Artificial Neural Network Analysis of Determinants of Tacrolimus Pharmacokinetics in Liver Transplant Recipients.

BACKGROUND: The efficacy and toxicity of tacrolimus are closely related to its trough blood concentrations. Identifying the influencing factors of pharmacokinetics of tacrolimus in the early postoperative period is conducive to the optimization of the individualized tacrolimus administration protocol and to help liver transplant (LT) recipients achieve the target blood concentrations. OBJECTIVE: This study aimed to develop an artificial neural network (ANN) for predicting the blood concentration of tacrolimus soon after liver transplantation and for identifying determinants of the concentration based on Shapley additive explanation (SHAP). METHODS: In this retrospective study, we enrolled 31 recipients who were first treated with liver transplantation from the Department of Liver Transplantation and Hepatic Surgery, the First Affiliated Hospital of Shandong First Medical University (Shandong Provincial Qianfoshan Hospital) from November 2020 to May 2021. The basic information, biochemical indexes, use of concomitant drugs, and genetic factors of organ donors and recipients were used for the ANN model inputs, and the output was the steady-state trough concentration (C0) of tacrolimus after oral administration in LT recipients. The ANN model was established to predict C0 of tacrolimus, SHAP was applied to the trained model, and the SHAP value of each input was calculated to analyze quantitatively the influencing factors for the output C0. RESULTS: A back-propagation ANN model with 3 hidden layers was established using deep learning. The mean prediction error was 0.27 ± 0.75 ng/mL; mean absolute error, 0.60 ± 0.52 ng/mL; correlation coefficient between predicted and actual C0 values, 0.9677; and absolute prediction error of all blood concentrations obtained by the ANN model, ≤3.0 ng/mL. The results indicated that the following factors had the most significant effect on C0: age, daily drug dose, genotype at CYP3A5 polymorphism rs776746 in both recipient and donor, and concomitant use of caspofungin. The predicted C0 value of tacrolimus in LT recipients increased in a dose-dependent manner when the daily dose exceeded 3 mg, whereas it decreased with age when LT recipients were older than 48 years. The predicted C0 was higher when recipients and donors had the genotype CYP3A5*3*3 than when they had the genotype CYP3A5*1. The predicted C0 value also increased with the use of caspofungin or Wuzhi capsule. CONCLUSION AND RELEVANCE: The established ANN model can be used to predict the C0 value of tacrolimus in LT recipients with high accuracy and good predictive ability, serving as a reference for personalized treatment in the early stage after liver transplantation.

Association between GLP-1R gene polymorphism and dyslipidemia in Chinese patients with type 2 diabetes mellitus: A case-control study.

OBJECTIVE: To evaluate the relationship between GLP-1R gene polymorphisms and type 2 diabetes mellitus with dyslipidemia and without dyslipidemia in China. METHODS: A total of 200 patients with Type 2 Diabetes Mellitus (T2DM) were included in this study, including 115 with dyslipidemia and 85 without dyslipidemia. We used Sanger double deoxygenation terminal assay and PCR-RFLP to detect genotype of the GLP-1R rs10305420 and rs3765467 loci. T-test was used to analyze the association between gene polymorphisms and lipid indicators. SHEsis online analysis software was used to analyze the linkage balance effect of loci, and SPSS 26 was used to calculate the gene interaction by dominant model. RESULTS: The genotype distribution of the two loci in the sample of this study was in accordance with Hardy-weinberg equilibrium. There were significant differences in the genotype distribution and allele frequency of rs3765467 between T2DM patients with and without dyslipidemia (GG 52.9%, GA + AA 47.1% vs. GG 69.6%, GA + AA 30.4%; P = 0.017). Under the dominant model, the effects of rs3765467 A allele and rs10305420 T allele on dyslipidemia had multiplicative interactions (P = 0.016) and additive interactions (RERI = 0.403, 95% CI [-2.708 to 3.514]; AP = 0.376, 95% CI [-2.041, 2.793]). Meanwhile, HbA1c levels in rs3765467 A allele carriers (GA + AA) were found to be significantly lower than those in patients with GG genotype (P = 0.006). CONCLUSION: The rs3765467 (G/A) variant is associated with the incidence of dyslipidemia, and G allele may be a risk factor for dyslipidemia.

