Effects of vaginal microbiota on human papillomavirus infection and its related diseases.

With the knowledge of female reproductive tract microbiota gradually increasing, the connection between vaginal microbiota (VMB) and its related diseases is increasingly highlighted. Manifestation of VMB keeps changing with various dominated bacteria, which can affect the immune response of mucosal barrier and the entrance of pathogens. Human papillomavirus (HPV), as an oncogenic virus, is closely related to viral-associated cancer, such as cervical cancer. According to HPV infection status, VMB can transform into different types, and result in accelerating or restraining the progression of diseases, which have exposed the inner link between VMB and HPV. Therefore, probiotics therapy promises to be a new complementary therapy to rebuild a healthy VMB for patients, but there's still a long way to go before its ready for the clinic. This review focuses on composition, immune response, and application of VMB in HPV and its associated diseases and aims to provide the new ideas and directions for the research on VMB.

Quantitation of levetiracetam concentrations in plasma and saliva samples by ultra-performance liquid chromatography-tandem mass spectrometry: Application to therapeutic drug monitoring for pregnant women with epilepsy.

Although levetiracetam (LEV) has favorable linear pharmacokinetic properties, therapeutic drug monitoring (TDM) is necessary for pregnant women with epilepsy. This study aims to build a simple, reliable, and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for determining LEV concentrations in plasma and saliva samples, to support the routine TDM of LEV in Chinese pregnant women with epilepsy. The stable isotope-labeled LEV-d6 was used as the internal standard. The extracted samples were analyzed using a UPLC-MS/MS system with positive electrospray ionization. Mobile phase A was water containing 5 mM ammonium acetate and 0.1% formic acid, and phase B was 1:1 methanol-acetonitrile with 0.1% formic acid. The method was validated and utilized to determine LEV concentrations in non-pregnant and pregnant patients with epilepsy. The developed method was validated in both plasma and saliva samples over a concentration range of 0.1-50 µg/mL. The intra- and inter-batch accuracy for LEV ranged from -7.0% to 2.9%, with precisions between 2.7% and 9.3%. In pregnant patients, the mean dose-standardized LEV trough plasma concentrations were significantly lower than those in non-pregnant patients (4.73 ± 2.99 vs. 7.74 ± 3.59 ng/mL per mg/day; P < 0.0001). It is recommended that the TDM of LEV should be routinely performed during the different stages of pregnancy.

Highly Efficient Visible-Blind Ultraviolet Photodetector Based on Scalably Produced Titanium Dioxide Nanowire Arrays.

Here, we report a novel, feasible, and cost-effective method for the preparation of one-dimensional TiO2 nanowire arrays using a super-aligned carbon nanotube film as a template. Pure-anatase-phase TiO2 nanowires were scalably prepared in a suspended manner, and a high-performance ultraviolet (UV) photodetector was realized on a flexible substrate. The large surface area and one-dimensional nanostructure of the TiO2 nanowire array led to a high detectivity (1.35 × 1016 Jones) and an ultrahigh photo gain (2.6 × 104), respectively. A high photoresponsivity of 7.7 × 103 A/W was achieved under 7 µW/cm2 UV (λ = 365 nm) illumination at a 10 V bias voltage, which is much higher than those of commercial UV photodetectors. Additionally, by taking advantage of its anisotropic geometry, we found the TiO2 nanowire array showed polarized photodetection. The concept of using nanomaterial systems shows the potential for realization of nanostructured photodetectors for practical applications.

Pharmacokinetics and pharmacodynamics of sacubitril/valsartan in peritoneal dialysis patients.

