Population pharmacokinetics of vancomycin (VAN) in the Chinese patients was described by using nonlinear mixed-effects modeling (NONMEM). 619 VAN serum concentrations data from 260 patients including 177 males and 83 females were collected separately from two centers. A one-compartment model was used to describe this sparse data. No significant difference was observed between two center datasets by introducing SID covariate. The final model was as CL= (θ (base0+ θ(max) x(1 -e(-θ(Age)(Age/72) and V = θ x θ (Age)(Age/72). The creatinine clearance (CL(Cr)) and Age were identified as the most significant covariate in the final model. Typical values of clearance (CL) and volume of distribution (V) in the final model were 2.91 L x h(-1) and 54.76 L, respectively. Internal model validation by Bootstrap and NPDE were performed to evaluate the robustness and prediction of the final model. The median and 95% confidence intervals for the final model parameters were based on 1000 Bootstraps. External model evaluation was conducted using an independent dataset that consisted of 34 patients to predict model performance. Pharmacodynamic assessment for VAN by AUC (0-24 h) to MIC ratios of over 400 was considered to be the best to predict treatment outcomes for patients. AUC (0-24 h) was calculated by clearance based on the above population model. The results indicate that the conventional dosing regimen probably being suboptimal concentrations in aged patients. The approach via population pharmacokinetic of VAN combined with the relationship of MIC, Age, CL(Cr) and AUC(0-24 h)/MIC can predict the rational dose for attaining efficacy.

Objective:To explore the value of current indications for fetal pulmonary valvuloplasty (FPV) by summarizing the postnatal diagnosis, treatment, and prognosis of fetuses with pulmonary atresia with intact ventricular septum (PA/IVS) and right ventricular hypoplasia (RVH).Methods:This prospective study was conducted at the Heart Center of Women and Children's Hospital, Qingdao University from September 2018 to March 2021, which included pregnant women who were (1) with fetal PA/IVS and RVH; (2) unable to receive FPV due to fetal position or gestational age despite the indications; (3) given integrated pre- and postnatal management. Prenatal fetal echocardiography assessment, postnatal diagnosis, treatment, and follow-up were summarized using Wilcoxon matched-pair signed-rank test.Results:A total of 35 singleton pregnant women were diagnosed with fetal PA/IVS and RVH by ultrasonic cardiogram and admitted during the study period. Among the 28 fetuses meeting the FPV indications, 18 underwent FPV, while the other 10 did not due to inappropriate fetal position or gestational age. After excluding four terminated pregnancies, the rest six cases were enrolled. The median gestational age at the initial prenatal fetal echocardiography diagnosis was 28.9 weeks (28.3-30.4 weeks). Compared with the initial evaluation, the fetal right ventricular to left ventricular length/diameter ratio [0.8 (0.6-0.9) vs 0.6 (0.5-0.8)] and tricuspid regurgitation velocity [4.7 m/s (3.2-5.1 m/s) vs 4.1 m/s (3.3-4.8 m/s)] were increased, while tricuspid valve Z value [－0.8(－1.6-0.8) vs 0.4 (－0.3-1.9)] and single-ventricular predictive score [0.5 (0.0-2.0) vs 2.0 (1.0-3.0)] were decreased when re-evaluated six weeks later ( T were－2.21, 2.00,－2.20, and 2.00; all P<0.05). All of the six fetuses were born alive with a median gestational age of 38.9 weeks (37.3-40.1 weeks). The median weight was 3 425 g (3 100-4 160) g after being transferred to cardiac intensive care unit. The median age was 12.5 d (0.0-20.0 d) at the first surgical intervention. The median follow-up duration was 15 months (11.8-18.5 months). At initial diagnosis, the single-ventricular predictive score was 1-2 points in four fetuses, and =3 points in two fetuses. There was no death during follow-up. Four patients achieved anatomical biventricular circulation, one achieved clinical biventricular circulation, and one still needed further follow-up, with single-ventricular predictive score at initial diagnosis of 1-3, 3, and 2 points, respectively. Conclusions:The prognosis is good in fetuses with PA/IVS and RVH who have FPV indications but do not receive intrauterine intervention, which suggests that the current FPV indications may be too broad, and a more suitable FPV indication need to be further explored given the difficulty of implementing FPV.

