PI3K-AKT/mTOR Signaling in Psychiatric Disorders: A Valuable Target to Stimulate or Suppress?

Economic development and increased stress have considerably increased the prevalence of psychiatric disorders in recent years, which rank as some of the most prevalent diseases globally. Several factors, including chronic social stress, genetic inheritance, and autogenous diseases, lead to the development and progression of psychiatric disorders. Clinical treatments for psychiatric disorders include psychotherapy, chemotherapy, and electric shock therapy. Although various achievements have been made researching psychiatric disorders, the pathogenesis of these diseases has not been fully understood yet, and serious adverse effects and resistance to antipsychotics are major obstacles to treating patients with psychiatric disorders. Recent studies have shown that the mammalian target of rapamycin (mTOR) is a central signaling hub that functions in nerve growth, synapse formation, and plasticity. The PI3K-AKT/mTOR pathway is a critical target for mediating the rapid antidepressant effects of these pharmacological agents in clinical and preclinical research. Abnormal PI3K-AKT/mTOR signaling is closely associated with the pathogenesis of several neurodevelopmental disorders. In this review, we focused on the role of mTOR signaling and the related aberrant neurogenesis in psychiatric disorders. Elucidating the neurobiology of the PI3K-AKT/mTOR signaling pathway in psychiatric disorders and its actions in response to antidepressants will help us better understand brain development and quickly identify new therapeutic targets for the treatment of these mental illnesses.

Echocardiographic assessment of Xenopus tropicalis heart regeneration.

BACKGROUND: Recently, it was reported that the adult X. tropicalis heart can regenerate in a nearly scar-free manner after injury via apical resection. Thus, a cardiac regeneration model in adult X. tropicalis provides a powerful tool for recapitulating a perfect regeneration phenomenon, elucidating the underlying molecular mechanisms of cardiac regeneration in an adult heart, and developing an interventional strategy for the improvement in the regeneration of an adult heart, which may be more applicable in mammals than in species with a lower degree of evolution. However, a noninvasive and rapid real-time method that can observe and measure the long-term dynamic change in the regenerated heart in living organisms to monitor and assess the regeneration and repair status in this model has not yet been established. RESULTS: In the present study, the methodology of echocardiographic assessment to characterize the morphology, anatomic structure and cardiac function of injured X. tropicalis hearts established by apex resection was established. The findings of this study demonstrated for the first time that small animal echocardiographic analysis can be used to assess the regeneration of X. tropicalis damaged heart in a scar-free perfect regeneration or nonperfect regeneration with adhesion manner via recovery of morphology and cardiac function. CONCLUSIONS: Small animal echocardiography is a reliable, noninvasive and rapid real-time method for observing and assessing the long-term dynamic changes in the regeneration of injured X. tropicalis hearts.

Applying Simulation Optimization to Minimize Drug Inventory Costs: A Study of a Case Outpatient Pharmacy.

Drug inventory management is an important part of hospital management. The large amounts of drug data in hospitals bring challenges to optimizing the setting values for the safety stock and the maximum inventory of each drug. This study combined a two-stage clustering method with an inventory policy (s, S) and established a simulation optimization model for the case hospital's outpatient pharmacy. This research used the simulation optimization software Arena OptQuest, developed by Rockwell Automation Inc (Rockwell Automation, Coraopolis, PA, USA), in order to determine the minimum and maximum values (s, S) of the best stock amounts for each drug under the considerations of cost and related inventory constraints. The research results showed that the minimum and maximum inventory settings for each drug in the simulation model were better than those set by the case outpatient pharmacy system. The average inventory cost was reduced by 55%, while the average inventory volume was reduced by 68%. The proposed method can improve management efficiency and inventory costs of hospital pharmacies without affecting patient services and increasing the inventory turnover rate of the drugs.

Sex Disparities in the Association of Serum Uric Acid With Kidney Stone: A Cross-Sectional Study in China.

