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Yi Zheng,1 Pan-Pan Ye,2 Yue Zhou,1 Su-Ying Wu,3 Xi-Ting Liu,1 Bin Du,1 Bo-Hao Tang,1 Min Kan,1 Ai-Qing Nie,1 Rui Yin,1 Meng Wang,1 Guo-Xiang Hao,1 Lin-Lin Song,2 Xin-Mei Yang,2 Xin Huang,2 Le-Qun Su,2 Wen-Qi Wang,2 John van den Anker,4– 6 Wei Zhao1,2 1Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, People’s Republic of China; 2Department of Clinical Pharmacy, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Engineering and Technology Research Center for Pediatric Drug Development, Shandong Medicine and Health Key Laboratory of Clinical Pharmacy, Jinan, 250014, People’s Republic of China; 3Shandong University of Traditional Chinese Medicine, Jinan, People’s Republic of China; 4Division of Clinical Pharmacology, Children’s National Hospital, Washington, DC, USA; 5Departments of Pediatrics, Pharmacology & Physiology, Genomics & Precision Medicine, George Washington University, School of Medicine and Health Sciences, Washington, DC, USA; 6Department of Paediatric Pharmacology and Pharmacometrics, University Children’s Hospital Basel, University of Basel, Basel, SwitzerlandCorrespondence: Wei ZhaoDepartment of Clinical Pharmacy, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, People’s Republic of ChinaEmail zhao4wei2@hotmail.comPurpose: Inflammation has a significant impact on CYP3A activity. We hypothesized that this effect might be age dependent. Our objective was to conduct a population pharmacokinetic study of midazolam in mice at different developmental stages with varying degrees of inflammation to verify our hypothesis.Methods: Different doses (2 and 5 mg/kg) of lipopolysaccharide (LPS) were used to induce different degrees of systemic inflammation in Swiss mice (postnatal age 9– 42 days, n = 220). The CYP3A substrate midazolam was selected as the pharmacological probe to study CYP3A activity. Postnatal age, current body weight, serum amyloid A protein 1 (SAA1) levels and LPS doses were collected as covariates to perform a population pharmacokinetic analysis using NONMEM 7.2.Results: A population pharmacokinetic model of midazolam in juvenile and adult mice was established. Postnatal age and current body weight were the most significant and positive covariates for clearance and volume of distribution. LPS dosage was the most significant and negative covariate for clearance. LPS dosage can significantly reduce the clearance of midazolam by 21.8% and 38.7% with 2 mg/kg and 5 mg/kg, respectively. Moreover, the magnitude of the reduction was higher in mice with advancing postnatal age.Conclusion: Both inflammation and ontogeny have an essential role in CYP3A activity in mice. The effect of LPS-induced systemic inflammation on midazolam clearance in mice is dependent on postnatal age.Keywords: CYP3A activity, ontogeny, inflammation, pharmacokinetic, mice

Objective: This study aims to obtain the prevalence and features associated with Violence Against Children (VAC) in China and, thus, formulate a prevention strategy. Methods: The mortality-related data of VAC was sourced from the National Disease Surveillance Points System (DSP) during 2013-2021. We analyzed the DSP data regarding children aged 0-17 years old who died from violence. The hospital cases of VAC was sourced from the National Injury Surveillance System (NISS), 2013-2021. We analyzed the data from NISS with the parameter of "intentional injury" caused by VAC in children aged between 0-17 years. Using robust linear regression, we analyze the time trend in the proportion of violence incidence. To understand the variations in the incidence of different types of violence across genders, we apply the chi-square test and adjusted Pearson residuals. Results: The overall trend of death caused by VAC has declined; it was reduced to 0.14/100 000 in 2021 from 0.33/100 000 in 2013. In 2021, male VAC mortality (0.15/100 000) was higher than females (0.13/100 000). The proportion of VAC cases to all injury cases has declined from 3.34% in 2013 to 2.29% in 2021. Among 9 344 VAC cases supervised by hospitals in 2021, the number of males (7 503 cases) was around 4 times that of females (1 841 cases), and the top three modes of violence were blunt tools (64.77%), falls (7.46%) and sharp instruments (6.18%), and 45 cases of sexual violence included 38 girls and 7 boys. Conclusions: The declining death rate due to VAC may be related to the benign development of Chinese society. Prevention strategies targeting training in parenting skills and problem-solving should be prioritized.

Objectives: Simnotrelvir is a small-molecule highly specific 3C-like protease inhibitor for anti-SARS-CoV-2 and was approved as a combination drug with ritonavir (simnotrelvir/ritonavir) in China. Simnotrelvir is a substrate of cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp), and a weak inhibitor of CYP3A. Ritonavir is a substrate and inhibitor of CYP3A and an inhibitor of P-gp. Hence, the drug-drug interaction potential of simnotrelvir/ritonavir should be investigated., Methods: This drug-drug interaction study was an open-label, fixed-sequence, two-period phase I clinical trial in Chinese healthy adult subjects, divided into three cohorts, including simnotrelvir/ritonavir co-administrated with a strong CYP3A and P-gp inhibitor (itraconazole) and inducer (rifampicin), and with a specific CYP3A substrate (midazolam)., Results: The results demonstrated that compared with administration of simnotrelvir/ritonavir alone, the co-administration with itraconazole increased the geometric least-square mean ratio (GMR) of the expose (area under the plasma concentration-time curve from time zero to the lowest detectable plasma concentration [AUC 0-t ]) of simnotrelvir by 25% (GMR 125%, 90% CI 114-137%), whereas co-administration with rifampicin significantly decreased the AUC 0-t of simnotrelvir by 81.5% (GMR 18.5%, 90% CI 16.4-20.9%). Notably, simnotrelvir/ritonavir increased the AUC 0-t of midazolam by 16.69-fold (GMR 1769%, 90% CI 1551-2018%). The co-administration of simnotrelvir/ritonavir and rifampicin caused the increased amount and severity of treatment-emergent adverse events, especially hepatotoxicity., Discussion: The co-administration of simnotrelvir/ritonavir with CYP3A and P-gp inhibitors can be safely used, whereas the co-administration with CYP3A and P-gp strong inducer should be avoided to minimize the risk of under-exposure. Co-administration of midazolam with simnotrelvir/ritonavir increased systemic exposure of midazolam., Clinicaltrials: gov Identifier: NCT05665647., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: To summarize the clinical features and genetic characteristics of Congenital bile acid synthetic disorder type 3 (BASD3) disorder caused by CYP7B1 gene variation. Methods: This was a case series study. Clinical data and genetic results of 2 cases of congenital bile acid synthetic disorder type 3 caused by CYP7B1 gene variations in the Department of Infectious Diseases, Children's Hospital of Fudan University at Xiamen and Department of Pediatrics, Women and Children's Hospital, School of Medicine, Xiamen University from January 2021 to December 2023 were retrospectively collected and analyzed. Literature up to December 2023 was searched from electronic databases of China National Knowledge Infrastructure (CNKI), Wanfang Data and PubMed with the combined keywords of " Congenital bile acid synthetic disorder type 3""Oxysterol 7-alpha-hydroxylase""Oxysterol 7α-Hydroxylase Deficiency""BASD3" and "CYP7B1 liver" both in Chinese and English. The main clinical features and genetic characteristics of BASD3 disorder caused by CYP7B1 gene variations were summarized. Results: Two BASD3 patients, 1 male and 1 female, were admitted at the ages of 3 months and 18 days, and 2 months and 7 days, respectively. Both patients presented with neonatal cholestasis and hepatomegaly. Biochemical evidence indicated direct hyper-bilirubinemia with elevated aminotransferase levels, while gamma-glutamyltransferase (GGT) and total bile acid levels were normal or nearly normal. Patient 1 was a compound heterozygotes of the CYP7B1 gene variants c.525-526insCAAGTTGG(p.Asp176GInfs*15) and c.334C>T(p.Arg112Ter). Patient 1 jaundice resolved and liver function tests normalized after oral administration of chenodeoxycholic acid (CDCA). Patient 2 was homozygous for variant c.334C>T(p.Arg112Ter) in CYP7B1 gene. Patient 2 was in liver failure status already and not reactive to oral CDCA administration. Patient 2 received living-related liver transplantation for enhanced abdominal CT revealed a liver tumor likely vascular origin. Literature review revealed no cases of BASD3 reported in Chinese literature, including 2 patients in this study, while 12 patients (9 males and 3 females) were reported in 9 English literatures. All of the 12 manifested jaundice and hepatosplenomegaly in infancy, with cirrhosis, liver failure, kidney enlargement, hypoglycemia, and spontaneous bleeding in some cases, polycystic kidney disease was demonstrated in 5 cases of them. The c.334C>T (p.Arg112Ter) of the CYP7B1 gene was homozygous in 4 cases and compound heterozygous in 2 cases. Among the 12 children, 6 cases received CDCA treatment, while 6 cases not. Four survived with their native liver in the 6 cases who received CDCA therapy, while none in the 6 cases not received CDCA therapy. Conclusions: BASD3 is a rare hereditary cholestatic disorder. Markedly elevated levels of conjugated bilirubin and aminotransferases, with normal or nearly normal GGT and total bile acid levels can serve as diagnostic clue. c.334C>T is the most common pathogenic variant of the CYP7B1 gene. Timely administration of CDCA may save the liver.

