Background/Aims: Belching can occur either independently or concurrently with reflux symptoms. This study aims to explore the relationship between belching and reflux and explore the underlying mechanisms involved. Methods: Firstly, patients with isolated belching symptoms or concurrent belching and reflux symptoms were retrospectively enrolled. High-resolution esophageal impedance manometry (HRIM) and 24-hour pH impedance monitoring were used to assess belching types and temporal relationship between belching and reflux. Secondly, subjects with belching disorder were prospectively recruited. Postprandial HRIM monitoring was used to clarify the relationship and underlying mechanisms between belching and reflux. Results: In the initial phase, 139 subjects were enrolled. Regardless of patients' symptom spectrum (with or without gastroesophageal reflux symptoms), the proportion of preceding-reflux belching was significantly higher in those with objective evidence of gastroesophageal reflux disease, compared to those without (both P < 0.05), which indicated that belching could trigger reflux events and led to more severe reflux burden. To clarify the potential mechanisms involved, 44 belching subjects were prospectively enrolled in the second phase of this study. HRIM analysis demonstrated that maximum intragastric pressure, gastric–lower esophageal sphincter pressure gradient and gastric–esophageal pressure gradient were significantly higher in preceding-reflux belching than those in independent belching. Conclusions This study demonstrated that belching might trigger reflux by increasing intragastric pressure, elevating the gastric-sphincter pressure gradient, which enables gastric contents to pass through the esophagogastric junction.These findings have crucial clinical significance, suggesting that reducing the occurrence of belching might be a potential treatment for refractory reflux.

Objective To evaluate the cost-effectiveness of the combination therapy of ribociclib plus fulvestrant compared to fulvestrant monotherapy as a second-line treatment for postmenopausal patients with hormone receptor-positive(HR+)/human epidermal growth factor receptor 2-negative(HER2-)advanced metastatic breast cancer from the perspective of the Chinese healthcare system.Methods A partitioned survival model was constructed based on MONALEESA-3 study data,with the model cycle of 4 weeks and the time range of 15 years.Total cost,quality-adjusted life years(QALYs)and incremental cost-effectiveness ratio(ICER)were compared between ribociclib combined with fulvestrant and fulvestrant monotherapy as a second-line treatment for postmenopausal patients with HR+/HER2-advanced metastatic breast cancer.The robustness of the models was validated through one-way sensitivity analysis and probabilistic sensitivity analysis.Results Compared with the fulvestrant monotherapy regimen,the ICER for the ribociclib combined with fulvestrant regimen was 187,958.06 yuan/QALY,which was below the willingness-to-pay(WTP)threshold of three times China's per capita gross domestic product(GDP)in 2024(287,247 yuan/QALY).The one-way sensitivity analysis revealed that the ICER was primarily influenced by the proportion of patients receiving subsequent treatments with the combination therapy or fulvestrant monotherapy,and the utility value of progression-free survival.The probabilistic sensitivity analysis showed that at a WTP threshold of three times China's per capita GDP in China in 2024(287,247 yuan/QALY),the probability of the ribociclib combination therapy being cost-effective was 100%.Conclusion In the context of the Chinese healthcare system,the combination therapy of ribociclib and fulvestrant is more cost-effective than fulvestrant monotherapy for the second-line treatment of postmenopausal patients with HR+/HER2-advanced metastatic breast cancer.

