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Marie Weinreich Petersen,1,2 Tina Birgitte Wisbech Carstensen,1,2 Lisbeth Frostholm,1,2 Kaare Bro Wellnitz,1,2 Eva Ørnbøl,1,2 Torben Jørgensen,3,4 Lene Falgaard Eplov,5 Thomas Meinertz Dantoft,3 Per Fink1,2 1Research Clinic for Functional Disorders and Psychosomatics, Aarhus University Hospital, Aarhus, Denmark; 2Department of Clinical Medicine, University of Aarhus, Aarhus, Denmark; 3Center for Clinical Research and Prevention, Bispebjerg/Frederiksberg Hospital, Frederiksberg, Capital Region, Denmark; 4Department of Public Health, Faculty of Medical Sciences, Copenhagen University, Copenhagen, Denmark; 5Copenhagen Research Center for Mental Health – CORE, Mental Health Centre Copenhagen, Copenhagen, Capital Region, DenmarkCorrespondence: Marie Weinreich Petersen, Research Clinic for Functional Disorders and Psychosomatics, Aarhus University Hospital, Palle Juul-Jensens Boulevard 11, Aarhus, 8200, Denmark, Tel +45 7846 4310, Email mawept@rm.dkObjective: Several psychological factors have been proposed to be associated with functional somatic disorders (FSD) including functional somatic syndromes, such as irritable bowel, chronic widespread pain, and chronic fatigue. However, large randomly selected population-based studies of this association are sparse. This study aimed to investigate the association between FSD and perceived stress and self-efficacy, respectively, and to investigate if FSD differed from severe physical diseases on these aspects.Methods: This cross-sectional study included a random sample of the adult Danish population (n = 9656). FSD were established using self-reported questionnaires and diagnostic interviews. Perceived stress was measured with Cohen’s Perceived Stress Scale and self-efficacy with the General Self-Efficacy Scale. Data were analysed with generalized linear models and linear regression models.Results: FSD were associated with higher perceived stress and lower self-efficacy, especially for the multi-organ and the general symptoms/fatigue FSD types and for chronic fatigue. However, controlling for the personality trait neuroticism altered the associations with self-efficacy so it became insignificant. The analysis did not support an important interaction between perceived stress and self-efficacy on the likelihood of having FSD. Individuals with FSD presented levels of perceived stress that were not equal, ie higher, to those in individuals with severe physical diseases.Conclusion: FSD were positively associated with perceived stress and negatively associated with self-efficacy. Our study may point to stress being part of the symptomatology of FSD. This underlines the severity of having FSD and stresses the relevance of the resilience theory in the understanding of the condition.Keywords: functional somatic disorders, functional somatic syndromes, perceived stress, self-efficacy, irritable bowel syndrome, fibromyalgia, chronic fatigue syndrome, population-based

Background: Evidence of incidence of functional somatic disorders (FSD) is hampered by unclear delimitations of the conditions and little is known about the possible interchangeability between syndromes. Further, knowledge on remission and persistence of FSD in the general population is limited. We aimed to assess the natural course of various FSD over 5 years in the general population., Methods: A follow-up study (Danish Study of Functional Disorders-DanFunD) was conducted in a random sample of the general population comprising 5,738 participants aged 18-76 years at baseline. Both at baseline and five-year follow-up, participants filled in validated questionnaires on symptoms to delimitate two approaches of FSD, the bodily distress syndrome (BDS) and four functional somatic syndromes (FSS): irritable bowel (IB), chronic fatigue (CF), chronic widespread pain (CWP), and multiple chemical sensitivity (MCS)., Results: Both BDS and FSS showed a five-year incidence around 11%. Incidence of the individual FSS varied from 0.8% (MCS) to 5.7% (CF). BDS and FSS showed a remission proportion close to 50%. We found a high degree of interchangeability between each FSS varying from 15.0% to 23.4%., Conclusion: We identified a marked fluctuation pattern of FSD during a five-year period, with a high degree of interchangeability between each FSS. The study stresses the importance of large population-based cohorts with transparent delimitation of FSD in future research to understand these complex conditions., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Schovsbo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Persistent physical symptoms (PPS) remain a challenge in the healthcare system due to time-constrained consultations, uncertainty and limited specialised care capacity. Self-help interventions may be a cost-effective way to widen the access to treatment. As a foundation for future interventions, we aimed to describe intervention components and their potential effects in self-help interventions for PPS. A systematic literature search was made in PubMed, EMBASE, PsycINFO and CENTRAL. Fifty-one randomised controlled trials were included. Interventions were coded for effect on outcomes (standardised mean difference ≥0.2) related to symptom burden, anxiety, depression, quality of life, healthcare utilisation and sickness absence. The Behaviour Change Technique (BCT) Taxonomy v1 was used to code intervention components. An index of potential was calculated for each BCT within an outcome category. Each BCT was assessed as 'potentially effective' or 'not effective' based on a two-sided test for binomial random variables. Sixteen BCTs showed potential effect as treatment components. These BCTs represented the themes: goals and planning, feedback and monitoring, shaping knowledge, natural consequences, comparison of behaviour, associations, repetition and substitution, regulation, antecedents and identity. The results suggest that specific BCTs should be included in new PPS self-help interventions aiming to improve the patients' physical and mental health.

