FLT3 stop mutation increases FLT3 ligand level and risk of autoimmune thyroid disease.

Autoimmune thyroid disease is the most common autoimmune disease and is highly heritable1. Here, by using a genome-wide association study of 30,234 cases and 725,172 controls from Iceland and the UK Biobank, we find 99 sequence variants at 93 loci, of which 84 variants are previously unreported2-7. A low-frequency (1.36%) intronic variant in FLT3 (rs76428106-C) has the largest effect on risk of autoimmune thyroid disease (odds ratio (OR) = 1.46, P = 2.37 × 10-24). rs76428106-C is also associated with systemic lupus erythematosus (OR = 1.90, P = 6.46 × 10-4), rheumatoid factor and/or anti-CCP-positive rheumatoid arthritis (OR = 1.41, P = 4.31 × 10-4) and coeliac disease (OR = 1.62, P = 1.20 × 10-4). FLT3 encodes fms-related tyrosine kinase 3, a receptor that regulates haematopoietic progenitor and dendritic cells. RNA sequencing revealed that rs76428106-C generates a cryptic splice site, which introduces a stop codon in 30% of transcripts that are predicted to encode a truncated protein, which lacks its tyrosine kinase domains. Each copy of rs76428106-C doubles the plasma levels of the FTL3 ligand. Activating somatic mutations in FLT3 are associated with acute myeloid leukaemia8 with a poor prognosis and rs76428106-C also predisposes individuals to acute myeloid leukaemia (OR = 1.90, P = 5.40 × 10-3). Thus, a predicted loss-of-function germline mutation in FLT3 causes a reduction in full-length FLT3, with a compensatory increase in the levels of its ligand and an increased disease risk, similar to that of a gain-of-function mutation.

DeSUMOylation of chromatin-bound proteins limits the rapid transcriptional reprogramming induced by daunorubicin in acute myeloid leukemias.

Genotoxicants have been used for decades as front-line therapies against cancer on the basis of their DNA-damaging actions. However, some of their non-DNA-damaging effects are also instrumental for killing dividing cells. We report here that the anthracycline Daunorubicin (DNR), one of the main drugs used to treat Acute Myeloid Leukemia (AML), induces rapid (3 h) and broad transcriptional changes in AML cells. The regulated genes are particularly enriched in genes controlling cell proliferation and death, as well as inflammation and immunity. These transcriptional changes are preceded by DNR-dependent deSUMOylation of chromatin proteins, in particular at active promoters and enhancers. Surprisingly, inhibition of SUMOylation with ML-792 (SUMO E1 inhibitor), dampens DNR-induced transcriptional reprogramming. Quantitative proteomics shows that the proteins deSUMOylated in response to DNR are mostly transcription factors, transcriptional co-regulators and chromatin organizers. Among them, the CCCTC-binding factor CTCF is highly enriched at SUMO-binding sites found in cis-regulatory regions. This is notably the case at the promoter of the DNR-induced NFKB2 gene. DNR leads to a reconfiguration of chromatin loops engaging CTCF- and SUMO-bound NFKB2 promoter with a distal cis-regulatory region and inhibition of SUMOylation with ML-792 prevents these changes.

Association Between Autoimmune Diseases and Monoclonal Gammopathy of Undetermined Significance : An Analysis From a Population-Based Screening Study.

BACKGROUND: Monoclonal gammopathy of undetermined significance (MGUS) is a precursor of multiple myeloma (MM) and related conditions. In previous registry-based, retrospective studies, autoimmune diseases have been associated with MGUS. However, these studies were not based on a screened population and are therefore prone to ascertainment bias. OBJECTIVE: To examine whether MGUS is associated with autoimmune diseases. DESIGN: A cross-sectional study within iStopMM (Iceland Screens, Treats, or Prevents MM), a prospective, population-based screening study of MGUS. SETTING: Icelandic population of adults aged 40 years or older. PATIENTS: 75 422 persons screened for MGUS. MEASUREMENTS: Poisson regression for prevalence ratios (PRs) of MGUS among persons with or without an autoimmune disease, adjusted for age and sex. RESULTS: A total of 10 818 participants had an autoimmune disorder, of whom 599 had MGUS (61 with a prior clinical diagnosis and 538 diagnosed at study screening or evaluation). A diagnosis of an autoimmune disease was not associated with MGUS (PR, 1.05 [95% CI, 0.97 to 1.15]). However, autoimmune disease diagnoses were associated with a prior clinical diagnosis of MGUS (PR, 2.11 [CI, 1.64 to 2.70]). LIMITATION: Registry data were used to gather information on autoimmune diseases, and the homogeneity of the Icelandic population may limit the generalizability of these results. CONCLUSION: The study did not find an association between autoimmune disease and MGUS in a systematically screened population. Previous studies not done in systematically screened populations have likely been subject to ascertainment bias. The findings indicate that recommendations to routinely screen patients with autoimmune disease for MGUS may not be warranted. PRIMARY FUNDING SOURCE: The International Myeloma Foundation and the European Research Council.

