Queen Elizabeth II Hospital

S ummary . The mouse yolk sac has been shown to contain in‐vivo colony forming cells capable of producing granulocytic, megakaryocytic and erythroid spleen colonies; in‐vitro colony forming cells producing granulocytic and mononuclear‐macrophage colonies in agar; and cells capable of repopuiating the lymphoid and myeloid tissue of lethally irradiated hosts. Similar haemopoietic precursor cells were also demonstrated in the blood at the time of initiation of the circulation and in the early embryonic liver. Organ cultures of 7 day embryos with intact yolk sacs, and embryos or yolk sacs after separation have shown the autonomous nature of the development of haemopoiesis in the yolk sac and the dependence of intra‐embryonic haemopoiesis, particularly in embryonic liver, on colonization by yolk sac haemopoietic cells. Both in‐vivo and in‐vitro colony forming cells have been involved in the first migration stream, between yolk sac and embryonic liver, and evidence has been presented for the role of local environmental factors in controlling the differentiation of these cell types. These results support the view that development of haemopoietic organs in both embryo and adult is dependent on colonization by circulating cells and that these circulating stem cells originate initially in the yolk sac. This indicates that the yolk sac is the only site of genuine de novo formation of haemopoietic stem cells.

OBJECTIVE: Obsessive-compulsive disorder (OCD) is characterized by repetitive, ritualistic behaviors and thought patterns. Although patients with OCD report that these compulsive behaviors are unproductive and often senseless, they are unable to desist. This study investigated whether the urge to perform compulsive acts is mediated by a disruption in the balance between flexible, goal-directed action control and habitual behavior. METHOD: A total of 21 patients with OCD and 30 healthy comparison subjects participated in a set of tasks designed to assess relative goal-directed versus habitual behavioral control. In the training stage, participants were asked to respond to different pictured stimuli in order to gain rewarding outcomes. In the subsequent (instructed) outcome devaluation test and in a novel "slips-of-action" test, the authors assessed whether participants were able to flexibly adjust their behavior to changes in the desirability of the outcomes. The authors also used a questionnaire to test explicit knowledge of the relationships between stimuli, responses, and outcomes. RESULTS: Patients with OCD showed no deficit in their ability to use feedback to respond appropriately to stimuli in the training stage. However, their knowledge of the outcomes of these responses was impaired relative to healthy comparison subjects, and patients were more prone to slips of action, indicating a deficit in goal-directed control and an overreliance on habits. CONCLUSIONS: This study provides the first experimental evidence for selective impairment in flexible and goal-directed behavioral control in patients with OCD. The impairment forces patients with OCD to rely instead on habits that can be triggered by stimuli regardless of the desirability of the consequences. Goal-directed actions are supported by orbitofronto-striatal circuitry, and the study findings are thus in line with findings from research that implicate dysfunction in this circuitry in the neuropathology of OCD.

BACKGROUND: Comparison of quality of life (QoL) across disease areas requires the use of appropriate tools. Although many studies have investigated QoL in constipation, most used disease-specific tools that are inappropriate for cross-comparisons. AIMS: To identify studies of QoL in constipation and to compare these results with other chronic conditions. METHODS: A comprehensive literature search identified studies in constipation that used a generic QoL tool. Results were statistically pooled where possible and compared with published results using the same tools in other chronic conditions. RESULTS: A total of 13 qualifying studies were identified, 10 in adults and three in children. Results from eight studies using the SF-36/12 tools were pooled; the remaining five were narratively reported. Mental and physical components of QoL scores were consistently impaired in both adult and child populations, with the greatest impact being seen in secondary care studies. Mental health effects predominated over physical domains. The magnitude of impact was comparable with that seen in patients with allergies, musculoskeletal conditions and inflammatory bowel disease. CONCLUSIONS: The impact of constipation on QoL is significant and comparable with other common chronic conditions. Improving management may prove to be an effective way of improving QoL for a substantial number of patients.

Obsessive-compulsive disorder (OCD) is characterized by repetitive thoughts and behaviors associated with underlying dysregulation of frontostriatal circuitry. Central to neurobiological models of OCD is the orbitofrontal cortex, a neural region that facilitates behavioral flexibility after negative feedback (reversal learning). We identified abnormally reduced activation of several cortical regions, including the lateral orbitofrontal cortex, during reversal learning in OCD patients and their clinically unaffected close relatives, supporting the existence of an underlying previously undiscovered endophenotype for this disorder.