Objectives: It has been hypothesised that functional somatic disorders (FSD) could be initiated by sympathetic predominance in the autonomic nervous system as measured by low heart rate variability (HRV). Earlier studies on the association between HRV and FSD are small case-control studies hampered by selection bias and do not consider the great overlap between the various FSDs. The aim of the present study is to assess any associations between HRV and various FSDs and whether chronic stress confounds such an association., Design: A cross-sectional general population-based study., Setting: The Danish Study of Functional Somatic Disorders conducted 2013-2015 in 10 municipalities in the western part of Greater Copenhagen, Denmark., Participants: A total of 6891 men and women aged 18-72 years were included in the analyses after exclusion of 602 persons with missing HRV data. Various delimitations of FSD (chronic fatigue, chronic widespread pain, irritable bowel and bodily distress syndrome) were identified by validated questionnaires and diagnostic interviews. HRV parameters in time and frequency domains were calculated from successive beat-to-beat heart rate (HR) data using the 'E-motion' HR monitor device during 7 min of supine rest. Chronic stress was assessed by Cohen's self-perceived stress scale., Outcome Measures: Logistic regression analyses were used to calculate possible associations between the various delimitations of FSD and HRV adjusting for chronic stress., Results: Persons with FSD had a slightly higher mean HR and lower HRV as measured by time domain parameters, whereas associations with frequency domain parameters were not consistent. Adjusting for chronic stress attenuated associations slightly., Conclusion: The study supports a sympathetic predominance in persons with FSD, which could not be entirely explained by chronic stress. However, it is not possible to conclude whether the association is a causal factor to or a consequence of FSD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: The autonomic nervous system includes parasympathetic and sympathetic components that monitor and regulate most of the bodily functions and play a central role in the physiology and homeostasis of the human body. Heart rate variability is a non-invasive tool for quantification of rhythmic fluctuations in heart rate that reflects the function of the autonomic nervous system. The study aims to describe the heart rate variability distribution in the general population, stratified in sex and age groups, which is currently insufficiently described., Methods: A cross-sectional population-based study recruited participants in 10 municipalities in the western part of the greater Copenhagen area in Denmark, including 6891 men and women aged 18-72 years (participation rate was 29.5%). Short-term heart rate variability measures were obtained and related to age and gender., Results: Both time and frequency domain measures showed a huge variation in the different sex and age groups. Women had a higher median heart rate than men, and the association with age was U-shaped. Measures indicating a predominance of the parasympathetic component in relation to the sympathetic component were more frequent in women and younger age groups., Conclusions: Both sex and age influence the heart rate variability in this adult Danish population. Therefore, our age- and sex-related reference values of heart rate variability in the time and frequency domain should be used in further epidemiological and clinical research., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: Earlier studies on the association between plasma lipid profiles and functional somatic disorders (FSD) are mainly small case control studies hampered by selection bias and do not consider the great overlap between the various FSDs. The aim of the present study was to investigate the associations between various FSDs and plasma lipid profiles (total cholesterol, HDL cholesterol, non-HDL cholesterol and triglycerides) in a large, unselected population., Design: A cross-sectional general population-based study., Setting: The Danish Study of Functional Somatic Disorders (DanFunD) conducted in 2011-2015 in 10 municipalities in the western part of greater Copenhagen, Denmark., Participants: A total of 8,608 men and women aged 18-76 years were included in the analyses. Various delimitations of FSD such as chronic fatigue, chronic widespread pain, irritable bowel, and bodily distress syndrome were measured using validated self-administrated questionnaires. Lipid parameters were measured from fasting plasma samples using colorimetric slide methods with Vitros 4600/5600 Ortho Clinical Diagnostics., Outcome Measures: Logistic regression analyses were used to calculate possible associations between plasma lipids and the various delimitations of FSD. Associations are presented by OR (95% CI) and shown in boxplots., Results: We found a positive association between bodily distress syndrome and triglycerides and non-HDL cholesterol and a negative association with HDL-cholesterol, but no consistent association with total cholesterol. A similar pattern was observed for persons with chronic fatigue, and to some degree for persons with chronic widespread pain, whereas persons with irritable bowel did not show a clear association with the lipid profiles., Conclusion: This is the first major study on plasma lipid profiles and FSD indicating an association between some delimitations of FSD and an unfavorable lipid profile. Due to the cross-sectional design, it cannot be determined whether the findings are consequences or determinants of FSD. Further studies-preferable prospective studies-are needed., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Jørgensen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Functional somatic disorder (FSD) is a unifying diagnosis that includes functional somatic syndromes such as irritable bowel, chronic widespread pain (CWP) and chronic fatigue. Several psychological factors are associated with FSD. However, longitudinal population-based studies elucidating the causal relationship are scarce., Aims: To explore if neuroticism, perceived stress, adverse life events (ALEs) and self-efficacy can predict the development of FSD over a 5-year period., Method: A total of 4288 individuals who participated in the DanFunD baseline and 5-year follow-up investigations were included. FSD was established at both baseline and follow-up, with symptom questionnaires and diagnostic interviews. Neuroticism was measured with the short-form NEO Personality Inventory, perceived stress with the Cohen's Perceived Stress Scale, ALEs with the Danish version of the Cumulative Lifetime Adversity Measure and self-efficacy with the General Self-Efficacy Scale. Associations were investigated with multiple logistic regression models., Results: Perceived stress predicted incident FSD, irritable bowel, CWP and chronic fatigue (odds ratios: 1.04-1.17). Neuroticism predicted incident FSD and chronic fatigue (odds ratios: 1.03-1.16). ALEs predicted incident FSD, CWP and chronic fatigue (odds ratios: 1.06-1.18). An increase in perceived stress from baseline to follow-up was associated with incident FSD, irritable bowel, CWP and chronic fatigue (odds ratios: 1.05-1.22). Contrary, an increase in self-efficacy seemed to be a protective factor (odds ratios: 0.89-0.99)., Conclusions: High neuroticism, high perceived stress and a high number of ALEs are risk factors for the development of FSD. Particularly perceived stress seems to be an important contributor to the onset of FSD.

An increasing number of sexual assaults (SAs) are being reported. This study investigated associations between SA and FSD, conceptualized as bodily distress syndrome (BDS), and five functional somatic syndromes (FSSs): chronic widespread pain (CWP), irritable bowel (IB), chronic fatigue (CF), multiple chemical sensitivity (MCS), and whiplash-associated disorder (WAD). Participants ( n = 7493) from the population-based cohort Danish Study of Functional Disorders (DanFunD) completed questionnaires on FSD, emotional distress, SA, and sociodemographics. Risk ratios (RRs) for each FSD and emotional distress were calculated in nine models with SA as the primary exposure using generalized linear models with binomial family and log link and were adjusted for other potential risk factors. The results showed that SA was associated with single-organ FSD (RR = 1.51; 95% CI = 1.22-1.87), multi-organ FSD (RR = 3.51; 95% CI = 1.89-6.49), CWP (RR = 1.28; 95% CI = 0.83-1.98), IB (RR = 2.00; 95% CI = 1.30-3.07), CF (RR = 1.81; 95% CI = 1.42-2.32), WAD (RR = 2.62; 95% CI = 1.37-5.03), MCS (RR = 3.04; 95% CI = 1.79-5.17), emotional distress (RR = 1.75; 95% CI = 1.21-2.54), and health anxiety (RR = 1.65; 95% CI = 1.10-2.46). Overall, SA victims experienced significantly more somatic symptoms than individuals not exposed to SA. Adjusting for physical and emotional abuse did not change the observed associations. Our results suggest a large impact of SA on the overall somatic and mental health of SA victims. Due to the cross-sectional study design, further studies are required.

