BACKGROUND:The incidence rate of chronic non-specific neck pain is high and the etiology is unknown.Myofascial pain and deep cervical flexor atrophy are the key factors.Extracorporeal shockwave therapy can improve microcirculation,relieve local pain,and delay the degenerative development of the cervical spine,while motion control training can significantly improve neck muscle strength and endurance and reduce neck pain.However,both methods have limited effectiveness when applied individually.OBJECTIVE:To explore the therapeutic efficacy of extracorporeal shock wave intervention combined with motion control training at the upper trapezius muscle on chronic non-specific neck pain.METHODS:Forty-two patients with chronic non-specific neck pain recruited from Shenyang Sport University were randomly divided into three groups:a shock wave group(n=14),in which extracorporeal shockwave intervention at the upper trapezius muscle was given for 10-15 minutes,once a week for 4 weeks;a training group(n=14),in which motion control training was given for 40-50 minutes,three times a week for 4 weeks;and a combination group(n=14),in which extracorporeal shockwave intervention at the upper trapezius muscle combined with motion control training was performed for 4 weeks.Patients were assessed for pain intensity,cervical spine function,upper trapezius muscle thickness,hemodynamic parameters,and serum interleukin 6 and tumor necrosis factor α levels before intervention,1 week and 4 weeks after intervention.RESULTS AND CONCLUSION:(1)Compared with the pre-intervention period,the visual analogue scale scores and neck disability index in the three groups were lower after 1 and 4 weeks of intervention(P＜0.05),and the visual analogue scale scores and neck disability index in the combination group were lower than those of the shock wave group and the training group(P＜0.05).(2)Compared with the pre-intervention period,the upper trapezius thickness increased in the training group and the combination group after 4 weeks of intervention(P＜0.05);the upper trapezius thickness was greater in the combination group than in the shock wave group and the training group after 4 weeks of intervention(P＜0.05).(3)The shock wave group and the combination group had an increase in the peak systolic velocity of the ascending segment of the transverse carotid artery(P＜0.05)and a decrease in the resistance index(P＜0.05)after 1 and 4 weeks of intervention,while the training group showed an increase in the peak systolic velocity of the ascending segment of the transverse carotid artery(P＜0.05)and a decrease in the resistance index(P＜0.05)after 4 weeks of intervention.The peak systolic velocity of the ascending segment of the transverse carotid artery in the combination group was higher(P＜0.05)and the resistance index was lower(P＜0.05)than those in the shockwave group and the training group after 1 and 4 weeks of intervention.(4)Compared with the pre-intervention period,the levels of interleukin 6 and tumor necrosis factor α were reduced in the shock wave and combination groups after 1 and 4 weeks of intervention(P＜0.05),and in the training group after 4 weeks of intervention(P＜0.05).After 1 and 4 weeks of intervention,the levels of interleukin 6 and tumor necrosis factor α were lower in the combination group than in the shock wave group and the training group(P＜0.05).To conclude,extracorporeal shock wave combined with motion control training for chronic non-specific neck pain significantly reduces pain and improves neck function,and the mechanism of action may be to promote the blood flow velocity at the trigger point,reduce blood flow resistance,reduce the serum levels of interleukin 6 and tumor necrosis factor α,and increase the thickness of the upper trapezius muscle.

