Research progress in pharmacokinetics and therapeutic drug monitoring of tyrosine kinase inhibitors in the treatment of gastrointestinal stromal tumors / 中国药房

Tyrosine kinase inhibitors （TKIs） represent a class of small-molecule targeted drugs that improve the survival time of patients with gastrointestinal stromal tumor （GIST）. Imatinib， sunitinib， regorafenib， ripretinib， and avapritinib are commonly used TKIs in the clinical treatment of various types of GIST. This article provides a comprehensive review of the pharmacokinetics and therapeutic drug monitoring （TDM） of these five drugs， finding that there is significant individual variability in the pharmacokinetics of these drugs. Among them， the absorption of imatinib， regorafenib， and avapritinib are influenced by food intake. Imatinib should be taken with meals and 200 mL of water， regorafenib is taken with a low-fat meal， while avapritinib is taken on an empty stomach. TKIs are mainly metabolized by cytochrome P450 3A4 （CYP3A4）， and when used in combination with CYP3A4 inducers or inhibitors， drug exposure levels will significantly change； apart from metabolic enzymes， the exposure levels of TKIs are also influenced by interactions with the transporter proteins P-glycoprotein and breast cancer resistance protein. Currently， research on TDM for TKIs is still in the exploratory stage， with a substantial amount of literature reporting the effective concentrations of imatinib， sunitinib and regorafenib. However， the precise relationship between exposure levels and efficacy/ toxicity needs further exploration. Currently， there is a lack of research on the correlation between exposure levels and efficacy/ toxicity of ripretinib and avapritinib. It is recommended to implement TDM in patients taking these drugs and explore their therapeutic window in combination with pharmacokinetic models. The commonly used methods for clinical TDM of TKIs include immunoassay， chromatography， and surface-enhanced Raman spectroscopy， providing a technical basis for clarifying the therapeutic window of TKIs.

Inhibitory effect and mechanism of total flavonoids from Melicope pteleifolia on transplanted tumor of colorectal cancer in nude mice / 中国药房

OBJECTIVE To study the inhibitory effect and mechanism of total flavonoids from Melicope pteleifolia （TF-MPL） on transplanted tumor of colorectal cancer in nude mice. METHODS The transplanted tumor model of colorectal cancer was induced by injecting 0.2 mL colorectal cancer cell LoVo subcutaneously via the right armpit of nude mice. After successful modeling， nude mice were randomly divided into model group， 5-fluorouracil group （positive control， 10 mg/kg）， TF-MPL high- dose and low-dose groups （25， 12.5 mg/kg）； a normal group （normal saline containing 0.3% carboxymethyl cellulose sodium） without modeling was additionally set up， with 6 mice in each group. Each group was intraperitoneally injected with the corresponding drug solution/solvent for 21 consecutive days. The inhibitory rate of the transplanted tumor， liver and spleen index， and the levels of tumor necrosis factor-α （TNF-α） and interleukin-6 （IL-6） in serum were detected after the last medication； the morphological changes of tumor tissue were observed； immunohistochemical staining was used to detect protein expressions of Toll- like receptor 4 （TLR4） and nuclear factor-κB subunit p65 （NF-κB p65） in tumor tissue of nude mice. Western blot assay was used to detect protein expressions of TLR4， myeloid differentiation factor 88 （MyD88）， TNF receptor-associated factor 6 （TRAF6）， interleukin-1 receptor-associated kinase 1 （IRAK-1）， NF-κB p65 and caspase-3 in tumor tissue of nude mice. RESULTS Compared with the model group， TF-MPL high-dose group showed a significant decrease in tumor weight （inhibitory rate of 36.91%）， liver and spleen index， serum levels of TNF-α and IL-6 and protein expressions of TLR4， MyD88， TRAF6，IRAK-1 and NF- κB p65 （P＜0.05 or P＜0.01）； the expression of caspase-3 protein was increased significantly （P＜0.05）， and more tumor cell shrinkage and deformation， nuclear pyknosis and fragmentation were observed. CONCLUSIONS TF-MPL can significantly inhibit the growth of transplanted tumor of colorectal cancer in nude mice， the mechanism of which may be associated with reducing inflammatory response， inhibiting TLR4/MyD88/NF-κB signaling pathway， and promoting apoptosis in colorectal cancer cells.