Background and Aims: Increasingly, gambling features migrate into non-gambling platforms (e.g., online gaming) making gambling exposure and problems more likely. Therefore, exploring how to best treat gambling disorder (GD) remains important. Our aim was to review systematically and quantitatively synthesize the available evidence on psychological intervention for GD., Methods: Records were identified through searches for randomized controlled trials (RCTs) evaluating psychological intervention for GD via six academic databases without date restrictions until February 3, 2023. Study quality was assessed with the revised Cochrane risk-of-bias tool for randomized trials (RoB2). Primary outcomes were GD symptom severity and remission of GD, summarized as Hedges' g and odds ratios, respectively. The study was preregistered in PROSPERO (#CRD42021284550)., Results: Of 5,541 records, 29 RCTs (3,083 participants analyzed) were included for meta-analysis of the primary outcomes. The efficacy of psychological intervention across modality, format and mode of delivery corresponded to a medium effect on gambling severity (g = -0.71) and a small effect on remission (OR = 0.47). Generally, risk of bias was high, particularly amongst early face-to-face interventions studies., Discussion and Conclusions: The results indicate that psychological intervention is efficacious in treating GD, with face-to-face delivered intervention producing the largest effects and with strongest evidence for cognitive behavioral therapy. Much remains to be known about the long-term effects, and investigating a broader range of treatment modalities and digital interventions is a priority if we are to improve clinical practice for this heterogeneous patient group.

Background and Aim: It is generally accepted that functional somatic disorders (FSDs) are a product of biological, psychological, and social factors. Social position might be part of this complex, but the literature on this issue is currently heterogeneous and inconsistent. The aim of the present study was - in a population-based cohort - to test the hypothesis that lower social position would be associated with higher a risk of FSD., Method: The association between social position and FSD was examined in a cross-sectional study with various measures of social position (education as measured by vocational training; employment; cohabitation; subjective social status) and delimitations of FSD (irritable bowel syndrome, chronic fatigue syndrome, fibromyalgia, bodily distress syndrome, and symptom profiles). The associations were analyzed using logistic regressions to calculate odds ratios and 95% confidence intervals. Each social measure was analyzed independently and was adjusted for age and sex., Results: Lower levels of vocational training, being unemployed, and living alone were associated with higher risk of FSD, regardless of the FSD delimitation. There was also a significant negative association between subjective evaluated social status and FSD. The associations remained after multiple adjustments, and seemed to be strongest for the more severe FSD-types., Conclusions: Lower social position is associated with higher risk of FSD, especially the more severe FSD delimitations, which might constitute an especially vulnerable group. However, the mechanisms behind the relations remain unknown.

Objectives: It has been suggested that infections can trigger functional somatic disorders (FSD). However, current evidence is limited by inconsistent findings in smaller studies conducted in clinical settings within selected populations and short follow-up times. We aimed to test the hypothesis that former infections are associated with FSD using data from nationwide registries and a large population-based cohort study, the Danish Study of Functional Disorders study., Design: FSD cases were identified in a cross-sectional population-based cohort and linked retrospectively to former hospital contacts with infections identified in the Danish National Patient Registry. The associations between FSD and former infections within 17 years were analysed using logistic regressions to calculate ORs and 95% CIs adjusted for age, sex and subjective social status., Setting: A population-based cohort in Denmark examined between 2011 and 2015., Participants: A total of 9656 men and women aged 18-76 years., Main Outcome Measures: FSD measured by various delimitations, including bodily distress syndrome (BDS), irritable bowel (IB), chronic fatigue (CF), chronic widespread pain (CWP), and multiple chemical sensitivity (MCS)., Results: Overall, infections were associated with increased risk of all delimitations of FSD. The associations were more pronounced for multisystemic FSD. The number of prior infections increased the risk in a dose-response manner (p<0.0001). Bacterial but not viral infections were significantly associated with BDS (OR 1.69 (95% CI 1.46 to 1.96)), IB (OR 1.41 (95% CI 1.06 to 1.88)), CWP (OR 1.47 (95% CI 1.13 to 1.90)) and CF (OR 1.62 (95% CI 1.34 to 1.96)), but not MCS., Conclusion: Former infections leading to hospital contacts were associated with a higher risk of having FSD. These associations were more pronounced for bacterial than viral infections, and more infections increased the risk in a dose-response manner. These results tend to support the idea that severe infections could play a role in FSD., 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: Adverse experiences in childhood are a major public health concern, promoting social inequality in health through biopsychosocial mechanisms. So far, no known measures comprehend the complexity and variations of severity of adverse events. This study aims to develop and validate a new index: the Weighted Index for Childhood Adverse Conditions (WICAC)., Methods: The population consists of 7493 randomly invited men and women aged 18-72 years. Data were collected in 2012-2015 as part of the Danish Study of Functional Disorders (DanFunD). Content and construct validation of the WICAC was performed with the hypothesis testing of multiple biopsychosocial outcomes: cardiovascular disease, cancer, poor health, back pain, BMI, obesity, anxiety, depression, low vitality, subjective social status, lower education, smoking, and alcohol consumption. Data were analysed with binominal and linear regression models with risk ratios (RR) and mean differences (MD)., Results: Content validation is fitting for WICAC. The strongest associations observed were for most severe adversity: Poor Health RR = 2.16 (1.19-2.91), Anxiety RR = 3.32 (2.32-4.74), Heavy Drinking RR = 4.09 (1.85-9.04), and Subjective Social Status MD = -0.481 (-0.721-(-0.241)). Similar results were found for the remaining outcomes. Discriminative validation was undecided., Conclusions: WICAC is an adequate instrument for measuring cumulative adverse life events in childhood and adolescence for research purposes.