BACKGROUND AND AIMS: Urolithiasis is characterized by high rates of prevalence and recurrence. Hyperuricemia is related to various diseases. We hope to determine the association between serum uric acid (UA) level and kidney stone (KS). METHODS: In this population-based cross-sectional study, a total of 82,017 Chinese individuals who underwent a comprehensive examination in 2017 were included. The KS was diagnosed based on ultrasonography examination outcomes. Fully adjusted odds ratio (OR) for KS, and mean difference between the two groups were applied to determine the association of UA level with KS. RESULTS: Among the 82,017 participants included in this study (aged 18~99 years), 9,435 participants (11.5%) are diagnosed with KS. A proportion of 56.3% of individuals is male. The mean UA level of overall participants is 341.77 µmol/L. The participants with KS report higher UA level than the participants without KS [mean UA level 369.91 vs. 338.11 µmol/L; mean difference (MD), 31.96 (95% CI, 29.61~34.28) µmol/L]. In men, the OR for KS significantly increases from 330 µmol/L UA level. Every 50 µmol/L elevation of UA level increases the risk of KS formation by about 10.7% above the UA level of 330 µmol/L in men. The subgroup analysis for male is consistent with the overall result except for the participants presenting underweight [adjusted OR, 1.035 (0.875~1.217); MD, -5.57 (-16.45~11.37)], low cholesterol [adjusted OR, 1.088 (0.938~1.261); MD, 8.18 (-7.93~24.68)] or high estimated glomerular filtration rate (eGFR) [adjusted OR, 1.044 (0.983~1.108); MD, 5.61 (-1.84~13.36)]. However, no significant association is observed in women between UA and KS either in all female participants or in female subgroups. CONCLUSION: Among Chinese adults, UA level is associated with KS in a dose-response manner in men but not in women. However, the association becomes considerably weak in male participants with malnutrition status.

Methacholine bronchial provocation test for assessment of bronchial hyperresponsiveness in preschool children.

BACKGROUND: Bronchial hyperresponsiveness (BHR) has not been extensively performed in preschool children, possibly because of the difficulty in cooperating with the tests. We sought to determine the usefulness and safety of methacholine bronchial provocation test (MCh-BPT) for BHR assessment in preschool children. METHODS: We recruited 252 preschool children (190 healthy and 62 with wheezing) who underwent MCh-BPT at baseline. MCh-BPT was re-scheduled in case initial attempts failed. Forced expiratory volumes in 0.5 (FEV0.5), 0.75 (FEV0.75) and one second (FEV1) were measured. We recorded the provocative dose causing 15% (PD15) or 20% reduction (PD20) in FEV0.5, FEV0.75 and FEV1, thus allowing for comparison of the diagnostic value of PD15 and PD20. RESULTS: A total of 209 children [156 (82.1%) healthy, 53 (85.5%) with wheezing] successfully completed MCh-BPT. Compared with healthy children, a significantly greater proportion of children with wheezing had measurable PD15FEV0.5, PD15FEV0.75 and PD15FEV1 (P<0.01), and PD20FEV0.5, PD20FEV0.75 and PD20FEV1 (P<0.05). The sensitivity was 92.5% and 94.3% for PD20FEV1, and PD15FEV1 and the specificity was 93.6% and 93.6% respectively, for discriminating asthmatic from healthy children. CONCLUSIONS: Most preschool children successfully and safely complete MCh-BPT, with higher success rate in larger age group. PD20FEV0.5 and PD20FEV0.75 can be surrogates of PD20FEV1 among children whose expiration lasted for less than one second. PD15 has a good diagnostic value as PD20 for diagnosing of BHR in preschool children, which are also more suitable for children five years old or elder.

Cost-Effectiveness of Bariatric Surgery versus Medication Therapy for Obese Patients with Type 2 Diabetes in China: A Markov Analysis.

