Association between general anesthesia and contrast-induced encephalopathy after endovascular treatment on neurovascular diseases.

Objective: Contrast-induced encephalopathy (CIE) is a rare neurological complication that can occur in the context of various endovascular procedures. Although many potential risk factors for CIE have been reported, it is still unclear whether anesthesia is a risk factor for the occurrence of CIE. The goal of this study was to investigate the incidence of CIE in patients who underwent endovascular treatment under different anesthesia methods and anesthetics administration and to explore whether general anesthesia was a potential risk factor for CIE. Methods: We retrospectively reviewed available clinical data from 1,043 patients with neurovascular diseases undergoing endovascular treatment between June 2018 and June 2021 in our hospital. A propensity score-based matching strategy and logistic regression were used to analyze the association between anesthesia and the occurrence of CIE. Results: In this study, we implemented the embolization of intracranial aneurysm in 412 patients, stent implantation of extracranial artery stenosis in 346, stent implantation of intracranial artery stenosis in 187, embolization of cerebral arteriovenous malformation or dural arteriovenous fistula in 54, endovascular thrombectomy in 20, and other endovascular treatments in 24. A total of 370 patients (35.5%) received treatment under local anesthesia, while the remaining 673 (64.5%) underwent treatment under general anesthesia. In total, 14 patients were identified as CIE, resulting in a total incidence rate of 1.34%. After propensity score-based matching of anesthesia methods, the occurrence of CIE was significantly different between the general anesthesia and local anesthesia group (P = 0.007). After propensity score-based matching of CIE, the anesthesia methods were significantly different between the two groups. Pearson contingency coefficients and logistic regression showed a significant correlation between general anesthesia and the risk of CIE. Conclusion: General anesthesia might be a risk factor for CIE, and propofol might be associated with the increased occurrence of CIE.

Electrochemical sensing mechanism of ammonium ions over an Ag/TiO2 composite electrode modified by hematite.

Here, we demonstrate a new electrochemical sensing mechanism of ammonium ions (NH4+) involving a two-electron oxygen reduction reaction (ORR) and a hydrazine reaction. The NH4+ are electrooxidized to hydrazine by H2O2 derived from the ORR over a self-supporting Ag/TiO2 nanotube array composite electrode modified by hematite (Ag/Fe2O3/TNTs). The Ag/Fe2O3/TNT sensor exhibits a high sensitivity of 1876 µA mM-1 cm-2 with a detection limit of 0.18 µM under non-alkaline conditions, a short response time of 3 s, good reproducibility, and fine selectivity among various interferents, and is also successfully used in real water bodies to display high accuracy. Furthermore, this new mechanism has a certain universality in a range of Ag (main catalyst)/transition metal oxide (cocatalyst)/TNT sensing systems. This work offers a new design basis for the urgently needed electrochemical ammonia nitrogen sensors.

An interpretable stacking ensemble learning framework based on multi-dimensional data for real-time prediction of drug concentration: The example of olanzapine.

Background and Aim: Therapeutic drug monitoring (TDM) has evolved over the years as an important tool for personalized medicine. Nevertheless, some limitations are associated with traditional TDM. Emerging data-driven model forecasting [e.g., through machine learning (ML)-based approaches] has been used for individualized therapy. This study proposes an interpretable stacking-based ML framework to predict concentrations in real time after olanzapine (OLZ) treatment. Methods: The TDM-OLZ dataset, consisting of 2,142 OLZ measurements and 472 features, was formed by collecting electronic health records during the TDM of 927 patients who had received OLZ treatment. We compared the performance of ML algorithms by using 10-fold cross-validation and the mean absolute error (MAE). The optimal subset of features was analyzed by a random forest-based sequential forward feature selection method in the context of the top five heterogeneous regressors as base models to develop a stacked ensemble regressor, which was then optimized via the grid search method. Its predictions were explained by using local interpretable model-agnostic explanations (LIME) and partial dependence plots (PDPs). Results: A state-of-the-art stacking ensemble learning framework that integrates optimized extra trees, XGBoost, random forest, bagging, and gradient-boosting regressors was developed for nine selected features [i.e., daily dose (OLZ), gender_male, age, valproic acid_yes, ALT, K, BW, MONO#, and time of blood sampling after first administration]. It outperformed other base regressors that were considered, with an MAE of 0.064, R-square value of 0.5355, mean squared error of 0.0089, mean relative error of 13%, and ideal rate (the percentages of predicted TDM within ± 30% of actual TDM) of 63.40%. Predictions at the individual level were illustrated by LIME plots, whereas the global interpretation of associations between features and outcomes was illustrated by PDPs. Conclusion: This study highlights the feasibility of the real-time estimation of drug concentrations by using stacking-based ML strategies without losing interpretability, thus facilitating model-informed precision dosing.