Multiple chemical sensitivity (MCS) is a multifactorial somatic disorder characterized by physical reactions triggered by even extremely low levels of different airborne chemicals. In most individuals with MCS, these reactions have substantial negative impact on social, occupational, and everyday life often including limited or no engagement in physical activities. The aim of this study was to explore associations between MCS and objective measurements of anthropometry, cardiorespiratory health, and physical performance. From the Danish population-based cohort DanFunD counting 9656 participants aged 18-76 years, 1.95% ( n = 188) were categorized as MCS individuals (MCS All). Of those 188, 109 participants were subcategorized as having MCS without functional somatic disorders (FSD) (MCS with no comorbid FSD). The remaining study population without any FSD were regarded controls. We used adjusted multiple linear regression analyses to evaluate associations between MCS and anthropometry, cardiorespiratory fitness, and physical performance. Compared with the general population, MCS All had less optimal body composition, increased risk of obesity, impaired cardiorespiratory fitness, and physical performance which was not seen in MCS with no comorbid FSD. MCS individuals may be inhibited to maintain an active lifestyle which can increase risk of obesity and consequently have negatively impact on general health, which may not be the case among MCS with no comorbid FSD.

Background: Disrupted pain regulation has been proposed as a component in functional somatic disorders (FSD). The objective of this study was to examine a general population sample, encompassing three delimitations of FSD while assessing pain sensitivity and conditioning pain modulation (CPM)., Methods: Pressure pain thresholds (PPTs) at the tibialis and trapezius muscles were recorded at baseline. During cold pressor stimulation of the hand, the tibialis PPTs were re-assessed and the difference from baseline measures defined the CPM effect. Participants (n = 2,198, 53% females) were randomly selected from the adult Danish population. FSD was established by self-reported symptom questionnaires., Results: With a few exceptions, only weak associations were seen between PPTs and CPM in cases with FSD (p > .1). A high PPT was associated with lower odds of having multi-organ bodily distress syndrome (OR PPT trapezius : 0.66, 95% CI: 0.49-0.88, p = .005), with the symptom profile characterized by all symptoms (OR PPT trapezius : 0.72, 95% CI: 0.58-0.90, p = .003 and OR PPT tibialis : 0.75, 95% CI: 0.62-0.91, p = .004), and with multiple chemical sensitivity (OR PPT trapezius : 0.81, 95% CI: 0.67-0.97, p = .022). High CPM was associated with high odds of having irritable bowel (OR CPM relative : 1.22, 95% CI: 1.04-1.43, p = .013 and OR CPM absolute  = 2.66, 95% CI: 1.07-6.45, p = .033)., Conclusion: However, only PPT measured over the trapezius muscle were still significant after correction for multiple testing for the symptom profile characterized by all symptoms. Findings from this study do not support altered pain regulation in questionnaire-based FSD which is in contrast with the existing presumption. Further epidemiological studies in this field are needed., Significance: Disrupted pain regulation as measured by abnormal pain thresholds has been hypothesized as a central mechanism in Functional Somatic Disorders (FSD). The hypothesis has been raised in clinical setting where patients presented subjective and objective features of hypersensitivity. The present population-based study does not support this notion. This points to the importance of further studies into the underlying pathophysiology mechanisms of FSD., (© 2021 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC ®.)

Multiple chemical sensitivity (MCS) is a multisystem syndrome, and limited knowledge of its pathophysiology exists. Based on the population-based Danish cohort DanFunD , this study investigated metabolic health in people with MCS compared to individuals who did not have MCS. From 9656 cohort participants aged 18-76 years old, 1.95% were categorized as MCS individuals with comorbid functional somatic disorders (MCS + FSD , n = 188), and 1.13% were categorized as MCS without functional somatic disorders (MCS ÷ FSD , n = 109). MCS was characterized based on three criteria: the experience of symptoms upon exposure to common odors and airborne chemicals, symptoms related the central nervous systems and others organ symptoms, and significant impact on every day, social, and occupational life. The remaining study population without MCS or any other functional somatic disorders were regarded as controls. We used adjusted multiple linear regression with link-function to evaluate the associations between lipid and glucose metabolism markers and MCS. We also tested the odds ratio of metabolic syndrome in MCS. Results did not point to statistically significant associations between lipid biomarkers or metabolic syndrome and both MCS groups compared to the controls. We found that MCS individuals may be more insulin resistant and that MCS ÷ FSD may have an impaired glucose metabolism when compared to controls.

Background: In the continuation of the first wave of the Covid-19 outbreak in Denmark, unprecedented restrictions with great impact on the citizen's everyday life were implemented. The objectives of this study were to investigate the influence of the Covid-19 pandemic on mental and physical health in the Danish population during the spring 2020 first wave outbreak and lockdown., Methods: A sample from the adult Danish population (n = 2190) were included. Self-reported measures of illness worry (Whiteley-6-R), emotional distress (SCL-90), and physical symptom load (SLC-90) were obtained before and during the first wave of the pandemic and compared with Wilcoxon signed-rank tests. Impact of covariates on physical and mental health was evaluated with ordinal regression analyses. Results from a tailored questionnaire regarding the Covid-19 pandemic were presented to explore the direct impact of the pandemic., Results: We only found minor increases in illness worry, emotional distress and physical symptom load (0-1 points difference, p ≤ 0.007) during the Covid-19 pandemic compared to before the pandemic. Sex, age, education, and physical disease were not associated with illness worry, emotional distress, or physical symptom load. Overall, the participants were trustful in the authorities' recommendations and felt that they managed the pandemic and the restrictions to a great extent despite that some expected great/major future consequences of the pandemic., Conclusions: This study suggested that the first wave of the Covid-19 pandemic only had minor impact on mental and physical health in the Danish general population. Future studies should address the impact of the second wave of the pandemic and the renewed implementation of the concomitant restrictions., (© 2021. The Author(s).)

Objective: Self-reported symptom questionnaires are often used for identifying individuals with functional somatic disorders (FSD) in epidemiological research. Studies on their validity in establishing clinically valid cases are, however, lacking. We aimed to compare and dissect the processes of identifying participants with FSD with symptom questionnaires and FSD diagnoses established by diagnostic interviews., Methods: Individuals from the adult Danish population (n = 1590) filled in symptom questionnaires and participated in a diagnostic research interview, performed over telephone by trained family physicians. The two methods were described and compared in different steps: 1) Agreement on presence of symptoms, 2) agreement after FSD symptom pattern criteria had been applied, and 3) agreement on final FSD diagnoses., Results: Agreement on symptom presence was high (>82%). Using FSD symptom pattern criteria, the two methods agreed in 30-62% of cases within each category. Discrepancies were mainly due to participants fulfilling symptom patterns in the interview but not in the questionnaires. Agreement between final FSD questionnaire cases and final FSD interview diagnoses was moderate (>68%) with lower FSD prevalence in the interview (26.2% vs 44.5%). Discrepancies were largely explained by the interviewers assessing the symptom patterns to be caused by an alternative physical or mental condition., Conclusion: Prevalence of final FSD diagnoses were markedly lower in the diagnostic interview compared to self-reported questionnaires cases; mainly because of the clinical evaluation of symptom attribution and impairment. Symptom questionnaires may be valuable as screening tools and as trans-diagnostic comparison while diagnostic interviews are necessary in establishing clinically significant FSD diagnoses., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

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.)

