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.

Background Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders in children and adolescents. Current research suggests that environmental factors, such as per- and polyfluoroalkyl substances (PFAS), may be associated with an increased risk of ADHD in offspring. However, most epidemiological evidence originates from non-Chinese populations, with limited research investigating the association between prenatal PFAS and ADHD-like symptoms in Chinese school-aged children. Objective To examine the association between prenatal PFAS exposure and ADHD-like symptoms in 7-year-old children. Methods Based on the Shanghai Birth Cohort, this study included 488 mother-child pairs. PFAS were measured in maternal serum during the second trimester using ultra-performance liquid chromatography-tandem mass spectrometry. The analysis focused on eight specific compounds from three PFAS categories [perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), and perfluorohexanesulfonic acid (PFHxS)]. The hyperactivity subscale of the Strengths and Difficulties Questionnaire (SDQ) was used to assess ADHD-like symptoms in children at age 7. Basic demographic information was collected via questionnaires and medical records. Negative binomial regression models were used to evaluate the relationship between individual exposures to the three typical PFAS categories (PFOA, PFOS, and PFHxS) and children's ADHD-like symptoms, while the bayesian kernel machine regression (BKMR) mixture model was employed to assess the overall effect of PFAS mixture exposure on ADHD-like symptoms. Results The detection rates of the eight target PFAS in maternal second-trimester serum were all above 85%, with PFOA exhibiting the highest median concentration (10.21 ng·mL⁻¹). Overall, 14.75% of the children exhibited ADHD-like symptoms. Results from the negative binomial regression models showed that second-trimester exposures to PFOA (IRR=1.15, 95%CI: 1.05, 1.26), n-PFOS (IRR=1.08, 95%CI: 1.01, 1.15), 6m-PFOS (IRR=1.13, 95%CI: 1.05, 1.21), and 1m-PFOS (IRR=1.11, 95%CI: 1.03, 1.18) were associated with an increased risk of ADHD-like symptoms in 7-year-old children. Stratified analyses suggested potentially statistically significant associations in girls [e.g., for PFOA, boys vs. girls: 1.09 (0.96, 1.23) vs. 1.25 (1.09, 1.44), P-int=0.31]. The BKMR mixture model indicated that the risk of ADHD-like symptoms trended upward with increasing PFAS mixture concentrations, although this association was statistically significant only among girls (P < 0.05). Conclusion Prenatal PFAS exposure may be associated with an increased risk of ADHD-like symptoms in 7-year-old children, and this adverse association appears to be more prominent in girls.

Objective To explore the method for establishing a pig left lung orthotopic transplantation model. Methods A total of 4 male Yorkshire pigs weighing (40.0±2.5) kg underwent surgical procedures, including anesthesia, tracheal intubation, donor lung procurement, and recipient lung transplantation. Histological morphology and blood gas analysis of the transplanted lungs were assessed 2 hours after reperfusion to evaluate the histological changes and function of the transplanted lungs. Results The pigs underwent left lung in situ transplantation, effectively simulating conditions relevant to human lung transplantation. Two hours after the transplantation, arterial blood gas analysis showed that arterial partial pressure of oxygen was 155.4-178.6 mm Hg, arterial partial pressure of carbon dioxide was 53.1-62.4 mm Hg, and the oxygenation index was 310.8-357.2 mm Hg. Hematoxylin and eosin staining indicated a low degree of pulmonary edema and minimal cellular infiltration. Conclusion The pig left lung orthotopic transplantation model possesses strong operability and stability. Researchers can replicate this model according to the described methods and further conduct basic research and explore clinical translational applications.

Neurofibromatosis type 1 (NF1) presents with a diverse range of symptoms that can affect the skin, bones, eyes, central nervous system, and other organs. This article reports the diagnosis and treatment process of a patient with NF1 complicated by bilateral severe-to-profound sensorineural hearing loss. Genetic testing revealed a heterozygous variant of NF1 NM_ 000267.3: c.4054_ 4058del(p.Ser1352LeufsTer20, supporting the diagnosis of NF1. After thorough evaluation, a right cochlear implantation was performed, yielding satisfactory postoperative results. This case suggests that NF1 patients may exhibit phenotypic heterogeneity and atypicality, providing a reference for clinicians in the diagnosis and treatment of such patients.