Integrating machine learning with electronic health record data to facilitate detection of prolactin level and pharmacovigilance signals in olanzapine-treated patients.

Background and aim: Available evidence suggests elevated serum prolactin (PRL) levels in olanzapine (OLZ)-treated patients with schizophrenia. However, machine learning (ML)-based comprehensive evaluations of the influence of pathophysiological and pharmacological factors on PRL levels in OLZ-treated patients are rare. We aimed to forecast the PRL level in OLZ-treated patients and mine pharmacovigilance information on PRL-related adverse events by integrating ML and electronic health record (EHR) data. Methods: Data were extracted from an EHR system to construct an ML dataset in 672×384 matrix format after preprocessing, which was subsequently randomly divided into a derivation cohort for model development and a validation cohort for model validation (8:2). The eXtreme gradient boosting (XGBoost) algorithm was used to build the ML models, the importance of the features and predictive behaviors of which were illustrated by SHapley Additive exPlanations (SHAP)-based analyses. The sequential forward feature selection approach was used to generate the optimal feature subset. The co-administered drugs that might have influenced PRL levels during OLZ treatment as identified by SHAP analyses were then compared with evidence from disproportionality analyses by using OpenVigil FDA. Results: The 15 features that made the greatest contributions, as ranked by the mean (|SHAP value|), were identified as the optimal feature subset. The features were gender_male, co-administration of risperidone, age, co-administration of aripiprazole, concentration of aripiprazole, concentration of OLZ, progesterone, co-administration of sulpiride, creatine kinase, serum sodium, serum phosphorus, testosterone, platelet distribution width, α-L-fucosidase, and lipoprotein (a). The XGBoost model after feature selection delivered good performance on the validation cohort with a mean absolute error of 0.046, mean squared error of 0.0036, root-mean-squared error of 0.060, and mean relative error of 11%. Risperidone and aripiprazole exhibited the strongest associations with hyperprolactinemia and decreased blood PRL according to the disproportionality analyses, and both were identified as co-administered drugs that influenced PRL levels during OLZ treatment by SHAP analyses. Conclusions: Multiple pathophysiological and pharmacological confounders influence PRL levels associated with effective treatment and PRL-related side-effects in OLZ-treated patients. Our study highlights the feasibility of integration of ML and EHR data to facilitate the detection of PRL levels and pharmacovigilance signals in OLZ-treated patients.

Population pharmacokinetics and dosing optimization of olanzapine in Chinese paediatric patients: Based on the impact of sex and concomitant valproate on clearance.

WHAT IS KNOWN AND OBJECTIVE: Olanzapine is an atypical antipsychotic drug used for mental disorders. There are limited studies providing sufficient pharmacokinetic data, thus the variability of concentrations of olanzapine used in Chinese paediatric patients aged 10 to 17 years remains to be evaluated. METHODS: Therapeutic drug monitoring data were collected from 151 paediatric patients aged 10 to 17 years who received olanzapine. The model was developed with a NONMEM software program. The final model validation and evaluation were assessed by bootstrap, diagnostic scatter plots, and normalized prediction distribution error (NPDE). Regimens of different dosages were simulated to reach the target concentration levels of 20 ng/ml, by using the final model with typical parameters. RESULTS: The one-compartment model was considered the best fit for the data. Typical estimates of the absorption rate constant (Ka), apparent clearance (CL/F), and apparent distribution volume (V/F) in the final model were 0.142 h-1 , 15.4 L/h, and 322 L, respectively. Sex and concomitant valproate (VPA) were included as significant predictors of olanzapine clearance, which was described by the following equation: CL/F = 15.4 × (1 + 0.546 × SEX) × (1 + 0.264 × VPA). Results of Monte-Carlo simulation suggested that male paediatric patients with concomitant VPA were advised to take no less than 15 mg per day of olanzapine orally, and in female paediatric patients with concomitant VPA, a dosing regimen of 10 mg may be sufficient to achieve the therapeutic range of olanzapine. WHAT IS NEW AND CONCLUSION: Our results identified concomitant valproate and sex as significant covariates in olanzapine population pharmacokinetics. Our model may be a useful tool for recommending dosage adjustments for physicians. The pharmacokinetics of olanzapine in patients aged 10 to 17 years was generally similar to that of adults and the elderly.