Objective:To summarize and analyze the clinical and genetic characteristics of Chinese patients with adrenomyeloneuropathy (AMN).Methods:Clinical data were collected and analyzed retrospectively on AMN patients who were diagnosed by genetic testing in Shanghai Sixth People′s Hospital, Shanghai Jiao Tong University School of Medicine from May 2008 to August 2022. Clinical characteristics of AMN patients with different types of gene mutations were compared. Loe score was used to evaluate the severity of white matter demyelinating, and the serum levels of very long-chain fatty acids (VLCFA) in patients with or without white matter demyelinating were compared. The motor function of the AMN patients was assessed using the Expanded Disability Status Scale (EDSS), and the association between EDSS scores and the course of disease was analyzed.Results:A total of 23 male patients with onset age of (29.52±9.91) years were included in this study. The first symptom of all patients was abnormal lower extremities, of which 17 patients showed stiffness and weakness in their lower limbs (73.9%, 17/23), and 6 patients showed numbness and pain in both lower limbs (26.1%, 6/23). The occurrence of symptoms was not related to the type of gene mutation. White matter demyelination occurred in 33.3% (7/21) of patients over a disease duration of (7.67±4.46) years. There was no statistically significant difference in serum VLCFA level between the white-matter demyelination group and the non-demyelination group. The EDSS score was positively correlated with the disease duration ( r=0.57, P=0.006). Sixteen ABCD1 gene mutations were found in this study, among which c.5_19delinsTCTCCAGG (p.P2Lfs *12) was reported for the first time. Four probands belonging to different families carried the c.1415_1416del (p.Q472Rfs *83) variant. Conclusions:Lower limb movement disorders and sensory dysfunction are the prominent clinical manifestations in AMN patients, with deterioration of motor function associated with the course of disease. AMN may be converted to cerebral type and VLCFA concentration is not associated with the phenotypic changes. The c.1415_1416del (p.Q472Rfs *83) mutation is a hot spot mutation of the disease.

Objective: To analyze the effects of twirling reinforcing and reducing manipulations on protein expres-sion in parietal cortex of spontaneously hypertensive rats (SHRs), and elucidate the main mechanisms and differences between two manipulations in hypertension treatment. Methods: Rats were randomly divided into the control, model, twirling reinforcing manipulation (TRFM), and twirling reducing manipulation (TRDM) groups. The control and model groups received catch and fixation stimulations once a day for 14 days. The TRFM and TRDM groups were intervened once a day for 20 min for 14 days. On days 0, 2, 6, 10, and 14 after acupuncture, rat systolic blood pressures (SBPs) were measured. Differential protein (DP) expression in the rat parietal cortices was detected. Thereafter, GO functional significance and KEGG pathway enrichment analyses were performed. Results: Compared with the model group, SBP of rats in the TRDM and TRFM groups decreased on days 6 and 10 of acupuncture, respectively (P=.009; P<.001). Moreover, SBP of the TRDM group was signif-icantly lower than that of the TRFM group on days 10 and 14 of acupuncture (P = .015; P = .013). Compared with control group, 601 and 1040 DPs were up-and downregulated, respectively, in the model group. Compared with model group, 44 and 28 up-and downregulated DPs were expressed, respectively, in the TRFM group. Compared with model group, expression of 616 and 427 up-and downregulated DPs, respectively, was found in the TRDM group. After combining the results of GO and KEGG enrichment analyses, five and one pathways were found to be related to the central antihypertensive mechanism of the parietal cortex during twirling reducing and reinforcing manipulations, respectively. Conclusion: TRDM showed a more effective antihypertensive effect on SHRs than TRFM; this antihy-pertensive effect was related to the regulation of different proteins and their biological functions.

Objective:To calculate the yield and relative biological effectiveness (RBE) of proton radiation-induced DNA damage to C. elegans germ cells using the Geant4-DNA toolkit in order to explore the biological effects of proton radiation on Caenorhabditis elegans. Methods:A DNA model for a 20-μm-diameter C. elegans germ cell was built using Hilbert curves within the Geant4-DNA toolkit. By simulating DNA damage induced by proton radiation at varying energy levels (100, 50, 20, 5 and 2 MeV), the correlations between DNA double-strand break yields (YDSBs) and different parameters such as physics constructors, energy threshold (ET) models, and free radical scavenging distances were explored, and the result were compared with biological experimental data (20 MeV proton). The DNA damage types from varying energy levels of protons were defined, and the relative biological effectiveness of DNA double-strand breaks (RBE DSB) values were calculated using the RBE DSB mathematical model. Results:The analysis of proton radiation-induced DNA damage under varying physics constructors, ET models, and free radical scavenging distances indicated that the proton radiation-induced YDSBs were the lowest when physics constructor 2 was utilized, while the YDSBs under physics constructors 4 and 6 differed slightly. The proton radiation-induced YDSBs gradually decreased with a rise in both the single ET and free radical scavenging distance. The comparison revealed that the simulation result were the closest to biological experimental data under physics constructor 4, a single ET model of 21.25 eV, and a radical scavenging distance of 9 nm, with disparities approximating 8.3%. Calculated RBE DSB values for protons spanned 1.02 to 1.85, with a lower proton energy corresponding to higher RBE DSB values. Conclusions:Proton radiation-induced YDSBs in C. elegans derived using Geant4-DNA simulations align well with relevant assessments using molecular biology. This study provides a vital means for understanding and predicting the biological effects stemming from proton radiation