Background: Multiple chemical sensitivity (MCS) is characterized by widespread symptoms attributed to exposure to airborne chemicals. MCS is categorized as a functional somatic syndrome (FSS), and MCS cases often meet the criteria for other types of FSS, e.g. fibromyalgia. The primary aim was to characterize MCS regarding symptom triggers, symptoms, lifestyle and describe demographics, socioeconomics and lifestyle factors associated with MCS. A secondary aim was to examine the implication of FSS comorbidity., Methods: Data were derived from a random sample of the Danish adult population enrolled in the Danish Study of Functional Disorders (DanFunD; n = 9,656). Questionnaire data comprised information used to delimit MCS and four additional types of FSS, as well as data on demographics, socioeconomics and lifestyle. MCS cases (n = 188) was stratified into subgroups; MCS only (n = 109) and MCS with comorbid FSS (n = 73). Information regarding FSS comorbidities were missing for six MCS cases. MCS subgroups and controls without FSS comorbidities (n = 7,791) were compared by means of logistic regression analyses, adjusted for age and sex., Results: MCS was associated with female sex, not being in occupation and low social status, but not with age or education. MCS cases reported normal dietary intake and smoking habits and lower alcohol consumption. Additional associations were found between MCS and low rate of cohabitation, sedentarism, daily physically limitations, and poor quality of sleep. However, subgroup analysis revealed that these findings were primarily associated with MCS with comorbid FSS., Conclusions: MCS was associated with lower socioeconomic status, physically inactivity and poor quality of sleep. Subgroup analysis revealed that several associations was explained by FSS comorbidity, i.e. MCS cases with no comorbid FSS showed normal rate of cohabitation and did not report physical limitations or difficulties sleeping. Overall, our findings emphasise the importance of screening MCS cases for FSS comorbidity both in epidemiological and clinical settings., Competing Interests: The authors have declared that no competing interests exist.

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.)

Importance: Effective therapies for patients with coronavirus disease 2019 (COVID-19) are needed, and clinical trial data have demonstrated that low-dose dexamethasone reduced mortality in hospitalized patients with COVID-19 who required respiratory support., Objective: To estimate the association between administration of corticosteroids compared with usual care or placebo and 28-day all-cause mortality., Design, Setting, and Participants: Prospective meta-analysis that pooled data from 7 randomized clinical trials that evaluated the efficacy of corticosteroids in 1703 critically ill patients with COVID-19. The trials were conducted in 12 countries from February 26, 2020, to June 9, 2020, and the date of final follow-up was July 6, 2020. Pooled data were aggregated from the individual trials, overall, and in predefined subgroups. Risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 statistic. The primary analysis was an inverse variance-weighted fixed-effect meta-analysis of overall mortality, with the association between the intervention and mortality quantified using odds ratios (ORs). Random-effects meta-analyses also were conducted (with the Paule-Mandel estimate of heterogeneity and the Hartung-Knapp adjustment) and an inverse variance-weighted fixed-effect analysis using risk ratios., Exposures: Patients had been randomized to receive systemic dexamethasone, hydrocortisone, or methylprednisolone (678 patients) or to receive usual care or placebo (1025 patients)., Main Outcomes and Measures: The primary outcome measure was all-cause mortality at 28 days after randomization. A secondary outcome was investigator-defined serious adverse events., Results: A total of 1703 patients (median age, 60 years [interquartile range, 52-68 years]; 488 [29%] women) were included in the analysis. Risk of bias was assessed as "low" for 6 of the 7 mortality results and as "some concerns" in 1 trial because of the randomization method. Five trials reported mortality at 28 days, 1 trial at 21 days, and 1 trial at 30 days. There were 222 deaths among the 678 patients randomized to corticosteroids and 425 deaths among the 1025 patients randomized to usual care or placebo (summary OR, 0.66 [95% CI, 0.53-0.82]; P < .001 based on a fixed-effect meta-analysis). There was little inconsistency between the trial results (I2 = 15.6%; P = .31 for heterogeneity) and the summary OR was 0.70 (95% CI, 0.48-1.01; P = .053) based on the random-effects meta-analysis. The fixed-effect summary OR for the association with mortality was 0.64 (95% CI, 0.50-0.82; P < .001) for dexamethasone compared with usual care or placebo (3 trials, 1282 patients, and 527 deaths), the OR was 0.69 (95% CI, 0.43-1.12; P = .13) for hydrocortisone (3 trials, 374 patients, and 94 deaths), and the OR was 0.91 (95% CI, 0.29-2.87; P = .87) for methylprednisolone (1 trial, 47 patients, and 26 deaths). Among the 6 trials that reported serious adverse events, 64 events occurred among 354 patients randomized to corticosteroids and 80 events occurred among 342 patients randomized to usual care or placebo., Conclusions and Relevance: In this prospective meta-analysis of clinical trials of critically ill patients with COVID-19, administration of systemic corticosteroids, compared with usual care or placebo, was associated with lower 28-day all-cause mortality.

Introduction: Severe acute respiratory syndrome coronavirus-2 has caused a pandemic of coronavirus disease (COVID-19) with many patients developing hypoxic respiratory failure. Corticosteroids reduce the time on mechanical ventilation, length of stay in the intensive care unit and potentially also mortality in similar patient populations. However, corticosteroids have undesirable effects, including longer time to viral clearance. Clinical equipoise on the use of corticosteroids for COVID-19 exists., Methods: The COVID STEROID trial is an international, randomised, stratified, blinded clinical trial. We will allocate 1000 adult patients with COVID-19 receiving ≥10 L/min of oxygen or on mechanical ventilation to intravenous hydrocortisone 200 mg daily vs placebo (0.9% saline) for 7 days. The primary outcome is days alive without life support (ie mechanical ventilation, circulatory support, and renal replacement therapy) at day 28. Secondary outcomes are serious adverse reactions at day 14; days alive without life support at day 90; days alive and out of hospital at day 90; all-cause mortality at day 28, day 90, and 1 year; and health-related quality of life at 1 year. We will conduct the statistical analyses according to this protocol, including interim analyses for every 250 patients followed for 28 days. The primary outcome will be compared using the Kryger Jensen and Lange test in the intention to treat population and reported as differences in means and medians with 95% confidence intervals., Discussion: The COVID STEROID trial will provide important evidence to guide the use of corticosteroids in COVID-19 and severe hypoxia., (© 2020 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

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.