Current status of AIDS knowledge, attitudes, practices and associated factors of high risk sexual behavior among college students in Tianjin City / 中国学校卫生

Objective@#To understand the current status of acquired immunodeficiency syndrome (AIDS) knowledge, attitudes, and practices of college students in Tianjin City and to further investigate the associated factors of high risk sexual behaviors, so as to provide a scientific and theoretical basis for accurate prevention and treatment of AIDS.@*Methods@#A stratified cluster random sample of 64 697 students in 56 colleges and universities in Tianjin City in November to December 2022 was investigated about the current status of AIDS knowledge, attitudes and practices. Information was collected using online survey via Questionnaire Star. Descriptive analysis was used for the current status of AIDS knowledge, attitudes and practices among college students. Chi square test and multiple Logistic regression analysis were used to analyze the influencing factors of high risk sexual behavior among college students.@*Results@#The AIDS awareness rate of college students in Tianjin City reached 87.33%. The sexual openness rate was 70.73 %. Among the 3 463 students who had sex during the past year, 42.13% of students reported high risk sexual behavior. Multivariate Logistic regression showed that female, having a romantic partner, having received sex education and prevention and treatment knowledge of AIDS were negatively associated with high risk sexual behavior ( OR =0.66, 0.59, 0.81, 0.59, P <0.05). Being in sophomore year, non heterosexuality (homosexuality, bisexuality, not knowing), prejudice against AIDS, and misunderstanding the testing methods for AIDS showed positive correlations with highrisk sexual behavior ( OR =1.22, 2.49, 2.30, 3.17, 1.43, 1.22 , P <0.05).@*Conclusions@#The awareness rate of AIDS in college students in Tianjin is high, but high risk sexual behaviors are still at a high level. Further targeted knowledge education and behavioral interventions are needed to scientifically prevent the spread of AIDS.

Mitochondria-specific near-infrared photoactivation of peroxynitrite upconversion luminescent nanogenerator for precision cancer gas therapy

Gas therapy is emerging as a highly promising therapeutic strategy for cancer treatment. However, there are limitations, including the lack of targeted subcellular organelle accuracy and spatiotemporal release precision, associated with gas therapy. In this study, we developed a series of photoactivatable nitric oxide (NO) donors NRh-R-NO (R = Me, Et, Bn, iPr, and Ph) based on an N-nitrosated upconversion luminescent rhodamine scaffold. Under the irradiation of 808 nm light, only NRh-Ph-NO could effectively release NO and NRh-Ph with a significant turn-on frequency upconversion luminescence (FUCL) signal at 740 nm, ascribed to lower N-N bond dissociation energy. We also investigated the involved multistage near-infrared-controlled cascade release of gas therapy, including the NO released from NRh-Ph-NO along with one NRh-Ph molecule generation, the superoxide anion O2⋅- produced by the photodynamic therapy (PDT) effect of NRh-Ph, and highly toxic peroxynitrite anion (ONOO‒) generated from the co-existence of NO and O2⋅-. After mild nano-modification, the nanogenerator (NRh-Ph-NO NPs) empowered with superior biocompatibility could target mitochondria. Under an 808 nm laser irradiation, NRh-Ph-NO NPs could induce NO/ROS to generate RNS, causing a decrease in the mitochondrial membrane potential and initiating apoptosis by caspase-3 activation, which further induced tumor immunogenic cell death (ICD). In vivo therapeutic results of NRh-Ph-NO NPs showed augmented RNS-potentiated gas therapy, demonstrating excellent biocompatibility and effective tumor inhibition guided by real-time FUCL imaging. Collectively, this versatile strategy defines the targeted RNS-mediated cancer therapy.

Preliminary identification of the cloning， expression， and function of Marmota himalayana type I interferon receptor β subunit / 临床肝胆病杂志

ObjectiveTo clone the gene of Marmota himalayana type ‍Ⅰ interferon receptor β subunit （mhIFNAR2）， and to perform antibody preparation and functional identification. MethodsRT-PCR was used for amplification in the spleen tissue of Marmota himalayana to obtain the sequence， which was cloned to the prokaryotic expression vector pRSET-B to express the recombinant protein. Electrophoresis and Western blot were used for identification. BALB/c mice were immunized with the recombinant protein to prepare the polyclonal antibody of its extracellular domain； immunohistochemistry， immunofluorescence assay， and Western Blot were used for identification， and the method of siRNA blockade was used to investigate its function. An analysis of variance was used for comparison of continuous data between multiple groups， and the least significant difference t-test was used for comparison between two groups. ResultsA fragment of mhIFNAR2 （149‍ ‍—‍ ‍1 ‍300 bp） was obtained from spleen tissue， which showed the highest homology of 98.05% in marmot. A prokaryotic expression plasmid was successfully constructed for expression of the extracellular domain of the mhIFNAR2（50-181aa） and was named pRSET-B.mhIFNAR2， and the recombinant protein expressed by this plasmid had a molecular weight of 27 kD， a purity of about 95% after purification， and a concentration of 160 μg/mL. After BALB/c mice were immunized with the purified recombinant protein， 1∶1 000 specific polyclonal antibodies were obtained， and immunohistochemistry and immunofluorescence assay showed the expression in cell membrane and cytoplasm. Among the three siRNAs synthesized， the siRNA starting from the 277 locus （siRNA277） could silence the expression of target genes and weaken the interferon signaling pathway compared with the blank control group and the negative control group （both P<0.05）. ConclusionThe fragment of mhIFNAR2 is obtained， and the polyclonal antibody for the extracellular domain of mhIFNAR2 is successfully prepared， with relatively high titer and specificity， and can be used for immunohistochemistry， immunofluorescence assay， and Western blot.