Impulsivity and compulsivity represent useful conceptualizations that involve dissociable cognitive functions, which are mediated by neuroanatomically and neurochemically distinct components of cortico-subcortical circuitry. The constructs were historically viewed as diametrically opposed, with impulsivity being associated with risk-seeking and compulsivity with harm-avoidance. However, they are increasingly recognized to be linked by shared neuropsychological mechanisms involving dysfunctional inhibition of thoughts and behaviors. In this article, we selectively review new developments in the investigation of the neurocognition of impulsivity and compulsivity in humans, in order to advance our understanding of the pathophysiology of impulsive, compulsive, and addictive disorders and indicate new directions for research.

Objective: Problems with inhibiting certain pathological behaviors are integral to obsessive-compulsive disorder (OCD), trichotillomania, and other putative obsessive-compulsive spectrum disorders. The authors assessed and compared motor inhibition and cognitive flexibility in OCD and trichotillomania for the first time, to their knowledge. Method: The Stop-Signal Task and the Intradimensiona/Extradimensional Shift Task were administered to 20 patients with OCD, 17 patients with trichotillomania, and 20 healthy comparison subjects. Results: Both OCD and trichotillomania showed impaired inhibition of motor responses. For trichotillomania, the deficit was worse than for OCD, and the degree of the deficit correlated significantly with symptom severity. Only patients with OCD showed deficits in cognitive flexibility. Conclusions: Impaired inhibition of motor responses (impulsivity) was found in OCD and trichotillomania, whereas cognitive inflexibility (thought to contribute to compulsivity) was limited to OCD. This assessment will advance the characterization and classification of obsessive-compulsive spectrum disorders and aid the development of novel treatments.

Endophenotypes (intermediate phenotypes) are objective, heritable, quantitative traits hypothesized to represent genetic risk for polygenic disorders at more biologically tractable levels than distal behavioural and clinical phenotypes. It is theorized that endophenotype models of disease will help to clarify both diagnostic classification and aetiological understanding of complex brain disorders such as obsessive-compulsive disorder (OCD). To investigate endophenotypes in OCD, we measured brain structure using magnetic resonance imaging (MRI), and behavioural performance on a response inhibition task (Stop-Signal) in 31 OCD patients, 31 of their unaffected first-degree relatives, and 31 unrelated matched controls. Both patients and relatives had delayed response inhibition on the Stop-Signal task compared with healthy controls. We used a multivoxel analysis method (partial least squares) to identify large-scale brain systems in which anatomical variation was associated with variation in performance on the response inhibition task. Behavioural impairment on the Stop-Signal task, occurring predominantly in patients and relatives, was significantly associated with reduced grey matter in orbitofrontal and right inferior frontal regions and increased grey matter in cingulate, parietal and striatal regions. A novel permutation test indicated significant familial effects on variation of the MRI markers of inhibitory processing, supporting the candidacy of these brain structural systems as endophenotypes of OCD. In summary, structural variation in large-scale brain systems related to motor inhibitory control may mediate genetic risk for OCD, representing the first evidence for a neurocognitive endophenotype of OCD.

