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Enclosed public spaces are hotspots for airborne disease transmission. To measure and maintain indoor air quality in terms of airborne transmission, an open source, low cost and distributed array of particulate matter sensors was developed and named Dynamic Aerosol Transport for Indoor Ventilation, or DATIV, system. This system can use multiple particulate matter sensors (PMSs) simultaneously and can be remotely controlled using a Raspberry Pi-based operating system. The data acquisition system can be easily operated using the GUI within any common browser installed on a remote device such as a PC or smartphone with a corresponding IP address. The software architecture and validation measurements are presented together with possible future developments.

Background: Multisystem functional somatic disorder is characterized by specific patterns of persistent physical symptoms with a complex biopsychosocial etiology. The disorder can lead to disability and personal suffering. Current treatment options require specialized settings, therefore patients often wait a long time to receive specific treatment. Patient education is considered important in most treatment programs, but has only been investigated sparsely as a stand-alone treatment. Pharmacological treatment is limited to tricyclic antidepressants in low doses with no antidepressant properties. Duloxetine has been found effective in single organ functional disorders. As a treatment for multisystem functional somatic disorder, duloxetine could reduce symptoms and treat comorbid anxiety and depression. It may furthermore enhance the effect of patient education through a hypothesized effect on cognitive functioning. The purpose of the EDULOX trial is to study psycho-EDUcation and duLOXetine alone and in combination., Methods: This is a nested study design. The parent trial "EDULOX1" (n = 424) will compare a patient education program with enhanced usual care in an open-labelled, randomized controlled trial. In addition to this, eligible participants will furthermore receive either duloxetine or active placebo in the nested, double-blinded, randomized controlled trial, "EDULOX2" (n = 212). Patient and clinician reported outcomes will be collected through questionnaires., Conclusion: The EDULOX trial may establish evidence for treatments applicable for the majority of patients with multisystem functional somatic disorder. If effective, duloxetine would be a more tolerable pharmacological treatment option that can target comorbid depression and anxiety, and potentially boost the effect of patient education. Trial registration number The study is registered at www., Clinicaltrials: gov (NCT06232473) and the internal list of research projects at the Region of Central Denmark (Case number 1-16-02-305-23). Approval from the Danish Medical Research Ethics Committees (Case number: 2212291) and the Danish Medicines Agency was obtained under EudraCT Number: 2022-002780-30 and Sponsor's Protocol Code Number: 9515., Competing Interests: Declaration of competing interest NBF has received consultancy fees from PharmNovo, Vertex, NeuroPN, Saniona, Nanobiotix, and Neurvati, and has undertaken consultancy work for Aarhus University with remunerated work for Biogen, Merz, and Confo Therapeutics. She has received grants from IMI2PainCare an EU IMI 2 (Innovative medicines initiative) public-private consortium and the companies involved are: Grunenthal, Bayer, Eli Lilly, Esteve, and Teva, outside the submitted work. All other 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 Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The aim of the study was to explore the association between tuberculosis (TB) and common mental disorders (CMD), in an area with high prevalence of TB., Methods: We performed a case-control study of TB patients and unmatched healthy controls, from a demographic surveillance site in Guinea-Bissau. Screening for CMD was performed once for controls and at inclusion and follow-up for TB patients. Kessler 10 (K-10) and a brief version of Hopkins Symptom Checklist 25 (SCL-8d) were used as screening instruments., Results: 571 controls were interviewed and 416 interviews were performed for 215 TB cases. Estimated CMD prevalence at the time of diagnosis of TB was 33.6 % (SCL-8d) and 46.2 % (K-10), compared with 6.8 % (SCL-8d) and 6.7 % (K-10) among controls; adjusted OR 7.18 (95 % CI 4.07 to 12.67) and 14.52 (95 % CI 8.15 to 25.84), respectively. No significant difference in CMD prevalence rates was observed between TB patients, after 6 months of treatment, and controls., Conclusion: Psychological distress and common mental disorders were more prevalent among TB patients at the time of diagnosis compared with the background population, but after completion of TB treatment no increased prevalence of psychological distress was found.

Infections with COVID-19 in enclosed public spaces, where virus-laden aerosol particles can accumulate over time, have significantly contributed to the rapid spread of the virus. It is therefore of great importance to understand the transport and dispersion process of aerosol particles in such spaces, especially against the background of future pandemics. In this work, we present a Lagrangian-Particle-Tracking experiment to assess the mixed convective flow in a classroom with different ventilation strategies. For this purpose, thermal plumes were created by heated dummies, and a collimated LED light-sheet with ∼0.4 m thickness was used for illumination of helium filled soap bubbles (HFSB) acting as passive tracer particles. In this way, the Lagrangian trajectories of the particles were recorded at two approximately 4.2 m × 2.8 m large fields using the novel 2D-Shake-The-Box-Method. As a result, time-resolved trajectories of over 300,000 simultaneously tracked HFSB have been reconstructed, so that both small-scale and large-scale properties of the flow are visualized quantitatively across the entire cross-section of the room. The trajectories show that the thermal plumes create lengthwise circulating vortices, which cannot be destroyed across the entire cross-section of the room by opening or tilting a window. Furthermore, the mixing in the room through the operation of an air purifier is higher compared to opening a window, which suggests that this strategy in combination with its air filtering capability is the most effective strategy to prevent infections., 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.)

Background: This umbrella review systematically assesses the variety and relative dominance of current aetiological views within the scientific literature for the three most investigated symptom-defined functional somatic syndromes (FSS) and their classificatory analogues within psychiatry and psychology., Method: An umbrella review of narrative and systematic reviews with and without meta-analyses based on a search of electronic databases (PubMed, Web of Science, Embase, PsychINFO) was conducted. Eligible reviews were published in English, focused on research of any kind of aetiological factors in adults diagnosed with fibromyalgia syndrome (FMS), irritable bowel syndrome (IBS), chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), and somatic symptom disorder (SSD)/somatoform disorder (SFD)., Results: We included 452 reviews (132 systematic reviews including meta-analyses, 133 systematic reviews, 197 narrative reviews), of which 132 (29%) focused on two or more of the investigated health conditions simultaneously. Across diagnoses, biological factors were addressed in 90% (k = 405), psychological in 33% (k = 150), social in 12% (k = 54), and healthcare factors in 5% (k = 23) of the reviews. The methodological quality of the included systematic reviews (k = 255) was low (low/critically low: 41% [k = 104]; moderate: 49% [k = 126]; high quality: 10% [k = 25]). The high-quality systematic reviews suggest that deficient conditioned pain modulation, genetic factors, changes in the immune, endocrinological, gastrointestinal, cardiovascular, and nervous system, and psychosocial factors such as sexual abuse and pain catastrophizing increase the risk for FSS., Conclusion: Only very few systematic reviews have used comprehensive, biopsychosocial disease models to guide the selection of aetiological factors in FSS research. Future research should strive for higher scientific standards and broaden its perspective on these health conditions., Competing Interests: Omer Van den Bergh is a Subject Editor for Clinical Psychology in Europe but played no editorial role in this particular article or intervened in any form in the peer review process.

When a round jet impinges on a convex cylindrical surface, complex three-dimensional (3D) flow structures occur, accompanied by the Coanda effect. To characterize the flow and turbulence properties of the general system, ensemble averages of 3D Lagrangian particle tracking velocimetry measurements were taken. The radial bin-averaging method was used in post-processing the tracked particles and corresponding instantaneous velocity vectors to generate appropriate ensemble-averaged statistics. Two impinging angles were selected, and at a fixed Reynolds number, the ensemble-averaged volumetric velocity field and turbulent stress tensor components were measured. The flow and turbulence characteristics of the impinging jet on the cylinder were notably different based on the impinging angle, especially in the downstream region. Surprisingly, the attached wall jet with a half-elliptic shape was abruptly thickened in the wall-normal direction, similar to the axis switching phenomenon observed in elliptic jets in the case of oblique impingement. In the jet-impinging region, the flow spread in all directions with high mean vorticity values. With the development of a 3D curved wall jet, both the Coanda effect and centrifugal force played a significant role in the flow behavior. A notable feature of the self-preserving region was the similarity of mean velocity profiles with scaling by the maximum velocity and the jet half-width for both impinging angle cases. Local isotropy of turbulent normal stresses was observed in this region, supporting the existence of self-preservation in the 3D curved wall jet. The volumetric ensemble-averaged Reynolds stress tensor revealed strong inhomogeneous turbulence in the boundary layer region and the curvature effect on the Reynolds shear stress in the free shear layer., (© 2023. The Author(s).)

