Outcome variables were degree to which pain interfered with daily activities (i.e., pain interference, sleep, and physical and school functioning), socioemotional functioning (i.e., depressive symptoms, emotional, and social functioning), psychological inflexibility, and pain intensity. Autistic traits and ADHD symptoms, pain frequency, and pain duration were measured at pretreatment only. Higher autistic traits were associated with greater pain interference, higher depression, and greater psychological inflexibility. Higher ADHD symptomatology was associated with greater pretreatment pain interference, lower emotional functioning, greater depression, and longer duration of pain. Across patients, all outcome variables, except for sleep disturbances and school functioning, significantly improved from pre- to post-ACT. Higher autistic traits were associated with greater pre- to post-ACT improvements in emotional functioning and sleep disturbance and non-significant improvements in pain interference. ADHD symptomatology was not associated with treatment outcome. The current results showed that neuropsychiatric symptoms in pediatric chronic pain patients are associated with lower functioning, particularly pain interfering with daily life and lower socioemotional functioning. The results suggest that not only pediatric chronic pain patients low in neuropsychiatric symptoms may benefit from ACT, but also those high in autism traits and ADHD symptoms. With the present results in mind, pediatric chronic pain patients higher in autistic traits may actually derive extra benefit from ACT. Future research could assess whether increased psychological flexibility, the core focus of ACT, enabled those higher in autism traits to cope relatively better with pain-related distress and thus to gain more from the treatment, as compared to those lower in autism traits. Moreover, to address specific effects of ACT, inclusion of an appropriate control group is key., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Balter, Wiwe Lipsker, Wicksell and Lekander.)

Insomnia is highly prevalent among adolescents with psychiatric conditions and is known to aggravate psychiatric symptoms. Research on cognitive behaviour therapy for adolescents with comorbid insomnia (CBT-I) is still limited. The aim of this study was to investigate feasibility and preliminary effects of internet-delivered CBT for adolescents with insomnia comorbid to a psychiatric condition. Twenty-one patients (13-17 years) with comorbid insomnia were recruited from Child and Adolescent Psychiatry. All patients received 7 weeks of internet-delivered CBT-I with therapist support. Outcomes were assessed at baseline, post-treatment, and at a 4-month follow-up. The proportion of completed assessments was overall acceptable. Participants on average completed 4.48 ( sd  = 1.97) of the seven treatment modules and therapists on average spent 12.80 minutes ( sd  = 6.23) per patient and week. Results showed large statistically significant improvements on insomnia severity, sleep efficiency, sleep onset latency and sleep quality. Medium to large improvements were also seen on the psychiatric symptoms of depression, obsessive-compulsive symptoms, interpersonal sensitivity, paranoid ideation and psychoticism. These findings indicate that internet-delivered CBT is feasible and potentially promising for improving sleep and reducing psychiatric symptoms in adolescent psychiatric patients with insomnia and co-morbid psychiatric disorders. A larger randomised trial is warranted to verify these preliminary results.