BackgroundObsessive-compulsive disorder (OCD) is a psychiatric condition that typically manifests in compulsive urges to perform irrational or excessive avoidance behaviors. A recent account has suggested that compulsivity in OCD might arise from excessive stimulus-response habit formation, rendering behavior insensitive to goal value. We tested if OCD patients have a bias toward habits using a novel shock avoidance task. To explore how habits, as a putative model of compulsivity, might relate to obsessions and anxiety, we recorded measures of contingency knowledge, explicit fear, and physiological arousal.MethodsTwenty-five OCD patients and 25 control subjects completed a shock avoidance task designed to induce habits through overtraining, which were identified using goal-devaluation. The relationship between habitual behavior, erroneous cognitions, and physiological arousal was assessed using behavior, questionnaires, subjective report, and skin conductance responses.ResultsA devaluation sensitivity test revealed that both groups could inhibit unnecessary behavioral responses before overtraining. Following overtraining, OCD patients showed greater avoidance habits than control subjects. Groups did not differ in conditioned arousal (skin conductance responses) at any stage. Additionally, groups did not differ in contingency knowledge or explicit ratings of shock expectancy following the habit test. Habit responses were associated with a subjective urge to respond.ConclusionsThese data indicate that OCD patients have a tendency to develop excessive avoidance habits, providing support for a habit account of OCD. Future research is needed to fully characterize the causal role of physiological arousal and explicit fear in habit formation in OCD. Obsessive-compulsive disorder (OCD) is a psychiatric condition that typically manifests in compulsive urges to perform irrational or excessive avoidance behaviors. A recent account has suggested that compulsivity in OCD might arise from excessive stimulus-response habit formation, rendering behavior insensitive to goal value. We tested if OCD patients have a bias toward habits using a novel shock avoidance task. To explore how habits, as a putative model of compulsivity, might relate to obsessions and anxiety, we recorded measures of contingency knowledge, explicit fear, and physiological arousal. Twenty-five OCD patients and 25 control subjects completed a shock avoidance task designed to induce habits through overtraining, which were identified using goal-devaluation. The relationship between habitual behavior, erroneous cognitions, and physiological arousal was assessed using behavior, questionnaires, subjective report, and skin conductance responses. A devaluation sensitivity test revealed that both groups could inhibit unnecessary behavioral responses before overtraining. Following overtraining, OCD patients showed greater avoidance habits than control subjects. Groups did not differ in conditioned arousal (skin conductance responses) at any stage. Additionally, groups did not differ in contingency knowledge or explicit ratings of shock expectancy following the habit test. Habit responses were associated with a subjective urge to respond. These data indicate that OCD patients have a tendency to develop excessive avoidance habits, providing support for a habit account of OCD. Future research is needed to fully characterize the causal role of physiological arousal and explicit fear in habit formation in OCD.

OBJECTIVE: To evaluate the impact of telling patients their estimated spirometric lung age as an incentive to quit smoking. DESIGN: Randomised controlled trial. SETTING: Five general practices in Hertfordshire, England. PARTICIPANTS: 561 current smokers aged over 35. INTERVENTION: All participants were offered spirometric assessment of lung function. Participants in intervention group received their results in terms of "lung age" (the age of the average healthy individual who would perform similar to them on spirometry). Those in the control group received a raw figure for forced expiratory volume at one second (FEV1). Both groups were advised to quit and offered referral to local NHS smoking cessation services. MAIN OUTCOME MEASURES: The primary outcome measure was verified cessation of smoking by salivary cotinine testing 12 months after recruitment. Secondary outcomes were reported changes in daily consumption of cigarettes and identification of new diagnoses of chronic obstructive lung disease. RESULTS: Follow-up was 89%. Independently verified quit rates at 12 months in the intervention and control groups, respectively, were 13.6% and 6.4% (difference 7.2%, P=0.005, 95% confidence interval 2.2% to 12.1%; number needed to treat 14). People with worse spirometric lung age were no more likely to have quit than those with normal lung age in either group. Cost per successful quitter was estimated at 280 pounds sterling (366 euros, $556). A new diagnosis of obstructive lung disease was made in 17% in the intervention group and 14% in the control group; a total of 16% (89/561) of participants. CONCLUSION: Telling smokers their lung age significantly improves the likelihood of them quitting smoking, but the mechanism by which this intervention achieves its effect is unclear. TRIAL REGISTRATION: National Research Register N0096173751.

Pharmacological strategies for the treatment of obsessive-compulsive disorder (OCD) continue to develop apace but deficiencies remain. We present an updated literature review of the evidence supporting available strategies. We aim to answer key questions including: (1) What are the first-line treatments? (2) Does pharmacotherapy improve health-related quality of life? (3) How do we evaluate clinical response and relapse? (4) How long should treatment continue? (5) Can we predict treatment outcomes? (6) What is the management of treatment-refractory OCD? Selective serotonin reuptake inhibitors (SSRIs) remain the pharmacological treatment of choice for most patients and are associated with improved health-related quality of life. However, discontinuation is associated with relapse and loss of quality of life, implying treatment should continue long term. A substantial minority of patients fail to respond to SSRI. Such patients may respond to strategies such as dose elevation or adjunctive antipsychotic, although long-term trials validating the effectiveness and tolerability of these strategies are relatively lacking. Newer compounds targeting other neurotransmitter systems, such as glutamate, are undergoing evaluation.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist.

