Driving Records of Persons Convicted of Driving under the Influence of Alcohol

The average interval between convictions of driving under the influence decreases from 2 years between first and second convictions to 17, 11 and 8 months, respectively, between the second and third, the third and fourth and the fourth and fifth convictions

Factors associated with the effectiveness and reach of NHS Stop Smoking Services for pregnant women in England

Background The UK National Health Service provides Stop Smoking Services for pregnant women (SSSP) but there is a lack of evidence concerning how these are best organised. This study investigates influences on services’ effectiveness and also on their propensity to engage pregnant smokers with support in stopping smoking. Methods Survey data collected from 121/141 (86%) of SSSP were augmented with data from Hospital Episode Statistics and the 2011 UK National Census. ‘Reach’ or propensity to engage smokers with support was defined as the percentage of pregnant smokers setting a quit date with SSSP support, and ‘Effectiveness’ as the percentage of women who set a quit date who also reported abstinence at four weeks later. A bivariate (i.e. two outcome variable) response Markov Chain Monte Carlo model was used to identify service-level factors associated with the Reach and Effectiveness of SSSP. Results Beta coefficients represent a percentage change in Reach and Effectiveness by the covariate. Providing the majority of one-to-one contacts in a clinic rather than at home increased both Reach (%) (β: 6.97, 95% CI: 3.34, 10.60) and Effectiveness (%) (β: 7.37, 95% CI: 3.03, 11.70). Reach of SSSP was also increased when the population served was more deprived (β for increase in Reach with a one unit increase in IMD score: 0.55, 95% CI: 0.25, 0.85), had a lower proportion of people with dependent children (β: -2.52, 95% CI: -3.82, −1.22), and a lower proportion of people in managerial or professional occupations (β: -0.31, 95% CI: -0.59, −0.03). The Effectiveness of SSSP was decreased in those areas that had a greater percentage of people >16 years with no educational qualifications (β: -0.51, 95% CI: -0.95, −0.07). Conclusions To engage pregnant smokers and to encourage them to quit, it may be more efficient for SSSP support to be focussed around clinics, rather than women’s homes. Reach of SSSP is inversely associated with disadvantage and efforts should be made to contact these women as they are less likely to achieve abstinence in the short and longer term

Prospective Trial of CPAP in Community-Dwelling Adults with Down Syndrome and Obstructive Sleep Apnea Syndrome

Adults with Down syndrome (DS) are predisposed to obstructive sleep apnoea (OSA), but the effectiveness and acceptability of continuous positive airway pressure treatment (CPAP) in this group has rarely been formally assessed. This study was designed as a pilot randomised, parallel controlled trial for one month, continuing as an uncontrolled cohort study whereby the control group also received the intervention. Symptomatic, community-dwelling DS individuals exhibiting ≥10 apnoeas/hypopneas per hour in bed on a Type 3 home sleep study were invited to participate in this study, with follow-up at 1, 3, 6, and 12 months from baseline. Measurements of sleepiness, behaviour, cognitive function and general health were undertaken; the primary outcome was a change in the pictorial Epworth Sleepiness Scale (pESS) score. Twenty-eight participants (19 male) were enrolled: age 28 ± 9 year; body mass index 31.5 ± 7.9 kg/m2; 39.6 ± 32.2 apnoeas/hypopneas per hour in bed; pESS 11 ± 6/24. The pilot randomised controlled trial at one month demonstrated no change between the groups. At 12 months, participant (p = 0.001) pESS and Disruptive (p 0.0001), Anxiety/Antisocial (p = 0.024), and Depressive (p = 0.008) behaviour scores were reduced compared to baseline. Improvement was noted in verbal (p = 0.001) and nonverbal intelligence scores (p = 0.011). General health scores also improved (p = 0.02). At the end of the trial, 19 participants continued on treatment. Use of CPAP in adults with DS and OSA led to a number of significant, sustained improvements in sleepiness and behavioural/emotional outcomes at 12 months

Differential α4(+)/(-)β2 Agonist-Binding Site Contributions To α4β2 Nicotinic Acetylcholine Receptor Function Within And Between Isoforms