The predictive accuracy of CT radiomics combined with machine learning in predicting the invasiveness of small nodular lung adenocarcinoma.

Background: Conventionally, the judgment of whether small pulmonary nodules are invasive is mainly made by thoracic surgeons according to the chest computed tomography (CT) features of patients. However, there are limits to how much useful information can be obtained from this approach. A large number of feature information was extracted from CT images by CT radiomics. The machine learning algorithm was used to construct models based on radiomic characteristics to predict the invasiveness of lung adenocarcinoma (LUAD) with a good prediction accuracy. Methods: A total of 416 patients with pathologically confirmed preinvasive lesions and LUAD after video-assisted thoracoscopic surgery (VATS) in the Department of Thoracic Surgery of the First People's Hospital of Yunnan Province from February 2020 to February 2022 were retrospectively analyzed. According to random classification, patients were divided into 2 groups. The RadCloud platform was used to extract radiomics features, and the most relevant radiomics features were selected by continuous dimension reduction method. Then, 6 machine learning algorithms were used to establish and verify the prediction model of small lung nodular adenocarcinoma invasiveness. Receiver operating characteristic (ROC) curve and area under curve (AUC) were used to evaluate the predictive performance. Results: There were 78 cases of pre-invasive lesions and 226 cases of invasive lesions in the training group, and 34 cases of pre-invasive lesions and 78 cases of invasive lesions in the validation group. In the training group, the AUC values of the 6 models were all more than 0.914, the 95% confidence interval (CI) was 0.857-1.00, the sensitivity was equal or more than 0.87, and the specificity was equal or more than 0.85. In the validation group, the AUC values of the 6 models were all equal or more than 0.732, the 95% CI was 0.651-1.00, the sensitivity was equal or more than 0.7, and the specificity was more than 0.77. Conclusions: Machine learning algorithms were used to construct models to predict the invasiveness of small nodular LUAD based on radiomics features, which it could provide more evidence for doctors to make diagnoses and more personalized treatment plans for patients.

Comparison of two preoperative positioning techniques and unpositioning methods in non-intubated video-assisted thoracoscopic surgery.

Background: Using the non-intubated video-assisted thoracoscopic surgery (VATS) approach for small pulmonary nodules (SPNs) can accelerate patients' postoperative recovery. However, locating the SPNs intraoperatively by palpation can be difficult for thoracic surgeons. The advantages of using different preoperative positioning materials are different, especially for pulmonary-nodule-location-needle (P-N-L-N) and the microcoil. This retrospective study analyzed the advantages of two preoperative positioning techniques for VATS under non-intubation anesthesia. Methods: The data were collected for a total of 150 patients with pulmonary nodules who underwent non-intubated VATS at the First People's Hospital of Yunnan Province from January 2018 to January 2021. The patients were divided into a preoperative positioning group (including a P-N-L-N group and microcoil group) and an unlocalized group. These included patients were all compliant with surgical guidelines and were suitable for preoperative localization. Their intraoperative and postoperative indicators were compared, and among these indicators, the operative time, number of postoperative drainage days, postoperative total drainage volume, postoperative discharge time was efficacy group and the intraoperative blood loss was safety group. Results: Preoperative localization helped surgeons to explore nodules faster intraoperatively and remove SPNs precisely under non-intubated VATS. But the advantages of using different preoperative positioning materials are different. Positioning with either microcoil or P-N-L-N resulted in less operation time (P-N-L-N group: 94.90±28.42 min, microcoil group: 112.80±28.6 min, P<0.05), less intraoperative blood loss (P-N-L-N group: 35.80±21.17 mL, microcoil group: 75.00±65.22 mL, P<0.001) and less postoperative thoracic drainage volume (P-N-L-N group: 64.90±181.96 mL, microcoil group: 648.52±708.81 mL, P<0.001). However, the postoperative discharge time (P-N-L-N group: 5.02±1.35 days, microcoil group: 5.40±2.79 days, P=0.38) and postoperative drainage time(P-N-L-N group: 2.58±1.70 days, microcoil group: 3.18±2.49 days, P=0.16) was not statistically significant. Positioning with P-N-L-N seemed to have a better auxiliary effect for non-intubated VATS, suggesting its use can assist surgeons to determine the location of the lesion more accuracy intraoperatively. There was no significant difference in the pathological results among the groups. Conclusions: Localization of SPNs is beneficial in non-intubated VATS, and the use of P-N-L-N was more effective than the microcoil in reducing operative time, intraoperative blood loss, postoperative total drainage volume, and postoperative discharge time.