Background and Aims: Randomized studies have demonstrated that a distal attachment cap with rubber side arms, the Endocuff Vision (ECV; Olympus America, Center Valley, Pa, USA), increased colonoscopic adenoma detection rate (ADR) in various mixed patient collectives. This is the first study to evaluate its use in a primary colonoscopic screening program., Methods: Patients over age 55 years undergoing screening colonoscopy in 9 German private offices in Berlin and Hamburg were randomized to either the study group using ECV or the control group using high-definition colonoscopies (standard of care). The main outcome parameter was ADR, whereas secondary outcomes were detection rates of all adenomas per colonoscopy (APCs), of adenoma subgroups, and of hyperplastic polyps., Results: Of 1416 patients (mean age, 61.1 years; 51.8% women), with a median of 41 examinations per examiner (n = 23; interquartile range, 12-81), 700 were examined with ECV and 716 without. Adjusting for the effects of the colonoscopies, ADR was 39.5% (95% confidence interval [CI], 32.6%-46.3%) in the ECV group versus 32.2% (95% CI, 25.9%-38.6%) in the control group, which resulted in an increase of 7.2% (95% CI, 2.3%-12.2%; P = .004). The increase in ADR was mainly because of small polyps, with adjusted ADRs for adenomas <10 mm of 33.3% (95% CI, 26.5%-40.2%) for study patients versus 24.0% (95% CI, 18.2%-29.8%) for control patients (P < .001). APC was also significantly increased (.57 ECV vs .51 control subjects, P = .045)., Conclusions: A distal attachment cap with side arms significantly increased the ADR in patients undergoing primary colonoscopic screening. Because of the correlation of ADR and interval cancer, its use should be encouraged, especially in this setting. (Clinical trial registration number: NCT03442738.)., (Copyright © 2023 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Over the past two decades, several distinct solution concepts for rate-independent evolutionary systems driven by non-convex energies have been suggested in an attempt to model properly jump discontinuities in time. Much attention has been paid in this context to the modelling of crack propagation. This paper studies two fully discrete (in time and space) approximation schemes for the rate-independent evolution of a single crack in a two-dimensional linear elastic material. The crack path is assumed to be known in advance, and the evolution of the crack tip along it relies on the Griffith theory. On the time-discrete level, the first scheme is based on local minimization, whereas the second scheme is a regularized version of the first one. The crucial feature of the schemes is their adaptive time-stepping nature, with finer time steps at those points where the evolution of the crack tip might develop a discontinuity. The set of discretization parameters includes the mesh size, crack increment, locality parameter and regularization parameter. In both cases, we explore the interplay between the discretization parameters and derive sufficient conditions on them ensuring the convergence of discrete interpolants to parametrized balanced viscosity solutions of the continuous model. To illustrate the performance of the approximation schemes, we support our theoretical analysis with numerical simulations. This article is part of the theme issue 'Non-smooth variational problems and applications'.

Background: Persistent post-concussion symptoms (PCS) are associated with prolonged disability, reduced health-related quality of life and reduced workability. At present, no strong evidence for treatments for people with persistent PCS exists. Our research group developed a novel intervention, "Get going After concussIoN (GAIN)", that incorporates multiple evidence-based strategies including prescribed exercise, cognitive behavioural therapy, and gradual return to activity advice. In a previous randomised trial, GAIN provided in a hospital setting was effective in reducing symptoms in 15-30-year-olds with PCS 2-6 months post-injury. In the current study, we describe the protocol for a trial designed to test the effectiveness of GAIN in a larger municipality setting. Additionally, we test the intervention within a broader age group and evaluate a broader range of outcomes. The primary hypothesis is that participants allocated to enhanced usual care plus GAIN report a higher reduction in PCS 3 months post-intervention compared to participants allocated to enhanced usual care only., Methods: The study is a stepped-wedge cluster-randomised trial with five clusters. The 8-week interdisciplinary GAIN program will be rolled out to clusters in 3-month intervals. Power calculation yield at least 180 participants to be enrolled. Primary outcome is mean change in PCS measured by the Rivermead Post-Concussion Symptoms Questionnaire from enrolment to 3 months after end of treatment. Secondary outcomes include participation in and satisfaction with everyday activities, labour market attachment and other behavioural measures. Self-reported outcomes are measured at baseline, by end of treatment and at 3, 6, and 18 months after end of treatment. Registry-based outcomes are measured up to 36 months after concussion., Discussion: The trial will provide important information concerning the effectiveness of the GAIN intervention in a municipality setting. Furthermore, it will provide knowledge of possible barriers and facilitators that may be relevant for future implementation of GAIN in different settings., Trial Registration: The current GAIN trial is registered in ClinicalTrials.gov (study identifier: NCT04798885 ) on 20 October 2020., (© 2022. The Author(s).)

This study retrospectively compares two previous parallel running, randomized, controlled trials of pharmacotherapy (imipramine) and psychotherapy (acceptance and commitment therapy) for multi-organ functional somatic disorder (FSD). Differences in demographics, psychiatric comorbidity, illness severity, and illness duration associated with eligibility for the two trials and patients' willingness to participate are explored using linear or binary regression models. 418 patients with multi-organ FSD was included. We found that 377 (95%) were eligible for psychotherapy and 257 patients (61%) for pharmacotherapy. Patients eligible for pharmacotherapy were less severely impaired, less often received disability pension, reported shorter illness duration and experienced less psychological distress than patients eligible for psychotherapy. Whilst exclusion criteria for both trials differed markedly, it was not possible to clearly identify patient or illness characteristics associated with patients' willingness to participate. The study showed that trial-specific exclusion criteria led to the selection of less complex and less severely impaired patients in the pharmacological trial in this sample of multi-organ FSD. Our findings have important implications for the interpretation and comparability of RCT results of different treatments in multi-organ FSD and may point to some common flaws in study design and interpretation of pharmacological vs. psychotherapeutic intervention trials in psychiatry., (Copyright © 2022. Published by Elsevier B.V.)

Characteristics of persistent post-traumatic headache (PTH) in young individuals are poorly known leading to diagnostic problems and diverse management. We aimed to describe headache phenotypes and self-reported management strategies in young individuals with PTH following mild traumatic brain injury (mTBI). A comprehensive structured questionnaire was used to evaluate headache phenotypes/characteristics and management strategies to relieve headache in 107, 15-30-year-old individuals with PTH. Around 4 months post-injury, migraine-like headache in combination with tension-type like headache (40%) was the most commonly encountered headache phenotype followed by migraine-like headache (36%). Around 50% reported aura-like symptoms before/during the headache attack. Medication-overuse headache was diagnosed in 10%. Stress, sleep disturbances, and bright lights were the most common trigger factors. More than 80% reported that their headache was worsened by work-related activity and alleviated by rest/lying down. Simple analgesics were commonly used (88%) whereas prophylactic drugs were rarely used (5%). Bedrest and physiotherapy were also commonly used as management strategies by 56% and 34% of the participants, respectively. In conclusion, most young individuals with PTH after mTBI presented with combined migraine-like and tension-type-like headache followed by migraine-like headache, only. Preventive headache medication was rarely used, while simple analgesics and bedrest were commonly used for short-term headache relief., (© 2022. The Author(s).)