Two α4β2 nicotinic acetylcholine receptor (α4β2-nAChR) isoforms exist with (α4)2(β2)3 and (α4)2(β2)3 subunit stoichiometries and high versus low agonist sensitivities (HS and LS), respectively. Both isoforms contain a pair of α4(+)/(-)β2 agonist- binding sites. The LS isoform also contains a unique α4(+)/(-)α4 site with lower agonist affinity than the α4(+)/(-)β2 sites. However, the relative roles of the conserved α4(+)/(-)β2 agonist-binding sites in and between the isoforms have not been studied. We used a fully linked subunit concatemeric nAChR approach to express pure populations of HS or LS isoform α4β2∗-nAChR. This approach also allowed us to mutate individual subunit interfaces, or combinations thereof, on each isoform background. We used this approach to systematically mutate a triplet of β2 subunit (-)-face E-loop residues to their non-conserved α4 subunit counterparts or vice versa (β2HQT and α4VFL, respectively). Mutant-nAChR constructs (and unmodified controls) were expressed in Xenopus oocytes. Acetylcholine concentration-response curves and maximum function were measured using two-electrode voltage clamp electrophysiology. Surface expression was measured with 125I-mAb 295 binding and was used to define function/nAChR. If the α4(+)/(-)β2 sites contribute equally to function, making identical β2HQT substitutions at either site should produce similar functional outcomes. Instead, highly differential outcomes within the HS isoform, and between the two isoforms, were observed. In contrast, α4VFL mutation effects were very similar in all positions of both isoforms. Our results indicate that the identity of subunits neighboring the otherwise equivalent α4(+)/(-)β2 agonist sites modifies their contributions to nAChR activation and that E-loop residues are an important contributor to this neighbor effect

Combining trait models of impulsivity to improve explanation of substance use behaviour

The UPPS-P model of impulsivity is gaining popularity among personality and substance use researchers, but questions remain as to whether its five facets have incremental validity in explaining substance use over a more parsimonious model specifying only two facets: reward drive and rash impulsiveness. In three cross-sectional studies (total N = 486), we investigated whether the novel components of the UPPS-P model (negative Urgency, Premeditation, Perseverance, Sensation seeking, Positive urgency) predicted typical and problematic alcohol and cannabis use after accounting for reward drive, rash impulsiveness and trait neuroticism (assessed with the Eysenck Personality Questionnaire). Reward drive and rash impulsiveness scores were calculated using principal components analysis of multiple scales, including UPPS-P premeditation and sensation seeking. Results showed that rash impulsiveness was a robust predictor of typical and problematic substance use. The novel facets of the UPPS-P did not improve prediction of typical substance use. The urgency scales inconsistently predicted problematic use. Specifically, negative urgency predicted one of three measures of negative consequences from alcohol use, and positive urgency only predicted negative consequences from cannabis use. Results suggest that the three novel facets of the UPPS-P model add little over a two component model in explaining substance use, although may provide preliminary evidence for the utility of a revised global urgency construct in explaining problematic substance use

Prevalence and clinical characteristics of serum neuronal cell surface antibodies in first-episode psychosis: a case-control study

$\textbf{Background}$ Psychosis is a common presenting feature in antibody-mediated encephalitis, for which prompt recognition and treatment usually leads to remission. We aimed to investigate whether people with circumscribed schizophrenia-like illnesses have such antibodies—especially antibodies against the N-methyl-D-aspartate receptor (NMDAR)—more commonly than do healthy controls. $\textbf{Methods}$ We recruited patients aged 14–35 years presenting to any of 35 mental health services sites across England with first-episode psychosis, less than 6 weeks of treatment with antipsychotic medication, and a score of 4 or more on at least one selected Positive and Negative Syndrome Scale (PANSS) item. Patients and controls provided venous blood samples. We completed standardised symptom rating scales (PANSS, ACE-III, GAF) at baseline, and tested serum samples for antibodies against NMDAR, LGI1, CASPR2, the GABAA receptor, and the AMPA receptor using live cell-based assays. Treating clinicians assessed outcomes of ICD diagnosis and functioning (GAF) at 6 months. We included healthy controls from the general population, recruited as part of another study in Cambridge, UK. $\textbf{Findings}$ Between Feb 1, 2013, and Aug 31, 2014, we enrolled 228 patients with first-episode psychosis and 105 healthy controls. 20 (9%) of 228 patients had serum antibodies against one or more of the neuronal cell surface antibodies compared with four (4%) of 105 controls (unadjusted odds ratio 2·4, 95% CI 0·8–7·3). These associations remained non-significant when adjusted for current cigarette smoking, alcohol consumption, and illicit drug use. Seven (3%) patients had NMDAR antibodies compared with no controls (p=0·0204). The other antibodies did not differ between groups. Antibody-positive patients had lower PANSS positive, PANSS total, and catatonia scores than did antibody-negative patients. Patients had comparable scores on other PANSS items, ACE-III, and GAF at baseline, with no difference in outcomes at 6 months. $\textbf{Interpretation}$ Some patients with first-episode psychosis had antibodies against NMDAR that might be relevant to their illness, but did not differ from patients without NMDAR antibodies in clinical characteristics. Our study suggests that the only way to detect patients with these potentially pathogenic antibodies is to screen all patients with first-episode psychosis at first presentation.Medical Research Counci

