Model-informed drug development (MIDD) in the development of pediatric drugs is drawing more and more attention due to the insufficiency of subjects, lack of research on ontogeny, and the limitation of ethic. The core of MIDD used for dose selection includes the population pharmacokinetic (PopPK) model and physiologically based pharmacokinetic (PBPK) model, as well as model-based simulation and prediction. PBPK model has the advantage of predicting the optimal pediatric dose before the clinical trials and has the ability of extrapolation from adult model to pediatric model. PopPK model characterizes the pediatric PK feature based on the analysis of clinical data and can be used to explore the significant covariates, which is a power tool for individualized medicine in children. With their own advantages and disadvantages, PBPK and PopPK model should be jointly used in the pediatric drug development to refine the dose regimen for children at different ages. In this study, the pediatric drug development of rivaroxaban was taken as an example to introduce the combined application of PBPK model and PopPK model in the design and validation of pediatric dose regimen in Phase Ⅰ, Ⅱ and Ⅲ trials, which may provide reference to MIDD in other pediatric drug development.

This text has introduces a new-type laser treatment device. It utilizes the ultrasound atomized gas passage as its optics and makes the laser beams together with the atomized medicine to be transmitted to the patient's respiratory track and lungs for treatment.
Drug Delivery Systems ; instrumentation ; Equipment Design ; Humans ; Laser Therapy ; instrumentation ; Nebulizers and Vaporizers ; Ultrasonics

In this report, we study the effects of over-expression of Lin28a and Lin28b on let-7 family activity in HeLaS3. Firstly, we constructed pAAV2neo-Lin28a and pAAV2neo-Lin28b to express Lin28a and Lin28b, respectively. Then, pAAV2neo-Lin28a and pAAV2neo-Lin28b were transfected into HeLaS3, selected with G418 and obtained cell lines, HeLaS3/pAAV2neo-Lin28a and HeLaS3/pAAV2neo-Lin28b, to express Lin28a and Lin28b stably. Thereafter, we constructed eight plasmid vectors for detection of let-7 family activity based on pAAV2neo-Gluc-(Fluc). These vectors were further packaged into recombinant adeno-associated viral vectors (rAAV) which were used as sensors, nominated as Asensors, to detect inhibition activity of miRNA at post-transcriptional level. Subsequently, with HeLaS3 as a control, we assayed expression levels of Lin28a and Lin28b by Western blot, detected expression levels of let-7 family by QRT-PCR, and tested let-7 family activity by Asensors in HeLaS3/pAAV2neo-Lin28a and HeLaS3/pAAV2neo-Lin28b. Results demonstrated that both HeLaS3/pAAV2neo-Lin28a and HeLaS3/pAAV2neo-Lin28b could express Lin28a and Lin28b effectively. Compared with HeLaS3, the expression level of let-7 family except let-7e declined in HeLaS3/pAAV2neo-Lin28a. But declining extent among members of let-7 family was different. The let-7 family activity also decreased while the decreasing extent varied among members. Furthermore, the activity level was not consistent with its expression level for the same member in let-7 family. Compared with HeLaS3, both expression level and activity level of let-7 family in HeLaS3/ pAAV2neo-Lin28b were decreased. However, the decreasing extent of let-7 family expression changes was larger than that of HeLaS3/pAAV2neo-Lin28a while the decreasing extent of activity changes was similar. In this study, we established a method to detect and compare post-transcriptional inhibition level mediated by miRNA complementary targets. We firstly clarified the effect of Lin28a and Lin28b on let-7 family activity profile and found that this effect was not the same as that at expression level of let-7 family, suggesting that it was more comprehensive to understand miRNA regulation roles to detect both miRNA expression and activity. This paves a way for further research on mechanism of regulation of let-7 family.
Cell Line, Tumor ; DNA-Binding Proteins ; genetics ; metabolism ; HeLa Cells ; Humans ; MicroRNAs ; genetics ; metabolism ; Protein Processing, Post-Translational ; genetics ; RNA-Binding Proteins