AIMS/INTRODUCTION: The present study estimated the cost-effectiveness of bariatric surgery versus medication therapy for the management of recently diagnosed type 2 diabetes mellitus (T2DM) in obese patients from a Chinese health insurance payer perspective. MATERIALS AND METHODS: A Markov model was established to compare the 40-year time costs and quality-adjusted life-years (QALYs) between bariatric surgery and medication therapy. The health-care costs in the bariatric surgery group, proportion of patients in each group with remission of diabetes, and state transition probabilities were calculated based on observed resource utilization from the hospital information system (HIS). The corresponding costs in the medication therapy group were derived from the medical insurance database. QALYs were estimated from previous literature. Costs and outcomes were discounted 5% annually. RESULTS: In the base case analysis, bariatric surgery was more effective and less costly than medication therapy. Over a 40-year time horizon, the mean discounted costs were 86,366.55 RMB per surgical therapy patient and 113,235.94 CNY per medication therapy patient. The surgical and medication therapy patients lived 13.46 and 10.95 discounted QALYs, respectively. Bariatric surgery was associated with a mean health-care savings of 26,869.39 CNY and 2.51 additional QALYs per patient compared to medication therapy. Uncertainty around the parameter values was tested comprehensively in sensitivity analyses, and the results were robust. CONCLUSIONS: Bariatric surgery is a dominant intervention over a 40-year time horizon, which leads to significant cost savings to the health insurance payer and increases in health benefits for the management of recently diagnosed T2DM in obese patients in China.

Potential travel cost saving in urban public-transport networks using smartphone guidance.

Public transport (PT) is a key element in most major cities around the world. With the development of smartphones, available journey planning information is becoming an integral part of the PT system. Each traveler has specific preferences when undertaking a trip, and these preferences can also be reflected on the smartphone. This paper considers transit assignment in urban public-transport networks in which the passengers receive smartphone-based information containing elements that might influence the travel decisions in relation to line loads, as well as passenger benefits, and the paper discusses the transition from the current widespread choosing approach to a personalized decision-making approach based on smartphone information. The approach associated with smartphone guidance that considers passengers' preference on travel time, waiting time and transfer is proposed in the process of obtaining his/her preferred route from the potential travel routes generated by the Deep First Search (DFS) method. Two other approaches, based on the scenarios reflecting reality, include passengers with access to no real time information, and passengers that only have access to the arrival time at the platform are used as comparisons. For illustration, the same network proposed by Spiess and Florian is utilized on the experiments in an agent-based model. Two experiments are conducted respectively according to whether each passenger's choosing method is consistent. As expected, the results in the first experiment showed that the travel for consistent passengers with smartphone guidance was clearly shorter and that it can reduce travel time exceeding 15% and weighted cost exceeding 20%, and the average saved time approximated 3.88 minutes per passenger. The second experiment presented that travel cost, as well as cost savings, gradually decreased by employing smartphone guidance, and the maximum cost savings accounted for 14.2% of the total weighted cost.

Kaleido: Visualizing Big Brain Data with Automatic Color Assignment for Single-Neuron Images.

Effective 3D visualization is essential for connectomics analysis, where the number of neural images easily reaches over tens of thousands. A formidable challenge is to simultaneously visualize a large number of distinguishable single-neuron images, with reasonable processing time and memory for file management and 3D rendering. In the present study, we proposed an algorithm named "Kaleido" that can visualize up to at least ten thousand single neurons from the Drosophila brain using only a fraction of the memory traditionally required, without increasing computing time. Adding more brain neurons increases memory only nominally. Importantly, Kaleido maximizes color contrast between neighboring neurons so that individual neurons can be easily distinguished. Colors can also be assigned to neurons based on biological relevance, such as gene expression, neurotransmitters, and/or development history. For cross-lab examination, the identity of every neuron is retrievable from the displayed image. To demonstrate the effectiveness and tractability of the method, we applied Kaleido to visualize the 10,000 Drosophila brain neurons obtained from the FlyCircuit database ( http://www.flycircuit.tw/modules.php?name=kaleido ). Thus, Kaleido visualization requires only sensible computer memory for manual examination of big connectomics data.

Fairness in optimizing bus-crew scheduling process.

This work proposes a model considering fairness in the problem of crew scheduling for bus drivers (CSP-BD) using a hybrid ant-colony optimization (HACO) algorithm to solve it. The main contributions of this work are the following: (a) a valid approach for cases with a special cost structure and constraints considering the fairness of working time and idle time; (b) an improved algorithm incorporating Gamma heuristic function and selecting rules. The relationships of each cost are examined with ten bus lines collected from the Beijing Public Transport Holdings (Group) Co., Ltd., one of the largest bus transit companies in the world. It shows that unfair cost is indirectly related to common cost, fixed cost and extra cost and also the unfair cost approaches to common and fixed cost when its coefficient is twice of common cost coefficient. Furthermore, the longest time for the tested bus line with 1108 pieces, 74 blocks is less than 30 minutes. The results indicate that the HACO-based algorithm can be a feasible and efficient optimization technique for CSP-BD, especially with large scale problems.

