Development and Psychopathology, 17(3), 865-891, Oppositional defiant disorder (ODD) and conduct disorder (CD) are common behavioural disorders in childhood and adolescence and are associated with brain abnormalities. This systematic review and meta-analysis investigates structural (sMRI) and functional MRI (fMRI) findings in individuals with ODD/CD with and without attention-deficit hyperactivity disorder (ADHD). Online databases were searched for controlled studies, resulting in 12 sMRI and 17 fMRI studies. In line with current models on ODD/CD, studies were classified in hot and cool executive functioning (EF). Both the meta-analytic and narrative reviews showed evidence of smaller brain structures and lower brain activity in individuals with ODD/CD in mainly hot EF-related areas: bilateral amygdala, bilateral insula, right striatum, left medial/superior frontal gyrus, and left precuneus. Evidence was present in both structural and functional studies, and irrespective of the presence of ADHD comorbidity. There is strong evidence that abnormalities in the amygdala are specific for ODD/CD as compared to ADHD, and correlational studies further support the association between abnormalities in the amygdala and ODD/CD symptoms. Besides the left precuneus, there was no evidence for abnormalities in typical cool EF related structures, such as the cerebellum and dorsolateral prefrontal cortex. Resulting areas are associated with emotion-processing, error-monitoring, problem-solving and self-control; areas associated with neurocognitive and behavioural deficits implicated in ODD/CD. Our findings confirm the involvement of hot, and to a smaller extent cool, EF associated brain areas in ODD/CD, and support an integrated model for ODD/CD (e.g. Blair,  In recent years, magnetic resonance imaging (MRI) studies have provided insight into the underlying brain mechanisms of disruptive behaviour disorders, including oppositional defiant disorder (ODD) and conduct disorder (CD). This review will integrate and discuss studies using structural (sMRI) and functional MRI (fMRI) in these disorders. ODD and CD are developmental disorders that are among the most commonly diagnosed mental health conditions in childhood . EF is the sum of neurocognitive processes that maintain an appropriate problem-solving set to attain a goal , one of the most commonly diagnosed disruptive behaviour disorders in children. The percentage of individuals diagnosed with ODD/CD that additionally qualify for a comorbid ADHD diagnosis ranges up to 35 %, and up to 50 % of children with disruptive behaviours show symptoms of both ADHD and ODD/CD  meta-analysis was performed. ALE is a technique that is used to identify significant anatomical locations for which effects are consistent, and that is robust to publication bias  the study reported on functional or structural magnetic resonance imaging results, comparing (a) individuals with ODD/CD with or without comorbid ADHD to control subjects, and if included, to individuals with ADHD-only, or (b) individuals with ODD/CD without ADHD to ODD/CD individuals with ADHD. The control group of each study was carefully checked on reported psychiatric disorders, and when a study reported on the presence of any psychiatric disorder in participants of the control group, that study was excluded from the current study. This resulted in the exclusion of two studies. (2) Diagnosis of the participants had to be based on DSM-III, DSM-IV or DSM-5 criteria. (3) The study had to be published in a peer-reviewed English language journal. No limits were set on the ages of participants. All relevant studies published up till June 2015 were incorporated.The databases PubMed, EMBASE, PsycInfo and Web of Science were searched, using the search terms ODD, CD, disruptive behavioural disorder, disruptive behaviour, externalising behavioural disorder, externalising behaviour, MRI, neuroimaging, and equivalent MeSH terms. Furthermore, reference lists of selected studies and reviews were checked for additional relevant studies. A total of 576 studies were initially retrieved and screened, after which a total of 67 studies remained that fulfilled inclusion criteria based on screening of the title and abstract. These 67 studies were further assessed for eligibility using the full text of the study, resulting in 29 studies that met inclusion criteria and were incorporated in the present review; see Fig. In this review, we distinguished the following samples: (1) ODD/CD-only, including only individuals with ODD/CD without comorbid ADHD, (2) ODD/CD-mixed, including both individuals with ODD/CD-only and individuals with ODD/CD+ADHD, and (3) ODD/CD+ADHD, including only individuals classifying for both ODD/CD and ADHD. We included a total of 10 ODD/CD-only studies , 14 ODD/CD-mixed studies , and 5 ODD/CD+ADHD studies . By differentiating between these three samples, it was possible to discern whether an abnormality was related to ODD/CD and not confounded by comorbid ADHD, which would be suggested when an abnormality is found in an ODD/CD-only sample. Alternatively, when an abnormality is found in an ODD/CD-mixed or ODD/CD+ADHD sample, it may be possible that the abnormality is also related to comorbid ADHD. Therefore, results are discussed separately for ODD/CD-only samples versus controls and for ODD/CD-mixed and ODD/CD+ADHD samples versus controls. When included in a study, results from additional comparisons with an ADHD-only sample were provided.The section on structural neuroimaging findings reports all brain areas, not distinguishing between hot and cool EF. The section on functional neuroimaging findings is divided in two parts: the first part is focused on hot EF and the second part is focused on cool EF. Classification of studies as hot or cool was done in line with the literature. Two authors independently inspected the task characteristics and the reported contrasts for each study and judged these as assessing either hot or cool EF. In case of disagreement, the third author was consulted, resulting in full agreement on all studies. One study . The algorithm used by GingerALE applies a random-effects approach to identify anatomical locations for which effects are observed most consistently, and which renders it robust for the possible effects of publication bias  meta-analysis was performed using the Brainmap GingerALE software package  correction for multiple comparisons, and a minimum cluster size of 100 mm3 .All coordinates originally reported in MNI space were normalised to Talairach space using Lancaster’s Transform; coordinates which were already in Talairach space were converted back to MNI coordinates and subsequently normalised to Talairach space using Lancaster’s Transform, to account for divergent analyses procedures and minimise differences in coordinates between studies  approach, thus a hypothesis driven pre-selection of specific brain areas, and studies using a whole brain analyses (WBA) approach, thus studying the entire brain, were included in this review. To test the possibility that studies using an ROI approach might bias meta-analytic results due to less stringent statistical criteria, the resulting map of all studies (using both WBA and ROI approach) was compared to the resulting map from studies with a WBA approach. When differences between the maps were present, results from the map including only the WBA studies were reported. The ALE map was overlaid onto a Talairach anatomical template for visualisation purposes, and the areas reported in our Results section refer to the locations of the extrema.Results of the reviewed studies are discussed in two main sections with the first section summarising the structural neuroimaging findings and the second section summarising the functional neuroimaging findings. Both sections start with a general overview of all included studies, after which the results from the meta-analysis are reported, followed by the results from the narrative review. The narrative parts contain a summary of the main findings for ODD/CD-only groups first since those are not biased by comorbid ADHD, followed by the main findings in ODD/CD-mixed and ODD/CD+ADHD groups, and ends with the correlational findings and the specificity of findings regarding ODD/CD.After presentation of the meta-analytic and narrative results of the structural and functional studies, structural and functional findings are integrated in order to provide an overview of all relevant literature and resulting conclusions in terms of hot and cool EF related brain areas. Since an ALE meta-analysis cannot include studies that reported on non-significant group differences, but rather identifies anatomical locations for which effects are observed most consistently, findings from the ALE meta-analysis are combined with the results of the narrative review to provide a comprehensive and balanced overview of available evidence.Table All studies investigated children/adolescents. For information regarding group and study characteristics of the included studies, see Table a in Table Eight structural studies, all using a WBA approach, reported coordinates and were included in the meta-analysis (studies marked with 3) was located in the left amygdala, with three foci inside this cluster. A second cluster (456 mm3) was found in the left insula, containing three foci. A third cluster (352 mm3) was located in the left medial/superior frontal gyrus, containing two foci. The fourth cluster (216 mm3) was located in the right insula, containing two foci.The ALE analysis revealed four significant clusters of altered grey matter volumes that differed between patients and controls . For total grey matter volume, one of three studies reported a reduction in the ODD/CD-only group. In terms of regional grey matter volumes, abnormalities in the insula , amygdala , the cingulate cortex , the inferior frontal gyrus (left and right), and the left dorsomedial prefrontal cortex were repetitively reported (two out of three studies).ODD/CD-mixed and ODD/CD+ADHD (9 studies). Two of the four studies investigating total grey matter in ODD/CD-mixed and ODD/CD+ADHD samples reported smaller volumes in the diagnostic groups, compared to controls. In accordance with results from the studies in the ODD/CD-only group, three of the nine studies in ODD/CD-mixed and ODD/CD+ADHD groups provided support for abnormalities in the left