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Substance use occurs at a high rate in persons with a psychiatric disorder. Genetically informative studies have the potential to elucidate the etiology of these phenomena. Recent developments in genome-wide association studies (GWAS) allow new avenues of investigation.
Using results of GWAS meta-analyses, we performed a factor analysis of the genetic correlation structure, a genome-wide search of shared loci, and causally informative tests for six substance use phenotypes (four smoking, one alcohol, and one cannabis use) and five psychiatric disorders (ADHD, anorexia, depression, bipolar disorder, and schizophrenia).
Two correlated externalizing and internalizing/psychosis factor were found, although model fit was beneath conventional standards. Of 458 loci reported in previous univariate GWAS of substance use and psychiatric disorders, about 50% (230 loci) were pleiotropic with additional 111 pleiotropic loci not reported from past GWAS. Of the 341 pleiotropic loci, 152 were associated with both substance use and psychiatric disorders, implicating neurodevelopment, cell morphogenesis, biological adhesion pathways, and enrichment in 13 different brain tissues. Seventy-five and 114 pleiotropic loci were specific to either psychiatric disorders or substance use phenotypes, implicating neuronal signaling pathway and clathrin-binding functions/structures, respectively. No consistent evidence for phenotypic causation was found across different Mendelian randomization methods.
Genetic etiology of substance use and psychiatric disorders is highly pleiotropic and involves shared neurodevelopmental path, neurotransmission, and intracellular trafficking. In aggregate, the patterns are not consistent with vertical pleiotropy, more likely reflecting horizontal pleiotropy or more complex forms of phenotypic causation.
Soybean meal is rich in soybean isoflavones, which exhibit antioxidant, anti-inflammatory, antiviral and anticancer functions in humans and animals. This study was conducted to investigate the effects of soybean isoflavones on the growth performance, intestinal morphology and antioxidative properties in pigs. A total of 72 weaned piglets (7.45 ± 0.13 kg; 36 males and 36 females) were allocated into three treatments and fed corn-soybean meal (C-SBM), corn-soy protein concentrate (C-SPC) or C-SPC supplemented with equal levels of the isoflavones found in the C-SBM diet (C-SPC + ISF) for a 72-day trial. Each treatment had six replicates and four piglets per replicate, half male and half female. On day 42, one male pig from each replicate was selected and euthanized to collect intestinal samples. The results showed that compared to pigs fed the C-SPC diet, pigs fed the C-SBM and C-SPC + ISF diets had higher BW on day 72 (P < 0.05); pigs fed the C-SBM diet had significantly higher average daily gain (ADG) during days 14 to 28 (P < 0.05), with C-SPC + ISF being intermediate; pigs fed the C-SBM diet tended to have higher ADG during days 42 to 72 (P = 0.063), while pigs fed the C-SPC + ISF diet had significantly higher ADG during days 42 to 72 (P < 0.05). Moreover, compared to pigs fed the C-SPC diet, pigs fed the C-SBM diet tended to have greater villus height (P = 0.092), while pigs fed the C-SPC + ISF diet had significantly greater villus height (P < 0.05); pigs fed the C-SBM and C-SPC + ISF diets had significantly increased villus height-to-crypt depth ratio (P < 0.05). Compared with the C-SPC diet, dietary C-SPC + ISF tended to increase plasma superoxide dismutase activity on days 28 (P = 0.085) and 42 (P = 0.075) and reduce plasma malondialdehyde (MDA) content on day 42 (P = 0.089), as well as significantly decreased jejunal mucosa MDA content on day 42 (P < 0.05). However, no significant difference in the expression of tight junction genes among the three groups was found (P > 0.05). In conclusion, our results suggest that a long-term exposure to soybean isoflavones enhances the growth performance, protects the intestinal morphology and improves the antioxidative properties in pigs.