Residual volume/total lung capacity ratio confers limited additive significance to lung clearance index for assessment of adults with bronchiectasis.

BACKGROUND: Mosaicism and hyperinflation are common pathophysiologic features of bronchiectasis. The magnitude of ventilation heterogeneity might have been affected by the degree of hyperinflation. Some studies have evaluated the discriminative performance of lung clearance index (LCI) in bronchiectasis patients, but the additive diagnostic value of hyperinflation metrics to LCI is unknown. OBJECTIVE: To compare LCI and the ratio of residual volume to total lung capacity (RV/TLC), along with the LCI normalized with RV/TLC, in terms of discriminative performance, correlation and concordance with clinical variables in adults with bronchiectasis. METHODS: Measurement items included chest high-resolution computed tomography, multiple-breath nitrogen washout test, spirometry, and sputum culture. We analyzed bronchodilator responses by stratifying LCI and RV/TLC according to their median levels (LCIHigh/RV/TLCHigh, LCILow/RV/TLCHigh, LCIHigh/RV/TLCLow, and LCILow/RV/TLCLow). RESULTS: Data from 127 adults with clinically stable bronchiectasis were analyzed. LCI had greater diagnostic value than RV/TLC in discriminating moderate-to-severe from mild bronchiectasis, had greater concordance in reflecting clinical characteristics (including the number of bronchiectatic lobes, radiological severity score, and the presence of cystic bronchiectasis). Normalization of LCI with RV/TLC did not contribute to greater discriminative performance or concordance with clinical variables. The LCI, before and after normalization with RV/TLC, correlated statistically with age, sex, HRCT score, Pseudomonas aeruginosa colonization, cystic bronchiectasis, and ventilation heterogeneity (all P<0.05). Different bronchodilator responses were not significant among the four subgroups of bronchiectasis patients, including those with discordant LCI and RV/TLC levels. CONCLUSION: LCI is superior to RV/TLC for bronchiectasis assessment. Normalization with RV/TLC is not required. Stratification of LCI and RV/TLC is not associated with significantly different bronchodilator responses.

Adenosine monophosphate is not superior to histamine for bronchial provocation test for assessment of asthma control and symptoms.

BACKGROUND: Adenosine monophosphate (AMP) may reflect airway inflammation and hyperresponsiveness, but relationship between AMP and histamine (His, a conventional stimulus) bronchial provocation test (BPT) in asthma is not fully elucidated. OBJECTIVES: To compare both BPTs and determine their utility in reflecting changes of asthmatic symptoms. METHODS: BPTs were performed in a cross-over fashion, at 2-4 day intervals. Cumulative doses eliciting 20% FEV1 fall (PD20 FEV1 ), diagnostic performance and adverse events (AEs) were compared. Patients with PD20 FEV1 lower than geometric mean were defined as responders, otherwise poor responders. Patients with uncontrolled and partly controlled asthma, who maintained their original inhaled corticosteroids therapy, underwent reassessment of airway responsiveness and asthmatic symptoms 3 and 6 months after. RESULTS: Nineteen uncontrolled, 22 partly controlled and 19 controlled asthmatic patients and 24 healthy subjects were recruited. Lower PD20 FEV1 geometric means were associated with poorer asthma control in His-BPT (0.424 µmol vs 1.684 µmol vs 3.757 µmol), but not AMP-BPT (11.810 µmol vs 7.781 µmol vs 10.220 µmol). Both BPTs yielded similar overall diagnostic performance in asthma (area under curve: 0.842 in AMP-BPT vs 0.850 in His-BPT). AEs, including wheezing and tachypnea, were similar and mild. Ten patients with uncontrolled and 10 partly controlled asthma were followed-up. At months 3 and 6, we documented an increase in PD20 FEV1 -AMP and PD20 FEV1 -His, which did not correlate with reduction asthmatic symptom scores. This overall applied in responders and poor responders of AMP-BPT and His-BPT. CONCLUSION: Despite higher screening capacity of well-controlled asthma, AMP-BPT confers similar diagnostic performance and safety with His-BPT. AMP-BPT might not preferentially reflect changes asthmatic symptoms.