Development of a Multivariable Model to Predict the Need for Bone Marrow Sampling in Persons With Monoclonal Gammopathy of Undetermined Significance : A Cohort Study Nested in a Clinical Trial.

BACKGROUND: Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic precursor conditions to multiple myeloma and related disorders. Smoldering multiple myeloma is distinguished from MGUS by 10% or greater bone marrow plasma cells (BMPC) on sampling, has a higher risk for progression, and requires specialist management. OBJECTIVE: To develop a multivariable prediction model that predicts the probability that a person with presumed MGUS has 10% or greater BMPC (SMM or worse by bone marrow criteria) to inform the decision to obtain a bone marrow sample and compare its performance to the Mayo Clinic risk stratification model. DESIGN: iStopMM (Iceland Screens, Treats or Prevents Multiple Myeloma), a prospective population-based screening study of MGUS. (ClinicalTrials.gov: NCT03327597). SETTING: Icelandic population of adults aged 40 years or older. PATIENTS: 1043 persons with IgG, IgA, light-chain, and biclonal MGUS detected by screening and an interpretable bone marrow sample. MEASUREMENTS: Monoclonal gammopathy of undetermined significance isotype; monoclonal protein concentration; free light-chain ratio; and total IgG, IgM, and IgA concentrations were used as predictors. Bone marrow plasma cells were categorized as 0% to 4%, 5% to 9%, 10% to 14%, or 15% or greater. RESULTS: The c-statistic for SMM or worse was 0.85 (95% CI, 0.82 to 0.88), and calibration was excellent (intercept, -0.07; slope, 0.95). At a threshold of 10% predicted risk for SMM or worse, sensitivity was 86%, specificity was 67%, positive predictive value was 32%, and negative predictive value was 96%. Compared with the Mayo Clinic model, the net benefit for the decision to refer for sampling was between 0.13 and 0.30 higher over a range of plausible low-risk thresholds. LIMITATION: The prediction model will require external validation. CONCLUSION: This accurate prediction model for SMM or worse was developed in a population-based cohort of persons with presumed MGUS and may be used to defer bone marrow sampling and referral to hematology. PRIMARY FUNDING SOURCE: International Myeloma Foundation and the European Research Council.

Prior cancer and risk of monoclonal gammopathy of undetermined significance: a population-based study in Iceland and Sweden.

There is some evidence that a prior cancer is a risk factor for the development of multiple myeloma (MM). If this is true, prior cancer should be associated with a higher prevalence or increased progression rate of monoclonal gammopathy of undetermined significance (MGUS), the precursor of MM and related disorders. Those with a history of cancer might therefore constitute a target population for MGUS screening. This two-part study is the first study to evaluate a relationship between MGUS and prior cancers. First, we evaluated whether prior cancers were associated with having MGUS at the time of screening in the Iceland Screens Treats or Prevents Multiple Myeloma (iStopMM) study that includes 75,422 individuals screened for MGUS. Next, we evaluated the association of prior cancer and the progression of MGUS to MM and related disorders in a population-based cohort of 13,790 Swedish individuals with MGUS. A history of prior cancer was associated with a modest increase in the risk of MGUS (odds ratio=1.10; 95% confidence interval: 1.00-1.20). This excess risk was limited to prior cancers in the year preceding MGUS screening. A history of prior cancer was associated with progression of MGUS, except for myeloid malignancies which were associated with a lower risk of progression (hazard ratio=0.37; 95% confidence interval: 0.16-0.89; P=0.028). Our findings indicate that a prior cancer is not a significant etiological factor in plasma cell disorders. The findings do not warrant MGUS screening or different management of MGUS in those with a prior cancer.