OBJECTIVES/GOALS: The history of immune suppression, especially CD4 nadir, has been shown to be a strong predictor of HIV-associated neurocognitive disorders (HAND). However, the potential mechanism of this association is not well understood. This study examined the relationship between CD4 nadir and brain atrophy. METHODS/STUDY POPULATION: Fifty-nine people with HIV participated in the cross-sectional study (mean age, 56.5 ± 5.8; age range, 41-69; 15 females; 46 African-Americans). High resolution structural MRI images were obtained using a 3T Siemens scanner. From a comprehensive 7-domain neuropsychological test battery, a global deficit score (GDS) and HAND diagnoses were determined for each participant. The correlation between CD4 nadir (the lowest ever lymphocyte CD4 count) and cortical thickness was investigated using a vertex-wise non-parametric approach with a conservative statistical threshold of p < 0.05 (FWE-corrected). RESULTS/ANTICIPATED RESULTS: Out of the 59 participants, 12 met standard Frascati criteria for asymptomatic neurocognitive impairment (ANI) and two met the criteria for mild neurocognitive disorder (MND). Across all participants, low CD4 nadir was associated with widespread cortical thinning, especially in the frontal and temporal regions. Higher GDS (indicating worse global neurocognitive function) was associated with bilateral frontal cortical thinning, and the association largely persisted in the subset of participants who did not meet HAND criteria. DISCUSSION/SIGNIFICANCE OF IMPACT: These results suggest that the low CD4 nadir may be associated with widespread neural injury in the brain, especially in the frontal and temporal regions. This spatial profile might contribute to the prevalence/phenotypes of HAND in the cART era, such as the frequently observed deficits in the executive domain.
The meat quality of chicken is an important factor affecting the consumer’s health. It was hypothesized that n-3 polyunsaturated fatty acid (n-3 PUFA) could be effectively deposited in chicken, by incorporating antioxidation of soybean isoflavone (SI), which led to improved quality of chicken meat for good health of human beings. Effects of partial or complete dietary substitution of lard (LA) with linseed oil (LO), with or without SI on growth performance, biochemical indicators, meat quality, fatty acid profiles, lipid-related health indicators and gene expression of breast muscle were examined in chickens. A total of 900 males were fed a corn–soybean meal diet supplemented with 4% LA, 2% LA + 2% LO and 4% LO and the latter two including 30 mg SI/kg (2% LA + 2% LO + SI and 4% LO + SI) from 29 to 66 days of age; each of the five dietary treatments included six replicates of 30 birds. Compared with the 4% LA diet, dietary 4% LO significantly increased the feed efficiency and had no negative effect on objective indices related to meat quality; LO significantly decreased plasma triglycerides and total cholesterol (TCH); abdominal fat percentage was significantly decreased in birds fed the 4% LO and 4% LO + SI diets. Chickens with LO diets resulted in higher contents of α-linolenic acid (C18:3n-3), EPA (C20:5n-3) and total n-3 PUFA, together with a lower content of palmitic acid (C16:0), lignoceric acid (C24:0), saturated fatty acids and n-6:n-3 ratio in breast muscle compared to 4% LA diet (P < 0.05); they also significantly decreased atherogenic index, thrombogenic index and increased the hypocholesterolemic to hypercholesterolemic ratio. Adding SI to the LO diets enhanced the contents of EPA and DHA (C22:6n-3), plasma total superoxide dismutase, reduced glutathione (GSH)/oxidized glutathione and muscle GSH content, while decreased plasma total triglyceride and TCH and malondialdehyde content in plasma and breast muscle compared to its absence (P < 0.05). Expression in breast muscle of fatty acid desaturase 1 (FADS1), FADS2, elongase 2 (ELOVL2) and ELOVL5 genes were significantly higher with the LO diets including SI than with the 4% LA diet. Significant interactions existed between LO level and inclusion of SI on EPA and TCH contents. These findings indicate that diet supplemented with LO combined with SI is an effective alternative when optimizing the nutritional value of chicken meat for human consumers.