BACKGROUND: There is little information on the pharmacokinetics and pharmacodynamics of sacubitril/valsartan (SV) in patients undergoing peritoneal dialysis (PD) complicated with hypertension or heart failure (HF). This study was designed to evaluate the pharmacokinetics and pharmacodynamics of SV in PD patients with complications of hypertension or HF. METHODS: This was an open-label and cross-sectional study investigating PD patients diagnosed with hypertension or New York Heart Association Class II-IV HF. The concentrations of valsartan, sacubitril and sacubitrilat (LBQ657) were measured by ultra-performance liquid chromatography tandem mass spectrometry in plasma, urine and peritoneal dialysate samples. Pharmacodynamics were evaluated by comparing changes in mean sitting systolic blood pressure (msSBP), mean sitting diastolic blood pressure (msDBP), mean sitting heart rate, N-terminal-pro B-type natriuretic peptide (NT-proBNP) and left ventricular ejection fraction (LVEF). RESULTS: Forty patients with PD were enrolled including 27 (67.5%) patients with hypertension, 4 (10%) patients with HF and 9 (22.5%) patients with both hypertension and HF. This study included three treatment cohorts: 50 mg twice daily (BID), 100 mg once daily and 100 mg BID. The plasma maximum drug concentrations in the 100 mg BID group were 1995 ± 1499 ng/mL for valsartan, 171 ± 148 ng/mL for sacubitril and 13 686 ± 7418 ng/mL for LBQ657. The 24-h recovery rate of LBQ657 was 3.77% in urine and 2.23% in peritoneal dialysate. After taking SV, msSBP and msDBP decreased by 19.25 ± 10.32 mmHg and 10.10 ± 8.00 mmHg from baseline, respectively. NT-proBNP decreased by 1436.50 (0.00-18 198.00) from baseline, while LVEF increased by 5.00 (-0.25 to 9.25) from baseline after SV treatment. CONCLUSIONS: PD and residual renal function contributed only to a minor degree to the elimination of LBQ657. Additionally, a dose of 100 mg BID SV is safe and effective in patients with PD with complications of hypertension or HF.

The pharmacokinetics and safety of lidocaine in liver cancer patients undergoing hepatic resection.

PURPOSE: The purpose of this study was to explore the pharmacokinetics (PK) characteristics and safety of continuous lidocaine infusion during hepatectomy in liver cancer patients. METHODS: This study included thirty-five patients undergoing laparoscopic hepatectomy from January 2021 to December 2021. Patients received a short infusion of 1% lidocaine at a dose of 1.5 mg/kg based on ideal body weight, followed by a continuous infusion of 1 mg/kg/h during the operation. The plasma concentrations of lidocaine and its active metabolites were measured using validated ultra-performance liquid chromatography-tandem mass spectrometry. Safety was evaluated by monitoring and recording all adverse events (AEs). RESULTS: The concentrations of lidocaine were within the safe range, except one patient's concentration of lidocaine which reached the toxic range (> 5 µg/mL). The mean half-life (T1/2), the mean time to maximum observed concentration (Tmax), and the mean maximum observed concentration (Cmax) of lidocaine were 3.96 h, 2.85 h, and 2030 ng/mL, respectively; the mean T1/2, Tmax, and Cmax (n = 32) of MEGX were 6.59 h, 5.05 h, and 333.28 ng/mL, respectively; and the mean T1/2, Tmax, and Cmax of GX (n = 18) were 25.98 h, 7.33 h, and 75.81 ng/mL. Although eight subjects with AEs were reported, there were no serious AEs or deaths. No patients had serious postoperative complications. No deaths occurred within 30 days after the operation. CONCLUSIONS: Under the administration regimen of this study, intravenous infusion of lidocaine is safe and tolerable for liver cancer patients with laparoscopic hepatectomy. Fine safety and PK characteristics support the application of lidocaine in such patients and further clinical research. TRIAL REGISTRATION: China Clinical Trial Registration Center (ChiCTR2100042730), Registered 27 January 2021.

Potential value of gastrointestinal myoelectrical activity in the diagnosis of anxiety-depression disorder: a population-based study.

