Transarterial chemoembolization plus a PD-1 inhibitor with or without lenvatinib for intermediate-stage hepatocellular carcinoma.

AIM: Transarterial chemoembolization (TACE) combined with a PD-1 inhibitor and TACE combined with a PD-1 inhibitor and lenvatinib have recently been reported as promising treatments to improve the prognosis of hepatocellular carcinoma (HCC) patients. This study aims to compare the efficacy of these two treatments. METHODS: A retrospective study was conducted, and patients were recruited from two centers in China. Progression-free survival (PFS) and overall survival (OS) were compared, and the objective response rate (ORR) and disease control rate (DCR) were evaluated according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Treatment-related adverse events (AEs) were analyzed to assess safety. RESULTS: The median follow-up for the entire cohort was 11.4 months. Of the 103 patients included in this study, 56 received triple therapy, and 47 received doublet therapy. PFS was significantly higher in the triple therapy group than in the doublet therapy group (mPFS 22.5 vs. 14.0 months, P < 0.001). Similar results were obtained in terms of OS (P = 0.001). The ORR and DCR were also better in the triple therapy group (64.3% vs. 38.3%, P = 0.010; 85.7% vs. 57.4%, P = 0.002). The most common AEs in the triple therapy group were decreased albumin (55.3%), decreased platelet count (51.8%) and hypertension (44.6%). CONCLUSIONS: The combination of TACE with a PD-1 inhibitor and lenvatinib in patients with BCLC stage B HCC might result in significantly improved clinical outcomes with a manageable safety profile compared with TACE with a PD-1 inhibitor.

Circulating Tumor Cells Expressing Krüppel-Like Factor 8 and Vimentin as Predictors of Poor Prognosis in Pancreatic Cancer Patients.

BACKGROUND: Circulating tumor cells (CTCs) with an epithelial-mesenchymal transition phenotype in peripheral blood may be a useful marker of carcinomas with poor prognosis. The aim of this study was to determine the prognostic significance of CTCs expressing Krüppel-like factor 8 (KLF8) and vimentin in pancreatic cancer (PC). METHODS: CTCs were isolated by immunomagnetic separation from the peripheral blood of 40 PC patients before undergoing surgical resection. Immunocytochemistry was performed to identify KLF8+ and vimentin+ CTCs. The associations between CTCs and time to recurrence (TTR), clinicopathologic factors, and survival were assessed. Univariate and multivariate analyzes were performed to identify risk factors. RESULTS: Patients with CTCs (n = 30) had a higher relapse rate compared to those without (n = 10) (70.0% vs 20.0%; P < 0.01). The proportion of KLF8+/vimentin+ CTCs to total CTCs was inversely related to TTR (r = -0.646; P < 0.01); TTR was reduced in patients with > 50% of CTCs identified as KLF8+/vimentin+ (P < 0.01). Independent risk factors for recurrence were perineural invasion and > 50% KLF8+/vimentin+ CTCs (both P < 0.05). CONCLUSION: Poor prognosis can be predicted in PC patients when > 50% of CTCs are positive for KLF8 and vimentin.

[Mechanism of Taohong Siwu Decoction in treating soft tissue injury based on UPLC-Q-TOF-MS,network pharmacology and experimental verification].

To explore the action mechanism of Taohong Siwu Decoction(THSWD) in the treatment of soft tissue injury(STI) based on UPLC-Q-TOF-MS technique, network pharmacology and experimental verification method. UPLC-Q-TOF-MS technique was used to identify the chemical constituents of THSWD. The active ingredients and predicted target proteins of THSWD were screened out through TCMSP database. Cytoscape software was used to construct the active component-target-pathway network, and STRING database was used for protein interaction analysis. GeneCards and CTD databases were used to screen out relevant targets of STI. GO function and KEGG pathway enrichment analysis were performed through DAVID database. The rat model of STI was constructed, and Western blot was used to verify the effect of THSWD on key targets of relevant pathways. The results showed 40 active ingredients in THSWD, and 141 potential targets and 20 targets of STI. Target enrichment analysis of the active components produced 128 KEGG pathways, which were mainly concentrated in amino acid synthesis and metabolism, disease signaling pathways, apoptosis, inflammation and other relevant pathways. Western blot showed that THSWD intervention could significantly decrease PTGS2, CASP3, NFKB1, p-CASP3 and p-NFKB1, while enhancing the expression of TP53 protein in the STI samples of rats. According to the results of UPLC-Q-TOF-MS, network pharmacology and experimental verification, active ingredients in THSWD may play anti-inflammatory and antioxidant effects in NF-κB signaling pathway and apoptotic pathway, thus playing a role in the treatment of STI.

