Lysosomes represent a promising target for cancer therapy and reducing drug resistance. However, the short treatment time and low efficiency of lysosomal targeting have limited the application in lysosome-targeting anticancer drugs. In this study, we proposed an adhesive-bandage approach and synthesized a new lysosomal targeting drug, namely long-term lysosome-targeting anticancer drug (LLAD). It contains a SLC38A9-targeting covalently bound moiety and an alkaline component both to prolong the inhibition of SLC38A9 in lysosomes and alkalinize lysosomes. Upon short term and low-dose treatment of HeLa cells, at passage 0, with LLAD, it rapidly alkalinized lysosomes and also can be detected in lysosomes even at passage 15. LLAD induced apoptosis in HeLa cells through long-term lysosomal damage, and showed better long-term anticancer effect than cisplatin in vivo. Overall, our study paves the way for developing long-term lysosomal targeting drugs to treat cancer and overcome the drug resistance of cancer cells, and also provides a candidate drug, LLAD, for treating cancer.

Objective:To understand the current status of pubertal sexual characteristics development of girls aged 6-18 years in Tongzhou District of Beijing and to compare the differences in sexual characteristics development among girls characterized as thin, normal, overweight, and obese.Methods:A cross-sectional survey was conducted among 2 844 girls aged 6-18 years in Tongzhou District of Beijing from September 2022 to July 2023. The developmental stages of breast and pubic hair were assessed on site, and menarche status was inquired. Weight and height were measured. The girls were subsequently characterized into thin, normal, overweight and obese groups. Basic information (including family and personal history) was obtained through questionnaires. Probit probability unit regression was applied to calculate the age of each Tanner stage of sexual characteristics development and the age of menarche. The χ 2 test was applied to compare the counting data between two or multiple groups. Results:A total of 2 844 girls were surveyed and 2 704 girls met the inclusion criteria, resulting in a valid response rate of 95.1%. Among these girls, 1 105 (40.9%) were aged 6-9 years, 1 053 (38.9%) were aged 10-13 years, and 546 (20.2%) were aged 14-18 years. The of height-for-age Z-score (HAZ), weight-for-age Z-score (WAZ), and body mass index-for-age Z-score (BAZ) were 0.46(-0.23,1.16), 0.69(-0.16,1.67), and 0.67(-0.27,1.73) respectively. The prevalences of thin, overweight, and obesity were respectively 1.7% (45/2 704), 17.3% (467/2 704), and 19.9% (538/2 704), respectively. There were 45 girls in the thin group, 1 654 girls in the normal weight group, 1 005 girls in the overweight and obesity group. The age of Tanner stage breast 2 (B2), Tanner stage pubic hair 2 (P2), and menarche was 9.0 (95% CI 8.9-9.1), 10.5 (95% CI 10.4-10.6), and 11.4 (95% CI 11.3-1.5) years, respectively. The current status of breast and pubic hair maturity in girls with pubertal development shows that 64.6% (1 211/1 874) of these girls had breast development preceding pubic hair development, 32.4% (607/1 874) had concurrent breast and pubic hair development, and 3.0% (56/1 874) had pubic hairs development preceding breast development. The interval age between B2 and B5 was 4.7 (95% CI 4.6-4.8) years, between P2 and P5 was 4.5 (95% CI 4.4-4.6) years, and between B2 and menarche was 2.4 (95% CI 2.3-2.5) years. The ages of sexual characteristics development in overweight and obese groups were earlier than that in normal and thin groups. The ages of B2 in thin, normal, overweight, and obese groups were 10.0 (95% CI 9.5-10.6), 9.3 (95% CI 9.2-9.4), and 8.6 (95% CI 8.4-8.7) years, respectively. The age of menarche in thin, normal, overweight, and obese groups were 13.1 (95% CI 12.4-13.7), 11.6 (95% CI 11.4-11.7), and 11.1 (95% CI 11.0-11.2) years, respectively. The interval ages between B2 and B5 and between P2 and P5 was 4.5 and 4.1 years, respectively in the overweight and obese groups, and those in normal group and thin group was 4.7 and 4.5 years, 4.6 and 4.7 years, respectively. Conclusions:The ages of sexual characteristics development and menarche tend in Tongzhou District of Beijing to be earlier than that being reported of Beijing's survey 20 years ago. Girls characterized as overweight and obese not only start puberty at an earlier age than girls of normal weight, but also have a shorter developmental process.