OBJECTIVE To evaluate the cost-effectiveness of culmerciclib combined with fulvestrant as second-line treatment for patients with hormone receptor-positive（HR+）/human epidermal growth factor receptor 2-negative （HER2–） locally advanced or metastatic breast cancer， within the context of the Chinese healthcare system. METHODS A partitioned survival model was established based on the CULMATE-1 study， with a simulation time horizon set at 15 years and a cycle length of 28 days. The incremental cost-effectiveness ratio （ICER） of culmerciclib combined with fulvestrant versus fulvestrant monotherapy as second-line treatment for HR+/HER2– breast cancer was calculated. One-way sensitivity analysis and probabilistic sensitivity analysis were performed to assess the robustness of the model. Meanwhile， scenario analysis of culmerciclib price reduction was conducted； the required price reduction and price to reach the willingness-to-pay （WTP） threshold in this study were calculated. RESULTS The results of the base-case analysis indicated that， compared with the fulvestrant monotherapy regimen， culmerciclib combined with fulvestrant yielded an additional 0.823 quality-adjusted life year （QALY）， with a corresponding ICER of 371 696.26 yuan/QALY， which exceeded the WTP threshold （199 330 yuan/QALY）. The results of the univariate sensitivity analysis indicated that the cost of culmerciclib， the discount rate， the utility values for progression disease and progression free survival status were significant factors influencing the ICER； both the univariate sensitivity analysis and the probabilistic sensitivity analysis validated the robustness of the model results. Scenario analysis indicated that when the price of culmerciclib was reduced by 30%， 55% and 85% respectively， the corresponding ICER values fell below 3， 2， and 1 times China’s per capita GDP in 2025， with the probability of cost-effectiveness being 3.00%， 94.90%， 100%. When the cost of culmerciclib （60 mg） was reduced by 52.6% to 50.96 yuan， the ICER value met the WTP threshold established in this study. CONCLUSIONS When the WTP threshold is set at twice China’s per capita GDP in 2025， second-line treatment with culmerciclib combined with fulvestrant for HR+/HER2– locally advanced or metastatic breast cancer does not exhibit cost-effectiveness advantage over fulvestrant monotherapy. Therefore， a reasonable price reduction is required to alleviate the financial burden on patients.

OBJECTIVE: To summarize the clinical features and management of two brothers affected with X-linked inhibitor of apoptosis protein (XIAP) deficiency. METHODS: This study retrospectively analyzed the clinical presentations, treatment, and follow-up of two brothers with XIAP deficiency diagnosed at Shanghai Children's Hospital in 2020, and summarized similar cases recorded in databases such as PubMed, Wanfang, Chinese Medical Association Journals, and WIP from January 2006 to November 2024. This study was approved by the Medical Ethics Committee of our hospital (Ethics No.: 2025R128-E01). RESULTS: Patient 1 was the younger brother, who presented at 8 years of age with growth retardation, folliculitis, erythema nodosum, and perineal abscess. Sequencing revealed that he has carried a hemizygous c.566T>C (p.Leu189Pro) variant of the XIAP gene, which was inherited from his mother. He was allergic to infliximab treatment and underwent allogeneic stem cell transplantation (HSCT) in January 2021. During a follow-up of 3 years and 10 months post-transplantation, he showed no gastrointestinal symptoms and had a good outcome. Patient 2 was the elder brother, who presented at 10 years and 6 months of age with growth retardation, rash, and anal fistula. Genetic testing revealed the same variant. He was treated with oral azathioprine but did not have regular follow-ups. At 14-years-and-6-months of age, he had developed severe gastrointestinal infection and hemophagocytic lymphohistiocytosis, which was alleviated after treatment with antibiotics, glucocorticoids, immunoglobulin, and rituximab. He is currently being prepared for HSCT. A total of 13 publications were retrieved, which involved 64 patients from 23 families, with 23 different variants identified. The main clinical manifestations included splenomegaly (34 cases, 53.1%), hemophagocytic lymphohistiocytosis (27 cases, 42.2%), and inflammatory bowel disease or colitis (20 cases, 31.8%). There were significant phenotypic differences among patients from the same family. Thirteen patients (20.3%) underwent HSCT, with a survival rate of 61.5%. CONCLUSION For male children with early onset, poor treatment response, especially those with unexplained splenomegaly and IBD-like symptoms, early genetic testing is recommended. HSCT is a safe and effective treatment for XIAP deficiency. For patients with developmental delay, early onset, and severe IBD phenotype, early transplantation is recommended.