Background: Evidence for treatment of adolescents with multiple functional somatic syndromes (FSS) is sparse. This study examined the efficacy of 'Acceptance and Commitment Therapy for Health in Adolescents' (AHEAD), a generic group-based treatment for adolescents with co-occurrence of multiple FSS., Methods: A randomized trial was conducted at a specialized university hospital clinic. Adolescents (15-19 years) with multiple FSS of at least 1 year's duration were randomly assigned to AHEAD or enhanced usual care (EUC). AHEAD consisted of nine modules (i.e., 27 h) and one follow-up meeting. Primary outcome was physical health (SF-36). Various secondary outcomes and treatment targets were included (e.g., symptom severity, symptom impact, and illness perception). A linear mixed-effects model was used for analysis. Trial-registration: ClinicalTrials.gov NCT02346071., Results: Ninety-one patients were included. At 12 months, no significant difference in physical health was identified between groups (mean adjusted difference 1.2 [95% CI -1.6 to 4.0], p  = .404). However, different developments over time were seen with an interaction effect between intervention arm and time (χ 2 (5) = 14.1, p  = .0148). AHEAD patients ( n  = 44) reported a clinically relevant improvement at end of treatment and at 8 and 12 months, while EUC patients ( n  = 47) displayed a clinically relevant improvement at 12 months. Furthermore, AHEAD patients showed a faster improvement on symptom severity, symptom impact and illness perception. EUC patients received more psychological treatment outside the trial ( p  ≤ .001) than AHEAD patients. Treatment satisfaction with AHEAD was high in contrast to EUC., Conclusions: Compared with EUC, AHEAD had no additional advantage on the improvement of physical health at the primary endpoint of 12 months. However, a faster improvement of physical health was seen in AHEAD and considerably more psychological treatment was received outside the trial in EUC with clinically meaningful improvements in both groups. The results underpin the importance of an organised and systematic treatment offer for the most severely affected youth., Competing Interests: The authors have declared that they have no competing or potential conflicts of interest., (© 2021 The Authors. JCPP Advances published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Purpose: The CLASSICAL-Lung clinical trial tested the combination of pepinemab, an IgG4 humanized mAb targeting semaphorin 4D, with the PD-L1 inhibitor avelumab to assess the effects of coupling increased T-cell infiltration and reversal of immune suppression via pepinemab with sustained T-cell activation via checkpoint inhibition., Patients and Methods: This phase Ib/II, single-arm study was designed to evaluate the safety, tolerability, and efficacy of pepinemab in combination with avelumab in 62 patients with advanced non-small cell lung cancer (NSCLC), including immunotherapy-naïve (ION) patients and patients whose tumors progressed following anti-PD-1/L1 monotherapy (IOF). The main objectives were to evaluate safety/tolerability, establish a recommended phase 2 dose (RP2D), obtain a preliminary evaluation of antitumor activity, and investigate candidate biomarker activity., Results: The combination was well tolerated with no major safety signals identified. Pepinemab, 10 mg/kg with avelumab, 10 mg/kg, every 2 weeks, was selected as the RP2D. Among 21 evaluable ION patients, 5 patients experienced partial responses (PR), 4 patients evidenced clinical benefit ≥1 year, and the disease control rate (DCR) was 81%. Notably, overall response rate with the combination therapy was higher than previously reported for single-agent avelumab in the PD-L1-negative/low population. Among 29 evaluable IOF patients, the combination resulted in a DCR of 59%, including 2 PR and 7 patients with durable clinical benefit of ≥23 weeks. Biomarker analysis of biopsies demonstrated increased CD8 T-cell density correlating with RECIST response criteria., Conclusions: The combination of pepinemab with avelumab was well tolerated in NSCLC and showed signs of antitumor activity in immunotherapy-resistant and PD-L1-negative/low tumors., (©2021 American Association for Cancer Research.)

Objective: The Danish Study of Functional Disorders (DanFunD) approaches functional somatic disorders (FSD) with three delimitations: Five functional somatic syndromes (FSS), Bodily Distress Syndrome (BDS), and eight data-driven symptom profiles (SP). This paper presents each delimitation and discusses optimal approaches for further original research into FSD epidemiology., Methods: A total of 9656 adults from the general Danish population participated in this cross-sectional study. Case assignment of the three FSD delimitations was based on self-reported symptom questionnaires. Overlap of FSS, BDS, and SP and their association with poor self-perceived health were calculated as descriptive statistics and shown with Venn diagrams. Difference in self-perceived health between participants with severe FSD were compared with participants with no FSD and calculated as risk ratios with generalized linear models with binomial family and log link., Results: We found pronounced overlaps between any FSS, BDS, and the SP with multiple symptoms as well as for multi-organ BDS and the SP with all symptoms. Symptoms and syndromes related to clusters of musculoskeletal and general symptoms contributed particularly to poor health as did multi-organ BDS and categories of SP with multiple symptoms., Conclusion: Each of the three delimitations has its strengths and weaknesses, and with this study, we offer a contribution to a more valid delimitation of FSD. Future research within DanFunD and other epidemiological studies may benefit from using more than just one delimitation for capturing the diverse nature of the FSD., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of Competing Interest None.

A recent randomized controlled trial in young patients with long-term post-concussion symptoms showed that a novel behavioral intervention "Get going After concussIoN" is superior to enhanced usual care in terms of symptom reduction. It is unknown whether these interventional effects are associated with microstructural brain changes. The aim of this study was to examine whether diffusion-weighted MRI indices, which are sensitive to the interactions between cellular structures and water molecules' Brownian motion, respond differently to the interventions of the above-mentioned trial and whether such differences correlate with the improvement of post-concussion symptoms. Twenty-three patients from the intervention group (mean age 22.8, 18 females) and 19 patients from the control group (enhanced usual care) (mean age 23.9, 14 females) were enrolled. The primary outcome measure was the mean kurtosis tensor, which is sensitive to the microscopic complexity of brain tissue. The mean kurtosis tensor was significantly increased in the intervention group (p = 0.003) in the corpus callosum but not in the thalamus (p = 0.78) and the hippocampus (p = 0.34). An increase in mean kurtosis tensor in the corpus callosum tended to be associated with a reduction in symptoms, but this association did not reach significance (p = 0.059). Changes in diffusion tensor imaging metrics did not differ between intervention groups and were not associated with symptoms. The current study found different diffusion-weighted MRI responses from the microscopic cellular structures of the corpus callosum between patients receiving a novel behavioral intervention and patients receiving enhanced usual care. Correlations with improvement of post-concussion symptoms were not evident., (© 2020 Wiley Periodicals LLC.)

Objective: The bodily distress syndrome (BDS) checklist has proven to be useful in the diagnostic categorisation and as screening tool for functional somatic disorders (FSD). This study aims to investigate whether the BDS checklist total sum score (0-100) can be used as a measure of physical symptom burden and FSD illness severity., Design: Cross-sectional., Setting: Danish general population, primary care and specialised clinical setting., Participants: A general population cohort (n=9656), a primary care cohort (n=2480) and a cohort of patients with multiorgan BDS from specialised clinical setting (n=492)., Outcome Measures: All data were self-reported. Physical symptoms were measured with the 25-item BDS checklist. Overall self-perceived health was measured with one item from the 36-item Short-Form Health Survey (SF-36). Physical functioning was measured with an aggregate score of four items from the SF-36/SF-12 scales 'physical functioning', 'bodily pain' and 'vitality'. Emotional distress was measured with the mental distress subscale (SCL-8) from the Danish version of the Hopkins Symptom Checklist-90. Illness worry was measured with the six-item Whiteley Index., Results: For all cohorts, bifactor models established that despite some multidimensionality the total sum score of the BDS checklist adequately reflected physical symptom burden and illness severity. The BDS checklist had acceptable convergent validity with measures of overall health (r=0.25-0.58), physical functioning (r=0.22-0.58), emotional distress (r=0.47-0.62) and illness worry (r=0.36-0.55). Acceptability was good with a low number of missing responses to items (<3%). Internal consistency was high (α ≥0.879). BDS score means varied and reflected symptom burden across cohorts (13.03-46.15). We provide normative data for the Danish general population., Conclusions: The BDS checklist total sum score can be used as a measure of symptom burden and FSD illness severity across settings. These findings establish the usefulness of the BDS checklist in clinics and in research, both as a diagnostic screening tool and as an instrument to assess illness severity., Competing Interests: Competing interests: None declared., (© 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.)