Purification, Identification and Molecular Docking of Immunomodulatory Peptides from the Heads of Litopenaeus vannamei.

In order to realize the high-value utilization of Litopenaeus vannamei (L. vannamei) heads, immunomodulatory peptides were prepared from the enzymatic hydrolysate of L. vannamei heads, and the action mechanism of immunomodulatory peptides was determined by molecular docking. The results showed that six proteases were used to hydrolyze L. vannamei head proteins, with the animal protease hydrolysate exhibiting the highest macrophage relative proliferation rate (MRPR). The enzymatic products were then sequentially purified by ultrafiltration, Sephadex G-15 gel chromatography, identified by liquid chromatography-mass spectrometry (LC-MS/MS), and finally selected for six immunomodulatory peptides (PSPFPYFT, SAGFPEGF, GPQGPPGH, QGF, PGMR, and WQR). These peptides maintained good immune activity under heat treatment, pH treatment, and in vitro gastrointestinal digestion. Molecular docking analysis indicated that these peptides showed great binding to both toll-like receptor 2 and 4 (TLR2 and TLR4/MD-2), leading to immunomodulation. The discarded L. vannamei heads in this article are considered to be promising food-borne immunomodulators that contribute to enhancing the immune function of the body.

Clinical Outcomes of Tanezumab With Different Dosages for Patient With Osteoarthritis: Network Meta-Analysis.

Background: Osteoarthritis (OA) high disability rate will increase as people getting older, and is the most prevalent form of arthritis in the future. This study identified the clinical effects of optimum doses of tanezumab for patients with OA. Method: Three electronic databases were searched up until January 15, 2021. The mean difference (MD) or odds ratio (OR) was considered an effect measure. The design-by-treatment interaction model was adopted for network meta-analyses. Analyses were conducted using WinBUGS 1.4.3 and R 4.0.5 software. Results: nine publications with 10 studies were included. Compared with placebo in network meta-analysis, except the outcomes of Western Ontario and McMaster Universities Osteoarthritis (WOMAC) stiffness subscale and joints replaced, all dosages of tanezumab in the other effectiveness outcome were superior to placebo, and the difference was statistically significant. However, there was no statistical difference among all different doses of tanezumab. Compared with placebo, except the outcomes of adverse events (AEs) and AEs of abnormal peripheral sensation, all different dosages of tanezumab weren't superior to placebo in the other effectiveness outcome, and the difference was statistically significant. The 10 mg of tanezumab with highest SUCRA had the best effect, but it was associated with a higher safety event. Compared with placebo, except the outcomes of WOMAC stiffness subscale and joints replaced, all dosages of tanezumab in the other effectiveness outcome were superior to placebo, and the difference was statistically significant. Compared with placebo, except for the outcomes of AEs and AEs of abnormal peripheral sensation, all dosages of tanezumab in the other effectiveness outcome were superior to placebo, and the difference was statistically significant. Other direct comparisons showed no statistical difference. Conclusion: This study recommended that clinicians should give priority to the treatment of OA patients with a low dose of 2.5 mg according to the patient's condition and actual situation. If the effect using tanezumab with 2.5 mg is not satisfactory, the increase up to 10 mg should be carefully pondered, because of a more unbalanced risk/benefit ratio.

Air-Stability Improvement of Solar Selective Absorbers Based on TiW-SiO2 Cermet up to 800 °C.