Humans ; Male ; X-Linked Inhibitor of Apoptosis Protein/deficiency* ; Child ; Genetic Diseases, X-Linked/therapy* ; Phenotype ; Siblings ; Retrospective Studies ; Hematopoietic Stem Cell Transplantation

ObjectiveTo explore the mechanism of Shenmai injection in improving cisplatin resistance in non-small cell lung cancer （NSCLC） based on the endoplasmic reticulum stress through protein kinase R-like endoplasmic reticulum kinase （PERK）/activated transcription factor 4 （ATF4）/C/EBP homologous protein （CHOP） signaling pathway. MethodsBALB/c nude mice bearing cisplatin-resistant human lung cancer cell line （A549/cisplatin） were randomly divided into four groups： Blank control group （0.9% sodium chloride）， cisplatin group （5 µg·g^-1cisplatin）， Shenmai injection group （5.2 mg·g^-1 Shenmai injection）， and combination therapy group （5.2 mg·g^-1 Shenmai injection +5 µg·g^-1cisplatin）. The drug intervention lasted for 4 weeks， and the changes in body weight and tumor volume were monitored. Hematoxylin-eosin （HE） staining was performed to observe tumor tissue pathology. Transmission electron microscopy （TEM） was used to assess the morphology of the endoplasmic reticulum. Immunohistochemical assay was conducted to measure the positive expressions of PERK， ATF4， and CHOP in tumor tissues. Western blot quantified the protein expression of immunoglobulin heavy chain binding protein （BIP）， PERK， phosphorylated PERK （p-PERK）， eukaryotic translation initiation factor 2α （eIF2α）， phosphorylated eIF2α （p-eIF2α）， ATF4， CHOP， B-cell lymphoma -2 （Bcl-2）， and Bcl-2 Associated X protein （Bax）. A549/cis cells were divided into blank group： Blank control group （normal culture medium）， cisplatin group （23.3 µmol·L^-1 cisplatin）， Shenmai Injection group （20 g·L^-1 Shenmai injection）， and combination therapy group （20 g·L^-1 Shenmai injection+23.3 µmol·L^-1 cisplatin）. Cell counting kit-8 （CCK-8） method was used to detect cell viability， TEM was used to observe the morphology of endoplasmic reticulum， and Western blot was used to detect endoplasmic reticulum stress and apoptosis-related proteins. ResultsCompared with the cisplatin group， the combination therapy group showed increased body weight （P<0.05）， decreased tumor volume （P<0.05）， and expanded endoplasmic reticulum in tumor cells. The positive expressions of PERK， ATF4， and CHOP increased （P<0.05）. Western blot revealed elevated protein expression levels of BIP， p-PERK/PERK， p-eIF2α/eIF2α， ATF4， CHOP， and Bax （P<0.05）， while Bcl-2 expression decreased （P<0.05）. As shown in the in vitro experiment， compared with the cisplatin group， the combination therapy group exhibited a reduced cell survival rate （P<0.05）. TEM revealed increased endoplasmic reticulum dilation and vesicular degeneration. Western blotting showed increased protein levels of BIP， p-PERK/PERK， p-eIF2α/eIF2α， ATF4， CHOP and Bax （P<0.05）， with decreased Bcl-2 expression （P<0.05）. ConclusionShenmai injection combined with cisplatin has a synergistic antitumor effect in NSCLC， which may be attributed to the activation of endoplasmic reticulum stress response mediated by the PERK/eIF2α/ATF4/CHOP signaling pathway and the induction of tumor cell apoptosis.

OBJECTIVE To evaluate the cost-effectiveness of anlotinib combined with penpulimab versus sorafenib as first- line treatment for unresectable hepatocellular carcinoma （uHCC） from the perspective of China’s healthcare system. METHODS Based on data from the APOLLO study， a partitioned survival model was established with a 21-day model cycle to simulate patient survival status over 10 years under anlotinib combined with penpulimab regimen or sorafenib monotherapy. Quality-adjusted life year （QALY） was used as the core evaluation parameter to assess the incremental cost-effectiveness ratio （ICER） of different treatment regimens. Using 3 times China’s per capita gross domestic product （GDP） in 2024 （287 247 yuan/QALY） as the willingness-to-pay （WTP） threshold， cost-utility analysis was performed to evaluate the cost-effectiveness of the treatment regimens. Sensitivity analysis was conducted to validate the robustness of the baseline analysis conclusion. Scenario analysis was performed to consider the impact of anlotinib and penpulimab assistance programs on the results； the price reduction of penpulimab to ensure the cost-effectiveness of the combination regimen was examined under varying WTP thresholds （specifically， 1， 2， and 3 times China’s per capita GDP in 2024）. RESULTS The baseline analysis revealed that the ICER of anlotinib combined with penpulimab regimen relative to the sorafenib regimen was 338 611.20 yuan/QALY， which exceeded the WTP threshold set in this study. Univariate sensitivity analysis indicated that the utility value of progression free survival and penpulimab price significantly influenced the baseline analysis results. Probabilistic sensitivity analysis validated the robustness of the baseline results. The results of scenario analysis indicated that when considering the assistance programs for anlotinib and penpulimab， the obtained ICER values were all below the WTP threshold set at 3 times China’s per capita GDP in 2024. When the price of penpulimab was reduced by 58%， 35%， and 13%， the ICER values were below the WTP threshold， which was 1， 2 and 3 times the per capita GDP of China in 2024， respectively. CONCLUSIONS From the perspective of China’s healthcare system， anlotinib combined with penpulimab regimen for first-line treatment of uHCC lacks cost-effectiveness compared to sorafenib regimen. However， this conclusion would be reversed if the anlotinib and penpulimab assistance programs are taken into account or if the price of penpulimab is reduced by more than 13% and above.