Probiotic characteristics of Lactobacillus plantarum E680 and its effect on Hypercholesterolemic mice.

BACKGROUND: Probiotics have been reported to reduce total cholesterol levels in vitro, but more evidence is needed to determine the clinical relevance of this activity. Chinese traditional fermented pickles are a good source of lactic acid bacteria. Therefore, pickle samples were collected for screening lactic acid bacteria based on their ability to survive stresses encountered during gastrointestinal passage and cholesterol reducing potency. RESULTS: Seventy five lactic acid bacteria strains were isolated from 22 fermented pickles. From these bacteria, Lactobacillus plantarum E680, showed the highest acid (85.25%) and bile tolerance (80.79%). It was sensitive to five of the eight antibiotics tested, inhibited the growth of four pathogenic bacteria, and reduced the total cholesterol level by 66.84% in broth culture. In vivo testing using hypercholesterolemic mice fed high-fat emulsion, independent of food intake, found that L. plantarum E680 suppressed body weight gain and reduced total cholesterol and low-density lipoprotein cholesterol levels, with no effect on high-density lipoprotein cholesterol. CONCLUSIONS: Chinese traditional fermented pickles are a good source for probiotics. L. plantarum E680, isolated from pickles, was acid and bile tolerant, sensitive to antibiotics, and reduced cholesterol levels both in vitro and in vivo. Based on these results, L. plantarum E680 may have potential as a novel probiotic for the development of cholesterol-lowering functional food.

Labilibacter sediminis sp. nov., isolated from marine sediment.

A Gram-stain-negative, rod-shaped and facultatively anaerobic strain, designated CG51T, was isolated from marine sediment collected from a coastal area in Weihai, PR China. Strain CG51T grew at 4-37 °C (optimum, 28-30 °C), with 1.0-6.0 % (w/v) NaCl (2.0-3.0 %) and at pH 6.0-8.5 (pH 7.0-7.5). The predominant fatty acids were iso-C15 : 0, anteiso-C15 : 0 and iso-C14 : 0. Major polar lipids included an unidentified lipid and a phospholipid. The respiratory quinone was MK-7 and the genomic DNA G+C content was 35.9 mol%. The results of phylogenetic analysis based on 16S rRNA gene sequences placed strain CG51T in the genus Labilibacter with the close relatives being Labilibacter marinus Y11T and Labilibacter aurantiacus HQYD1T, exhibiting 96.5 and 96.3 % 16S rRNA pairwise similarity, values which are clearly below the 98.7 % threshold value recommended for species demarcation. Based on the phylogenetic, physiological, chemotaxonomic and genetic data, strain CG51T represents a novel species within the genus Labilibacter, for which the name Labilibacter sediminis sp. nov. is proposed. The type strain is CG51T (=MCCC 1K03739T=JCM 33138T).

Transformation of Fe-P Complexes in Bioreactors and P Recovery from Sludge: Investigation by XANES Spectroscopy.

The transformation of Fe-P complexes in bioreactors can be important for phosphorus (P) recovery from sludge. In this research, X-ray absorption near-edge structure analysis was conducted to quantify the transformation of Fe and P species in the sludge of different aging periods and in the subsequent acidogenic cofermentation for P recovery. P was readily removed from wastewater by Fe-facilitated coprecipitation and adsorption and could be extracted and recovered from sludge via acidogenic cofermentation and microbial iron reduction with food waste. The fresh Fe-based sludge mainly contained fresh ferrihydrite and amorphous FePO4 with sufficient accessible surface area, which was favorable for Fe-P mobilization and dissolution via microbial reaction. Ferric iron dosed into wastewater underwent rapid hydrolysis, clustering, aggregation, and slow crystallization to form hydrous iron oxides (HFO) with various complicated structures. With the aging of sludge in bioreactors, the HFO densified into phases with much reduced surface area and reactivity (e.g., goethite), which greatly increased the difficulty of P release and recovery. Thus, aging of P-containing sludge should be minimized in wastewater treatment systems for the purpose of P recovery.

Hepatocyte nuclear factor 4α suppresses the aggravation of colon carcinoma.