Objective:To investigate the variation of reference ranges of hemodynamic parameters in normal pregnancy and their relation to maternal basic characteristics.Methods:A total of 598 healthy pregnant women who underwent regular prenatal examination at the Third Affiliated Hospital of Guangzhou Medical University from January to December 2023 were prospectively enrolled, and noninvasive hemodynamic monitors were used to detect changes in hemodynamic parameters of the pregnant women with the week of gestation, including cardiac output (CO), stroke volume (SV), thoracic fluid content (TFC), systemic vascular resistance (SVR), mean arterial pressure (MAP), and heart rate (HR). Relationships between hemodynamic parameters and maternal basic characteristics, including age, height, and weight, were analyzed using restricted cubic spline.Results:(1) CO ( r=0.155, P<0.001), TFC ( r=0.338, P<0.001), MAP ( r=0.204, P<0.001), and HR ( r=0.352, P<0.001) were positively correlated with the week of gestation, and SV was negatively correlated with the week of gestation ( r=-0.158, P<0.001). There was no significant correlation between SVR and gestational age ( r=-0.051, P=0.258). (2) CO exhibited a positive correlation with maternal height and weight (all P<0.001). The taller and heavier of pregnant women, the higher their CO. A linear relationship was observed between maternal weight and SV, MAP and HR (all P<0.01). As maternal weight increased, SV, MAP and HR showed an upward trend. Furthermore, there was an inverse association between maternal age and SVR ( P<0.001). (3) There was a significant nonlinear association observed between TFC and body mass index during pregnancy ( P<0.05). Additionally, a nonlinear relationship was found between SVR and MAP in relation to maternal age (all P<0.05). Notably, when the age exceeded 31 years old, there was an evident upward trend observed in both SVR and MAP. Conclusions:The hemodynamic parameters of normal pregnant women are influenced by their height, body weight, and age. It is advisable to maintain a reasonable weight during pregnancy and give birth at an appropriate age.

Kidney deficiency syndrome is a common clinical syndrome in traditional Chinese medicine （TCM）. With the progress of science and technology， clinical and animal experiments on kidney deficiency syndrome have made remarkable progress. Research on kidney deficiency and the nature of "kidney" involves a large number of physiological and pathological bases， which are closely related to physiological and pathological links in the human body， among which the neuroendocrine-immune network shares the closest relationship. However， there are still many challenges in modern research on kidney deficiency syndrome， such as expert consensus on clinical diagnostic criteria and evaluation indexes and optimization of animal experimental models. In the past decade， a large number of clinical and animal experiments have been reported in the literature on kidney deficiency syndrome， among which the literature focusing on the combination of disease and syndrome is predominant， and most of them focus on kidney Yang deficiency and kidney Yin deficiency， involving the exploration of many pathological mechanisms. Research on the mechanisms related to kidney deficiency syndrome encompasses multiple signaling pathways and various biochemical indicators， including the phosphatidylinositol 3-kinase/protein kinase B/nuclear factor-erythroid 2-relatedfactor-2（PI3K/Akt/Nrf2） signaling pathway， the Toll-like receptor 4/myeloid differentiation factor88/nuclear factor-κB（TLR4/MyD88/NF-κB） signaling pathway， the Janus kinase 2/signal transducer and activator of transcription 3（JAK2/STAT3） signaling pathway， Osteoprotectin/nuclear factor-κB receptor activator ligand/receptor activator of nuclear factor-κB （OPG/RANKL/RANK） signaling pathway. The biochemical indicators cover the cyclic adenosine monophosphate/cyclic guanosine monophosphate （cAMP/cGMP） ratio， Na⁺-K⁺-ATPase activity， Ca²⁺-Mg²⁺-ATPase activity， adrenocorticotropic hormone （ACTH）， polycorticosterone （CORT）， 17-OHCS， and other sex hormone indicators， providing crucial reference values for diagnosing kidney Yang deficiency or kidney Yin deficiency. The literature related to kidney deficiency syndrome over the past decade was collated and excavated， with a view to providing a reference for research on kidney deficiency syndrome.