Background: Pre-exposure prophylaxis (PrEP) utilization among cisgender women (subsequently 'women') is low across age groups, relative to their risk of HIV acquisition. We hypothesize that age-related differences in psychosocial factors also influence women's intention to initiate oral PrEP in Washington, D.C., Methods: A secondary analysis of a cross-sectional survey data was performed to evaluate factors influencing intention to initiate oral PrEP among women seen at a family planning and a sexual health clinic. A bivariate analysis was performed to identify differences by age group in demographic characteristics, indications for PrEP, and attitudes toward PrEP; we then performed additional bivariate analysis to assess these variables in relation to PrEP intention., Results: Across age groups, perceived risk of HIV acquisition was not significantly different and was not associated with intention to initiate PrEP. Awareness of and attitude toward PrEP, injunctive norms, descriptive norms, and self-efficacy were not different across age, however there were significant age-associated differences in relation to PrEP intention. Specifically, among 18-24-year-olds, intention to start PrEP was associated with support from provider ( p  = 0.03), main sexual partner ( p  < 0.01), and peers ( p  < 0.01). For women 25-34 years old, having multiple sexual partners ( p  = 0.03) and support from casual sexual partners ( p  = 0.03) was also important. Among women 35-44 years old, prior awareness of PrEP ( p  = 0.02) and their children's support of PrEP uptake ( p  < 0.01) were associated with intention to initiate PrEP. Among 45-55 year-old women intention to initiate PrEP was positively associated with engaging in casual sex ( p  = 0.03) and negatively associated with stigma ( p  < 0.01)., Conclusion: Overall, there were more similarities than differences in factors influencing intention to initiate PrEP across age groups. Observed differences offer an opportunity to tailor PrEP delivery and HIV prevention interventions to increase awareness and uptake for cisgender women., (© The Author(s), 2024.)

The strong-fragrant rapeseed oil (SFRO) is a popular rapeseed oil in China with a low refining degree only degumming with hot water, which remarkably affects its storage stability. The present study compared the overall changes of physical/chemical/nutrient quality of FROs at various temperatures, light wavelengths and headspace volumes. Results showed that red light (680 nm) had a most significant adverse effect on the overall quality of SFRO with the higher correlation coefficients to PV and TOTOX of 0.71 and 0.70, and lower correlation coefficients to chlorophyll and tocopherol of -0.95 and -0.53, respectively. Further studies revealed that red light accelerated the oxidation of fragrant rapeseed oils by degrading chlorophyll to initiate the photo-oxidation process and synthesize high amount of secondary oxidation products including aliphatic and aromatic oxidized compounds from linolenic acid. These findings provided a reference to control the deterioration of FROs by preventing the transmittance of red light., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: To assess the effectiveness of a 6-month Ba Duan Jin exercise program in improving the balance of community-dwelling older adults. Methods: A two arms, parallel-group, cluster randomized controlled trial was conducted in 1 028 community residents aged 60-80 years in 40 communities in 5 provinces of China. Participants in the intervention group (20 communities, 523 people) received Ba Duan Jin exercise 5 days/week, 1 hour/day for 6 months, and three times of falls prevention health education, and the control group (20 communities, 505 people) received falls prevention health education same as the intervention group. The Berg balance scale (BBS) score was the leading outcome indicator, and the secondary outcome indicators included the length of time of standing on one foot (with eyes open and closed), standing in a tandem stance (with eyes open and closed), the closed circle test, and the timed up to test. Results: A total of 1 028 participants were included in the final analysis, including 731 women (71.11%) and 297 men (28.89%), and the age was (69.87±5.67) years. After the 3-month intervention, compared with the baseline data, the BBS score of the intervention group was significantly higher than the control group by 3.05 (95% CI : 2.23-3.88) points ( P <0.001). After the 6-month intervention, compared with the baseline data, the BBS score of the intervention group was significantly higher than the control group by 4.70 (95% CI : 4.03-5.37) points ( P <0.001). Ba Duan Jin showed significant improvement ( P <0.05) in all secondary outcomes after 6 months of exercise in the intervention group compared with the control group. Conclusions: This study showed that Ba Duan Jin exercise can improve balance in community-dwelling older adults aged 60-80. The longer the exercise time, the better the improvement.

Plerixafor, an analog of C-X-C motif chemokine receptor 4 (CXCR4), which allows the release of stem cells from the bone marrow into peripheral blood (PB) by disrupting the interaction of CXCR4 with stromal cell-derived factor-1 (SDF-1), is effective in mobilization for peripheral blood stem cells (PBSC). Due to its market approval has not been long and its high price in China, the clinical application of plerixafor is still very limited. The clinicians are actively seeking the optimal use of plerixafor to improve the success rate of PBSC collection and reduce the cost. This article reviews the latest research progress related to plerixafor application, in order to summarize the optimal use of plerixafor in autologous hematopoietic stem cell transplantation (auto-HSCT).

Objectives: INS068 is a novel, soluble, and long-acting insulin analog. In this study, we evaluated the pharmacokinetics and relative bioavailability of two formulations of INS068 in healthy Chinese subjects: a reference formulation packaged in vials and administered via syringe (R), and a test formulation packaged and administered via pen injector (T). Methods: A randomized, open-label, two-period, two-sequence crossover study was conducted with 24 healthy Chinese subjects. Subjects were randomized and administered subcutaneously in the abdomen at 0.4 U/kg of test or reference INS068 injection according to an open crossover design. INS068 concentrations in the serum were measured using LC-MS/MS, and the pharmacokinetic parameters of maximum concentration (C max ) and area under the concentration-time curve (AUC 0-t and AUC 0-∞ ) were used to evaluate relative bioavailability. Results: After a single dose at 0.4 U/kg, the median T max of INS068 was 12 h for both formulations, and the mean t 1/2 for T and R was 13.0 h and 12.6 h, respectively. The geometric means of C max and AUC 0-∞ were 3.99 nmol/L and 120 h·nmol/L for the T, and 4.05 nmol/L and 117 h·nmol/L for the R, respectively. The geometric mean ratios of C max , AUC 0-t and AUC 0-∞ of T over R were 98.7% (90% CI: 92.7%-105.2%), 102.6% (90% CI: 100.0%-105.3%) and 102.8% (90% CI: 100.1%-105.5%). Conclusion: The overall PK profile of the two formulations of INS068 injection was comparable in healthy subjects, and the pen injector of INS068 had adequate safety and tolerability, supporting it as a new formulation in a phase III study and bridging PK data from early phase clinical trials. Clinical Trial Registration: clinicaltrials.gov, identifier: NCT05336071., Competing Interests: Authors X-HG, KS, and SF were employed by the Jiangsu Hengrui Medicine Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chen, Zhang, Ye, Gao, Song, Zhou, Li, Zhao, Shi, Yang, Shen, Feng and Zhao.)