Hepatocyte nuclear factor 4-α (HNF4α), a nuclear receptor, is expressed at lower levels in colon carcinoma tissues than in adjacent normal tissues. However, the relation between HNF4α and colon cancer progression and the underlying molecular mechanisms remain unclear. Here, we investigated the role of HNF4α in the progression of colon carcinoma. We showed that HNF4α mRNA and protein were downregulated in colon carcinoma specimens. HNF4α expression was related to pT classification (P < 0.001), lymph node metastasis (P = 0.002), distant metastasis (P < 0.001) and clinical stage (P < 0.001) in colon carcinoma patients. Patients with low or negative HNF4α expression had worse 3-year progression-free survival (PFS, P = 0.006) and overall survival (OS, P = 0.005) than patients with high HNF4α expression. Low HNF4α expression was an independent prognostic factor for 3-year PFS (hazard ratio 2.94; 95% confidence interval 1.047-8.250; P = 0.041). Ectopic expression of HNF4α inhibited colon carcinoma cell (HT29, LoVo, and SW480) proliferation, migration, and invasion, induced G2/M phase arrest and promoted apoptosis. Ectopic expression of HNF4α upregulated E-cadherin and downregulated vimentin in vitro, and suppressed SW480 xenograft tumor growth and liver metastasis in vivo. Furthermore, HNF4α overexpression downregulated the expression of snail, slug and twist. HNF4α inhibited EMT through its effect on the Wnt/ß-catenin signaling pathway, and HNF4α downregulation may be mediated by promoter methylation in cancer tissues. Our results suggest that downregulation of HNF4α plays a critical role in the aggravation of colon carcinoma possibly by promoting EMT via the Wnt/ß-catenin signaling pathway and by affecting apoptosis and cell cycle progression.

Prevention of pancreatitis after papillary balloon dilatation by nasobiliary drainage: a randomized controlled trial.

BACKGROUND: Endoscopic papillary balloon dilation (EPBD) was associated with a higher rate of endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). AIM: The purpose of this study was to determine whether placement of an endoscopic nasobiliary drainage (ENBD) catheter can also prevent PEP after EPBD. METHODS: A total of 93 patients, who with proven common bile duct (CBD) stones, received EPBD were enrolled this trial. They were randomly divided into ENBD group (n = 45) and no-ENBD group (n = 48) according whether undergone an ENBD procedure after EPBD. Their demographics, laboratory, procedural data were collected, and pancreaticobiliary complications were followed. RESULTS: The number of patients with serum amylase levels above the normal upper limit (>180 U/L) did not differ between groups. However, compared with ENBD group, more patients in No-ENBD group had levels greater than three times the normal limit (>540 U/L) (11/48 vs 3/45, P = 0.0285), and more patients developed to PEP (7/48 vs 0/45, P = 0.0250). During follow-up, the numbers of patients undergone cholecystectomy, cholangitis and recurrence of CBD stones were similar. There was also no significant difference in the cumulative rate of recurrent pancreaticobiliary complications between the two groups (P = 0.452). CONCLUSIONS: EPBD followed by insertion of an ENBD catheter can prevent PEP, and routine ENBD catheter placement is recommended after an EPBD procedure.

Characteristics of sagittal spine-pelvis-leg alignment in patients with severe hip osteoarthritis.

