This study was aimed to develop a maximum a posteriori Bayesian (MAPB) estimation method to estimate individual pharmacokinetic parameters based on D-optimal sampling strategy. Meanwhile, the performance of MAPB was compared with the multiple linear regression (MLR) method in terms of accuracy and precision. Pharmacokinetic study of pioglitazone was employed as the example case. The population pharmacokinetics was characterized by nonlinear mixed effects model (NONMEM). The sparse sampling strategy (1-4 points) was identified by D-optimal algorithm using WinPOPT software. The simulated data generated by Monte Carlo method were used to access the performance of MAPB and MLR. As the number of samples per subject decreased, the accuracy and precision of MAPB method tended to get worse. The estimation for CL and Vby MAPB using D-optimal two-point design had less bias with low inter-individual variability, and had more bias and imprecision with high residue variability. The estimation of AUC by MAPB using D-optimal 2 points design had similar accuracy and precision to MLR. However, MAPB estimation was better than MLR while adjusting the sampling time to one hour. Overall, the MAPB method had similar predictive performance as MLR, but MAPB could provide more pharmacokinetic information with higher sampling flexibility.

The purpose of this study is to investigate the effects of multiple-trough sampling design and nonlinear mixed effect modeling (NONMEM) algorithm on the estimation of population and individual pharmacokinetic parameters. Oxcarbazepine and tacrolimus were used as one-compartment and two-compartment model drugs, respectively. Seven sampling designs were investigated using various number of trough concentrations per individual ranging from 1-4. Monte Carlo simulations were performed to produce state-steady trough concentrations. One-compartment model was used to fit simulated data from oxcarbazepine and tacrolimus. The accuracy and precision of the estimated parameters were evaluated using the median prediction error (PE), the median absolute PE and boxplot. The results indicated that trough concentrations could yield reliable estimates of apparent clearance (CL/F). For oxcarbazepine, as the number of trough concentrations per subject increased, the accuracy and precision of CL/F, between-subject variability (BSV) of CL/F and residual variability (RUV) tended to be improved. For tacrolimus, however, although no improvement were observed in the accuracy of CL/F and BSV of CL/F, the PE distribution ranges were significantly narrowed and the RUV estimates were less bias and imprecise. In terms of algorithm, Monte Carlo importance sampling (IMP) and IMP assisted by mode a posteriori estimation (IMPMAP) were consistently better than other methods. Additionally, the sampling design had no significant effects on the individual parameter estimates, which were only depended on the interaction between BSV and RUV in various algorithms. Decreased in BSV and RUV levels can improve the accuracy and precision of the estimation for both population and individual pharmacokinetic parameter estimates.

Background: Histone deacetylase 3 (HDAC3), which is expressed in liver, muscle and adipose tissue, is closely related to fat metabolism. Furthermore, HDAC3 expressed in intestinal epithelial cells is a critical factor that regulates host-commensal flora relationship and maintains intestinal homeostasis. Aims: To investigate the relationship between HDAC3 expression in terminal ileum and obesity and intestinal flora. Methods: Eight SPF C57BL/6 mice and eight germ-free C57BL/6 mice aged six weeks were randomly placed on a standard chow or a high-fat chow, respectively, for 5 weeks. Changes in body weight were recorded weekly, and the terminal ileum was obtained for detection of HDAC3 protein and mRNA expressions by immunohistochemistry and real-time PCR. Results: Increase of body weight of mice in SPF high-fat diet group was much more than that in SPF normal diet group (P<0.05). Meanwhile, HDAC3 protein and mRNA expressions in terminal ileum in SPF high-fat diet group was significantly higher than those in SPF normal diet group (P<0.05). On the other hand, whether fed with high-fat diet or normal diet, no significant change of body weight occurred in germ-free mice during the 5-week feeding (P>0.05). No significant differences were found in HDAC3 protein and mRNA expressions between germ-free high-fat diet group and germ-free normal diet group (P>0.05). Conclusions: Expression of HDAC3 in terminal ileum might be regulated by intestinal flora and participates in the occurrence of obesity.