Even though dysfunctional emotion regulation is prominent in depression and a link between depression and inflammation is well established, there is little knowledge about how inflammation affects the regulation of emotions. The aim of this pilot study was to explore the effect of experimentally induced inflammation on the cognitive reappraisal of emotions, and to assess domain specificity by comparing success in regulation of emotions towards two unpleasant stimuli classes (general negative stimuli and disgust stimuli). In a between-subject design, ten healthy participants were injected with an intravenous injection of lipopolysaccharide (2 ng/kg body weight) and eleven were injected with saline. Participants performed a cognitive reappraisal task, in which they had to down-regulate or up-regulate their emotions towards general negative stimuli and disgust stimuli, 5-6 h post-injection. Contrary to our hypotheses, participants injected with lipopolysaccharide reported greater success in down-regulating emotional responses towards unpleasant stimuli as compared to the saline group. In addition, both groups were poorer at down-regulating emotions towards disgust stimuli as compared to general negative stimuli. The current pilot study indicates that cognitive reappraisal of emotions is affected during experimental endotoxemia, and suggests that disgust stimuli might be difficult to reappraise., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Sleep loss results in state instability of cognitive functioning. It is not known whether this effect is more expressed when there is an increased cognitive demand. Moreover, while vulnerability to sleep loss varies substantially among individuals, it is not known why some people are more affected than others. We hypothesized that top-down regulation was specifically affected by sleep loss and that subclinical inattention and emotional instability traits, related to attention-deficit/hyperactivity disorder symptoms, predict this vulnerability in executive function and emotion regulation, respectively., Methods: Healthy subjects (ages 17-45 years) rated trait inattention and emotional instability before being randomized to either a night of normal sleep (n = 86) or total sleep deprivation (n = 87). Thereafter, they performed a neutral and emotional computerized Stroop task, involving words and faces. Performance was characterized primarily by cognitive conflict reaction time and reaction time variability (RTV), mirroring conflict cost in top-down regulation., Results: Sleep loss led to increased cognitive conflict RTV. Moreover, a higher level of inattention predicted increased cognitive conflict RTV in the neutral Stroop task after sleep deprivation (r = .30, p = .0055) but not after normal sleep (r = .055, p = .65; interaction effect β = 6.19, p = .065). This association remained after controlling for cognitive conflict reaction time and emotional instability, suggesting domain specificity. Correspondingly, emotional instability predicted cognitive conflict RTV for the emotional Stroop task only after sleep deprivation, although this effect was nonsignificant after correcting for multiple comparisons., Conclusions: Our findings suggest that sleep deprivation affects cognitive conflict variability and that less stable performance in executive functioning may surface after sleep loss in vulnerable individuals characterized by subclinical symptoms of inattention., (Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Olfactory dysfunction is a common symptom of various diseases, but the underlying pathophysiology has not been fully understood. Evidence from both animal and human studies suggests that local inflammation of the olfactory epithelium is linked to olfactory dysfunction. However, whether systemic inflammation causes olfactory dysfunction is yet to be determined. In the present behavioral study, we set out to test whether acute systemic inflammation impairs olfactory identification performance by inducing a transient and controlled state of systemic inflammation using an experimental endotoxemia model. We treated young healthy participants (N = 20) with a relatively high dose (2.0 ng/kg) of lipopolysaccharide (LPS) and a placebo treatment in a double-blind within-subject design, and assessed participants' ability to identify odors using the MONEX-40, a reliable method for experimental assessment of odor identification ability in healthy and young individuals. Our results show that olfactory identification performance was not affected by the acute systemic inflammation triggered by the injection of LPS. Moreover, odor identification performance following the LPS injection was not associated with levels of circulating proinflammatory cytokines (interleukin-6, interleukin-8, and tumor necrosis factor-α). Because experimental LPS-induced systemic inflammation does not affect olfactory identification performance, our findings suggest that chronic, rather than transient, systemic inflammation is a more likely mechanism to explore in order to explain the olfactory deficits observed in inflammatory diseases., (© The Author(s) 2021. Published by Oxford University Press.)

The aim of this study was to investigate insomnia symptom severity as a putative mediator of treatment response in therapist-guided internet-based cognitive behavioral therapy (ICBT) for chronic stress, using data from a randomized controlled trial. Participants (N = 100) were randomized to 12 weeks of ICBT or to a waitlist control condition (WLC). Insomnia severity was assessed weekly with the Insomnia Severity Index (ISI), as were the stress-related outcomes the Perceived Stress Scale (PSS) and the Shirom-Melamed Burnout Questionnaire (SMBQ). Latent growth models indicated that ICBT (vs. WLC) predicted a decrease in insomnia severity (α-path), and that growth in insomnia severity was predictive of growth in perceived stress and exhaustion (β-paths). Most importantly, there were also significant indirect effects (αβ products) such that the beneficial effects of ICBT on perceived stress and exhaustion were mediated by a reduction in insomnia symptom severity (PSS: αβ = -0.44, 95% CI [-0.92, -0.14]; SMBQ: αβ = -0.08, 95% CI [-0.15, -0.04]). Explorative analysis of moderated mediation showed that more severe insomnia symptoms at baseline were associated with larger mediated effects. We conclude that reducing insomnia severity could be of importance for achieving successful treatment outcomes in ICBT for chronic stress., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Cognitive behavioural therapy (CBT) can effectively treat common mental disorders (CMDs), but access to treatment is insufficient. Guided self-help (GSH) CBT has shown effects comparable to face-to-face CBT and may be a resource-efficient treatment alternative. However, not all patients respond to GSH. Learning more about predictors of outcome may increase knowledge regarding which patients respond to GSH. The aim of this study was to investigate predictors of outcome for GSH CBT for patients with CMDs in primary care. Consecutive patients (N = 396) with a principal disorder of depression, anxiety, insomnia or stress-related disorders were included. All patients received GSH CBT. Outcomes were remission status, reliable change and post-treatment depression ratings. Predictors investigated were clinical, demographic and therapy-related variables. Analyses were conducted using logistic and linear regression. Higher educational level predicted remission, higher quality of life ratings predicted remission and decreased depression, and higher age at onset predicted reliable change. Therapy-related variables, i.e. patient adherence to treatment and patients' and clinicians' estimation of treatment response, were all related to outcome. More large-scale studies are needed, but the present study points at the importance of therapy-related variables such as monitoring and supporting treatment adherence for an increased chance of remission.

