Trial Protocol: Randomised controlled trial of the effects of very low calorie diet, modest dietary restriction, and sequential behavioural programme on hunger, urges to smoke, abstinence and weight gain in overweight smokers stopping smoking

Background\ud Weight gain accompanies smoking cessation, but dieting during quitting is controversial as hunger may increase urges to smoke. This is a feasibility trial for the investigation of a very low calorie diet (VLCD), individual modest energy restriction, and usual advice on hunger, ketosis, urges to smoke, abstinence and weight gain in overweight smokers trying to quit. \ud \ud Methods\ud This is a 3 armed, unblinded, randomized controlled trial in overweight (BMI > 25 kg/$m^2$), daily smokers (CO > 10 ppm); with at least 30 participants in each group. Each group receives identical behavioural support and NRT patches (25 mg(8 weeks),15 mg(2 weeks),10 mg(2 weeks)). The VLCD group receive a 429-559 kcal/day liquid formula beginning 1 week before quitting and continuing for 4 weeks afterwards. The modest energy restricted group (termed individual dietary and activity planning(IDAP)) engage in goal-setting and receive an energy prescription based on individual basal metabolic rate(BMR) aiming for daily reduction of 600 kcal. The control group receive usual dietary advice that accompanies smoking cessation i.e. avoiding feeling hungry but eating healthy snacks. After this, the VLCD participants receive IDAP to provide support for changing eating habits in the longer term; the IDAP group continues receiving this support. The control group receive IDAP 8 weeks after quitting. This allows us to compare IDAP following a successful quit attempt with dieting concurrently during quitting. It also aims to prevent attrition in the unblinded, control group by meeting their need for weight management. Follow-up occurs at 6 and 12 months. \ud \ud Outcome measures include participant acceptability, measured qualitatively by semi-structured interviewing and quantitatively by recruitment and attrition rates. Feasibility of running the trial within primary care is measured by interview and questionnaire of the treatment providers. Adherence to the VLCD is verified by the presence of urinary ketones measured weekly. Daily urges to smoke, hunger and withdrawal are measured using the Mood and Physical Symptoms Scale-Combined (MPSS-C) and a Hunger Craving Score (HCS). 24 hour, 7 day point prevalence and 4-week prolonged abstinence (Russell Standard) is confirmed by CO < 10 ppm. Weight, waist and hip circumference and percentage body fat are measured at each visit. \ud \ud Trial Registration\ud Current controlled trials ISRCTN83865809\ud \u

Cholinergic modulation of disorder-relevant human defensive behaviour in generalised anxiety disorder

Drugs that are clinically effective against anxiety disorders modulate the innate defensive behaviour of rodents, suggesting these illnesses reflect altered functioning in brain systems that process threat. This hypothesis is supported in humans by the discovery that the intensity of threat-avoidance behaviour is altered by the benzodiazepine anxiolytic lorazepam. However, these studies used healthy human participants, raising questions as to their validity in anxiety disorder patients, as well as their generalisability beyond GABAergic benzodiazepine drugs. BNC210 is a novel negative allosteric modulator of the alpha 7 nicotinic acetylcholine receptor and we recently used functional Magnetic Resonance Imaging to show it reduced amygdala responses to fearful faces in generalised anxiety disorder patients. Here we report the effect of BNC210 on the intensity of threat-avoidance behaviour in 21 female GAD patients from the same cohort. We used the Joystick Operated Runway Task as our behavioural measure, which is a computerised human translation of the Mouse Defense Test Battery, and the Spielberger state anxiety inventory as our measure of state affect. Using a repeated-measures, within-subjects design we assessed the effect of BNC210 at two dose levels versus placebo (300 mg and 2000 mg) upon two types of threat-avoidance behaviour (Flight Intensity and Risk Assessment Intensity). We also tested the effects of 1.5 mg of the benzodiazepine lorazepam as an active control. BNC210 significantly reduced Flight Intensity relative to placebo and the low dose of BNC210 also significantly reduced self-reported state anxiety. Risk Assessment Intensity was not significantly affected. Results show both human defensive behaviour and state anxiety are influenced by cholinergic neurotransmission and there provide converging evidence that this system has potential as a novel target for anxiolytic pharmacotherapy

