Joint use of population pharmacokinetics and machine learning for prediction of valproic acid plasma concentration in elderly epileptic patients.

BACKGROUND: Valproic acid (VPA) is a commonly used broad-spectrum antiepileptic drug. For elderly epileptic patients, VPA plasma concentrations have a considerable variation. We aim to establish a prediction model via a combination of machine learning and population pharmacokinetics (PPK) for VPA plasma concentration. METHODS: A retrospective study was performed incorporating 43 variables, including PPK parameters. Recursive Feature Elimination with Cross-Validation was used for feature selection. Multiple algorithms were employed for ensemble model, and the model was interpreted by Shapley Additive exPlanations. RESULTS: The inclusion of PPK parameters significantly enhances the performance of individual algorithm model. The composition of categorical boosting, light gradient boosting machine, and random forest (7:2:1) with the highest R2 (0.74) was determined as the ensemble model. The model included 11 variables after feature selection, of which the predictive performance was comparable to the model that incorporated all variables. CONCLUSIONS: Our model was specifically tailored for elderly epileptic patients, providing an efficient and cost-effective approach to predict VPA plasma concentration. The model combined classical PPK with machine learning, and underwent optimization through feature selection and algorithm integration. Our model can serve as a fundamental tool for clinicians in determining VPA plasma concentration and individualized dosing regimens accordingly.

Prediction of teicoplanin plasma concentration in critically ill patients: a combination of machine learning and population pharmacokinetics.

BACKGROUND: Teicoplanin has been widely used in patients with infections caused by Staphylococcus aureus, especially for critically ill patients. The pharmacokinetics (PK) of teicoplanin vary between individuals and within the same individual. We aim to establish a prediction model via a combination of machine learning and population PK (PPK) to support personalized medication decisions for critically ill patients. METHODS: A retrospective study was performed incorporating 33 variables, including PPK parameters (clearance and volume of distribution). Multiple algorithms and Shapley additive explanations were employed for feature selection of variables to determine the strongest driving factors. RESULTS: The performance of each algorithm with PPK parameters was superior to that without PPK parameters. The composition of support vector regression, categorical boosting and a backpropagation neural network (7:2:1) with the highest R2 (0.809) was determined as the final ensemble model. The model included 15 variables after feature selection, of which the predictive performance was superior to that of models considering all variables or using only PPK. The R2, mean absolute error, mean squared error, absolute accuracy (±5 mg/L) and relative accuracy (±30%) of external validation were 0.649, 3.913, 28.347, 76.12% and 76.12%, respectively. CONCLUSIONS: Our study offers a non-invasive, fast and cost-effective prediction model of teicoplanin plasma concentration in critically ill patients. The model serves as a fundamental tool for clinicians to determine the effective plasma concentration range of teicoplanin and formulate individualized dosing regimens accordingly.

Cyclosporine-A induced cytotoxicity within HepG2 cells by inhibiting PXR mediated CYP3A4/CYP3A5/MRP2 pathway.

Cyclosporine-A (CsA) is currently used to treat immune rejection after organ transplantation as a commonly used immunosuppressant. Liver injury is one of the most common adverse effects of CsA, whose precise mechanism has not been fully elucidated. Pregnane X receptor (PXR) plays a critical role in mediating drug-induced liver injury as a key regulator of drug and xenobiotic clearance. As a nuclear receptor, PXR transcriptionally upregulates the expression of drug-metabolizing enzymes and drug transporters, including cytochrome P4503A (CPY3A) and multidrug resistance-associated protein 2 (MRP2). Our study established CsA-induced cytotoxic hepatocytes in an in vitro model, demonstrating that CsA dose-dependently increased the aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) level secreted in the HepG2 cell supernatant, as well as viability and oxidative stress of HepG2 cells. CsA also dose-dependently decreased the PXR, CYP3A4, CPY3A5, and MRP2 levels of HepG2 cells. Mechanistically, altering the expression of PXR, CYP3A4, CYP3A5, and MRP2 affected the impact of CsA on AST and LDH levels. Moreover, altering the expression of PXR also changed the level of CYP3A4, CPY3A5, and MRP2 of HepG2 cells treated by CsA. Our presented findings provide experimental evidence that CsA-induced liver injury is PXR tightly related. We suggest that PXR represents an attractive target for therapy of liver injury due to its central role in the regulation of the metabolizing enzymes CYP3A and MRP2-mediated bile acid transport and detoxification.

