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Metal-organic frameworks (MOFs) are promising new materials that have been intensively studied and possibly applied to various environmental remediation. However, little is known about the fate and risk of MOFs to living organisms in the water environment. Here, the toxic effects of ZIF-8 nanoparticles (NPs) on benthic organisms were confirmed by sub-chronic toxicity experiments (7 and 14 days) using Corbicula fluminea as the model organism. With exposure doses ranging from 0 to 50 mg/L, ZIF-8 NPs induced oxidative stress behaviors similar to the hormesis effect in the tissues of C. fluminea. The oxidative stress induced by ZIF-8 NPs and the released Zn

We have purified a novel caffeoylquinic acid named 3,4-di-O-caffeoylquinic acid isobutyl ester from the flower buds of Lonicera japonica Thunb., Caprifoliaceae. However, the biological function of 3,4-di-O-caffeoylquinic acid isobutyl ester is still unknown. Here, we found that 3,4-di-O-caffeoylquinic acid isobutyl ester effectively inhibited the proliferation and migration of hepatocellular carcinoma cells, and it displayed less toxicity to a normal liver cell line. Mechanistic studies showed that 3,4-di-O-caffeoylquinic acid isobutyl ester diminished the expression of YAP at the mRNA level. Overexpression of YAP significantly rescued HepG2 cells from the 3,4-di-O-caffeoylquinic acid isobutyl ester–induced suppression of proliferation and migration. Furthermore, the YAP downstream target gene CTGF was significantly repressed upon 3,4-di-O-caffeoylquinic acid isobutyl ester treatment, which was ameliorated by YAP overexpression. In addition, 3,4-di-O-caffeoylquinic acid isobutyl ester decreased the expression of β-catenin as well as CDK4/6. Collectively, 3,4-di-O-caffeoylquinic acid isobutyl ester exerts antihepatocellular carcinoma activity by inhibiting the YAP-CTGF pathway which controls the proliferation and migration of hepatocellular carcinoma cells. The Wnt/β-catenin pathway might be another pathway by which 3,4-di-O-caffeoylquinic acid isobutyl ester exerts antihepatocellular carcinoma activity. As a novel natural compound, 3,4-di-O-caffeoylquinic acid isobutyl ester might be a promising agent for hepatocellular carcinoma therapy. Graphical Abstract

In our previous work, we isolated a novel bisphenol named capillarisenol C (Cap C) from Artemisia capillaris. Preliminary studies indicated potential anti-hepatocellular carcinoma (HCC) activity. However, its mechanism remains unclear. In this study, we aimed to investigate the function and molecular mechanism of the anti-HCC activity of Cap C. First, We evaluated the inhibitory effect of Cap C on the viability of HepG2 and Huh7 cells using CCK8 assays. The results showed that Cap C sharply reduced the viability of HepG2 and Huh7 cells in a time- and concentration-dependent manner, however, lenvatinib (clinical drugs for the treatment of HCC) had no obvious growth inhibitory effect on HepG2 and Huh7 cells at the corresponding concentration. By calculation, the half maximal inhibitory concentrations (IC50) of Cap C were 8.58 and 4.96 µM for for HepG2 and Huh7 cells at 48 h. Then, we investigated its autophagic effects on liver cancer cells using immunofluorescence staining and CRISPR/Cas9 assays. To study the mechanism of Cap C, we used quantitative PCR and western blotting. We found that Cap C effectively inhibited the proliferation of HepG2 cells and increased MAP1LC3-II expression. Moreover, Cap C–induced cell death was attenuated by autophagy-related gene ATG7 knockdown. Mechanistic studies showed that Cap C significantly promoted the expression of endoplasmic reticulum (ER) stress–related proteins. Our results suggest that Cap C may lead to autophagic HCC cell death by inducing ER stress.

Mitochondrial complex I deficiency (MCID) and abbFINCA syndrome are lethal congenital diseases and cases in the neonatal period are rarely reported. Here, we identified a Chinese Hani minority neonate with rare MCID and FINCA syndrome. This study was to analyze the clinical manifestations and pathogenic gene variations, and to investigate causes of quick postnatal death of patient and possible molecular pathogenic mechanisms.A 17-day-old patient had reduced muscle tension, diminished primitive reflexes, significantly abnormal blood gas analysis, and progressively increased blood lactate and blood glucose. Imaging studies revealed pneumonia, pulmonary hypertension, and brain abnormalities.Whole-exome sequencing revealed that the NDUFS6 gene of the patient carried c. 344GT (p.C115F) novel homozygous variation, and the NHLRC2 gene carried c. 1749CG (p.F583L) and c. 2129CT (p.T710M) novel compound heterozygous variation.The patient was given endotracheal intubation, respiratory support, high-frequency ventilation, antishock therapy, as well as iNO and Alprostadil to reduce pulmonary hypertension and maintain homeostatic equilibrium. However, the patient was critically ill and died in 27 days.The patient has MCID due to a novel mutation in NDUFS6 and FINCA syndrome due to novel mutations in NHLRC2, which is the main reason for the rapid onset and quick death of the patient.