Objective:To investigate the effect of mini-retromandibular and transparotid approach in open reduction and internal fixation of middle or low condylar fractures.Methods:A total of 28 condylar fracture cases which were treated with mini-retromandibular approach from January 2016 to January 2019 in Nanjing Stomatological Hospital were included in this study. These cases included 18 males and 10 females with ameanage of 42.5 years. There were 11 cases of left condyle fractures, 13 cases of right condyle fractures and 4 of bilateral condyle fractures. During the operations, incisions of 2-3 cm long were made on the skin and subcutaneous tissue along the posterior margin of the mandible. Then we performed blunt dissections parallel to the facial nerves, directly passing through the parotid gland and masseter muscles, without the facial nerve injuried. After exposing the fracture line, the fracture ends were fixed and restored with two 4-hole titanium miniplates under direct vision.The medical reviews were performed on the third day and 3-6 months after operation by imaging examination and clinical examination. The contents included: postoperative hematoma, postoperative infection, nerve injury, salivary fistula, maximum mouth opening degree, mouth opening type, occlusal relationship, scar condition, etc.Results:All of the 28 patients had good restoration of fracture ends without nerve injury, salivary fistula or other complications. Only one patient suffered with postoperative infection. After 3 months, titanium miniplate was removed by second operation. The mouth opening of patients ranged 1.5-3.8 cm, with an average of 3.1 cm, which was significantly improved compared to the pre-operation (0.5-2.0 cm, average 1.2 cm). One patient’s chin was slightly deviated to the affected side at the time of opening, and the occlusal relationship was recovered well with intermaxillary elastic traction for 3-5 days.The mouth opening type of other patients was nearly normal. Followed up for 6-36 months, all of the patients had no obvious scars after operation.The patients were satisfied with the operation effect. All patients took postoperative CT and 3D reconstruction 3 to 6 months after operation, which showed that the fracture reduction was good.Conclusions:Mini-retromandibular and transparotid approach is effective, simple, efficient and fast in the treatment of condylar middle or low fracture, without facial nerve dissection. It can not only reduce the operation time and the possibility of facial nerve injury, but also make postoperative scar relatively inconspicuous.

Objective:To investigate the effect of mini-retromandibular and transparotid approach in open reduction and internal fixation of middle or low condylar fractures.Methods:A total of 28 condylar fracture cases which were treated with mini-retromandibular approach from January 2016 to January 2019 in Nanjing Stomatological Hospital were included in this study. These cases included 18 males and 10 females with ameanage of 42.5 years. There were 11 cases of left condyle fractures, 13 cases of right condyle fractures and 4 of bilateral condyle fractures. During the operations, incisions of 2-3 cm long were made on the skin and subcutaneous tissue along the posterior margin of the mandible. Then we performed blunt dissections parallel to the facial nerves, directly passing through the parotid gland and masseter muscles, without the facial nerve injuried. After exposing the fracture line, the fracture ends were fixed and restored with two 4-hole titanium miniplates under direct vision.The medical reviews were performed on the third day and 3-6 months after operation by imaging examination and clinical examination. The contents included: postoperative hematoma, postoperative infection, nerve injury, salivary fistula, maximum mouth opening degree, mouth opening type, occlusal relationship, scar condition, etc.Results:All of the 28 patients had good restoration of fracture ends without nerve injury, salivary fistula or other complications. Only one patient suffered with postoperative infection. After 3 months, titanium miniplate was removed by second operation. The mouth opening of patients ranged 1.5-3.8 cm, with an average of 3.1 cm, which was significantly improved compared to the pre-operation (0.5-2.0 cm, average 1.2 cm). One patient’s chin was slightly deviated to the affected side at the time of opening, and the occlusal relationship was recovered well with intermaxillary elastic traction for 3-5 days.The mouth opening type of other patients was nearly normal. Followed up for 6-36 months, all of the patients had no obvious scars after operation.The patients were satisfied with the operation effect. All patients took postoperative CT and 3D reconstruction 3 to 6 months after operation, which showed that the fracture reduction was good.Conclusions:Mini-retromandibular and transparotid approach is effective, simple, efficient and fast in the treatment of condylar middle or low fracture, without facial nerve dissection. It can not only reduce the operation time and the possibility of facial nerve injury, but also make postoperative scar relatively inconspicuous.