Single-Stage Endovascular Treatment of Severe Cranial Artery Stenosis Coexisted With Ipsilateral Distal Tandem Intracranial Aneurysm.

Objective: The coexistence of severe cranial artery stenosis and ipsilateral distal tandem intracranial aneurysm is an unusual phenomenon. Currently, there is no consensus to provide treatment guidelines for concomitant lesions. This study aims to evaluate the safety and effectiveness of single-stage endovascular treatment in patients under this special condition. Methods: We illustrated a case series of 10 patients with the coexistence of severe cranial artery stenosis and ipsilateral distal tandem intracranial aneurysm in our hospital. And a systematic PubMed search of English-language literature published between 1990 and 2021 was carried out using the keywords: "(carotid OR vertebral OR subclavian artery stenosis) AND (aneurysm) AND (coincident OR coexist OR concomitant OR simultaneous OR ipsilateral)." Clinical information, including age, gender of the patients, as well as symptoms (artery stenosis or aneurysm), localization of artery stenosis and aneurysm, treatment, and outcome, were collected and analyzed. Results: In the majority of the patients, symptoms were attributed to severe artery stenosis, and the coexisted lesions were located in the anterior circulation system. Most patients achieved an excellent clinical outcome, and no death was observed. No differences were found in a prognosis between single-stage or multiple-stage endovascular treatment. Conclusions: A single-stage endovascular procedure is technically feasible and effective to treat the coexistence of severe cranial artery stenosis and ipsilateral distal tandem intracranial aneurysm in the anterior circulation as well as in the posterior circulation.

Mineral-modulated Co catalyst with enhanced adsorption and dissociation of BH4- for hydrogenation of p-nitrophenol to p-aminophenol.

Slow adsorption and dissociation kinetics of NaBH4 onto the catalyst surface limit the hydrogenation reduction of hazardous p-nitrophenol to worthy p-aminophenol. Herein, we design a mineral-modulated catalyst to facilitate the rate-limiting step. Carbon-coated etched attapulgite (EAtp@C) is obtained by HF treatment. Co/EAtp@C is fabricated via anchoring cobalt nanoparticles (CoNPs) on the carrier EAtp@C. Compared to pure Co, the anchored CoNPs are more electronegative and stable, which provides abundant and stable active sites and accelerates the BH4- adsorption and dissociation. Therefore, Co/EAtp@C leads to nearly 100% reduction of p-nitrophenol to p-aminophenol within 8 min and its apparent rate constant Kapp (0.69 min-1) is 4 times higher than that of pure Co. Thermodynamic calculations show a lower activation energy (37.92 kJ mol-1) of Co/EAtp@C catalyst than that of pure Co. Co/EAtp@C also shows magnetic separability and good stability by remaining 98.6% of catalytic conversion rate after six cycles. Significantly, we detect the active species Co-H, and reveal the electron transfer mechanism between catalysts, BH4-, and p-nitrophenol by electrochemical method. These results offer a fundamental insight into the catalytic mechanism of p-nitrophenol hydrogenation for rational design of efficient catalysts.

Combined oncolytic adenovirus carrying MnSOD and mK5 genes both regulated by survivin promoter has a synergistic inhibitory effect on gastric cancer.

Gastric cancer (GC) is one of the major causes of cancer-related mortality. The use of oncolytic virus for cancer gene-virotherapy is a new approach for the treatment of human cancers. In this study, a novel Survivin promoter-driven recombinant oncolytic adenovirus carrying mK5 or MnSOD gene was constructed, which was modified after deletion of the E1B gene. Human plasminogen Kringle 5 mutant (mK5) and manganese superoxide dismutase (MnSOD) are both potential tumor suppressor genes. By constructing Ad-Surp-mK5 and Ad-Surp-MnSOD oncolytic adenoviruses, we hypothesized that the combination of the two viruses would enhance the therapeutic efficacy of GC as compared to the one virus alone. The results of the in vitro experiments revealed that the combination of adenovirus carrying mK5 and MnSOD gene exhibited stronger cytotoxicity to GC cell lines as compared to the virus alone. Additionally, the virus could selectively kill cancer cells and human somatic cells. Cell staining, flow cytometry, and western blot analysis showed that the combination of two adenoviruses containing therapeutic genes could promote the apoptosis of cancer cells. In vivo experiments further verified that Ad-Surp-mK5 in combination with Ad-Surp-MnSOD exhibited a significant inhibitory effect on the growth of GC tumor xenograft as compared to the virus alone, and no significant difference was observed in the bodyweight of treatment and the normal mice. In conclusion, the combination of our two newly constructed recombinant oncolytic adenoviruses containing mK5 or MnSOD therapeutic genes could significantly inhibit gastric cancer growth by inducing apoptosis, suggestive of its potential for GC therapy.