Escherichia coli is a common pathogen causing invasive bacterial infections in neonates. In recent years, clinical antimicrobial susceptibility testing has demonstrated an increased rate of drug-resistant E. coli infections. This study aimed to analyse the resistance characteristics of E. coli against common antimicrobial agents, and perform multilocus sequence typing (MLST) in clinical strains of E. coli collected from Chinese neonates.Culture-positive specimens of E. coli were collected from neonates in seven class A tertiary hospitals located in seven cities across different provinces in China between November 2019 and October 2020. E. coli isolated from these specimens were subjected to antimicrobial susceptibility testing (by broth microdilution method), extended-spectrum β-lactamase (ESBL) detection, and MLST.A total of 223 E. coli strains were isolated, with an overall resistance rate of 87.4%, an ESBL-positive rate of 48.0%, and a multidrug resistance rate of 42.2%. Among the 20 antimicrobial agents tested, E. coli strains showed the highest resistance rates against cefotaxime (59.2%), trimethoprim/sulfamethoxazole (56.5%), doxycycline (39.9%), ciprofloxacin (36.8%), and aztreonam (31.0%). The resistance rates of E. coli strains isolated from children's hospitals against piperacillin/tazobactam, cefotaxime, ciprofloxacin, trimethoprim/sulfamethoxazole, and carbapenems, were significantly higher than those of strains isolated from maternity and child health hospitals. The primary E. coli multilocus sequence types were ST1193, ST95, ST73, ST410, and ST131. The ESBL production rates and multidrug resistance rates of ST1193, ST410, and ST131 were significantly higher than those of ST95 and ST73. Significantly, more strains of E. coli ST1193 and ST410 were isolated from children's hospitals than from maternity and child health hospitals.The rates of antimicrobial agent resistance in E. coli isolates from hospitalised neonates in China were high. The increased number of strains of E. coli ST1193 and ST410 was the reason for higher resistance rates to multiple antimicrobial agents in E. coli from children's hospitals compared with those from maternal and child health hospitals.

Maintaining the health of the endothelium is of critical importance to prevention against cell aging. The current study was performed to clarify the role of sirtuin1 (SIRT1) in platelet phagocytosis in cell aging and identified its downstream molecular mechanism. Platelet phagocytosis by human endometrial microvascular endothelial cells (HEMECs) was characterized by transmission electron and fluorescence microscopy. Functional experiments were conducted to examine platelet phagocytosis and cell aging using the overexpression or knockdown plasmids of SIRT1 and G alpha-interacting, vesicle-associated protein (GIRDIN) as well as Akt inhibitor and activator. It was found that SIRT1 facilitated platelet phagocytosis by HEMECs, contributing to inhibition of cell aging. Akt activation facilitated platelet phagocytosis and repressed cell aging. GIRDIN overexpression accelerated platelet phagocytosis by HEMECs, leading to a delay in cell aging. GIRDIN phosphorylation at Ser1417 was induced by Akt activation, while activation of Akt was induced by SIRT1-mediated deacetylation, consequently augmenting platelet phagocytosis and delaying cell aging. Taken together, SIRT1 delayed aging of HEMECs by deacetylating Akt, phosphorylating GIRDIN, and inducing platelet phagocytosis. The study highlights a possible target for the prevention of HEMEC aging., Graphical Abstract, Activation of receptor tyrosine kinase activates SIRT1, causing deacetylation of AKT and PDK1. PDK1 activates AKT by phosphorylation at 308 and 473, leading to increased phosphorylated GIRDIN at Ser1417. Activated GIRDIN increases platelet phagocytosis and leads to delayed aging in human endometrial microvascular endothelial cells.

The partial oxygen pressure in the air decreases with increasing altitude. This study was designed to compare the pulse oxygen saturation (SpO2) among well full-term neonates at different altitudes during their first 2 h after birth and to establish cutoff values of SpO2 identifying hypoxemia between 30 and 120 min after birth.A multisite prospective cohort study was conducted at five participating hospitals from the Chinese High Altitude Neonatal Medicine Alliance. Healthy full-term infants were recruited and divided into four groups based on the altitude. Preductal SpO2 was recorded at 10 min, 10-30 min, and 30-120 min after birth. The 2.5th percentile of the SpO2 distribution range was considered as the cutoff for identifying hypoxemia at each altitude.A total of 727 infants were eligible for analysis. The SpO2 of neonates at different altitudes increased with the time after birth. A higher altitude was associated with lower SpO2, especially Shangri-La (3,509 m) and Yushu (4,360 m). The cutoff SpO2 for identifying hypoxemia during 30-120 min after birth were 94% in Xishuangbanna (847 m), 92% in Kunming (1,983 m), 89% in Shangri-La (3,509 m), and 83% in Yushu (4,360 m).An increase in altitude, especially Shangri-La (3,509 m) and Yushu (4,360 m), had a significant impact on SpO2 among healthy full-term neonates during their first 2 h of life. Establishing the cutoff value of SpO2 for identifying hypoxemia during the early postnatal period serves to optimize the oxygen therapy at different altitudes.

Nitric acid (HNO3) modified biochar (NBC) has been demonstrated to be a promising sorbent. However, the roles of their redox-active moieties (RAMs, i.e., environmentally persistent free radicals (EPFRs) and oxygen-containing function groups) in Cr(VI) removal under varying pH and O2 conditions remain poorly understood. In this study, HNO3 oxidation caused an obvious increase in specific surface area, porous volume, RAMs content, and surface potential of the biochar, leading to the more effective removal of Cr(VI) (with the removal rate reached 100% at pH 2.0) than that of the untreated biochar. Kinetics experiments revealed that O2 and pH are of great importance for the reduction efficiency and rate of Cr(VI). RAMs on NBC can either directly reduce Cr(VI)(predominant pathway) or activate O2 to produce •O2− for indirect Cr(VI) reduction. In addition, we examined the changes in the compositions of RAMs during the reaction by tuning the RAMs compositions using methanol and hydrogen peroxide. The results of electron paramagnetic resonance and X-ray photoelectron spectroscopy analysis demonstrated that the main electron donors on NBC were different at different pH values: oxygen-containing groups, e.g., –OH and C–O–C, played a dominant role in reducing Cr(VI) under acidic conditions while the neutral condition was beneficial to EPFRs-dominated reduction. This study investigated the roles of the EPFRs and oxygen-containing function groups on HNO3 modified biochar, which may provide new insights into the promoted reduction of Cr(VI) by applications of biochar.