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.)

Introduction: Early empirical broad-spectrum antimicrobial therapy is recommended for patients with severe infections, including sepsis. β-lactam/β-lactamase inhibitor combinations or carbapenems are often used to ensure coverage of likely pathogens. Piperacillin/tazobactam is proposed as a carbapenem-sparing agent to reduce the incidence of multidrug-resistant bacteria and superinfections. In the recently published MERINO trial, increased mortality from piperacillin/tazobactam was suggested in patients with bacteraemia with resistant Escherichia coli or Klebsiella species. Whether these findings also apply to empirical piperacillin/tazobactam in patients with other severe infections, including sepsis, is unknown. We aim to assess the benefits and harms of empirical and definitive piperacillin/tazobactam vs carbapenems for patients with severe bacterial infections., Methods and Analysis: This protocol has been prepared according to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols statement, the Cochrane Handbook and the Grading of Recommendations, Assessment, Development, and Evaluation approach. We will include randomised clinical trials assessing piperacillin/tazobactam vs carbapenems in patients with severe bacterial infections of any origin. The primary outcome will be all-cause short-term mortality ≤ 90 days. Secondary outcomes will include all-cause long-term mortality > 90 days, adverse events, quality of life, use of life support, secondary infections, antibiotic resistance, and length of stay. We will conduct meta-analyses, including pre-planned subgroup and sensitivity analyses for all assessed outcomes. The risk of random errors in the meta-analyses will be assessed by trial sequential analysis., (© 2019 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Background: Metronidazole is the preferred empirical anti-anaerobic agent for patients with suspected anaerobic infection. The balance between benefits and harms of empirical metronidazole is unclear. We aimed to assess patient-important benefits and harms of empirical metronidazole vs placebo/no treatment in adult patients with severe bacterial infection of any origin., Methods: We conducted a systematic review with meta-analysis and trial sequential analysis of randomized clinical trials assessing empirical metronidazole vs placebo/no treatment in adult hospitalized patients with severe bacterial infection. The review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement, the Cochrane Handbook and the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. A protocol and statistical analysis plan was published prior to conducting the review., Results: We included a total of nine trials (n = 1753 patients), all of which were adjudicated as having high risk of bias. We found no difference in the primary outcome mortality within 90 days (relative risk 1.56, 95% confidence interval 0.39-6.25). Fewer patients receiving metronidazole had secondary infections (relative risk 0.43, 95% CI: 0.27-0.68). Trial sequential analysis indicated high risk of random errors due to lack of data, and the quality of evidence was very low for all outcomes., Conclusions: There is low quantity and quality of evidence supporting the use of empirical metronidazole in adult patients with severe bacterial infections of any origin, and no firm evidence for benefit or harm., (© 2019 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

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.)

Purpose: Conflict of interest (COI) may compromise, or have the appearance of compromising, a researcher's judgment or integrity in conducting or reporting research. We sought to assess time trends of COI and funding statement reporting in the critical care literature., Methods: PubMed was searched by using Medical Subject Headings and the appropriate corresponding keywords: "INTENSIVE CARE UNIT" or "ICU" as a major topic. Four years in a 15-year time period (2001-2016) were arbitrarily chosen and one study month was randomly selected for each study period. Studies published during the selected months were included in the analysis., Results: Three hundred and seventy-four studies were evaluated, including five reviews (1.3%) and ten randomized clinical trials (RCTs) (2.7%). COI statements were available in 65% of the studies and 8% had declared COI. COI statement rate, declared COI and funding statements increased over time, while the number of authors affiliated with industry and the discordance between the lack of COI statement and affiliation with industry decreased. Declared COI were more frequent in 2011-2016 as compared to 2001-2010 (OR 4.06; 95% CI 1.15-25.79) and in the higher quartile of a journal's impact factor (OR of 16.73; 95% CI 3.28-306.20). Surprisingly, focus of the study, country of the first author and/or endorsement of the study by a trial group were not associated with COI statements., Conclusion: Our study suggests COI reporting to have been unintuitive to most investigators and unreliable before ICMJE statements, and that strong incentives are needed to implement adequate reporting of COI.

Introduction: Anaerobic bacteria are believed to be common pathogens in severe infections. Yet, they are difficult to culture and consequently often unrecognised in clinical infections. Metronidazole is often used empirically for potential anaerobic infections, as the resistance to metronidazole is low. However, disadvantages of metronidazole use exist, including drug interactions, side effects and economical expenses. Currently, the balance between the benefits and harms of empirical metronidazole for severe bacterial infections is unknown. We aim to assess patient-important benefits and harms of empirical metronidazole vs. placebo or no treatment in adult patients with severe bacterial infection of any origin in a systematic review of randomised clinical trials with meta-analysis and trial sequential analysis., Methods and Analysis: This protocol provides details on the planned systematic review, which will be prepared according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement, the Cochrane Handbook, and the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) criteria. The primary outcome is all-cause mortality. Secondary outcomes include adverse events, secondary infections, use of life support, antibiotic resistance and hospital length of stay. We will conduct conventional meta-analyses, including predefined subgroup- and sensitivity analyses. Additionally, we will assess the risk of random errors by trial sequential analysis., Ethics and Dissemination: Ethical approval is not needed, as the outlined review exclusively will include previously published data. We aim to publish in an international, peer-reviewed journal., (© 2018 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

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.)