A Conserved Motif Provides Binding Specificity to the PP2A-B56 Phosphatase.

Dynamic protein phosphorylation is a fundamental mechanism regulating biological processes in all organisms. Protein phosphatase 2A (PP2A) is the main source of phosphatase activity in the cell, but the molecular details of substrate recognition are unknown. Here, we report that a conserved surface-exposed pocket on PP2A regulatory B56 subunits binds to a consensus sequence on interacting proteins, which we term the LxxIxE motif. The composition of the motif modulates the affinity for B56, which in turn determines the phosphorylation status of associated substrates. Phosphorylation of amino acid residues within the motif increases B56 binding, allowing integration of kinase and phosphatase activity. We identify conserved LxxIxE motifs in essential proteins throughout the eukaryotic domain of life and in human viruses, suggesting that the motifs are required for basic cellular function. Our study provides a molecular description of PP2A binding specificity with broad implications for understanding signaling in eukaryotes.

Parents' experience and views on the assessment and treatment of children with OCD within the public mental health system in Iceland: a qualitative study.

PURPOSE: Obsessive-compulsive disorder (OCD) in children can lead to long-lasting symptoms and access to evidence-based evaluation and treatment is crucial for its prevention. In Iceland, the law guarantees public access to the highest quality healthcare services. To date, no study has evaluated the services available for children with OCD within the national healthcare system (NMHS). This qualitative study explored the experiences of parents navigating the Icelandic NMHS for their children with OCD. METHOD AND MATERIALS: Seven parents who had sought services within the NMHS for their children diagnosed with OCD at private clinics were interviewed using a semi-structured interview. The responses were analyzed using thematic framework analysis. RESULTS: Nineteen themes were identified, including three overarching themes and eight overarching sub-themes, and eight sub-themes within them. A prevalent theme was the giving up on the national mental healthcare system due to parents' experiences of accessing mental healthcare for their children being challenging. Other issues faced by parents included a lack of knowledge on where to seek help, inadequate evaluation of the issue, and the lack of access to psychotherapy for their children. The healthcare workers' responses and recommendations also resulted in parents seeking treatment at private clinics. CONCLUSIONS: These findings underscore the need for clearer pathways for seeking help, improved access to trained healthcare workers, and a more centralized evaluation process. These insights can potentially guide future research and policy decisions to better support families dealing with childhood OCD in Iceland.

How effective psychological treatments work: mechanisms of change in cognitive behavioural therapy and beyond.

BACKGROUND: Cognitive behavioural therapy (CBT) has, in the space of 50 years, evolved into the dominant modality in psychological therapy. Mechanism/s of change remain unclear, however. AIMS: In this paper, we will describe key features of CBT that account for the pace of past and future developments, with a view to identifying candidates for mechanism of change. We also highlight the distinction between 'common elements' and 'mechanisms of change' in psychological treatment. METHOD: The history of how behaviour therapy and cognitive therapy developed are considered, culminating in the wide range of strategies which now fall under the heading of cognitive behavioural therapy (CBT). We consider how the empirical grounding of CBT has led to the massive proliferation of effective treatment strategies. We then consider the relationship between 'common factors' and 'mechanisms of change', and propose that a particular type of psychological flexibility is the mechanism of change not only in CBT but also effective psychological therapies in general. CONCLUSION: Good psychological therapies should ultimately involve supporting people experiencing psychological difficulties to understand where and how they have become 'stuck' in terms of factors involved in maintaining distress and impairment. A shared understanding is then evaluated and tested with the intention of empowering and enabling them to respond more flexibly and thereby reclaim their life.

Uncovering SUMOylation dynamics during cell-cycle progression reveals FoxM1 as a key mitotic SUMO target protein.