Objective Vitamin D is an essential nutrient that regulates the activity of calcium and bone hormones throughout life; however, vitamin D levels in children, which is the most crucial period during human development, has not been established. Methods As the first descriptive study of serum vitamin D levels in children in Yunnan Province, we determined the serum vitamin D levels in children 0‒4 years of age who underwent physical examinations at Kunming Children's Hospital, and the association between the serum vitamin D level and the calcium, phosphorus and alkaline levels. Results Vitamin D levels in children were highest in the summer months and lowest in the winter months. Vitamin D deficiency was more common in girls than boys. A social-economic effect was shown, as evidenced by the significantly higher serum vitamin D levels in children from the top five cities compared with the lower-ranked cities. Moreover, we also demonstrated a significant correlation between vitamin D and serum calcium levels. Conclusion Our study suggested that sex and age affected the vitamin D levels of children, and a reasonable reference range in children 0–4 years of age in Yunnan Province was determined.

The associations of human chorionic gonadotropin (hCG), estrogen, and progesterone levels with threatened abortion have not been fully studied. Eighty women with threatened abortion were recruited sequentially, and the levels in their pregnancy hormones during the first trimester were compared with that of 160 normal early pregnancy controls. The natural logarithm transformed (Ln) hCG and Lnestrogen of women with threatened abortion and gestational age ≤ 6 weeks were significantly higher than values for the normal controls of the same gestational age (8.6 ± 1.2 vs. 7.4 ± 1.7 mIU/mL and 5.8 ± 0.4 vs. 5.4 ± 0.5 pg/mL); the two hormones reached similar levels in the groups of gestational age > 6 weeks. Among the group with gestational age ≤ 6 weeks, a univariate logistic regression showed that LnhCG and Lnestrogen were associated with threatened abortion, with odds ratios (ORs) of 1.85 [95% confidence interval (CI): 1.30-2.64] and 4.62 (95% CI: 1.67-12.80), respectively. The multivariate logistic regression model revealed that hCG and estrogen were mutually confounding factors, and only hCG was an independent factor for threatened abortion (OR 1.56; 95% CI: 1.06-2.28). None of the variables in the univariate or multivariate logistic regression was a factor associated with threatened abortion after 6 weeks gestational age. In conclusion, β-hCG and estrogen levels in the first half of the first trimester are factors associated with threatened abortion.

Efficient nano-scale chromium (Cr) remediating agents used in the water industry may find their application in soil difficult because of the strong aggregation effect. In this study, a millimeter-sized PANI/PVA/SA composite (PPS) was synthesized by embedding polyaniline (PANI) into polyvinyl alcohol (PVA)/sodium alginate (SA) gel beads. Additionally, the PPS was used to recover hexavalent chromium (Cr(VI)) contaminated water and soil to study the remediation impacts and mechanism. Results showed that the PPS was an irregular sphere with a pore size of 24.24 nm and exhibited strong adsorption capacity (83.1 mg/g) for removing Cr(VI) in water. The Cr(VI) adsorption by PPS could be well described with the pseudo-second-order kinetics and the Redlich-Peterson isotherm model, indicating that the chemical reactions were the controlling step in the Cr(VI) adsorption process. PPS also exhibited excellent physicochemical properties (13 mg/L TOC release) and reusability (efficiency of 95.25% after four runs) for Cr(VI) removal. Soil incubation results showed that the 5% PPS (5PPS) treatment could efficiently remove 24.17% of total Cr and 52.47% of Cr(VI) in the contaminated soil after 30 days. Meanwhile, the water-soluble and the leaching Cr contents were decreased by 43.37% and 61.78% in the 5PPS group, respectively. Elemental speciation by XPS revealed that Cr(VI) removal from solution and soil proceeded mainly by electrostatic attraction, reduction, and complexation/chelation. The study implied that PPS could be a useful amendment to remediate both the Cr(VI)-contaminated water and soil.

Neonatal metabolic acidosis (NMA) is a common problem, particularly in critically ill patients in neonatal intensive care units (NICUs). Complex etiologies and atypical clinical signs make diagnosis difficult; thus, it is crucial to investigate the underlying causes of NMA rapidly and provide disorder-specific therapies. Our study aims to provide an overview of the genetic causes of NMA in patients from NICUs. We performed next-generation sequencing (NGS) on neonates with NMA from January 2016 to December 2019. Clinical features, genetic diagnoses, and their effects on clinical interventions were collected for analysis. In the 354 enrolled patients, 131 (37%) received genetic diagnoses; 95 (72.5%) of them were autosomal recessively inherited diseases. Two hundred and fifteen variants spanning 57 genes were classified as pathogenic (P) or likely pathogenic (LP) in 131 patients. The leading cause was metabolic disorders due to 35 genes found in 89 patients (68%). The other 42 NMA patients (32%) with 22 genes had malformations and renal, neuromuscular, and immune-hematological disorders. Seven genes (MMUT, MMACHC, CHD7, NPHS1, OTC, IVD, and PHOX2B) were noted in more than four patients, accounting for 48.9% (64/131) of the identified P/LP variants. Forty-six diagnosed patients with uncorrected NMA died or gave up. In conclusion, 37% of neonates with metabolic acidosis had genetic disorders. Next-generation sequencing should be considered when investigating the etiology of NMA in NICUs. Based on early molecular diagnoses, valuable treatment options can be provided for some genetic diseases to achieve better outcomes.