New therapeutic targets and drugs are urgently needed to halt the fibrosing process in idiopathic pulmonary fibrosis (IPF). SHR-1906 is a novel fully humanized monoclonal antibody against the connective tissue growth factor, which plays an essential role in the genesis of IPF. We assessed the safety, tolerability, pharmacokinetics (PKs), and immunogenicity of single dose SHR-1906 in healthy participants. This was a randomized, double-blind, placebo-controlled, dose-escalation, phase I study. Twelve healthy participants for each dose level were enrolled to receive single ascending doses of SHR-1906 intravenously (1.5, 6, 12, 20, 30, and 45 mg/kg) or placebo and followed for 71 days. The primary end points were safety and tolerability. Treatment-related treatment-emergent adverse events occurred in 25 participants (46.3%) in the SHR-1906 group and 11 (61.1%) in the placebo group. No serious adverse events occurred. Over the dose range investigated, the geometric mean clearance was 0.14-0.63 mL/h/kg, the geometric mean volume of distribution at steady-state was 47.4-75.5 mL/kg, and the terminal elimination half-life was 51.9-349 h. SHR-1906 showed nonlinear PKs. The peak concentration increased in a dose-proportional manner, whereas the area under the concentration-time curve showed a greater than dose-proportional increase. Anti-drug antibodies of SHR-1906 were detected in nine of 54 participants (16.7%). A single dose of SHR-1906 up to 45 mg/kg demonstrated a favorable tolerability profile in healthy participants. The PKs and immunogenicity of SHR-1906 were evaluated, supporting further clinical development., (© 2023 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Graft-versus-host disease (GVHD) is one of the major complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT), which seriously affects the prognosis of patients. At present, a new regimen of post-transplantation cyclophosphamide (PTCy) combined with antithymocyte globulin (ATG) has been used to prevent GVHD, indicating that PTCy combined with ATG may have a good effect on the prevention of GVHD in different types of transplantation. However, the mechanism of this regimen, its effect on immune reconstitution and viral reactivation still needs to be further studied. Therefore, this article briefly reviews the research progress of PTCy combined with ATG in preventing GVHD after HSCT.

Safe and efficacious antiviral therapeutics are in urgent need for the treatment of coronavirus disease 2019. Simnotrelvir is a selective 3C-like protease inhibitor that can effectively inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We evaluated the safety, tolerability, and pharmacokinetics of dose escalations of simnotrelvir alone or with ritonavir (simnotrelvir or simnotrelvir/ritonavir) in healthy subjects, as well as the food effect (ClinicalTrials.gov Identifier: NCT05339646). The overall incidence of adverse events (AEs) was 22.2% (17/72) and 6.3% (1/16) in intervention and placebo groups, respectively. The simnotrelvir apparent clearance was 135-369 L/h with simnotrelvir alone, and decreased significantly to 19.5-29.8 L/h with simnotrelvir/ritonavir. The simnotrelvir exposure increased in an approximately dose-proportional manner between 250 and 750 mg when co-administered with ritonavir. After consecutive twice daily dosing of simnotrelvir/ritonavir, simnotrelvir had a low accumulation index ranging from 1.39 to 1.51. The area under the curve of simnotrelvir increased 44.0 % and 47.3 % respectively, after high fat and normal diet compared with fasted status. In conclusion, simnotrelvir has adequate safety and tolerability. Its pharmacokinetics indicated a trough concentration above the level required for 90 % inhibition of SARS-CoV-2 in vitro at 750 mg/100 mg simnotrelvir/ritonavir twice daily under fasted condition, supporting further development using this dosage as the clinically recommended dose regimen., Competing Interests: Declaration of Competing Interest Yang Yang, Shao-Ping Peng, Yu-Mei Yang, Pan Shu, Pei-Jin Li, Shan Li, Hong-Lin Hu and Ren-Hong Tang are employees of Jiangsu Simcere Pharmaceutical Co., Ltd. Yan Xu is employee of Simcere of America. Other authors declare that they have no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: Our objective was to identify the individual, interpersonal, community, health-system, and structural factors that influence HIV pre-exposure prophylaxis (PrEP) initiation among cisgender women seeking sexual and reproductive health care in a high HIV prevalence community to inform future clinic-based PrEP interventions., Methods: We collected anonymous, tablet-based questionnaires from a convenience sample of cisgender women in family planning and sexual health clinics in the District of Columbia. The survey used the lens of the socio-ecological model to measure individual, interpersonal, community, institutional, and structural factors surrounding intention to initiate PrEP. The survey queried demographics, behavioral exposure to HIV, perceived risk of HIV acquisition, a priori awareness of PrEP, intention to initiate PrEP, and factors influencing intention to initiate PrEP., Results: A total of 1437 cisgender women completed the survey. By socio-ecological level, intention to initiate PrEP was associated with positive attitudes toward PrEP (odds ratio [OR], 1.56; 95% confidence interval [CI], 1.13-2.15) and higher self-efficacy (OR, 1.32; 95% CI, 1.02-1.72) on the individual level, perceived future utilization of PrEP among peers and low fear of shame/stigma (OR, 1.65; 95% CI, 1.33-2.04) on the community level, and having discussed PrEP with a provider (OR. 2.39; 95% CI, 1.20-4.75) on the institutional level., Conclusion: Our findings highlight the importance of multilevel, clinic-based interventions for cisgender women, which promote sex-positive and preventive PrEP messaging, peer navigation to destigmatize PrEP, and education and support for women's health medical providers in the provision of PrEP services for cisgender women., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Most obstetric emergencies are initially managed in the emergency department (ED). The Supreme Court decision of Dobbs v. Jackson Women's Health Organization, overturning Roe v. Wade, in June 2022, eliminated constitutional protection of abortion rights, allowing states to swiftly enact laws that can greatly change reproductive medicine. In this post-Roe landscape, the ambiguity and uncertainty being imposed on clinicians regarding the legality of certain interventions may have catastrophic effects. To understand and plan for the changes that will come and attempt to mitigate adverse outcomes, the authors first assessed the current state of pregnancy-related complication care in the ED setting. This study utilized data obtained from the National Hospital Ambulatory Medical Care Survey (NHAMCS) to evaluate trends in pregnancy-related ED visits from 2016 to 2020 that could be impacted by restricted abortion access and trigger laws. The authors subsequently analyzed the legislative changes and translated the pertinent ones to dispel misunderstandings and provide a framework for appropriate medical practice., Methods: The retrospective study utilized data from the NHAMCS database from 2016 to 2020, encompassing an estimated total of 4,556,778 pregnancy-related ED visits. NHAMCS is a multi-stage probabilistic sample collected by the National Center for Health Statistics (NCHS) at the Centers for Disease Control and Prevention (CDC) using an annual survey of EDs in the United States. All data were summarized using descriptive statistics such as proportions and 95% confidence intervals Furthermore, the supreme court decision was analyzed in addition to multiple state laws and legal texts. The findings were summarized and discussed., Results: The majority (79.4%) of all studied visits were for patients between the ages of 18-34 years, capturing those in peak reproductive years. This age group also comprised of the bulk (76.4%) of visits for pathologic pregnancies, including ectopic and molar pregnancies, and 79.8% of visits for a spontaneous miscarriage or threatened miscarriage in early pregnancy. Black patients accounted for 25.7%, white patients 70.1%. Regarding ethnicity, patients were separated into Hispanic and non-Hispanic, with Hispanic patients comprising 27% of all ED visits for included diagnoses between 2016 and 2020. Most visits for complications following an induced abortion occurred in the south (70.8%) and were nearly twice as likely to occur in non-metropolitan areas. Approximately 18% patients presenting with a pathologic pregnancy required admission to the hospital and approximately 50% of those visits for pathologic pregnancies and visits for bleeding in pregnancy had a procedure in the ED (49.8% and 49.5%). There were 111,264 estimated visits in which methotrexate was administered, amounting to approximately 1 in 7 visits for ectopic or molar pregnancy. In this data set, approximately 14,000 miscarriage and early bleeding patients received misoprostol., Conclusion: Pregnancy-related ED visits comprise of a significant proportion of emergency care. As it relates to many of the trends previously elucidated on, the true extent of the burden cannot be predicted. It must be emphasized that contrary to popular belief, Dobbs v. Jackson does not prohibit termination of pregnancy in the setting of life-threatening conditions to the mother, including ectopic pregnancy, preeclampsia, and others, but the resultant uncertainty and ambiguity surrounding the constitutional change is leading to an over-compliance of the law, necessarily obstructing reproductive health care. The authors recommend that physicians be mindful of the rapidly-evolving laws in their particular state, and to also practice in accordance with Emergency Medical Treatment and Active Labor Act (EMTALA). Patient safety must be prioritized., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aims: Apatinib is widely used in Chinese cancer patients. As the in vivo drug disposition of apatinib has large individual differences, adverse events are prone to occur. Cytochrome P450 (CYP)3A5 and cancer types maybe the main factors affecting this individual differences. The objective of our study was to establish a population pharmacokinetics (PK) model of apatinib in adult cancer patients, and to explore optimal dosage regimens for individualized treatment., Methods: Adult patients with various types of cancer treated with apatinib were enrolled. The concentration of apatinib in plasma was determined by high-performance liquid chromatography-tandem mass spectrometry. CYP3A5 genotype was determined using TaqMan allelic discrimination technique. The population PK model was developed by NONMEM V7.4. The dosing regimen was optimized based on Monte Carlo simulations., Results: A population PK model of apatinib in adult cancer patient was established. CYP3A5 genotype and systemic cancer type (digestive system cancers, nondigestive system cancers) were the most significant covariates for PK parameters. Patients with CYP3A5*1 expressers (CYP3A5*1/*1 and CYP3A5*1/*3) had lower apparent clearance and apparent volume of distribution than patients who do not express CYP3A5*1 (CYP3A5*3/*3). Patients with nondigestive system cancer had higher apparent volume of distribution and absorption rate constant than digestive system cancer. The results of dose simulation suggest that the apatinib dose in patients who do not express CYP3A5*1 should be 33.33-50.00% higher than that in CYP3A5*1 expressers., Conclusions: A population PK model of apatinib in adult cancer patients was established. CYP3A5 genotype and systemic cancer type had concurrent effects on PK parameters. CYP3A5 patients who do not express CYP3A5*1 required higher doses., (© 2023 British Pharmacological Society.)