Loss of small ubiquitin-like modification (SUMOylation) in mice causes genomic instability due to the missegregation of chromosomes. Currently, little is known about the identity of relevant SUMO target proteins that are involved in this process and about global SUMOylation dynamics during cell-cycle progression. We performed a large-scale quantitative proteomics screen to address this and identified 593 proteins to be SUMO-2 modified, including the Forkhead box transcription factor M1 (FoxM1), a key regulator of cell-cycle progression and chromosome segregation. SUMOylation of FoxM1 peaks during G2 and M phase, when FoxM1 transcriptional activity is required. We found that a SUMOylation-deficient FoxM1 mutant was less active compared to wild-type FoxM1, implying that SUMOylation of the protein enhances its transcriptional activity. Mechanistically, SUMOylation blocks the dimerization of FoxM1, thereby relieving FoxM1 autorepression. Cells deficient for FoxM1 SUMOylation showed increased levels of polyploidy. Our findings contribute to understanding the role of SUMOylation during cell-cycle progression.

Genetic insight into sick sinus syndrome.

AIMS: The aim of this study was to use human genetics to investigate the pathogenesis of sick sinus syndrome (SSS) and the role of risk factors in its development. METHODS AND RESULTS: We performed a genome-wide association study of 6469 SSS cases and 1 000 187 controls from deCODE genetics, the Copenhagen Hospital Biobank, UK Biobank, and the HUNT study. Variants at six loci associated with SSS, a reported missense variant in MYH6, known atrial fibrillation (AF)/electrocardiogram variants at PITX2, ZFHX3, TTN/CCDC141, and SCN10A and a low-frequency (MAF = 1.1-1.8%) missense variant, p.Gly62Cys in KRT8 encoding the intermediate filament protein keratin 8. A full genotypic model best described the p.Gly62Cys association (P = 1.6 × 10-20), with an odds ratio (OR) of 1.44 for heterozygotes and a disproportionally large OR of 13.99 for homozygotes. All the SSS variants increased the risk of pacemaker implantation. Their association with AF varied and p.Gly62Cys was the only variant not associating with any other arrhythmia or cardiovascular disease. We tested 17 exposure phenotypes in polygenic score (PGS) and Mendelian randomization analyses. Only two associated with the risk of SSS in Mendelian randomization, AF, and lower heart rate, suggesting causality. Powerful PGS analyses provided convincing evidence against causal associations for body mass index, cholesterol, triglycerides, and type 2 diabetes (P > 0.05). CONCLUSION: We report the associations of variants at six loci with SSS, including a missense variant in KRT8 that confers high risk in homozygotes and points to a mechanism specific to SSS development. Mendelian randomization supports a causal role for AF in the development of SSS.

Genetic insight into sick sinus syndrome.

AIMS: The aim of this study was to use human genetics to investigate the pathogenesis of sick sinus syndrome (SSS) and the role of risk factors in its development. METHODS AND RESULTS: We performed a genome-wide association study of 6469 SSS cases and 1 000 187 controls from deCODE genetics, the Copenhagen Hospital Biobank, UK Biobank, and the HUNT study. Variants at six loci associated with SSS, a reported missense variant in MYH6, known atrial fibrillation (AF)/electrocardiogram variants at PITX2, ZFHX3, TTN/CCDC141, and SCN10A and a low-frequency (MAF = 1.1-1.8%) missense variant, p.Gly62Cys in KRT8 encoding the intermediate filament protein keratin 8. A full genotypic model best described the p.Gly62Cys association (P = 1.6 × 10-20), with an odds ratio (OR) of 1.44 for heterozygotes and a disproportionally large OR of 13.99 for homozygotes. All the SSS variants increased the risk of pacemaker implantation. Their association with AF varied and p.Gly62Cys was the only variant not associating with any other arrhythmia or cardiovascular disease. We tested 17 exposure phenotypes in polygenic score (PGS) and Mendelian randomization analyses. Only two associated with the risk of SSS in Mendelian randomization, AF, and lower heart rate, suggesting causality. Powerful PGS analyses provided convincing evidence against causal associations for body mass index, cholesterol, triglycerides, and type 2 diabetes (P > 0.05). CONCLUSION: We report the associations of variants at six loci with SSS, including a missense variant in KRT8 that confers high risk in homozygotes and points to a mechanism specific to SSS development. Mendelian randomization supports a causal role for AF in the development of SSS.