Sleep deprivation is proposed to inhibit top-down-control in emotion processing, but it is unclear whether sleep deprivation affects emotional mimicry and contagion. Here, we aimed to investigate effects of partial sleep deprivation on emotional contagion and mimicry in young and older humans. Participants underwent partial sleep deprivation (3 h sleep opportunity at the end of night), crossed-over with a full sleep condition in a balanced order, followed by a functional magnetic resonance imaging and electromyography (EMG) experiment with viewing of emotional and neutral faces and ratings of emotional responses. The final sample for main analyses was n = 69 (n = 36 aged 20-30 years, n = 33 aged 65-75 years). Partial sleep deprivation caused decreased activation in fusiform gyri for angry faces and decreased ratings of happiness for all stimuli, but no significant effect on the amygdala. Older participants reported more anger compared to younger participants, but no age differences were seen in brain responses to emotional faces or sensitivity to partial sleep deprivation. No effect of the sleep manipulation was seen on EMG. In conclusion, emotional contagion, but not mimicry, was affected by sleep deprivation. Our results are consistent with the previously reported increased negativity bias after insufficient sleep.The Stockholm sleepy brain study: effects of sleep deprivation on cognitive and emotional processing in young and old. https://clinicaltrials.gov/ct2/show/NCT02000076 .

Background: Insomnia is common in adolescents and often comorbid with psychiatric disorders. This study evaluated changes in insomnia, sleep, and comorbid symptoms following cognitive-behavioral therapy for insomnia (CBT-I) in adolescents with comorbid psychiatric disorders and chronic pain., Methods: In this non-controlled clinical pilot study, participants ( n  = 23, 78% female) were recruited from adolescent psychiatry and pediatric pain clinics. Assessments of self-reported insomnia, sleep onset latency, wake after sleep onset, total sleep time, sleep efficiency and depression, anxiety, functional disability, and pain intensity were completed at pre- and post-intervention and 3 months follow-up., Results: From pre- to post-intervention, statistically significant improvements were found for insomnia symptoms ( p  < .001; d  = 1.63), sleep onset latency ( p  < .001; d  = 1.04), wake after sleep onset ( p  < .001; d  = 0.38), total sleep time ( p  = .015; d  = 0.22), sleep efficiency ( p  < .001; d  = 1.00), depression ( p  < .001; d  = 0.87), and anxiety ( p  = .001; d  = 0.31). Only eight participants reported data at follow-up with maintained improvements for all measures., Conclusion: This study provides support that insomnia symptoms and sleep can improve following CBT-I delivered in a clinical setting and that co-occurring psychiatric symptoms can be reduced. The results should be interpreted with caution due to the uncontrolled conditions and limited sample size. Well-powered clinical trials are needed to validate the suggested effects.