To explore the pollution characteristics, ecological risks, and sources of heavy metals, soil surface samples of vegetable fields in 14 typical districts of the Three Gorges Reservoir area (Chongqing section) were collected in October 2021. The contents of seven types of heavy metals (As, Cd, Cr, Cu, Ni, Pb, and Zn) were analyzed. Based on the single-factor pollution index, the Nemerow integrated pollution index and potential ecological risk coefficient of heavy metals were evaluated. Additionally, the effects of different planting years and methods (open-field and greenhouse planting) on soil heavy metal accumulation were analyzed. The results indicated that the mean concentrations of heavy metals in vegetable soils in the area were lower than the national risk screening values for soil contamination of agricultural land (GB 15618-2018) but higher than their background values in Chongqing. According to the single-factor pollution index method, Pb, Zn, Cu, and Cd showed negligible slight hazards. The Nemerow pollution index showed that the study area was at a slight hazard level, and the main factors were Ni and Cd. Heavy metal pollution was found in 91.4% of the soil samples ( P N >1) with different degrees, and 9.19% of them were severely polluted. The potential ecological risk coefficient showed that the vegetable lands were polluted slightly, and 9.77% of soil samples polluted by Cd were at moderate ecological risk. According to cluster analysis, the sources of Cd-Cu-Pb-Zn and As-Cr-Ni were similar. The content of heavy metals in the open field and greenhouse showed an increasing trend with the increase in planting years, and the content of heavy metals in greenhouse soil were generally higher than that in open field soil.

Objective: To observe the clinical significance of translocator proteins (TSPO) gene in the treatment of FLT3 -ITD/ DNMT3A R882 double-mutated acute myeloid leukemia (AML)., Methods: Seventy-six patients with AML hospitalized in the Department of Hematology of the Affiliated People's Hospital of Ningbo University from June 2018 to June 2020 were selected, including 34 patients with FLT3 -ITD mutation, 27 patients with DNMT3A R882 mutation, 15 patients with FLT3 -ITD/ DNMT3A R882 double mutation, as well as 19 patients with immune thrombocytopenia (ITP) hospitalized during the same period as control group. RNA was routinely extracted from 3 ml bone marrow retained during bone puncture, and TSPO gene expression was detected by transcriptome sequencing (using 2-deltadeltaCt calculation)., Results: The expression of TSPO gene in FLT3 -ITD group and DNMT3A R882 group at first diagnosis was 2.02±1.04 and 1.85±0.76, respectively, which were both higher than 1.00±0.06 in control group, but the differences were not statistically significant ( P =0.671, P =0.821). The expression of TSPO gene in the FLT3 -ITD/ DNMT3A R882 group was 3.98±1.07, wich was significantly higher than that in the FLT3 -ITD group and DNMT3A R882 group, the differences were statistically significant ( P =0.032, P =0.021). The expression of TSPO gene in patients who achieved complete response after chemotherapy in the FLT3 -ITD/ DNMT3A R882 group was 1.19±0.87, which was significantly lower than that at first diagnosis, and the difference was statistically significant ( P =0.011)., Conclusion: TSPO gene may be used as an indicator of efficacy in FLT3 -ITD / DNMT3A R882 double-mutated AML.

Objectives: To assess the analgesic efficacy of preoperative gabapentin among patients undergoing dilation and evacuation (D&E) with moderate sedation., Study Design: We conducted a randomized, controlled, double-blind trial among patients undergoing same-day D&E at 14 to 19 weeks gestation under moderate sedation. We randomized participants 1:1 to gabapentin 600 mg or placebo after cervical preparation at least 1 hour prior to D&E. We assessed pain using a 100-mm visual analog scale before, during, and after the procedure. The primary outcome was postoperative recall of maximum procedural pain with a 13-mm a priori threshold for clinical significance. We standardized initial fentanyl and midazolam dosing. We assessed satisfaction with pain control, nausea, and vomiting via Likert scales and anxiety using a validated instrument., Results: We enrolled 126 participants and randomized 61 to gabapentin and 65 to placebo, with study medication administered a mean of 211 (SD 64) minutes preoperatively. Recall of maximum pain was 41 mm for gabapentin and 49 mm for placebo (p = 0.24). Gabapentin resulted in reduced pain during uterine aspiration (56 vs 71 mm, p= 0.003) compared to placebo, but not for any other time points. The gabapentin group had higher satisfaction (78% vs 65% very or somewhat satisfied, p= 0.01). Median fentanyl dose was lower in the gabapentin group (75 vs 100 mcg, p = 0.005). Midazolam dose, nausea, vomiting, and anxiety did not differ between groups. No serious adverse events occurred in the gabapentin group. Sedation reversal was not required., Conclusions: The addition of gabapentin to moderate sedation during D&E did not result in lower maximum recalled procedural pain. Gabapentin resulted in reduced intra-operative pain during uterine aspiration and increased satisfaction with pain control., Implications: Gabapentin reduces intraoperative pain and improves satisfaction with pain management when administered prior to second-trimester surgical abortion and may be considered as an adjunct to intravenous sedation. Moderate sedation may impair assessment and recall of pain. Additional research is needed to identify the most effective pain management regimens for D&E., (Copyright © 2022. Published by Elsevier Inc.)

The accumulation of antibiotics in farmland and its ecological risk have become a research hotspot at home and abroad. The objective of this study was to investigate the occurrence and accumulation of antibiotics and their potential environmental and ecological risks in vegetable fields in Kaizhou district of Chongqing country. The occurrence characteristics of antibiotics including tetracyclines, sulfonamides, quinolones, macrolides, and chloramphenicols were detected using experimental analysis. The results showed that there was an accumulation of antibiotics in the vegetable soil, and 18 antibiotics in five categories were detected (0-42.88 μg·kg -1 ), mainly for tetracyclines and quinolones. The detection rate of quinolone antibiotics was the highest (15.38%-100%), especially for norfloxacin and ofloxacin (100%), whereas the tetracyclines presented the highest concentration (0-42.88 μg·kg -1 ). The amount of total antibiotics in the vegetable soil was 1.64-233.11 μg·kg -1 , whereas different vegetable soils showed the following trend:water spinach soil (89.73 μg·kg -1 )>cabbage soil (32.53 μg·kg -1 )>pepper soil (32.16 μg·kg -1 )>tomato soil (32.13 μg·kg -1 )>cucumber soil (26.46 μg·kg -1 )>grassland (7.32 μg·kg -1 ). The correlation results showed that there was a significantly positive correlation between total antibiotic residues and organic fertilizer application ( P <0.05) but a significantly negative correlation with soil pH ( P <0.05). Quinolones and sulfonamides were negatively correlated with soil water content ( P <0.05), whereas quinolones positively correlated with soil available phosphorus and organic matter content ( P <0.05). The potential eco-environmental risk assessment results showed that tetracyclines and quinolones in vegetable soil in Kaizhou district had certain ecological risks, of which 62%-92% and 62%-100% of soil samples with quinolones had potential toxicity to soil animals and microorganisms.