amygdala. Additionally, abnormal volumes were reported in the ODD/CD-mixed and ODD/CD+ADHD groups for structures that were not found for ODD/CD-only groups, which might indicate that these abnormalities reflect the presence of comorbid ADHD rather than ODD/CD. These structures with smaller volumes were the temporal lobe  and the cerebellum .Correlational findings and specificity. A total of seven studies investigated relations between grey matter abnormalities and ODD/CD symptoms. Three out of seven studies reported associations for the amygdala, insula and temporal cortex. The three studies that reported associations between the amygdala and ODD/CD symptoms, showed either a positive association (thus a larger volume related to more ODD/CD symptoms) for the amygdala in an ODD/CD-only sample, or negative associations  for the bilateral or left amygdala in ODD/CD-mixed samples. For the insula, all three studies reported negative associations, one between the right insula and ODD/CD symptoms in an ODD/CD-only sample and two between the insula and ODD/CD symptoms in ODD/CD-mixed samples. For the three studies that found associations between the superior temporal cortex and ODD/CD symptoms, one study reported a positive association for the superior temporal cortex in an ODD/CD-only sample, while the other two studies reported a negative association for the right superior temporal cortex in an ODD/CD-only sample and for the left superior temporal cortex in an ODD/CD+ADHD sample.In terms of specificity of abnormalities for ODD/CD as compared to ADHD, one study reported grey matter reductions in the amygdala and frontal gyrus to be specific for ODD/CD-only, since these were not present in the ADHD-only group. In addition, another study looked at disorder specificity by covarying for ODD/CD in an ODD/CD-mixed group and reported that the grey matter reductions in the amygdala turned non-significant, suggesting that these grey matter reductions were specific for ODD/CD.Combining the results from the meta-analysis and the narrative review, structural neuroimaging studies most consistently implicated abnormalities of the left amygdala, insula and left frontal gyrus in ODD/CD.Tables www.brainmap.org).We reviewed the studies using the framework of hot and cool EF in ODD/CD, which resulted in 13 studies in the hot EF section and 5 studies in the cool EF section, of which 1 study appeared in both sections  it was not possible to perform an ALE meta-analysis on studies comparing ODD/CD-only groups and controls, thus the ALE meta-analysis was performed on all ODD/CD samples, therewith including both individuals with and without comorbid ADHD.There was a difference between the resulting maps of the ALE analysis with and without the ROI-only studies. Therefore, we reported the results from the map that included only WBA approach-based studies given the unbiased results. Total sample sizes for all included studies ranged between 30 and 75 individuals, adding up to a total of 423 subjects, of which 256 were patients and 167 were controls (age range 9–21 years). Three studies assessed a full male sample and six studies assessed a sample largely consisting of males (ranging from 56 to 79 %). The studies reported on different tasks associated with hot EF functions: three studies assessed processing of contingencies, two studies assessed passive viewing of emotional pictures, two studies assessed passive avoidance learning, one study assessed active viewing and rating of painful situations, and one study assessed implicit emotional processing.3) was located in the right globus pallidus, with two foci inside this cluster. The second (328 mm3) and third (256 mm3) clusters were located in the right and left amygdala, and contained three and two foci, respectively. The fourth cluster (208 mm3) was present in the left caudate, while the fifth cluster (200 mm3) was located in the left fusiform gyrus, both contained two foci.The included studies provided a total of 68 foci of areas showing altered activity in individuals with ODD/CD with and without comorbid ADHD. The ALE analysis revealed five significant clusters representing areas with altered activity in patients with ODD/CD-only or ODD/CD+ADHD that were most consistently reported across the studies . Two of the three studies reported abnormalities for ODD/CD-only compared to controls, of which one study reported lower activity in the right striatum, left amygdala, right insula, anterior cingulate cortex, and left medial and superior frontal gyrus, and the other study reported lower activity in the right lateral and medial orbitofrontal cortex.ODD/CD-mixed and ODD/CD+ADHD (10 studies). Studies assessing ODD/CD-mixed and ODD/CD+ADHD groups replicated findings of abnormal function of the striatum , including the caudate and putamen, and the amygdala . Additionally, functional abnormalities were reported in ODD/CD-mixed groups for the parietal cortex , which was not found for ODD/CD-only groups. This might indicate that the abnormal activity in the parietal cortex reflects the presence of comorbid ADHD rather than ODD/CD.Correlational findings and specificity. Five studies investigated relations between activity of specific structures and ODD/CD related symptoms. All five studies reported negative associations  between amygdala activity and ODD/CD related symptoms, one for an ODD/CD-only sample (left) and four for ODD/CD-mixed samples . Furthermore, two of the five studies reported negative associations between left and right anterior cingulate cortex activity and ODD/CD related symptoms, of which one assessed an ODD/CD-only sample and the other assessed an ODD/CD-mixed sample, respectively.In terms of specificity, four studies investigated disorder specificity of the abnormalities compared to ADHD-only groups. Of these four studies, one study reported the lower activity in the orbitofrontal cortex in an ODD/CD-only group to be disorder specific, while the other study reported lower activity in the amygdala in an ODD/CD-mixed group to be disorder specific.Combining the results from the meta-analysis and the narrative review, hot EF functional neuroimaging studies most consistently implicated abnormalities of the amygdala and insula. Even though the meta-analysis implicated the left fusiform gyrus in ODD/CD, the narrative reviews did not show support for abnormalities in this area in ODD/CD.Tables ODD/CD-only versus controls (5 studies). Four of the five studies reported less activation in the precuneus of ODD/CD-only groups, with two studies reporting the left precuneus, one the bilateral precuneus, and one the right precuneus. Furthermore, two of the five studies reported lower activity of the right insula, right anterior cingulate and right posterior cingulate cortex in ODD/CD-only.Correlational findings and specificity. Two studies investigated relations between activity of specific structures and ODD/CD related symptoms, of which one reported a negative association between dorsolateral prefrontal cortex and ODD/CD related symptoms and the other reported no associations. In terms of specificity, four studies investigated disorder specificity of the abnormalities for ODD/CD as compared to ADHD-only. One of these four studies reported abnormal activity in the insula, anterior cingulate cortex, cerebellum and hippocampus to be specific for ODD/CD-only, while another study reported specificity for lower activity in the left parietal-temporal cluster and the right parietal lobe.The number of available studies into cool EF did not allow a meta-analysis to be conducted. Based on the narrative review, abnormalities in the precuneus were most consistently implicated in ODD/CD.In order to determine which hot and cool EF related brain areas are implicated in ODD/CD, findings from both sMRI and fMRI meta-analyses as well as from the narrative reviews are integrated. Since the meta-analyses provide the strongest evidence for the convergence of findings, the main findings of the meta-analyses are discussed first. Second, findings from ODD/CD-only studies (10) are discussed, since these are not biased by comorbid ADHD, followed by findings from the ODD/CD-mixed and ODD/CD+ADHD studies (19). Finally, all these findings are integrated, resulting in an overall conclusion for neuroanatomical abnormalities related to ODD/CD.Table Meta-analytic results implicated both structural and functional abnormalities for one of the hot EF related structures: the amygdala . Other hot EF related areas were only implicated in the structural  or functional meta-analyses .Integration of the structural and functional findings implicated abnormalities in several hot EF related structures for ODD/CD, since these structures were reported in more than a quarter of the studies: the amygdala, right striatum, insula, and left frontal gyrus  there was no further supporting evidence from studies investigating specificity by comparing an ODD/CD-only sample with an ADHD-only sample, nor did correlational approaches provide evidence for associations between abnormalities in these areas and ODD/CD symptoms.Finally, driven by results from the cool EF section using only ODD/CD-only samples, some evidence was found for abnormalities in a cool EF related structure in ODD/CD: the left precuneus. However, studies that compared ODD/CD-only samples with ADHD-only samples did not provide evidence for these abnormalities to be specific for ODD/CD, nor did studies that assessed associations provide evidence for precuneus volume to be related to ODD/CD symptoms. Taken together, our results show strong evidence for involvement of the amygdala and the striatum, some evidence for involvement of the insula and the frontal gyrus, and weak evidence for involvement of the precuneus in ODD/CD.We reviewed 29 structural and functional neuroimaging studies into hot and cool EF in ODD/CD (with and without ADHD) and performed two meta-analyses on subsets of these studies. We hypothesized that, compared to controls, individuals with ODD/CD (with and without ADHD) would show both structural and functional brain abnormalities in areas related to hot and cool EF. In addition, we investigated the specificity of these abnormalities by discussing results separately for studies including an ODD/CD-only group and results from studies including an ODD/CD-mixed or ODD/CD+ADHD group, using a narrative approach. Furthermore, individuals with ODD/CD were