PURPOSE: The interaction between the sagittal alignment of the spine and pelvis and the compensatory mechanism in patients suffering from spinal disorders has been well documented. However, in patients with hip osteoarthritis (HOA), few studies have explored how the hip joint pathology could affect the sagittal alignment of the hip, pelvis and spine, and no reports have investigated whether these changes are involved in the pathogenesis of low back pain in these patients. The aims of this case-control study were to investigate the sagittal spine-pelvis-leg alignment in patients suffering from severe HOA and to understand whether the alignment was related to the occurrence of low back pain and the health-related quality of life in these patients. METHODS: Fifty-eight patients with severe HOA and 64 asymptomatic controls were studied. Digital lateral X-rays of the spine, pelvis and proximal femur were obtained with the patients placed in upright positions. The following radiographic parameters were measured to examine the sagittal alignment of the pelvis, hip and spine: pelvic incidence (PI), pelvic tilting (PT), sacral slope (SS), pelvic femoral angle (PFA), femoral inclination (FI), lumbar lordosis (LL), spino-sacral angle (SSA), C7 tilt (C7T) and T1 spinal-pelvic inclination (T1-SPI). The global balance patterns of spinal-pelvic alignment were classified as normal balance, slight unbalance and severe unbalance according to the relative position of the C7 plumb line to the sacrum and femoral heads. Short Form-36 questionnaire was carried out in the patients. Comparisons were carried out between the patients with HOA and the controls and between the HOA patients with or without low back pain. Correlation analysis was used to measure relationships between the HOA patients' parameters. RESULTS: There were no significant differences in the age and gender distribution between the HOA patients and control. Compared with the controls, the patients with HOA showed significantly higher SS and lower PT, similar PI in the pelvis, significantly smaller C7T, larger T1-SPI but comparable LL and SSA in the spine, and significantly smaller PFA but larger FI in the hip joint. In addition, the patients with HOA had a significantly greater incidence of severe unbalanced spinal-pelvic alignment than did the controls (22.4 vs 3.1 %, respectively). In patients with HOA, the PFA was significantly correlated with SS, SSA and FI but not with PI, LL or C7T; while the physical component score of short form-36 was significantly correlated with T1-SPI, C7T and FI. A comparison between the HOA patients with or without low back pain, however, showed no significant differences in the radiographic parameters, global sagittal balance patterns and Short Form-36. CONCLUSIONS: The sagittal morphology of the pelvis in patients with severe HOA was normal and might not be involved in the development and progression of this disorder. Although the whole spine was involved in compensating for the flexed hip joint, the poor ability resulted in severely unbalanced spinal-pelvic alignment in these patients. The forward inclined spine and retroverted femur would contribute to the poor physical activities in these patients. However, the abnormal sagittal spine-pelvis-leg alignment in patients with severe HOA might not be involved in the pathogenesis of low back pain.

Treatment of renal cell carcinoma with a level III or level IV inferior vena cava thrombus using cardiopulmonary bypass and deep hypothermic circulatory arrest.

BACKGROUND: The aim of this study was to investigate the minimally invasive cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA) approach in the management of renal cell carcinoma (RCC) with level III or IV inferior vena cava (IVC) thrombus and evaluate the survival outcomes. METHODS: We performed a retrospective analysis on 32 RCC patients with IVC thrombus that underwent nephrectomy and thrombectomy via the minimally invasive CPB/DHCA approach between January 2007 and December 2013. Perioperative variables (for example, operative time, CPB duration, and circulatory arrest duration), estimated blood loss, hospital stay, perioperative complications, and survival data were recorded and analyzed. RESULTS: Thirty-two patients (median age: 56 years) were treated surgically using the CPB and DHCA approach for RCC with a level III (n=25) or level IV (n=7) tumor thrombus. The median operation time was 360 min (interquartile range (IQR): 300 to 435 min) with median CPB and DHCA durations of 149 min and 23 min, respectively. The median estimated blood loss was 2,500 ml. Four complications were observed but no deaths occurred perioperatively. The median follow-up was 25 months (range: 4 to 64 months). The mean overall survival (OS) was 28.2±4.6 months while the disease-free survival (DFS) was 19.5±11.6 months. In patients with M0 disease, ten patients developed metastases and were treated with sorafenib as an adjuvant therapy. The mean OS and DFS of this subgroup were 25.4±12.8 months and 16.0±14.2 months, respectively. CONCLUSIONS: Radical nephrectomy and thrombectomy using CPB and DHCA to treat RCC is a relatively safe approach associated with low morbidity and mortality. This minimally invasive procedure may help minimize surgical trauma and improve perioperative outcomes.

Influence of prone positioning on potential risk of aorta injury from pedicle screw misplacement in adolescent idiopathic scoliosis patients.