A high-temperature air-stable solar selective absorber (SSA) based on TiW-SiO2 cermet is prepared by the co-sputtering method. The obtained SSA shows remarkable stability in spectrum, structure, and chemistry after air-annealing at 700 °C, demonstrating its resistance against air erosion at high temperature. Comparing with W-SiO2-based SSA, the addition of the Ti element is proved to be effective in enhancing the thermal stability of SSA. Nevertheless, as the temperature increases to 750 °C, perfectly round cavities appear and induce the deterioration of the coating. A phase transformation from α-W to ß-W is found at the interface of TiW/HMVF (high metal volume fraction layer) during deposition. Consequently, the inverse phase transformation from ß-W to α-W at above 750 °C results in small vacancies at the interface, being the incentive of cavity generation. Afterward, the violent morphological changes of oxidized TiW accelerate the cavities expansion. To enhance its tolerance ability of service temperature, a Cr barrier layer is introduced to prevent the diffusion of oxygen into the TiW layer. Therefore, the optimal SSA performs stably at 800 °C and the failure temperature is elevated to 850 °C, revealing that the air-stable TiW-SiO2-based SSA has outstanding potential in high-temperature photothermal conversion.

Comparative Efficacy and Acceptability of Pharmaceutical Management for Adults With Post-Traumatic Stress Disorder: A Systematic Review and Meta-Analysis.

The current clinical guidelines on post-traumatic stress disorder (PTSD) recommend selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) of drugs. However, there is uncertainty about the efficacy of other drugs and selecting which treatments work best for which patients. This meta-analysis evaluated efficacy and acceptability of pharmaceutical management for adults with PTSD. Randomized-controlled trials, which reported active comparators and placebo-controlled trials of pharmaceutical management for adults with PTSD, from the Ovid Medline, EMBase, CENTRAL, PsycINFO, Ovid Health and Psychosocial Instruments, and ISIWeb of Science, were searched until June 21, 2019. In terms of efficacy, all active drugs demonstrated superior effect than placebo (SMD = -0.33; 95% CI, -0.43 to -0.23). The medications were superior to placebo in reducing the symptom of re-experiencing, avoidance, hyperarousal, depression, and anxiety. For acceptability, medicine interventions for PTSD showed no increase in all-cause discontinuation compared with placebo. Nevertheless, in terms of safety, medicine interventions indicated a higher risk of adverse effect compared with placebo (RR = 1.47, 95% CI: 1.24 to 1.75). Compared with placebo, the SSRIs and atypical antipsychotics drugs had significant efficacy whether in patients with severe or extremely severe PTSD status. However, only atypical antipsychotics (SMD = -0.29, 95% CI: -0.48 to -0.10) showed superior efficacy than placebo in veterans. Medication management could be effective in intervention of PTSD, which demonstrated a sufficient improvement in the core symptoms. This meta-analysis supports the status of SSRIs and SNRIs as recommended pharmacotherapy. However, patients with different clinical characteristics of PTSD should consider individualized drug management.

Identification of hub genes in papillary thyroid carcinoma: robust rank aggregation and weighted gene co-expression network analysis.

BACKGROUND: Papillary thyroid carcinoma (PTC), which is the most common endocrine malignancy, has been steadily increasing worldwide in incidence over the years, while mechanisms underlying the pathogenesis and diagnostic for PTC are incomplete. The purpose of this study is to identify potential biomarkers for diagnosis of PTC, and provide new insights into pathogenesis of PTC. METHODS: Based on weighted gene co-expression network analysis, Robust Rank Aggregation, functional annotation, GSEA and DNA methylation, were employed for investigating potential biomarkers for diagnosis of PTC. RESULTS: Black and turquoise modules were identified in the gene co-expression network constructed by 1807 DEGs that from 6 eligible gene expression profiles of Gene Expression Omnibus database based on Robust Rank Aggregation and weighted gene co-expression network analysis. Hub genes were significantly down-regulated and the expression levels of the hub genes were different in different stages in hub gene verification. ROC curves indicated all hub genes had good diagnostic value for PTC (except for ABCA6 AUC = 89.5%, the 15 genes with AUC > 90%). Methylation analysis showed that hub gene verification ABCA6, ACACB, RMDN1 and TFPI were identified as differentially methylated genes, and the decreased expression level of these genes may relate to abnormal DNA methylation. Moreover, the expression levels of 8 top hub genes were correlated with tumor purity and tumor-infiltrating immune cells. These findings, including functional annotations and GSEA provide new insights into pathogenesis of PTC. CONCLUSIONS: The hub genes and methylation of hub genes may as potential biomarkers provide new insights for diagnosis of PTC, and all these findings may be the direction to study the mechanisms underlying of PTC in the future.