OBJECTIVES To determine the diagnostic and clinical utility of trio-rapid genome sequencing in critically ill infants. DESIGN In this prospective study, samples from critically ill infants were analyzed using both proband-only clinical exome sequencing and trio-rapid genome sequencing (proband and biological parents). The study occurred between April 2019 and December 2019. SETTING Thirteen member hospitals of the China Neonatal Genomes Project spanning 10 provinces were involved. PARTICIPANTS Critically ill infants (n = 202), from birth up until 13 months of life were enrolled based on eligibility criteria (e.g., CNS anomaly, complex congenital heart disease, evidence of metabolic disease, recurrent severe infection, suspected immune deficiency, and multiple malformations). INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Of the 202 participants, neuromuscular (45%), respiratory (22%), and immunologic/infectious (18%) were the most commonly observed phenotypes. The diagnostic yield of trio-rapid genome sequencing was higher than that of proband-only clinical exome sequencing (36.6% [95% CI, 30.1-43.7%] vs 20.3% [95% CI, 15.1-26.6%], respectively; p = 0.0004), and the average turnaround time for trio-rapid genome sequencing (median: 7 d) was faster than that of proband-only clinical exome sequencing (median: 20 d) (p < 2.2 × 10-16). The metagenomic analysis identified pathogenic or likely pathogenic microbes in six infants with symptoms of sepsis, and these results guided the antibiotic treatment strategy. Sixteen infants (21.6%) experienced a change in clinical management following trio-rapid genome sequencing diagnosis, and 24 infants (32.4%) were referred to a new subspecialist. CONCLUSIONS Trio-rapid genome sequencing provided higher diagnostic yield in a shorter period of time in this cohort of critically ill infants compared with proband-only clinical exome sequencing. Precise and fast molecular diagnosis can alter medical management and positively impact patient outcomes.

Aim: To investigate the vitamin D levels in children aged 0–4 years in Yunnan Province.Methods: This study selected children aged 0 to 4 years who underwent physical examination in the special needs clinic of the Hospital from October 2019 to December 2020 as subjects to analyze serum 25(OH)D levels.Result: Vitamin D deficiency was more common in girls than in boys. There was no significant difference in serum vitamin D levels between boys and girls at any age. However, there was a significant decrease in vitamin D levels after 2 years old in all chidren at all ages. The levels of vitamin D in children were highest in summer, which were significantly higher than other seasons, and were lowest in winter. At the same time, vitamin D levels were significantly different based on the economic level of cities. The serum vitamin D contents of infants and young children in the top five cities with the highest economic levels were significantly higher than in lower-ranked cities. There was a significant correlation between vitamin D content and serum calcium. Conclusion: This study preliminarily determined a reasonable reference range for serum 25 hydroxyvitamin D content in infants aged 0–4 years in Yunnan Province. Which will be of significance for the establishment of official guidelines on vitamin D supplementation in infants and young children in Yunnan and for policy formulation.

Objective: O6methylguanine-DNA methyltransferase (MGMT) promoter methylation is a biomarker widely used to predict the sensitivity of IDH-wildtype glioblastoma to temozolomide therapy. Given that the IDH status has critical effects on the survival and epigenetic features of glioblastoma, we aimed to assess the role of MGMT promoter methylation in IDH-mutant glioblastoma. Methods: This study included 187 IDH-mutant glioblastomas and used 173 IDH-wildtype glioblastomas for comparison. Kaplan-Meier curves and multivariate Cox regression were used to study the predictive effects. Results: Compared with IDH-wildtype glioblastomas, IDH-mutant glioblastomas showed significantly higher (P < 0.0001) MGMT promoter methylation. We demonstrated that MGMT promoter methylation status, as determined by a high cutoff value (≥30%) in pyrosequencing, could be used to significantly stratify the survival of 50 IDH-mutant glioblastomas receiving temozolomide therapy (cohort A); this result was validated in another cohort of 25 IDH-mutant glioblastomas (cohort B). The median progression-free survival and median overall survival in cohort A were 9.33 and 13.76 months for unmethylated cases, and 18.37 and 41.61 months for methylated cases, and in cohort B were 6.97 and 9.10 months for unmethylated cases, and 23.40 and 26.40 months for methylated cases. In addition, we confirmed that the MGMT promoter methylation was significantly (P = 0.0001) correlated with longer OS in IDH-mutant patients with GBM, independently of age, gender distribution, tumor type (primary or recurrent/secondary), and the extent of resection. Conclusions: MGMT promoter methylation has predictive value in IDH-mutant glioblastoma, but its cutoff value should be higher than that for IDH-wildtype glioblastoma.