Increasing evidence from animal and human studies suggests that inflammation may be involved in mood disorders. Sickness behavior and emotional changes induced by experimental inflammatory stimuli have been extensively studied in humans and rodents to better understand the mechanisms underlying inflammation-driven mood alterations. However, research in animals and humans have remained compartmentalized and a comprehensive comparison of inflammation-induced sickness and depressive-like behavior between rodents and humans is lacking. Thus, here, we highlight similarities and differences in the effects of bacterial lipopolysaccharide administration on the physiological (fever and cytokines), behavioral and emotional components of the sickness response in rodents and humans, and discuss the translational challenges involved. We also emphasize the differences between observable sickness behavior and subjective sickness reports, and advocate for the need to obtain both subjective reports and objective measurements of sickness behavior in humans. We aim to provide complementary insights for translational clinical and experimental research on inflammation-induced behavioral and emotional changes, and their relevance for mood disorders such as depression., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Acceptance and commitment therapy (ACT) is an evidence-based treatment to improve functioning and quality of life (QoL) for chronic pain patients, but outreach of this treatment is unsatisfactory. Internet-delivery has been shown to increase treatment access but there is limited evidence regarding feasibility and effectiveness of web-based ACT for chronic pain. The aim of the study was to evaluate and iterate a novel internet-delivered ACT program, iACT, in a clinical and a self-referred sample of chronic pain patients. The intervention was developed in close collaboration with patients. To enhance learning, content was organized in short episodes to promote daily engagement in treatment. In both the clinical and self-referred samples, three critical domains were evaluated: (I) feasibility (acceptability, practicality and usage); (II) preliminary efficacy on pain interference, psychological inflexibility, value orientation, QoL, pain intensity, anxiety, insomnia and depressive symptoms; and (III) potential treatment mechanisms., Methods: This was an open pilot study with two samples: 15 patients from a tertiary pain clinic and 24 self-referred chronic pain participants, recruited from October 2015 until January 2017. Data were collected via an online platform in free text and self-report measures, as well as through individual oral feedback. Group differences were analyzed with Chi square-, Mann-Whitney U- or t -test. Preliminary efficacy and treatment mechanism data were collected via self-report and analyzed with multilevel linear modeling for repeated measures., Results: Feasibility: patient feedback guided modifications to refine the intervention and indicated that iACT was acceptable in both samples. User insights provided input for both immediate and future actions to improve feasibility. Comprehensiveness, workability and treatment credibility were adequate in both samples. Psychologists spent on average 13.5 minutes per week per clinical patient, and 8 minutes per self-referred patient (P=0.004). Recruitment rate was 24 times faster in the self-referred sample (24 patients in 1 month, compared to 15 patients in 15 months, P<0.001) and the median distance to the clinic was 40 km in the clinical sample, and 426 km in the self-referred sample (P<0.001). Preliminary effects: post-assessments were completed by 26 participants (67%). Significant effects of time were seen from pre- to post-treatment across all outcome variables. Within group effect sizes (Cohen's d ) at post-treatment ranged from small to large: pain interference ( d =0.64, P<0.001), psychological inflexibility ( d =1.43, P<0.001), value progress ( d =0.72, P<0.001), value obstruction ( d =0.42, P<0.001), physical QoL ( d =0.41, P=0.005), mental QoL ( d = 0. 67, P=0.005), insomnia ( d= 0.31, P <0. 001), depressive symptoms ( d =0.47, P<0.001), pain intensity ( d =0.78, P=0.001) and anxiety ( d = 0. 46, P<0.001). Improvements were sustained at 1-year follow-up. Psychological inflexibility and value progress were found to be potential treatment mechanisms., Conclusions: The results from the present study suggests that iACT was feasible in both the clinical and the self-referred sample. Together with the positive preliminary results on all outcomes, the findings from this feasibility study pave the way for a subsequent large randomized efficacy trial., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/mhealth.2020.02.02). EA serves as the unpaid editorial board member of mHealth from Dec 2018 to Nov 2020. JR reports grants from AFA Insurance, during the conduct of the study. EA reports personal fees from Royalties from a book on health anxiety, outside the submitted work. BL reports other from Dahlia Behandlingsutvärdering AB, other from Pear Therapeutics Inc, outside the submitted work. RKW reports grants from AFA Insurance, grants from ALF grant provided by the Stockholm County Council, during the conduct of the study; grants from Clinical research appointment provided by the Stockholm County Council, outside the submitted work. The other authors have no other conflicts of interest to declare., (2020 mHealth. All rights reserved.)

Study Objectives: To determine how sleepiness and sleep deprivation drive the motivation to engage in different behaviors., Methods: We studied the sleepiness of 123 participants who had been randomized to sleep deprivation or normal sleep, and their willingness to engage in a range of everyday behaviors., Results: Self-reported sleepiness was a strong predictor of the motivation to engage in sleep-preparatory behaviors such as shutting one's eyes (OR = 2.78, 95% CI: 2.19-3.52 for each step up on the Karolinska Sleepiness Scale) and resting (OR = 3.20, CI: 2.46-4.16). Sleepiness was also related to the desire to be cared for by a loved one (OR = 1.49, CI: 1.22-1.82), and preparedness to utilize monetary and energy resources to get to sleep. Conversely, increased sleepiness was associated with a decreased motivation for social and physical activities (e.g. be with friends OR = 0.71, CI: 0.61-0.82; exercise OR = 0.65, CI: 0.56-0.76). Sleep deprivation had similar effects as sleepiness on these behaviors. Neither sleepiness nor sleep deprivation had strong associations with hunger, thirst, or food preferences., Conclusions: Our findings indicate that sleepiness is a dynamic motivational drive that promotes sleep-preparatory behaviors and competes with other drives and desired outcomes. Consequently, sleepiness may be a central mechanism by which impaired alertness, for example, due to insufficient sleep, contributes to poor quality of life and adverse health. We propose that sleepiness helps organize behaviors toward the specific goal of assuring sufficient sleep, in competition with other needs and incentives. A theoretical framework on sleepiness and its behavioral consequences are likely to improve our understanding of several disease mechanisms., (© Sleep Research Society 2019. Published by Oxford University Press on behalf of the Sleep Research Society.)