STUDY DESIGN: A prospective magnetic resonance imaging (MRI) study. OBJECTIVE: The aim of this study was to quantitatively analyze the potential risks of aorta injury from thoracic pedicle screw (TPS) misplacement in right thoracic adolescent idiopathic scoliosis (RT-AIS) patients who are in the prone position. SUMMARY OF BACKGROUND DATA: The aorta injuries are rare during posterior spinal surgery, but they can result in catastrophic complications when they do occur. However, we are aware of no prior studies that have used MRI images obtained with patients in the prone position for the purpose of systematically evaluating the potential risks of aorta injury due to TPS misplacement. MATERIALS AND METHODS: This prospective study included 38 RT-AIS patients who underwent MRI scans in the prone position. We evaluated on the MRI images the aorta position relative to the scoliotic spine, and simulated placement of a left TPS with a lateral deviation different from the medium trajectory using Surgimap Spine imaging software. The maximum error of lateral direction was set to 10, 20, or 30 degrees (3 scenarios), and the length of the TPS was set at 30, 35, or 40 mm (3 scenarios). Sensitivity analysis was performed by variable direction errors and TPS lengths. The potential risk of aorta impingement was defined as the virtual TPS crossing the aorta. The percentages of potential risk of aorta impingement were calculated at each level in 9 scenarios. RESULTS: In the RT-AIS patients, the aorta shifted gradually from the left side of the vertebrae at midthoracic levels to a more anterior position at the lower thoracic levels, and was close to the vertebral body at T5-T6 and far away from the left cortex of vertebrae at T12. In 9 scenarios, with the increment of the lengths or/and direction errors of the simulated TPS, the risks of aorta impingement were consistently elevated at all the levels. The simulated 40 mm TPS at T5, T6, and T11 posed a higher potential risk of aorta injury (66%-74%) with a 30-degree lateral direction error. CONCLUSIONS: Prone positioning may increase the potential risk of aorta injury in RT-AIS patients, particularly at T5-T6 and T11 even if a left TPS just barely touches the anteriolateral or lateral cortex of the vertebrae. Laterally misplaced TPSs should be removed at these high aorta-at-risk levels.

Does curve convexity affect the surgical outcomes of thoracic adolescent idiopathic scoliosis?

BACKGROUND: Major left thoracic (LT) curve is an atypical type in adolescent idiopathic scoliosis (AIS) and showed independent clinical characteristics and natural history compared to major right thoracic (RT) curve. However, it's unclear whether the convexity of major thoracic curve would affect the surgical outcomes and risk of complications. A retrospective follow-up study was conducted to investigate whether the convexity of major thoracic curve would affect the surgical outcomes of patients with main thoracic AIS. METHODS: Twelve LT-AIS patients underwent corrective spinal instrumentation and fusion were retrieved, and twelve patients with main RT-AIS matched for gender, chronological age, curve type, magnitude and surgical strategy were selected as control. All patients underwent at least 2-year follow-up. The pre- and post-operative radiographic parameters, intraoperative data and functional outcome assessed by Scoliosis Research Society questionnaire 22 (SRS-22) were analyzed and compared between two groups. RESULTS: Patients with LT- and RT-AIS presented with similar magnitudes of thoracic curves, flexibility, fusion level and correction rate. Compared with RT-AIS, patients with LT-AIS showed longer operation time (average, 364 vs. 348 min) and larger amount intraoperative estimated blood loss (2,060 vs. 1,720 ml) although the differences were not statistically significant (p > 0.05). With at least 2-year follow-up, patients in two groups showed comparable loss of correction, coronal and sagittal balance, and the sagittal profiles. With regard to functional outcome, the scores of five categories of SRS-22 questionnaire were similar between two groups. No neurological or vascular complication was observed in these patients. CONCLUSIONS: The radiographic and functional outcomes of LT-AIS patients underwent operation were comparable to those with RT-AIS. Longer operation time and more intraoperative blood loss may be expected in instrumentation and fusion for patients with LT-AIS, which might be because of the inconvenience on the surgical procedure.

Study on energy evolution and fractal characteristics of sandstone with different fracture dip angles under uniaxial compression.

In order to investigate the failure modes and instability mechanism of fractured rock. Uniaxial compression tests were conducted on sandstone specimens with different dip angles. Based on rock energy dissipation theory and fractal theory, the energy evolution characteristics and fragmentation fractal characteristics in the process of deformation and failure of specimens were analyzed. The results show that the peak strength and elastic modulus of fractured rock mass are lower than those of intact samples, and both show an exponential increase with the increase of fracture dip angle. The energy evolution laws of different fracture specimens are roughly similar and can be classified into four stages based on the stress-strain curve: pressure-tight, elastic, plastic, and post-destructive. The total strain energy, elastic strain energy, and dissipated strain energy of the specimen at the peak stress point increased exponentially with crack inclination, and the dissipated strain energy and compressive strength conformed to a power function growth relationship. The distribution of the fragments after the failure of the fracture sample has fractal characteristics, and the fractal dimension increases with the increase of the fracture dip angle. In addition, the higher the compressive strength of the specimen, the greater the energy dissipation, the more serious the degree of fragmentation, and the greater the fractal dimension. The data fitting further shows that there is a power function relationship between the dissipated strain energy and the fractal dimension. The research results can provide a theoretical basis for the stability of rock mass engineering and structural deformation control.