Truncated SALL1 Impedes Primary Cilia Function in Townes-Brocks Syndrome.

Townes-Brocks syndrome (TBS) is characterized by a spectrum of malformations in the digits, ears, and kidneys. These anomalies overlap those seen in a growing number of ciliopathies, which are genetic syndromes linked to defects in the formation or function of the primary cilia. TBS is caused by mutations in the gene encoding the transcriptional repressor SALL1 and is associated with the presence of a truncated protein that localizes to the cytoplasm. Here, we provide evidence that SALL1 mutations might cause TBS by means beyond its transcriptional capacity. By using proximity proteomics, we show that truncated SALL1 interacts with factors related to cilia function, including the negative regulators of ciliogenesis CCP110 and CEP97. This most likely contributes to more frequent cilia formation in TBS-derived fibroblasts, as well as in a CRISPR/Cas9-generated model cell line and in TBS-modeled mouse embryonic fibroblasts, than in wild-type controls. Furthermore, TBS-like cells show changes in cilia length and disassembly rates in combination with aberrant SHH signaling transduction. These findings support the hypothesis that aberrations in primary cilia and SHH signaling are contributing factors in TBS phenotypes, representing a paradigm shift in understanding TBS etiology. These results open possibilities for the treatment of TBS.

Adults referred to a national ADHD clinic in Iceland: clinical characteristics and follow-up status.

OBJECTIVE: Evaluate adults referred to a national ADHD clinic, by comparing those diagnosed with those who were not, and those who screened negative and to evaluate changes among those diagnosed at follow-up. METHOD: Data obtained from 531 patients' medical records (49.7% males). One hundred thirty-six screened negative, 395 positive and 305 met diagnostic criteria for ADHD. Eighty-three of them were contacted by phone at follow-up. RESULTS: ADHD diagnosis was associated with lower educational status and more concerns expressed by parents and teachers during childhood. Participants not diagnosed with ADHD more often met diagnostic criteria for dysthymia, agoraphobia and generalized anxiety, and were more likely to be diagnosed with two or more comorbid disorders. At follow-up, all reported a significant reduction of ADHD symptoms, irrespective of medication, but the medicated participants reported fewer symptoms of inattention and better functioning in daily life. CONCLUSION: Adults referred to ADHD clinics may have multiple mental health problems, regardless of whether they receive ADHD diagnosis or not. This could have implications for differential diagnoses of ADHD in adults and emphasises the need to have appropriate treatment available for both groups. Psychoeducation about ADHD may be very helpful in decreasing anxiety and ADHD symptoms.

Cognitive analysis of specific threat beliefs and safety-seeking behaviours in generalised anxiety disorder: revisiting the cognitive theory of anxiety disorders.

BACKGROUND: Generalised anxiety disorder (GAD) has been an uneasy member of the anxiety disorders group since its inclusion in the third edition of the DSM. Multiple theories and treatment protocols for GAD and its defining symptom, excessive worry, have comparable efficacy in treating GAD symptoms. Crucially, these theories of GAD and excessive worry fail to explain when and why worry is excessive and when it is adaptive. AIMS: In this paper we propose a cognitive behavioural account of the difference between excessive and adaptive states of worry and explore the theme of threat and the function of safety-seeking behaviours as seen in GAD. Specifically, we incorporate the concept of inflated responsibility in a cognitive behavioural analysis of threat appraisal and safety-seeking behaviours in excessive worry and GAD. CONCLUSION: It is proposed that when worry is used as a strategy intended to increase safety from perceived social or physical threat then it should be conceptualised as a safety-seeking behaviour. However, when worry is used as a strategy to solve a problem which the person realistically can resolve or to deal explicitly with the feeling of anxiety then it functions as an adaptive coping behaviour. We also propose that the theme of threat in GAD centres on an inflated sense of responsibility for external everyday situations, and the function of safety-seeking behaviours is to attain certainty that responsibility has been fulfilled. The clinical implications of this cognitive behavioural analysis of excessive worry are discussed, as well as future research directions.

[Prevalence of persistent physical symptoms and association with depression, anxiety and health anxiety in Iceland].