ObjectiveTo investigate the uric acid-lowering effects and mechanisms of acacetin on hyperuricemia （HUA） in mice. MethodsOteracil potassium and adenine were used to establish the mouse model of HUA. Male Kunming mice （n=48） were randomized into six groups： control， model， low-dose （12.5 mg·kg^-1） acacetin， medium-dose （25 mg·kg^-1） acacetin， high-dose （50 mg·kg^-1） acacetin， and allopurinol （10 mg·kg^-1）. Each group received continuous gavage administration for 21 days. An automatic biochemical analyzer was used to measure the levels of uric acid （UA）， creatinine （Cr）， urea nitrogen （BUN）， alanine aminotransferase （ALT） and aspartate aminotransferase （AST）. Additionally， the activity of xanthine oxidase （XOD） in the liver and the levels of tumor necrosis factor （TNF）-α， interleukin （IL）-1β， and IL-18 in the serum were measured by enzyme-linked immunosorbent assay （ELISA）. Pathological changes in the renal tissue were observed by hematoxylin-eosin （HE） staining. Western blot was employed to determine the levels of glucose transporter 9 （GLUT9）， urate transporter 1 （URAT1）， phospho-NF-κB p65 （p-NF-κB p65）， and nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 （NLRP3） in the renal tissue. ResultsCompared with the control group， the model group showed elevated levels of UA， Cr， BUN， ALT， and AST， increased activity of XOD in the liver（P<0.01）， raised levels of TNF-α， IL-1β and IL-18 in the serum（P<0.01）， and significantly up-regulated expression of GLUT9， URAT1， p-NF-κB p65， and NLRP3 in the renal tissue（P<0.01）. Compared with the model group， acacetin reduced the UA level in a dose-dependent manner， significantly improved liver and kidney functions， decreased the XOD activity in the liver， ameliorated the pathological changes in the renal tissue， down-regulated the expression of GLUT9， URAT1， p-NF-κB p65 and NLRP3 in the renal tissue（P<0.01）， and lowered the levels of TNF-α， IL-1β， and IL-18 in the serum（P<0.01）. ConclusionAcacetin can ameliorate HUA by decreasing uric acid production， increasing uric acid excretion， and inhibiting the NF-κB/NLRP3 signaling pathway. Therefore， acacetin may be a potential drug for the treatment of HUA.