Background: Recurrent and impairing functional somatic syndromes (FSS) are common in adolescents. Despite a high need for care, empirically supported treatments are lacking for youth. The aim of this uncontrolled pilot study was to assess feasibility and treatment potential of a new intervention with group-based Acceptance and Commitment Therapy (ACT) in a generic treatment approach for adolescents with multiple FSS., Methods: Twenty-one patients received 'ACT for Health in Adolescents' (AHEAD) (30 h), specifically developed for adolescents (aged 15-19 years) with moderate to severe FSS. Close relatives attended an information meeting to facilitate support of the patients throughout treatment. Treatment satisfaction was evaluated by means of self-report and relatives' impressions. Self-reported physical health at 3 months follow-up (FU) after end of treatment was the primary outcome whereas secondary outcomes included symptom burden, limitation due to symptoms, illness worry, emotional distress and physical and emotional symptoms. Treatment targets were assessed by measures on illness behaviour, illness perception and psychological inflexibility., Results: Nineteen patients (90.5%) completed the treatment with a high overall attendance rate of 93%. All would recommend the treatment to a friend with similar problems. Close relatives rated it valuable to participate in an information meeting. Patients' physical health improved significantly from assessment to FU with a clinically relevant mean change of 8.9 points (95% CI [5.4; 12.4]; SRM 0.91 [0.26;1.57]). Improvement was also seen on all secondary outcome measures, from assessment to FU. Maladaptive illness behaviours and perceptions as well as psychological inflexibility showed a significant decline from assessment to FU., Conclusion: AHEAD was feasible and potentially efficacious and warrants testing in a larger clinical trial., Trial Registration: Clinical Trials gov NCT04464447 , registration date July 9th, 2020. Retrospectively registered.

Aims: Little is known about the prevalence and characteristics of functional somatic syndromes (FSS) such as irritable bowel syndrome (IBS), fibromyalgia (FM), chronic fatigue syndrome (CFS), whiplash associated disorders (WAD), multiple chemical sensitivity (MCS), and bodily distress syndrome (BDS) in the general population when they are investigated simultaneously. Method : This cross-sectional study is based on the Danish Study of Functional Disorders (DanFunD) cohort consisting of 9656 adults from the general population. FSS and BDS were identified by questionnaires and characterized by age, sex, vocational training, physical health and comorbidity with physical and psychiatric disease. Results : In total, 16.3% (95% CI: 15.6-17.1) of the participants fulfilled the criteria for at least one FSS, ranging from 1.7% for WAD to 8.6% for CFS, and 16.1% (95% CI: 15.4-16.9) fulfilled the criteria for BDS. Cases had a high risk of poor self-perceived health, limitations in daily activities, and a high psychiatric comorbidity, all increasing with the number of syndromes in each individual. However, the associations differed across the various FSS. Mutual overlaps of IBS, FM and CFS were greater than could be expected by chance. Conclusions : FSS and BDS are prevalent in the adult Danish population, and cases have high risk of poor self-perceived health, limitation in daily activities, and psychiatric comorbidity. These associations were particularly strong for cases with multiple FSS and multi-organ BDS.

Prevalence of functional somatic syndromes (FSS) in the general population varies with observed overlap between syndromes. However, studies including a range of FSS are sparse. We investigated prevalence and characteristics of various FSS and the unifying diagnostic construct bodily distress syndrome (BDS), and identified mutual overlap of the FSS and their overlap with BDS. We included a stratified subsample of 1590 adults from a randomly selected Danish general population sample (n = 7493). Telephonic diagnostic interviews performed by three trained physicians were used to identify individuals with FSS and BDS. Prevalence of overall FSS was 9.3%; 3.8% for irritable bowel, 2.2% for chronic widespread pain, 6.1% for chronic fatigue, 1.5% for whiplash associated disorders, and 0.9% for multiple chemical sensitivity. Prevalence of BDS was 10.7% where 2.0% had the multi-organ type. FSS were highly overlapping with low likelihood of having a "pure" type. Diagnostic agreement of FSS and BDS was 92.0%. Multi-syndromatic FSS and multi-organ BDS were associated with female sex, poor health, physical limitations, and comorbidity. FSS are highly prevalent and overlapping, and multi-syndromatic cases are most affected. BDS captured the majority of FSS and may improve clinical management, making the distinction between multi- and mono-syndromatic patients easier.

Background: Chronic primary pain (CPP) is one of seven diagnostic groups within the proposed classification of chronic pain in ICD-11. Our aims were to apply the proposed ICD-11 criteria in a large cohort of chronic pain patients participating in the Chronic Pain Self-Management Program (CPSMP) and further investigate whether participants with CPP differed from participants with chronic secondary pain (CSP) regarding health, health expenditure and the effect of participating in the CPSMP., Methods: A secondary analysis of a randomized, controlled trial on the effect of the CPSMP. Four examiners categorized participants' pain according to ICD-11 using register-based medical diagnoses and patients' self-reported symptoms. Afterwards, differences between CPP and CSP were examined., Results: Out of 394 participants, 312 were successfully classified into CPP (n = 164) or CSP (n = 148) whereas 76 had a mixed pain condition. Participants with CPP were younger, more likely to be women, and had longer pain duration compared to participants with CSP. Participants with CPP reported worse health-related quality of life on the SF-36 Mental Component Summary and subscales of vitality, social functioning and bodily pain. Participants with CSP had more physical comorbidities and higher total health expenditure. None of the groups benefitted from the CPSMP., Conclusions: We successfully applied the new classification of chronic pain in ICD-11 on the basis of ICD-10 medical diagnoses and symptom self-report. Participants with CPP differed significantly from participants with CSP on baseline characteristics, self-reported health measures and total health expenditure. The CPSMP was not effective in any of the groups., Significance: The current study applies the proposed new classification of chronic pain in ICD-11 and shares the experiences of the diagnostic rating procedure of individuals with chronic pain. Furthermore, it evaluates the effect of the Stanford Self-Management Program., (© 2019 European Pain Federation - EFIC®.)

Objectives: Bodily distress syndrome (BDS) has been shown to encompass a range of functional somatic syndromes (FSS) such as irritable bowel syndrome (IBS), fibromyalgia (FM), and chronic fatigue syndrome (CFS) in clinical samples. This study aimed to explore symptom clusters and test classification of individuals with illness similar to the BDS criteria in a general population sample., Methods: A stratified subsample of 1590 individuals from the DanFunD part two cohort was included. Symptoms were assessed with the Research Interview for Functional somatic Disorders, performed by trained physicians. In 44 symptoms pooled from criteria of IBS, FM, CFS, and BDS, symptom clusters were explored with explorative factor analysis. Confirmation of symptom clusters of BDS in the previously described 25- and 30-item BDS checklists was performed with confirmatory factor analysis. Classification of individuals into illness groups was investigated with latent class analysis., Results: Four symptom clusters (cardiopulmonary, gastrointestinal, musculoskeletal, general symptoms/fatigue) corresponding to the BDS subtypes and their corresponding FSS were identified and confirmed. A three-class model including 25 BDS items had the best fit for dividing participants into classes of illness: One class with low probability, one class with medium probability, and one class with high probability of having ≥4 symptoms in all symptom clusters., Conclusion: The BDS concept was confirmed in the general population and constitutes a promising approach for improved FSS classification. It is highly clinical relevant being the only diagnostic construct defining the complex multi-organ type., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Evidence for effective interventions to prevent long-term sequelae after concussion is sparse. This study aimed to test the efficacy of Get going After concussIoN (GAIN), an interdisciplinary, individually-tailored intervention of 8 weeks duration based on gradual return to activities and principles from cognitive behavioural therapy., Methods: We conducted an open-label, parallel-group randomised trial in a hospital setting in Central Denmark Region. Participants were 15-30-year-old patients with high levels of post-concussion symptoms (PCS) 2-6 months post-concussion (i.e., a score ≥20 on the Rivermead Post-concussion Symptoms Questionnaire (RPQ)). They were randomly assigned (1:1) to either enhanced usual care (EUC) or GAIN+EUC. Masking of participants and therapists was not possible. The primary outcome was change in RPQ-score from baseline to 3-month FU. All analyses were done on an intention-to-treat basis using linear mixed-effects models. This trial is registered with ClinicalTrials.gov, number NCT02337101., Findings: Between March 1, 2015, and September 1, 2017, we included 112 patients. Patients allocated to GAIN+EUC ( n =57) reported a significantly larger reduction of PCS than patients allocated to EUC ( n =55) with a mean adjusted difference in improvement of 7·6 points (95% confidence interval (CI) 2·0-13·1, p =0·008), Cohen's d =0·5 (95% CI 0·1-0·9). Number needed to treat for prevention of one additional patient with RPQ ≥20 at 3-month FU was 3·6 (95% CI 2·2-11·3). No adverse events were observed., Interpretation: Compared with EUC, GAIN+EUC was associated with a larger reduction of post-concussion symptoms at 3-month FU., Funding: Central Denmark Region and the foundation "Public Health in Central Denmark Region - a collaboration between municipalities and the region"., Competing Interests: None., (© 2019 Published by Elsevier Ltd.)