Ethnicity and survival in bladder cancer: a population-based study based on the SEER database.

BACKGROUND: Bladder cancer is the most common cancer in the urinary system and the fourth most common cancer in males. This study aimed to examine differences in the survival of bladder cancer patients of different ethnicities. METHOD: We used the SEER database to obtain data pertaining to bladder cancer patients from 2010 to 2015. Univariate and multivariate Cox proportional hazards regression analyses were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between ethnicity and death. Kaplan-Meier survival and nomogram analyses were used to compare survival differences among patients with different ethnicities. RESULTS: Among 101,364 bladder cancer patients, 90,910 were white, 5893 were black, 337 were American Indian/Alaska Native (AIAN), and 4224 were Asian or Pacific Islander (API). Our multivariate analysis identified differences between different ethnicities. Compared to the API group, the AIAN (HR = 1.31, 95% CI = 1.09-1.57, P < 0.001), black (HR = 1.56, 95% CI = 1.46-1.67, P < 0.001), and white (HR = 1.18, 95% CI = 1.12-1.25, P < 0.001) groups showed lower survival probabilities. Based on data from all Kaplan-Meier survival curves, there was no significant difference in survival between the black and AIAN groups, but the survival of these two races was worse than that of the white and API groups. We also used a nomogram to estimate patient survival and validated its predictive value. CONCLUSION: Our results suggest that ethnic differences exist in patients with bladder cancer, that the survival of black and AIAN bladder cancer patients is worse than that of other ethnicities and that the survival of API patients is the best. The significant prognostic factors of overall survival, which include age, sex, ethnicity, summary stage, American Joint Committee on Cancer stage, surgery type, and histologic type, should be applied to bladder cancer patient prognostication.

[Predictive value of plasma cell-free DNA for prognosis of sepsis].

OBJECTIVE: To explore the predictive value of plasma cell-free DNA (cf-DNA) for prognosis in patients with sepsis. METHODS: 105 patients with sepsis admitted to department of emergency of the First Hospital of Quanzhou Affiliated to Fujian Medical University from June 2015 to June 2017 were enrolled. Patients were divided into sepsis group (n = 50) and severe sepsis group (n = 55). At the same time, 50 cases of physical examination center in our hospital were randomly selected as the healthy control group. The differences of cf-DNA, procalcitonin (PCT) and acute physiology and chronic health evaluation II (APACHE II) score among the three groups were compared. The correlation between cf-DNA and PCT or APACHE II were analyzed by Bivarite method. Logistic regression was used to analyze the independent predictors of sepsis. The receiver operating characteristic curve (ROC) was made to evaluate cf-DNA, PCT, APACHE II alone or combined ability to predict the prognosis of sepsis. RESULTS: The PCT, APACHE II and cf-DNA in the sepsis group and severe sepsis group were significantly higher than those in the healthy control group [PCT (µg/L): 5.80 (3.28, 8.85), 17.53 (8.40, 29.61) vs. 0.02 (0.01, 0.03); APACHE II: 13.04±3.03, 23.29±8.02 vs. 2.10±1.05; cf-DNA (µg/L): 1 438.0 (1 154.0, 1 576.0), 2 595.0 (2 162.0, 5 198.0) vs. 17.0 (13.0, 20.5); all P < 0.05], and the indicators in the severe sepsis group were further higher than the sepsis group (all P < 0.05). Correlation analysis showed that cf-DNA was significantly positive correlated with PCT [r = 0.675, 95% confidence interval (95%CI) = 0.575-0.766, P < 0.001] and APACHE II (r = 0.911, 95%CI = 0.874-0.939, P < 0.001). ROC curve analysis showed that the areas under ROC curve (AUC) of PCT, APACHE II, cf-DNA, PCT+APACHE II, cf-DNA+PCT, cf-DNA+APACHE II, cf-DNA+PCT+APACHE II to predict the prognosis of sepsis patients were 0.898, 0.905, 0.961, 0.941, 0.974, 0.976 and 0.982, respectively. It was shown that when predicted alone with PCT, APACHE II and cf-DNA, the AUC of cf-DNA was the largest (0.961), the sensitivity was 100%, and the specificity was 81.43%; the combined prediction of cf-DNA with PCT or APACHE II could further increase AUC, and the combined prediction of cf-DNA, PCT and APACHE II had the highest AUC (0.982), the sensitivity was 94.29%, the specificity was 98.57%. CONCLUSIONS: cf-DNA, PCT and APACHE II have certain predictive value for the prognosis of sepsis. The value of cf-DNA was the highest when predicted alone, but the predictive ability of cf-DNA combined with PCT and APACHE II was the best.