compared to individuals with ADHD. The results confirmed impairments in structure and function in most of the hypothesised hot EF related structures , and to a lesser extent results confirmed such impairments in cool EF related structures . Impairments were mainly present as reductions in volume or reductions in activity of the structures. Some of these abnormalities were reported to be specific to ODD/CD when compared to ADHD-only, or showed associations with ODD/CD symptom levels.In terms of hot EF related neuroanatomical correlates, several structures were consistently reported to be associated with ODD/CD (with and without ADHD) compared to controls  or psychopathy  whole brain analyses, rendering the results eligible to be included in a meta-analysis. In addition, because of the limited amount of studies into cool EF and the overlap in subjects in these studies, we were not able to perform a meta-analysis on these data; further research is needed in order to be able to draw firm conclusions on the possible involvement of cool EF abnormalities in ODD/CD, particularly since evidence from behavioural studies into cool EF impairments in ODD/CD is inconclusive.Secondly, in terms of sample characteristics, an important future direction is to study the role of callous-unemotional (CU) traits or psychopathic traits in individuals with ODD/CD. It has been reported that children with CD and high levels of CU traits show greater abnormalities in reward sensitivity, lower responsivity to treatment by parenting strategies, and are more resistant to psychosocial intervention than those with CD and few CU traits (Byrd et al. p < .005 (Marsh et al. p < .001 (Passamonti et al. p < .05. This implies that the results of both the meta-analyses and narrative reviews are in general reliable, but should be interpreted with some caution, since especially in WBA-based studies, these statistical methods are of importance (Chumbley and Friston Thirdly, at a statistical level, future studies should be more consistent in statistical corrections and thresholding. A significant proportion of the studies did not correct for multiple comparisons or Type 1 errors, nor applied cluster thresholding. Of these, most studies using a WBA approach did report Family Wise Error or False Discovery Rate corrected results, except for three structural and four functional studies (Bussing et al. Fourthly, future studies should look at other imaging techniques, such as DTI, to improve our knowledge on structural and functional brain abnormalities associated with ODD/CD. Up to date, eight studies have used DTI to study abnormalities in pathways in ODD/CD. Although there is relatively consistent evidence for involvement of the uncinate fasciculus (Wang et al. Finally, to advance our understanding of ODD and CD and the specificity of neural abnormalities future studies should assess well-defined and sufficiently sized samples. For example, the ideal study should at least compare ODD/CD-only, ADHD-only, comorbid ODD/CD+ADHD, and typically developing control groups with sufficient sample size, to investigate the possible confounding effect of comorbid ADHD. Furthermore, since there appears to be a difference in underlying mechanisms for childhood-onset and adolescent-limited ODD/CD Moffitt , future We reviewed 29 studies on structural and functional neuroimaging in samples with ODD/CD with and without comorbid ADHD, and performed meta-analyses on a subset of eight structural studies and nine hot EF functional studies. Despite some limitations and heterogeneity amongst studies, results indicated that individuals with ODD/CD primarily show abnormalities in the bilateral amygdala, bilateral insula, right striatum and left medial/superior frontal gyrus as well as the left precuneus. Evidence of involvement of these areas was present in both structural and functional studies, and irrespective of whether the study included individuals with ODD/CD-only or with ODD/CD with comorbid ADHD. Our results show strong evidence of specificity for abnormalities in the amygdala for ODD/CD as compared to ADHD, and correlational studies further support the association between abnormalities in the amygdala and ODD/CD symptoms. Besides the left precuneus that was revealed by the narrative review of cool EF, there was no evidence for abnormalities in typical cool EF related structures, such as the cerebellum and dorsolateral prefrontal cortex. Our findings confirm the involvement of hot, and to a smaller extent cool EF associated brain areas in ODD/CD, and support an integrated model of both hot and cool deficits for ODD/CD (e.g. Blair


Men also showed higher rates of central obesity, hypertension, and dyslipidemia than women . Compared with women, men were more likely to drink alcohol and smoke cigarettes but less likely to be under diet control. The sex-specific differences in prediabetes, CVD, and CVD risk factors between men and women were diminished or even reversed in the population aged 50 years and older. No sex-specific differences were found in the prevalences of a family history of diabetes, coronary heart disease, and hypertension (P > 0.05) in middle-aged population. Specific strategies to reduce modifiable risk factors for the prevention and control of diabetes and CVD may be warranted in this population.The sex difference in the prevalence rates of diabetes and cardiovascular diseases (CVDs) among the middle-aged population in China remain largely unknown. Therefore, we analyzed differences in the prevalence of diabetes, self-reported CVDs, and some CVD risk factors among men and women in the middle-aged population (30–49 years) and in individuals aged 50 years and older using data from the China National Diabetes and Metabolic Disorders Study of 2007–2008. Middle-aged men appeared to have significantly a higher prevalence of diabetes and self-reported CVDs than middle-aged women (8.07%  Sex-specific differences in the prevalence of diabetes are unclear except for a few specific types of diabetes. The China National Diabetes and Metabolic Disorders Study , a recenCardiovascular diseases (CVDs) represent a major cause of death in patients with type 2 diabetes. More than 80% of CVD- and diabetes-related deaths occur in low- and middle-income countries. China is still among the low- and middle-income countries and is home to the largest absolute number of diabetes patients. The prevention and control of diabetes and related CVDs have posed a serious challenge to the country. Data on the prevalence of diabetes in men and women have been made available through previous epidemiological studies. However, no study has elucidated the factors underlying the discrepancy in the prevalence between men and women in the middle-aged population. In the present study, using data from the 2007–2008 China National Diabetes and Metabolic Disorders Study, we aimed to analyze the differences in prevalence rates of diabetes, CVDs, and CVD risk factors between middle-aged men and women, in order to support the development of tailored measures for diabetes and CVD prevention and control in this working-age population.A population-based cross-sectional survey entitled “the China National Diabetes and Metabolic Disorders Study” was carried out from June 2007 to May 2008. The details of population sampling have been described previously. ThroughThe Clinical Research Ethics Committee of China-Japan Friendship Hospital reviewed and approved the study program (No. 2007–026). Each participant signed an informed consent form before data collection.Each participant was interviewed by trained and qualified physicians. Data regarding demographic characteristics, lifestyle risk factors, and personal and family medical histories were collected using a standard questionnaire. The intBlood pressure, body weight, height, and waist circumference were measured using standard methods described previously. Waist cPreviously diagnosed diabetes was defined by self-reporting of a prior history of diabetes, which was confirmed by a doctor according to a previous fasting plasma glucose level ≥7.0 mmol/L and⁄or information on glucose-lowering treatment regardless of the fasting plasma glucose level. Individuals without a history of diabetes were classified as having diabetes if their fasting plasma glucose was ≥7.0 mmol/L and⁄or the 2-h plasma glucose was ≥11.1mmol/L. Prediabetes was defined by a fasting plasma glucose of ≥6.1 mmol⁄L and <7.0 mmol⁄L and/or a 2-h glucose ≥7.8 and <11.1 mmol/L.Statistical analyses were conducted using the SUDAAN software . All calculations were weighted to represent the total Chinese adult population aged 20 years or older. Standard prevalence rates were calculated based on the overall population according to age, and the age-standardized prevalence was determined using the population distribution of China reported by the National Bureau of Statistics of China in 2006.The data are presented as means with 95% confidence intervals (CIs). The differences between group means and between-group frequencies were tested using a ‘PAIRWISE’ procedure in the SUDAAN software. The test for trends employed a polynominal contrast procedure. Variables without normal distribution were transformed logarithmically before analysis. A multiple logistic regression analysis was employed to examine the association between diabetes prevalence and possible risk factors, and adjusted odd ratios were obtained. All P-values were two-tailed, and a P-value of <0.05 was considered statistically significant.The differences in lifestyles and socioeconomic status between middle-aged men and women are presented in In the multivariable regression model, male sex, older age, family history of diabetes, higher BMI, elevated systolic blood pressure, elevated serum triglyceride level, and non-tertiary educational level were significantly associated with an increased risk of diabetes in the middle-aged population .We further stratified the middle-aged group into two age-based subgroups of 30–39 years (3971 men and 6286 women) and 40–49 years (4349 men and 7076 women) and compared the prevalence rates of diabetes, CVDs, and CVD risk factors between these groups . The preIn this nationwide population-based cross-sectional study of the Chinese population, we found that the prevalence of diabetes, self-reported CVDs, and CVD risk factors were remarkably higher in middle-aged men than women. However, among