What to Do About Missed Doses? A Retrospective Study of Olanzapine in the Elderly.

BACKGROUND: Schizophrenia is characterized by a high disease burden. Olanzapine is a common drug used in antipsychotic medication. Little is known about the population pharmacokinetics of olanzapine in elderly patients. Missed doses are a common and unavoidable issue during the treatment of psychiatric diseases, especially in elderly patients. This study aimed to identify what an elderly person should do if doses are inadvertently missed. METHODS: Data were collected from 140 elderly psychiatric patients (aged ≥65 years) who received olanzapine therapy. Olanzapine concentrations were determined by high pressure liquid chromatographic tandem mass spectrometry (HPLC-MS/MS) and a population-based approach was used to quantify the characteristics of elderly patients. A non-linear mixed-effects model was used for data analysis. Simulations based on the final model were applied to predict situations involving a single missed dose or three consecutive missed doses under several remedial regimens. RESULTS: A total of 474 samples from 140 elderly patients were included in the therapeutic drug monitoring (TDM) data analysis. A one-compartment model, with no significant covariates, was developed to describe the population pharmacokinetics of olanzapine in elderly patients. The population predicted systematic clearance (CL/F) and volumes of distribution (V/F) were 18 L/h and 785 L, respectively. The simulation demonstrated that in a missed dose situation, elderly patients should take the regular dose immediately; the refill dose used at the second remedial time point depends on the length of the time delay. CONCLUSION: Here, we used a simulation to provide a remedial regimen for missed doses of olanzapine in the elderly population. Our simulation can provide valuable suggestions for individualized therapy in elderly patients.

Comprehensive Bibliometric Analysis of the Kynurenine Pathway in Mood Disorders: Focus on Gut Microbiota Research.

Background: Emerging evidence implicates the dysregulated kynurenine pathway (KP), an immune-inflammatory pathway, in the pathophysiology of mood disorders (MD), including depression and bipolar disorder characterized by a low-grade chronic pro-inflammatory state. The metabolites of the KP, an important part of the microbiota-gut-brain axis, serve as immune system modulators linking the gut microbiota (GM) with the host central nervous system. Aim: This bibliometric analysis aimed to provide a first glimpse into the KP in MD, with a focus on GM research in this field, to guide future research and promote the development of this field. Methods: Publications relating to the KP in MD between the years 2000 and 2020 were retrieved from the Scopus and Web of Science Core Collection (WoSCC), and analyzed in CiteSpace (5.7 R5W), biblioshiny (using R-Studio), and VOSviewer (1.6.16). Results: In total, 1,064 and 948 documents were extracted from the Scopus and WoSCC databases, respectively. The publications have shown rapid growth since 2006, partly owing to the largest research hotspot appearing since then, "quinolinic acid." All the top five most relevant journals were in the neuropsychiatry field, such as Brain Behavior and Immunity. The United States and Innsbruck Medical University were the most influential country and institute, respectively. Journal co-citation analysis showed a strong tendency toward co-citation of research in the psychiatry field. Reference co-citation analysis revealed that the top four most important research focuses were "kynurenine pathway," "psychoneuroimmunology," "indoleamine 2,3-dioxygenase," and "proinflammatory cytokines," and the most recent focus was "gut-brain axis," thus indicating the role of the KP in bridging the GM and the host immune system, and together reflecting the field's research foundations. Overlap analysis between the thematic map of keywords and the keyword burst analysis revealed that the topics "Alzheimer's disease," "prefrontal cortex," and "acid," were research frontiers. Conclusion: This comprehensive bibliometric study provides an updated perspective on research associated with the KP in MD, with a focus on the current status of GM research in this field. This perspective may benefit researchers in choosing suitable journals and collaborators, and aid in the further understanding of the field's hotspots and frontiers, thus facilitating future research.