The co-contamination of anions and cations with cadmium (Cd) and arsenic (As) as typical pollutants in the water environment has attracted attention. In this study, Fe-Mn-incorporated titanosilicate material (ETFMS-10) with both adsorption and oxidation capacities was prepared by hydrothermal method to treat the Cd and As co-contaminated aqueous solution. SEM-EDS results confirmed the addition of Fe and Mn in the ETFMS-10 structure. The maximum adsorption capacities of ETFMS-10 for Cd (101.86 mg g−1) and As (3.18 mg g−1) were greater than those of ETS-10 for Cd (42.18 mg g−1) and As (0.51 mg g−1) in the single-pollutant system. The removal efficiencies of Cd and As by ETFMS-10 were more than 98% and 70% across pH 4 – 8, respectively. Adsorption kinetics revealed that the capture of Cd and As on ETFMS-10 was mainly controlled by chemical adsorption. XPS analysis showed that Fe mainly served as adsorption sites on ETFMS-10, while Mn was chiefly employed as an oxidant. The main mechanisms for Cd(II) and As(III) removal on ETFMS-10 included electrostatic attraction, ion exchange, and an inner-sphere M−O−As complex formation. These results indicated that the prepared ETFMS-10 had a broad application potential in the treatment of Cd and As co-contamination.

Background: To investigate the current situation of neonatal care resources (NCR), newborn mortality rates (NMR), regional differences and existing challenges in China. Methods: By using a self-designed questionnaire form and the cross-sectional method, we conducted a survey of all hospitals equipped with neonatal facilities in China from March 2019 to March 2020 with respect to the level and nature of these hospitals, the number of newborn beds and NICU beds, the number of neonatal pediatricians, and the development of therapeutic techniques. The data about the newborn births and deaths were retrieved from the annual statistics of the health commissions of the related provinces, autonomous regions and municipalities. Finding: Included in this nationwide survey were 3,020 hospitals from all 22 provinces, 5 autonomous regions and 4 municipalities directly under the Central Government of Mainland China, with a 100% response rate. They included 1,183 (39.2%) level-3 (L3) hospitals, 1629 (53.9%) L-2 hospitals and 208 (6.9%) L-1 hospitals. Geographically, 848 (31.4%) hospitals were distributed in Central China, 983 (32.5%) hospitals in East China, and 1,089 (36.1%) in West China. The 3,020 included hospitals were altogether equipped with 75,679 newborn beds, with a median of 20 (2-350) beds, of which 2,286 hospitals (75.7%) were equipped with neonatal intensive care units (NICU), totaling 28,076 NICU beds with a median of 5 (1-160) beds. There were altogether 27,698 neonatal pediatricians in these hospitals, with an overall doctor-bed ratio of 0.366. There were 48.18 newborn beds and 17.87 NICU beds per 10,000 new births in China. In East, Central and West China, the number of neonatal beds, NICU beds, neonatal pediatricians, and attending pediatricians or pediatricians with higher professional titles per 10,000 newborns was 42.57, 48.64 and 55.67; 17.07, 18.66 and 18.17; 16.26, 16.51 and 20.81; and 10.69, 10.81 and 11.29, respectively. However, when the population and area are taken into consideration and according to the health resources density index (HRDI), the number of newborn beds, NICU beds and neonatal pediatricians in West China was significantly lower than that in Central and East China. In addition, only 10.64% of the neonatal pediatricians in West China possessed the Master or higher degrees, vs. 31.7% in East China and 20.14% in Central China. On the contrary, the number of neonatal pediatricians with a lower than Bachelor degree in West China was significantly higher than that in Central and East China (13.28% vs. 7.36% and 4.28%). Technically, the application rate of continuous positive airway pressure (CPAP) and conventional mechanical ventilation (CMV) in L-1 hospitals of West China was lower than that in Central and East China. According to the statistics in 2018, the newborn mortality rate (NMR) in West China was significantly higher than that in Central and East China. Interpretation: China has already possessed relatively good resources for neonatal care and treatment, which is the primary reason for the rapid decrease in the NMR in China. However, there are still substantial regional differences. The density of health resources, the level of technical development and educational background of neonatal pediatricians in West China still lag behind those in other regions of China and need to be further improved and upgraded. Funding: This research work was funded by National Natural Science Foundation of China (81671504) and United Nations International Children's Emergency Fund (CHINA-UNICEF501MCH). 【摘要】: 目的 了解中国新生儿救治资源及新生儿死亡率现状,地区差异及存在的挑战.方法 2019年3月至2020年3月, 设计调查表格, 采取横断面调查方式, 对全国设置有新生儿床位的医院进行调查, 内容包括医院级别,性质,新生儿床位,NICU床位数,新生儿医师数量及救治技术开展情况等.新生儿出生数和死亡率来源于各省卫生健康委年度统计数据.结果 共纳入除港澳台地区外全国31个省3020家医院, 反馈率100%, 其中三级医院1183家 (39.2%), 二级医院1629家 (53.9%), 一级医院208家 (6.9%) .按地区分布, 中部地区948家 (31.4%), 东部983家 (32.5%), 西部1089家 (36.1%) .3020家医院共有新生儿床位75679张, 床位中位数20张 (2-350张), 其中2286家 (75.7%) 医院设置有NICU床位共28076张, NICU床位中位数为5张 (1-160张), 共拥有新生儿科医师27698人, 总医/床比为0.366.全国每万名出生新生儿拥有新生儿床位48.18张, 其中NICU床位17.87张.东部,中部,西部每万名出生新生儿拥有新生儿床位数分别为42.57张,48.64张和55.67张, 其中NICU床位分别为17.07张, 18.66张和18.17张, 拥有新生儿科医师分别为16.26人,16.51人和20.81人, 其中主治医师以上分别为10.69人,10.81人和11.29人.但如考虑到人口和面积, 按HRDI指数计算, 西部地区新生儿床位,NICU床位及新生儿科医师人数仍明显低于东,中部地区.且西部地区新生儿科医师中拥有硕士以上学历者仅10.64%, 明显低于东部 (31.7%) 和中部 (20.14%), 而本科以下学历比例为13.28%, 远高于东部 (4.28%) 和中部地区 (7.36%) .从技术开展情况看, 西部地区一级医院在CPAP,常频通气等技术开展率低于东,中部地区.西部地区2018年新生儿死亡率也明显低于东,中部地区.结论 中国已拥有较好的新生儿医疗救治资源, 这是新生儿死亡率得以迅速下降的基础.但地区差异仍较大, 西部地区卫生资源密度,技术发展水平和医师学历仍相对滞后, 需要进一步加强.