those aged 50 years and older, this sex-specific difference weakened to a non-significant level or even reversed. Being male and having a family history of diabetes, high BMI, elevated serum triglycerides, and higher systolic blood pressure were associated with diabetes in middle-aged individuals (30–49 years old).Previous studies have shown these sex-specific differences before. In the AusDiab study, which was conducted in 1999–2000, men were found to have a higher prevalence of diabetes 8.0%) than women 6.8%), and the sex-specific difference was most notable in those aged 45–64 years.8%, and . In cont.0% than A national epidemiological survey on diabetes was conducted in China in 1994. It covered a random sample of 224,251 participants aged 25–64 years from 19 provinces and regions in China[Our study also found that more middle-aged men suffered from central obesity, hypertriglyceridemia, high blood pressure, or hypercholesterolemia than women of the same age. This finding is consistent with the results of previous population-based studies in Taiwan Chinese and Swedish populations . A plausIt is notable that men aged 30–49 years appeared to have higher prevalence of diabetes and self-reported CVDs than women in this age range. Further analysis did not show any difference between men and women regarding the prevalence of a family history of diabetes, CVD, or hypertension. This suggests that the sex-specific differences in the prevalence rates of diabetes and self-reported CVDs may not be related to genetic factors. On the other hand, modifiable CVD risk factors such as smoking, lack of physical activity, obesity,Given the sex-specific differences in social psychological characteristics between men and women, diabetes prevention strategies tailored specifically for men are needed. Davies and colleagues reported that male college students are more inclined to maintain an independent social image and pay less attention to the impact of their current behavior on their future health status. Men areThe present study provides clues regarding the sex difference in the prevalence rates of diabetes and cardiovascular risk factors among the middle-aged Chinese population. Given the rapid modernization of Asia and many cultural similarities between China and other Asian countries, findings in mainland China may also be applicable across Asia and perhaps also for Asian immigrants in Western countries. The present study also has a number of limitations. First, the oversampling for women  may lead to a sex and health status selection bias. Particularly, healthy middle-aged men may have been less likely to respond to the survey. Unfortunately, no data were available for those who refused to participate in the study. To look for a potential sex bias among those who participated in the study, we analyzed the rates of undiagnosed diabetes and hypertension. A comparison analysis showed no sex-related difference in the rate of undiagnosed diabetes in middle-aged participants, but a higher rate of undiagnosed hypertension appeared in men of both age groups in the present study sample. Second, the data for the history of CVDs, family history of disease, income, exercise, and diet status were self-reported. A recalling bias may still appear though the self-reported CVDs were collected by a strict definition. Third, cases of CVD were identified only according to hospitalization for myocardial infarction, balloon angioplasty, cardiac stenting, and coronary artery bypass surgery, but not for angina and arrhythmias. Thus, the prevalence of CVD may be underestimated. Lastly, in this cross-sectional study, we could not investigate the causal relationship between lifestyle factors, risk factors for CVDs, and the development of diabetes in middle-aged men. Prospective data for this population will enable us to examine the interactions between lifestyle, CVD risk factors, and the incidences of diabetes and to test whether baseline disparities in healthy behavior and CVD risk factors between men and women predict future differences in CVD-related mortality.In conclusion, our study provides evidence that the prevalence rates of diabetes, CVDs, and CVD risk factors are higher in men than women among the middle-aged Chinese population. In order to control and reduce modifiable risk factors for diabetes and CVDs, special prevention strategies and implementation plans tailored for men are urgently needed.S1 FigPrevalence of diabetes, CVD, CVD risk factors and their 95% confidence intervals (bar) in a Chinese population-based sample aged 30–40 years 3971 men (dot) and 6286 women (grey), and aged 41–50 years 4349 men and 7076 women. ‡ P < 0.001 for comparison between men and women.(TIF)Click here for additional data file.S2 FigPrevalence of family history of diabetes, myocardial infarction, stroke, CVD, hypertension and their 95% confidence intervals (bar) in a Chinese population-based sample aged 30–40 years 3971 men (dot) and 6286 women (grey) and aged 41–50 years 4349 men and 7076 women. All P >0.05 for comparison between men and women.(TIF)Click here for additional data file.


New saponin adjuvant formulations with better toxicity profiles are needed. This study aims to evaluate the safety and tolerability of QS-21 and the improved saponin adjuvants  from vaccine trials.QS-21 shows ™, which included a placebo control group and reported safety outcomes. Pooled risk ratios (RRs) and their 95% confidence intervals (CIs) were calculated using a random-effects model. Jadad scale was used to assess the study quality.A systematic literature search was conducted from MEDLINE, EMBASE, Cochrane library and Clinicaltrials.gov. We selected for the meta-analysis randomized controlled trials (RCTs) of vaccines adjuvanted with QS-21, ISCOM, ISCOMATRIX or Matrix-M™ adjuvanted vaccines matching the inclusion criteria. Meta-analysis identified an increased risk for diarrhea in patients receiving QS21-adjuvanted vaccines . No increase in the incidence of the reported systemic AEs was observed for ISCOMATRIX-adjuvanted vaccines. QS-21- and ISCOMATRIX-adjuvanted vaccines caused a significantly higher incidence of injection site pain . ISCOMATRIX-adjuvanted vaccines also increased the incidence of injection site swelling .Nine RCTs were eligible for the meta-analysis: six trials on QS-21-adjuvanted vaccines and three trials on ISCOMATRIX-adjuvanted, with 907 patients in total. There were no studies on ISCOM or Matrix-MOur findings suggest that vaccines adjuvanted with either QS-21 or ISCOMATRIX posed no specific safety concern. Furthermore, our results indicate that the use of ISCOMATRIX enables a better systemic tolerability profile when compared to the use of QS-21. However, no better local tolerance was observed for ISCOMATRIX-adjuvanted vaccines in immunized non-healthy subjects. This meta-analysis is limited by the relatively small number of individuals recruited in the included trials, especially in the control groups. Adjuvants are substances that do not confer immunity on their own . HoweverQuillaja saponaria (Soapbark) [A group of immunoenhancers of great interest is saponins, whose strong adjuvant activity was first described in 1930s . Saponinoapbark) ,8. QS-21oapbark) . QS-21 hoapbark) ,12. It soapbark) . A numbein vitro and its use in vivo has been observed with side effects [However, the natural saponin QS-21 has inherent disadvantages such as chemical instability, limited supply, difficult and low-yielding purification, and dose-limiting toxicity, which prevent it from wider use . Importa effects . Saponin effects .et al. in 1984 [In order to reduce saponin-related toxicity, the formulation of immunostimulating complex (ISCOM) was developed by Morein  in 1984 . ISCOMs  in 1984 ,18. The  in 1984 . Neverth™ were developed. These matrix formulations contain the same components and have the same structure as the ISCOM but without the incorporated antigen [™ 703 and, more recently, ISCOPREP [™ is a combination of two individually formed matrix particles from different purified fractions of Quillaia saponins, namely Matrix-A™ and Matrix-C™ [Due to these technical problems and the fact that antigen incorporation is not necessary to achieve a potent immune stimulation, matrix formulations such as ISCOMATRIX and Matrix-M antigen ,21. ISCOISCOPREP . Matrix-atrix-C™ . The foratrix-C™ .™ adjuvanted vaccines have been tested in animal models and more recently in human clinical trials [™ have been shown to induce strong antibody and T-cell responses and to be well tolerated in both pre-clinical and clinical studies [™ is currently being investigated in vaccines for influenza, HSV type 2 and malaria [Both ISCOMATRIX and Matrix-Ml trials ,22,23. V studies ,25. ISCO studies , influen studies  and canc studies –30. Matr malaria . Current malaria .™) rather than combinations of adjuvants. Therefore, studies that used adjuvant systems, such as AS01, AS02 and AS04 developed by GlaxoSmithKline, were not included in the analysis.The benefits from adjuvant incorporation into any vaccine formulation have to be balanced with the risk of adverse events (AEs) . The purWe conducted a meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement . The proA systematic search of literature was performed using the electronic databases of MEDLINE (Ovid), EMBASE and Cochrane Central register of Controlled Trials (CENTRAL). The clinical trial register  was searched for unpublished trials. To define the studies of interest in these databases, the following keywords were used: “QS-21”, “ISCOMs”, “ISCOMATRIX”, “Matrix-M”, “randomized controlled trial” and “clinical trial”. Details of the search strategy are provided in the supporting information . Referen™); (2) which included a control group ; and (3) reporting information regarding safety and/or tolerability. The inclusion of only RCT studies was considered necessary to avoid the possible selection and reporting biases that may arise from observational studies.References were evaluated using the pre-defined inclusion criteria: (1) randomized controlled trials (RCTs) on vaccines with saponin adjuvants  performed primary evaluation of the retrieved articles for relevance based on the title and abstract. Disagreements were discussed with a third investigator (HL) until consensus was achieved. Potentially eligible publications were reviewed as full text. The acronym PICOS  group, outcomes and study