We perform a numerical study of the heat transfer and flow structure of Rayleigh–Bénard (RB) convection in (in most cases regular) porous media, which are comprised of circular, solid obstacles located on a square lattice. This study is focused on the role of porosity
in the flow properties during the transition process from the traditional RB convection with
(so no obstacles included) to Darcy-type porous-media convection with
approaching 0. Simulations are carried out in a cell with unity aspect ratio, for Rayleigh number
and varying porosities
, at a fixed Prandtl number
, and we restrict ourselves to the two-dimensional case. For fixed
, the Nusselt number
is found to vary non-monotonically as a function of
; namely, with decreasing
, it first increases, before it decreases for
approaching 0. The non-monotonic behaviour of
originates from two competing effects of the porous structure on the heat transfer. On the one hand, the flow coherence is enhanced in the porous media, which is beneficial for the heat transfer. On the other hand, the convection is slowed down by the enhanced resistance due to the porous structure, leading to heat transfer reduction. For fixed
, depending on
, two different heat transfer regimes are identified, with different effective power-law behaviours of
, namely a steep one for low
when viscosity dominates, and the standard classical one for large
. The scaling crossover occurs when the thermal boundary layer thickness and the pore scale are comparable. The influences of the porous structure on the temperature and velocity fluctuations, convective heat flux and energy dissipation rates are analysed, further demonstrating the competing effects of the porous structure to enhance or reduce the heat transfer.
Flexibility is one of the important mechanical performance parameters of stent. The flexibility of tapered stents, especially self-expanding tapered stents, remains unknown. In this study, we developed a new selfexpanding tapered stent for tapered arteries and performed a numerical investigation of stent flexibility by using finite element method. The effect of stent design parameters, including taper and link space width, on stent flexibility was studied. The flexibility of the proposed stent was also compared with that of traditional cylindrical stents. Results show that the tapered stent is more flexible than the traditional cylindrical stent. Furthermore, the flexibility of the tapered stent increases with increasing stent taper and stent link space width. The increase in the stent link space width can contribute to the reduction in the peak stress. Therefore, tapered stents with high link space width will improve the stent flexibility. This work provides useful information for improvement of stent design and clinical selection.
At present, analysis of diet and bladder cancer (BC) is mostly based on the intake of individual foods. The examination of food combinations provides a scope to deal with the complexity and unpredictability of the diet and aims to overcome the limitations of the study of nutrients and foods in isolation. This article aims to demonstrate the usability of supervised data mining methods to extract the food groups related to BC. In order to derive key food groups associated with BC risk, we applied the data mining technique C5.0 with 10-fold cross-validation in the BLadder cancer Epidemiology and Nutritional Determinants study, including data from eighteen case–control and one nested case–cohort study, compromising 8320 BC cases out of 31 551 participants. Dietary data, on the eleven main food groups of the Eurocode 2 Core classification codebook, and relevant non-diet data (i.e. sex, age and smoking status) were available. Primarily, five key food groups were extracted; in order of importance, beverages (non-milk); grains and grain products; vegetables and vegetable products; fats, oils and their products; meats and meat products were associated with BC risk. Since these food groups are corresponded with previously proposed BC-related dietary factors, data mining seems to be a promising technique in the field of nutritional epidemiology and deserves further examination.
This pooled analysis compared the efficacy of venlafaxine extended-release (XR) versus placebo in the treatment of social anxiety disorder (SAD).
Data were pooled from 5 randomized studies of patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) SAD (N=1459) who were treated with venlafaxine XR 75 mg/d to 225 mg/d or placebo for 12 weeks (4 studies) or 28 weeks (1 study). Response and remission rates were calculated for the overall sample, as well as stratified by gender and level of physical symptom severity at baseline. Response was defined as a score of 1 or 2 on the Clinical Global Impressions–Improvement (CGI-I) scale. Remission was defined as a total score of <30 on the Leibowitz Social Anxiety Scale (LSAS).
At baseline the mean LSAS score was 88.1 and 86.6 for the venlafaxine and placebo arms, respectively. Overall response rates at week 12 were 55% for venlafaxine XR and 33% for placebo (P<0.0001); remission rates were 25% and 12%, respectively (P<0.0001). Among patients with less severe physical symptoms, response rates were 52% and 32% for venlafaxine XR and placebo, respectively (P<0.0001); remission rates were 27% and 14%, respectively (P<0.0001). Response rates among patients with more severe physical symptoms were 56% for venlafaxine XR and 33% for placebo (P<0.0001); remission rates were 24% and 11%, respectively (P<0.0001).
Venlafaxine XR is effective in the treatment of SAD, regardless of gender or severity of physical symptoms.
Previous studies have shown that the polymorphisms in COMT gene and environmental factors affect the risk of drug dependence, but there’s no research shown in relapse of heroin dependence, and the mechanism underlying remains uncertain.
Examine the interaction between allelic variants of the catechol-O- methlytransferase (COMT) gene and environmental factors (encountering drug-related environmental situations, social support) in contribution to relapse in heroin dependence.