Pars plana vitrectomy for retinal detachment using perfluoro-n-octane as intraoperative tamponade: a multicenter, randomized, non-inferiority trial.

AIM: To evaluate the efficacy and safety of perfluoro-n-octane (PFO) for ophthalmic surgery versus F-Octane as an intraoperative tamponade in pars plana vitrectomy (PPV) in management of retinal detachment. METHODS: This multicenter, prospective, randomized, double-masked, parallel-controlled, non-inferiority trial was conducted in three ophthalmology clinical centers in China. Patients with retinal detachment, who were eligible for PPV were consecutively enrolled. Participants were assigned to PFO for ophthalmic surgery or F-Octane for intraocular tamponade in a 1:1 ratio. Best-corrected visual acuity (BCVA), intraocular pressure (IOP) measurement, and dilated fundus examination were performed preoperatively and at 1, 7±1, 28±3d postoperatively. The primary outcome was complete retinal reattachment rate at postoperative day one. The non-inferiority margin was set at 9.8%. The secondary outcomes included intraoperative retinal reattachment rate, and mean changes in IOP and BCVA from baseline to 1, 7±1, 28±3d postoperatively, respectively. Safety analyses were presented for all randomly assigned participates in this study. RESULTS: Totally 124 eligible patients completed the study between Mar. 14, 2016 and Jun. 7, 2017. Sixty of them were randomly assigned to the PFO for ophthalmic surgery group, and 64 were assigned to the F-Octane group. Baseline characteristics were comparable between the two groups. Both groups achieved 100% retinal reattachment at postoperative day one (difference 0, 95%CI: -6.21% to 5.75%, P=1). The pre-defined noninferiority criterion was met. No significant difference was observed in intraoperative retinal reattachment rate (difference 1.77%, P=0.61), mean changes in IOP (difference 0.36, -0.09, 2.22 mm Hg at 1, 7±1, 28±3d postoperatively, with all P>0.05) and BCVA (difference 0.04, -0.02, 0.06 logMAR at 1, 7±1, 28±3d postoperatively, all P>0.05) between the two groups. No apparent adverse events related to the utilization of PFO were reported. CONCLUSION: In patients with retinal detachment undergoing PPV, PFO for ophthalmic surgery is non-inferior to F-Octane as an intraocular tamponade, and both are safe and well-tolerated.

LC-MS/MS and EMIT measure the whole blood concentration of cyclosporine A: The two methods yield concordant results within the dynamic range of the latter, but the former shows broader application scenarios.

Cyclosporine A (CsA) is a widely used immunosuppressive drug with a narrow therapeutic index and large individual differences. Its therapeutic and toxic effects are closely related to blood drug concentrations, requiring routine therapeutic drug monitoring (TDM). The current main methods for TDM of CsA are enzyme multiplied immunoassay technique (EMIT) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). However, few study on the method comparison of the EMIT and LC-MS/MS for the measurement of whole blood CsA concentration in children has been reported. In this study, we developed a simple and sensitive LC-MS/MS assay for the determination of CsA, and 657 cases of CsA concentrations were determined from 197 pediatric patients by a routine EMIT assay and by the validated in-house LC-MS/MS method on the same batch of samples, aimed to address the aforementioned concern. Consistency between the two assays was evaluated using linear regression and Bland-Altman analysis. The linear range of LC-MS/MS was 0.500-2000 ng/mL and that of the EMIT was 40-500 ng/mL, respectively. Overall, the correlation between the two methods was significant (r-value ranging from 0.8842 to 0.9441). Unsatisfactory consistency was observed in the concentrations < 40 ng/mL (r = 0.7325) and 200-500 ng/mL (r = 0.6851). Bland-Altman plot showed a mean bias of -18.0 % (±1.96 SD, -73.8 to 37.8 %) between EMIT and LC-MS/MS. For Passing-Bablok regression between EMIT and LC-MS/MS did not differ significantly (p > 0.05). In conclusion, the two methods were closely correlated, but the CsA concentration by LC-MS/MS assay was slightly higher than that by EMIT method. Switching from the EMIT assay to the LC-MS/MS method was acceptable, and the LC-MS/MS method will receive broader application in clinical settings due to its better analytical capabilities, but the results need to be further verified in different laboratories.