INTRODUCTION: Persistent physical symptoms that are medically unexplained can result in significant functional impairment. The aim of this study was to estimate the prevalence of persistent physical symptoms among people seeking primary healthcare in Reykjavík, Iceland, how they relate to functional impairment, symptoms of depression, general anxiety and health anxiety, and estimate the proportion of people with such symptoms who would likely benefit from psychological treatment. MATERIALS AND METHODS: Questionnaires measuring persistent physical symptoms, functional impairment, and symptoms of depression, general anxiety and health anxiety were administered to 106 patients attending two primary healthcare clinics. RESULTS: The prevalence of persistent physical symptoms was 27.4% among the primary care patients and they had a strong relationship to symptoms of mental disorders. Participants with persistent physical symptoms were 8 times more likely to have clinical levels of depression and general anxiety than participants without such symptoms, 4 times more likely to have clinical levels of health anxiety and 13 times more likely to have clinical levels of functional impairment. At least two-thirds of participants with persistent physical symptoms would likely benefit from psychological treatment. CONCLUSION: The prevalence of persistent physical symptoms among health care patients in the capital area of Iceland is in line with previous studies. Similarly, the strong relationship between persistent physical symptoms and symptoms of depression and anxiety corresponds to previous studies. It is likely that at least two out of three patients with persistent physical symptoms would benefit from psychological treatment. Transdiagnostic cognitive behavioural therapy for persistent physical symptoms might be particularly useful as is focuses on the interplay between physical and mental symptoms.

SPOP promotes transcriptional expression of DNA repair and replication factors to prevent replication stress and genomic instability.

Mutations in SPOP, the gene most frequently point-mutated in primary prostate cancer, are associated with a high degree of genomic instability and deficiency in homologous recombination repair of DNA but the underlying mechanisms behind this defect are currently unknown. Here we demonstrate that SPOP knockdown leads to spontaneous replication stress and impaired recovery from replication fork stalling. We show that this is associated with reduced expression of several key DNA repair and replication factors including BRCA2, ATR, CHK1 and RAD51. Consequently, SPOP knockdown impairs RAD51 foci formation and activation of CHK1 in response to replication stress and compromises recovery from replication fork stalling. An SPOP interactome analysis shows that wild type (WT) SPOP but not mutant SPOP associates with multiple proteins involved in transcription, mRNA splicing and export. Consistent with the association of SPOP with transcription, splicing and RNA export complexes, the decreased expression of BRCA2, ATR, CHK1 and RAD51 occurs at the level of transcription.

Pregnancy complications, sick leave and service needs of women who experience perinatal distress, weak social support and dissatisfaction in their partner relationships.

INTRODUCTION: Although perinatal distress is acknowledged as a burdening condition for pregnant women, its effects on pregnancy are not well known. This study was conducted to increase knowledge regarding the effects of distress on pregnancy-related problems. The study also assessed women's need for sick leave and increased prenatal care due to distress, and the effects of weak social support and dissatisfaction with their partner relationships. METHODS: In total, 2523 women were screened for perinatal distress three times during pregnancy in this quantitative cohort study. Structured psychiatric interviews were conducted following the screening, with 562 of the participants. Data from participants' pregnancy records were also analysed. The study was conducted in primary healthcare centres in Iceland after receiving approval from the Icelandic National Bioethical Committee. The main outcome measures were pregnancy problems, sick leave issued and prenatal service needs. RESULTS: Data from 503 women were analysed. The perinatal distress group (PDG) was significantly more likely than was the nondistressed group (NDG) to experience fatigue, vomiting and pelvic pain after controlling for background variables. Distressed women who reported weak family support experienced symptoms of nausea and heartburn. The PDG needed more frequent prenatal care than did the NDG and was issued sick leave for up to 42 days longer. Dissatisfaction in the partner relationship and with the division of household tasks and childcare was strongly associated with distress, the development of complications and the need for sick leave. DISCUSSION: Identification of perinatal distress by midwives and other healthcare professionals is important, since distress may be linked to women's complaints of fatigue, vomiting, pelvic pain and need for prolonged sick leave, and additional prenatal care services will be needed. Perceived dissatisfaction in the partner relationship and with the division of household tasks should also form part of clinical practice and assistance provided.