Rationale Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive disease characterized by thrombocytopenia, small platelets, eczema, immunodeficiency, and an increased risk of autoimmunity and malignancies. X-linked thrombocytopenia (XLT), the milder phenotype of WAS, is always limited to thrombocytopenia with absent or slight infections and eczema. Here, we illustrated the clinical and molecular characteristics of 2 unrelated patients with WAS from Chinese minorities. Patient concerns Patient 1, a 13-day-old male newborn of the Chinese Lahu minority, showed a classic WAS phenotype, including thrombocytopenia, small platelets, buttock eczema, and recurrent infections. Patient 2, an 8-year-and 8-month-old boy of the Chinese Zhuang minority, presented an XLT phenotype without eczema and repeated infections. Diagnosis Next-generation sequencing was performed to investigate the genetic variations. Flow cytometry was used to quantify the expression of WAS protein and analyze the lymphocyte subsets. A novel frameshift WAS mutation (c.927delC, p.Q310Rfs∗135) and a known nonsense WAS mutation (c.1090C>T, p.R364X) were identified in Patient 1 and Patient 2, respectively. Both patients were confirmed to have WAS protein deficiency, which was more severe in Patient 1. Meanwhile, the analysis of lymphocyte subsets revealed an abnormality in Patient 1, but not in Patient 2. Combined with the above clinical data and genetic characteristics, Patient 1 and Patient 2 were diagnosed as classic WAS and XLT, respectively. In addition, many miliary nodules were accidentally found in abdominal cavity of Patient 2 during appendectomy. Subsequently, Patient 2 was confirmed with pulmonary and abdominal tuberculosis through further laboratory and imaging examinations. To our knowledge, there have been only a few reports about WAS/XLT with tuberculosis. Interventions Both patients received anti-infection therapy, platelet transfusions, and intravenous immunoglobulins. Moreover, Patient 2 also received antituberculosis treatment with ethambutol and amoxicillin-clavulanate. Outcomes The clinical symptoms and hematological parameters of these 2 patients were significantly improved. Regrettably, both patients discontinued the treatment for financial reasons. Lessons Our report expands the pathogenic mutation spectrum of WAS gene and emphasizes the importance of molecular genetic testing in diagnosing WAS. Furthermore, researching and reporting rare cases of WAS from different populations will facilitate diagnosis and treatment of this disease.

The main controlling factors of organic matter accumulation in the Upper Ordovician Wufeng–Lower Silurian Longmaxi Formations are complex and remain highly controversial. This study investigates the vertical variation of total organic carbon (TOC) content as well as major and trace element concentrations of four Ordovician–Silurian transition sections from the Upper Yangtze Platform of South China to reconstruct the paleoenvironment of these deposits and to improve our understanding of those factors that have influenced organic matter accumulation in these deposits. The residual TOC content of the Wufeng Formation averages 3.2% and ranges from 0.12 to 6.0%. The overlying lower Longmaxi Formation displays higher TOC content (avg. 4.4%), followed upsection by consistent and lower values that average 1.6% in the upper Longmaxi Formation. The concentration and covariation of redox-sensitive trace elements (Mo, U and V) suggest that organic-rich intervals of the Wufeng Formation accumulated under predominantly anoxic conditions. Organic-rich horizons of the lower Longmaxi Formation were deposited under strongly anoxic to euxinic conditions, whereas organic-poor intervals of the upper Longmaxi Formation accumulated under suboxic conditions. Positive correlations between redox proxies and TOC contents suggest that organic matter accumulation was predominantly controlled by preservation. Barium excess (Ba xs ) values indicate high paleoproductivity throughout the entire depositional sequence, with an increase in the lower Longmaxi Formation. Increased productivity may have been induced by enhanced P recycling, as evidenced by elevated C org /P tot ratios. Mo–U covariation and Mo/TOC values reveal that the Wufeng Formation was deposited under extremely restricted conditions, whereas the Longmaxi Formation accumulated under moderately restricted conditions. During the Late Ordovician, the extremely restricted nature of ocean circulation on the Upper Yangtze Platform in tandem with enhanced stratification of the water column promoted anoxic conditions favorable for the preservation of organic matter. During Early Silurian time, organic matter accumulation was principally controlled by changes in sea level, which affected terrigenous flux, redox conditions, and the degree of nutrition recycling.