BACKGROUND: Depression and anxiety are frequently coexisted mental illness. The lack of solid objective diagnostic criteria has led to a high rate of suicide. The brain-gut axis bridges the gastrointestinal system with neuropsychiatric disorders. However, it is still not possible to reflect mental disease with gastrointestinal information. The study aimed to explore the auxiliary diagnostic value of gastrointestinal myoelectrical activity in anxiety-depression disorders (ADD) without gastrointestinal disturbance. METHODS: A natural population cohort from 3 districts in Western China were established. The Patient Health Questionnaire-9 and the Generalized Anxiety Disorder-7 were used to assess ADD. Gastrointestinal myoelectrical activity of ADD were measured by multi-channel cutaneous electrogastroenterogram (EGEG). Then the parameters of EGEG between ADD and healthy controls were analyzed. RESULTS: The average amplitude and response area of intestinal channel in ADD were significantly lower than those of controls (153.49 ± 78.69 vs. 179.83 ± 103.90, 57.27 ± 29.05 vs. 67.70 ± 38.32), which were shown to be protective factors for ADD (OR = 0.944 and 0.844, respectively). Further, the scale item scores related to the core symptoms of anxiety and depression were also associated with these two channels (p < 0.05), and the gastrointestinal electrical signals of ADD are significantly changed in the elderly compared to the young adults. CONCLUSIONS: The intestinal myoelectrical activity has a certain auxiliary diagnostic value in psychiatric disorders and is expected to provide objective reference for the diagnosis of anxiety and depression.

Practical method for improving the accuracy of weakly stressed birefringence detection by circularly polarized instantaneous photoelasticity.

Due to the mismatch between the quarter-wave plate and the wavelength of the light source, the circularly polarized field photoelastic stress analysis method has an impact on the measurement of the phase delay and the stress direction angle. In particular, the measurement of the phase delay is inaccurate for weakly stressed samples with phase delays less than a quarter-wavelength. In this paper, we first give a method for calculating the mismatch value δ, which requires only one air calibration without prior calibration of the parameters of the quarter-wave plate with other equipment. We then introduce δ into the correction process for the phase delay, derive the correction equation, and give a theoretical comparison of the relative error curves. The results show that the correction method can theoretically limit the maximum amount of error. Finally, we have verified the accuracy of the method by measurements of the internal lens stress before and after the correction and by stitching measurements on SiC wafers.

Effect of Simmering Technology on Components and Activity of Myristica fragrans Houtt.

This study aims to optimize the processing of Myristica fragrans Houtt. by talcum powder simmering using single-factor and orthogonal experimental methods, and the overall desirability values of dehydrodiisoeugenol and essential oils content were selected as indicators of the process. The new process reduced the total content of the three toxic components, namely myristicin, safrole and elemicin, from 1.91% to 1.16% before and after processing, indicating that the toxic components were reduced by 39%. The IC50 of the essential oils before and after processing were 1.002 ± 0.05 and 0.233 ± 0.05 mg/mL for DPPH scavenging activity and 0.132 ± 0.04 and 0.057 ± 0.05 mg/mL for ABTS scavenging activity, respectively. And the absorbance of the antioxidant activity against Ferric reducing power ranged from 0.213 to 0.709 and from 0.225 to 0.755, respectively. The minimum inhibitory concentration for Staphylococcus aureus, Bacillus pumilus and Escherichia coli were all lower after processing than before. The antioxidant activity and antibacterial activity of the essential oils after processing were better than before. The results of the survival of zebrafish embryos at different concentrations of essential oils at 0-168 h post fertilisation were higher after processing than before. These findings suggest that processing plays the role of reducing toxicity and increasing beneficial effects. They provide a scientific basis not only for the processing of M. fragrans, but also for the processing of other foods.

Impact of target-mediated drug disposition on hetrombopag pharmacokinetics and pharmacodynamics in Chinese healthy subjects and patients with chronic idiopathic thrombocytopenic purpura.

AIMS: The pharmacokinetics (PK) of hetrombopag were found to be nonlinear across evaluated dose ranges. The aim of this study was to develop a mechanism-based population pharmacokinetic/pharmacodynamic (PopPK/PD) model and to provide a reasonable expected therapeutic dose for a future confirmatory clinical study of hetrombopag. METHODS: Nonlinear mixed-effects modelling was performed using pooled 2168 hetrombopag concentrations and 1526 platelet counts from 72 healthy subjects and 32 chronic idiopathic thrombocytopenic purpura (ITP) patients from two phase I studies and one phase II study. The final model was evaluated via goodness-of-fit plots, visual predictive check and nonparametric bootstrap. Simulations from the validated PopPK/PD model were used to devise an expected therapeutic dose for later confirmatory clinical study. RESULTS: The pharmacokinetic data of hetrombopag were well described by a modified target-mediated drug disposition (TMDD) model with dual sequential first-order absorption. Mean parameter estimates (interindividual variability) were CL/F 7.66 L/h (63.5%), Vc /F 30.0 L (77.2%) and Kdeg 0.693/h (87.1%). The pharmacodynamic profile was well described by a five-compartment lifespan model with four-transit and one-platelet compartments. Simulation results suggested that chronic ITP patients following 10 mg once-daily hetrombopag would able to achieve an ideal platelet count level (50-200 × 109 /L). CONCLUSION: TMDD was the primary reason leading to nonlinear PK profile of hetrombopag. Our PK/PD modelling and simulation results support 10 mg once-daily as the recommended therapeutic dose for chronic ITP patients in subsequent confirmatory clinical study of hetrombopag.