OBJECTIVE: The purpose of this study was to determine the neural correlates of excessive habit formation in obsessive-compulsive disorder (OCD). The authors aimed to test for neurobiological convergence with the known pathophysiology of OCD and to infer, based on abnormalities in brain activation, whether these habits arise from dysfunction in the goal-directed or habit system. METHOD: Thirty-seven OCD patients and 33 healthy comparison subjects learned to avoid shocks while undergoing a functional MRI scan. Following four blocks of training, the authors tested whether the avoidance response had become a habit by removing the threat of shock and measuring continued avoidance. Task-related differences in brain activity in three regions of interest (the caudate, the putamen, and the medial orbitofrontal cortex) were tested at a statistical threshold set at <0.05 (family-wise-error corrected). RESULTS: Excessive habit formation in OCD patients, which was associated with hyperactivation in the caudate, was observed. Activation in this region was also associated with subjective ratings of increased urge to perform habits. The OCD group, as a whole, showed hyperactivation in the medial orbitofrontal cortex during the acquisition of avoidance; however, this did not relate directly to habit formation. CONCLUSIONS: OCD patients exhibited excessive habits that were associated with hyperactivation in a key region implicated in the pathophysiology of OCD, the caudate nucleus. Previous studies indicate that this region is important for goal-directed behavior, suggesting that habit-forming biases in OCD may be a result of impairments in this system, rather than differences in the buildup of stimulus-response habits themselves.

Culture and susceptibility testing of Helicobacter pylori strains was performed in a large multinational, multicenter randomized clinical trial. Culture was carried out on gastric biopsy samples obtained from 516 patients at entry and had a sensitivity of 99% when the [(13)C]urea breath test was used as a reference. Susceptibility testing was performed for clarithromycin and metronidazole on 485 strains by an agar dilution method and the epsilometer test (Etest) and for amoxicillin by an agar dilution method only. Resistance to clarithromycin (>1 microgram/ml) was found in 3% of the H. pylori strains, with a perfect correlation between Etest and agar dilution methods. Resistance to metronidazole (>8 microliter/ml) was found in 27% of the strains by agar dilution, but there were important discrepancies between it and the Etest method. No resistance to amoxicillin was found. The logarithms of the MICs of the three antibiotics against susceptible strains had a distribution close to normal. The impact of resistance was tested in the four arms of the trial. There were not enough clarithromycin-resistant strains to evaluate the impact of resistance on the cure rate of clarithromycin-based regimens. For metronidazole-resistant strains, the impact noted in the clarithromycin-metronidazole arm was partially overcome when omeprazole was added (76% eradication for resistant strains versus 95% for susceptible strains). Secondary resistance to clarithromycin occurred in strains from 12 of 105 patients (11.4%) after the failure of a clarithromycin-based regimen to effect eradication. The detection of point mutations in clarithromycin-resistant strains was performed by a combination of PCR and restriction fragment length polymorphism. Mutations (A2142G and 2143G) were found in all strains tested except one. This study stresses the importance of performing susceptibility tests in clinical trials in order to explain the results of different treatments.

BACKGROUND: Oesophageal adenocarcinoma is the sixth most common cause of cancer death worldwide and Barrett's oesophagus is the biggest risk factor. We aimed to evaluate the efficacy of high-dose esomeprazole proton-pump inhibitor (PPI) and aspirin for improving outcomes in patients with Barrett's oesophagus. METHODS: The Aspirin and Esomeprazole Chemoprevention in Barrett's metaplasia Trial had a 2 × 2 factorial design and was done at 84 centres in the UK and one in Canada. Patients with Barrett's oesophagus of 1 cm or more were randomised 1:1:1:1 using a computer-generated schedule held in a central trials unit to receive high-dose (40 mg twice-daily) or low-dose (20 mg once-daily) PPI, with or without aspirin (300 mg per day in the UK, 325 mg per day in Canada) for at least 8 years, in an unblinded manner. Reporting pathologists were masked to treatment allocation. The primary composite endpoint was time to all-cause mortality, oesophageal adenocarcinoma, or high-grade dysplasia, which was analysed with accelerated failure time modelling adjusted for minimisation factors (age, Barrett's oesophagus length, intestinal metaplasia) in all patients in the intention-to-treat population. This trial is registered with EudraCT, number 2004-003836-77. FINDINGS: Between March 10, 2005, and March 1, 2009, 2557 patients were recruited. 705 patients were assigned to low-dose PPI and no aspirin, 704 to high-dose PPI and no aspirin, 571 to low-dose PPI and aspirin, and 577 to high-dose PPI and aspirin. Median follow-up and treatment duration was 8·9 years (IQR 8·2-9·8), and we collected 20 095 follow-up years and 99·9% of planned data. 313 primary events occurred. High-dose PPI (139 events in 1270 patients) was superior to low-dose PPI (174 events in 1265 patients; time ratio [TR] 1·27, 95% CI 1·01-1·58, p=0·038). Aspirin (127 events in 1138 patients) was not significantly better than no aspirin (154 events in 1142 patients; TR 1·24, 0·98-1·57, p=0·068). If patients using non-steroidal anti-inflammatory drugs were censored at the time of first use, aspirin was significantly better than no aspirin (TR 1·29, 1·01-1·66, p=0·043; n=2236). Combining high-dose PPI with aspirin had the strongest effect compared with low-dose PPI without aspirin (TR 1·59, 1·14-2·23, p=0·0068). The numbers needed to treat were 34 for PPI and 43 for aspirin. Only 28 (1%) participants reported study-treatment-related serious adverse events. INTERPRETATION: High-dose PPI and aspirin chemoprevention therapy, especially in combination, significantly and safely improved outcomes in patients with Barrett's oesophagus. FUNDING: Cancer Research UK, AstraZeneca, Wellcome Trust, and Health Technology Assessment.