To explore prognostic factors in intermediate-risk acute myeloid leukemia (AML) patients with minimal residual disease (MRD) negativity (MRD<0.1%,MRD-)receiving autologous hematopoietic stem cell transplantation (auto-HSCT).A total of 59 intermediate-risk AML patients with MRD-were treated with auto-HSCT from January 2015 to September 2021 at Affiliated People's Hospital of Ningbo University. The clinical data and laboratory results were collected retrospectively. Efficacy, clinical outcome and prognostic factors were analyzed. Univariate analysis was conducted by using log-rank test, the multivariate analysis by Cox proportional risk model.Among 59 patients, there were 27 males and 32 females with median age of 55 (31-69) years old.The median follow-up was 761(317-1 861)days. The 2-year overall survival (OS) rate and event-free survival (EFS) rate were 76.1%±11.4% and 73.4%±11.6% respectively.The univariate analysis showed that age older than 50 years, TET2 gene mutation (TET2 + ), achieving MRD negativity over 30 days (MRD 30+ ) were unfavorable factors of OS ( χ 2 =6.20, 33.20, 7.18; P= 0.013,<0.001, 0.007). TET 2+ , WT1 gene mutation (WT1 + ), CD34 + cells<2×10 6 /kg, MRD 30+ were negative factors of EFS ( χ 2 =17.29, 4.47, 3.94, 9.393; P< 0.001, 0.035, 0.047, 0.002).Multivariate analysis showed that MRD 30+ , TET2 + were independent prognostic factors of OS and EFS (OS: HR =9.251, 25.839, P= 0.036, 0.001;EFS: HR =5.851, 9.199, P= 0.043, 0.002). Intermediate-risk AML patients with MRD 30+ or TET2 + have very poor prognosis after auto-HSCT. Alternative regimens should be investigated.

Objective: We aimed to investigate and interpret the associations between socioeconomic factors and the prevalence, awareness, treatment, and control of hypertension at the provincial level in China., Methods: A nationally and provincially representative sample of 179,059 adults from the China Chronic Disease and Nutrition Surveillance study in 2015-2016 was used to estimate hypertension burden. The spatial Durbin error model was fitted to investigate socioeconomic factors associated with hypertension indicators., Results: Overall, it was estimated that 29.20% of the participants were hypertensive nationwide, among whom, 34.32% were aware of their condition, 27.69% had received antihypertensive treatment, and 7.81% had controlled their condition. Per capita gross domestic product (GDP) was associated with hypertension prevalence (coefficient: -2.95, 95% CI : -5.46, -0.45) and control (coefficient: 6.35, 95% CI : 1.36, 11.34) among adjacent provinces and was also associated with awareness (coefficient: 2.93, 95% CI : 1.12, 4.74) and treatment (coefficient: 2.67, 95% CI : 1.21, 4.14) in local province. Beds of internal medicine (coefficient: 2.66, 95% CI : 1.08, 4.23) was associated with control in local province. Old dependency ratio (coefficient: -3.58, 95% CI : -5.35, -1.81) was associated with treatment among adjacent provinces and with control (coefficient: -1.69, 95% CI : -2.42, -0.96) in local province., Conclusion: Hypertension indicators were not only directly influenced by socioeconomic factors of local area but also indirectly affected by characteristics of geographical neighbors. Population-level strategies should involve optimizing supportive socioeconomic environment by integrating clinical care and public health services to decrease hypertension burden., (Copyright © 2021 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.)

Augmented renal clearance (ARC) can cause underexposure to vancomycin, thereby increasing the risk of treatment failure. Our objective was to evaluate population pharmacokinetics and optimize the dosing regimen of vancomycin in a pediatric population with ARC. Sparse pharmacokinetic sampling and therapeutic drug monitoring (TDM) data were collected from pediatric patients with ARC treated with vancomycin. A pharmacokinetic model was developed using NONMEM 7.2. The dosing regimen was optimized using Monte Carlo dose simulations. A total of 242 vancomycin serum concentrations from 113 patients (age range, 0.4 to 14.9 years; 49 females and 64 males) were available. The mean vancomycin dose was 58.8 mg/kg body weight/day (13.6 mg/kg/dose), and the mean vancomycin serum trough concentration was 6.5 mg/liter. A one-compartment pharmacokinetic model with first-order elimination was developed. Body weight and age were the most significant and positive covariates for clearance and volume of distribution. For the pediatric population with ARC, the current recommended vancomycin dose of 60 mg/kg/day was associated with a high risk of underdosing. To reach the target area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC) ratio of 400 to 700 in these pediatric patients, the vancomycin dose should be increased to 75 mg/kg/day for infants and children between 1 month and 12 years of age and 70 mg/kg/day for adolescents between 12 and 18 years of age. In conclusion, a one-compartment pharmacokinetic model with first-order elimination was established with body weight and age as significant covariates. An optimal dosing regimen was developed in pediatric patients with ARC aged 1 month to 18 years.

Objective: To investigate the incidence of injuries among children aged 0-17 years from 28 counties in six provinces. Methods: According to the earlier study on data in different local areas and the current work plan, we selected the survey objects for a general survey on child injury prevalence in the last 12 months. The subjects included guardians of children who did not attend kindergartens, children from kindergartens, and primary school grades 1-3. Children from grades 4-6 primary school, junior high school, and senior high school were also included. Results: The overall rate of injured children was 4.83%, with the incidence of injuries as 5.75% in the last 12 months before the survey. Both the rate of injured children and incidence of injuries were higher in boys than that in girls. Children whose primary caregivers were relatives, grandparents, minors, or with an education level below the primary school had a relatively higher rate of both injured children and incidence of injuries. The first cause of child injury was fall. The time of child injury was mainly from June to October, mainly at home, with the main activity as playing. The significant injuries in children were contusion and abrasion, and the main parts injured were lower limbs, upper limbs, and head. Most of the injuries were cured, and the primary treatment was outpatient and emergency treatment. Conclusions: Boys and children whose parents can not take care of are the priority population for child injury prevention and control. Targeted prevention and control measures should be implemented according to the characteristics of injuries among children of different ages.

Objective: To landscape the contents, similarities, and differences of the objectives and strategies for unintentional injury prevention and control in the national and 31 provincial Children's Development Outlines from 2011 to 2020, and propose relevant suggestions. Methods: The content analysis method was used to extract, encode and classify the objective and strategy text of unintentional injury in all Children's Development Outlines and construct the theme of strategy text combined with the '5E' Injury Prevention Framework. Taking the national Children's Development Outline as the benchmark, the relevant contents of 31 provincial Children's Development Outlines in the same period were compared. Results: All Children's Development Outlines took child injury prevention and control as the primary objective set in health, environment, and safety. The national and most provincial Children's Development Outlines set this goal in health, while others put it in environment or safety. Reducing injury-induced death, disability and occurrence were designated as the main content in the objective of child injury prevention and control. However, there were no quantitative requirements for injury occurrence and disability in all the provincial outlines. The themes of unintentional injury prevention and control strategies in all Children's Development Outlines could be divided into the mechanism, law enforcement, education, environment, engineering, first aid, assessment, and economic strategies. Mechanism strategy was the primary domain, followed by law enforcement, education, environment, and engineering strategies, but less attention was put on first aid, assessment, and economic strategies. The unintentional injury prevention and control strategy in the provincial Children's Development Outlines was mainly based on the national outline. Still, it also varied with some emphasis and refinement in different items among all the provinces. Conclusions: Children's Development Outline is a vital policy guarantee for implementing child injury prevention and control work. Developing a system involving good primary data, mechanisms and strategies, law enforcement, and environmental and engineering-related strategies for more common types of child injuries has been attached to great importance. Actively carrying out assessments and encouraging the adoption of more economical strategies could further enrich and improve the unintentional injury prevention and control in Children's Development Outline and promote the progress of related work in China.