The Prevention and Treatment of Pulmonary Nodules “Nodule-cancer Transformation” Based on the View of “Disease with Latent Pathogen Induced by a New Pathogen” / 中医杂志

As one of the pathogenic mechanisms contained in The Inner Canon of Yellow Emperor （《黄帝内经》）， “disease with latent pathogen induced by a new pathogen” means that the induced new pathogen resulted to a combination of the latent previous pathogen and the new pathogen， which caused the disease. Based on this， it is believed that the change of “nodule-cancer transformation” of pulmonary nodules is actually based on the deficiency of original qi， and the new pathogen induces the latent pathogens like phlegm coagulation， qi stagnation， blood stasis， toxicity， so healthy qi can not drive the pathogens out， and the long-time detention generated into cancerous turbidity， and deve-loped into cancerous tumour at the end. Therefore， based on the three-stage treatment of unformed cancer， dense cancerous toxin， and developed cancer， the clinical practice applied six methods of clearing， expelling， dissipating， tonifying， harmonizing， and transforming， taking into account both the manifestation and root cause， moving the treatment window of pulmonary nodules forward， attacking the pathogens when the toxin was not yet overbearing， supporting the healthy qi before declining， delaying the process of nodules-cancer transformation， and providing ideas for the prevention and treatment of pulmonary nodules “nodule-cancer transformation” in traditional Chinese medicine.

Research progress in the diagnosis and treatment of neurotrophic keratitis / 国际眼科杂志(Guoji Yanke Zazhi)

Neurotrophic keratitis(NK)is a degenerative corneal disease caused by impairment of trigeminal innervations. It can lead to spontaneous corneal epithelial defects, corneal ulceration and perforation. Early diagnosis of NK is crucial and requires accurate investigation of clinical history and thorough examination of ocular surface to determine clinical stage. Treatment for NK needs to be divided into stages according to disease severity. In addition to conventional treatments including artificial tears, blepharorrhaphy, and amniotic membrane transplantation, there are also emerging treatments such as targeted drug therapy and corneal neurotization. This article summarized the epidemiology, clinical manifestations and classification, etiology, diagnosis, differential diagnosis and treatment of NK, aiming to provide reference for the early diagnosis and treatment of NK in the future.

Treatment of Inflammatory Bowel Disease by Targeting M1/M2 Macrophage Polarization Balance with Traditional Chinese Medicine and Active Components： A Review / 中国实验方剂学杂志

Inflammatory bowel disease （IBD）， consisting of ulcerative colitis and Crohn's disease， is a chronic relapsing inflammatory gastrointestinal disease closely associated with immune dysfunction. The pathogenesis of IBD is closely related to genetic susceptibility， immune system dysfunction， environmental change， and intestinal microbial dysbiosis. Modern research has found that macrophage polarization plays an important role in the development of IBD and can affect the level of inflammatory response， intestinal mucosal repair， and intestinal microbial balance， making it a potential target for IBD treatment. Increasing evidence suggests that traditional Chinese medicine and its active components can regulate macrophage polarization through multiple pathways and balance the M1/M2 macrophage ratio， thus inhibiting inflammatory response， promoting intestinal mucosal repair， and slowing down the progression of IBD. This article summarized the biological processes and targets involved in macrophage polarization and discussed its impact on IBD. It also provided a brief overview of the latest research on how traditional Chinese medicine and its active components can improve IBD by regulating macrophage polarization， so as to provide new directions and strategies for the clinical application of traditional Chinese medicine in IBD treatment.