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: Systematic reviews comparing untargeted antifungal treatment with placebo or no treatment in critically ill patients have provided conflicting results. We aimed to assess patient-important benefits and harms of untargeted antifungal therapy vs. placebo or no treatment in adult patients with complicated intra-abdominal infection., Methods: We conducted a systematic review with meta-analysis and trial sequential analysis of randomised clinical trials assessing untargeted antifungal therapy compared to placebo or no treatment in adults with complicated intra-abdominal infection. We used the Cochrane and GRADE methodologies and exclusively assessed patient-important outcomes. Two independent authors screened trials for eligibility, extracted data and assessed risk of bias. We performed conventional meta-analyses, including sensitivity and subgroup analyses, and trial sequential analysis to assess the risk of random errors and to estimate trial sequential analysis adjusted confidence intervals., Results: We included six trials (1,067 patients) in the review, and four trials reported data on the predefined outcome measures and were included in the meta-analysis. Three of the four trials had high risk of bias. We observed no statistically significant difference in mortality (relative risk 0.58, 95% confidence interval 0.24-1.39) or in any of the other patient-important outcomes between untargeted antifungal treatment and placebo or no treatment (low/very low quality of evidence). Trial sequential analysis demonstrated lack of data and high risk of random errors., Conclusions: The quantity and quality of evidence supporting untargeted antifungal treatment in adult patients with complicated intra-abdominal infection are low to very low with no firm evidence for benefit or harm., (© 2017 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Introduction: Intra-abdominal infections are the second most frequent cause of sepsis. In a recent cohort, fungal specimens were found in 51.9% of all patients with sepsis and peritonitis. Current systematic reviews comparing untargeted antifungal treatment with placebo or no treatment in patients who are critically ill have provided conflicting results, and clinical equipoise exists. Accordingly, we aim to assess patient-important benefits and harms of untargeted antifungal therapy versus placebo or no treatment in adult patients with complicated intra-abdominal infection., Methods and Analysis: We will conduct a systematic review with meta-analysis and trial sequential analysis of randomised clinical trials assessing any untargeted antifungal therapy compared with placebo or no treatment in adult patients with complicated intra-abdominal infections. The primary outcome is all-cause mortality, and secondary outcomes include adverse events, duration of mechanical ventilation and inotropic support, need for renal replacement therapy, emergence of antibiotic resistance and intensive care unit and hospital length-of-stay. Conventional meta-analysis, including sensitivity and subgroup analyses, and assessment of the risk of systematic (bias) and random errors will be conducted. The review will be prepared according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, the Cochrane methodology and the Grading of Recommendations, Assessment, Development and Evaluation., Ethics and Dissemination: Ethical approval is not required as this systematic review only includes previously published data. We aim to publish the review in an international peer-reviewed journal., Trial Registration Number: International Prospective Register of Systematic Reviews registration number: CRD42016053508., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

A systematic review was conducted to identify and summarize the available scientific literature addressing pressure pain threshold (PPT) values over the temporalis, masseter, and frontalis muscles in healthy humans, patients with tension-type headache (TTH), and those with migraine both in males and females. Six relevant medical databases for the literature search were included: PubMed, Web of Science, Cochrane, CINAHL, BioMed Central, and Embase. The search strategy was performed applying 15 keywords (eg, pressure pain threshold, temporalis muscle, tension type headache, pressure algometer) and their combinations. A total of 156 articles were identified, and 40 relevant articles were included. The main outcomes of the systematic review were extracted, and it was demonstrated that the PPT values in general were lower in patients compared with healthy subjects, and this was especially noted for temporalis in both females (migraine: 231.2 ± 38.3 kPa < TTH: 248.4 ± 39.3 kPa < healthy: 282.1 ± 70.8 kPa) and males (migraine: 225.5 ± 61.2 kPa < TTH: 264.2 ± 32.5 kPa < healthy: 314.8 ± 63.3 kPa). The masseter muscle seemed to be more sensitive than the other 2 muscles, in both females (healthy: masseter 194.1 ± 62.7 kPa < frontalis 277.5 ± 51.1 kPa < temporalis 282.1 ± 70.8 kPa) and males (healthy: masseter 248.2 ± 48.4 kPa < temporalis 314.8 ± 63.3 < frontalis 388 kPa). Females had lower PPT values than those of males in temporalis, masseter, and frontalis muscles. This work is the first to systematically review the scientific literature addressing PPT values over craniofacial muscles of healthy subjects, patients with TTH, and those with migraine to provide the PPT value ranges. Based on these findings, a set of guidelines was established to assist future studies including PPT assessments over craniofacial muscles.

Objective: To compare the benefit and harm of restrictive versus liberal transfusion strategies to guide red blood cell transfusions., Design: Systematic review with meta-analyses and trial sequential analyses of randomised clinical trials., Data Sources: Cochrane central register of controlled trials, SilverPlatter Medline (1950 to date), SilverPlatter Embase (1980 to date), and Science Citation Index Expanded (1900 to present). Reference lists of identified trials and other systematic reviews were assessed, and authors and experts in transfusion were contacted to identify additional trials., Trial Selection: Published and unpublished randomised clinical trials that evaluated a restrictive compared with a liberal transfusion strategy in adults or children, irrespective of language, blinding procedure, publication status, or sample size., Data Extraction: Two authors independently screened titles and abstracts of trials identified, and relevant trials were evaluated in full text for eligibility. Two reviewers then independently extracted data on methods, interventions, outcomes, and risk of bias from included trials. random effects models were used to estimate risk ratios and mean differences with 95% confidence intervals., Results: 31 trials totalling 9813 randomised patients were included. The proportion of patients receiving red blood cells (relative risk 0.54, 95% confidence interval 0.47 to 0.63, 8923 patients, 24 trials) and the number of red blood cell units transfused (mean difference -1.43, 95% confidence interval -2.01 to -0.86) were lower with the restrictive compared with liberal transfusion strategies. Restrictive compared with liberal transfusion strategies were not associated with risk of death (0.86, 0.74 to 1.01, 5707 patients, nine lower risk of bias trials), overall morbidity (0.98, 0.85 to 1.12, 4517 patients, six lower risk of bias trials), or fatal or non-fatal myocardial infarction (1.28, 0.66 to 2.49, 4730 patients, seven lower risk of bias trials). Results were not affected by the inclusion of trials with unclear or high risk of bias. Using trial sequential analyses on mortality and myocardial infarction, the required information size was not reached, but a 15% relative risk reduction or increase in overall morbidity with restrictive transfusion strategies could be excluded., Conclusions: Compared with liberal strategies, restrictive transfusion strategies were associated with a reduction in the number of red blood cell units transfused and number of patients being transfused, but mortality, overall morbidity, and myocardial infarction seemed to be unaltered. Restrictive transfusion strategies are safe in most clinical settings. Liberal transfusion strategies have not been shown to convey any benefit to patients., Trial Registration: PROSPERO CRD42013004272., (© Holst et al 2015.)