BACKGROUND: Recurrent apnea is common in preterm infants, particularly at very early gestational ages. These episodes of loss of effective breathing can lead to hypoxemia and bradycardia which may be severe enough to require resuscitation including use of positive pressure ventilation. Methylxanthines have been used to stimulate breathing and prevent apnea and its consequences. OBJECTIVES: The objective of this review is to determine if methylxanthine treatment in preterm infants with recurrent apnea leads to a clinically important reduction in apnea and use of intermittent positive pressure ventilation (IPPV), without clinically important side effects. SEARCH STRATEGY: Searches were made of the Oxford Database of Perinatal Trials, MEDLINE, EMBASE, previous reviews including cross references, abstracts of conferences and symposia proceedings, expert informants, journal handsearching mainly in the English language. SELECTION CRITERIA: All trials utilising random or quasi-random patient allocation, in which methylxanthine (theophylline or caffeine) was compared with placebo or no treatment for apnea in preterm infants, were included. DATA COLLECTION AND ANALYSIS: Methodological quality was assessed independently by the two authors. Data were extracted independently by the two authors. Treatment effects were expressed as relative risk (RR) and risk difference (RD) and their 95% confidence intervals, using a fixed effect model. For significant results, the inverse of the risk difference (1/RD) was used to calculate the number needed to treat (NNT). MAIN RESULTS: The results of four trials which enrolled a total of 110 preterm infants with apnea indicate that methylxanthine therapy leads to a reduction in apnea and use of IPPV in the first 2 - 7 days. There are insufficient data to evaluate side effects and no data to examine effects within different gestational age groups. There are no trial data which examine long term effects. REVIEWER'S CONCLUSIONS: Methylxanthines are effective in reducing the number of apneic attacks and the use of mechanical ventilation in the two to seven days after starting treatment. In view of its lower toxicity, caffeine would be the preferred drug. Although the safety of methylxanthine therapy has been suggested in cohort studies, there are no trial data on longterm outcome. In order to indicate which infants are likely to benefit from treatment, there is a need for stratification by gestation and/or other risk factors in future studies. In any future studies the longer term effects of treatment on growth and development should be evaluated.