Mediating Effect of White Blood Cells and Tobacco Exposure on Cervical Neoplasm Risk Among Taiwanese Women.

Background: Both the high-risk human papillomavirus (HR-HPV) infection and tobacco exposure are significantly associated with cervical neoplasm risk. Immune cells play important roles in carcinogenesis. However, it is still unclear whether immune cells have a mediating effect on the HR-HPV infection and tobacco exposure with cervical neoplasm development. Aim: The aim of this study was to determine how the increased white blood cell (WBC) count affects the relationship between HR-HPV DNA load and tobacco exposure in the development of cervical neoplasia. Methods: A hospital-based case-control study design was conducted with a total of 108 cases of Taiwanese women with ≥ cervical intraepithelial neoplasia (CIN) I confirmed by biopsy, and 222 healthy Taiwanese female subjects with negative findings on a Pap smear were assigned to the control group. The study evaluated HR-HPV status and immune cell counts (WBCs, natural killer (NK) cells) and tobacco exposure by a self-construct questionnaire. Results: Both HR-HPV DNA load and tobacco exposure significantly independently increased cervical neoplasm risk (AORs: 1.28 and 1.42, respectively). Similar significant results were found for WBCs and NK cells, with respective AORs of 1.20 and 1.00. Moreover, increased WBCs (ß = 0.04, 95% CI corrected: 0.01-0.07) and tobacco exposure (ß = 0.02, 95% CI corrected: 0.01-0.04) mediated the relationship between the high-risk HPV DNA load and cervical neoplasm risk. Conclusions: Elevated WBC count acts as both predictor and mediator in cervical neoplasm development linked to HR-HPV DNA load. Monitoring and maintaining WBC levels within the normal range could be a preventive strategy for cervical neoplasm development.

Population pharmacokinetics of valproic acid in children with epilepsy: Implications for dose tailoring when switching from oral syrup to sustained-release tablets.

Significant pharmacokinetic (PK) differences exist between different forms of valproic acid (VPA), such as syrup and sustained-release (SR) tablets. This study aimed to develop a population pharmacokinetic (PopPK) model for VPA in children with epilepsy and offer dose adjustment recommendation for switching dosage forms as needed. The study collected 1411 VPA steady-state trough concentrations (Ctrough) from 617 children with epilepsy. Using NONMEM software, a PopPK model was developed, employing a stepwise approach to identify possible variables such as demographic information and concomitant medications. The final model underwent internal and external evaluation via graphical and statistical methods. Moreover, Monte Carlo simulations were used to generate a dose tailoring strategy for typical patients weighting 20-50 kg. As a result, the PK characteristics of VPA were described using a one-compartment model with first-order absorption. The absorption rate constant (ka) was set at 2.64 and 0.46 h-1 for syrup and SR tablets. Body weight and sex were identified as significant factors affecting VPA's pharmacokinetics. The final PopPK model demonstrated acceptable prediction performance and stability during internal and external evaluation. For children taking syrup, a daily dose of 25 mg/kg resulted in the highest probability of achieving the desired target Ctrough, while a dose of 20 mg/kg/day was appropriate for those taking SR tablets. In conclusion, we established a PopPK model for VPA in children with epilepsy to tailor VPA dosage when switching between syrup and SR tablets, aiming to improve plasma VPA concentrations fluctuations.

Individualized atomoxetine response and tolerability in children with ADHD receiving different dosage regimens: the need for CYP2D6 genotyping and therapeutic drug monitoring to dance together.