Traumatic gas gangrene is a fatal infection mainly caused by Clostridium perfringens. It is a challenge to manage gas gangrene in open wounds and control infection after debridement or amputation. The aim of the present study was to use vacuum sealing drainage (VSD) with continuous irrigation of potassium permanganate to manage infective wounds of gas gangrene and observe its clinical efficacy. A total of 48 patients with open traumatic gas gangrene infection were included in this study. Amputations were done for 27 patients, and limb salvage procedures were performed for the others. After amputation or aggressive debridement, the VSD system, including polyvinyl alcohol (PVA) foam dressing and polyurethane (PU) film, with continuous irrigation of 1:5000 potassium permanganate solutions, was applied to the wounds. During the follow-up, all the patients healed without recurrence within 8-18 months. There were four complications. Cardiac arrest during amputation surgery occurred in one patient who suffered from severe septic shock. Emergent resuscitation was performed and the patient returned to stable condition. One patient suffered from mixed infection of Staphylococcal aureus, and a second-stage debridement was performed. One patient suffered from severe pain of the limb after the debridement. Exploratory operation was done and the possible reason was trauma of a local peripheral nerve. Three cases of crush syndrome had dialysis treatment for concomitant renal failure. In conclusion, VSD can convert open wound to closed wound, and evacuate necrotic tissues. Furthermore, potassium permanganate solutions help eliminate anaerobic microenvironment and achieve good therapeutic effect on gas gangrene and mixed infection. VSD with continuous irrigation of potassium permanganate is a novel, simple and feasible alternative for severe traumatic open wounds with gas gangrene infection.
Adolescent ; Adult ; Aged ; Child ; Drainage ; Female ; Gas Gangrene ; etiology ; therapy ; Humans ; Male ; Middle Aged ; Negative-Pressure Wound Therapy ; methods ; Potassium Permanganate ; therapeutic use ; Retrospective Studies ; Therapeutic Irrigation ; Treatment Outcome ; Young Adult

A new method was developed for simultaneous detection of total 19 kinds of organophosphate esters(OPEs)and their diester metabolites(di-OPEs)in human serum(1.0 mL)and urine(1.5 mL)with low volume of samples.The target compounds were determined using ultra-high performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS)after acetonitrile liquid-liquid extraction combined with purification using an ENVI-18 solid-phase extraction(SPE)column.OPEs and di-OPEs were separated using a Shim-pack GIST C18 column(100 mm×2.1 mm,2 μm)with a Shim-pack GIST-HP(G)C18 guard column.An electrospray ionization source(ESI)was employed in mass spectrometry analysis,with positive/negative ion mode using the multiple reaction monitoring(MRM).All target compounds were separated within 15 min,and exhibited good linear relationships in the concentration range of 2-100 ng/mL,with correlation coefficients(R2)above 0.994.The method detection limits(MDL)in serum ranged from 0.001 to 0.178 ng/mL and the MDL in urine ranged from 0.001 to 0.119 ng/mL.The recoveries of the analytes spiked in serum and urine matrices at two concentration levels were 30.5%-126.8%,with the relative standard deviations(RSDs)ranged from 1%to 23%.In addition,paired serum and urine samples from 11 patients were analyzed.For all samples tested,the internal standards of OPEs exhibited recoveries between 61%and 114%,whereas the internal standards for di-OPEs had recoveries ranging from 43%to 103%.OPEs and di-OPEs exhibited high detection frequencies in 22 serum and urine samples.Triethyl phosphate(TEP),tributyl phosphate(TBP),tris(2-ethylhexyl)phosphate(TEHP),tris(2-butoxyethyl)phosphate(TBEP),tris(1-chloro-2-propyl)phosphate(TCIPP),triphenyl phosphate(TPHP),tri-m-tolyl-phosphate(TMTP)and 2-ethylhexyl diphenyl phosphate(EHDPP)were universally detected in all serum samples.TCIPP was identified at the highest concentrations(median 0.548 ng/mL)in serum samples.In urine samples,the detection frequency for 12 kinds of target compounds reached 100%.Notably,TBP emerged as the predominant OPE in urine,demonstrating a median concentration of 0.506 ng/mL.Regarding di-OPEs,bis(2-chloroethyl)phosphate(BCEP)and bis(2-butoxyethyl)hydrogen phosphate(BBOEP)were the most abundant in urine,with median concentrations of 6.404 and 2.136 ng/mL,respectively.The total concentrations of OPEs and di-OPEs in serum and urine were 1.580-3.843 ng/mL and 5.149-17.537 ng/mL,respectively.These results not only confirmed the effectiveness of the method in detection of OPEs and di-OPEs in biological matrices,but also revealed the widespread presence of OPE compounds in human body and pointed to potential exposure risks.