design) was used to assess if the references fully complied with the inclusion criteria. In order to lower the between-study heterogeneity and due to the fact that there were not enough eligible RCTs in healthy volunteers to be included for the meta-analysis, we limited our study selection to RCTs that recruited adult (18 years and older) non-healthy subjects. References for which full-text could not be acquired electronically or were reported not in English language were excluded.Two independent reviewers (EB and ED) identified potentially relevant articles and collected the following data: the first author’s last name, the year of publication, clinicaltrials.gov identifier (if applicable), study design, total number of participants, age range, gender, disease background, study arms with number of vaccinated participants in each arm, doses of adjuvants used for the preparation of vaccines, immunization route and number of injections.The following safety outcomes were identified from the included studies and considered for the meta-analysis: serious, systemic and local AEs. The commonly reported systemic AEs across the selected studies included headache, fatigue, insomnia, pyrexia, myalgia, nausea, diarrhea, dizziness, anxiety and back pain. The local AEs included injection site pain, redness, erythema and swelling.Following Cochrane guidelines for systematic reviews of interventions , two ind2 and I2 statistics were used to assess the heterogeneity among the included studies. Values of I2 can be interpreted as low (25–50%), moderate (50–75%), and high (75% and greater) levels of heterogeneity [p value of <0.05. In addition to the meta-analysis, descriptive reports on serious adverse events (SAEs) and treatment discontinuations were given.To evaluate the safety and tolerability of saponin adjuvanted vaccines, the dichotomous data on the number of subjects experiencing a systemic or local AE in the saponin-adjuvanted study vaccine group and placebo group were extracted from each study with subsequent determination of the risk ratios (RR) and their 95% confidence intervals (CI). Of note, within each study we pooled all subjects that received adjuvanted vaccine, regardless the concentration of the adjuvant and antigen in vaccine formulation. We combined data statistically using random effects (Mantel-Haenszel method) model due the differences in among the studies in e.g. vaccine formulation, adjuvant dose and the disease background of subjects. Chiogeneity . Meta-anOur analysis relies solely on the existing data.Due to the limited number of studies available for meta-analysis, assessment of publication bias was not applicable. The review is subject to publication bias.A total of 813 references were identified from electronic databases during the search performed during 03–04.03.2016 . Additio™ adjuvanted vaccines matched the inclusion criteria. Briefly, the trials on ISCOM  and Matrix-M™  adjuThe six trials on QS-21-adjuvanted vaccines enrolled a total of 755 individuals, of which 510 in the treatment group (i.e. subjects received antigen with adjuvant) and 245 in the control groups . A total of 152 non-healthy subjects were recruited for the three RCTs on ISCOMATRIX-adjuvanted vaccines and included 98 and 54 in the treatment and control groups, respectively. The selected trials for both adjuvants recruited adult non-healthy subjects. Studies that involved healthy volunteers could not be included for the meta-analysis due to the limited number of identified studies that fulfilled the pre-defined inclusion criteria. The age of the enrolled subjects in the nine studies varied from 19 to 85 years, among which 44.9% were males.et al. [et al. [et al. [et al. [et al. [All studies reported the number of subjects experiencing a specific AE. Studies of Anderson et al.  and Fraz [et al.  used a s [et al. , an addi [et al.  and Wald [et al.  did not  [et al. , the saf [et al.  and NCT0 [et al.  AEs were [et al.  and NCT0 [et al.  recordedet al. [et al. [The methodological quality of the included RCTs was satisfying , except et al.  Accordin [et al.  has a scet al. [et al [Wald et al.  reported. [et al . The SAEAll Pfizer studies –46 reporThe most frequent systemic AEs observed across the six studies include headache, fatigue, insomnia, pyrexia, nausea, diarrhea, dizziness, anxiety and back pain. The results of the meta-analysis demonstrated that out of the nine systemic AEs selected for the analysis, only cases of diarrhea were significantly more frequent in non-healthy subjects receiving QS-21-adjuvanted vaccines than in those receiving placebo  . Furtheret al. [Regarding the local AEs, we were not able to retrieve dichotomous data from RCT reported by Gilman et al.  However,et al.  was not The meta-analysis showed that QS-21-adjuvanted vaccines caused significantly more cases of injection site pain  than placebo . No statet al. [et al [Together with SAEs, systemic and local AEs, we were interested in the cases of discontinuations due to the AEs. Wald et al.  reported. [et al . However. [et al ,44 resul. [et al . In gene. [et al  resultedet al. [et al. [Studies of Anderson et al.  and Fraz [et al.  reported [et al.  detectedThe most commonly reported systemic AEs across the selected studies include headache, fatigue, pyrexia, nausea, myalgia and insomnia. In general, the observed systemic AEs were mild to moderate in severity and lasted for 2–3 days. The proportion of subjects reporting systemic AEs was greater in the ISCOMATRIX-adjuvanted vaccine group than in the placebo group. The meta-analysis comparing the incidence of systemic AEs between the ISCOMATRIX adjuvanted vaccine group and placebo group showed no statistically significant differences in any selected for the analysis systemic AE . Furtheret al. [et al. [The reported local AEs were usually associated with injection site pain, redness/erythema and swelling. Individual studies reported also other local AEs such as warmth, bruising, injection site hematoma and injection site pruritus. Trials of Anderson et al.  and Fraz [et al.  specifieet al. [et al. [Anderson et al.  reported [et al.  reported [et al.  reportedIn order to study the general effect of saponin adjuvantation on the safety and tolerability of tested vaccines, we performed meta-analysis on the reported AEs from all nine eligible studies.In the case of frequently reported systemic AEs, we were able to combine the dichotomous data on the number of non-healthy subjects experiencing headache, fatigue, insomnia, pyrexia, myalgia, nausea, diarrhea, dizziness, anxiety and back pain after immunization with QS-21- or ISCOMATRIX-adjuvanted vaccines . The metWhen combining the data on the frequently reported local AEs from all selected trials, the performed meta-analysis confirmed that immunization of non-healthy subjects with saponin-adjuvanted vaccines increased the risk for injection site pain  and injection site swelling , when compared to placebo . Further™) including a placebo control group and reporting information regarding safety and/or tolerability. The effect of saponin-adjuvantation was evaluated by the RR with 95% CI for systemic and local AEs. Reports on SAEs and the number of subjects who discontinued treatment due to the AEs were discussed descriptively. We identified three studies reported on ISCOMATRIX-adjuvanted vaccines and six studies on vaccines adjuvanted with QS-21. All nine studies included adult (≥ 18 years) non-healthy subjects. Overall, we included in the meta-analysis 98 subjects receiving ISCOMATRIX-adjuvanted vaccines, 510 subjects receiving QS-21-adjuvanted vaccines and 138 receiving placebo. Eight of the nine trials have a Jadad score of 3 or 4 indicating an adequate trial quality.The objective of this meta-analysis was to assess the safety and tolerability of vaccines containing QS-21 and new saponin adjuvant formulations such as ISCOM and ISCOMATRIX. References were included if they reported on a RCT of vaccines with saponin adjuvants . Only one out of three trials on ISCOMATRIX-adjuvanted vaccines  and fourThe results of the meta-analysis should be interpreted with caution due to the several limitations. To have direct information about the safety and tolerability of adjuvants, the adjuvanted test vaccines should be compared to an active control group . Although there were five eligible RCTs –45,56,57No major safety concern was identified for both ISCOMATRIX-adjuvanted vaccines and vaccines containing QS-21 based on the reported SAEs. Most AEs reported by non-healthy subjects in the nine selected trials were generally mild to moderate, self-limiting and of short duration. The performed meta-analysis showed that the use of QS-21-adjuvanted vaccines resulted in a statistically significant increase in the incidence of diarrhea when compared to placebo, while no systemic AEs were found to be associated with the use of ISCOMATRIX-adjuvanted vaccines. Both QS-21- and ISCOMATRIX-adjuvanted vaccines were associated with a higher incidence of injection site pain. The observed elevated risk for local pain was lower for the vaccines containing ISCOMATRIX. On the other hand, an increased incidence of injection site swelling was only observed from the use of ISCOMATRIX-adjuvanted vaccines. Furthermore, the pooled analysis on ISCOMATRIX- and QS-21-adjuvanted vaccines further confirmed that subjects receiving a saponin-adjuvanted vaccine experienced significantly more injection site pain and swelling when compared to placebo. In addition, for both adjuvants the number of subjects who discontinued treatment was higher in the group of subjects receiving the adjuvanted vaccine than in the placebo group. Our results indicate that the use of ISCOMATRIX results in a better systemic tolerability profile when compared to the use of QS-21. However, no better local tolerance was observed for ISCOMATRIX-adjuvanted vaccines in immunized non-healthy subjects. The relatively small number of published studies, however, limited our ability to calculate robust estimates for other AEs and to draw strong conclusions on the effects of QS-21- and ISCOMATRIX-adjuvanted vaccines. Therefore, further studies are needed, particularly with properly defined and reported safety outcomes and including an active control group, to better evaluate the risks of saponin adjuvanted vaccines.S1 Appendix(PDF)Click here for additional data file.S2 Appendix(PDF)Click here for additional data file.