Objective:To investigate the current situation of health emergency response literacy among emergency nurses, analyze the potential profile of emergency nurses′ health emergency response literacy and explore the influencing factors of different categories, so as to provide reference for formulating targeted and specific training intervention programs.Methods:From September to October 2022, 386 emergency nurses from 5 tertiary A-level hospitals in Shandong Province were selected as the research objects by convenient sampling method. A cross-sectional survey was conducted by using the general information questionnaire, the Literacy Self-assessment Scale of Public Health Emergency Response In Nurses, the Chinese version of Modified Self-leadership Questionnaire, and Nurse Perceived Professional Value Scale. The latent profile analysis was carried out with the results of 3 explicit indexes of the Literacy Self-assessment Scale of Public Health Emergency Response In Nurses. At the same time, the influencing factors of different latent profiles of health emergency literacy were explored by univariate analysis and ordered multi-classification Logistic regression.Results:The health emergency literacy of emergency department nurses was divided into three latent profiles: high health emergency literacy type accounting for 45.4% (175/386), medium health emergency literacy type accounting for 41.5% (160/386), and low health emergency literacy type accounting for 13.1% (51/386). Ordinal Logistic regression showed that the main emergency work post was pre hospital first aid, participated in public health emergency rescue operations, self leadership, and professional value were protective factors of health emergency literacy (all P<0.05). Age≤25 years old and junior college degree were risk factors of health emergency literacy (both P<0.05). Conclusions:Nursing managers can implement personalized training and intervention strategies according to different demographic characteristics of the health emergency literacy of emergency nurses, develop self leadership improvement plans from individual and organizational factors, and actively cultivate their sense of professional value, in order to comprehensively improve the health emergency literacy of emergency nurses.

Objective To evaluate the safety and efficacy of 125I seed strands cavity brachytherapy for ureteral carcinoma.Methods To tally 10 patients with ureteral carcinoma underwent Carm CT and DSA guided percutaneous nephrostomy with 125I seed strands cavity brachytherapy.The technical success rate,complications,tumor local control rate,ureteral patency andsurvival time,and compared the Karnofsky scores,Girignon grade,pain score before and after treatment were evaluated.The dose related parameters were compared between pre-and post-treatment.Results 125I seed strands implantation was successfully completed in all patients with technical success rate of 100％.The mean procedure time was (12.3 ±3.8) min.No severe complications such as ureteral perforation,infection,severe bleeding occurred.Local tumor response was CR in 4 cases and PR in 6 cases,showing local control efficiency (CR + PR) 100％ after 2-3 months.Ureteral patency rate was 50％ (5/10).Postprocedure Karnofsky scores,Girignon grades,and pain scores were significantly improved (Z =-2.72,-2.88,-2.83,P＜0.01).The average follow-up time was (14.6 ±6.5) months (5-25 months),tumor progression was observed in 3 cases,stable disease in 7 cases.Nine cases were alive and one died due to multiple organ failure.The differences of D90％,mPD,V100％,V150％,V200％,CI,EI,HI between the preand post-treatment were not statistically significant (P ＞ 0.05).Conclusions 125I seed strands cavity brachytherapy for ureteral carcinoma is an effective and safe procedure without serious complications,and an effective alternative treatment for patients who are unable to undergoor refuse surgery.

With the improvement of medical care the survival rate of preterm infants (gestational age ＜ 37 weeks) increased dramatically,however long-term neurodevelopmental and behavioral problems are still a concern.During their stay in neonatal intensive care unit preterm patients suffer lots of repeated painful procedures while it's a period of rapid brain development.Preterm infants have the nociceptive circuitry to feel the pain,but this system is functionally immature.Because the spinal neuromodulation system is immature that repeated pain stimulation leads to increased nociceptive signaling in the central nervous system.Besides,specific cell populations in the central nervous system of preterm infants are particularly vulnerable to oxidative stress and inflammation.Therefore,it is important that pain-related stress in preterm infants is appropriately managed.

Colorectal cancer (CRC) is one of the leading causes of death worldwide. Thus, the development of new therapeutic targets for CRC treatment is urgently needed. SGK1 is involved in various cellular activities, and its dysregulation can result in multiple cancers. However, little is known about its roles and associated molecular mechanisms in CRC. In present study, we found that SGK1 was highly expressed in tumor tissues compared with peri-tumor samples from CRC patients. In vitro experiments revealed that SGK1 overexpression promoted colonic tumor cell proliferation and migration and inhibited cell apoptosis induced by 5-fluorouracil (5-FU), while SGK1 shRNA and inhibitors showed the inverse effects. Using CRC xenograft mice models, we demonstrated that knockdown or therapeutic inhibition of SGK1 repressed tumor cell proliferation and tumor growth. Moreover, SGK1 inhibitors increased p27 expression and promoted p27 nuclear accumulation in colorectal cancer cells, and p27 siRNAs could attenuate the repression of CRC cell proliferation induced by SGK1 inhibitors. Collectively, SGK1 promotes colorectal cancer development via regulation of CRC cell proliferation, migration and survival. Inhibition of SGK1 represents a novel strategy for the treatment of CRC.
Animals ; Apoptosis ; Cause of Death ; Cell Proliferation ; Colon ; Colorectal Neoplasms* ; Fluorouracil ; Heterografts ; Humans ; In Vitro Techniques ; Mice ; Repression, Psychology ; RNA, Small Interfering

OBJECTIVETo evaluate the clinical efficacy of a new formulation of albendazole emulsion (AbzE) in cases of liver cystic hydatidosis.