Objectives: Irritable bowel syndrome (IBS) is associated with increased healthcare use and work absenteeism. We aimed to investigate long-term use of healthcare services and social benefits across IBS symptom groups. Additionally, we estimated excess healthcare costs. Methods: A longitudinal population-based study comprising two 5-year follow-up studies: The Danish part of the Multinational Monitoring of Trends and Determinants in Cardiovascular Disease (Dan-MONICA) 1 (1982-1987) and Inter99 (1999-2004) recruited from the western part of Copenhagen County. The total study population ( n = 7278) was divided into symptom groups according to degree of IBS definition fulfillment at baseline and/or 5-year follow-up and was followed until 31 December 2013 in Danish central registries. Poisson regression was used for the analyses adjusting for age, sex, length of education, comorbidity, cohort membership and mental vulnerability. Results: IBS symptom groups compared to no IBS symptoms were associated with an increased number of contacts with primary and secondary healthcare, as well as weeks on sickness and disability benefits. Accounting for mental vulnerability decreased the estimates and all but two associations between IBS symptom groups and outcomes remained statistically significant. The two associations that became insignificant were contacts with psychiatric hospitals and weeks on disability pension. The excess unadjusted healthcare costs for IBS were 680 Euros per year and the overall association between symptom groups and total healthcare costs were statistically significant. Conclusions: IBS symptoms influence the long-term use and costs of healthcare, as well as the use of social benefits in the general population. Mental vulnerability explained some, but not all, of the use of healthcare and social benefits.

PRéCIS:: Significant intraocular pressure (IOP) reduction was achieved using a novel suture-probe canaloplasty (SPCP) procedure in patients with glaucoma. The effect and low rate of surgical complications were comparable with those of iTrack canaloplasty., Purpose: Ab externo canaloplasty using the iTrack microcatheter has been established as a safe surgical procedure to treat open-angle glaucoma. This article, however, describes the results of a novel technique using a cost-efficient suture-probe as an alternative to iTrack canaloplasty and presents 12-month follow-up results., Patients and Methods: SPCP was performed on 50 eyes of 50 patients with primary open-angle glaucoma, pseudoexfoliation glaucoma, and steroid-induced glaucoma. The mean±SD preoperative IOP was 21.9±7.0 mm Hg. A suture-probe was used to dilate Schlemm canal and to place a trabecular tensioning suture. Postoperative results were noted and statistically analyzed on the day of discharge from the clinic, and at 1.5, 3, 6, and 12 months of follow-up., Results: In all eyes, the mean postoperative IOP 12 months after SPCP was 13.7±3.0 mm Hg. The number of medications decreased from 2.8±0.9 to 0.1±0.4, and visual acuity was 0.3±0.3 logMAR. Postoperative course and complications included: hyphema >1 mm (2%); microhyphema (4%); bleb leakage (2%); bleb suture (2%); laser goniopuncture (18%); laser suture lysis (4%); scleral flap lifting (4%); and iris incarceration following laser goniopuncture (4%)., Conclusions: SPCP is an inexpensive procedure that can achieve significant IOP reduction in patients with glaucoma. The IOP-lowering effect and low rate of surgical complications were very similar to those of iTrack canaloplasty.

Background & Aims: Point of care tests (POCTs) might be used to identify patients with undiagnosed celiac disease who require further evaluation. We performed a large multicenter study to determine the performance of a POCT for celiac disease and assessed celiac disease prevalence in endoscopy centers., Methods: We performed a prospective study of 1055 patients (888 adults; median age, 48 yrs and 167 children; median age, 10 yrs) referred to 8 endoscopy centers in Germany, for various indications, from January 2016 through June 2017. Patients were tested for celiac disease using Simtomax, which detects immunoglobulin (Ig)A and IgG antibodies against deamidated gliadin peptides (DGP). Results were compared with findings from histologic analyses of duodenal biopsies (reference standard). The primary aim was to determine the accuracy of this POCT for the detection of celiac disease, to identify candidates for duodenal biopsy. A secondary aim was to determine the prevalence of celiac disease in adult and pediatric populations referred for outpatient endoscopic evaluation., Results: The overall prevalence of celiac disease was 4.1%. The POCT identified individuals with celiac disease with 79% sensitivity (95% CI, 64%-89%) and 94% specificity (95% CI, 93%-96%). Positive and negative predictive values were 37% and 99%. When we analyzed the adult and pediatric populations separately, we found the test to identify adults with celiac disease (prevalence 1.2%) with 100% sensitivity and 95% specificity. In the pediatric population (celiac disease prevalence 19.6%), the test produced false-negative results for 9 cases; the test therefore identified children with celiac disease with 72% sensitivity (95% CI 53%-86%). Analyses of serologic data revealed significantly lower DGP titers in the false-negative vs the true-positive group., Conclusions: In a study of more than 1000 adults and children, we found the Simtomax POCT to detect celiac disease with lower overall levels of sensitivity than expected. Although the test identifies adults with celiac disease with high levels of sensitivity and specificity, the prevalence of celiac disease was as low as 1.2% among adults. The test's lack of sensitivity might be due to the low intensity of the POCT bands and was associated with low serum DGP titers. Study ID no: DRKS00012499., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objective: Epidemiological research in functional somatic disorders such as irritable bowel syndrome, fibromyalgia, chronic fatigue syndrome, and bodily distress syndrome and related conditions such as health (illness) anxiety is often based on self-reported questionnaires or layman interviews. This study presents and describes the Research Interview for Functional somatic Disorders (RIFD) and provides first data regarding RIFD's ability to identify cases with functional somatic disorders and health anxiety in a two-phase design following self-reported symptom questionnaires., Methods: RIFD was performed by phone by trained family physicians on a stratified subsample of 1590 adults from a Danish general population cohort (n = 7493). Criterion validity was tested in a small preliminary test including 25 RIFD participants using Schedules of Clinical Assessment in Neuropsychiatry (SCAN), performed by a specialist in functional somatic disorders, as gold standard. Interrater reliability between interviewers was tested in 15 participants., Results: Compared with the comprehensive SCAN, preparation and conduction of RIFD were feasible and prompt. RIFD was well accepted by both interviewers and interviewees. RIFD identified cases with significantly more impairment than identified non-cases. Based on small preliminary tests, RIFD showed promising psychometric properties., Conclusion: RIFD was a feasible, well-accepted and promising instrument for use in large epidemiological studies. However, larger studies investigating its psychometric properties are needed., (Copyright © 2019 Elsevier Inc. All rights reserved.)