Objective: To understand the epidemiological characteristic and influencing factors of animal injuries among children from 28 counties/districts in 6 provinces of China to provide evidence for formulating related prevention measures and strategies. Methods: Data was obtained from 'Children injury prevention project, 2016-2020'. Variables on the characteristics, including incidence, locations, related activities, time, and outcomes among children, were described. The negative binomial regression model analyzed animal injury frequency influencing factors. Results: There were 107 029 boys and 97 599 girls, with a gender ratio of 1.10, among the 204 628 children aged 0-17 in 28 counties/districts in 6 provinces of China. Per-person and per-time incidence rates of animal injuries were 0.70% and 0.72%, both higher in boys than in girls. Animal injuries among children mainly occurred in home (73.20%), road/street (7.51%), and open space of community/village (6.77%), during playing (63.15%), with the peak time between 12:01-18:00 (45.03%). Upper limbs (47.89%), lower limbs (35.31%), and head (8.44%) were the most injured body parts. Outpatient or emergency treatment (85.19%) had been carried out. The negative binomial regression showed that sex, grade, guardian educational level, urban or rural, and daily communication between guardians and children as influencing factors in the frequency of animal injuries among children. Conclusions: Special attention should be given to boys, at home, in projects on animal injury prevention and control. There were many influencing factors of animal injury frequency. Knowledge of injury prevention should be popularized to children and guardians. Related comprehensive intervention should be developed in families, schools, and social settings.

Objective: To investigate the incidence of traffic injuries among children aged 0-17 years in 28 counties of 6 provinces and to provide prevention suggestions. Methods: Using the general survey method, a questionnaire survey was conducted on the road traffic injuries of children in 28 counties of 6 provinces in 2017. Results: A total of 204 628 students were surveyed, 908 of whom had experiences of road traffic injuries. Road traffic injuries were 0.44% among children in 28 counties of 6 provinces in China and 0.94% among children who did not attend kindergartens. July is a high incidence period of road traffic injuries among children (12.92%). When children suffer from road traffic injuries, the first three activities were playing (21.61%), riding an electric bicycle (20.40%), walking (20.07%). Most injuries appeared as contusion/abrasion, accounting for 42.26% of the total cases. The injured parts were mainly lower limbs, upper limbs, and heads, accounting for 38.85%, 23.29%, and 20.20%. Most children with road traffic injuries recovered after related treatments, accounting for 85.43% of all cases. The median length of hospital stay of children with road traffic injuries was seven days, and the median expense in hospitals was 3 000 Yuan (RMB). Conclusions: The incidence of road traffic injuries among males appeared higher than females, and the children who did not attend the kindergartens were the highest. During playing, riding an electric bicycle and walking were the top three activities prone to road traffic injuries.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been regarded as a potential strategy for myeloid sarcoma (MS). The previous reports focused mainly on matched sibling donor (MSD) or matched unrelated donor (MUD) transplantation. There are no reports on haploidentical HSCT (haplo-HSCT) in MS. We retrospectively reviewed 14 MS patients who underwent haplo-HSCT. All patients achieved complete donor engraftment. The median time for neutrophil engraftment and platelet engraftment were 10 (12-21) days and 18 (8-31) days. The 100-day cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) and 3-year cumulative incidence of chronic GVHD were 37.7% (95%CI, 23.2-52.1%) and 35.7% (95%CI, 22.2-49.2%). Cytomegalovirus (CMV) reactivation was documented in 86% patients, and only one patient developed CMV pneumonia. Treatment-related mortality occurred in one (7%) patient. The 1- and 3-year cumulative incidence of relapse was 21.4% (95%CI, 11.8-31.1%) and 35.7% (95%CI, 22.4-49.0%). The probability of overall survival at 1 and 3 years was 71.4% (95%CI, 51.3-99.5%) and 64.3% (95%CI, 43.5-95.0%), respectively. The probability of disease-free survival at 1 and 3 years was 71.4% (95%CI, 51.3-99.5%) and 57.1% (95%CI, 36.3-89.9%), respectively. In conclusion, haplo-HSCT is a feasible method for patients with MS who have no MSD or MUD.

Background: The prolapse of a ruptured and extruded bladder after vaginal hysterectomy is rare in clinical practice. We report the case of a significant mass that prolapsed from the vagina after a vaginal hysterectomy in a multiparous postmenopausal woman., Case Presentation: A 67-year old multiparous postmenopausal Chinese woman was found to have a significant mass extruding from the vagina after a vaginal hysterectomy. The mass was a ruptured and everted bladder, and the diagnosis was confirmed after physical and imaging examinations and urethral catheterization. The patient underwent an emergency operation for mass reduction, bladder repair, and partial colpocleisis under general anesthesia. She recovered without prolapse or urinary drainage complications after 35 months of follow-up., Conclusions: The present case serves as a guide for the management of patients with pelvic organ prolapse. The condition of patients should be carefully evaluated before surgery, and individualized operation should be performed. Careful postoperative follow-up is crucial for the timely exclusion of complications, especially in elderly patients with persistently increased abdominal pressure.

Objective: To understand the epidemiologic characteristics of fall in people aged 60 years and above in China from 2015 to 2018, and provide basis for the prevention of fall in old people and the development of related policies. Methods: Descriptive analysis was conducted on general information, injury occurrence information and injury clinical characteristics of fall cases in people aged 60 years and above by using the data from Chinese National Injury Surveillance System(NISS). Results: A total of 205 670 fall cases were reported to NISS from 2015 to 2018 with the male to female ratio of 1.37. Falls mainly occurred during 10:00-10:59 am (11.91%). The top three places where fall might occur were home (56.41%), road (17.24%) and public residence (14.36%). Leisure activity(37.56%), housework (24.20%) and walk (15.07%) were top three activities in which fall occurred. Bruise/scrape (42.17%), fracture (31.79%) and sprain/strain (14.62%) were the major injuries. The most common body parts involved were low limbs (31.38%), head (22.46%) and truncus(20.71%). Moderate and severe injuries accounted for 37.21% of all cases, and 22.49% of the elderly seeking medical care due to fall required hospitalization. Conclusions: The number of fall in people aged 60 years and above increased from 2015 to 2018. The elderly is a key population in the prevention and control of fall.

First dose prediction is challenging in neonates. Our objective in this proof-of-concept study was to perform a pharmacokinetic (PK) bridging study from juvenile mice to neonates for drugs metabolized by CYP3A. We selected midazolam and clindamycin as model drugs. We developed juvenile mice population PK models using NONMEM. The PK parameters of these two drugs in juvenile mice were used to bridge PK parameters in neonates using different correction methods. The bridging results were evaluated by the fold-error of 0.5- to 1.5-fold. Simple allometry with and without a correction factor for maximum lifespan potential could be used for a bridging of clearance (CL) and volume of distribution (V d ), respectively, from juvenile mice to neonates. Simulation results demonstrated that for midazolam, 100% of clinical studies for which both the predictive CL and V d were within 0.5- to 1.5-fold of the observed. For clindamycin, 75% and 100% of clinical studies for which the predictive CL and V d were within 0.5- to 1.5-fold of the observed. A PK bridging of drugs metabolized by CYP3A is feasible from juvenile mice to neonates. It could be a complement to the ADE and PBPK models to support the first dose in neonates.

Purpose: To determine the ability of nonperfusion, vessel density, and morphologic measurements using projection-resolved optical coherence tomography angiography to detect early retinal microvasculature impairments in diabetes mellitus., Methods: A retrospective review was performed on Type 2 diabetes mellitus patients with no diabetic retinopathy (DR) or mild nonproliferative DR and age-matched controls imaged with optical coherence tomography angiography. Foveal avascular zone-related metrics and extrafoveal avascular area were measured in optical coherence tomography angiography images. Vessel density and fractal dimension were calculated with and without a skeletonization process. The vessel diameter index and vessel tortuosity were computed. The area under the receiver operating characteristic curve (AUC) estimated diagnostic performances., Results: Dilated capillary diameter was observed in the deep capillary plexus in the diabetic groups. Vessel density and fractal dimension of skeletonized deep capillary plexus significantly and progressively decreased in the no DR and mild nonproliferative DR groups compared with controls. Superficial extrafoveal avascular area, vessel density, and fractal dimension of the skeletonized deep capillary plexus had the highest diagnostic performance to differentiate mild nonproliferative DR from control eyes, with AUCs of 0.885, 0.876, and 0.876, respectively., Conclusion: Vessel density and fractal dimension from the skeletonized deep capillary network may be the most sensitive for detecting early retinal capillary loss in diabetes mellitus.