OBJECTIVE: To observe the clinical efficacy of acupuncture combined with thunder-fire moxibustion in treating low back pain with cold-damp. METHODS: Seventy-two patients of low back pain with cold-damp were randomly divided into an observation group (36 cases, 1 case was eliminated) and a control group (36 cases, 1 case dropped out). The control group received acupuncture at Jizhong (GV6), Yaoyangguan (GV3), ashi points, bilateral Shenshu (BL23), Dachangshu (BL25), and Weizhong (BL40) for 30 min daily. The observation group was treated with thunder-fire moxibustion in addition to the same acupuncture regimen as the control group, once daily. Both groups were treated for 6 consecutive days followed by one rest day, for a total duration of 4 weeks. The visual analog scale (VAS) score, Oswestry disability index (ODI) score, Japanese Orthopedic Association (JOA) score, present pain intensity (PPI) score, and serum levels of β-endorphin (β-EP), 5-hydroxytryp tamin (5-HT), and substance P (SP) were compared before and after treatment, and the clinical efficacy was also compared between the two groups. RESULTS: Compared before treatment, the VAS scores, ODI scores, PPI scores, and serum levels of 5-HT and SP were decreased (P<0.01), while JOA scores and serum levels of β-EP were increased (P<0.01) in both groups after treatment. The observation group showed lower VAS, ODI, and PPI scores and serum levels of 5-HT and SP than those in the control group (P<0.05), as well as higher JOA score and serum level of β-EP (P<0.05). The total effective rate in the observation group was 94.3% (33/35), higher than 82.9% (29/35) in the control group (P<0.05). CONCLUSION Acupuncture combined with thunder-fire moxibustion could effectively alleviate pain and improve lumbar function in patients of low back pain with cold-damp, possibly by regulating β-EP, 5-HT, and SP levels.
Humans ; Moxibustion ; Low Back Pain/blood* ; Male ; Female ; Adult ; Middle Aged ; Acupuncture Therapy ; Acupuncture Points ; Treatment Outcome ; Combined Modality Therapy ; beta-Endorphin/blood* ; Young Adult ; Aged

OBJECTIVE: To investigate the clinical effect on functional dyspepsia differentiated as liver-stomach disharmony treated with acupoint application of Chinese herbal medicine and wax therapy on the basis of Professor TIAN Conghuo's theory, "regulating qi movement". METHODS: A total of 120 patients with functional dyspepsia of liver-stomach disharmony were randomly assigned to a combined therapy group (30 cases, 1 case dropped out), an acupoint application group (30 cases, 1 case dropped out), a wax therapy group (30 cases, 1 case dropped out) and a basic therapy group (30 cases, 2 cases dropped out). In the basic therapy group, omeprazole magnesium enteric-coated tablets were administered orally, 20 mg each time, once daily. Besides the treatment as the basic therapy group, the Chinese herbal acupoint application was used at Zhongwan (CV12) and Shenque (CV8) in the acupoint application group, and remained for 4 h in each intervention; and in the wax therapy group, wax therapy was delivered at the sites of Zhongwan (CV12) and Shenque (CV8) of the abdominal region and remained for 20 min in each intervention; and in the combined therapy group, the acupoint application was combined with wax therapy, administered once every other day or every two days, 3 times weekly. The duration of treatment was 4 weeks in the four groups. Before and after treatment, the score of main symptoms, the score of 36-item short-form health survey (SF-36) and the score of liver-stomach disharmony pattern were observed; and the clinical effect was evaluated in the four groups. RESULTS: After treatment, regarding main symptoms and liver-stomach disharmony pattern, the score of every item was lower than that before treatment in the 4 groups (P<0.01). The score for each dimension in SF-36 was higher than that before treatment in the combined therapy group and the acupoint application group (P<0.01, P<0.05). In the wax therapy group, the scores for physiological activities, bodily pain, general health, vitality, social activities and mental health in SF-36 were higher than those before treatment (P<0.01, P<0.05). In the basic therapy group, the scores for physiological performance, bodily pain, general health and mental health in SF-36 were higher than those before treatment (P<0.05, P<0.01). After treatment, in the combined therapy group, the score for gastric distension and discomforts was lower than those of the basic therapy group and the wax therapy group (P<0.01), and the scores for gastric fullness in the morning, pain in the upper abdominal region and burning sensation in the upper abdominal region, as well as the score for liver-stomach disharmony pattern were lower than those in the rest 3 groups (P<0.01, P<0.05). In the combined therapy group, the scores for physiological activities, physiological performance, and bodily pain were higher than those of the basic therapy group (P<0.01, P<0.05), the scores for physiological activities and bodily pain were higher when compared with those in the acupoint application group (P<0.01, P<0.05) and the scores for physiological activities and vitality were higher when compared with those in the wax therapy group (P<0.05). After treatment, the score for each item of main symptoms, the score for liver-stomach disharmony pattern in the acupoint application group, and the score for liver-stomach disharmony pattern in the wax therapy group were all lower in comparison with those in the basic therapy group (P<0.01, P<0.05). The total effective rates was 93.3% (28/30), 73.3% (22/30), 66.7% (20/30) and 50.0% (15/30) in the combined therapy group, the acupoint application group, the wax therapy group and the basic therapy group, respectively; and the total effective rate in the combined therapy group was superior to the other 3 groups (P<0.01); the total effective rates in the acupoint application group and the wax therapy group were higher than that in the basic therapy group (P<0.01). CONCLUSION The combination of acupoint application with Chinese herbal medicine and wax therapy, based on Professor TIAN Conghuo's theory of "regulating qi movement", can effectively treat functional dyspepsia, alleviate main symptoms and improve the quality of life in the patients.
Humans ; Acupuncture Points ; Dyspepsia/therapy* ; Male ; Drugs, Chinese Herbal/therapeutic use* ; Female ; Adult ; Middle Aged ; Liver/drug effects* ; Combined Modality Therapy ; Stomach/drug effects* ; Young Adult ; Aged ; Waxes