Management of Acute Hemorrhage Caused by Cerebral Arteriovenous Malformation During Pregnancy-Case Series and Literature Review.

OBJECTIVE: Acute hemorrhage caused by cerebral arteriovenous malformation (cAVM) during pregnancy is uncommon but life-threatening for both mother and fetus and presents a great challenge to clinical management. However, there is still no consensus on the treatment strategy and the treatment timing of acute hemorrhage from cAVM during pregnancy. The aim of this study was to amalgamate reported case series and our cases regarding the clinical management of pregnant patients under this special condition. METHODS: We report a case series of 3 pregnant patients with acute hemorrhage caused by cAVM in our hospital. A systematic PubMed search of the English-language literature published between 1970 and 2020 was carried out. Clinical information including patients' age, gestational age, imaging studies, treatment strategy, treatment timing, delivery mode, and outcomes were collected and analyzed. RESULTS: The rebleed rate is about 7.1% and the mortality from rebleeding is up to 25%. Treatment modalities included radical surgery, endovascular embolization, radiosurgery/stereotactic radiosurgery, palliative surgery, and conservative treatment. There were no maternal deaths in either the intrapartum intervention group and the postpartum intervention subgroup of gestational age <34 weeks. CONCLUSIONS: A high rebleed rate and high mortality from rebleeding indicate that the intervention of ruptured cAVM should not be delayed. Intervention of ruptured cAVM within 2 weeks after initial hemorrhage is advisable in patients at gestational age <34 weeks, whereas termination of pregnancy as soon as possible followed by timely intervention of ruptured cAVM is practicable in patients at gestational age ≥34 weeks.

Optimization of the Administration Strategy for the Armed Oncolytic Adenovirus ZD55-IL-24 in Both Immunocompromised and Immunocompetent Mouse Models.

ZD55-IL-24 is an armed oncolytic adenovirus similar but superior to ONYX-015. Virotherapeutic strategies using ZD55-IL-24 have been demonstrated to be effective against several cancer types. However, it is unclear whether the traditional administration strategy is able to exert the maximal antitumor efficacy of ZD55-IL-24. In this study, we sought to optimize the administration strategy of ZD55-IL-24 in both A375-bearing immunocompromised mouse model and B16-bearing immunocompetent mouse model. Although the underlying antitumor mechanisms are quite different, the obtained results are similar in these two mouse tumor models. We find that the antitumor efficacy of ZD55-IL-24 increases as injection times increase in both of these two models. However, no obvious increase of efficacy is observed as the dose of each injection increases. Our further investigation reveals that the administration strategy of sustained ZD55-IL-24 therapy can achieve a better therapeutic effect than the traditional administration strategy of short-term ZD55-IL-24 therapy. Furthermore, there is no need to inject every day; every 2 or 3 days of injection achieves an equivalent therapeutic efficacy. Finally, we find that the sustained rather than the traditional short-term ZD55-IL-24 therapy can synergize with anti-PD-1 therapy to reject tumors in B16-bearing immunocompetent mouse model. These findings suggest that the past administration strategy of ZD55-IL-24 is in fact suboptimal and the antitumor efficacy can be further enhanced through administration strategy optimization. This study might shed some light on the development of clinically applicable administration regimens for ZD55-IL-24 therapy.

Enhanced anti-melanoma efficacy through a combination of the armed oncolytic adenovirus ZD55-IL-24 and immune checkpoint blockade in B16-bearing immunocompetent mouse model.

Although the recent treatment in melanoma through the use of anti-PD-1 immunotherapy is successful, the efficacy of this approach remains to be improved. Here, we explore the feasibility of combination strategy with the armed oncolytic adenovirus ZD55-IL-24 and PD-1 blockade. We find that combination therapy with localized ZD55-IL-24 and systemic PD-1 blockade leads to synergistic inhibition of both local and distant established tumors in B16-bearing immunocompetent mouse model. Our further mechanism investigation reveals that synergistic therapeutic effect is associated with marked promotion of tumor immune infiltration and recognition in both local and distant tumors as well as spleens. PD-1 blockade has no obvious effect on promotion of tumor immune infiltration and recognition. Localized therapy with ZD55-IL-24, however, can help PD-1 blockade to overcome the limitation of relatively low tumor immune infiltration and recognition. This study provides a rationale for investigation of such combination therapy in the clinic.

[Effect of acupoint thread-embedding on macrophage polarization of epididymis adipose tissue in obese mice].