Integrating CYP2D6 genotyping and therapeutic drug monitoring (TDM) is crucial for guiding individualized atomoxetine therapy in children with attention-deficit/hyperactivity disorder (ADHD). The aim of this retrospective study was (1) to investigate the link between the efficacy and tolerability of atomoxetine in children with ADHD and plasma atomoxetine concentrations based on their CYP2D6 genotypes; (2) to offer TDM reference range recommendations for atomoxetine based on the CYP2D6 genotypes of children receiving different dosage regimens. This retrospective study covered children and adolescents with ADHD between the ages of 6 and <18, who visited the psychological and behavioral clinic of Children's Hospital of Nanjing Medical University from June 1, 2021, to January 31, 2023. The demographic information and laboratory examination data, including CYP2D6 genotype tests and routine TDM of atomoxetine were obtained from the hospital information system. We used univariate analysis, Mann-Whitney U nonparametric test, Kruskal-Wallis test, and the receiver operating characteristic (ROC) curve to investigate outcomes of interest. 515 plasma atomoxetine concentrations of 385 children (325 boys and 60 girls) with ADHD between 6 and 16 years of age were included for statistical analysis in this study. Based on genotyping results, >60% of enrolled children belonged to the CYP2D6 extensive metabolizer (EM), while <40% fell into the intermediate metabolizer (IM). CYP2D6 IMs exhibited higher dose-corrected plasma atomoxetine concentrations by 1.4-2.2 folds than those CYP2D6 EMs. Moreover, CYP2D6 IMs exhibited a higher response rate compare to EMs (93.55% vs 85.71%, P = 0.0132), with higher peak plasma atomoxetine concentrations by 1.67 times than those of EMs. Further ROC analysis revealed that individuals under once daily in the morning (q.m.) dosing regimen exhibited a more effective response to atomoxetine when their levels were ≥ 268 ng/mL (AUC = 0.710, P < 0.001). In addition, CYP2D6 IMs receiving q.m. dosing of atomoxetine were more likely to experience adverse reactions in the central nervous system and gastrointestinal system when plasma atomoxetine concentrations reach 465 and 509 ng/mL, respectively. The findings in this study provided promising treatment strategy for Chinese children with ADHD based on their CYP2D6 genotypes and plasma atomoxetine concentration monitoring. A peak plasma atomoxetine concentration higher than 268 ng/mL might be requisite for q.m. dosing. Assuredly, to validate and reinforce these initial findings, it is necessary to collect further data in controlled studies with a larger sample size.

Preoperative pelvic axial rotation: a possible predictor for postoperative coronal decompensation in thoracolumbar/lumbar adolescent idiopathic scoliosis.

BACKGROUND: The pelvis as the biomechanical foundation of spine, plays an important role in the balance of the stance and gait through the multi-link spinal-pelvic system. If the pelvic axial rotation (PAR) exists in adolescent idiopathic scoliosis (AIS) patients, it should theoretically have some effects on the body balance. PURPOSE: To explore the probable effects of preoperative PAR on the spinal balance in coronal plane in AIS patients with main thoracolumbar/lumbar (TL/L) curve after posterior spinal instrumentation. METHODS: Thirty-eight AIS patients (age: 15 ± 1.5 years) with main TL/L curve (51° ± 6.2°) were recruited retrospectively into this study. The mean follow-up period was 27 months (24-36 months). Standing full spine posteroanterior radiographs were taken preoperatively, 3 month and 1 year postoperatively, and at last follow-up. The convex/concave ratio (CV/CC ratio) of the anterior superior iliac spine laterally and the inferior ilium at the sacroiliac joint medially was measured on posteroanterior radiographs. According to the preoperative CV/CC ratios, the patients were divided into two groups: normal group (N-group: 0.95 ≤ CV/CC ≤ 1.05); and the asymmetrical group (A-group: CV/CC < 0.95, or >1.05). RESULTS: In all the patients, the 3-month-postoperative CV/CC ratio (1.026 ± 0.087) was significantly different from the preoperative CV/CC ratio (0.969 ± 0.095, P < 0.001), indicating that the pelvis had rotated in the opposite direction of the corrective derotation load applied to the TL/L spine after surgery. No significant change was found in the CV/CC ratio from 3-month-postoperative to the last follow-up (1.013 ± 0.103, P > 0.05). There was no significant difference in the demographic, phenotypic, and treatment variables between the N- (n = 16) and A-groups (n = 22) (P > 0.05). However, more coronal decompensation occurred in the A-group after surgery (36.4 vs. 0.0 %, P = 0.013): two patients having trunk translation, three having lower instrumented vertebra (LIV) translation, and one having LIV tilt; meanwhile, one patient having both LIV translation and LIV tilt, and one having both trunk translation and LIV tilt. CONCLUSIONS: The present study confirmed the existence of PAR in AIS patients, and indicated that the pelvis would experience an active rebalancing in the transverse plane within 3 months after spinal correction, and since then, its position would remain stable. Moreover, TL/L-AIS patients with preoperative asymmetrical PAR probably had greater risk of coronal decompensation postoperatively.