Three-dimensional stitching of stereo-deflectometry based on marker points.

As a non-contact and three-dimensional (3D) mirror surface measurement method, stereo-deflectometry has been developing rapidly in recent years. For solving the problem of the measurement of large surface inclination with traditional stereo-deflectometry, 3D stitching of stereo-deflectometry based on marker points is proposed. In this method, the 3D points in the subregions under different perspectives were measured. Meanwhile, the 3D coordinates of the marker points on the sample table, which were calculated by binocular stereo vision, were used for coarse stitching, and the ICP algorithm was used for fine stitching. In order to verify the 3D stitching algorithm, we built a measurement system for the freeform surface of an ultra-short lens with a diameter of about 100 mm and a steepness of 52.6°. The spherical fitting error of the reflective bowl after stitching is within 60 mm. The experimental results verify the feasibility of the method, leading to potential mass application of stereo-deflectometry in 3D measurement of complex optical surfaces with a large aperture and high steepness.

LC-MS/MS assay for the determination of tat-K13, a novel interfering peptide for the treatment of ischemic stroke, in human plasma and its application to a pharmacokinetics study.

A sensitive and robust method has been developed using an ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) assay to quantify Tat-K13, a novel interfering peptide for the treatment of ischemic stroke, in human plasma. Automated solid-phase extraction on a Waters Oasis WCX (30 µm, 10 mg) 96-well plate was used to extract Tat-K13 from human plasma and the extracts were separated on a Waters Acquity CSH column (2.1 × 50 mm i.d., 1.7 µm) with a gradient elution method by mobile phase A (nonafluoropentanoic acid-acetic acid-water, 1:2:1000, v/v/v) and B (nonafluoropentanoic acid-acetic acid-water-acetonitrile, 1:2:100:900, v/v/v/v). The method was fully validated following international bioanalytical guidelines and showed good linearity from 2.10 to 1,050 ng/ml. The method was successfully applied to investigate the clinical pharmacokinetics of Tat-K13 in health volunteers. Rapid elimination of Tat-K13 from the body was observed, with half-life ranging from 0.26 to 0.78 h across different dose levels. The exposure of Tat-K13 was approximately dose-dependent in terms of the area under the concentration-time curve and peak concentration.

Pharmacokinetics and safety of tiotropium+olodaterol 5 µg/5 µg fixed-dose combination in Chinese patients with COPD.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is one of the major causes of morbidity and mortality worldwide and in China. For patients with more severe symptoms, initial treatment with long acting ß2-agonists and long-acting muscarinic antagonists combination therapy is recommended. Tiotropium + olodaterol fixed-dose combination (Tio + Olo FDC) is an aqueous solution of tiotropium bromide and olodaterol delivered by the RESPIMAT® Soft Mist™ inhaler for patients with moderate to very severe COPD. METHODS: This single site, open-label, phase Ib clinical study assessed the pharmacokinetic (PK) and safety profiles of once-daily Tio + Olo FDC (5 µg/5 µg) after single dose and at steady state in Chinese patients with moderate to severe COPD over 3 weeks. The PK and safety profiles of Japanese and Caucasian populations from 2 independent COPD studies were provided for comparison. RESULTS: A total of 12 Chinese patients received Tio + Olo FDC. After multiple inhaled administration of Tio + Olo FDC, tiotropium and olodaterol were rapidly absorbed and reached peak plasma concentration at about 5 and 25 min, respectively. The accumulation ratios after multiple administrations were 1.3 and 1.6 for tiotropium and olodaterol in Chinese patients. Tio + Olo FDC was well-tolerated; all AEs were mild. CONCLUSION: Tio + Olo FDC (5 µg/5 µg) was rapidly absorbed and had a good safety profile in Chinese patients with COPD.