CV9201 is an RNActive ® -based cancer immunotherapy encoding five non-small cell lung cancer-antigens: New York esophageal squamous cell carcinoma-1, melanoma antigen family C1/C2, survivin, and trophoblast glycoprotein. In a phase I/IIa dose-escalation trial, 46 patients with locally advanced (n = 7) or metastatic (n = 39) NSCLC and at least stable disease after first-line treatment received five intradermal CV9201 injections (400-1600 µg of mRNA). The primary objective of the trial was to assess safety. Secondary objectives included assessment of antibody and ex vivo T cell responses against the five antigens, and changes in immune cell populations. All CV9201 dose levels were well-tolerated and the recommended dose for phase IIa was 1600 µg. Most AEs were mild-to-moderate injection site reactions and flu-like symptoms. Three (7%) patients had grade 3 related AEs. No related grade 4/5 or related serious AEs occurred. In phase IIa, antigen-specific immune responses against ≥ 1 antigen were detected in 63% of evaluable patients after treatment. The frequency of activated IgD + CD38 hi B cells increased > twofold in 18/30 (60%) evaluable patients. 9/29 (31%) evaluable patients in phase IIa had stable disease and 20/29 (69%) had progressive disease. Median progression-free and overall survival were 5.0 months (95% CI 1.8-6.3) and 10.8 months (8.1-16.7) from first administration, respectively. Two- and 3-year survival rates were 26.7% and 20.7%, respectively. CV9201 was well-tolerated and immune responses could be detected after treatment supporting further clinical investigation.

Background: Psychological treatment for functional somatic syndromes (FSS) has been found moderately effective. Information on how much treatment is needed to obtain improvement is sparse. We assessed the efficacy of a brief and extended version of group-based Acceptance and Commitment Therapy (ACT) v. enhanced care (EC) for patients with multiple FSS operationalised as Bodily Distress Syndrome multi-organ type., Methods: In a randomised controlled three-armed trial, consecutively referred patients aged 20-50 with multiple FSS were randomly assigned to either (1) EC; (2) Brief ACT: EC plus 1-day workshop and one individual consultation; or (3) Extended ACT: EC plus nine 3-h group-based sessions. Primary outcome was patient-rated overall health improvement on the five-point clinical global improvement scale 14 months after randomisation. A proportional odds model was used for the analyses., Results: A total of 180 patients were randomised; 60 to EC, 61 to Brief ACT, and 59 to Extended ACT. Improvement on the primary outcome after Extended ACT was significantly greater than after EC with an unadjusted OR of 2.9 [95% CI (1.4-6.2), p = 0.006]. No significant differences were found between Brief ACT and EC. Of the 18 secondary outcomes, the only significant difference found was for physical functioning in the comparison of Extended ACT with EC., Conclusions: Patients rated their overall health status as more improved after Extensive ACT than after EC; however, clinically relevant secondary outcome measures did not support this finding. Discrepancies between primary and secondary outcomes in this trial are discussed.

Background: Preclinical studies demonstrate synergism between cancer immunotherapy and local radiation, enhancing anti-tumor effects and promoting immune responses. BI1361849 (CV9202) is an active cancer immunotherapeutic comprising protamine-formulated, sequence-optimized mRNA encoding six non-small cell lung cancer (NSCLC)-associated antigens (NY-ESO-1, MAGE-C1, MAGE-C2, survivin, 5T4, and MUC-1), intended to induce targeted immune responses., Methods: We describe a phase Ib clinical trial evaluating treatment with BI1361849 combined with local radiation in 26 stage IV NSCLC patients with partial response (PR)/stable disease (SD) after standard first-line therapy. Patients were stratified into three strata (1: non-squamous NSCLC, no epidermal growth factor receptor (EGFR) mutation, PR/SD after ≥4 cycles of platinum- and pemetrexed-based treatment [n = 16]; 2: squamous NSCLC, PR/SD after ≥4 cycles of platinum-based and non-platinum compound treatment [n = 8]; 3: non-squamous NSCLC, EGFR mutation, PR/SD after ≥3 and ≤ 6 months EGFR-tyrosine kinase inhibitor (TKI) treatment [n = 2]). Patients received intradermal BI1361849, local radiation (4 × 5 Gy), then BI1361849 until disease progression. Strata 1 and 3 also had maintenance pemetrexed or continued EGFR-TKI therapy, respectively. The primary endpoint was evaluation of safety; secondary objectives included assessment of clinical efficacy (every 6 weeks during treatment) and of immune response (on Days 1 [baseline], 19 and 61)., Results: Study treatment was well tolerated; injection site reactions and flu-like symptoms were the most common BI1361849-related adverse events. Three patients had grade 3 BI1361849-related adverse events (fatigue, pyrexia); there was one grade 3 radiation-related event (dysphagia). In comparison to baseline, immunomonitoring revealed increased BI1361849 antigen-specific immune responses in the majority of patients (84%), whereby antigen-specific antibody levels were increased in 80% and functional T cells in 40% of patients, and involvement of multiple antigen specificities was evident in 52% of patients. One patient had a partial response in combination with pemetrexed maintenance, and 46.2% achieved stable disease as best overall response. Best overall response was SD in 57.7% for target lesions., Conclusion: The results support further investigation of mRNA-based immunotherapy in NSCLC including combinations with immune checkpoint inhibitors., Trial Registration: ClinicalTrials.gov identifier: NCT01915524 .

Objective: The mechanisms underlying the perception and experience of persistent physical symptoms are not well understood, and in the models, the specific relevance of peripheral input versus central processing, or of neurobiological versus psychosocial factors in general, is not clear. In this article, we proposed a model for this clinical phenomenon that is designed to be coherent with an underlying, relatively new model of the normal brain functions involved in the experience of bodily signals., Methods: Based on a review of recent literature, we describe central elements of this model and its clinical implications., Results: In the model, the brain is seen as an active predictive processing or inferential device rather than one that is passively waiting for sensory input. A central aspect of the model is the attempt of the brain to minimize prediction errors that result from constant comparisons of predictions and sensory input. Two possibilities exist: adaptation of the generative model underlying the predictions or alteration of the sensory input via autonomic nervous activation (in the case of interoception). Following this model, persistent physical symptoms can be described as "failures of inference" and clinically well-known factors such as expectation are assigned a role, not only in the later amplification of bodily signals but also in the very basis of symptom perception., Conclusions: We discuss therapeutic implications of such a model including new interpretations for established treatments as well as new options such as virtual reality techniques combining exteroceptive and interoceptive information.

Objectives: The current delimitation of functional somatic syndromes (FSS) is inconsistent. We aimed to investigate somatic symptom profiles in the general adult population to contribute to a new, data-driven delimitation of FSS., Methods: Information on 31 self-reported somatic symptoms used in the delimitation of various FSS and bodily distress syndrome (BDS) was obtained from the DanFunD study-a population-based cohort study on 9656 adults (participation 33.6%) from Greater Copenhagen, Denmark. Latent class analysis was used to identify symptom profiles. The profiles were described by their relation with sex, age, chronic disease, self-perceived health, symptom impact, self-reported FSS, and BDS case-status., Results: Eight symptom profiles were identified. The largest profile had no symptoms (49% of the population). Three profiles were characterized by a few, specific symptoms: muscle and joint pain (17%), gastrointestinal symptoms (6%), and general symptoms (13%). Three profiles had multiple symptoms in specific combinations: musculoskeletal and general symptoms (7%); fatigue, musculoskeletal and gastrointestinal symptoms (3%); and cardiopulmonary, gastrointestinal and general symptoms (3%). Lastly, one profile (2%) had high probability of all symptoms. The last four profiles (15%) were strongly associated with BDS case-status, poor self-perceived health and high impact of symptoms. Analyses excluding persons with multi-symptomatic chronic disease showed similar results., Conclusions: We identified eight symptom profiles characterized by specific combinations of symptoms. Four of these had multiple symptoms from several bodily systems showing large overlap with BDS, possibly indicating subtypes of FSS. The profiles contribute to a new delimitation of FSS by illustrating the importance of specific symptom combinations., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The spatial architecture of signaling pathways and the interaction with cell size and morphology are complex, but little understood. With the advances of single cell imaging and single cell biology, it becomes crucial to understand intracellular processes in time and space. Activation of cell surface receptors often triggers a signaling cascade including the activation of membrane-attached and cytosolic signaling components, which eventually transmit the signal to the cell nucleus. Signaling proteins can form steep gradients in the cytosol, which cause strong cell size dependence. We show that the kinetics at the membrane-cytosolic interface and the ratio of cell membrane area to the enclosed cytosolic volume change the behavior of signaling cascades significantly. We suggest an estimate of average concentration for arbitrary cell shapes depending on the cell volume and cell surface area. The normalized variance, known from image analysis, is suggested as an alternative measure to quantify the deviation from the average concentration. A mathematical analysis of signal transduction in time and space is presented, providing analytical solutions for different spatial arrangements of linear signaling cascades. Quantification of signaling time scales reveals that signal propagation is faster at the membrane than at the nucleus, while this time difference decreases with the number of signaling components in the cytosol. Our investigations are complemented by numerical simulations of non-linear cascades with feedback and asymmetric cell shapes. We conclude that intracellular signal propagation is highly dependent on cell geometry and, thereby, conveys information on cell size and shape to the nucleus.