Long noncoding RNAs (lncRNAs) are commonly associated with various biological functions, in which the function of lncRNA maternally expressed gene 3 (MEG3) has been identified in various cancers. Strikingly, an association between MEG3 with microRNAs (miRNAs), mRNAs, and proteins has been reported. This study investigates the role of MEG3 in vascular endothelial cell (VEC) senescence. Expression of Girdin and miR-128 was monitored in the blood vessel samples of young and old mice/healthy volunteers, along with the measurement of human umbilical vein endothelial cells (HUVECs). The relationship between MEG3/Girdin and miR-128 was determined and verified. Loss- and gain-of-function approaches were applied to analyze the regulatory effects of MEG3 on platelet phagocytosis and lipoprotein oxidation of HUVEC membrane. In addition, the effect of MEG3 on HUVEC senescence was evaluated by detection of the reactive oxygen species, telomerase activity, and telomere length. To further analyze the MEG3-mediated regulatory mechanism, miR-128 upregulation and inhibition were introduced into the HUVECs. Downregulated Girdin and upregulated miR-128 were found in the blood vessels of old individuals and old mice, as well as in senescent HUVECs. MEG3 downregulation was found to be capable of inhibiting Girdin but enhancing miR-128 expression. It was also indicated to inhibit platelet phagocytosis and reduce telomerase activity and telomere length, while enhancing lipoprotein oxidation and reactive oxygen species production, which ultimately contributed in preventing and protecting HUEVCs from senescence. These findings provide evidence supporting that MEG3 leads to miR-128 downregulation and Girdin upregulation, which promotes platelet phagocytosis, thus protecting VECs from senescence.

Endothelial cells are critical in angiogenesis and maintain the homeostasis of the blood‑brain barrier (BBB). Platelets (PLTs) are essential in vascular biology, including angiogenesis. The present study aimed to investigate the effect of PLTs on the aging of endothelial cells. Human brain microvascular endothelial cells (HBMECs) and human astrocytes were co‑cultured to mimic the BBB. Transmission electron microscopy was used to observe the engulfment of PLTs. Confocal microscopy was used to observe the co‑localization of PLTs, girders of actin filament (girdin) and phosphorylated (p‑)girdin. Senescence‑associated β‑galactosidase (β‑gal) staining, 3‑(4,5‑dimethylthiazol‑2‑yl)‑2,5‑diphenyltetrazolium bromide and flow cytometry were performed to examine the cell senescence, viability and apoptosis, respectively. Transwell assays were performed to examine cell invasion and migration. Western blot analysis was performed to detect the expression of girdin, AKT and p‑AKT. PLTs delayed senescence, and promoted the viability and resistance to apoptosis of the HBMECs. Cell invasion and migration were enhanced by PLTs. In addition, girdin and p‑girdin were essential to the engulfment of HBMECs to PLTs. Mechanically, the inhibition of AKT signals reversed the effect of PLTs on HBMECs by increasing the activity of β‑gal, decreasing the cell viability, and inhibiting the invasion and migration of the HBMECs. The engulfment of PLTs assisted in delaying the aging of endothelial cells via girdin and p‑girdin, in which the AKT signal was involved. The present study indicated a potential strategy for delaying endothelial cell aging in the treatment of central nervous system diseases.

Germ cells are the only cell type that passes genetic information to the next generation. In most metazoan species, primordial germ cells (PGCs) were induced from epiblasts by signals from the neighboring tissues. In vitro derivation of germ cells from the pluripotent stem cells (PSCs) such as embryonic stem cells (ESCs) and induced PSCs (iPSCs) are of great values for the treatment of infertility, for animal breeding, and for studying the mechanism of germ cell development. Although the derivations of male germ cells from PSCs have been previously reported, most of the studies failed to conduct the induction in a well-controlled and highly efficient manner. Here, we report the derivation of induced PGC-like cells (iPGCLCs) from mouse iPSCs via induced epiblast-like cells (iEpiLCs) as being monitored by the expression of enhanced green fluorescent protein gene under the control of the promoter of stimulated by retinoic acid 8 (Stra8-EGFP). The identity of iPGCLCs was characterized by examining the expression of multiple marker genes as well as by the recovery of spermatogenesis after they were transplanted to the testis of infertile W/W(v) mice. Furthermore, iPGCLCs were either induced to germline stem cell-like cells (iGSCLCs) or reverted back to embryonic germ cell-like cells (iEGCLCs). In conclusion, we have established an efficient procedure for inducing iPSCs into iPGCLCs that can be further expanded and induced to more developed germ cells. This work indicates that the technology of in vitro germ cell induction is becoming more sophisticated and can be further improved.

The blood-brain barrier (BBB) is a dynamic and complex interface between blood and the central nervous system (CNS). It protects the brain by preventing toxic substances from entering the brain but also limits the entry of therapeutic agents. ATP-binding cassette (ABC) efflux transporters are critical for the functional barrier and present a formidable impediment to brain delivery of therapeutic agents including antibiotics. The aim of this study was to investigate the possible involvement of multidrug resistance-associated protein 1 and 4 (MRP1 and MRP4), two ABC transporters, in benzylpenicillin efflux transport using wild-type (WT) MDCKII cells and cells overexpressing those human transporters, as well as non-selective and selective inhibitors. We found that inhibiting MRP1 or MRP4 significantly increased [3H]benzylpenicillin uptake in MDCKII-WT, -MRP1 or -MRP4 cells. Similar results were also found in HepG2 cells, which highly express MRP1 and MRP4, and hCMEC/D3 cells which express MRP1. The results indicate that human and canine MRP1 and MRP4 are involved in benzylpenicillin efflux transport. They could be potential therapeutic targets for improving the efficacy of benzylpenicillin for treating CNS infections since both MRP1 and MRP4 express at human blood-brain barrier.