BACKGROUND:Previous studies have shown that gelatin modified by methacrylic anhydride(GelMA)/treated dentin matrix(TDM)composite hydrogel scaffolds can promote the proliferation and differentiation of human dental pulp stem cells.Hydrogels loaded with bone morphogenetic protein 2 are considered to be promising materials for bone repair.OBJECTIVE:To observe the effect of GelMA/TDM composite hydrogels loaded with different concentrations of bone morphogenetic protein-2 on the induction of osteogenic differentiation of human dental pulp stem cells.METHODS:GelMA/TDM composite hydrogels containing 0,50,100,and 200 μg/mL bone morphogenetic protein 2 were prepared,denoted as GelMA/TDM,bone morphogenetic protein-2(50 ng/mL)GelMA/TDM,bone morphogenetic protein-2(100 ng/mL)GelMA/TDM,and bone morphogenetic protein-2(200 ng/mL)GelMA/TDM,respectively,and the in vitro sustained release of bone morphogenetic protein 2 from the composite hydrogels was detected.Human dental pulp stem cells were extracted by the modified tissue block enzymatic digestion method and seeded on the surfaces of the four kinds of hydrogels.Cell proliferation was detected by CCK-8 assay and cell adhesion was detected by DAPI staining.Human dental pulp stem cells on the surfaces of each group of hydrogels were induced to osteoblastically,and alkaline phosphatase staining,alkaline phosphatase activity detection,and alizarin red staining were performed.RT-PCR was used to detect the expression of related osteogenic genes(Runx2,bone morphogenetic protein 2,osteopontin,osteocalcin,and type Ⅰ collagen).RESULTS AND CONCLUSION:(1)The GelMA/TDM composite hydrogel could continuously release bone morphogenetic protein 2 for up to 21 days,with a faster release from day 3 to day 6 and a steady release after 6 days.(2)All four kinds of hydrogels could promote the proliferation of human dental pulp stem cells,among which the bone morphogenetic protein-2(100 ng/mL)-GelMA/TDM composite hydrogel had the most obvious effect.Compared with the GelMA/TDM composite hydrogel,the bone morphogenetic protein-2-GelMA/TDM composite hydrogel could promote the adhesion of human dental pulp stem cells,among which the bone morphogenetic protein-2(200 ng/mL)-GelMA/TDM composite hydrogel had the most obvious effect.(3)Compared with the GelMA/TDM composite hydrogel,the bone morphogenetic protein-2-GelMA/TDM composite hydrogel could increase the activity of alkaline phosphatase,the content of calcium nodules,and the expression of related osteogenic genes.Comprehensive analysis showed that the effect of the bone morphogenetic protein-2(100 ng/mL)-GelMA/TDM composite hydrogel was more obvious.(4)The results show that the bone morphogenetic protein-2(100 ng/mL)-GelMA/TDM composite hydrogel has a more obvious ability to promote the osteogenic differentiation of dental pulp stem cells.

Aim To establish and evaluate an alternative meth-od for detecting skin sensitization of cosmetics based on local lymph node assay using bromodeoxyuridine(BrdU)with flow cytometry(FCM).Methods(1)25％hexyl cinnamic alde-hyde(HCA)was chosen as a positive control with an acetone:olive oil(4∶1,V/V,AOO)mixture as a vehicle control for the experiment.The dorsal sides of both ears of mice were treated with test solutions on day 1,day 2,and day 3.Brdu solution was injected inter-peritoneally on day 5.On day 6,the bilateral ears and mandibular lymph nodes were excised,and the number of Brdu positive cells was measured by flow cytometry.The stim-ulation index(SI)was calculated to identify whether it was ≥3,in order to establish the method of LLNA:Brdu-FCM.(2)BrdU-FCM test was conducted using a blind method with the fif-teen reference substances listed in OECD TG429 whose skin sensitization potentials were known.The test substances were dissolved in AOO,N,N-dimethylformamide(DMF)or dimeth-yl sulfoxide(DMSO)at three different concentrations.Tests were performed the same as above.SI and EC2.7 were calculat-ed to evaluate whether the test substance was categorized as a skin sensitizer.The reliability and accuracy of the method were validated by comparing the classification of test substances with that in OECD TG429.Results The SI for 25％HCA was 3.9,showing positive in the skin sensitization test.It demonstrated that the LLNA:Brdu-FCM test method was properly implemen-ted.Nine test substances(2,4-dinitrochlorobenzene,4-pheny-lenediamine,cobalt chloride,2-mercaptobenzothiazole,hexyl-cinnamaldehyde,eugenol,phenyl benzoate,cinnamic alcohol,imidazolidinyl urea)were positive,and six test substances(methyl methacrylate,chlorobenzene,isopropanol,lactic acid,methyl salicylate,salicylic acid)were negative.The method was evaluated with sensitivity of 90％,specificity of 100％,positive prediction rate of 100％,negative prediction rate of 83％,false positive rate of 0％,false negative rate of 17％and accuracy of 93％.The LLNA:BrdU-FCM assay could correctly categorize the test substances that were skin sensitizers or non-sensitizers.Conclusion The LLNA:BrdU-FCM assay appears to be a relia-ble predictor of skin sensitization protential of chemicals,and it is expected to an alternative method for identifying skin sensitization as a supplementary in safety evaluation of cosmetic ingredient.