Objective: To describe the use of prescription drugs and their association with patient characteristics in patients with multiple functional somatic syndromes (FSS) focusing on drugs generally recommended and not recommended in FSS treatment., Method: Using data from a national prescription registry, we describe the drug use during a two-year period for 239 trial participants. Using regression models, we analyse the associations of patient characteristics with the patterns of use of antidepressants, anticonvulsants, opioids and sedatives., Results: The use of prescription drugs was highly heterogeneous. Antidepressants were used at least temporarily by 34% (88/239), anticonvulsants by 7% (16/239), opioids by 26% (61/239) and sedatives by 20% (47/239) of the patients. Severe impairment due to multiple FSS was associated with use of opioids or sedatives (OR 6.49 (95% CI 2.68-15.68; p < 0.001)) but also with use of antidepressants or anticonvulsants (OR 3.42 (95% CI 1.35-8.65; p = 0.009)). Poor self-reported physical health, additional physical comorbidities and low socioeconomic status were associated with use of opioids or sedatives only., Conclusion: Antidepressants and anticonvulsants were modestly used. Opioids and sedatives were especially used by the severely affected patients. Balancing treatment expectations and enhancing patients' understanding of FSS may direct treatments towards more generally recommended drugs., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Patients with multiple functional somatic syndromes show markedly reduced functioning and numerous somatic symptoms that cannot be explained by conventionally-defined physical disease. Whilst the comorbidity of functional somatic syndromes with mental disorders is well-known, knowledge about physical comorbidity and mortality is scarce., Aim: To compare number of physical diseases between patients with multiple functional somatic syndromes (operationalized as multi-organ bodily distress syndrome) and the general population with regard to: 1) All conventionally-defined physical diseases, and 2) Severe mortality-associated physical diseases., Materials and Methods: Patients with multiple functional somatic syndromes (n=239) were compared with age- and gender-matched population-based controls (n=5975). The number of physical diseases during a four-year period was estimated by means of registered ICD-10 codes in relation to hospital admissions and ambulatory care. We counted individual diagnoses indicating conventionally-defined physical disease based on a previously developed diagnosis sorting algorithm and an additional clinical evaluation, excluding unspecific (symptom) diagnoses and functional somatic syndromes. An updated version of Charlson Comorbidity Index (CCI 12 ) was used to estimate severe, mortality-associated physical diseases., Results: Patients with multiple functional somatic syndromes had an increased number of conventionally-defined physical disease compared to controls (Ratio: 2.17, 95% CI: 1.96-2.41). Groups were similar as regards CCI 12 (P=0.55)., Conclusions: Patients with multiple functional somatic syndromes showed substantial physical comorbidity. Their burden of severe, mortality-associated physical diseases was comparable to the general population. Further research is needed to clarify the nature, clinical significance, and long-term consequences of the comorbid physical diseases., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: About 5-15 % of patients with concussion experience persistent post-concussion symptoms (PCS) longer than 3 months post-injury., Objective: To explore the feasibility of a new intervention for young patients with persistent PCS and long-term changes after intervention., Methods: Thirty-two consecutive patients (15-30 years) with persistent PCS 2-4 months post-injury were recruited from a cohort study or referred to a non-randomized feasibility study of an individually tailored, 8-week, multidisciplinary intervention. Assessment was performed at baseline, end of intervention (EOI), and at 3- and 12-month follow-up (FU). Main measures were The Experience of Service Questionnaire (ESQ), Rivermead Post-Concussion Symptoms Questionnaire (RPQ) and The Quality of Life after Brain Injury - Overall Scale (QOLIBRI-OS)., Results: Twenty-three (72%) patients completed the intervention. The ESQ demonstrated high patient satisfaction. There was a decrease of PCS and an increase in quality of life from baseline to EOI: RPQ score -8.9 points, 95% CI 4.5 to 13.3, p < 0.001; QOLIBRI-OS score +10.5 points, 95% CI 2.5 to 18.5, p = 0.010. Improvement was maintained at 3- and 12-month FU., Conclusion: The new early intervention is feasible and may prevent chronification of PCS. An RCT is currently performed to evaluate the effect of the intervention.

Primary Objectives: We hypothesized that the microstructure of the corpus callosum, thalamus and hippocampus, as measured with diffusion and Mean of the Kurtosis Tensor (MKT) MRI, differs between healthy subjects and patients with extensive and minimal post-concussion symptoms (PCS) and that MKT measures correlate with PCS severity and self-reported cognitive symptoms., Research Design: A cross-sectional study comparing patients with extensive PCS and patients with minimal PCS 2-5 months after mild traumatic brain injury (mTBI) with each other and with an external healthy control group., Methods and Procedures: Diffusion MRI was obtained in 25 patients with extensive PCS and in 25 patients with minimal PCS as measured by the Rivermead Post-concussion Symptoms Questionnaire. The patients were matched on age, sex and time since accident. Data from an external healthy control group (n = 27) was included., Main Outcome and Results: There was no difference in MKT between the two groups with mTBI and no correlation between MKT and PCS. There was no difference between the three groups in other diffusion measures., Conclusions: Our results did not point to microstructural changes in the corpus callosum, thalamus and hippocampus in relation to PCS after mTBI.

Objective: The harmonization of core outcome domains in clinical trials facilitates comparison and pooling of data, and simplifies the preparation and review of research projects and comparison of risks and benefits of treatments. Therefore, we provide recommendations for the core outcome domains that should be considered in clinical trials on the efficacy and effectiveness of interventions for somatic symptom disorder, bodily distress disorder, and functional somatic syndromes., Methods: The European Network on Somatic Symptom Disorders group of more than 20 experts in the field met twice in Hamburg to discuss issues of assessment and intervention research in somatic symptom disorder, bodily distress disorder, and functional somatic syndromes. The consensus meetings identified core outcome domains that should be considered in clinical trials evaluating treatments for somatic symptom disorder and associated functional somatic syndromes., Results: The following core domains should be considered when defining ascertainment methods in clinical trials: a) classification of somatic symptom disorder/bodily distress disorder, associated functional somatic syndromes, and comorbid mental disorders (using structured clinical interviews), duration of symptoms, medical morbidity, and prior treatments; b) location, intensity, and interference of somatic symptoms; c) associated psychobehavioral features and biological markers; d) illness consequences (quality of life, disability, health care utilization, health care costs; e) global improvement and treatment satisfaction; and f) unwanted negative effects., Conclusions: The proposed criteria are intended to improve synergies of clinical trials and to facilitate decision making when comparing different treatment approaches. These recommendations should not result in inflexible guidelines, but increase consistency across investigations in this field.