A Shortcut to the Optimization of Cellulase Production Using the Mutant Trichoderma reesei YC-108.

Trichoderma reesei YC-108, a strain isolated by a kind of newly invented plate was found to over produce cellulase and it was then used as a cellulase producer. To get the maximum amount of cellulase, the combination of the medium ingredients, which has a profound influence on metabolic pathway was optimized using response surface methodology. The optimum composition was found to be 24.63 g/L wheat bran, 30.78 g/L avicel, and 19.16 g/L soya-bean cake powder. By using the optimized medium, the filter paper activity (FPA) increased nearly five times to 15.82 IU/mL in a 30 L stirred fermenter, carboxymethyl cellulase activity (CMCase) was increased from 83.02 to 628.05 IU/mL and the CMCase/FPA ratio was nearly doubled compared with the parent strain at initial medium.

[A multi-step distillation method for sample preparation in gas chromatographic analysis].

A sample pretreatment device based on multi-step distillation principle was constructed and evaluated. Trace components in the sample were extracted, separated and enriched at the cold receptor of the molecular diffusion distillation device. The cold receptor was designed as an exchangeable part to avoid the cross interferences from one sample to another one. A model sample containing four kinds of organophosphorus pesticides in ethyl actate was tested in the device, and the distillated and enriched solution was analyzed by a gas chromatograph. It was proven that the interferential components to gas chromatography such as protein, lipid and pigment could be removed effectively, and the enrichment factor for trace target components was more than 150 times. The recoveries of the method were from 90% to 117%, and the relative standard deviations (RSDs) from 1.3% to 10%. The limit of detection (LOD) of this method was 1 ng/mL without further concentration. The reused ratio of the organic reagents was more than 95%. Practical application was performed by using a spiked tea sample. The device can treat more than 100 g of samples with a boiling point range of 120 - 600 degrees C.

Development of two enzyme-linked immunosorbent assays for detection of endosulfan residues in agricultural products.

Two competitive immunoassays, a laboratory assay based on microwell plates and a field test based on the use of polystyrene tubes, have been developed for the detection of endosulfan in agricultural products. The limit of detection for the microwell plate format was 0.8 +/- 0.1 microg/kg, and the limit of detection for the tube format was 1.6 +/- 0.2 microg/kg. A simple, rapid, and efficient extraction method was employed, and 76-112% recoveries of spiked samples were obtained. Methanol extracts of some agricultural product samples such as grape, carrot, spinach, and tobacco could be analyzed directly by immunoassay after dilution in 0.5% fish skin gelatin-phosphate buffered saline. In contrast, extracts of green tea caused significant interference in the assay, and a number of simple cleanup methods were ineffective in removing interference. However, use of the coagulating reagent polyvinyl pyrrolidone removed the matrix effect effectively. For the validation of the enzyme-linked immunosorbent assay (ELISA) tests, samples were analyzed by ELISA and gas chromatography (GC) after solid phase extraction. The relationship between data obtained using the tube assay and microwell assay was good (the lowest r(2) value was 0.94), and also, the immunoassay assay data correlated well with data obtained from GC analysis (the lowest r(2) value was 0.93). The developed immunoassay methods are the suitable methods for the rapid quantitative and reliable determination of endosulfan residues in agricultural products.