Anti-HMGCR immune-mediated necrotizing myopathy: A case report / 北京大学学报(医学版)

The patient was a 55-year-old man who was admitted to hospital with "progressive myalgia and weakness for 4 months, and exacerbated for 1 month". Four months ago, he presented with persistent shoulder girdle myalgia and elevated creatine kinase (CK) at routine physical examination, which fluctuated from 1 271 to 2 963 U/L after discontinuation of statin treatment. Progressive myalgia and weakness worsened seriously to breath-holding and profuse sweating 1 month ago. The patient was post-operative for renal cancer, had previous diabetes mellitus and coronary artery disease medical history, had a stent implanted by percutaneous coronary intervention and was on long-term medication with aspirin, atorvastatin and metoprolol. Neurological examination showed pressure pain in the scapularis and pelvic girdle muscles, and V- grade muscle strength in the proximal extremities. Strongly positive of anti-HMGCR antibody was detected. Muscle magnetic resonance imaging (MRI) T2-weighted image and short time inversion recovery sequences (STIR) showed high signals in the right vastus lateralis and semimembranosus muscles. There was a small amount of myofibrillar degeneration and necrosis, CD4 positive inflammatory cells around the vessels and among myofibrils, MHC-Ⅰ infiltration, and multifocal lamellar deposition of C5b9 in non-necrotic myofibrils of the right quadriceps muscle pathological manifestation. According to the clinical manifestation, imageological change, increased CK, blood specific anti-HMGCR antibody and biopsy pathological immune-mediated evidence, the diagnosis of anti-HMGCR immune-mediated necrotizing myopathy was unequivocal. Methylprednisolone was administrated as 48 mg daily orally, and was reduced to medication discontinuation gradually. The patient's complaint of myalgia and breathlessness completely disappeared after 2 weeks, the weakness relief with no residual clinical symptoms 2 months later. Follow-up to date, there was no myalgia or weakness with slightly increasing CK rechecked. The case was a classical anti-HMGCR-IMNM without swallowing difficulties, joint symptoms, rash, lung symptoms, gastrointestinal symptoms, heart failure and Raynaud's phenomenon. The other clinical characters of the disease included CK as mean levels >10 times of upper limit of normal, active myogenic damage in electromyography, predominant edema and steatosis of gluteus and external rotator groups in T2WI and/or STIR at advanced disease phase except axial muscles. The symptoms may occasionally improve with discontinuation of statins, but glucocorticoids are usually required, and other treatments include a variety of immunosuppressive therapies such as methotrexate, rituximab and intravenous gammaglobulin.

Association between periconceptional supplementation of folic acid or multiple-micronutrients containing folic acid and preterm delivery in women / 北京大学学报(医学版)

OBJECTIVE@#To explore the association between periconceptional supplementation of folic acid or multiple-micronutrients containing folic acid(MMFA) and risk of preterm delivery in women with natural conception, singleton pregnancy and vaginal delivery.@*METHODS@#A retrospective cohort study was performed based on the prenatal health care system and hospital information system of Tongzhou Maternal and Child Health Hospital of Beijing and the women who had their prenatal care in the hospital from January 2015 to December 2018 were included. The information of 16 332 women who conceived naturally, had a singleton pregnancy, and delivered vaginally was collected. Compliance scores were constructed based on the time of initiation and the frequency of taking nutritional supplements. The association between maternal periconceptional micronutrient supplementation, including pure folic acid (FA) pills or MMFA and the rate of preterm delivery was evaluated using Logistic regression models.@*RESULTS@#The preterm delivery rate (gestational week < 37 weeks) of the study population was 3.8%, and the mean (standard deviation) of gestational age was (38.98±1.37) weeks. A total of 6 174 (37.8%) women took FA during the periconceptional period, 8 646 (52.9%) women took MMFA, and 1 512 (9.3%) women did not take any nutritional supplements. The association between periconceptional supplementation of FA or MMFA and risk of preterm delivery in women was not statistically significant [adjusted odds ratio (aOR)=1.01, 95%CI: 0.74-1.37]. The associations with preterm birth were not statistically significant in further analysis by the type of nutritional supplements, time of initiation, and the frequency of supplementation. In addition, the association between the compliance score of taking supplements and the rate of preterm delivery was not statistically significant, either.@*CONCLUSION@#This study did not find an association between the risk of preterm delivery and the use of FA or MMFA during the periconcep-tional period in women with natural conception, singleton pregnancy, and vaginal delivery. In the future, multicenter studies with large-scale prospective cohort or population-based randomized controlled trials are warranted to confirm the association between taking FA or MMFA during the periconceptional period and preterm delivery among women.