Purpose: The aim of this study was to identify and describe somatic symptom profiles in the general adult population in order to enable further epidemiological research within multiple somatic symptoms., Methods: Information on 19 self-reported common somatic symptoms was achieved from a population-based questionnaire survey of 36,163 randomly selected adults in the Capital Region of Denmark (55.4% women). The participants stated whether they had been considerably bothered by each symptom within 14 days prior to answering the questionnaire. We used latent class analysis to identify the somatic symptom profiles. The profiles were further described by their association with age, sex, chronic disease, and self-perceived health., Results: We identified 10 different somatic symptom profiles defined by number, type, and site of the symptoms. The majority of the population (74.0%) had a profile characterized by no considerable bothering symptoms, while a minor group of 3.9% had profiles defined by a high risk of multiple somatic symptoms. The remaining profiles were more likely to be characterized by a few specific symptoms. The profiles could further be described by their associations with age, sex, chronic disease, and self-perceived health., Conclusion: The identified somatic symptom profiles could be distinguished by number, type, and site of the symptoms. The profiles have the potential to be used in further epidemiological studies on risk factors and prognosis of somatic symptoms but should be confirmed in other population-based studies with specific focus on symptom burden., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Objective: To analyze the effectiveness of psychological treatments on symptom load and associated disability in children with functional somatic symptoms, and to explore potential moderators of effects., Study Design: Cochrane, PubMed, PsycINFO, EMBASE, and CINAHL were searched for randomized controlled trials published in peer-reviewed journals. Randomized controlled trials studying the effect of a psychological treatment on symptom load and disability in children with functional somatic symptoms were selected. Data on symptom load, disability, and school absence directly post-treatment and at follow-up were extracted by 2 assessors. Studies were appraised with the Cochrane risk of bias tool. Standardized mean differences were pooled in a random-effects model. Heterogeneity in effect-sizes was explored by use of meta-regressions. PROSPERO Registration ID: CRD42015029667., Results: Out of 4098 identified records, 27 studies were included in this review of which 21 were included in meta-analyses. Psychological treatments reduced symptom load (Hedges g = -0.61), disability (Hedges g = -0.42), and school absence (Hedges g = -0.51) post-treatment in children suffering from various functional somatic symptoms. Effects were maintained at follow-up. Type and duration of symptoms, age, and treatment dose did not explain heterogeneity in effect-sizes between studies. Effect-sizes should be interpreted with caution because of the variety in outcome measures, unexplained heterogeneity in found effects and potential publication bias., Conclusions: Psychological interventions reduce symptom load, disability, and school absence in children with functional somatic symptoms. Future research should clarify which patient and treatment characteristics modify outcomes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Irritable bowel syndrome (IBS) is associated with mental vulnerability, and half of patients report comorbid somatic and mental symptoms. We aimed to investigate the relationship between an IBS symptom continuum and the subsequent development of common mental disorders (CMDs) and functional somatic syndromes (FSSs)., Methods and Study Design: A longitudinal population-based study comprising two 5-year follow-up studies, Dan-MONICA 1 (1982-1987) and Inter99 (1999-2004), recruited from the western part of Copenhagen County. The total study population (n = 7,278) was divided into symptom groups according to the degree of IBS definition fulfillment at baseline and/or follow-up and was followed until December 2013 in Danish central registries. Cox regression was used for the analyses, adjusting for age, sex, length of education and cohort membership. In a subsequent analysis, we adjusted for mental vulnerability as a risk factor for both CMDs and FSSs, including IBS., Results: Over a 5-year period, 51% patients had no IBS symptoms, 17% patients had IBS symptoms without abdominal pain, 22% patients had IBS symptoms including abdominal pain and 10% patients fulfilled the IBS definition. IBS and IBS symptoms including abdominal pain were significantly associated with the development of CMDs and other FSSs identified in secondary care. When adjusting for mental vulnerability, IBS and IBS symptoms including abdominal pain were no longer associated with CMDs, but the significant relationship to other FSSs remained., Conclusion: In a clinical setting, the perspective should be broadened to individuals not fulfilling the symptom cluster of IBS but who report frequent abdominal pain. Additionally, it is important to combine symptom-based criteria of IBS with psychosocial markers such as mental vulnerability, because it could guide clinicians in decisions regarding prognosis and treatment., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Background: Functional somatic syndromes, including chronic fatigue syndrome or irritable bowel syndrome, often co-exist. Treatment guidelines supported by high quality evidence exist for most functional somatic syndromes, but are lacking for multiple comorbid functional somatic syndromes. We aimed to assess the effect of the tricyclic antidepressant, imipramine, in patients with multiple functional somatic syndromes defined by the criteria for multiorgan bodily distress syndrome, a unifying diagnosis that encompasses most functional somatic syndromes and somatoform disorders., Methods: In this single-centre, double-blind, randomised trial done in a Danish university hospital setting, participants were patients consecutively referred (age 20-50 years) fulfilling criteria for multiorgan bodily distress syndrome with no concurrent comorbid depression or anxiety disorder. Participants were randomly assigned (1:1) to receive either 10 weeks of low-dose imipramine or placebo (oral daily doses of 25-75 mg). The hospital pharmacy handled randomisation (computer-generated) and masking, providing sequentially numbered packs of study drug that were given serially to the participants. All others involved were masked to allocation. Primary outcome was patient-rated overall health improvement on a 5-point clinical global improvement scale. Improvement was defined as patients responding "better" or "much better" as opposed to "unchanged" and "worse" or "much worse" when rating their overall health status after 10 weeks of minimum 25 mg study drug. Analyses included patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01518634., Findings: Between Jan 30, 2012, and Nov 24, 2014, 138 patients were randomly assigned; 70 to receive imipramine and 68 to receive placebo. The study was completed on May 1, 2015. 125 patients received at least one dose of study drug: 65 received imipramine and 60 received placebo. Treatment was terminated prematurely for eight (12%) patients receiving imipramine and seven (12%) patients receiving placebo. Data were missing for two (3%) patients receiving imipramine and three (5%) patients receiving placebo. Of the 120 patients (96%) who provided primary outcome data, 33 (53%) receiving imipramine reported their overall health status as "better" or "much better" compared with 14 patients (25%) receiving placebo. The improvement after imipramine was significantly greater than after placebo (odds ratio 3·3 [95% CI 1·6-6·8]; p=0·001). Number needed to treat was 3·6 (95% CI 2·3-8·9). Analysis of the worst-case scenario for patients with missing outcome did not change the interpretation of the results. 32 patients (49%) receiving imipramine and 10 patients (17%) receiving placebo had at least one adverse event of moderate intensity (p=0·0001); eight patients (12%) receiving imipramine and three patients (5%) receiving placebo had at least one adverse event of severe intensity (p=0·1496). One patient (1%) receiving placebo experienced a serious adverse event (a subdural haematoma sustained after an accident). Adverse events caused dropout in four patients (6%) receiving imipramine and three patients (5%) receiving placebo., Interpretation: Imipramine treatment compared with placebo significantly improved overall health in patients with multiple functional somatic syndromes when both treatments were supported by regular contacts with clinicians. Adverse events were more common in the imipramine group, but only rarely led to discontinuation of treatment., Funding: The Danish Foundation, Trygfonden., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: Patients with functional somatic syndromes (FSS) such as fibromyalgia and chronic fatigue syndrome have a poor outcome and can incur high healthcare and societal costs. We aimed to compare the medium-term (16months) cost-effectiveness and the long-term (40months) economic outcomes of a bespoke cognitive-behavioural group treatment (STreSS) with that of enhanced usual care (EUC)., Methods: We obtained complete data on healthcare and indirect costs (i.e. labour marked-related and health-related benefits) from public registries for 120 participants from a randomised controlled trial. Costs were calculated as per capita public expenses in 2010 €. QALYs gained were estimated from the SF-6D. We conducted a medium-term cost-effectiveness analysis and a long-term cost-minimization analysis from both a healthcare (i.e. direct cost) and a societal (i.e. total cost) perspective., Results: In the medium term, the probability that STreSS was cost-effective at thresholds of 25,000 to 35,000 € per QALY was 93-95% from a healthcare perspective, but only 50-55% from a societal perspective. In the long term, however, STreSS was associated with increasing savings in indirect costs, mainly due to a greater number of patients self-supporting. When combined with stable long-term reductions in healthcare expenditures, there were total cost savings of 7184 € (95% CI 2271 to 12,096, p=0.004) during the third year after treatment., Conclusion: STreSS treatment costs an average of 1545 €. This cost was more than offset by subsequent savings in direct and indirect costs. Implementation could both improve patient outcomes and reduce costs., (Copyright © 2017 Elsevier Inc. All rights reserved.)