ObjectiveTaking Aurantii Fructus Immaturus juice（AFI）-processed Atractylodis Macrocephalae Rhizoma（AMR） as an example， this study aims to systematically compare the volatile and non-volatile components of AMR and its processed products， investigate the key differential components， evaluate their anti-inflammatory activities， and elucidate the synergistic mechanism of processing. MethodsThe chemical compositions of volatile and non-volatile components in AMR and AFI-processed AMR were systematically characterized using gas chromatography-mass spectrometry（GC-MS） and ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry（UPLC-Q-TOF-MS）， with relative mass fractions and response values determined separately. Volatile components were identified through searches in the National Institute of Standards and Technology（NIST）17 database， comparison with retention index（RI） and fragmentation pattern matching. Non-volatile components were identified by searching Waters Traditional Chinese Medicine （TCM） spectral library， in conjunction with PubChem and MassBank， characteristic fragmentation patterns and response values were also used to support identification. Differential components were screened using principal component analysis（PCA）， orthogonal partial least squares-discriminant analysis（OPLS-DA）， with variable importance in the projection（VIP） value >1. Components with high log₂fold change（FC） among major differential groups were selected as those exhibiting significant changes before and after processing. The anti-inflammatory activity of the differential compounds was evaluated by assessing their effects on nitric oxide（NO） production in a lipopolysaccharide（LPS）-induced RAW264.7 macrophage model. Enzyme-linked immunosorbent assay（ELISA） was used to detect the effects of the differential components on tumor necrosis factor（TNF）-α， interleukin（IL）-1β， IL-6， and monocyte chemotactic protein（MCP）-1 levels， and immunofluorescence（IF） was employed to assess their effects on nuclear transcription factor（NF）-κB p65 translocation， thereby elucidating the underlying molecular mechanisms. ResultsA total of 36 compounds were identified in the volatile components of AMR and AFI-processed AMR， among which， sesquiterpenes and monoterpenes were significantly increased after processing. In the non-volatile components， 36 compounds were identified， and the main differential components were flavonoids， sesquiterpenoids， and triterpenoids. Flavonoids were the primary differential components distinguishing AMR from its processed products， representing compounds directly introduced during processing. Five compounds， including atractylenolide Ⅲ， tangeritin， nobiletin， hesperidin and narirutin， were selected as representatives of three classes based on their most prominent differential expression among different compound types for subsequent anti-inflammatory activity studies. The results showed that 100 μmol·L^-1 tangerine and narirutin could significantly inhibit LPS-induced NO production（P<0.01） in a concentration-dependent manner. Tangeritin was able to significantly inhibit the levels of TNF-α and MCP-1 secreted by RAW264.7（P<0.05）， while narirutin significantly inhibited the levels of TNF-α， IL-1β， MCP-1 and IL-6（P<0.01）. IF revealed that both tangeritin and narirutin significantly blocked the translocation of NF-κB p65 from the cytoplasm to the nucleus. ConclusionAFI-processed AMR significantly alters the chemical composition profile of AMR， and the newly introduced flavonoid components during processing may be key to its enhanced anti-inflammatory effects.

OBJECTIVE To prepare an intelligent responsive liposome-hydrogel nanopreparation co-loaded with gambogic acid （GA）， and characterize its antitumor activity in vitro . METHODS GA-ICG-Lip-gel was prepared by ethanol injection and cold dissolution， incorporating GA and the photosensitizer indocyanine green （ICG）. The appearance and microscopic morphology of GA-ICG-Lip-gel were observed， its encapsulation efficiency and drug loading capacity were measured， and its photothermal conversion performance， photothermal stability， and infrared imaging properties were investigated， along with the determination of its in vitro release profile. Human breast cancer MCF-7 cells were used as objects to investigate the effects of GA-ICG-Lip-gel （or with near-infrared light irradiation） on cell viability， migration ability， and the cellular uptake capacity of GA-ICG-Lip-gel. RESULTS GA-ICG-Lip-gel existed in a solution state at room temperature and transformed into a gel state at 37 ℃. Its microstructure was dense with small pores， and its encapsulation efficiency and drug loading were （96.07±0.86） % and （6.28±1.16） %， respectively. After exposure to near-infrared light， the temperature of GA-ICG-Lip-gel rose above 42 ℃， with no significant attenuation observed in the heating curve. The heating efficiency was dependent on both the irradiation time and drug concentration. Compared to media without gelatinase， the cumulative release rate of GA-ICG-Lip-gel increased in media containing gelatinase. In vitro studies showed that GA-ICG-Lip-gel could be efficiently taken up by MCF-7 cells； GA-ICG-Lip-gel significantly inhibited the viability and migration ability of MCF-7 cells （ P ＜0.05）， and this inhibitory effect was further enhanced under near-infrared light irradiation. CONCLUSIONS This study successfully prepares GA-ICG-Lip-gel， which exhibits favorable photothermal conversion properties and temperature/enzyme dual-responsive drug release characteristics， and demonstrates significant inhibitory effects on the proliferation and migration of breast cancer cells.