Psychiatric classifications have traditionally recognized a number of conditions as representing impulse control disorders. These have included pathological gambling, intermittent explosive disorder, kleptomania, pyromania, and trichotillomania. In 1992, the World Health Organization (WHO) described habit and impulse disorders (F63) as characterized by repeated acts that have no clear rational motivation, generally harm the person's own interests and those of other people, and are associated with impulses the person experiences as uncontrollable 1. In DSM-IV-TR, the American Psychiatric Association further characterized these impulse control disorders as being preceded by a rise in tension before the behaviour or when resisting the behaviour, and followed by pleasure, gratification, or relief of tension 2. In the past two decades, the public health importance of these disorders has become increasingly apparent. For example, pathological gambling and intermittent explosive disorder are prevalent conditions (lifetime prevalence rates of 1% and 3%, respectively) that are recognized to represent a substantial burden of disease (for example, increased health concerns, family discord, and financial problems) 3, 4. Furthermore, there is a growing literature addressing the psychobiology and management of all of these impulse control disorders 5-7. Some animal models and clinical imaging studies suggest that these conditions represent “behavioural addictions”, characterized by abnormalities in reward processing 8-11. As a result, proposals have been made to include compulsive sex, compulsive buying, and compulsive Internet use under this rubric, on the grounds that they too represent a large burden of disease and deserve appropriate diagnosis and treatment 7, 12-14. The WHO's development of the ICD-11 provides an important opportunity to optimize the classification and description of impulse control disorders and to address some of the controversies surrounding these putative “behavioural addictions”. The WHO has emphasized that ICD-11 should pay particular attention to issues of clinical utility, global applicability, and scientific validity 15. The ICD-11 Working Group on Obsessive-Compulsive and Related Disorders was asked to review the scientific and other information about use, clinical utility, and experience with relevant ICD-10 diagnoses, including impulse control disorders; to review the approach of the DSM-5 to these conditions, with a focus on whether this approach might be suitable and useful for global applications; and to develop proposals for ICD-11, with a particular emphasis on improving clinical utility in a broad range of settings. The Working Group has recommended that a grouping of impulse control disorders be retained in ICD-11. These disorders should be defined by the repeated failure to resist an impulse, drive, or urge to perform an act that is rewarding to the person (at least in the short-term), despite longer-term harm either to the individual or others. Impulse control disorders would therefore include pathological gambling, intermittent explosive disorder, kleptomania, and pyromania, as well as compulsive sexual behaviour disorder. In the ICD-10, many of these behaviours are already conceptualized in this manner under the grouping of habit and impulse disorders. Trichotillomania is also listed under the same heading, but the Working Group has recommended it to be moved to the grouping of obsessive-compulsive and related disorders in ICD-11, and that skin picking (excoriation) disorder also be added to the same grouping. Compulsive sexual behaviour disorder will be new to this grouping, and would replace the ICD-10 category of excessive sexual drive. Other putative impulse control disorders such as problematic Internet use and compulsive buying do not appear at this time to have enough data to support their inclusion as independent mental health conditions. A first key controversy in the field is whether pathological gambling and related conditions should be characterized as “behavioural addictions” and thereby be subsumed under a larger category that is more closely related to substance-related disorders. While a good deal of literature supports the idea that individuals with pathological gambling have altered reward circuitry 6, they also have other brain abnormalities. For example, prefrontal cortical dysfunction appears similar between gamblers and individuals with mania 16, 17. Additionally, although there is a shared genetic vulnerability between gambling and alcohol addiction, pathological gambling also shares genetic vulnerability factors with major depressive disorder 18. Therefore, categorizing gambling behaviour as an addiction, although heuristically appealing, seems premature based on the evidence. Furthermore, the change in categorization does not have clear clinical utility, insofar as a range of treatment approaches, other than those used in the treatment of substance addictions, may be useful for pathological gambling (for example, lithium and exposure therapies) 19, 20. A second key controversy in the field is whether compulsive sexual behaviour disorder should be included in the nosology. On the one hand, it is important that the classification does not pathologize normal behaviour. On the other, it is desirable that the classification allows for appropriate diagnosis and treatment of disorders that impact public health 21. Based on the definition of impulse control disorders as characterized by the inability to control behaviour despite its negative consequences, the Working Group recommended that compulsive sexual behaviour disorder be included in that grouping. A third key controversy in the field is whether problematic Internet use is an independent disorder. The Working Group noted that this is a heterogeneous condition, and that use of the Internet may in fact constitute a delivery system for various forms of impulse control dysfunction (e.g., pathological game playing or pornography viewing). Importantly, the descriptions of pathological gambling and of compulsive sexual behaviour disorder should note that such behaviours are increasingly seen using Internet forums, either in addition to more traditional settings, or exclusively 