Construct the gene-environment interaction model in order to understand the mechanism for relapse in heroin dependence.
The 249 heroin dependent subjects who followed up at one year after abstinent by using the natural history interview (NHI), social support rateing Scale (SSRS), and other questionnaires were genotyped for eight tagging single nucleotide polymorphisms (SNP) on the COMT gene. General Multifactor Dimensionality Reduction (GMDR) was used to construct the gene-environment interaction model which impacting relapse in heroin dependence.
The relapse group had higher frequencies of encountering drug-related environment (EDE) and G allele and GG genotype frequencies on COMT gene rs4680 locus and less Social Support Scale scores than that in the abstinence group. Logistic regression analysis showed that encountering more drug-related environment and GG genotype carriers were the risk factors for relapse in heroin dependence. GMDR analysis showed that the COMT gene was interact with the frequency of EDE and social support level to impact the relapse in heroin dependence.
Gene-environment interaction between COMT gene and the frequency of EDE and social support were related to heroin dependence relapse.
Finding the prediction factors for the risks of post-stroke depression (PSD) is important to stroke survivors. However, most existing studies focused only on general clinical data, which limited the predictive ability. To improve the predictive ability, this study proposed a comprehensive PSD risk prediction model with social psychological factors, neurological, cognitive functional factors and general clinical factors.
The study recruited 188 stroke patients. Patients were diagnosed by DSM-IV criteria. Predictors were collected within a week after stroke. Boosted regression trees (BRT) was used to classify these predictors, and then a predictive model was constructed based on the selected predictors. The receiver operating characteristic (ROC) curve was used to determine the performance of the predictive model .
The risk prediction model was constructed with 6 factors: Body Mass Index (BMI), cerebral infraction history (CI), Social Support Rating Scale (SSRS), Eysenck Personality Questionnaire-Neuroticism (EPQ-N), factor 1 of the 20 items Toronto Alexithymia Scale (TAS-F1) and Snaith-Hamilton-Pleasure Scale (SHARPS). In the contribution of risk prediction factors, social psychological factors was more than 0.60. ROC curve of prediction model was 0.826 (p<0.001; 95% CI) and the accuracy of prediction was 0.81 (p<0.001). Transforming the prediction model to a tree diagram, it was convenient to clinic operation.
A PSD risk prediction model with good prediction performance was constructed to achieve diagnose concisely and clearly. The social psychological factors play an important role for diagnosing PSD in the early period.
The aim of this study was to develop and externally validate a simple-to-use nomogram for predicting the survival of hospitalised human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) patients (hospitalised person living with HIV/AIDS (PLWHAs)). Hospitalised PLWHAs (n = 3724) between January 2012 and December 2014 were enrolled in the training cohort. HIV-infected inpatients (n = 1987) admitted in 2015 were included as the external-validation cohort. The least absolute shrinkage and selection operator method was used to perform data dimension reduction and select the optimal predictors. The nomogram incorporated 11 independent predictors, including occupation, antiretroviral therapy, pneumonia, tuberculosis, Talaromyces marneffei, hypertension, septicemia, anaemia, respiratory failure, hypoproteinemia and electrolyte disturbances. The Likelihood χ2 statistic of the model was 516.30 (P = 0.000). Integrated Brier Score was 0.076 and Brier scores of the nomogram at the 10-day and 20-day time points were 0.046 and 0.071, respectively. The area under the curves for receiver operating characteristic were 0.819 and 0.828, and precision-recall curves were 0.242 and 0.378 at two time points. Calibration plots and decision curve analysis in the two sets showed good performance and a high net benefit of nomogram. In conclusion, the nomogram developed in the current study has relatively high calibration and is clinically useful. It provides a convenient and useful tool for timely clinical decision-making and the risk management of hospitalised PLWHAs.
This paper proposes a fault-tolerant control (FTC) method based on fast fault observer (FFO) to solve the problem of actuator gain loss fault and stuck fault for hypersonic vehicles. Firstly, an input-output feedback linearisation model is presented that considers parametric uncertainties, control input saturation, disturbances and actuator faults. Secondly, the above factors are defined as an integrated fault item, and an improved fast fault observer is designed to estimate the integrated fault in real time. Finally, the fault-tolerant controller is constructed based on the sliding mode and fault estimation. In case of unknown faults, the effects of gain loss fault or stuck fault happen on elevators and the engine can be quickly processed, Also, the asymptotically stable tracking of the flight output reference command is completed to achieve fault-tolerant control. The final simulation experiment verifies the effectiveness of the proposed method.