Two cold atmospheric plasma devices were used (either in an indirect or a direct way) for the treatment of physiologically contaminated forearms in 12 healthy volunteers. After 30 s of plasma treatment, the log reduction of the bacterial load in the plasma treated area was evaluated. It was found that both the indirect and direct plasma application resulted in a highly significant reduction of the bacterial load in the target area. Given the same plasma treatment time, the direct application showed higher mean log reduction in comparison to the indirect one and proved to be significantly more effective.

Non-thermal plasma technology emerged the medical field in an age of increasing bacterial and fungal resistance and global concerns about hygiene in different health care settings. Thus, the expectations regarding this new promising tool are very high. After teething problems different non-thermal plasma technologies were developed and used in different clinical trials in patients possessing chronic and acute wounds, diverse skin and itching diseases. The results from these trials and the preceding in vitro and ex vivo experiments opened up new fields of applications, which one had not thought of before. More than 5 years of clinical experience so far demonstrated that this plasma technology could be applied in a safe and effective setting to human beings. However, the potential and knowledge is far from being completely exhausted.

Cold atmospheric plasma is an innovative tool in medicine and hygiene. However, there are no regulations or recommendations for experiments to prove the safety of upcoming devices yet. Healthy ex vivo human skin samples were treated with new upcoming plasma devices (FlatPlaSter 2.0 and MiniFlatPlaSter) for safety purposes. The results indicate—besides the safety measurements/calculations of toxic by-products (O3, NO, and NO2) and the UV power density—that a plasma treatment of up to 2 min is tolerable for the skin (histology and electron microscopy experiments) and safe concerning DNA damages (gamma-H2AX stain assay).

In the past few years, cold atmospheric plasma (CAP) has evolved into a new tool in the fight against nosocomial infections and antibiotic-resistant microorganisms. The products generated by the plasma-electrons, ions, reactive species and UV light-represent a 'lethal cocktail' for different kinds of pathogen, which opens up possible applications in hygiene and medicine. Nevertheless, to ensure the safe usage of CAP on skin (e.g., to treat wounds or skin diseases) several pre-clinical in vitro studies have to be performed before implementing clinical trials on humans. In the study presented here, inactivation experiments with Escherichia coli were carried out to identify the necessary plasma dosage for a 5 log reduction: with a small hand-held battery-operated CAP device, these disinfection properties were achieved after application during 30s. This and higher plasma dosages were then used to analyze the mutagenicity induced in V79 Chinese hamster cells-to furthermore define a 'safe application window'-with the HPRT (hypoxanthine-guanine phosphoribosyl transferase) mutation assay. The results show that a CAP treatment of up to 240 s and repeated treatments of 30s every 12h did not induce mutagenicity at the Hprt locus beyond naturally occurring spontaneous mutations.

Background The development of antibiotic resistance by microorganisms is an increasing problem in medicine. In chronic wounds, bacterial colonization is associated with impaired healing. Cold atmospheric plasma is an innovative promising tool to deal with these problems. Objectives The 5-min argon plasma treatment has already demonstrated efficacy in reducing bacterial numbers in chronic infected wounds in vivo. In this study we investigated a 2-min plasma treatment with the same device and the next-generation device, to assess safety and reduction in bacterial load, regardless of the kind of bacteria and their resistance level in chronic wounds. Methods Twenty-four patients with chronic infected wounds were treated in a prospective randomized controlled phase II study with 2 min of cold atmospheric argon plasma every day: 14 with MicroPlaSter alpha device, 10 with MicroPlaSter beta device (next-generation device) in addition to standard wound care. The patient acted as his ⁄her own control. Bacterial species were detected by standard bacterial swabs and bacterial load by semiquantitative count on nitrocellulose filters. The plasma settings were the same as in the previous phase II study in which wounds were exposed for 5 min to argon plasma. Results Analysis of 70 treatments in 14 patients with the MicroPlaSter alpha device revealed a significant (40%, P

While the blood-brain barrier (BBB) protects the brain by controlling the access of solutes and toxic substances to brain, it also limits drug entry to treat central nervous system disorders. Many drugs are substrates for ATP-binding cassette (ABC) transporters at the BBB that limit their entry into the brain. The role of those transporters in limiting the entry of the widely prescribed therapeutic, benzylpenicillin, has produced conflicting results. This study investigated the possible potential involvement of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), two ABC transporters, in benzylpenicillin transport at BBB in human using MDCKII cells overexpressing those transporters as well as pharmacological inhibition. MDCKII cells overexpressing human BCRP (MDCKII-BCRP) but not those overexpressing human P-gp (MDCKII-MDR cells) had reduced [3H]benzylpenicillin uptake. Similarly, inhibiting BCRP increased [3H]benzylpenicillin uptake in MDCKII-BCRP cells, while inhibiting P-gp in MDCKII-MDR cells had no effect on uptake although there was evidence that benzylpenicillin is a substrate for canine P-gp. While inhibiting BCRP affected [3H]benzylpenicillin cell concentrations it did not affect transepithelial flux in MDCKII-BCRP cells. In summary, the results indicate that human BCRP and not human P-gp is involved in benzylpenicillin transport. However, targeting BCRP alone was not sufficient to alter transepithelial flux in MDCKII cells. Whether it would be sufficient to alter blood-to-brain flux at the human BBB remains to be investigated.