Recommendations for diagnosis and treatment of systemic lupus erythematosus / 中华内科杂志

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with complicated pathogenesis and diverse clinical manifestations. The current recommendations of the Chinese Rheumatology Association are based on a comprehensive investigation of evidence based medicine, domestic and international guidelines for SLE, and experts' proposals, and aim to provide a more scientific and authoritative reference for the diagnosis and management of SLE. The recommendations focus on four aspects; clinical manifestations, laboratory evaluation, diagnosis and disease assessment, and disease treatment and monitoring. The goal of the recommendations is to standardize the diagnosis and treatment of SLE in China so as to improve the prognosis of SLE patients.

Cardiovascular health status of Chinese adults based on "Life's Essential 8" score / 中华流行病学杂志

Objective: To assess the cardiovascular health status of adults in China by using the "Life's Essential 8" score, and provide reference for the development and improvement of cardiovascular disease prevention and control policies and measures. Methods: Chronic Disease and Nutrition Surveillance was conducted in 298 counties/districts in 2015 in 31 provinces (autonomous regions, municipalities) across China, multi-stage stratified cluster random sampling was used to select 45 households in each village or neighborhood, and 20 households were further selected to conduct dietary surveys. In this study, a total of 70 093 adults aged ≥20 years who completed the dietary survey and had complete information were included, their cardiovascular health status were assessed by using the "Life's Essential 8" score, a cardiovascular health scoring standard released by the American Heart Association in 2022. All results were adjusted using complex design-based sampling weights to achieve a better estimate of the population. Results: In 2015, the overall cardiovascular health score of Chinese adults aged ≥20 years was 73.3±12.6, the score was significantly higher in women (77.9±11.6) than in men (68.7±11.8), and higher in urban area (74.5±12.8) than in rural area (71.9±12.2), the differences were significant (P<0.001). It was estimated that about 0.25% (95%CI: 0.16%-0.33%) of adults in China had cardiovascular health score of 100, and 33.0% (95%CI: 31.6%-34.3%), 63.2% (95%CI: 62.1%-64.3%), and 3.9% (95%CI: 3.5%-4.2%) of adults had high, moderate and low cardiovascular health scores, respectively. The proportion of those with high cardiovascular health scores was relatively low in men, those with low education level, those with low income, those living in rural areas, and those living in southwest China (P<0.001). Of the eight factors, diet had the lowest mean score (46.0, 95%CI: 44.7-47.3), followed by blood pressure (59.4, 95%CI: 58.2-60.6) and tobacco exposure (61.4, 95%CI: 60.6-62.2). Conclusions: The cardiovascular health status of two-thirds of adult population in China needs to be improved. Diet, tobacco exposure, and blood pressure are the factors affecting the cardiovascular health of Chinese population, to which close attention needs to be paid, and men, rural residents, and those with lower socioeconomic status are key groups in cardiovascular health promotion.

Safety of delayed vaccination with the national immunization program vaccines in children aged 0-6 years from 2019 to 2021 in Xuhui District, Shanghai City in China / 中华预防医学杂志

Objective: To understand the incidence of delayed vaccination with the national immunization program vaccines among children aged 0-6 years in Xuhui District, Shanghai, and to evaluate the safety of delayed vaccination. Methods: A stratified random sampling was used to obtain six vaccination clinics in Xuhui District, Shanghai. The vaccination records of children 0-6 years from these six vaccination clinics were collected from the Shanghai Immunization Program Information Management System. Adverse events following immunization (AEFI) data were collected from the China Information System for Disease Control and Prevention. Descriptive epidemiology was used to analyze the data. Children were divided into the timely vaccination group and delayed vaccination group according whether they were delayed in vaccination (received one month or more after the recommended age among children aged ≤1 year; received three months or more after the recommended age among children aged >1 year). The safety of four vaccination methods-individual vaccination, simultaneous vaccination, routine vaccination and combined vaccination-were further compared. Differences between groups were compared using chi-square test. Results: From 2019 to 2021, six vaccination clinics in Xuhui District administered 124 031 doses of the national immunization program vaccines among children aged 0-6 years, and delayed vaccinations accounted for 25.99% (32 234/124 031) of these doses. In 2020, the delayed vaccination rate during the first-level COVID-19 public health emergency response period in Shanghai was significantly higher than that in the same period in 2019 (34.70% vs. 24.19%, χ2=136.23, P<0.05). The delayed vaccination rate during the COVID-19 vaccination campaign in 2021 was significantly higher than that in the same period in 2019 (25.27% vs. 22.55%, χ2=82.80, P<0.05). From 2019 to 2021, a total of 475 cases of AEFI were reported in six vaccination clinics, with a reported incidence of 382.97 per 100 000 doses, including 421 cases of common adverse reaction (88.63%, 339.43 per 100 000 doses), 51 cases of rare adverse reaction (10.74%, 41.12 per 100 000 doses) and 3 cases of coincidences (0.63%, 2.42 per 100 000 doses). The reported incidence of AEFI among delayed vaccinations was significantly lower than that among timely vaccinations (291.62 per 100 000 doses vs. 415.05 per 100 000 doses). The incidence of AEFI for the four delayed vaccination methods (individual vaccination, simultaneous vaccination, routine vaccination and combined vaccination) was lower than that for timely vaccination. There were significant differences between the groups except for the routine vaccination group (χ2=9.82, P<0.05; χ2=5.46, P<0.05; χ2=2.97, P>0.05; χ2=11.89, P<0.05). Conclusions: In Xuhui District of Shanghai, 25.99% of doses of the national immunization program vaccines administered to children 0-6 years were delayed. Delayed vaccination does not increase the risk of AEFI compared with timely vaccination.