The fatty acid composition of chicken’s meat is largely influenced by dietary lipids, which are often used as supplements to increase dietary caloric density. The underlying key metabolites and pathways influenced by dietary oils remain poorly known in chickens. The objective of this study was to explore the underlying metabolic mechanisms of how diets supplemented with mixed or a single oil with distinct fatty acid composition influence the fatty acid profile in breast muscle of Qingyuan chickens. Birds were fed a corn-soybean meal diet supplemented with either soybean oil (control, CON) or equal amounts of mixed edible oils (MEO; soybean oil : lard : fish oil : coconut oil = 1 : 1 : 0.5 : 0.5) from 1 to 120 days of age. Growth performance and fatty acid composition of muscle lipids were analysed. LC-MS was applied to investigate the effects of CON v. MEO diets on lipid-related metabolites in the muscle of chickens at day 120. Compared with the CON diet, chickens fed the MEO diet had a lower feed conversion ratio (P < 0.05), higher proportions of lauric acid (C12:0), myristic acid (C14:0), palmitoleic acid (C16:1n-7), oleic acid (C18:1n-9), EPA (C20:5n-3) and DHA (C22:6n-3), and a lower linoleic acid (C18:2n-6) content in breast muscle (P < 0.05). Muscle metabolome profiling showed that the most differentially abundant metabolites are phospholipids, including phosphatidylcholines (PC) and phosphatidylethanolamines (PE), which enriched the glycerophospholipid metabolism (P < 0.05). These key differentially abundant metabolites – PC (14:0/20:4), PC (18:1/14:1), PC (18:0/14:1), PC (18:0/18:4), PC (20:0/18:4), PE (22:0/P-16:0), PE (24:0/20:5), PE (22:2/P-18:1), PE (24:0/18:4) – were closely associated with the contents of C12:0, C14:0, DHA and C18:2n-6 in muscle lipids (P < 0.05). The content of glutathione metabolite was higher with MEO than CON diet (P < 0.05). Based on these results, it can be concluded that the diet supplemented with MEO reduced the feed conversion ratio, enriched the content of n-3 fatty acids and modified the related metabolites (including PC, PE and glutathione) in breast muscle of chickens.
This paper provides an up-to-date review of the problems related to the generation, detection and mitigation of strong electromagnetic pulses created in the interaction of high-power, high-energy laser pulses with different types of solid targets. It includes new experimental data obtained independently at several international laboratories. The mechanisms of electromagnetic field generation are analyzed and considered as a function of the intensity and the spectral range of emissions they produce. The major emphasis is put on the GHz frequency domain, which is the most damaging for electronics and may have important applications. The physics of electromagnetic emissions in other spectral domains, in particular THz and MHz, is also discussed. The theoretical models and numerical simulations are compared with the results of experimental measurements, with special attention to the methodology of measurements and complementary diagnostics. Understanding the underlying physical processes is the basis for developing techniques to mitigate the electromagnetic threat and to harness electromagnetic emissions, which may have promising applications.
Three-dimensional printing is a revolutionary technology that is disrupting the status quo in surgery. It has been rapidly adopted by otolaryngology as a tool in surgical simulation for high-risk, low-frequency procedures. This systematic review comprehensively evaluates the contemporary usage of three-dimensional printed otolaryngology simulators.
A systematic review of the literature was performed with narrative synthesis.
Twenty-two articles were identified for inclusion, describing models that span a range of surgical tasks (temporal bone dissection, airway procedures, functional endoscopic sinus surgery and endoscopic ear surgery). Thirty-six per cent of articles assessed construct validity (objective measures); the other 64 per cent only assessed face and content validity (subjective measures). Most studies demonstrated positive feedback and high confidence in the models’ value as additions to the curriculum.
Whilst further studies supported with objective metrics are merited, the role of three-dimensional printed otolaryngology simulators is poised to expand in surgical training given the enthusiastic reception from trainees and experts alike.