Background: Subjective cognitive impairments are frequent, but poorly understood in patients with chronic fatigue. We hypothesized that maladaptive metacognitive beliefs at baseline were associated with baseline subjective cognitive impairments, that they predict subjective cognitive impairments at treatment termination, and that a reduction in maladaptive metacognitive beliefs was associated with less subjective cognitive impairments at treatment termination, independent of changes in fatigue, pain, insomnia, depression, and anxiety.Methods: In this non-controlled study, patients (n = 137) on sick leave due to chronic fatigue received a 3.5-week inpatient RTW rehabilitation program. Of these patients 69 (50.4%) was referred with a ICPC-2 diagnosis of chronic fatigue. Patients completed questionnaires about metacognitive beliefs, somatic complaints, psychological complaints, and cognitive impairments before and after treatment. To test the hypotheses we performed paired t-tests of change, as well as seven hierarchical linear regressions.Results: Results showed that baseline maladaptive metacognitive beliefs were significantly associated with subjective cognitive impairments at baseline, controlling for symptoms. Score on baseline metacognitive beliefs did not predict impairments post-treatment. Testing specific maladaptive beliefs, pre-treatment scores on cognitive confidence were associated with subjective cognitive impairments both pre and post-treatment, controlling for symptoms. Post-treatment metacognitive beliefs and post-treatment cognitive confidence were associated with post-treatment subjective cognitive impairments, controlling for pre-treatment impairments and pre-treatment metacognitive beliefs, as well as pre and post-scores on symptom measures.Conclusion: This study reports associations between maladaptive metacognitive beliefs and subjective cognitive impairments in patients with chronic fatigue. Targeting metacognitive beliefs could prove an effective therapeutic intervention for subjective cognitive impairments in these patients. Chronic fatigue syndrome (CFS) is a prevalent condition characterized by persistent mental and somatic fatigue  model  occupational rehabilitation program at Hysnes Rehabilitation Center, St. Olav's University Hospital, Trondheim, Norway. In Norway a work week includes working Monday through Friday, or 5 days of work of 7, 5 h each. A work week is then 37, 5 h in total. Since the program lasted 3 work weeks and 2 work days, it consisted of a total of 17, 7, 5-h workdays during which there was an active intervention from the institution. The intervention was shaped this way to emulate a normal work week making the transition to work life easier for the patients. The choice of an inpatient setting for this program was due to geographical challenges specific to Norway. However, the treatment delivered did not exceed that of a day-based outpatient program with regard to hours and available personnel . For details about the intervention see Fimland et al. .Prior to the enrolment in this program, the patients had been referred from their general practitioner and examined by an outpatient multidisciplinary team consisting of a physician, a psychologist, and a physiotherapist. This team evaluated whether the referred patients met the requirements for participating in the RTW-program, which included, but were not limited to the inclusion and exclusion criteria for the current study. Before beginning the rehabilitation program, all patients were asked to complete different questionnaires through an internet-administrated self-report survey. At the end of the study, which coincided with the end of the rehabilitation program, the patients again answered several questionnaires.The inclusion criteria for the study were age (18 to 59 years) and having been on sick leave for at least 8 weeks due to fatigue. Further, participants should have self-defined goals of increasing labor participation, to be adequately assessed and treated beforehand for any specific illnesses, and be able to attend a rehabilitation program from 8:30 to 3:00 p.m. all weekdays. The exclusion criteria were severe mental illness , substance abuse and addiction or pregnancy. Moreover, patients who could not communicate in Norwegian or who needed 24-h personal assistance were not eligible.To be eligible for this study, participants had to report a score of five or more on the fatigue questionnaire, a cut-off validated through previous studies of Norwegian adults .Details on the rehabilitation program are published elsewhere  . Cronbach's alpha for HADS-A varied from 0.68 to 0.93 (mean 0.83) and for HADS-D from 0.67 to 0.90   scale, rated difficulties falling asleep, night-time awakenings, early morning awakenings, impairment of daytime functioning due to sleep problems, notice ability of impairments, distress or worry caused by sleep difficulties, and dissatisfaction with sleep. The items were summed; giving a scale of 0–28, where ≥15 was used as a moderate cut-off indicating sleep problems. This cut-off has been validated in previous studies and the internal consistency of the ISI was reported to be 0.74 . This scale has been validated as a self-report measure of chronic pain in Norwegian populations. As this is a one-item measurement, alpha values are not applicable. The item has been shown to have an intra-class correlation coefficient of 0.66  and means  with standard deviations. Paired To test for associations between maladaptive metacognitive beliefs (MCQ-30) and subjective cognitive impairments at baseline, we performed two hierarchical linear regression models: First, using subjective cognitive impairments pre-treatment as a dependent variable we performed a hierarchical regression model with two steps. In step one, we entered participants' sex and age, and in step two we entered pre-treatment MCQ-30 sum total score. Then, we performed a hierarchical linear regression with three steps. In step one, we entered participants' sex and age, and in step two we entered pre-treatment scores on the five symptom measures. In step three we entered pre-treatment MCQ-30 sum total score.Next, we performed a third hierarchical regression model testing the associations of the five subscales of MCQ-30  with subjective cognitive impairments. In step one, we entered participants' sex and age, and in step two we entered pre-treatment scores on symptom measures. In step three we entered pre-treatment scores on cognitive confidence need to control thoughts, positive beliefs, danger/uncontrollability, and cognitive consciousness.To test whether maladaptive metacognitive beliefs (MCQ-30) at treatment start were associated with subjective cognitive impairments at treatment termination, we performed a hierarchical linear regression using subjective cognitive impairments post-treatment as a dependent variable. In this regression model we entered sex and age in step one, in step two we entered pre-treatment values for subjective cognitive impairments. In step three we entered pre-treatment sum total scores for MCQ-30.To test whether a reduction in maladaptive metacognitive beliefs (MCQ-30) were associated with change in subjective cognitive impairments, we added fourth step in the hierarchical linear regression using subjective cognitive impairments at treatment termination as the dependent variable. We entered sex and age in step one, in step two we entered pre-treatment scores for subjective cognitive impairments, in step three we entered pre-treatment sum total score for MCQ-30. In step four, we entered the MCQ-30 sum total score at treatment end.To test whether maladaptive metacognitive beliefs (MCQ-30) was associated with subjective cognitive impairments (EMQ) controlling for levels of fatigue, pain, insomnia, depression, and anxiety, we performed a hierarchical linear regression using subjective cognitive impairments at treatment termination as the dependent variable. We entered sex and age in step one, in step two we entered pre-scores for EMQ, and in step three we entered pre-treatment sum total scores on MCQ-30. In step four we entered pre-treatment scores on the five symptom measures. In step five we entered post-treatment sum total scores for MCQ-30 and in step six we entered post-treatment scores on the five symptom measures.To test whether the subscales of the maladaptive metacognitive beliefs (MCQ-30) questionnaire were associated with subjective cognitive impairments (EMQ) controlling for levels of fatigue, pain, insomnia, depression, and anxiety, we performed a hierarchical linear regression using subjective cognitive impairments at treatment termination as the dependent variable. We entered sex and age in step one, in step two we entered pre-scores for EMQ, and in step three we entered pre-treatment scores on the subscales of MCQ-30. In step four we entered pre-treatment scores on the five symptom measures. In step five we entered post-treatment scores on the subscales of MCQ-30 and in step six we entered post-treatment scores on the five symptom measures.All analyses were performed using the Statistical Package for the Social Sciences . In all regressions we estimated correlations and colinearity in order to ensure the validity of the models.t-tests, and represented the study population. All participants reported fatigue above the chosen cut off. They were predominantly female (80.3%) with a mean age of 43.6 (SD 9.4) years, and with education at a high school level or above (87.6%). For an overview of participant characteristics, see Table t-tests of change for subjective cognitive impairments and maladaptive metacognitive beliefs are presented