Analysis of clinical features and ATRX gene variants in a Chinese pedigree affected with X-linked alpha thalassemia mental retardation (ATR-X) syndrome / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical characteristics and genetic basis of two brothers featuring X-linked alpha thalassemia mental retardation (ATR-X) syndrome.@*METHODS@#An infant who had presented at the Qilu Children's Hospital in 2020 for unstable upright head and inability to roll over and his family were selected as the study subjects. The clinical features of the child and one of his brothers were summarized, and their genomic DNA was subjected to targeted capture and next generation sequencing (NGS).@*RESULTS@#The brothers had presented with mental retardation and facial dysmorphisms. NGS revealed that they had both harbored a hemizygous c.5275C>A variant of the ATRX gene located on the X chromosome, which was inherited from their mother.@*CONCLUSION@#The siblings were diagnosed with ATR-X syndrome. The discovery of the c.5275C>A variant has enriched the mutational spectrum of the ATRX gene.

Diagnosis of a case with Hermansky-Pudlak syndrome type 5 through high-throughput sequencing and a literature review / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical and genetic characteristics of a patient with Hermansky-Pudlak syndrome type 5 (HPS-5).@*METHODS@#A child with HPS-5 who had attended the Children's Hospital Affiliated to Shandong University on October 3, 2019 was selected as the study subject. Clinical data of the child were collected. Genetic variant was analyzed through high-throughput sequencing. A literature review was also carried out.@*RESULTS@#The child, a 1-year-and-5-month-old girl, had nystagmus since childhood, lost of retinal pigmentation by fundus examination and easy bruising. High-throughput sequencing revealed that she has harbored compound heterozygous variants of the HPS5 gene, namely c.1562_1563delAA (p.F521Sfs*27) and c.1404C>A (p.C468X), which were inherited from his father and mother, respectively. Based on the guidelines from the American College for Medical Genetics and Genomics (ACMG), both variants were predicted to be pathogenic (PVS+PM2_Supporting+PM3+PP4). Among 18 previously reported HPS-5 patients, all had had eye problems, and most of them had tendency for bleeding. Eight cases had carried compound heterozygous variants of the HPS5 gene, 8 carried homozygous variants, 2 carried double homozygous variants, and most of them were null mutations.@*CONCLUSION@#The c.1562_1563delAA(p.F521Sfs*27) and c.1404C>A (p.C468X) compound heterozygous variants of the HPS5 gene probably underlay the HPS-5 in this child. High-throughput sequencing has provided an important tool for the diagnosis. HSP-5 patients usually have typical ocular albinism and/or oculocutaneous albinism and tendency of bleeding, which are commonly caused by compound heterozygous and homozygous variants of the HPS5 gene, though serious complications have been rare.

Clinical and ASS1 gene variant analysis of three Chinese pedigrees affected with Citrullinemia type I / 中华医学遗传学杂志

OBJECTIVE@#To analyze the clinical and genetic characteristics of three Chinese pedigrees affected with Citrullinemia type I (CTLN1).@*METHODS@#Three children diagnosed at the Children's Hospital Affiliated to Shandong University from 2017 to 2020 were selected as the study subjects. Genomic DNA was extracted from peripheral blood samples of the probands and their parents. Next generation sequencing (NGS) was carried out to detect pathological variants of the probands. Sanger sequencing was used for validating the candidate variant among the pedigrees.@*RESULTS@#The probands have respectively carried compound heterozygous variants of c.207_209delGGA and c.1168G>A, c.349G>A and c.364-1G>A, c.470G>A and c.970G>A of the ASS1 gene, which were respectively inherited from their parents.@*CONCLUSION@#The newly discovered c.207_209delGGA and c.364-1G>A variants have enriched the mutational spectrum of the ASS1 gene. And the mutation spectrum of Chinese CTLN1 patients is heterogeneous.