OBJECTIVE: To observe the effect of acupoint thread-embedding at "Zusanli" (ST 36) and "Fenglong" (ST 40) on the macrophage polarization of epididymis adipose tissue in obese mice, and to explore the action mechanism of acupoint thread-embedding on weight control. METHODS: Among 30 male C57BL/6 mice, 10 mice were randomly selected and fed with normal diet, and the remaining 20 mice were fed with high-fat diet to establish the obesity model. Sixteen mice with successful obesity model were randomly divided into a model group and an acupoint thread-embedding group, 8 mice in each group. Eight mice were selected from mice which were fed with normal diet as the normal group. On the next day of successful modeling, acupoint thread-embedding was performed at "Zusanli" (ST 36) and "Fenglong" (ST 40) in the acupoint thread-embedding group, once every 10 days for 4 times. The body weight was recorded at 0, 8, 16, 24, 32, 40 days into intervention; the level of glucose metabolism was compared after intervention; the level of lipid metabolism and weight of epididymal adipose tissue were compared at the end of the intervention; the mRNA expression of M1 and M2 macrophage-related cytokines interleukin-10 (IL-6), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) were detected by real-time PCR; the mRNA and protein expression of M1 macrophage labeled inducible nitric oxide synthase (iNOS) and M2 macrophage labeled arginase-1 (Arg-1) were detected by real-time PCR and Western blot. RESULTS: Compared with the normal group, the body weight at 0, 8, 16, 24, 32, 40 days into intervention in the model group was increased (P<0.05); the results of glucose tolerance test at 0, 30, 60, 120 min and insulin tolerance test at 0, 30, 60, 90, 120 min in the model group were higher than those in the normal group (P<0.05); the levels of total cholesterol and triacylglycerol in the model group were significantly higher than those in the normal group (P<0.001, P<0.01); the weight of epididymal adipose tissue in the model group was significantly higher than that in the normal group (P<0.001); the mRNA expression of IL-6, MCP-1, TNF-α and iNOS was increased (P<0.05, P<0.01, P<0.001), that of IL-10, Arg-1 was decreased (P<0.01), the protein expression of iNOS was up-regulated (P<0.01), and that of Arg-1 was down-regulated (P<0.001). Compared with the model group, the body weight at 16, 24, 32, 40 days into treatment in the acupoint thread-embedding group was reduced (P<0.05); the results of glucose tolerance test at 30, 60, 120 min and insulin tolerance test at 30, 60 min in the acupoint thread-embedding group were lower than those in the model group (P<0.05); the levels of total cholesterol and triacylglycerol in the acupoint thread-embedding group were significantly lower than those in the model group (P<0.01, P<0.05); the weight of epididymal adipose tissue in the acupoint thread-embedding group was significantly lower than that in the model group (P<0.01); the mRNA expression of IL-6, MCP-1, TNF-α and iNOS was reduced (P<0.05), that of IL-10, Arg-1 was increased (P<0.05), the protein expression of iNOS was down-regulated (P<0.05), and that of Arg-1 was up-regulated (P<0.01). CONCLUSION: Acupoint thread-embedding at "Zusanli" (ST 36) and "Fenglong" (ST 40) may play a role in weight control by regulating the polarization of macrophages.

A machine learning approach to personalized dose adjustment of lamotrigine using noninvasive clinical parameters.

The pharmacokinetic variability of lamotrigine (LTG) plays a significant role in its dosing requirements. Our goal here was to use noninvasive clinical parameters to predict the dose-adjusted concentrations (C/D ratio) of LTG based on machine learning (ML) algorithms. A total of 1141 therapeutic drug-monitoring measurements were used, 80% of which were randomly selected as the "derivation cohort" to develop the prediction algorithm, and the remaining 20% constituted the "validation cohort" to test the finally selected model. Fifteen ML models were optimized and evaluated by tenfold cross-validation on the "derivation cohort," and were filtered by the mean absolute error (MAE). On the whole, the nonlinear models outperformed the linear models. The extra-trees' regression algorithm delivered good performance, and was chosen to establish the predictive model. The important features were then analyzed and parameters of the model adjusted to develop the best prediction model, which accurately described the C/D ratio of LTG, especially in the intermediate-to-high range (≥ 22.1 µg mL-1 g-1 day), as illustrated by a minimal bias (mean relative error (%) = + 3%), good precision (MAE = 8.7 µg mL-1 g-1 day), and a high percentage of predictions within ± 20% of the empirical values (60.47%). This is the first study, to the best of our knowledge, to use ML algorithms to predict the C/D ratio of LTG. The results here can help clinicians adjust doses of LTG administered to patients to minimize adverse reactions.