The sense of bitter taste is critical for chickens to acquire and select feeds. It is important to understand the roles and mechanisms of bitter taste transduction in chickens. Denatonium is extensively used as a bitter taste receptor agonist to activate bitter taste receptors in recent studies. The objective of this study was to investigate the physiological effects and the potential molecular mechanisms of dietary exposure to a strong bitter taste receptor agonist on the jejunal epithelial cells of yellow-feathered chickens. A total of 240 yellow-feathered chickens were divided into four treatments receiving a normal diet (Control), a low-dose denatonium treatment (Control + 5 mg/kg denatonium), a middle-dose denatonium treatment (Control + 20 mg/kg denatonium) and a high-dose denatonium treatment (Control + 100 mg/kg denatonium) for 56 days, respectively. The results showed that dietary denatonium reduced (P < 0.05) the growth performance of chickens. High-dose denatonium damaged the morphology of the jejunal epithelium and decreased (P < 0.05) the activities of Ca2+-ATPase, sucrase and maltase after 56 days of exposure. Meanwhile, high-dose denatonium increased (P < 0.05) mRNA expressions of bitter taste receptors, which resulted in enhanced apoptosis in jejunal epithelial cells after 56 days of exposure. Furthermore, middle-dose and high-dose denatonium exhibited increased (P < 0.05) mRNA level of claudin 2 and decreased (P < 0.05) mRNA level of occludin after 28 days of exposure. Only high-dose denatonium decreased (P < 0.05) mRNA level of occludin after 56 days of exposure. In conclusion, denatonium manifested deleterious effects on the jejunum of chickens in a dose–effect manner via damaging the morphology of the jejunal epithelium, and inducing apoptosis associated with bitter taste receptors. Our data suggest that bitter-tasting feed additives may have side effects on the growth and development of intestines in chickens.
Positive symptoms are a useful predictor of aggression in schizophrenia. Although a similar pattern of abnormal brain structures related to both positive symptoms and aggression has been reported, this observation has not yet been confirmed in a single sample.
To study the association between positive symptoms and aggression in schizophrenia on a neurobiological level, a prospective meta-analytic approach was employed to analyze harmonized structural neuroimaging data from 10 research centers worldwide. We analyzed brain MRI scans from 902 individuals with a primary diagnosis of schizophrenia and 952 healthy controls.
The result identified a widespread cortical thickness reduction in schizophrenia compared to their controls. Two separate meta-regression analyses revealed that a common pattern of reduced cortical gray matter thickness within the left lateral temporal lobe and right midcingulate cortex was significantly associated with both positive symptoms and aggression.
These findings suggested that positive symptoms such as formal thought disorder and auditory misperception, combined with cognitive impairments reflecting difficulties in deploying an adaptive control toward perceived threats, could escalate the likelihood of aggression in schizophrenia.
Like any therapy, acupuncture is effective for some patients, while not helpful for others. Understanding from a patients' perspective what makes one respond or not to acupuncture can help guide further intervention development. This study aimed to identify factors that influence the perception of acupuncture's therapeutic effect among cancer survivors with insomnia.
We conducted post-treatment semi-structured interviews with cancer survivors who were randomized to the acupuncture group in a clinical trial for the treatment of insomnia. Survivors were categorized into Responders and Non-Responders to acupuncture treatment based on the change in the Insomnia Severity Index with a reduction of eight points or greater as the cut-off for the response. An integrated approach to data analysis was utilized by merging an a priori set of codes derived from the key ideas and a set of codes that emerged from the data through a grounded theory approach. Codes were examined for themes and patterns.
Among 28 cancer survivors interviewed, 18 (64%) were classified as Responders. Participants perceived the ability to respond to acupuncture as dependent on treatment that effectively: (1) alleviated co-morbidities contributing to insomnia, (2) supported sleep hygiene practices, and (3) provided a durable therapeutic effect. Acupuncture treatment that did not address one of these themes often detracted from positive treatment outcomes and diminished perceived benefit from acupuncture.
Significance of results
We identified patient-perceived contributors to response to acupuncture, such as co-morbid medical conditions, adequate support for sleep hygiene practices, and temporary therapeutic relief. Addressing these factors may improve the overall effectiveness of acupuncture for insomnia.