Tumor-infiltrating CD4+ T cells in patients with gastric cancer.

BACKGROUND: T lymphocytes play an indispensably important role in clearing virus and tumor antigen. There is little knowledge about impacts of inhibitory molecules with cytokine on tumor-infiltrating CD4+ T-cells in the presence of gastric cancer (GC). This study investigated the distribution of tumor-infiltrating T-cells subset and the differentiation as well as inhibitory phenotype of T-cells from blood and tissues of GC patients. MATERIALS AND METHODS: Patients with GC diagnosed on the basis of pre-operative staging and laparotomy findings were approached for enrollment between 2014 and 2015 at the Affiliated Cancer Hospital of Zhengzhou University, China. Phenotypic analysis based on isolation of tumor-infiltrating lymphocytes and intracellular IFN-γ staining assay is conducted. Statistical analysis is performed to show significance. RESULTS: The results showed that the percentage of CD4+ T-cells among CD3+ cells in tumors was significantly higher than that in the matched paraneoplastic tissue. CD4+ CD25high CD127low regulatory T-cells (Tregs), PD-1+, Tim-3+, and PD-1+ Tim-3+ cells were up-regulated on tumor infiltrating T-cells from patients with GC compared to their expressions on corresponding peripheral blood and peritumoral T-cells. Blockades of PD-1+ and Tim-3+ were effective in restoring tumor infiltrating T-cells' production of interferon-gamma (IFN-γ). Combined PD-1+ and Tim-3+ inhibition had a synergistic effect on IFN-γ secretion by CD4+ T-cells. CONCLUSION: The results suggested that the composition, inhibitors, and location of the immune infiltrate should be considered when evaluating antitumor immunotherapy. A new insight into the mechanisms underlying T cell dysfunction is provided.

MicroRNA-340 Inhibits Esophageal Cancer Cell Growth and Invasion by Targeting Phosphoserine Aminotransferase 1.

BACKGROUND/AIMS: Emerging evidence indicates that microRNA (miR)-340 is downregulated in various human cancers, suggesting that it acts as a tumor suppressor. The aim of the present study was to evaluate the expression and role of miR-340 in human esophageal squamous cell carcinoma (ESCC). METHODS: The expression of miR-340 was examined in 64 paired ESCC and adjacent non-tumor tissues by quantitative real time PCR. The effects of miR-340 on ESCC cell proliferation and metastasis were examined by MTT and Matrigel invasion assays. Tumor growth was assessed by subcutaneous inoculation of cells into BALB/c nude mice. Targets of miR-340 were identified by bioinformatics and verified by luciferase reporter assays, quantitative real-time PCR, and western blotting. RESULTS: MiR-340 was significantly downregulated in ESCC tumor tissues compared to adjacent non-tumor tissues and in ESCC cell lines compared to esophageal endothelial cells. Overexpression of miR-340 inhibited ESCC cell growth, colony formation, and invasion, and tumor growth in a xenograft mouse model. PSAT1 was identified as a direct target of miR-340 and its ectopic expression partially reversed the miR-340 mediated inhibition of viability, invasion and EMT in ESCC cells. The expression of miR-340 was negatively correlated with that of PSAT1 in human ESCC samples. CONCLUSION: MiR-340 functions as a tumor suppressor by modulating the expression of PSAT1 and may contribute to the progression and invasiveness of ESCC.

MicroRNA-378-5p suppresses cell proliferation and induces apoptosis in colorectal cancer cells by targeting BRAF.