METHODSTwo regimens of AbzE (10 mg.kg(-1).d(-1) and 12.5 mg.kg(-1).d(-1)) were given to 212 patients with liver cystic hydatidosis in courses ranging from 3 months to more than one year. Assessment of drug efficacy was essentially based on imaging signs with ultrasonography as the main tool. Assessments were performed at the end of different courses and in the follow-up study of 1 - 4 years after the cessation of therapy.

RESULTSAt the end of therapeutic courses, the overall cure rate of the 212 cases was 74.5%, with a 99.1% effective rate. In the follow-up study, the cure rate was 83.1%, effective rate was 89.3%, ineffective rate was 0.6%, and recurrence rate was 10.2%. The highest cure rate was observed in cases receiving AbzE 12.5 mg.kg(-1).d(-1) for 9 months. Retreatment of recurrent cases with AbzE obtained satisfactory results.

CONCLUSIONSAbzE surpassed other currently used antihydatidosis drugs or formulations with its promising efficacy and mild side effects, and could be recommended as a drug of choice in the treatment of cystic hydatidosis.

Adolescent ; Adult ; Aged ; Aged, 80 and over ; Albendazole ; administration & dosage ; adverse effects ; Child ; Child, Preschool ; Echinococcosis, Hepatic ; drug therapy ; Emulsions ; Female ; Humans ; Male ; Middle Aged

Objective:To report embryonic testicular regression syndrome(ETRS) caused by DHX37 heterozygous variant for the first time in China and summarize the clinical manifestations of ETRS as to improve the understanding of doctors for this disease.Methods:The clinical data and whole exome sequencing results of five cases of ETRS from Shenzhen Children′s Hospital were collected. The reported cases of DHX37 heterozygous variant were reviewed.Results:Five patients with ETRS visited the doctors at the age of 2 months to 5 years and 5 months. Three patients raised as males came to hospital due to virilition and 2 female patients visited a doctor due to clitoral hypertrophy. No uterus was detected by ultrasound in all patients. The gonadal pathologies from 4 cases displayed no testicular tissue or gonadal dysgenesis, complicated with gonadoblastoma in one case. The genetic testing revealed that the heterozygous variant(c.923G>A, p. R308Q) in DHX37 was found in 2 cases, without variant in other 3 cases. According to the review, ETRS and 46, XY gonadal dysgenesis due to DHX37 herozygous variant was firstly reported in 2019. A total of 40 cases, including 21 cases of ETRS, presented with the virilition or female phenotype, with the disappearance of testicular tissue as the main pathologies. There is no report in China.Conclusion:The article summarized the clinical manifestations and whole exome sequencing results of 5 patients with ETRS, among which two cases were caused by DHX37 variants and one was complicated with gonadoblastoma.

Objective:To explore the value of metagenomics next generation sequencing of cerebrospinal fluid in the diagnosis test of the pathogen of neurobrucellosis.Methods:Medical records of neurobrucellosis patients who were admitted to Xuanwu Hospital, Capital Medical University from May 2017 to February 2021 were reviewed. Seven patients who underwent cerebrospinal fluid metagenomics next generation sequencing were enrolled. Their clinical characteristics, cerebrospinal fluid results, serological and pathogenic results were analyzed.Results:Among the seven neurobrucellosis patients, including five males and two females, the age was from 21 to 49 [38 (24, 47)] years. Three patients had a history of exposure to cattle and sheep. The duration from onset to diagnosis was 2 to 30 [12 (5, 18)] months. The main neurological manifestations were headache for seven patients, loss of hearing for three patients, paralysis for four patients and urinary and fecal dysfunction for four patients. The blood tests showed that the rose bengal test was positive in three of seven patients, Brucella serum agglutination test was positive in four of six patients, and the blood culture was negative in four patients. The cerebrospinal fluid tests showed that rose bengal test was positive in one of five patients, Brucella serum agglutination test was positive in two of four patients, and the cerebrospinal fluid culture was positive in two of five patients. Cerebrospinal fluid metagenomics next generation sequencing was positive for Brucella in five patients.Conclusions:Comparing with the cerebrospinal fluid Brucella serum agglutination test and cerebrospinal fluid culture, cerebrospinal fluid metagenomics next generation sequencing is sensitive to the diagnosis of neurobrucellosis. It is recommended to perform cerebrospinal fluid metagenomics next generation sequencing in patients with clinically suspected neurobrucellosis or central nervous system infections of which the pathogen cannot be confirmed.