The vagina contains at least a billion microbial cells,dominated by lactobacilli.Here we perform metagenomic shotgun sequencing on cervical and fecal samples from a cohort of 516 Chinese women of reproductive age,as well as cervical,fecal,and salivary samples from a second cohort of 632 women.Factors such as pregnancy history,delivery history,cesarean section,and breastfeeding were all more important than menstrual cycle in shaping the microbiome,and such information would be necessary before trying to interpret differences between vagino-cervical micro-biome data.Greater proportion of Bifidobacterium breve was seen with older age at sexual debut.The relative abundance of lactobacilli especially Lactobacillus crispatus was negatively associated with pregnancy history.Potential markers for lack of menstrual regularity,heavy flow,dysmenor-rhea,and contraceptives were also identified.Lactobacilli were rare during breastfeeding or post-menopause.Other features such as mood fluctuations and facial speckles could potentially be predicted from the vagino-cervical microbiome.Gut and salivary microbiomes,plasma vitamins,metals,amino acids,and hormones showed associations with the vagino-cervical microbiome.Our results offer an unprecedented glimpse into the microbiota of the female reproductive tract and call for international collaborations to better understand its long-term health impact other than in the settings of infection or pre-term birth.

The acute combination fractures of the atlas and axis in adults have a higher rate of neurological injury and early death compared with atlas or axial fractures alone. Currently, the diagnosis and treatment choices of acute combination fractures of the atlas and axis in adults are controversial because of the lack of standards for implementation. Non-operative treatments have a high incidence of bone nonunion and complications, while surgeries may easily lead to the injury of the vertebral artery, spinal cord and nerve root. At present, there are no evidence-based Chinese guidelines for the diagnosis and treatment of acute combination fractures of the atlas and axis in adults. To provide orthopedic surgeons with the most up-to-date and effective information in treating acute combination fractures of the atlas and axis in adults, the Spinal Trauma Group of Orthopedic Branch of Chinese Medical Doctor Association organized experts in the field of spinal trauma to develop the Evidence-based guideline for clinical diagnosis and treatment of acute combination fractures of the atlas and axis in adults ( version 2023) by referring to the "Management of acute combination fractures of the atlas and axis in adults" published by American Association of Neurological Surgeons (AANS)/Congress of Neurological Surgeons (CNS) in 2013 and the relevant Chinese and English literatures. Ten recommendations were made concerning the radiological diagnosis, stability judgment, treatment rules, treatment options and complications based on medical evidence, aiming to provide a reference for the diagnosis and treatment of acute combination fractures of the atlas and axis in adults.

OBJECTIVE: To observe the impact of energy saving light,incandescent light and circadian light on the ethology of depressive rats and explore its possible mechanism on affecting the secretion of melatonin. METHODS: Thirty rats aged 6weeks were randomly selected from 40 specific pathogen free health female SD rats after they adapted to the living environment,depressive rat models were established in the rats by bilateral ovariectomy combined with isolated living and chronic unpredictable mild stress stimulation at the age of 11-14 weeks. Then these 30 ovariectomized rats were randomly divided into 3 intervention groups,including an energy saving light group,an incandescent light group and a circadian light group,with 10 rats in each group. The rats in these 3 groups were given specific experimental light intervention for 3 weeks respectively at the age of 17 weeks. The other 10 rats were raised in conventional environment as the control group. Their body weights were measured at the age of 17,19,20 and 21 weeks. The ethology tests were carried out by sucrose preference test and the open-field test at the age of 7,14 and 20 weeks respectively. The melatonin levels in peripheral blood of 7 time points from 19: 30 to 8: 30 were measured in the rats at age of 21 weeks. One rat in each group at every time point was randomly selected for examination. RESULTS: At the age of 17 weeks before light-intervention,the body weights of rats in 4 groups showed no significant difference( P > 0. 05). After light-intervention,at the age of 17-20 weeks,the body weights of rats in 3 intervention groups were gradually increased with the increase of age( P < 0. 05).There was no significant difference between body weights of rats at the age of 21 weeks and those at the age of 20 weeks in each group( P > 0. 05). At age of 7 weeks,no significant differences were found in sucrose consumption and standing scores among these 4 groups( P > 0. 05). After the depressive models were established,at the age of 14 weeks before light-intervention,in rats of these 3 intervention groups,the sucrose consumption and standing scores were lower than those of the control group( P < 0. 05),and there was no significant difference found in the above 2 indexes among these 3intervention groups( P > 0. 05). At the age of 20 weeks after light-intervention,the sucrose consumption and standing scores were not significantly different from each other among the 4 groups( P > 0. 05). The peak levels of melatonin in the peripheral blood of rats in these 3 intervention groups were higher than that in the control group. The peak levels onsets of melatonin in peripheral blood of rats in the circadian light group and the energy saving light group were earlier or 2 hours delayed compared to that of control group,while it was similar between the incandescent light group and control group.CONCLUSION: The circadian light,the energy saving light and the incandescent light are similarly effective in improving the behaviors of depressive rats. The circadian light can delay the onset of peak level of melatonin in peripheral blood.