MicroRNAs (miRNAs) are a group of small non-coding RNA molecules that potentially play a critical role in tumorigenesis. Increasing evidences indicate that miR-378-5p is dysregulated in numerous human cancers including colorectal cancer (CRC) which hypothesizes that miR-378-5p may play an important role in tumorigenesis. However, its role in CRC carcinogenesis remains poorly defined because of lacking target genes information. In the present study, it was demonstrated that the expression of miR-378-5p was down-regulated in CRC tissues and cell lines as determined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Furthermore, overexpression of miR-378-5p suppressed cell proliferation, as indicated by CCK-8 assay. Flow cytometric analysis demonstrated that overexpression of miR-378-5p induced cell cycle arrest and promoted apoptosis in CRC cells. A luciferase reporter assay indicated that BRAF was a direct target of miR-378-5p. Western blot and qRT-PCR analysis indicated that BRAF was significantly down-regulated by miR-378-5p in CRC cells. Moreover, miR-378-5p was negatively associated with BRAF in CRC tissues compared to adjacent non-tumor tissues. These results demonstrate that down-regulation of miR-378-5p promotes CRC cells growth by targeting BRAF and restoration of their levels is a potentially promising therapeutic in CRC.

Placement of a duodenal stents bridge the duodenal papilla may predispose to acute pancreatitis.

BACKGROUND/AIMS: To retrospective evaluate the incidence, predictive factors, and management of acute pancreatitis after placement of duodenal stent in patients with malignant gastroduodenal obstruction. METHODOLOGY: Among 242 patients with symptomatic malignant gastroduodenal obstruction successfully treated with duodenal stent placement, acute pancreatitis occurred in 10 (4.1%) of the patients 1-7 days after stent placement. The variables were analyzed. Univariate and multivariate analysis was performed to evaluate factors predictive of acute pancreatitis. Management of acute pancreatitis also was evaluated. RESULTS: All patients with acute pancreatitis were presented with abdominal pain and distention with vomiting 1-7 days after stent placement, in which 7 patients developed acute janudice. Four patients were cured by fasting and intravenous nutrition, and the remaining 6 cases were managed with percutaneous cholangiography and drain placement (PTCD). Univariate analysis showed acute pancreatitis was associated with location in the descending duodenum (p = 0.001) and stent bridge the duodenal papilla (p < 0.001). Multivariate analysis exhibited that the presence of stent bridged the duodenal papilla (odds ratio (OR), 18.48; 95% CI, 2.298-148.48; p = 0.006) was independent predictors of acute pancreatitis. CONCLUSIONS: Acute pancreatitis is an uncommon early complication of placement of duodenal stents in patients with malignant gastroduodenal obstruction. Acute pancreatitis occurred most commonly in descending duodenum, and in patients with stent bridged the duodenal papilla. Stent bridged the duodenal papilla may be the most important predictors for acute pancreatitis. Acute pancreatitis can be managed conservatively or by PTCD when developed to acute jaundice.

Two-Time Scale Tracking Control of Flexible Robots With Primal-Dual Inverse Reinforcement Learning.

Flexible robots (FRs) are generally designed to be lightweight to achieve rapid motion. However, accompanying vibrations and modeling errors influence tracking control, especially in situations involving reference signal loss. This article develops a two-time scale primal-dual inverse reinforcement learning (PD-IRL) framework for FRs to perform tracking tasks with incomplete reference signals. First, consider the admissible policy as a nonconvex input constraint to guarantee the stable operation of the equipment. Then, FRs imitate the demonstration behaviors of an expert, including both rigid and flexible motions, to achieve a balance in tracking speed and vibration suppression. During the imitation process, nonconvex optimization problems of FRs are transformed into corresponding dual problems to obtain the global optimal policy. Moreover, employing multiple linearly independent paths to explore the state space simultaneously can improve convergence speed. Convergence and stability are studied rigorously. Finally, simulations and comparisons show the effectiveness and superiority of the proposed method.

TiO2-Ti3C2 Nanocomposites Utilize Their Photothermal Activity for Targeted Treatment of Colorectal Cancer.