Impact of air pollution on the burden of chronic respiratory diseases in China: time for urgent action.

In China, where air pollution has become a major threat to public health, public awareness of the detrimental effects of air pollution on respiratory health is increasing-particularly in relation to haze days. Air pollutant emission levels in China remain substantially higher than are those in developed countries. Moreover, industry, traffic, and household biomass combustion have become major sources of air pollutant emissions, with substantial spatial and temporal variations. In this Review, we focus on the major constituents of air pollutants and their impacts on chronic respiratory diseases. We highlight targets for interventions and recommendations for pollution reduction through industrial upgrading, vehicle and fuel renovation, improvements in public transportation, lowering of personal exposure, mitigation of the direct effects of air pollution through healthy city development, intervention at population-based level (systematic health education, intensive and individualised intervention, pre-emptive measures, and rehabilitation), and improvement in air quality. The implementation of a national environmental protection policy has become urgent.

Maximal mid-expiratory flow is a surrogate marker of lung clearance index for assessment of adults with bronchiectasis.

Little is known about the comparative diagnostic value of lung clearance index (LCI) and maximal mid-expiratory flow (MMEF) in bronchiectasis. We compared the diagnostic performance, correlation and concordance with clinical variables, and changes of LCI and MMEF% predicted during bronchiectasis exacerbations (BEs). Patients with stable bronchiectasis underwent history inquiry, chest high-resolution computed tomography (HRCT), multiple-breath nitrogen wash-out test, spirometry and sputum culture. Patients who experienced BEs underwent these measurements during onset of BEs and 1 week following antibiotics therapy. Sensitivity analyses were performed in mild, moderate and severe bronchiectasis. We recruited 110 bronchiectasis patients between March 2014 and September 2015. LCI demonstrated similar diagnostic value with MMEF% predicted in discriminating moderate-to-severe from mild bronchiectasis. LCI negatively correlated with MMEF% predicted. Both parameters had similar concordance in reflecting clinical characteristics of bronchiectasis and correlated significantly with forced expiratory flow in one second, age, HRCT score, Pseudomonas aeruginosa colonization, cystic bronchiectasis, ventilation heterogeneity and bilateral bronchiectasis. In exacerbation cohort (n = 22), changes in LCI and MMEF% predicted were equally minimal during BEs and following antibiotics therapy. In sensitivity analyses, both parameters had similar diagnostic value and correlation with clinical variables. MMEF% predicted is a surrogate of LCI for assessing bronchiectasis severity.

A Decision Tree Based Classifier to Analyze Human Ovarian Cancer cDNA Microarray Datasets.

Ovarian cancer is the deadliest gynaecological disease because of the high mortality rate and there is no any symptom in cancer early stage. It was often the terminal cancer period when patients were diagnosed with ovarian cancer and thus delays a good opportunity of treatment. The current common method for detecting ovarian cancer is blood testing for analyzing the tumor marker CA-125 of serum. However, specificity and sensitivity of CA-125 are insufficient for early detection. Therefore, it has become an urgent issue to look for an efficient method which precisely detects the tumor markers for ovarian cancer. This study aims to find the target genes of ovarian cancer by different algorithms of information science. Feature selection and decision tree were applied to analyze 9600 ovarian cancer-related genes. After screening the target genes, candidate genes will be analyzed by Ingenuity Pathway Analysis (IPA) software to create a genetic pathway model and to understand the interactive relationship in the different pathological stages of ovarian cancer. Finally, this research found 9 oncogenes associated with ovarian cancer and some genes had not been discovered in previous studies. This system will assist medical staffs in diagnosis and treatment at cancer early stage and improve the patient's survival.

Quality Assessment of Clinical Practice Guidelines for Respiratory Diseases in China: A Systematic Appraisal.