Clinical and genetic analysis of a very early-onset inflammatory bowel disease type 28 child with atypical clinical manifestation / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical and genetic characteristics of a very early-onset inflammatory bowel disease (VEO-IBD) type 28 child with atypical clinical manifestations.@*METHODS@#A VEO-IBD type 28 child with atypical clinical manifestations admitted to the Department of Neonatology, Children's Hospital Affiliated to Shandong University on November 5, 2021 was selected as the study subject. Clinical data of the child was collected. Peripheral venous blood samples of the child and his parents were collected for high-throughput sequencing. Candidate variants were verified by Sanger sequencing and bioinformatic analysis.@*RESULTS@#The child, a 50-day-old male, had manifested bronchitis, ulcerative stomatitis, eczema and slightly loose stool. High-throughput sequencing revealed that he has harbored compound heterozygous variants of the IL-10RA gene, namely c.299T>G (p.V100G) and c.301C>T (p.R101W), which were inherited from his father and mother, respectively. Bioinformatic analysis showed that both variants have been recorded in the HGMD database, though the c.299T>G variant has not been included in the gnomAD, 1000 Genomes, ExAC and ESP6500 databases, while the c.301C>T variant has a low population frequency. Both variants were predicted to be deleterious by the online software including SIFT, PolyPhen-2 and Mutation Taster. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were predicted to be pathogenic (PS3+PM2_Supporting+PP3).@*CONCLUSION@#The c.299T>G and c.301C>T variants of the IL-10RA gene probably underlay the VEO-IBD type 28 in this child. Above finding has expanded the phenotypic spectrum of VEO-IBD type 28 due to variants of the IL-10RA gene and provided a reference for the clinical diagnosis of this disease.

Advances in revision surgery after primary total hip arthroplasty for Crowe type Ⅳ developmental dysplasia of the hip / 中国修复重建外科杂志

OBJECTIVE@#To review research advances of revision surgery after primary total hip arthroplasty (THA) for patients with Crowe type Ⅳ developmental dysplasia of the hip (DDH).@*METHODS@#The recent literature on revision surgery after primary THA in patients with Crowe type Ⅳ DDH was reviewed. The reasons for revision surgery were analyzed and the difficulties of revision surgery, the management methods, and the related prosthesis choices were summarized.@*RESULTS@#Patients with Crowe type Ⅳ DDH have small anteroposterior diameter of the acetabulum, large variation in acetabular and femoral anteversion angles, severe soft tissue contractures, which make both THA and revision surgery more difficult. There are many reasons for patients undergoing revision surgery after primary THA, mainly due to aseptic loosening of the prosthesis. Therefore, it is necessary to restore anatomical structures in primary THA, as much as possible and reduce the generation of wear particles to avoid postoperative loosening of the prosthesis. Due to the anatomical characteristics of Crowe type Ⅳ DDH, the patients have acetabular and femoral bone defects, and the repair and reconstruction of bone defects become the key to revision surgery. The acetabular side is usually reconstructed with the appropriate acetabular cup or combined metal block, Cage, or custom component depending on the extent of the bone defect, while the femoral side is preferred to the S-ROM prosthesis. In addition, the prosthetic interface should be ceramic-ceramic or ceramic-highly cross-linked polyethylene wherever possible.@*CONCLUSION@#The reasons leading to revision surgery after primary THA in patients with Crowe type Ⅳ DDH and the surgical difficulties have been clarified, and a large number of clinical studies have proposed corresponding revision modalities based on which good early- and mid-term outcomes have been obtained, but further follow-up is needed to clarify the long-term outcomes. With technological advances and the development of new materials, personalized prostheses for these patients are expected to become a reality.