BackgroundHome-based intervention occupies a prominent place in the treatment of autism spectrum disorder （ASD） in children， whereas previous studies on the effect of home-based early intensive behavioral intervention on verbal ability of children with ASD are somewhat inadequate. ObjectiveTo study the effects of intensive family behavioral of intervention based on Verbal Behavior Milestones Assessment and Placement Program （VB-MAPP） on the language ability of children with ASD， so as to provide references for the development of family intervention strategies for children with ASD. MethodsChildren aged 2 to 3 years old who attended the Children's Rehabilitation Department of the Second Affiliated Hospital of Shantou University Medical College from September 2020 to December 2021 and met the Diagnostic and Statistical Manual of Mental Disorders， fifth edition （DSM-5） diagnostic criteria for ASD were selected as the study objects. A non-randomized concurrent control trial was conducted to compare a study group （n=24） receiving home-based early intensive behavioral intervention using VB-MAPP with a control group （n=14） receiving training from other special institutions or early childhood education institutions. The intervention lasted for 6 months in both groups. Before and after the intervention， the VB-MAPP milestone assessment was performed in the two groups， and the VB-MAPP milestone score， mand， trac and listener responds were selected as the study indicators. Then the intervention effect was compared between two groups， and the multiple linear regression was performed to screen the related influencing factors. ResultsAfter intervention， the total milestone assessment score， mand， tact and listener responds scores of study group were higher than those of control group， with statistical difference （Z=-4.339~-2.195， P<0.05 or 0.01）. Multiple linear regression analysis denoted that the average weekly hours of home-based intervention in the first three months had certain effect on listener responds （β=1.029， P<0.05）. ConclusionApplication of home-based early intensive behavior intervention using VB-MAPP may contribute to the improvement of verbal abilities such as mand， tact and listener responds in children with ASD. ［Funded by 2020 Guangdong Provincial Science and Technology Innovation Strategy Special Fund （number， 20200601）］

Smart manufacturing still remains critical challenges for pharmaceutical manufacturing. Here, an original data-driven engineering framework was proposed to tackle the challenges. Firstly, from sporadic indicators to five kinds of systematic quality characteristics, nearly 2,000,000 real-world data points were successively characterized from Ginkgo Folium tablet manufacturing. Then, from simplex to the multivariate system, the digital process capability diagnosis strategy was proposed by multivariate C_pk integrated Bootstrap-t. The C_pk of Ginkgo Folium extracts, granules, and tablets were discovered, which was 0.59, 0.42, and 0.78, respectively, indicating a relatively weak process capability, especially in granulating. Furthermore, the quality traceability was discovered from unit to end-to-end analysis, which decreased from 2.17 to 1.73. This further proved that attention should be paid to granulating to improve the quality characteristic. In conclusion, this paper provided a data-driven engineering strategy empowering industrial innovation to face the challenge of smart pharmaceutical manufacturing.

Objective:To investigate the clinical diagnostic value of combined detection of serum and bronchoalveolar lavage fluid (BALF) galactomannan (GM) for invasive pulmonary aspergillosis (IPA) in children with non-neutropenia.Methods:An analysis was made on 100 children with non-neutropenia suspected of invasive pulmonary aspergillosis in the respiratory ward of the Children′s Hospital Affiliated to Capital Institute of Pediatrics from January 2019 to March 2020. All of them were tested by serum and BALF GM tests as well as sputum and BALF culture for fungi. The sensitivity, specificity and accuracy of serum and BALF GM in the diagnosis of IPA in non-neutropenic children were analyzed. The receiver operating characteristic (ROC) curve and the area under the ROC curve (AUC) were used to evaluate the clinical diagnostic value of serum and BALF GM tests for IPA in children with non-neutropenia.Results:The recruited 100 cases included one confirmed case, 85 clinically diagnosed cases and two suspected cases, while the 12 cases were excluded. The accuracy and 95% confidence interval (95%CI) of serum and BALF GM tests used alone and in combination in the clinical diagnosis of IPA in non-neutropenic children were 29.0% (95%CI: 20.1%-37.9%), 75.0% (95%CI: 66.5%-83.5%) and 81.0% (95%CI: 73.3%-88.7%), respectively. The AUC and 95%CI were 0.645 (95%CI: 0.513-0.778), 0.785 (95%CI: 0.644-0.926) and 0.819 (95%CI: 0.681-0.953), respectively.Conclusions:The combined detection of serum and BALF GM was better than a single indicator in the clinical diagnosis of IPA in non-neutropenic children, suggesting the combined detection was of great value in clinical diagnosis.