Adverse life experiences and common mental health problems in pregnancy: a causal pathway analysis.

Risk factors for antenatal common mental problems include a history of depression, lack of social support and a history of both childhood and adulthood sexual and physical abuse. However, it is less clear whether pregnancy is a time of particular susceptibility to mental disorders due to prior childhood experiences. The aim of the paper was to investigate the potential pathways to antenatal mental health problems. A total of 521 women attending prenatal care attended a clinical interview and answered psychological questionnaires. Univariate analysis, sequential binary logistic regression and structural equation modelling (SEM) were used to analyse the relationships between variables. Having experienced parental maladjustment, maltreatment and serious physical illness in childhood and domestic violence, financial difficulties and serious spousal substance abuse in adulthood significantly predicted antenatal common mental health symptoms. SEM showed that history of depression and adverse experiences in adulthood had mediating effects on the relationship between adverse childhood events and symptoms of antenatal common mental disorders. Adverse childhood experiences are distal risk factors for antenatal common mental health problems, being significant indicators of history of depression and adverse experiences in adulthood. We therefore conclude that pregnancy is not a time of particular susceptibility to common mental health problems as a result of childhood abuse, but rather, these childhood experiences have increased the risk of adulthood trauma and prior mental disorders. Women at risk for antenatal common mental disorders include those with a history of depression, domestic violence, financial difficulties, spousal substance abuse and lack of social support.

Effects of a Brief Transdiagnostic Cognitive Behavioural Group Therapy on Disorder Specific Symptoms.

BACKGROUND: In recent years, cognitive behavioural group therapies (CBGT) have been increasingly deployed as a strategy to increase the efficiency and cost-effectiveness in treatment of common mental health problems. The vast majority of these therapies are disorder specific, but in the last few years there has been growing interest in transdiagnostic CBGT. AIMS: The aim of this study was twofold: to evaluate the treatment effects of transdiagnostic CBGT on disorder specific symptoms and what (if any) differences would be observed in the treatment effects with regard to general as opposed to disorder specific symptoms measured pre- and post-treatment. METHOD: The participants were 233 adult patients diagnosed with depression and/or anxiety disorders. They underwent a 6-week transdiagnostic CBGT. To compare treatment effects on general and disorder specific symptoms, raw scores on all measures were converted to standardized scores. RESULTS: Pre-post differences were significant and there was no evidence that treatment was differentially effective for general and disorder specific symptoms. Effect sizes ranged from medium to large. CONCLUSION: The 6-week transdiagnostic CBGT is feasible for a wide range of mood and anxiety disorders. The results indicate that low-intensity transdiagnostic group therapies may have similar effects on both general and disorder specific symptoms.

A randomized controlled trial reporting functional outcomes of cognitive-behavioural therapy in medication-treated adults with ADHD and comorbid psychopathology.

Studies assessing psychological treatment of attention deficit hyperactivity disorder (ADHD) in adults are increasingly reported. However, functional outcomes are often neglected in favour of symptom outcomes. We investigated functional outcomes in 95 adults with ADHD who were already treated with medication and randomized to receive treatment as usual (TAU/MED) or psychological treatment (CBT/MED) using a cognitive-behavioural programme, R&R2ADHD, which employs both group and individual modalities. RATE-S functional outcomes associated with ADHD symptoms, social functioning, emotional control and antisocial behaviour were given at baseline, end of treatment and three-month follow-up. The Total composite score of these scales is associated with life satisfaction. In addition, independent evaluator ratings of clinicians who were blind to treatment arm were obtained on the Clinical Global Impression scale at each time point. CBT/MED showed overall (combined outcome at end of treatment and 3-month follow-up) significantly greater functional improvement on all scales. Post-group treatment effects were maintained at follow-up with the exception of emotional control and the Total composite scales, which continued to improve. The largest treatment effect was for the RATE-S Total composite scale, associated with life satisfaction. CGI significantly correlated with all outcomes except for social functioning scale at follow-up. The study provides further evidence for the effectiveness of R&R2ADHD and demonstrates the importance of measuring functional outcomes. The key mechanism associated with improved functional outcomes is likely to be behavioural control.