The armed oncolytic adenovirus ZD55-IL-24 eradicates melanoma by turning the tumor cells from the self-state into the nonself-state besides direct killing.

ZD55-IL-24 is similar but superior to the oncolytic adenovirus ONYX-015, yet the exact mechanism underlying the observed therapeutic effect is still not well understood. Here we sought to elucidate the underlying antitumor mechanism of ZD55-IL-24 in both immunocompetent and immunocompromised mouse model. We find that ZD55-IL-24 eradicates established melanoma in B16-bearing immunocompetent mouse model not through the classic direct killing pathway, but mainly through the indirect pathway of inducing systemic antitumor immunity. Inconsistent with the current prevailing view, our further results suggest that ZD55-IL-24 can induce antitumor immunity in B16-bearing immunocompetent mouse model in fact not due to its ability to lyse tumor cells and release the essential elements, such as tumor-associated antigens (TAAs), but due to its ability to put a "nonself" label in tumor cells and then turn the tumor cells from the "self" state into the "nonself" state without tumor cell death. The observed anti-melanoma efficacy of ZD55-IL-24 in B16-bearing immunocompetent mouse model was practically caused only by the viral vector. In addition, we also notice that ZD55-IL-24 can inhibit tumor growth in B16-bearing immunocompetent mouse model through inhibiting angiogenesis, despite it plays only a minor role. In contrast to B16-bearing immunocompetent mouse model, ZD55-IL-24 eliminates established melanoma in A375-bearing immunocompromised mouse model mainly through the classic direct killing pathway, but not through the antitumor immunity pathway and anti-angiogenesis pathway. These findings let us know ZD55-IL-24 more comprehensive and profound, and provide a sounder theoretical foundation for its future modification and drug development.

Effect of venlafaxine dosage, valproic acid concentration, sex, and age on steady state dose-corrected concentrations of venlafaxine and O-desmethylvenlafaxine: A retrospective analysis of therapeutic drug monitoring data in a Chinese population.

PURPOSE: This study aimed to investigate the influence of diagnosis, body weight, sex, age, smoking, formulations, and concomitant drugs on steady-state dose-corrected serum concentrations (C/D) of venlafaxine (VEN) and O-desmethylvenlafaxine (ODV). METHODS: A retrospective analysis of therapeutic drug monitoring (TDM) was carried out. Patients' demographic data, therapeutic regimens, and concentrations were collected. RESULTS: We included 91 verified samples from 80 patients. Females had by average 13% smaller body weight, 50% higher C/D of VEN, and VEN + ODV and 25% smaller ODV/VEN than males. Patients >60 years had by average 33-59% higher C/D levels of ODV and VEN + ODV than younger patients. The concomitant use of valproic acid caused an average 51% higher C/D of ODV and a 2.2-fold larger ODV/VEN, while clozapine was related with 40% smaller ratio of ODV/VEN and 38% lower C/D levels of ODV. Positive correlations were detected between valproic acid concentrations and the C/D of VEN and VEN + ODV. In a multiple linear regression analysis, variance in the C/D of VEN + ODV was partly attributed to the daily dose of VEN, sex, age and valproic acid concentration. CONCLUSION: Our results suggested daily dose of VEN, sex, age, and valproic acid as indicators for the C/D of VEN + ODV in Chinese patients. TDM as a valuable tool was suggested in elderly female patients and patients receiving polypharmacy.

Development and Validation of a Hydrophilic Interaction Liquid Chromatography Tandem Mass Spectrometry Method for the Determination of Asparagine in Human Serum.

L-Asparagine (ASN) is the catalyze substrate of L-asparaginase (ASNase), which is an important drug for acute lymphoblastic leukemia (ALL) patients. The ASN level is found to be closely associated with the effectiveness of ASNase treatment. In this study, a hydrophilic interaction liquid chromatography tandem mass spectrometry (HILIC-MS/MS) method was developed for the determination of ASN in the human serum using a stable isotope-labeled internal standard (ASN-D3). Serum samples were prepared by a one-step precipitation procedure using methanol and separated by an Agilent HILIC Plus column with the mobile phase of methanol-water (95 : 5, v/v, containing 5 mM ammonium formate and 0.1% formic acid), at a constant flow rate of 0.3 mL/min. Mass spectrometric analysis was conducted using multiple-reaction monitoring in the positive electrospray ionization mode. Serum ASN concentrations were determined over a linear calibration curve range of 2-200 µM, with acceptable accuracies and precisions. The validated HILIC-MS/MS method was successfully applied to the quantification of ASN levels in the serum from patients with ALL. Collectively, the research may shed new light on an alternative rapid, simple, and convenient quantitative method for determination of serum ASN in ALL patients treated with ASNase.