A 47-Year-Old Man with Hyperphosphatemia Due to Chronic Renal Failure Treated with Lanthanum Carbonate Tablets Presenting Acutely with Partial Large Bowel Obstruction.

BACKGROUND Hyperphosphatemia is a complication of chronic renal failure (CRF) due to reduction in the glomerular filtration rate. Lanthanum carbonate is a commonly used phosphate binder for patients with CRF and hyperphosphatemia, but has adverse effects if patients are not monitored. This report is of a 47-year-old man with hyperphosphatemia due to CRF treated with lanthanum carbonate tablets who presented acutely with partial large bowel obstruction. The incidence of lanthanum carbonate causing intestinal obstruction is rare, and few cases in the literature have described the course of the disease in detail. CASE REPORT A 47-year-old man diagnosed with diabetic nephropathy underwent hemodialysis treatment and was prescribed 0.5 g/day of chewable lanthanum carbonate tablets. After taking lanthanum carbonate for 5 months, the patient experienced symptoms of decreased bowel movements and exhaustion, which progressively worsened. Abdominal computed tomography (CT) revealed multiple hyperdensities in the large bowel, indicating the presence of lanthanum deposition. Lanthanum carbonate was promptly discontinued. After undergoing enema and catharsis treatment, the large bowel obstruction was relieved, and the hyperdensities in the abdominal CT disappeared. The colonoscopy and histologic examination revealed ulcerations and inflammatory changes in the large bowel mucosa. CONCLUSIONS This report highlights the rare association between the use of lanthanum carbonate tablets and intestinal obstruction. Healthcare providers should enhance their vigilance regarding lanthanum carbonate-induced serious gastrointestinal adverse reactions and actively seek to detect lanthanum deposition by abdominal CT or radiography (X-ray). After the occurrence of lanthanum deposition, drug withdrawal and promotion of defecation are primary treatment methods.

An integration of oil price volatility, green energy consumption, and economic performance: assessing the mediating role of trade.

The economic development of globalized economies is facing severe challenges in the context of a new era. Therefore, the purpose of the study is to assess how crucial factors like oil price fluctuations, renewable energy use, economic growth, the exchange rate, exports, imports, and trade affect the economic performance in the top 25 oil-importing countries using panel data from 2005 to 2021 collected annually. The present investigation employs a method for calculating the stability of associations between variables called AMG estimation. The robustness and reliability of CCEMG and DCCEMG estimates are tested in the present study. Consumption, exports, and trade in renewable energy all had a favorable effect on economic growth. The fluctuation of oil prices, the state of the economy, the currency exchange rate, and imports make things worse. In addition, the findings of the study indicate that the moderate effect of trade with fluctuating oil prices, rising finance, and economic expansion is aided by the current exchange rate. In addition to helping create an appropriate path forward for economic growth, the computed coefficients have policy implications for both the chosen developing economy and the other markets.

Tacrolimus inhibits insulin release and promotes apoptosis of Min6 cells through the inhibition of the PI3K/Akt/mTOR pathway.