in Table One hundred and eighty-one participants were included in the current study. Of these 181 participants, 137 had no missing data, were available for multivariable analysis and p < 0.0001; t = 4.5; B = 0.34; 95% Confidence Interval of B (CI) = 0.19, 0.49), controlling for sex, age and pre-scores on symptom scales. Fatigue score pre-treatment  and depression score pre-treatment  were also significantly associated with EMQ sum score at baseline.The sum score on maladaptive metacognitive beliefs (MCQ-30) at baseline was significantly associated with the subjective cognitive impairments (EMQ) sum score at baseline  was significantly associated with the EMQ sum score, controlling for pre-treatment symptom scores, as was the pre-score on the chosen fatigue scale . The subscales of positive beliefs, need to control thoughts, danger and cognitive consciousness were not. Zero order correlations between the self-report measures ranged from (−0.2 to 0.6), with cognitive confidence being the highest and need for thought control the lowest. Both collinearity tolerance (1.0–0.5) and variance inflation factor values (1.0–2.4) were acceptable in the regression model.Investigating the subscales of MCQ-30, the subscale of cognitive confidence .A hierarchical regression analysis showed that the pre-treatment sum total score on MCQ-30 was not associated with EMQ sum score post-treatment, when controlling for pre-scores on the EMQ .As pre-treatment cognitive confidence was the only subscale associated with pre-treatment score on EMQ, we performed an additional analysis looking specifically at this subscale. Pre-treatment scores on cognitive confidence were significantly associated with post-treatment scores on EMQ, controlling for scores on all symptom measures both pre and post-treatment . Analytic details of the regression are presented in Table Results from a hierarchical regression showed that a reduction on MCQ-30 was significantly associated with a reduced post-treatment score on EMQ, controlling for pre-treatment MCQ-30 scores, fatigue scores (pre-post), pain (pre-post), insomnia severity (pre-post), anxiety and depression (pre-post) .As pre-treatment cognitive confidence was associated with pre-treatment and post-treatment score on EMQ, we again performed an additional analysis looking specifically at this subscale. Post-treatment scores on cognitive confidence were significantly associated with post-treatment scores on EMQ, controlling for scores on all symptom measures both pre and post-treatment (This is the first study to report associations between maladaptive metacognitive beliefs and subjective cognitive impairments in chronically fatigued patients. Maladaptive metacognitive beliefs were associated with subjective cognitive complaints at baseline. Investigating the subscales of MCQ-30, only the scale asking beliefs about cognitive confidence had pre-treatment scores associated with pre-treatment subjective cognitive impairments. When looking at whether maladaptive metacognitive beliefs at baseline predicted subjective impairments at treatment end, we found that the sum of MCQ-30 did not predict subjective ratings. However, baseline scores on the subscale of cognitive confidence did predict subjective impairments at treatment end. Moreover, when testing if a reduction in sum total maladaptive metacognitive beliefs predicted less subjective cognitive impairments at treatment termination, we found a significant association that remained when controlling for baseline subjective cognitive complaints, and pre-post scores on fatigue, pain, insomnia, depression and anxiety. This was also the case for a reduction in post-treatment values on the cognitive confidence subscale, indicating that this subscale is particularly relevant in subjective cognitive impairments.Our finding that baseline metacognitive beliefs concerning cognitive confidence were associated with baseline scores on subjective cognitive complaints is new. According to metacognitive theory, metacognitive beliefs about the lack of cognitive confidence will stop adaptive cognitive coping strategies when patients are feeling mental fatigue. Indeed, maladaptive metacognitive beliefs about cognitive confidence have been previously been associated with symptom severity in CFS patients (Fernie et al., The current results may have interesting clinical implications. According to recent theorizing in metacognition, cognitive processes are split into two interrelated levels: the meta-level and the object level Wells, . The metobjective cognitive abilities will vary over a span of 10 weeks (Fuentes et al., Our finding that cognitive confidence at baseline predicted subjective cognitive complaints at treatment end is also interesting in this regard. Previous data have shown that CFS patient's The main finding in this study was that a reduction in dysfunctional metacognitive beliefs during treatment was associated with less subjective cognitive impairments at treatment termination. This relationship was not affected by symptoms of fatigue, pain, insomnia, anxiety or depression. Previous studies have attributed subjective cognitive impairments in CFS to the level of depressive symptoms in patients (Wearden and Appleby, However, the reported relationship between depressive symptoms, anxiety, and subjective cognitive complaints does add a second argument for investigating metacognitions further. Metacognitive therapy has previously shown promising results with depressed patients lacking success from traditional cognitive behavioral therapy (CBT; Wells et al., Of particular relevance to the current results is a recent text comparing subjective vs. objective cognitive impairment in chronic fatigue syndrome (Cockshell and Mathias, Considering this, it is tempting to further speculate on how subjective cognitive complaints could be a prime target for intervention. Perseverative thinking in the form of subjective cognitive complaints may lead to physiological changes or prolonged activation, and that in turn might change the patients experience of fatigue and/or disrupt recovery (Brosschot et al., It is important to note that this study used an ACT intervention, not metacognitive therapy. While our results imply that targeting metacognitive beliefs through metacognitive therapy is perhaps not necessary to change them, it does not answer whether using a therapy specifically focused on changing metacognitive beliefs could increase this change. The reported change in this study is minor, and it could very well be that a targeted metacognitive therapy would have made more impact on the patients'.The current study has some limitations, the foremost being the lack of a control group. Another limitation is that outcome variables are based on self-report and not clinical or objective evaluations. Self-reported fatigue on the Chalder Fatigue Questionnaire was used as a cut-off for fatigue, opposed to a clinical examination, semi-structured interviews or fitness tests. Thus, the participants' results may not be generalizable to the group of patients who meet the full diagnostic criteria for CFS. However, the mean pre-treatment scores on Chalder Fatigue Scale are in line with other studies of patients with diagnosed CFS (White et al., This non-controlled study reports significant associations between dysfunctional metacognitive beliefs and subjective cognitive impairments in chronically fatigued patients. These associations highlight the potential importance of targeting maladaptive metacognitive beliefs in chronic fatigue. Finally, our results give cause to investigate metacognitive therapy as a potential supplemental or novel psychological treatment for CFS.We all have participated in the conception of this report and have assisted in revising the manuscript for important intellectual content. We have all provided final approval of the enclosed report. More specifically: JA assisted with conceptual framework and writing as well as organized the data collection. PB was the project leader and essential in data collection as well as writing the methods and introduction. NL co-developed the experimental design, study aims and contributed to the discussion. TS supervised the entire production of the manuscript, co-developed the design, helped write the study aims and contributed to the introduction, results and discussion.This study was done using government funding through the Central Norway Regional Health Authority. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In mental health, the term dual-diagnosis is used for the co-occurrence of Substance Use Disorder (SUD) with another mental disorder. These co-occurring disorders can have a shared cause, and can cause/intensify each other’s expression. Forming a threat to health and society, dual-diagnosis is associated with relapses in addiction-related behavior and a destructive lifestyle. This is due to a persistent failure to control impulses and the maintaining of inadequate self-regulatory behavior in daily life. Thus, several aspects of executive functioning like inhibitory, shifting and updating processes seem impaired in dual-diagnosis. Executive (dys-)function is currently even seen as a shared underlying key component of most mental disorders. However, the number of studies on diverse aspects of executive functioning in dual-diagnosis is limited. In the present review, a systematic overview of various aspects of executive functioning in dual-diagnosis is presented, striving for a prototypical profile of patients with dual-diagnosis. Looking at empirical results, inhibitory and shifting processes appear to be impaired for SUD combined with schizophrenia, bipolar disorder or cluster B personality disorders. Studies involving updating process tasks for dual-diagnosis were limited. More research that zooms in to the full diversity of these executive functions is needed in order to strengthen these findings. Detailed insight in the profile of strengths and weaknesses that underlies one’s behavior and is related to diagnostic classifications, can lead to tailor-made assessment and indications for treatment, pointing out which aspects need attention and/or training in one’s self-regulative abilities. In dual-diagnosis, a Substance Use Disorder (SUD) co-occurs with another psychiatric condition such as psychotic disorder, mood disorder, anxiety disorder or personality disorder . The EpiIn most SUDs and other mental disorders self-regulatory behavior to manage daily life situations (involving work and relationships) falls short. Coping strategies are impaired, resulting in affective breakdowns . These fShifting concerns the switch of attention between tasks/operations and/or mental sets. Translated into daily life, it involves mental flexibility to repeatedly let go of irrelevant and/or inappropriate behaviors  and switch to more adequate/relevant behaviors (like sporting or switch of television-channel). Secondly, Updating involves the process of actively manipulating and monitoring relevant information in working memory, in order to keep track of information that is old and needs actualization  shifting is needed to get up earlier than before and to repeatedly let go of attention biases triggering late night out fantasies, (ii) inhibition is needed to prevent this late night ‘going out’ with friends by stopping yourself from drinking/using and going home, (iii) updating is involved in checking an alternative work-route, thereby avoiding and replacing the old, coffee-shop route that would trigger craving. The interplay between EF aspects can influence self-regulation in daily life by reducing problem-behavior and raising more goal-directed behavior. In addition, EF can facilitate one’s controlled coping with negative feelings and externalizing problem behaviors like substance-abuse/aggressive outbursts. On the contrary part, executive dysfunction can cause/aggravate negative feelings/behavioral outbursts by the perceived lack of control . If severe executive dysfunctioning is expected, the use of both global and specific EF tasks is recommended by Inhibition can be measured by Go–NoGo, Stop Signal, Approach Avoidance Tasks, the Stroop, Anti-saccade, Event Related Potential components like P300, self-report/rating measures such as the Frontal Systems Behavioral Scale, BIS-BAS scales  and by the MMPI-2 Impulse-Control index1  inhibitory impairment of impulsive responses, (iii) sticking attention to disorder-linked cues like substances that interfere with adequate shifting, (iv) impaired cognitive control (inhibition) and distorted anticipational planning, (v) reduced  stress regulation, and (vi) cognitive inflexibility  a failure to maintain goals when confronted with interfering desires that are difficult to xibility . These minhibition of undesired responses, or a flexible shift from one behavioral strategy to another. Recommendations for treatment can be formed when one oversees the differentiated profile of strengths and weaknesses, particularly in EF.Executive functioning impairments were described in several mental conditions like schizophrenia, bipolar-, anxiety-, personality-, developmental disorder, and SUD. For the separate disorders, a high number of studies have been undertaken and multiple reviews are present . Search terms were Executive Functioning, dual-diagnosis, Substance Use Disorder, alcohol use disorder, inhibition, updating, shifting, comorbidity, schizophrenia, bipolar disorder, personality disorder, anxiety disorder, mood disorder, developmental disorder, and addiction. The independent variable was the dual-diagnosis; the dependent variable was the level of functioning on EF tasks.The inclusion criteria for studies were as follows: (i) A Method section that contains information concerning: (a) gender, age, test-materials and pre-assessment abstinence period of patients, and (b) diagnostic procedures that were used to determine if a dual-diagnosis was present or not; (ii) Comparisons by use of a healthy control group and/or a group without dual-diagnosis; and (iii) An abstinence period involving less risk for interfering influence of (sub-) acute substance effects, in order to only measure residual effects. The substance of study should not be traceable anymore. Studies with an abstinence period of at least one week were included. For cannabis, a period of four weeks was adhered to (for substance detection times see Table 1).Findings are presented for 11 studies that involve the dual-diagnoses of SUD-Schizophrenia (six), SUD-Bipolar disorder (two), SUD-Personality disorders (two) and SUD-Conduct disorder (one). For SUD-Anxiety and SUD-Developmental disorder no studies were found. Results are organized by disorder, tasks and EF aspect. Significance levels and effect sizes are described if present  and inhibition tasks than patients with Sch- (shifting abilities for Sch+ patients (schizophrenia-cannabis) as compared to healthy controls.ng tasks . Contradbilities . Furtherith Sch- . Lastly,shifting ability as compared to healthy controls, measured by the Wisconsin Card Sorting Test. That is, dual-diagnosis patients completed fewer categories than controls  dysfunctions than controls and patients with bipolar disorder without SUD.Patients with SUD-bipolar disorder showed poorer functioning on mental controls . Marshalinhibitory control. Patients with SUD-cluster C personality disorders, that is, more inhibited and obsessive personality types, showed more problems in working memory and updating ability. Patients with SUD as compared to the dual-diagnosis group had a better inhibitory control. However, compared to healthy controls, the SUD group also showed impairments in shifting and working memory. Patients with dual-diagnosis SUD-Personality disorders as a group consistently functioned less on shifting, updating and inhibitory abilities as compared to healthy controls  and cluster C  personality disorders were studied at diverse EF. Patients with SUD-cluster B personality disorders, that is, more impulsive personality types, showed impairments in nearly all EF aspects as compared to controls and most specifically in controls .inhibition and planning ability as compared to healthy controls  turbulence and sensory sensitivity, since both substances and psychotic/bipolar/other symptoms have an interfering influence on the balance of several brain processes. Elaborating on this, maintaining a realistic view of daily life situations with flexible participation and properly timed inhibition when needed, is likely to be impaired. As compared to Sch-, patients with Sch+ show less inhibitory control. One possible explanation for this difference may be that patients with a SUD-combination show relatively more impulsivity, partly because the use of substances may negatively influence their dopaminergic inhibitory brain processes. Thereby, they seem to be less capable of inhibiting desires than patients without SUD. Furthermore, with a view to negative symptomatology, the schizophrenia patient-group is possibly more avoidant/inhibited than approaching in behavior manner. In terms of impulsivity, this hypothetical explanation also applies to the finding that patients with cluster B (impulsive type) personality disorder and SUD perform inhibitory control tasks less adequately than patients with only SUD. Whereas impulsive behavior has shown to negatively interfere with inhibitory control, it can also be influenced vice versa: common impulsive behavior in dual-diagnoses such as SUD-Bipolar disorder, SUD-cluster B Personality disorder and SUD-Conduct disorder (shifting abilities than Sch- patients may be linked to a higher tendency for impulsiveness and search for novelty in patients with SUD-combinations. This means that a flexible switch from familiar pathways to other routes may be easier for persons that are more impulsive and less rigid in behavior than for more avoidant persons that may seek and/or persevere in familiar styles of behavior.Findings Shifting and disorder  may be mSome conflicting findings reduce the certainty with which conclusions can be stated. These contradictions may be partly caused by factors that influenced several studies, and that may have restricted the validity and reliability of the observed empirical findings in those studies. For instance, the study of Findings lead to the following future research recommendations. Firstly, studying dual-diagnosis has value, when methods are described in a valid manner. Secondly, sufficiently long abstinence periods before assessment, preferably approximately 6 weeks, should be attained to prevent findings from being influenced by acute or sub-acute substance use effects . ThirdlyJD was first and corresponding author. She performed the literature search for this mini-review and wrote several concepts of the manuscript. She consulted CV on a regular basis as second author to revise concept manuscript versions and sharpen the described theoretical and empirical issues. CV revised concept versions and JE as last author was available for consultation during the project and revised the final concept version of the manuscript. In the end, the final manuscript and cover letter to be submitted was carefully revised by all three authors en JD eventually submitted the manuscript as first author.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.