OBJECTIVE To evaluate the cost-effectiveness of amivantamab combined with lazertinib （hereinafter referred to as “AL”） regimen as first-line treatment for EGFR -mutated advanced non-small cell lung cancer （NSCLC） from the perspective of China’s healthcare system. METHODS A partitioned survival model was established based on updated data from the MARIPOSA study， with a 10-year time horizon and 28-day cycles. The primary outcome index was quality adjusted life year （QALY）， and the willingness-to-pay （WTP） threshold was set at three times China’s per capita GDP in 2024 （287 247 yuan/QALY）. Cost-utility analysis was used to calculate the incremental cost-effectiveness ratio （ICER） of AL regimen versus osimertinib monotherapy regimen as first-line treatment for EGFR -mutated advanced NSCLC. One-way and probabilistic sensitivity analyses were performed to test model robustness. Scena rio analyses were conducted to explore the impact of utility values for different health states on the outcomes and determine the required price reductions of amivantamab and lazertinib to achieve cost-effectiveness. RESULTS Compared with the osimertinib monotherapy regimen， the ICER for the AL regimen as first-line treatment for advanced EGFR -mutated NSCLC was 2 062 096.15 yuan/QALY， significantly exceeding the WTP threshold established in this study. One-way sensitivity analysis revealed that the utility value of progression-free survival state and the price of amivantamab were the primary factors influencing the ICER. Probabilistic sensitivity analysis revealed that the AL regimen only became cost-effective when the WTP threshold was set at 2 050 000 yuan/QALY. Scenario analysis indicated that altering the utility value still rendered the AL regimen non-cost-effective. When amivantamab （350 mg） prices decreased by 80%， 85%， and 90% respectively， lazertinib （80 mg） prices would need to decrease by 95.97%， 40.63%， 5.29%， respectively. This would enable the AL regimen’s ICER to consistently fall within the WTP threshold established in this study. CONCLUSIONS At the WTP threshold established in this study， the AL regimen does not demonstrate cost-effectiveness for first-line treatment of advanced EGFR -mutated NSCLC compared to the osimertinib monotherapy regimen. Significant price reductions for both drugs would be required to alleviate the financial burden on patients.

OBJECTIVE To establish the graded management standards for off-label use of Shenqi fuzheng injection. METHODS Systematic searches were conducted in databases including CNKI， PubMed and the Cochrane Library to retrieve guidelines/consensuses， systematic reviews/meta-analyses， and randomized controlled trials （RCTs） of Shenqi fuzheng injection. The quality of evidence was evaluated using AGREE Ⅱ， AMSTAR Ⅱ， and the Risk of Bias 1.0 tool recommended by Cochrane Collaboration， and the graded management standard for off-label use of Shenqi fuzheng injection was developed by using the Thomson grading system. RESULTS A total of 534 articles were involved， including 11 guidelines， 22 systematic reviews/meta-analysis， and 501 RCTs. They covered 79 off-label indications for Shenqi fuzheng injection： cancer-related fatigue， colorectal cancer and breast cancer， all with high-quality evidence were classified under grade A management （grade Ⅰ commendation）， allowing all physicians across the hospital to prescribe relevant treatments； five diseases， such as ovarian cancer， liver cancer， leukemia， heart failure and cerebral infarction， were classified under grade B management （grade Ⅱa commendation）， with prescription restricted to physicians with intermediate or higher professional titles in specific departments； eleven diseases， including sepsis， cervical cancer， esophageal cancer， etc.， were classified under grade C management （grade Ⅱb commendation）， requiring strict evaluation by senior physicians before prescription； the use of Shenqi fuzheng injection for other conditions was explicitly prohibited due to a lack of sufficient evidence. CONCLUSIONS Off-label use of Shenqi fuzheng injection is prevalent. The graded management standard established by evidence-based medical approach provides a scientific basis for standardizing the clinical application of traditional Chinese medicine injections and offers an operable paradigm for implementing differentiated drug use supervision in medical institutions.