As a calcineurin inhibitor, tacrolimus is commonly used as a first­line immunosuppressant in organ transplant recipients. Post­transplantation diabetes mellitus (PTDM) is a common complication following kidney transplantation and is associated with immunosuppressant drugs, such as tacrolimus. PTDM caused by tacrolimus may be related to its influence on insulin secretion and insulin resistance. However, the specific mechanism has not been fully elucidated. The aim of the present study was to investigate whether the PI3K/Akt/mTOR signaling pathway served an important role in the pathogenesis of PTDM induced by tacrolimus. In the present study, the Cell Counting Kit­8 assay was used to measure the effect of tacrolimus on the viability of Min6 mouse insulinoma cells. The effects of tacrolimus on the insulin secretion and the activity of caspase­3 of Min6 cells stimulated by glucose exposure were measured by ELISA. Superoxide dismutase (SOD) and malondialdehyde (MDA) levels were measured using WST­8 and thiobarbituric acid assays, respectively. The effects of tacrolimus on the mRNA expression levels of PI3K, Akt and mTOR were detected by reverse transcription­quantitative PCR (RT­qPCR), whereas the protein expression levels of PI3K, Akt, mTOR, phosphorylated (p)­AKT and p­mTOR in Min6 cells were assessed using western blotting. The present data indicated that, compared with the control group, 5, 25 and 50 ng/ml tacrolimus treatment could inhibit the insulin secretion of Min6 cells stimulated by glucose solution, and 50 ng/ml tacrolimus could notably decrease the stimulation index (P<0.05). Moreover, 50 ng/ml tacrolimus markedly increased the activity of caspase­3 by 175.1% (P<0.05), it also decreased the SOD activity (P<0.01) and increased MDA levels (P<0.05). The RT­qPCR results demonstrated that the mRNA expression levels of PI3K, Akt and mTOR were downregulated by 25 and 50 ng/ml tacrolimus (P<0.01). Furthermore, the western blotting results suggested that tacrolimus had no significant effects on the expression levels of total PI3K, Akt and mTOR proteins (P>0.05), but 25 and 50 ng/ml tacrolimus could significantly inhibit the expression levels of p­Akt and p­mTOR (P<0.01). In conclusion, tacrolimus decreased the activity and insulin secretion of pancreatic ß cells and induced the apoptosis of islet ß cells by inhibiting the mRNA expression levels of PI3K, Akt and mTOR and reducing the phosphorylation of Akt and mTOR proteins in the PI3K/Akt/mTOR signaling pathway, which may ultimately lead to the occurrence of diabetes mellitus, and may be considered as one of the specific mechanisms of PTDM caused by tacrolimus.

Sponge symbiosis is facilitated by adaptive evolution of larval sensory and attachment structures in barnacles.

Symbiotic relations and range of host usage are prominent in coral reefs and crucial to the stability of such systems. In order to explain how symbiotic relations are established and evolve, we used sponge-associated barnacles to ask three questions. (1) Does larval settlement on sponge hosts require novel adaptations facilitating symbiosis? (2) How do larvae settle and start life on their hosts? (3) How has this remarkable symbiotic lifestyle involving many barnacle species evolved? We found that the larvae (cyprids) of sponge-associated barnacles show a remarkably high level of interspecific variation compared with other barnacles. We document that variation in larval attachment devices are specifically related to properties of the surface on which they attach and metamorphose. Mapping of the larval and sponge surface features onto a molecular-based phylogeny showed that sponge symbiosis evolved separately at least three times within barnacles, with the same adaptive features being found in all larvae irrespective of phylogenetic relatedness. Furthermore, the metamorphosis of two species proceeded very differently, with one species remaining superficially on the host and developing a set of white calcareous structures, the other embedding itself into the live host tissue almost immediately after settlement. We argue that such a high degree of evolutionary flexibility of barnacle larvae played an important role in the successful evolution of complex symbiotic relationships in both coral reefs and other marine systems.

Dual-functional probe based on rhodamine for sequential Cu2+ and ATP detection in vivo.

A rhodamine-based fluorescent probe for Cu2+ and ATP has been designed. The fluorescence intensity/absorbance was significantly enhanced upon the addition of Cu2+ owning to the opening of the spiro-ring of rhodamine, which quickly returned to the original level due to the reconstruction of the probe by the reacting with ATP. Cu2+/ATP-induced fluorescent intensity/aborbance changes showed a good linear relationship with the concentration of Cu2+/ATP in the range of 2-20 µM/0-10 µM with a detection limit of 0.1 µM/1.0 µM. The proposed method is simple in design and fast in operation, and is suitable for the reversible monitoring of Cu2+ and ATP in bioanalytical applications.

Descriptions of four new sponge-inhabiting barnacles (Thoracica: Archaeobalanidae: Acastinae).

Within the family Archaeobalanidae, the sponge-inhabiting barnacles include species from the subfamilies Acastinae and Bryozobiinae as well as from the genus Membranobalanus in the subfamily Archaeobalaninae. Members of these groups are obligatory symbionts of poriferans, but the Acastinae can also be found in association with alcyonaceans and antipatharians. Acasta sulcata Lamarck, 1818, is one of the most widely reported sponge-inhabiting barnacle species, with numerous records across the Indo-West Pacific region revealing significant morphological variation. A combined morphological and molecular approach has revealed high diversity in recent collections of sponge-inhabiting barnacles in Taiwan and Australia, and four new species, namely Acasta aspera sp. nov., Acasta huangi sp. nov., Acasta radenta sp. nov., and Acasta undulaterga sp. nov., have been described here. All four species are morphologically close to A. sulcata, and the morphological similarity between these proposed species has led to the proposal of a "sulcata species complex."