Purpose: The search for effective and low-risk treatment methods for colorectal cancer (CRC) is a pressing concern, given the inherent risks and adverse reactions associated with traditional therapies. Photothermal therapy (PTT) has emerged as a promising approach for cancer treatment, offering advantages such as non-radiation, non-invasiveness, and targeted treatment. Consequently, the development of nanoparticles with high stability, biocompatibility, and photothermal effects has become a significant research focus within the field of PTT. Methods: In this study, TiO2-Ti3C2 nanocomposites were synthesized and characterized, and their photothermal conversion efficiency in the near-infrared region II (NIR-II) was determined. Then studied the in vivo and in vitro photothermal activity and anti-tumor effect of TiO2-Ti3C2 in human colorectal cancer cell lines and nude mice subcutaneous tumor model. Results: The results showed that TiO2-Ti3C2 nanocomposites have strong absorption ability in the NIR-II, and have high photothermal conversion efficiency under 1064 nm (0.5 W/cm2, 6 min) laser stimulation. In addition, in vitro experiments showed that TiO2-Ti3C2 nanocomposites significantly inhibited the invasion, migration, and proliferation of colorectal cancer cells, and induced cell apoptosis; in vivo, experiments showed that TiO2-Ti3C2 nanocomposites-mediated PTT had good biocompatibility and efficient targeted inhibition of tumor growth. Conclusion: In conclusion, TiO2-Ti3C2 nanocomposites can be used as NIR-II absorption materials in PTT to suppress the invasion, migration, and proliferation of colorectal cancer cells, induce colorectal cancer cell apoptosis, and thus inhibit the development of CRC. Therefore, TiO2-Ti3C2 nanocomposites can be used as potential anti-tumor drugs for photothermal ablation of colorectal cancer cells.

Monitoring levetiracetam concentration in saliva during pregnancy is stable and feasible.

AIMS: This multicenter prospective cohort study (registration no. ChiCTR2000032089) aimed to investigate the relationship between saliva and plasma levetiracetam concentrations to determine whether saliva could be used for routine monitoring of levetiracetam during pregnancy. METHODS: The slot concentrations of levetiracetam in simultaneously obtained saliva and plasma samples were measured using UPLC-MS/MS. The correlations between saliva and plasma levetiracetam concentrations and the dose-normalized concentrations were compared among pregnant women in different stages and nonpregnant control participants with epilepsy. RESULTS: In total, 231 patients with 407 plasma and saliva sample pairs were enrolled from 39 centers. Linear relationships between salivary and plasma levetiracetam concentrations were reported in the enrolled population (r = 0.898, p < 0.001), including pregnant (r = 0.935, p < 0.001) and nonpregnant participants (r = 0.882, p < 0.001). Plasma concentrations were moderately higher than saliva concentrations, with ratios of saliva to plasma concentrations of 0.98 for nonpregnant women, 0.98, 1, and 1.12 for pregnant women during the first trimester, the second trimester, the and third trimester, respectively. The effective range of saliva levetiracetam concentration was found to be 9.98 µg/mL (lower limit) with an area under the curve (AUC) of 0.937 (95% confidence intervals, 0.915-0.959), sensitivity of 88.9%, specificity of 86.8%, and p < 0.001, to 24.05 µg/mL (upper limit) with an AUC of 0.952 (0.914-0.99), sensitivity of 100%, specificity of 92.3%, and p = 0.007. CONCLUSION: The saliva/plasma concentration ratio of levetiracetam remains constant during pregnancy and is similar to that in non-pregnant individuals. Monitoring levetiracetam concentration in saliva during pregnancy should be widely promoted.

Adaptive Dosage Strategy of Levetiracetam in Chinese Epileptic Patients: Focus on Pregnant Women.

There is presently no efficient dose individualization strategy for the use of antiseizure medications in epileptic pregnant patients. This study aimed to develop a population pharmacokinetics model for levetiracetam and propose a tailored adaptive individualized dosage strategy for epileptic pregnant patients. A total of 322 levetiracetam plasma concentrations from 238 patients with epilepsy were included, including 216 women with epilepsy (20.83% of whom were pregnant). The levetiracetam plasma concentration was measured using a validated ultra-performance liquid chromatography-tandem mass spectrometry assay, and the data were modeled using a nonlinear mixed-effects model. The resultant model served as the basis for simulating the dosage adjustment strategy. A one-compartment model with first-order elimination best described the pharmacokinetic data of levetiracetam. The apparent clearance (CL/F) was 3.43 L/h (95% CI 3.30-3.56) and the apparent volume of distribution was 43.7 L (95% CI 40.4-47.0) for a typical individual of 57.2 kg. Pregnancy and body weight were found to be significant covariates of CL/F of levetiracetam. The recommended regimen of levetiracetam could be predicted by the population pharmacokinetic model based on body weight, gestational age, and the daily dose of levetiracetam taken before pregnancy.