Purpose: Drug elimination alteration has been well reported in acute lymphoblastic leukemia (ALL). Considering that transporters and glomerular filtration influence, to different extents, the drug disposition, and possible side effects, we evaluated the effects of ALL on major renal transporters and glomerular filtration mediated pharmacokinetic changes, as well as expression of renal drug transporters., Methods: ALL xenograft models were established and intravenously injected with substrates of renal transporters and glomerular filtration separately in NOD/SCID mice. The plasma concentrations of substrates, after single doses, were determined using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS)., Results: With the development of ALL, protein expression of MDR1, OAT3 and OCT2 were increased by 2.62-fold, 1.70-fold, and 1.45-fold, respectively, whereas expression of MRP2 and MRP4 were significantly decreased by 30.98% and 45.28% in the kidney of ALL groups compared with control groups. Clearance of MDR1-mediated digoxin, OAT3-mediated furosemide, and OCT2-mediated metformin increased by 3.04-fold, 1.47-fold, and 1.26-fold, respectively. However, clearance of MRPs-mediated methotrexate was reduced by 39.5%. These results are consistent with mRNA expression. Clearance of vancomycin and amikacin, as markers of glomerular filtration rate, had a 2.14 and 1.64-fold increase in ALL mice, respectively., Conclusions: The specific alteration of renal transporters and glomerular filtration in kidneys provide a rational explanation for changes in pharmacokinetics for ALL.

The clinical epidemiological features of cognitive impairment in Chinese older adult patients undergoing hemodialysis are not clear, we aimed to identify the extent and patterns of cognitive impairment among those patients. We conducted a cross-sectional study of 613 hemodialysis patients aged 50 to 80 from 11 centers in Beijing. A neuropsychological battery of 11 tests covering domains of attention/processing speed, executive function, memory, language, and visuospatial function was applied, patients were classified as none, mild, or major cognitive impairment according to the fifth version of the Diagnostic and Statistical Manual of Mental Disorders criteria for cognitive impairment. Compared with Chinese population norms, 37.2% of the participants had mild cognitive impairment, 43.7% had major cognitive impairment. Memory and language were the most severe impaired domains in the mild cognitive impairment group, attention and visuospatial function domains were the most serious impaired domains in the major cognitive impairment group. Concomitant impairment across multiple cognitive domains was common. Factors associated with major cognitive impairment included age, education level, history of stroke and hypertension, dialysis vintage, and single-pool Kt/V. There is a high frequency of cognitive impairment in Chinese older adult hemodialysis patients, with varying severity and concomitant impairment across multiple domains.

We aimed to systematically evaluate the feasibility of integrating HIV prevention services, including pre-exposure prophylaxis (PrEP), into a family planning setting in a high-prevalence community. We used the RE-AIM Framework (Reach, Efficacy, Adoption, Implementation, Maintenance) to evaluate the integration of HIV prevention services into a family planning clinic over 6 months. Before the integration, PrEP was not offered. We implemented a staff training program on HIV PrEP. We determined the proportion of women presenting to the clinic who were screened, eligible for, and initiated PrEP through chart review. We assessed staff comfort with PrEP pre- and post-integration. We compared planned and actual implementation, interviewed staff to determine barriers and facilitators, and tracked systems adaptations. We assessed maintenance of PrEP after the study concluded. There were 640 clinical encounters for 515 patients; the rate of HIV counseling and PrEP screening was 50%. The rate was 10% in month 1 and peaked to 65% in month 3. Nearly all screened patients were eligible for PrEP (98.4%) and 15 patients (6%) initiated PrEP. Staff knowledge and comfort discussing PrEP improved after education. Facilitators included partnering with local experts, continuing education, clinical tools for providers, and patient education materials. Barriers included competing priorities during clinical encounters, limited woman-centered patient education materials, and insurance-related barriers. Embedding HIV prevention services in the family planning setting was feasible in this pilot. The proportion of women screened for PrEP rapidly increased. In this high HIV prevalence community, nearly all screened women were eligible and 6% initiated PrEP.

Purpose: Opportunities exist to detect osteoporotic vertebral deformities (VDs) on frontal radiograph (FR) indicated for lung or abdominal diseases, while literature have been mostly based on lateral radiograph (LR). This study analyzed the detectability of moderate and severe grades VD on FR., Methods: There were 105 female cases (mean 72 years, range 55~93 year), who were referred for digital spine FR and LR with back and/or leg pain. The LR and FR were read, osteoporotic VDs with < 20%, 20-25%, 25-40%, and > 40% vertebral body height loss were recorded as minimal, mild, moderate, and severe grades, respectively. After a 10-month interval, only FRs were read again, and each vertebra was classified as (1) no notable VD, (2) with notable VD, and (3) ambiguous. The first reading was the reference, while the second reading was allowed to miss minimal/mild VCD and endplate/cortex fracture., Results: Counting by subjects, for 98 cases, the two reading sessions had agreement, including 43 "true negative" cases and 55 true positive cases. There were two false positive cases, and five ambiguous cases. In total, 1286 vertebra were assessed, FR reading had 1126 vertebrae "true negative," 130 vertebrae true positive, one vertebra false negative, 3 vertebrae false positive, and 26 ambiguous vertebrae (65.4% being true negative and 34.6% being true positive). Most of the disagreements were associated with kyphosis or poor X-ray projection. Nineteen illustrative cases are presented graphically., Conclusion: Moderate and severe grades of VD are identifiable on FR as long as the involved vertebrae are clearly filmed.

Background: The relationship between spinal sagittal subtypes and lumbar disc degeneration is unclear. Thus, we aimed to investigate the relationship between lumbar intervertebral disc degeneration and age in asymptomatic healthy individuals with different sagittal alignments., Methods: In this cross-sectional observational study, we examined 209 asymptomatic young and middle-aged volunteers (123 women and 86 men) who were divided into the following three groups according to age: groups A (20-30 years), B (31-40 years), and C (41-50 years). The volunteers underwent full-spine standing lateral radiography and magnetic resonance imaging (MRI, 3.0 T) of the lumbar spine. Based on panoramic radiography, two observers measured the spinopelvic parameters and classified the spine into Roussouly subtypes. The degree of disc degeneration was assessed based on T2-weighted images according to the Pfirrmann classification., Results: There was a statistically significant difference in the degree of degeneration of type I spine between groups B and C at L4-L5 (P < 0.03) and L5-S1 (P < 0.01) and between groups A and C at L1-L2 (P < 0.04) and L4-L5 (P < 0.01). The degeneration degree of type II spine at all levels were significantly different between groups A and C. No statistically significant difference was found between groups A and B in all subtypes except for type II spine at L1-L2 (P < 0.04). A significant difference was found at four levels between groups B and C in type III spine (P < 0.05) and between groups A and C. For type IV spine, there was a significant difference in the degree of degeneration at L4-L5 (P < 0.02) between groups A and C. Moreover, almost all single parameters were not strongly correlated with the degree of disc degeneration., Conclusion: The different spinal subtypes have characteristics of lumbar disc degeneration at specific levels with age. We considered that spinal classification could be used as a predictor of lumbar disc degeneration. Our data may be helpful to increase awareness of the relationship between spinal subtypes and lumbar disc degeneration., Level of Evidence: 3.