BACKGROUND: Disease-modifying therapies have been approved for the treatment of relapsing multiple sclerosis (RMS). The present study aims to examine the safety of teriflunomide in Chinese patients with RMS. METHODS: This non-randomized, multi-center, 24-week, prospective study enrolled RMS patients with variant (c.421C>A) or wild type ABCG2 who received once-daily oral teriflunomide 14 mg. The primary endpoint was the relationship between ABCG2 polymorphisms and teriflunomide exposure over 24 weeks. Safety was assessed over the 24-week treatment with teriflunomide. RESULTS: Eighty-two patients were assigned to variant ( n  = 42) and wild type groups ( n  = 40), respectively. Geometric mean and geometric standard deviation (SD) of pre-dose concentration (variant, 54.9 [38.0] μg/mL; wild type, 49.1 [32.0] μg/mL) and area under plasma concentration-time curve over a dosing interval (AUC tau ) (variant, 1731.3 [769.0] μg∙h/mL; wild type, 1564.5 [1053.0] μg∙h/mL) values at steady state were approximately similar between the two groups. Safety profile was similar and well tolerated across variant and wild type groups in terms of rates of treatment emergent adverse events (TEAE), treatment-related TEAE, grade ≥3 TEAE, and serious adverse events (AEs). No new specific safety concerns or deaths were reported in the study. CONCLUSION: ABCG2 polymorphisms did not affect the steady-state exposure of teriflunomide, suggesting a similar efficacy and safety profile between variant and wild type RMS patients. REGISTRATION NCT04410965, https://clinicaltrials.gov .
Humans ; Crotonates/adverse effects* ; Toluidines/adverse effects* ; Nitriles ; Hydroxybutyrates ; Female ; Male ; Adult ; ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics* ; Middle Aged ; Multiple Sclerosis, Relapsing-Remitting/genetics* ; Prospective Studies ; Young Adult ; Neoplasm Proteins/genetics* ; East Asian People

BACKGROUND: Enzalutamide, a second-generation androgen receptor (AR) pathway inhibitor, is widely used in the treatment of castration-resistant prostate cancer. However, after a period of enzalutamide treatment, patients inevitably develop drug resistance. In this study, we characterized leucine-rich repeated G-protein-coupled receptor 5 (LGR5) and explored its potential therapeutic value in prostate cancer. METHODS: A total of 142 pairs of tumor and adjacent formalin-fixed paraf-fin-embedded tissue samples from patients with prostate cancer were collected from the Pathology Department at Sun Yat-sen Memorial Hos-pital. LGR5 was screened by sequencing data of enzalutamide-resistant cell lines combined with sequencing data of lesions with different Gleason scores from the same patients. The biological function of LGR5 and its effect on enzalutamide resistance were investigated in vitro and in vivo . Glutathione-S-transferase (GST) pull-down, coimmunoprecipitation, Western blotting, and immunofluorescence assays were used to explore the specific binding mechanism of LGR5 and related pathway changes. RESULTS: LGR5 was significantly upregulated in prostate cancer and negatively correlated with poor patient prognosis. Overexpression of LGR5 promoted the malignant progression of prostate cancer and reduced sensitivity to enzalutamide in vitro and in vivo . LGR5 promoted the phosphorylation of glycogen synthase kinase-3β (GSK-3β) by binding heat shock protein 90,000 alpha B1 (HSP90AB1) and mediated the activation of the Wingless/integrated (WNT)/β-catenin signaling pathway. The increased β-catenin in the cytoplasm entered the nucleus and bound to the nuclear AR, promoting the transcription level of AR, which led to the enhanced tolerance of prostate cancer to enzalutamide. Reducing HSP90AB1 binding to LGR5 significantly enhanced sensitivity to enzalutamide. CONCLUSIONS LGR5 directly binds to HSP90AB1 and mediates GSK-3β phosphorylation, promoting AR expression by regulating the WNT/β-catenin signaling pathway, thereby conferring resistance to enzalutamide treatment in prostate cancer.
Male ; Humans ; Phenylthiohydantoin/pharmacology* ; Benzamides ; Receptors, G-Protein-Coupled/genetics* ; Nitriles ; Cell Line, Tumor ; HSP90 Heat-Shock Proteins/metabolism* ; Drug Resistance, Neoplasm/genetics* ; Prostatic Neoplasms/drug therapy* ; beta Catenin/metabolism* ; Receptors, Androgen/genetics* ; Animals ; Mice ; Wnt Signaling Pathway/physiology*