Effects of Medial Prefrontal Cortical Administration of the Orexin-2 Receptor Antagonist, TCS-OX2-29, on Attentional Performance in Rats

Orexins are excitatory neuropeptides that come in two isoforms, Orexin A and Orexin B, and serve as ligands for the G-protein coupled orexin 1 and orexin 2 receptors (Ox1R and Ox2R, respectively). Changes in orexinergic transmission are thought to contribute to attentional processing. While several studies have examined the role of Ox1Rs in attention, less research has assessed the contribution of Ox2Rs. Moreover, several lines of evidence suggest that the right medial prefrontal cortex is particularly critical for visual attentional performance. Taking all of this into consideration, the goal of the present experiment was to test the effects Ox2R blockade, via administration of TCS-OX2-29, in the left or right medial prefrontal cortex on visual attention. The results suggest that low dose administration of TCS-OX2-29 into the right, but not into the left, medial prefrontal cortex enhanced attentional performance. We speculate that relatively mild antagonism of Ox2Rs may have increased the sensitivity of these receptors to subsequent orexin transmission, thereby enhancing attentional performance. Ongoing projects in our laboratory are assessing whether these effects are observed when TCS-OX2-29 is infused into other brain regions known to be critical for attentional performance

Relapse according to antipsychotic treatment in schizophrenic patients: a propensity-adjusted analysis

<p>Abstract</p> <p>Objective</p> <p>To compare the rate of relapse as a function of antipsychotic treatment (monotherapy vs. polypharmacy) in schizophrenic patients over a 2-year period.</p> <p>Methods</p> <p>Using data from a multicenter cohort study conducted in France, we performed a propensity-adjusted analysis to examine the association between the rate of relapse over a 2-year period and antipsychotic treatment (monotherapy vs. polypharmacy).</p> <p>Results</p> <p>Our sample consisted in 183 patients; 50 patients (27.3%) had at least one period of relapse and 133 had no relapse (72.7%). Thirty-eight (37.7) percent of the patients received polypharmacy. The most severely ill patients were given polypharmacy: the age at onset of illness was lower in the polypharmacy group (p = 0.03). Patients that received polypharmacy also presented a higher general psychopathology PANSS subscore (p = 0.04) but no statistically significant difference was found in the PANSS total score or the PANSS positive or negative subscales. These patients were more likely to be given prescriptions for sedative drugs (p < 0.01) and antidepressant medications (p = 0.03). Relapse was found in 23.7% of patients given monotherapy and 33.3% given polypharmacy (p = 0.16). After stratification according to quintiles of the propensity score, which eliminated all significant differences for baseline characteristics, antipsychotic polypharmacy was not statistically associated with an increase of relapse: HR = 1.686 (0.812; 2.505).</p> <p>Conclusion</p> <p>After propensity score adjustment, antipsychotic polypharmacy is not statistically associated to an increase of relapse. Future randomised studies are needed to assess the impact of antipsychotic polypharmacy in schizophrenia.</p

Alcohol use and burden for 195 countries and territories, 1990-2016 : a systematic analysis for the Global Burden of Disease Study 2016

Background Alcohol use is a leading risk factor for death and disability, but its overall association with health remains complex given the possible protective effects of moderate alcohol consumption on some conditions. With our comprehensive approach to health accounting within the Global Burden of Diseases, Injuries, and Risk Factors Study 2016, we generated improved estimates of alcohol use and alcohol-attributable deaths and disability-adjusted life-years (DALYs) for 195 locations from 1990 to 2016, for both sexes and for 5-year age groups between the ages of 15 years and 95 years and older. Methods Using 694 data sources of individual and population-level alcohol consumption, along with 592 prospective and retrospective studies on the risk of alcohol use, we produced estimates of the prevalence of current drinking, abstention, the distribution of alcohol consumption among current drinkers in standard drinks daily (defined as 10 g of pure ethyl alcohol), and alcohol-attributable deaths and DALYs. We made several methodological improvements compared with previous estimates: first, we adjusted alcohol sales estimates to take into account tourist and unrecorded consumption; second, we did a new meta-analysis of relative risks for 23 health outcomes associated with alcohol use; and third, we developed a new method to quantify the level of alcohol consumption that minimises the overall risk to individual health. Findings Globally, alcohol use was the seventh leading risk factor for both deaths and DALYs in 2016, accounting for 2.2% (95% uncertainty interval [UI] 1.5-3.0) of age-standardised female deaths and 6.8% (5.8-8.0) of age-standardised male deaths. Among the population aged 15-49 years, alcohol use was the leading risk factor globally in 2016, with 3.8% (95% UI 3.2-4-3) of female deaths and 12.2% (10.8-13-6) of male deaths attributable to alcohol use. For the population aged 15-49 years, female attributable DALYs were 2.3% (95% UI 2.0-2.6) and male attributable DALYs were 8.9% (7.8-9.9). The three leading causes of attributable deaths in this age group were tuberculosis (1.4% [95% UI 1. 0-1. 7] of total deaths), road injuries (1.2% [0.7-1.9]), and self-harm (1.1% [0.6-1.5]). For populations aged 50 years and older, cancers accounted for a large proportion of total alcohol-attributable deaths in 2016, constituting 27.1% (95% UI 21.2-33.3) of total alcohol-attributable female deaths and 18.9% (15.3-22.6) of male deaths. The level of alcohol consumption that minimised harm across health outcomes was zero (95% UI 0.0-0.8) standard drinks per week. Interpretation Alcohol use is a leading risk factor for global disease burden and causes substantial health loss. We found that the risk of all-cause mortality, and of cancers specifically, rises with increasing levels of consumption, and the level of consumption that minimises health loss is zero. These results suggest that alcohol control policies might need to be revised worldwide, refocusing on efforts to lower overall population-level consumption.Peer reviewe

Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden

Generation, Analysis, and Evaluation of Patient-Specific, Osteoligamentous, Spine Meshes

Scoliosis, an abnormal curvature of the spine, is traditionally corrected with bracing treatments or by a highly invasive posterior spinal fusion (PSF) operation. These correction strategies are constrained by current imaging modalities, which fail to elucidate the soft tissue anatomy that is known to play a critical role in spinal stiffness and overall structure. Osteoligamentous segmentations of the spinal column offer a foundation for downstream finite element (FE) studies seeking to optimize bracing treatments or determine ideal surgical approaches. This thesis presents methods for automatically and semi-automatically segmenting vertebrae and surrounding soft tissues of the spinal column using X-ray computed tomography (CT) volumes of asymptomatic to severely symptomatic scoliotic patients. The automatic process further develops the osteoligamentous segmentations into FE meshes of individual anatomy, such as the ligaments and intervertebral discs. The FE meshes and an originally developed osteoligamentous lumbar spine FE mesh are analyzed in a FE solver. Additionally, a novel validation technique is presented, which uses synthetic CT volumes to confirm the surmised soft tissue positions of the patient-specific segmentations. Extremely competitive dice similarity coefficients and submillimeter average Hausdorff distances demonstrate vertebrae and intervertebral disc segmentation accuracy of the automatic methodology tested on CT and multimodal datasets. The osteoligamentous FE meshes display desirable characteristics within the FE solver environment and the FE lumbar spine is expectedly stiff compared to counterpart FE meshes. With the novel validation approach, the specificity of soft tissue localization is determined to be nearly perfect, and the presented osteoligamentous segmentation method is shown to outperform current studies when testing on severe cases. The orthopedic surgical community will greatly benefit from the knowledge of soft tissue anatomy that has been localized in CT volumes. Patient-specific, osteoligamentous FE meshes can provide the basis for biomechanical simulations seeking to correct scoliosis through bracing, minimally invasive operations, or patient-specific, surgical procedures. The proposed validation method, which employs synthetic CT, is achieved fully in silico and may be generically applied to evaluate soft tissue anatomy segmented using future approaches or can be adapted to embody pathology for additional neural network training that ultimately improves neural network segmentation abilities

Competition between Direct and Indirect Exchange Couplings in MnFeAs: A First-Principles Investigation

The electronic and magnetic structures of the tetragonal and hexagonal MnFeAs were examined using density functional theory to understand the reported magnetic orderings and structural change induced by high-pressure synthesis. The reported magnetic ground states were confirmed using VASP total energy calculations. Effective exchange parameters for metal–metal contacts obtained from SPRKKR calculations indicate indirect exchange couplings are dominant in tetragonal MnFeAs. Weak direct exchange couplings for adjacent Fe–Fe and Fe–Mn contacts cause the coexistence of several low-energy magnetic structures in tetragonal MnFeAs and result in a near zero magnetic moment on the Fe atoms. On the other hand, the nearest-neighbor Fe–Fe and Fe–Mn interactions in hexagonal MnFeAs are a combination of direct and indirect exchange couplings. In addition, indirect exchange couplings in tetragonal MnFeAs are rationalized by both RKKY and superexchange mechanisms. Finally, to probe the high-pressure-induced phase transition, total energy changes with the change of volume was studied on both tetragonal and hexagonal MnFeAs.Reprinted (adapted) with permission from J. Phys. Chem. C, 2015, 119 (1), pp 580–589. Copyright 2015 American Chemical Society.</p