Animals detect sick conspecifics by way of body odor that enables the receiver to avoid potential infectious transmission. Human observational studies also indicate that different types of disease are associated with more or less aversive smells. In addition, body odors from otherwise healthy human individuals smell more aversive as a function of experimentally induced systemic inflammation. To investigate if naturally occurring immune activation also gives rise to perceivable olfactory changes, we collected body odor samples during two nights from individuals with a respiratory infection as well as when they were healthy. We hypothesized that independent raters would rate the body odor originating from sick individuals as smelling more aversive than when the same individuals were healthy. Even though body odor samples from sick individuals nominally smelled more intense, more disgusting, and less pleasant and healthy than the body odor from the same individuals when healthy, these effects were not statistically significant. Moreover, raters filled out three questionnaires, Perceived Vulnerability to Disease, Disgust Scale, and Health Anxiety, to assess potential associations between sickness-related personality traits and body odor perception. No such association was found. Since experimentally induced inflammation have made body odors more aversive in previous studies, we discuss whether this difference between studies is due to the level of sickness or to the type of trigger of the sickness response., (Copyright © 2020 Sarolidou, Tognetti, Lasselin, Regenbogen, Lundström, Kimball, Garke, Lekander, Axelsson and Olsson.)

For humans, like other social animals, behaviour acts as a first line of defence against pathogens. A key component is the ability to detect subtle perceptual cues of sick conspecifics. The present study assessed the effects of endotoxin-induced olfactory and visual sickness cues on liking, as well as potential involved mechanisms. Seventy-seven participants were exposed to sick and healthy facial pictures and body odours from the same individual in a 2 × 2 factorial design while disgust-related facial electromyography (EMG) was recorded. Following exposure, participants rated their liking of the person presented. In another session, participants also answered questionnaires on perceived vulnerability to disease, disgust sensitivity and health anxiety. Lower ratings of liking were linked to both facial and body odour disease cues as main effects. Disgust, as measured by EMG, did not seem to be the mediating mechanism, but participants who perceived themselves as more prone to disgust, and as more vulnerable to disease, liked presented persons less irrespectively of their health status. Concluding, olfactory and visual sickness cues that appear already a few hours after the experimental induction of systemic inflammation have implications for human sociality and may as such be a part of a behavioural defence against disease. This article is part of the Theo Murphy meeting issue 'Olfactory communication in humans'.

Objectives: The prevalence of neck/back pain (NBP) is high worldwide. Limited number of studies have investigated workers with occasional NBP regarding the risk of developing long-duration activity limiting NBP (LNBP). The objectives were to assess (1) the effect of poor work ability and sleep disturbances in persons with occasional NBP on the risk of LNBP, and (2) the interaction effect of these exposures., Design: Cohort study based on three subsamples from the Stockholm Public Health Cohort., Settings: The working population in Stockholm County., Participants: Persons aged 18-60 years, reporting occasional NBP the past 6 months at baseline year 2010 (n=16 460)., Measures: Work ability was assessed with items from the Work Ability Index, perceived mental and/or physical work ability. Sleep disturbances were self-reported current mild/severe disturbances. The outcome in year 2014 was reporting NBP the previous 6 months, occurring ≥couple of days per week and resulting in decreased work ability/restricted other daily activities. The additive effect of having both poor work ability and sleep disturbances was modelled with a dummy variable, including both exposures. Poisson log-linear regression was used to calculate risk ratios (RRs) and 95% CIs., Results: At follow-up, 9% had developed LNBP. Poor work ability and sleep disturbances were independent risk factors for LNBP; adjusted RR 1.7 (95% CI: 1.4 to 2.0) and 1.4 (95% CI: 1.2 to 1.5), respectively. No additive interaction was observed., Conclusion: Workers with occasional NBP who have poor work ability and/or sleep disturbances are at risk of developing LNBP. Having both conditions does not exceed additive risk., Competing Interests: Competing interests: Drs ES and LWH are scientific consultants at the Scandinavian College of Naprapathic Manual Medicine and members of their Scientific Board., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)