Objective:To analyze the sensitization characteristics and change of major allergens in children from 2010 to 2020 in Beijing, so as to provide basis for diagnosis, treatment and prevention of allergic diseases in children.Methods:A retrospective study was conducted to analyze the children who were suspected of allergic diseases and tested for serum immunoglobulin E (total IgE and specific IgE) in the children′s Hospital Affiliated to the Capital Institute of Pediatrics from January 2010 to December 2020. A total of 45 746 children aged 0-17 years in Beijing were enrolled with a median (interquartile range) of 3.8 (2.5, 5.3) years. There were 28 918 boys (63.2%) and 16 828 girls (36.8%) and 14 984 cases (32.8%) in the infant group (<3 years old), 22 049 cases (48.2%) in the preschool group (3-6 years old), and 8 713 cases (19.0%) in the school-age group (6 years old and above). Immunocap allergen detection system (fluorescence enzyme-linked immunosorbent assay) was used to detect and the characteristics and change trend of allergens during 11 years were statistically analyzed by Chi square test.Results:The top three positive rates of single food allergens sIgE were egg white 42.6% (2 788/6 577 tests), milk 38.4% (2 606/6 782 tests) and wheat 31.8% (1 417/4 449 tests), and the sequence of single inhaled allergens were Ragweed 42.6% (440/1 034 tests), Artemisia 38.4% (1 045/3 191 tests) and Alternaria alternata 31.3% (3 358/10 725 tests). The positive detection rates of egg white 47.0%(1 904/4 048 tests), milk 41.9%(1 769/4 226 tests) and wheat 33.9%(973/2 870 tests) in the infant group were the highest, and there have statistically significant(χ 2=91.495, 73.907, 16.966, P<0.05). The positive rates of fx1 (22.5%, 121/537 tests), peanut (24.9%, 111/446 tests), soybean (20.0%, 74/370 tests) and shrimp (7.48%, 44/588 tests) were the highest in the school-age group(χ2=14.436, 10.751, 11.569, 13.703, P<0.05). The most common inhaled allergens were Alternaria alternata (14.8%, 422/2 859 tests) in the infant group, Ambrosia (34.5%, 143/415 tests) and Alternaria alternata (33.5%, 1 762/5 254 tests) in the preschool group, while in the school-age group were Ambrosia (56.4%, 282/500 tests) and Artemisia (48.2%, 573/1 189 tests). The positive rates of egg white, milk, wheat, sesame seed and peanut varied from 2010 to 2020, showing a trend of falling first and then rising(χ2=10.293,χ2=12.066,χ2=7.402,χ2=32.458,χ 2=31.747, P<0.05).The positive detection rates of soybean showed a significant downward trend (21.4%, 173/809 tests in 2010, 15.4%, 70/455 tests in 2020, χ2=6.751, P=0.009), while that of shrimp and crab were at a stable low level(χ2=0.263, 1.346; P>0.05). From 2010 to 2020, mold (26.7%, 1 066/3 998 tests in 2010, 40.2% 1 705/4 243 tests in 2020), grass pollen (19.8%, 259/1 308 tests in 2010, 39.3%, 1 472/3 746 tests in 2020), tree pollen(17%, 180/1 058 tests in 2010, 29.8%, 916/3 075 tests in 2020) and animal dander (18.5%, 111/601 tests in 2010, 26.6%, 672/2 522 tests in 2020) were all showed significant upward trend (χ2=168.600, 163.601, 65.931 and 17.271 respectively, P<0.001) but dust mites (30.7%, 1 270/4 132 tests in 2010, 26.7%, 1 126/4 221 tests in 2020) showed a significant downward trend(χ2=16.822, P<0.001).In 2010, the most common inhaled allergen was dust mite 30.7% (1 270/4 132 tests), followed by mold 26.7% (1 066/3 998 tests), while they were mold 40.2% (1 705/1 243 tests), and grass pollen 39.3% (1 472/3 746 texts) respectively in 2020. Conclusion:In the past 11 years, the main food allergens in children were still egg white and milk, wheat, but the mold and pollen gradually replaced dust mite as the most common inhaled allergen.

Objective:To explore the effect of intensive nursing risk control in schizophrenic (SP) patients undergoing modified electroconvulsive treatment (MECT) .Methods:Using the convenient sampling method, total 202 SP patients who received MECT at the Department of Psychiatry in Fuyang Third People's Hospital from January 2019 to January 2021 were selected as the research objects. According to the random number table, the patients were divided into the observation group and control group with 101 cases each. Patients in the control group received routine care, while patients in the observation group underwent intensive nursing risk control on this basis. The anesthesia cooperation during MECT and the incidence of adverse reactions during anesthesia resuscitation were compared between the two groups.Results:The anesthesia cooperation of the observation group during MECT was better than that of the control group, and the difference was statistically significant ( P<0.05) . The total incidence of adverse reactions during anesthesia resuscitation in the observation group was lower than that in the control group, with a statistically significant difference ( P<0.05) . Conclusions:Intensive nursing risk control can improve the anesthesia cooperation of SP patients during MECT and reduce the occurrence of adverse reactions during anesthesia resuscitation, which is worth promoting in clinical practice.