22, 23. The DSM-5 has included Internet gaming disorder in the section “Conditions for further study”. Although potentially an important behaviour to understand, and one certainly with a high profile in some countries 12, it is questionable whether there is enough scientific evidence at this time to justify its inclusion as a disorder. Based on the limited current data, it would therefore seem premature to include it in the ICD-11. A fourth key controversy is how best to draw thresholds for these disorders so that inappropriate diagnoses are not rendered for behaviours that are either normative (for example, sex) or simply illegal (for example, stealing). The WHO has emphasized a distinction between symptoms and disability 24. Where there is a continuum between normal and pathological behaviour, associated impairment may become a key determinant of whether or not a behaviour is disordered. An additional important consideration, from a public health perspective, is whether efficacious treatments are available. As noted above, these have now been developed for all impulse control disorders, particularly pathological gambling and intermittent explosive disorder 25, 26. There are a number of important differences between the proposals for the ICD-11 and the approach taken in the DSM-5. These stem in part from the WHO's emphasis on clinical utility in a broad range of settings. In the DSM-5, the impulse control disorders grouping was dismantled, and pathological gambling was moved to the same section as substance addictions. Although evidence may indicate that pathological gambling resembles substance addictions in many ways, data also support its relationship to other impulse control disorders such as kleptomania, intermittent explosive disorder, and compulsive sexual behaviour 14. The outward clinical similarities of these disorders (that all of these behaviours are rewarding, at least initially, that they lead to feeling out of control, that the person reports urges or cravings, that no substance is taken into the body, and that there are no indications or outward signs of intoxication) further supports their unique categorization as impulse control disorders. Another difference between the proposals for ICD-11 and DSM-5 is that the DSM-5 rejected its own Sexual and Gender Identity Disorders Work Group's proposal to include “hypersexuality”. One objection to this proposal was its implicit normative reference to the “right amount” of sexuality. The ICD-11 Working Group believes that it is more clinically useful – both in terms of conceptualizing the symptomatology and of treatment strategies – to view compulsive sexual behaviour disorder as being related to other disorders that are also characterized by repeated failures to resist impulses, drives, or urges despite longer-term harm. Therefore, the Working Group has proposed replacing the ICD-10 concept of excessive sexual drive with a term that places greater emphasis on behaviour, and moving this condition to the grouping of impulse control disorders rather than placing the primary focus on the fact that the behaviour involved is sexual in nature. The ICD-11 will be used globally, in a broad range of specialist and primary care settings, often by non-specialized health workers. There has been growing emphasis on encouraging screening for substance use disorders in these settings, and one advantage of expanding the substance use category to include behavioural addictions would be the encouragement of similar assessment and treatment approaches for a range of conditions, which taken together do constitute a major health problem but are often neglected by individual practitioners as well as by health care systems. At the same time, however, much remains unknown about the underlying psychobiology and optimal management of these conditions, some of them have only been described in Western contexts, and the boundaries between disorder and normality remain contested. The Working Group therefore recommends, based on the current evidence, that there be a category of impulse control disorders and that it include pathological gambling, kleptomania, pyromania, compulsive sexual disorder, and intermittent explosive disorder. This approach differs from DSM-5, which splits these disorders across diagnostic categories. Instead, the ICD-11 proposal recommends keeping these together, so that clinicians can screen for them all. We believe that this approach is much simpler, will be easier for clinicians to use, is more continuous with the previous classification, and will be more feasible in low-resource settings than the DSM-5 approach. All proposals for the ICD-11 will be made publically available for review and comment. These recommendations therefore represent only a starting point, and set the stage for a global exchange about how best to address the nosology of these behaviours with the goal of improving its clinical utility. In addition, the proposals for ICD-11 will be field tested using two main approaches: an Internet-based approach and a clinical settings (clinic-based) approach. Internet-based field studies will be implemented primarily through the Global Clinical Practice Network, a network currently consisting of nearly 10,000 individual mental health and primary care professionals in more than 100 countries (www.globalclinicalpractice.net). Clinic-based studies will be implemented through the network of collaborating international field study centers appointed by the WHO. The timing of the review and comment processes and of field studies will be such that their results can be integrated into the ICD-11 prior to it submission to the World Health Assembly for approval. The authors of this paper are members of the WHO ICD-11 Working Group on the Classification of Obsessive-Compulsive and Related Disorders, reporting to the WHO International Advisory Group for the Revision of ICD-10 Mental and Behavioural Disorders. However, the views expressed in this paper are those of the authors and, except as specifically noted, do not represent the official policies or positions of the International Advisory Group or the World Health Organization. The authors thank G. Reed for his guidance of the Working Group and inputs to this paper.