BACKGROUND:Previous studies have shown that gelatin modified by methacrylic anhydride(GelMA)/treated dentin matrix(TDM)composite hydrogel scaffolds can promote the proliferation and differentiation of human dental pulp stem cells.Hydrogels loaded with bone morphogenetic protein 2 are considered to be promising materials for bone repair.OBJECTIVE:To observe the effect of GelMA/TDM composite hydrogels loaded with different concentrations of bone morphogenetic protein-2 on the induction of osteogenic differentiation of human dental pulp stem cells.METHODS:GelMA/TDM composite hydrogels containing 0,50,100,and 200 μg/mL bone morphogenetic protein 2 were prepared,denoted as GelMA/TDM,bone morphogenetic protein-2(50 ng/mL)GelMA/TDM,bone morphogenetic protein-2(100 ng/mL)GelMA/TDM,and bone morphogenetic protein-2(200 ng/mL)GelMA/TDM,respectively,and the in vitro sustained release of bone morphogenetic protein 2 from the composite hydrogels was detected.Human dental pulp stem cells were extracted by the modified tissue block enzymatic digestion method and seeded on the surfaces of the four kinds of hydrogels.Cell proliferation was detected by CCK-8 assay and cell adhesion was detected by DAPI staining.Human dental pulp stem cells on the surfaces of each group of hydrogels were induced to osteoblastically,and alkaline phosphatase staining,alkaline phosphatase activity detection,and alizarin red staining were performed.RT-PCR was used to detect the expression of related osteogenic genes(Runx2,bone morphogenetic protein 2,osteopontin,osteocalcin,and type Ⅰ collagen).RESULTS AND CONCLUSION:(1)The GelMA/TDM composite hydrogel could continuously release bone morphogenetic protein 2 for up to 21 days,with a faster release from day 3 to day 6 and a steady release after 6 days.(2)All four kinds of hydrogels could promote the proliferation of human dental pulp stem cells,among which the bone morphogenetic protein-2(100 ng/mL)-GelMA/TDM composite hydrogel had the most obvious effect.Compared with the GelMA/TDM composite hydrogel,the bone morphogenetic protein-2-GelMA/TDM composite hydrogel could promote the adhesion of human dental pulp stem cells,among which the bone morphogenetic protein-2(200 ng/mL)-GelMA/TDM composite hydrogel had the most obvious effect.(3)Compared with the GelMA/TDM composite hydrogel,the bone morphogenetic protein-2-GelMA/TDM composite hydrogel could increase the activity of alkaline phosphatase,the content of calcium nodules,and the expression of related osteogenic genes.Comprehensive analysis showed that the effect of the bone morphogenetic protein-2(100 ng/mL)-GelMA/TDM composite hydrogel was more obvious.(4)The results show that the bone morphogenetic protein-2(100 ng/mL)-GelMA/TDM composite hydrogel has a more obvious ability to promote the osteogenic differentiation of dental pulp stem cells.