Objective:To analyze the sensitization characteristics and change of major allergens in children from 2010 to 2020 in Beijing, so as to provide basis for diagnosis, treatment and prevention of allergic diseases in children.Methods:A retrospective study was conducted to analyze the children who were suspected of allergic diseases and tested for serum immunoglobulin E (total IgE and specific IgE) in the children′s Hospital Affiliated to the Capital Institute of Pediatrics from January 2010 to December 2020. A total of 45 746 children aged 0-17 years in Beijing were enrolled with a median (interquartile range) of 3.8 (2.5, 5.3) years. There were 28 918 boys (63.2%) and 16 828 girls (36.8%) and 14 984 cases (32.8%) in the infant group (<3 years old), 22 049 cases (48.2%) in the preschool group (3-6 years old), and 8 713 cases (19.0%) in the school-age group (6 years old and above). Immunocap allergen detection system (fluorescence enzyme-linked immunosorbent assay) was used to detect and the characteristics and change trend of allergens during 11 years were statistically analyzed by Chi square test.Results:The top three positive rates of single food allergens sIgE were egg white 42.6% (2 788/6 577 tests), milk 38.4% (2 606/6 782 tests) and wheat 31.8% (1 417/4 449 tests), and the sequence of single inhaled allergens were Ragweed 42.6% (440/1 034 tests), Artemisia 38.4% (1 045/3 191 tests) and Alternaria alternata 31.3% (3 358/10 725 tests). The positive detection rates of egg white 47.0%(1 904/4 048 tests), milk 41.9%(1 769/4 226 tests) and wheat 33.9%(973/2 870 tests) in the infant group were the highest, and there have statistically significant(χ 2=91.495, 73.907, 16.966, P<0.05). The positive rates of fx1 (22.5%, 121/537 tests), peanut (24.9%, 111/446 tests), soybean (20.0%, 74/370 tests) and shrimp (7.48%, 44/588 tests) were the highest in the school-age group(χ2=14.436, 10.751, 11.569, 13.703, P<0.05). The most common inhaled allergens were Alternaria alternata (14.8%, 422/2 859 tests) in the infant group, Ambrosia (34.5%, 143/415 tests) and Alternaria alternata (33.5%, 1 762/5 254 tests) in the preschool group, while in the school-age group were Ambrosia (56.4%, 282/500 tests) and Artemisia (48.2%, 573/1 189 tests). The positive rates of egg white, milk, wheat, sesame seed and peanut varied from 2010 to 2020, showing a trend of falling first and then rising(χ2=10.293,χ2=12.066,χ2=7.402,χ2=32.458,χ 2=31.747, P<0.05).The positive detection rates of soybean showed a significant downward trend (21.4%, 173/809 tests in 2010, 15.4%, 70/455 tests in 2020, χ2=6.751, P=0.009), while that of shrimp and crab were at a stable low level(χ2=0.263, 1.346; P>0.05). From 2010 to 2020, mold (26.7%, 1 066/3 998 tests in 2010, 40.2% 1 705/4 243 tests in 2020), grass pollen (19.8%, 259/1 308 tests in 2010, 39.3%, 1 472/3 746 tests in 2020), tree pollen(17%, 180/1 058 tests in 2010, 29.8%, 916/3 075 tests in 2020) and animal dander (18.5%, 111/601 tests in 2010, 26.6%, 672/2 522 tests in 2020) were all showed significant upward trend (χ2=168.600, 163.601, 65.931 and 17.271 respectively, P<0.001) but dust mites (30.7%, 1 270/4 132 tests in 2010, 26.7%, 1 126/4 221 tests in 2020) showed a significant downward trend(χ2=16.822, P<0.001).In 2010, the most common inhaled allergen was dust mite 30.7% (1 270/4 132 tests), followed by mold 26.7% (1 066/3 998 tests), while they were mold 40.2% (1 705/1 243 tests), and grass pollen 39.3% (1 472/3 746 texts) respectively in 2020. Conclusion:In the past 11 years, the main food allergens in children were still egg white and milk, wheat, but the mold and pollen gradually replaced dust mite as the most common inhaled allergen.