Objectives: To compare procedure times following same-day cervical preparation using misoprostol 400 mcg alone or misoprostol 400 mcg plus hygroscopic dilators for dilation and evacuation (D&E) before 20 weeks gestation and to compare side effects of buccal and vaginal misoprostol administration., Study Design: We randomized women undergoing D&E at 14 weeks 0 days-19 weeks 6 days gestation to receive (1) hygroscopic dilators or not and (2) buccal or vaginal misoprostol using a 2 × 2 factorial design. We assessed two primary outcomes: (1) total procedure time, defined as time to insert hygroscopic dilators plus D&E time, and (2) side effects of misoprostol 4-6 h after initiation of cervical preparation using a 5-point Likert scale assessing nausea, emesis, diarrhea, chills and cramps., Results: We randomized 163 women and 161 completed the study. We completed all procedures in one day. Mean total procedure time was 14.0 and 10.8 min. with and without hygroscopic dilators (difference 3.2 minutes, 95% CI 1.7, 4.6). Mean D&E procedure time was 0.7 (95% CI -0.8, 2.1) min longer without hygroscopic dilators. Initial cervical dilation was 15.6 and 11.7 mm with and without hygroscopic dilators (difference 3.9 mm, 95% CI 3.1, 4.8). Participants receiving buccal misoprostol reported less chills (1.9) than women receiving vaginal misoprostol (2.3), p = 0.04., Conclusions: Hygroscopic dilators with misoprostol requires more time and increases cervical dilation without shortening D&E time when used for cervical preparation 4-6 h prior to D&E before 20 weeks. Women receiving vaginal misoprostol may have more chills compared to buccal misoprostol., Implications: Adding hygroscopic dilators to misoprostol for same day D&E procedures at less than 20 weeks gestation increases total intervention time without reducing D&E time and is less favored by patients. Clinical judgment requires balancing relative effectiveness with patient preference. Further studies should evaluate the side effect profile of vaginal misoprostol., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Ovarian cancer is one of the most fatal female malignancies while targeting apoptosis is critical for improving ovarian cancer patients' lives. Survivin is regarded as the most robust anti-apoptosis protein, and its overexpression in ovarian cancer is related to poor survival and apoptosis resistance. Piperlongumine (PL) extracted from peppers is defined as an active alkaloid/amide and exhibits a broad spectrum of antitumor effects. Here, we demonstrate that PL induces the rapid depletion of survivin protein levels via reactive oxygen species (ROS)-mediated proteasome-dependent pathway in vitro , while exerting a remarkable inhibitory influence on the proliferation of ovarian cancer cells. Overexpression of survivin raises the survival rate of ovarian cancer cells to PL. Moreover, PL inhibits ovarian cancer cells xenograft tumor growth and downregulates survivin in vivo . Our findings reveal a previously unrecognized mechanism of PL in suppressing survivin expression as well as survivin promotes piperlongumine resistance in ovarian cancer and suggest that ROS-mediated proteasome-dependent pathway can be exploited to overcome apoptosis resistance triggered by aberrant expression of survivin., (Copyright © 2019 Nan, Gong, Chen, Zhou, Ye, Yang, Xing, Wei, Li, Wang, Liu, Shi and Yan.)

Objective: To analyze and compare the disease burden of falls in Chinese population aged 0-19, in 1990 and 2017. Methods: Indicators including number of deaths, mortality rates, years of life lost due to premature mortality (YLL), years lived with disability (YLD) and disability-adjusted of life years (DALY), on falls, were gathered from the Global Burden of Disease (GBD) 2017 and used to describe the disease burden and corresponding parameters on falls, between 1990 and 2017, in China. Results: In 2017, number of death, YLLs, YLDs, DALYs caused by falls were 5 321, 0.43 million person years, 0.14 million person years and 0.57 million person years respectively, among aged 0-19 group. Rates on standardized mortality, YLLs, YLDs and DALYs on falls were 1.76/100 000, 141.49/100 000, 46.99/100 000, and 188.48/100 000, respectively. The burden of falls decreased with the increase of age. Compared with 1990, disease burden of falls decreased in all age groups, both in male and female, with more seen in the lower age groups. Compared with 1990, the number of deaths, rates on YLLs, YLDs and DALYs caused by falls decreased by 65.08 % , 46.63 % , 47.38 % and 36.33 % respectively, in 2017. However, the YLDs rate increased by 73.31 % between 1990 and 2017. The ratio of YLLs to DALYs decreased from 90.84 % in 1990 to 75.07 % in 2017, with a proportion as 17.36 % . Conclusion: Compared with 1990, although the disease burden of falls among aged 0-19 group showed a decreasing trend, falls still caused serious disease burden for the aged 0-19 group. Research that targeting prevention on falls, should be continued.

Objective: To describe the trends and potential reasons responsible for injury mortality among children under 18 years old in different stages of the China Children's Development Outlines (CCDO) for children from 1990 to 2017, in China. Methods: Data derived from the Global Burden of Disease 2017 (GBD2017) were used to analyze the change of injury mortality, among children under 18 years old, by sex and provinces. Results: Since 1990, the Chinese government had formulated and implemented three CCDOs on Children. Each CCDO proposed corresponding main targets and strategic measures based on the development of children under current situation, in each area, accordingly. The first two CCDOs failed to set clear targets for child injury prevention and control, but the third one did propose a quantifiable target. The injury mortality rate of children under 18 years old showed a declining trend in all periods of the three CCDOs, by 26.07 % , 40.68 % and 26.48 % , respectively. Both boys and girls showed significant downward trend in these three stages. Mortality rate on child injury differed in these three stages in all the 31 provinces. Conclusion: Thanks to the contribution of CCDO in different stages that providing important policies and impetus for the prevention and control of child injury, the number of deaths caused by child injury kept reducing, from 1990 to 2017, in China.

Objective: To understand the current situation of road traffic injuries among primary and secondary school students in Mengzi city. Methods: Using the cluster random sampling method, more than 9 000 primary and secondary school students from 20 primary and secondary schools in Mengzi city, were randomly sampled. A questionnaire survey was conducted on the occurrence of road traffic injuries in school students. Results: A total of 9 197 students were surveyed, including 150 from road traffic injuries. The incidence rates of road traffic injuries was 1.63 % among students in Mengzi city and 2.85 % among junior high school students, with the high incidence in May. The leading places of injuries were village roads (38.00 % ), city roads (33.33 % ) and district roads (12.67 % ), respectively. 26.67 % of the traffic injuries occurred on the way to or from schools, with riding on electric bicycle (52.00 % ) as the major cause and contusion/abrasion (75.33 % ) appeared as the major signs. Both lower and upper limbs plus multiple parts were accounting for 45.51 % , 22.16 % and 16.17 % , respectively of all the injuries. 70.67 % of all the cases with road traffic injuries in children, recovered after treatment. Children with road traffic injuries would stay in the hospital for up to 90 days but spent less than 30 000 Yuan. Conclusion: The incidence of road traffic injuries among students in Mengzi city seemed relatively high, with junior high school students reached the highest. Riding electric bicycle appeared as the leading cause for traffic injuries in children in Mengzi city of Yunnan province.

Objective: To understand the injuries among 16 459 left-behind children from 27 poor rural areas in 12 provinces of China, 2016. Methods: Data were collected from the survey of 'Health Service Needs Assessment' (HSNA) program on left-behind children, from poor rural areas in the middle and western parts of China. Factors including causes, types, locations, related activities, ways of treatment and outcomes among left-behind children with injuries in 2016, were described and analyzed by gender and age groups. Results: In 2016, per-person and person-time incidence rates of injuries were 8.88 % and 11.21 % , among the 16 459 left-behind children from 27 poor rural areas in 12 provinces of China, both higher in boys, than in girls. Most injuries were unintentional with its proportion higher in older children. The main types of injuries were seen as falls, blunt and sharp injuries, with burns and animal injuries more common in younger children. Injuries among left-behind children mainly took place at home, kindergarten/school, and on the highways/streets/roads, during playing. Most common ways of treatment would include at the emergency settings, self-treated, with older children more likely to treat by themselves. Most injuries were cured. Conclusions: In programs on prevention and control of injuries targeting the left-behind children in poor rural areas, special attention should be given to older boys, on falls and blunt/sharp injuries, at home or kindergarten/school. Education programs should pinpoint on self-rescue skills and guidance on kids by the parents, with behavioral norms and social support included. Related comprehensive prevention and control mechanism should be developed in families, schools and communities, with medical resources and insurance mechanism explored to serve these population and districts, including those left-behind children.

Objective: To establish the model of the self-confidence, motivation and authoritative advice factors influencing the use of child restraint and use structural equation model to test it to provide scientific basis for promoting the advocacy of use of child restraint. Methods: Using multi-stage cluster random sampling method, 9 112 parents from the family with one or more private cars and 0-6 years old children in Shanghai and Shenzhen were investigated about the use of child restraint. A theoretical model of the self-confidence, motivation and authoritative advice factors influencing the use of child restraint was constructed. The theoretical model was validated and quantitatively analyzed by structural equation model. Results: The overall model accords with the expected theoretical model, and the goodness of model fit was fine. The indicators had met the standard. RMSEA=0.03, CFI=0.97. The standardization coefficients of each route showed statistical significance ( P <0.05). The standardization coefficients of the influence of authoritative suggestions and motives on self-confidence were 0.45 and 0.30 respectively, and the standardization coefficients of the influence of self-confidence on the use of child restraint was 0.40. The standardization coefficient of the influence of authoritative suggestions on motivation was 0.61. Conclusions: In the advocacy of the use of child restraint, we should attach importance to the use of recommendations from experts and organizations with professional authority, good credibility and public welfare. We should take the status of children's road traffic safety and the mechanism of the role of child restraint as one of the key points of propaganda.