A new species of sponge inhabiting barnacle Bryozobia (Archaeobalanidae, Bryozobiinae) in the West Pacific.

This paper describes a new species, Bryozobia rossi sp. n., collected by scuba diving in both Taiwan and Japan. Bryozobia rossi sp. n., a member of the subfamily Bryozobiinae (Ross and Newman 1996), has atria and open end portals and a single irregular basal whorl of portals at the same level as basal hemiportals; this morphology varies from all previously described bryozobiines. According to our review of relevant literature, this is the first reported Bryozobia in the Pacific, and this study is the first to describe the morphology of oral cone, cirri, and penis for the genus Bryozobia.

Artesunate reduces serum lipopolysaccharide in cecal ligation/puncture mice via enhanced LPS internalization by macrophages through increased mRNA expression of scavenger receptors.

Innate immunity is the first line of defense in human beings against pathogen infection; monocytes/macrophages are the primary cells of the innate immune system. Recently, macrophages/monocytes have been discovered to participate in LPS clearance, and the clearance efficiency determines the magnitude of the inflammatory response and subsequent organ injury. Previously, we reported that artesunate (AS) protected sepsis mice against heat-killed E. coli challenge. Herein, we further confirmed that AS protected cecal ligation/puncture (CLP) sepsis mice. Its protection on sepsis mice was related to not only reduction of pro-inflammatory cytokines and serum LPS levels but also improvement of liver function. Based on the fact that AS did not directly bind and neutralize LPS, we hypothesized that the reduction of serum LPS level might be related to enhancement of LPS internalization and subsequent detoxification. Our results showed that AS increased FITC-LPS internalization by peritoneal macrophage and liver Kupffer cell, but enhancement of LPS internalization by AS was not related to the clathrin-dependent pathway. However, AS induced mRNA expression of important scavenger receptors (SRs); SR-A and MARCO mRNA expression was upregulated, suggesting that AS enhancement of LPS internalization and inhibition of pro-inflammatory cytokines was related to changes in mRNA expression of SRs.

Leucine-rich repeat 11 of Toll-like receptor 9 can tightly bind to CpG-containing oligodeoxynucleotides, and the positively charged residues are critical for the high affinity.

TLR9 is a receptor for sensing bacterial DNA/CpG-containing oligonucleotides (CpG ODN). The extracellular domain (ECD) of human TLR9 (hTLR9) is composed of 25 leucine-rich repeats (LRR) contributing to the binding of CpG ODN. Herein, we showed that among LRR2, -5, -8, and -11, LRR11 of hTLR9 had the highest affinity for CpG ODN followed by LRR2 and -5, whereas LRR8 had almost no affinity. In vitro, preincubation with LRR11 more significantly decreased CpG ODN internalization, subsequent NF-κB activation, and cytokine release than with LRR2 and -5 in mouse peritoneal macrophages treated with CpG ODN. The LRR11 deletion mutant of hTLR9 conferred decreased cellular responses to CpG ODN. Single- or multiple-site mutants at five positively charged residues of LRR11 (LRR11m1-9), especially Arg-337 and Lys-367, were shown to contribute to hTLR9 binding of CpG ODN. LRR11m1-9 showed reduced inhibition of CpG ODN internalization and CpG ODN/TLR9 signaling, supporting the above findings. Prediction of whole hTLR9 ECD-CpG ODN interactions revealed that Arg-337 and Lys-338 directly contact CpG ODN through hydrogen bonding, whereas Lys-347, Arg-348, and His-353 contribute to stabilizing the shape of the ligand binding region. These findings suggested that although all five positively charged residues within LRR11 contributed to its high affinity, only Arg-337 and Lys-338 directly interacted with CpG ODN. In conclusion, the results suggested that LRR11 could strongly bind to CpG ODN, whereas mutations at the five positively charge residues reduced this high affinity. LRR11 may be further investigated as an antagonist of hTLR9.