The prevalence and incidence of mental ill-health in adults with autism and intellectual disabilities

The prevalence, and incidence, of mental ill-health in adults with intellectual disabilities and autism were compared with the whole population with intellectual disabilities, and with controls, matched individually for age, gender, ability-level, and Down syndrome. Although the adults with autism had a higher point prevalence of problem behaviours compared with the whole adult population with intellectual disabilities, compared with individually matched controls there was no difference in prevalence, or incidence of either problem behaviours or other mental ill-health. Adults with autism who had problem behaviours were less likely to recover over a two-year period than were their matched controls. Apparent differences in rates of mental ill-health are accounted for by factors other than autism, including Down syndrome and ability level

Self-Reported Memory Complaints: Implications from a Longitudinal Cohort with Autopsies

OBJECTIVE: We assessed salience of subjective memory complaints (SMCs) by older individuals as a predictor of subsequent cognitive impairment while accounting for risk factors and eventual neuropathologies. METHODS: Subjects (n = 531) enrolled while cognitively intact at the University of Kentucky were asked annually if they perceived changes in memory since their last visit. A multistate model estimated when transition to impairment occurred while adjusting for intervening death. Risk factors affecting the timing and probability of an impairment were identified. The association between SMCs and Alzheimer-type neuropathology was assessed from autopsies (n = 243). RESULTS: SMCs were reported by more than half (55.7%) of the cohort, and were associated with increased risk of impairment (unadjusted odds ratio = 2.8, p \u3c 0.0001). Mild cognitive impairment (dementia) occurred 9.2 (12.1) years after SMC. Multistate modeling showed that SMC reporters with an APOE ε4 allele had double the odds of impairment (adjusted odds ratio = 2.2, p = 0.036). SMC smokers took less time to transition to mild cognitive impairment, while SMC hormone-replaced women took longer to transition directly to dementia. Among participants (n = 176) who died without a diagnosed clinical impairment, SMCs were associated with elevated neuritic amyloid plaques in the neocortex and medial temporal lobe. CONCLUSION: SMC reporters are at a higher risk of future cognitive impairment and have higher levels of Alzheimer-type brain pathology even when impairment does not occur. As potential harbingers of future cognitive decline, physicians should query and monitor SMCs from their older patients

Natural Variation in Interleukin-2 Sensitivity Influences Regulatory T-Cell Frequency and Function in Individuals With Long-standing Type 1 Diabetes.

Defective immune homeostasis in the balance between FOXP3+ regulatory T cells (Tregs) and effector T cells is a likely contributing factor in the loss of self-tolerance observed in type 1 diabetes (T1D). Given the importance of interleukin-2 (IL-2) signaling in the generation and function of Tregs, observations that polymorphisms in genes in the IL-2 pathway associate with T1D and that some individuals with T1D exhibit reduced IL-2 signaling indicate that impairment of this pathway may play a role in Treg dysfunction and the pathogenesis of T1D. Here, we have examined IL-2 sensitivity in CD4+ T-cell subsets in 70 individuals with long-standing T1D, allowing us to investigate the effect of low IL-2 sensitivity on Treg frequency and function. IL-2 responsiveness, measured by STAT5a phosphorylation, was a very stable phenotype within individuals but exhibited considerable interindividual variation and was influenced by T1D-associated PTPN2 gene polymorphisms. Tregs from individuals with lower IL-2 signaling were reduced in frequency, were less able to maintain expression of FOXP3 under limiting concentrations of IL-2, and displayed reduced suppressor function. These results suggest that reduced IL-2 signaling may be used to identify patients with the highest Treg dysfunction and who may benefit most from IL-2 immunotherapy.This work was supported by the JDRF UK Centre for Diabetes Genes, Autoimmunity and Prevention (D-GAP; 4-2007-1003), the Wellcome Trust (WT061858/091157) and the NIHR Cambridge Biomedical Research Centre (CBRC). The Cambridge Institute for Medical Research (CIMR) is in receipt of a Wellcome Trust Strategic Award (100140).This is the author accepted manuscript. The final version is available from the American Diabetes Association via http://dx.doi.org/10.2337/db15-051