Sexual dimorphisms and prediction of conversion in the NAPLS psychosis prodrome

Sex differences in age at onset, symptomatology, clinical course (see Walker, Walder, Lewine and Loewy, 2002) and functional impairment (Thorup et al., 2007) are well documented in psychosis. The general pattern of findings is that males manifest an earlier onset, more severe symptoms and poorer prognosis than females. Limited studies examining individuals at clinical high-risk (CHR) suggest a similar pattern of sexual dimorphism (Holtzman et al., in review; Corcoran et al., 2011). As part of the North American Prodrome Longitudinal Study (NAPLS), the current study prospectively examined sexual dimorphisms differences in relationships among CHR symptoms, childhood (premorbid) academic and social functioning, baseline social and role functioning, and conversion to psychosis. Subjects included 276 (113F/163M) CHR NAPLS participants (ages 12–36.8 years). All measures/criteria were assessed at baseline except conversion status, assessed at 6-month intervals up to 30 months. Results show sex differences in baseline social and role functioning (though not in early childhood adjustment) that predate psychosis onset, with sexually dimorphic patterns in relation to prodromal symptoms. Among male (but not female) CHRs, baseline social functioning and positive prodromal symptoms predicted conversion. These findings help elucidate early course of vulnerability for, and maximally sensitive and specific etiological and prediction models of, psychosis conversion. Findings highlight the importance of considering sexually differentiated predictors of longitudinal course and outcome, in the context of emerging risk profiles. This may optimize efforts at early identification and individually tailored preventive interventions targeting different neurobiological markers/systems and/or cognitive-behavioral approaches. We speculate a contemporary, multidimensional model of psychosis risk that posits a role of sexually dimorphic, genetically linked influences that converge with a modulating role of gonadal hormones (see Walder et al., 2012) across a temporally sensitive neurodevelopmental trajectory towards conferring risk

Covert observation in practice: lessons from the evaluation of the prohibition of smoking in public places in Scotland

Background: A ban on smoking in wholly or substantially enclosed public places has been in place in Scotland since 26th March 2006. The impact of this legislation is currently being evaluated in seven studies, three of which involve direct observation of smoking in bars and other enclosed public places. While the ethical issues around covert observation have been widely discussed there is little practical guidance on the conduct of such research. A workshop was therefore convened to identify practical lessons learned so far from the Scottish evaluation. Methods: We convened a workshop involving researchers from the three studies which used direct observation. In addition, one of the fieldwork managers collected written feedback on the fieldwork, identifying problems that arose in the field and some solutions. Results: There were four main themes identified: (i) the difficulty of achieving and maintaining concealment; (ii) the experience of being an observer; (iii) the risk of bias in the observations and (iv) issues around training and recruitment. These are discussed. Conclusion: Collecting covert observational data poses unique practical challenges, in particular in relation to the health and safety of the researcher. The findings and solutions presented in this paper will be of value to researchers designing similar studies

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (OR=1.11, P=5.7×10−15), which persisted after excluding loci implicated in previous studies (OR=1.07, P=1.7 ×10−6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 ×10−11) and neurobehavioral phenotypes in mouse (OR = 1.18, P= 7.3 ×10−5). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by non-allelic homologous recombination

Age at first birth in women is genetically associated with increased risk of schizophrenia

Prof. Paunio on PGC:n jäsenPrevious studies have shown an increased risk for mental health problems in children born to both younger and older parents compared to children of average-aged parents. We previously used a novel design to reveal a latent mechanism of genetic association between schizophrenia and age at first birth in women (AFB). Here, we use independent data from the UK Biobank (N = 38,892) to replicate the finding of an association between predicted genetic risk of schizophrenia and AFB in women, and to estimate the genetic correlation between schizophrenia and AFB in women stratified into younger and older groups. We find evidence for an association between predicted genetic risk of schizophrenia and AFB in women (P-value = 1.12E-05), and we show genetic heterogeneity between younger and older AFB groups (P-value = 3.45E-03). The genetic correlation between schizophrenia and AFB in the younger AFB group is -0.16 (SE = 0.04) while that between schizophrenia and AFB in the older AFB group is 0.14 (SE = 0.08). Our results suggest that early, and perhaps also late, age at first birth in women is associated with increased genetic risk for schizophrenia in the UK Biobank sample. These findings contribute new insights into factors contributing to the complex bio-social risk architecture underpinning the association between parental age and offspring mental health.Peer reviewe