BACKGROUND: There has been a significant increase in the publication of clinical practice guidelines (CPGs) for respiratory diseases in China. However, little is known about the quality and potential impacts of these CPGs. Our objective was to critically evaluate the quality of Chinese CPGs for respiratory diseases that were published in peer-reviewed medical journals. METHODS: A systematic search of scientific literature published between 1979 and 2013 was undertaken to identify and select CPGs that were related to respiratory diseases. Four Chinese databases (the Chinese Biomedical Literature database [CBM], the China National Knowledge Infrastructure [CNKI], the VIP database, and the WANFANG database) were used. The quality of eligible guidelines was assessed independently by four reviewers using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. The overall agreement among reviewers was evaluated using an intraclass correlation coefficient. RESULTS: A total of 109 guidelines published in 27 medical journals from 1979 to 2013 were evaluated. The overall agreement among reviewers was considered good (intraclass correlation coefficient, 0.838; 95% CI, 0.812-0.862). The scores of the six AGREE domains were low: 57.3% for scope and purpose (range, 4.2%-80.5%), 23.8% for stakeholder involvement (range, 2.8%-54.2%), 7.7% for rigor of development (range, 0%-27.1%), 59.8% for clarity and presentation (range, 22.2%-80.6%), 10.9% for applicability (range, 0%-22.9%), and 0.6% for editorial independence (range, 0%-16.7%). Scores for all guidelines were below 60%, and only three guidelines (2.8%) were recommended for clinical practice with modifications. CONCLUSIONS: The quality of the guidelines was low, and stakeholder involvement, rigor of development, applicability, and editorial independence should be considered in the future development of CPGs for respiratory diseases in China.

The effect of socioeconomic and individual factors on acceptance levels of bariatric surgery among Chinese patients.

BACKGROUND: The prevalence of obesity has been increasing over the past years in China. Bariatric surgery is an effective treatment that has been gradually accepted by obese patients. This study explored the effect of different factors on the acceptance levels of bariatric surgery. METHODS: A total of 186 obese patients (body mass index [BMI] ≥ 32 kg/m(2)) answered a questionnaire, including questions about their marital status, income level, education level, health insurance, and obesity-associated co-morbidities; 84 of these patients underwent bariatric surgery. The data was analyzed using the χ(2) test. RESULTS: Univariate analyses found that age, BMI, gluttonous behavior, income level, health insurance, medications, and weight loss expectations were correlated with the acceptance of bariatric surgery. Multivariate analyses found that BMI (P = .034) and weight loss expectations (P = .001) were positively correlated with the acceptance of bariatric surgery. Patients with gluttonous behavior accepted bariatric surgery (P = .003). However, income levels (P<.001) and health insurance (P = .001) were negatively correlated with the acceptance of bariatric surgery. CONCLUSION: Obesity was more prevalent in families of low social status and income levels; this group requires medical assistance, and education is still necessary for obese individuals of high social status and income levels.

[Assessment on the criminal responsibility of drug-induced mental disorders: a questionnaire survey].

OBJECTIVE: To understand the assessment on the criminal responsibility of drug-induced mental disorders and judicial experts' opinions. METHODS: The judicial experts from institutes of forensic psychiatry in Shanghai were selected. They were asked to finish a self-made questionnaire of assessment on the criminal responsibility of drug-induced mental disorders by letters and visits. RESULTS: Most of experts knew the special regulation, "not suitable for evaluation" towards the criminal responsibility of drug-induced mental disorders of the guideline promulgated by Ministry of Justice. Before and after the guideline was issued, no expert made a no-responsibility opinion in such cases. After the guideline was issued, some experts made a full-responsibility or limited-responsibility opinion in such cases. There was a little disagreement among the experts in the case that the crime was unrelated with mental symptoms or the criminals used drugs even though he knew it could induced insanity. But there were still many obvious disagreements among experts in the case that crime was related to such symptoms and person was no ability to debate. Most experts agreed to settle the disagreements with improved legislative perfection. CONCLUSION: Most experts are not strictly complying with the assessment guidelines during their practice, and there is still an obvious disagreement towards the criminal responsibility of drug-induced mental disorders.