A Retrospective Analysis of Steady-State Olanzapine Concentrations in Chinese Patients Using Therapeutic Drug Monitoring: Effects of Valproate and Other Factors.

BACKGROUND: The objective of this study was to investigate the serum concentrations of olanzapine in relation to age, sex, and other factors in Chinese patients aged between 10 and 90 years. METHODS: Data for 884 olanzapine patients, deposited between 2016 and 2017, were retrieved from the therapeutic drug monitoring database of the Affiliated Brain Hospital of Guangzhou Medical University. The effects of covariates on serum olanzapine concentration, dose-normalized concentration (C/D ratio), and normalized concentration (C/D/weight) were investigated. RESULTS: Generally, male patients had lower olanzapine concentration, C/D ratio, and C/D/weight than female patients (P < 0.001). Smoking and drinking reduced olanzapine concentration, C/D ratio, and C/D/weight (P < 0.001). Coadministration with valproate decreased olanzapine concentration, C/D ratio, and C/D/weight by about 16%, 30%, and 40%, respectively (P < 0.001). Patients younger than 60 years had higher olanzapine concentrations (P < 0.05) but lower C/D ratios and C/D/weight (P < 0.001) than patients older than 60 years. Age was correlated with olanzapine concentration (r = -0.082, P < 0.05), C/D ratio (r = 0.196, P < 0.001), and C/D/weight (r = 0.169, P < 0.001). Sample timing after dose and diagnostic factors also contributed to the olanzapine concentrations. Multiple linear regression analysis revealed significant influences of dosage, age, sex, valproate comedication, smoking, postdose interval, and schizophrenia (vs bipolar affective disorders) on serum olanzapine concentrations. CONCLUSIONS: The metabolism of olanzapine may be altered by several factors. Patients characterized with a combination of factors may benefit from therapeutic drug monitoring for the adjustment of olanzapine dose to minimize adverse reactions.

Bibliometric and Visual Analysis of Research on the Links Between the Gut Microbiota and Depression From 1999 to 2019.

Background: There is a crucial link between the gut microbiota and the host central nervous system, and the communication between them occurs via a bidirectional pathway termed the "microbiota-gut-brain axis." The gut microbiome in the modern environment has markedly changed in response to environmental factors. These changes may affect a broad range of host psychiatric disorders, such as depression, by interacting with the host through metabolic, immune, neural, and endocrine pathways. Nevertheless, the general aspects of the links between the gut microbiota and depression have not been systematically investigated through bibliometric analysis. Aim: This study aimed to analyze the current status and developing trends in gut microbiota research in the depression field through bibliometric and visual analysis. Methods: A total of 1,962 publications published between 1999 and 2019 were retrieved from the Web of Science Core Collection. CiteSpace (5.6 R5) was used to perform collaboration network analysis, co-citation analysis, co-occurrence analysis, and citation burst detection. Results: The number of publications has been rapidly growing since 2010. The collaboration network analysis revealed that the USA, University College Cork, and John F. Cryan were the most influential country, institute, and scholar, respectively. The most productive and co-cited journals were Brain Behavior and Immunity and Proceedings of the National Academy of Sciences of the United States of America, respectively. The co-citation analysis of references revealed that the most recent research focus was in the largest theme cluster, "cytokines," thus reflecting the important research foundation in this field. The co-occurrence analysis of keywords revealed that "fecal microbiota" and "microbiome" have become the top two research hotspots since 2013. The citation burst detection for keywords identified several keywords, including "Parkinson's disease," "microbiota-gut-brain axis," "microbiome," "dysbiosis," "bipolar disorder," "impact," "C reactive protein," and "immune system," as new research frontiers, which have currently ongoing bursts. Conclusions: These results provide an instructive perspective on the current research and future directions in the study of the links between the gut microbiota and depression, which may help researchers choose suitable cooperators or journals, and promote their research illustrating the underlying molecular mechanisms of depression, including its etiology, prevention, and treatment.