Background: Continuous monitoring of cerebral blood flow (CBF) may be valuable in critically ill patients with sepsis. In this study, we compared spatially resolved near-infrared spectroscopy (NIRS) to transcranial Doppler ultrasound (TCD)-derived estimates of noradrenaline-associated changes in CBF in such patients., Methods: Mean arterial blood pressure (MAP) was elevated by increasing the noradrenaline infusion rate in eight mechanically ventilated, critically ill patients diagnosed with severe sepsis or septic shock. The associated changes in CBF were assessed by simultaneous ipsilateral NIRS (ScO(2)) and TCD (middle cerebral artery blood flow velocity, MCAv) measurements., Results: A total of fifteen simultaneous NIRS- and TCD-derived assessments of noradrenaline-associated changes in CBF were obtained. MAP was increased from 74 (median; interquartile range (IQR), 71-90) to 100 (median; IQR, 93-115) mmHg (P<0·05), which was associated with an increase in MCAv of 14% (median; IQR, 2-22; P<0·05), whereas no changes were observed in ScO(2) ; 1% (median; IQR, [-4]-3; P = 0·96). A Bland-Altman plot was used to compare the two methods and showed a poor agreement between NIRS- and TCD-derived estimates with a relative bias of 14% and limits of agreement of -18% to 45% change in CBF., Conclusion: Our findings stress that TCD and NIRS cannot be used interchangeably for monitoring changes in cerebral haemodynamics in critically ill patients with sepsis receiving vasopressor treatment with noradrenaline., (© 2014 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.)

Single transgene copy, vector backbone-free transgenic crop plants are highly desired for functional genomics and many biotechnological applications. We demonstrate that binary vectors that use a replication origin derived from the Ri plasmid of Agrobacterium rhizogenes (oriRi) increase the frequency of single copy, backbone-free transgenic plants in Agrobacterium tumefaciens mediated transformation of soybean, canola, and corn, compared to RK2-derived binary vectors (RK2 oriV). In large scale soybean transformation experiments, the frequency of single copy, backbone-free transgenic plants was nearly doubled in two versions of the oriRi vectors compared to the RK2 oriV control vector. In canola transformation experiments, the oriRi vector produced more single copy, backbone-free transgenic plants than did the RK2 oriV vector. In corn transformation experiments, the frequency of single copy backbone-free transgenic plants was also significantly increased when using the oriRi vector, although the transformation frequency dropped. These results, derived from transformation experiments using three crops, indicate the advantage of oriRi vectors over RK2 oriV binary vectors for the production of single copy, backbone-free transgenic plants using Agrobacterium-mediated transformation.

Conventional Agrobacterium-mediated plant transformation often produces a significant frequency of transgenic events containing vector backbone sequence, which is generally undesirable for biotechnology applications. We tested methods to reduce the frequency of transgenic plants containing vector backbone by incorporating genes into the backbone that inhibit the development of transgenic plants. Four backbone frequency reduction genes, bacterial levansucrase (sacB), maize cytokinin oxidase (CKX), Phaseolus GA 2-oxidase (GA 2-ox), and bacterial phytoene synthase (crtB), each expressed by the enhanced CaMV 35S promoter, were placed individually in a binary vector backbone near the left border (LB) of binary vectors. In transformed soybean plants, the lowest frequency of backbone presence was observed when the constitutively expressed CKX gene was used, followed by crtB. Higher backbone frequencies were found among the plants transformed with the GA 2-oxidase and sacB vectors. In some events, transfer of short backbone fragments appeared to be caused by LB readthrough and termination within the backbone reduction gene. To determine the effect of the backbone genes on transformation frequency, the crtB and CKX vectors were then compared to a control vector in soybean transformation experiments. The results revealed that there was no significant transformation frequency difference between the crtB and control vectors, but the CKX vector showed a significant transformation frequency decrease. Molecular analysis revealed that the frequency of transgenic plants containing one or two copies of the transgene and free of backbone was significantly increased by both the CKX and crtB backbone reduction vectors, indicating that there may be a correlation between transgene copy number and backbone frequency.

A gene (FbL2A) that is preferentially expressed in cotton (Gossypium barbadense L. cv Sea Island) fiber was isolated and characterized. Genomic and cDNA analyses suggest multiple FbL2A genes in cotton. The gene is developmentally regulated and is activated during late primary and early secondary wall synthesis stages. FbL2A encodes a polypeptide of 43.4 kD and a predicted isoelectric point of 5.97. The nucleotide-derived protein is highly hydrophilic except for a hydrophobic N terminus and has a compositional bias for glutamic acid (26.3 mol%) and lysine (18.9 mol%). Sixty-two percent of the putative protein is composed of repeat motifs. A 55-amino-acid peptide region is repeated four times in a concatenate fashion within the protein. The function of the protein in the fiber cells is not known. A 2.3-kb DNA fragment 5' from the FbL2A gene is shown to direct expression of heterologous proteins in transgenic cotton in a fiber-specific and developmentally regulated fashion. The FbL2A promoter was used to express in transgenic cotton genes encoding acetoacetyl-coenzyme A reductase and polyhydroxyalkanoic acid synthase, which are involved in the synthesis of the thermoplastic polymer polyhydroxybutyric acid. Transgenic plants containing both enzymes produced polyhydroxybutyric acid in fiber. Thus, the FbL2A promoter is useful in genetic engineering schemes to modify cotton fiber.

A gene (G9) expressed during late microsporogenesis in cotton (Gossypium hirsutum L.) was isolated. Sequence analysis of the cDNA (1.3 kb) as well as the gene (2.6 kb) revealed an open reading frame of 1233 bases encoding a protein of 43.9 kDa. The coding region of the gene is interrupted by three introns. Northern analysis of the RNA from developing anthers showed that the transcripts appear 12 days before anthesis and that the maximal concentration of RNA occurs in pollen on the day of anthesis. This pattern of gene expression suggests functions in post-anthesis events. Sequence comparisons with other known plant genes indicated that G9 is homologous to polygalacturonases. The G9 promoter conferred tissue and temporal specificity of beta-glucuronidase (GUS) expression in transgenic tobacco plants. Thus, the G9 promoter can be used to drive gene expression in homologous as well as heterologous plants in a tissue-specific manner.