AIM: The aim of this paper is to increase awareness of the prevalence and cost of psychiatric and neurological disorders (brain disorders) in the UK. METHOD: UK data for 18 brain disorders were extracted from a systematic review of European epidemiological data and prevalence rates and the costs of each disorder were summarized (2010 values). RESULTS: There were approximately 45 million cases of brain disorders in the UK, with a cost of €134 billion per annum. The most prevalent were headache, anxiety disorders, sleep disorders, mood disorders and somatoform disorders. However, the five most costly disorders (€ million) were: dementia: €22,164; psychotic disorders: €16,717; mood disorders: €19,238; addiction: €11,719; anxiety disorders: €11,687. Apart from psychosis, these five disorders ranked amongst those with the lowest direct medical expenditure per subject (<€3000). The approximate breakdown of costs was: 50% indirect costs, 25% direct non-medical and 25% direct healthcare costs. DISCUSSION: The prevalence and cost of UK brain disorders is likely to increase given the ageing population. Translational neurosciences research has the potential to develop more effective treatments but is underfunded. Addressing the clinical and economic challenges posed by brain disorders requires a coordinated effort at an EU and national level to transform the current scientific, healthcare and educational agenda.

In DSM-III, DSM-III-R, and DSM-IV, obsessive-compulsive disorder (OCD) was classified as an anxiety disorder. In ICD-10, OCD is classified separately from the anxiety disorders, although within the same larger category as anxiety disorders (as one of the "neurotic, stress-related, and somatoform disorders"). Ongoing advances in our understanding of OCD and other anxiety disorders have raised the question of whether OCD should continue to be classified with the anxiety disorders in DSM-V. This review presents a number of options and preliminary recommendations to be considered for DSM-V. Evidence is reviewed for retaining OCD in the category of anxiety disorders, and for moving OCD to a separate category of obsessive-compulsive (OC)-spectrum disorders, if such a category is included in DSM-V. Our preliminary recommendation is that OCD be retained in the category of anxiety disorders but that this category also includes OC-spectrum disorders along with OCD. If this change is made, the name of this category should be changed to reflect this proposed change.

BACKGROUND: Pre-eclampsia is a relatively common complication of pregnancy. Anticonvulsants are used in the belief they help prevent eclamptic fits and subsequent poor outcomes for mother and infant. OBJECTIVES: The objective of this review was to assess the effects of anticonvulsants for women with pre-eclampsia on the women and their children. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group trials register, and the Cochrane Controlled Trials Register, 1999 Issue 3. SELECTION CRITERIA: Randomised trials comparing anticonvulsants with placebo or no anticonvulsants or comparisons of different anticonvulsants in women with pre-eclampsia. DATA COLLECTION AND ANALYSIS: Trial quality was assessed and data were extracted independently by two reviewers. MAIN RESULTS: Nine studies were included. Comparing magnesium sulphate with placebo/no anticonvulsant the relative risk (RR) of eclampsia was 0.33, 95% confidence interval (CI) 0.11 to 1.02. There was no significant difference detected in the risk of caesarean section (RR 1.04, 95% CI 0.92 to 1.17). Magnesium sulphate appeared to be better than phenytoin at reducing the risk of eclampsia (RR 0.05, 95% CI 0.00 to 0.84). However there was an increased risk of caesarean section with magnesium sulphate compared to phenytoin (RR 1.21, 95% CI 1.05 to 1. 41). No statistically significant differences were reported for any other clinically important outcomes. Studies comparing magnesium sulphate and diazepam were too small for any reliable conclusions. REVIEWER'S CONCLUSIONS: There is not enough evidence to establish the benefits and hazards of anticonvulsants for women with pre-eclampsia. If an anticonvulsant is used, magnesium sulphate appears to be the best choice.

Obsessive-compulsive disorder is a prevalent and disabling lifespan disorder. Clomipramine and the SSRIs have been found to be effective across the range of symptoms, both in acute and longer-term studies. Meta-analyses have reported a larger treatment effect for clomipramine relative to the SSRIs, but this is not supported by evidence from head-to-head comparator studies and, based on their superior safety and tolerability, SSRIs are the preferred option for long-term treatment in most cases. The treatment-effect is usually gradual and partial, and many patients fail to respond adequately to first-line treatment. Pharmacological options for refractory cases include switching SRI, increasing the dose, or augmenting with an antipsychotic agent. Novel strategies are under investigation for this highly morbid group. This paper reviews the key questions related to OCD pharmacotherapy, synthesizing evidence derived from randomized controlled trials, meta-analyses and consensus guidelines.