Aim To establish and evaluate an alternative meth-od for detecting skin sensitization of cosmetics based on local lymph node assay using bromodeoxyuridine(BrdU)with flow cytometry(FCM).Methods(1)25％hexyl cinnamic alde-hyde(HCA)was chosen as a positive control with an acetone:olive oil(4∶1,V/V,AOO)mixture as a vehicle control for the experiment.The dorsal sides of both ears of mice were treated with test solutions on day 1,day 2,and day 3.Brdu solution was injected inter-peritoneally on day 5.On day 6,the bilateral ears and mandibular lymph nodes were excised,and the number of Brdu positive cells was measured by flow cytometry.The stim-ulation index(SI)was calculated to identify whether it was ≥3,in order to establish the method of LLNA:Brdu-FCM.(2)BrdU-FCM test was conducted using a blind method with the fif-teen reference substances listed in OECD TG429 whose skin sensitization potentials were known.The test substances were dissolved in AOO,N,N-dimethylformamide(DMF)or dimeth-yl sulfoxide(DMSO)at three different concentrations.Tests were performed the same as above.SI and EC2.7 were calculat-ed to evaluate whether the test substance was categorized as a skin sensitizer.The reliability and accuracy of the method were validated by comparing the classification of test substances with that in OECD TG429.Results The SI for 25％HCA was 3.9,showing positive in the skin sensitization test.It demonstrated that the LLNA:Brdu-FCM test method was properly implemen-ted.Nine test substances(2,4-dinitrochlorobenzene,4-pheny-lenediamine,cobalt chloride,2-mercaptobenzothiazole,hexyl-cinnamaldehyde,eugenol,phenyl benzoate,cinnamic alcohol,imidazolidinyl urea)were positive,and six test substances(methyl methacrylate,chlorobenzene,isopropanol,lactic acid,methyl salicylate,salicylic acid)were negative.The method was evaluated with sensitivity of 90％,specificity of 100％,positive prediction rate of 100％,negative prediction rate of 83％,false positive rate of 0％,false negative rate of 17％and accuracy of 93％.The LLNA:BrdU-FCM assay could correctly categorize the test substances that were skin sensitizers or non-sensitizers.Conclusion The LLNA:BrdU-FCM assay appears to be a relia-ble predictor of skin sensitization protential of chemicals,and it is expected to an alternative method for identifying skin sensitization as a supplementary in safety evaluation of cosmetic ingredient.

Objective:To analyze policy differences in general outpatient fund pooling of employee basic medical insurance in Yangtze River Delta Region and raise suggestions from the perspective of coordinated development.Methods:The study analyzed policy documents on general outpatients financing,outpatient chronic and special diseases,and inclusion of retail pharmacies into risk pooling at provincial level and in some economically developed cities before August,2024.Typical cases were selected for detailed introduction.Results:General outpatient coverage of employee medical insurance in Yangtze River Delta Region is high,with individual account payment scenarios expanding to commercial health insurance,Long Term Care Insurance and family physician contracted service fees.Number of outpatient chronic and special diseases ranges from 3 to 83.Retail pharmacy policies differ less in access conditions and treatment and e-prescription is advancing rapidly.Suzhou is actively exploring total budget management of retail pharmacies.Conclusions:Outpatient fund pooling policies should be gradually promoted under the principle of"differentiated coordination".It is necessary to transform outpatient chronic and special diseases from"disease coverage"to"cost coverage";strengthen the management of retail pharmacies under the outpatient fund pooling scheme,and improve the coordinated regulatory mechanism for direct settlement of outpatient and medication expenses incurred in other places in the Yangtze River Delta.

Background/Aims: Reflux symptoms frequently present in patients diagnosed with functional dyspepsia (FD). This investigation sought to elucidate the contribution of gastroesophageal reflux in the overlap relationship. Methods: Consecutive patients presenting with reflux symptoms and/or FD symptoms were prospectively included. Comprehensive assessments, including symptoms evaluation, endoscopy, esophageal functional examinations (high-resolution manometry and reflux monitoring), and proton pump inhibitor (PPI) treatment efficacy evaluation, were conducted in these patients. Results: The study enrolled 315 patients, 43.2% of which had concurrent FD symptoms and overlapping reflux symptoms. Notably, a mere 28.7% of patients in the overlap symptoms group had objective gastroesophageal reflux disease evidences (the grade of esophagitis≥ B or the acid exposure time ≥ 4.2%). Functional heartburn was demonstrated to be the main cause of overlapping reflux symptoms(55.1%). Reflux parameters analysis revealed that the reflux burden in the overlap symptoms group paralleled that of the FD symptoms group, with both registering lower levels than the reflux symptoms group (P < 0.05). Furthermore, PPI response rates were notably diminished in the overlap symptoms group (P < 0.001), even for those with objective gastroesophageal reflux disease evidences. Conclusions The study illuminated that overlapping reflux symptoms in FD was common. Strikingly, these symptoms primarily diverged from reflux etiology and exhibited suboptimal responses to PPI intervention. These findings challenge prevailing paradigms and accentuate the imperative for nuanced therapeutic approaches tailored to the distinctive characteristics of overlapping reflux symptoms in the context of FD.