Clinical comprehensive evaluation of Ruyi Zhenbao Pills in treatment of osteoarthritis / 中国中药杂志

This study evaluated the clinical effectiveness of Ruyi Zhenbao Pills in the treatment of osteoarthritis, aiming to clarify its clinical advantages and promote rational drug use and related policy transformation. Following the relevant standards in Guidelines for the Comprehensive Evaluation of Drugs in Clinical Practice and Technical Specifications for the Clinical Comprehensive Evaluation of Chinese Patent Medicine, comprehensive research and related data on Ruyi Zhenbao Pills in the treatment of osteoarthritis were collected in the dimensions of safety, effectiveness, economy, innovation, suitability, accessibility, and traditional Chinese medicine(TCM) cha-racteristics(referred to as the "6+1" dimensions). Through evidence-based medicine, questionnaire surveys, health technology assessment, pharmacoeconomic evaluation, and other methods, a multi-criteria decision analysis(MCDA) model and CSC v2.0 software were used to comprehensively evaluate the clinical value of Ruyi Zhenbao Pills. Spontaneous reporting system data on adverse reactions and literature data indicate that the adverse reactions of Ruyi Zhenbao Pills are mostly general adverse reactions, with no reports of se-rious adverse reactions. The known risks are small, and its safety is rated as class A. It has been shown to effectively relieve joint pain and restore joint function in the treatment of osteoarthritis. However, more high-quality, large-sample randomized controlled trials are needed to further validate its effectiveness, which is rated as class B. There is evidence supporting its economic viability, and its economic is rated as class B. It demonstrates good clinical innovation, innovative enterprise service system, and industrial innovation, and innovation is rated as class A. Medical professionals and patients have a favorable perception of the suitability of Ruyi Zhenbao Pills, and further improvement can be made in terms of convenience of administration and promotion to facilitate rational drug use by healthcare professionals and patients. Suitability is rated as class B. The drug has a favorable price level, availability, and affordability, and accessibility is rated as class A. Ruyi Zhenbao Pills are a classic Tibetan medicinal prescription with excellent TCM theoretical characteristics. However, further research is needed on its use in human studies. TCM characteristics are rated as class B. Based on the evaluation results of the "6+1" dimensions, the comprehensive clinical evaluation is rated as grade B. Ruyi Zhenbao Pills have good clinical value in the treatment of osteoarthritis, and it is recommended to undergo the necessary procedures for conditional transformation into a policy for the management of essential clinical drugs.

Efficacy and mechanism of Xuefu Zhuyu Decoction on model rats of coronary heart disease with heart blood stasis syndrome based on metabolomics / 中国中药杂志

This study investigated the effects of Xuefu Zhuyu Decoction on myocardial metabolites in a rat model of coronary heart disease with heart blood stasis syndrome and explored the therapeutic mechanism of blood circulation-promoting and blood stasis-removing therapy. SD rats were randomly divided into a sham operation group, a model group, a Xuefu Zhuyu Decoction group(14.04 g·kg~(-1)), and a trimetazidine group(5.4 mg·kg~(-1)). The sham operation group underwent thread insertion without ligation, while the other groups underwent coronary artery left anterior descending branch ligation to induce a model of coronary heart disease with heart blood stasis syndrome. Three days after modeling, drug intervention was performed, and samples were taken after 14 days of intervention. General conditions were observed, and electrocardiogram and cardiac ultrasound indices were measured. Hematoxylin-eosin(HE) staining and Masson staining were used to observe tissue pathological morphology. The enzyme linked immunosorbent assay(ELISA) was used to measure the levels of triglyceride(TG) and total cholesterol(TC) in the serum. Ultra high performance liquid chromatography-quantitative exactive-mass spectrometry(UHPLC-QE-MS) technology was used to screen differential metabolites in myocardial tissue and conduct metabolic pathway enrichment analysis. The results showed that Xuefu Zhuyu Decoction significantly improved the general condition of the model rats, reduced heart rate and ST segment elevation in the electrocardiogram, increased left ventricular ejection fraction(LVEF) and left ventricular fractional shortening(LVFS), and decreased left ventricular internal diameter in diastole(LVIDd) and left ventricular internal diameter in systole(LVIDs). HE staining and Masson staining showed that Xuefu Zhuyu Decoction effectively alleviated myocardial tissue structural disorders, inflammatory cell infiltration, and collagen fiber deposition in the model rats. ELISA results showed that Xuefu Zhuyu Decoction effectively regulated serum TG and TC levels in the model rats. There were significant differences in the metabolic phenotypes of myocardial samples in each group. Fourteen differential metabolites were identified in the Xuefu Zhuyu Decoction group, involving five metabolic pathways, including arginine and proline metabolism, glycerophospholipid metabolism, aminoacyl-tRNA biosynthesis, ether lipid metabolism, and alanine, aspartate, and glutamate metabolism. Xuefu Zhuyu Decoction improved cardiac function and myocardial structural damage in the rat model of coronary heart disease with heart blood stasis syndrome, and its biological mechanism involved the regulation of lipid metabolism, choline metabolism, amino acid metabolism, energy metabolism, and protein synthesis pathways.