Background Amid global climate change, extreme environmental events are occurring more frequently, and it is imperative to investigate the impacts of combined exposure to fine particluate matter (PM_2.5) and cold spells (CS) on population mortality. Objective To analyze the association between sequential extreme PM_2.5-cold spell (EP-CS) events and non-accidental mortality among residents in Zigong City from 2016 to 2021. Methods Using time-series study design, meteorological data in Zigong were collected from the Zigong Meteorological Bureau for the period from January 1, 2016 to December 31, 2021, while daily non-accidental mortality data were obtained from the mortality surveillance system of the Zigong Center for Disease Control and Prevention. We adopted the percentile method to define extreme PM_2.5 events and cold spells. We analyzed the risk effect of EP-CS events on non-accidental mortality among residents in this city and explored the potential amplification of damage resulting from different patterns of consecutive extreme events by using distributed lag nonlinear model (DLNM). We also conducted stratified analyses based on age, gender, education level, and marital status. Results The EP-CS events demonstrated a significant impact on non-accidental mortality among the local residents, exhibiting a certain lagged effect. The effects on the overall residents lasted from lag0 (RR=1.030, 95%CI: 1.013, 1.048) to lag14 (RR=1.035, 95%CI: 1.019, 1.052). Notably, the effects were more pronounced among females, individuals aged 65 years and above, and those who were never married, divorced, or widowed. Different patterns of EP-CS events all associated with adverse effects, the health impact of EP-CS events was significantly greater than that of individual PM_2.5 pollution or CS events. The analysis of lag effects across different event patterns revealed that the overall effect of EP-CS events with shorter intervals (0–7 d) had a stronger effect compared to EP-CS with longer intervals (8–14 d), and the RR values of lag14 were 1.034 (95%CI: 1.015, 1.054) and 1.017 (95%CI: 1.007, 1.027), suggesting that the damaging effect of compound events occurring in the short term was more significant. Conclusion All sequential extreme EP-CS events have an impact on non-accidental mortality among residents in this city, with compound events demonstrating a stronger effect. Females, individuals aged ≥65 years, and those who were never married, divorced, or widowed are more sensitive to EP-CS events.

Objective:To compare the efficacy of body posture combined with pharmacotherapy and pharmacotherapy alone in the treatment of chronic subdural hematoma(CSDH).Methods:Firstly, retrospective case series study was conducted. Thirty cases of CSDH that had received body posture combined with pharmacotherapy at Department of Neurosurgery, Huashan Hospital Affiliated to Fudan University from December 2016 to October 2020 were studied retrospectively. Twenty-seven patients were male, and 3 patients were female. The age of patients ( M(IQR)) was 66(16) years (range:28 to 84). Nineteen patients had unilateral hematoma, and 11 patients had bilateral hematoma. All patients received pharmacotherapy and body posture therapy that was to raise their lower limbs 20 to 30 cm with leg lift pad and get abdominal compressed with customized abdominal belt in supine position. Patients were required to maintain the body posture as much as possible, with the maximum to 16 to 18 hours per day. Patients with unilateral hematoma should tilt the head to the affected side and avoid tilting it to the opposite side. For patients with bilateral hematoma, there was no need for head lateralization. Patient were treated with oral dexamethasone and atorvastatin simultaneously. The preliminary efficacy of body posture combined with pharmacotherapy was determined by hematoma improvement rate which was analyzed by Clopper-Pearson method. Then, the multi-center, prospective, randomized controlled trial had carried out in 9 medical centers from August 2020 to November 2021. The stratified block randomization method was adopted. Patients were randomized in a ratio of 1∶1 to either receive pharmacotherapy alone(the control group) or body posture combined with pharmacotherapy(the experiment group) for 3 months and followed up for 6 months. Effective treatment was defined as complete absorption of hematoma, or the hematoma volume decreased by more than 10 ml and Markwalder grading scale score had improved by more than 1 point compared to the baseline. The efficacy rate and surgery conversion rate at 3 months and recurrence at 6 months were observed. Comparison between groups was performed with paired sample t test, Mann-Whitney U test, χ2 test, corrected χ2 test, or Fisher exact probability method. Logistic regression was used to compare the effective rate and operation rate between the two groups. Results:In the respective study, 30 patients completed follow-up 13 to 353 days after treatment. At the last follow-up, the incidence of almost complete absorption or significantly absorption of hematoma (hematoma volume was significantly reduced accompanied by symptom improvement) was 93.3%. The 95% CI for the incidence that analyzed by the Clopper-Pearson method was 77.9% to 99.2%. One hundred and six patients were enrolled in the multicenter study. Fifty-five patients underwent body posture combined with pharmacotherapy. The age was 74(17) years (range:26 to 92). Thirty-nine patients were males and 16 were females. Fifty-one patients underwent pharmacotherapy alone. The age was 69(12) years (range:48 to 84). Thirty-seven patients were males and 14 were females. The length of body posture recorded in diary card was (15.7±2.3) hours(range:7.6 to 19.3 hours). The efficacy rate in the body posture combined with pharmacotherapy group and pharmacotherapy alone group were 83.6% (46/55) and 56.9% (29/51), respectively at 3 months. The result of the logistic regression analysis showed that the efficacy of body posture combined with pharmacotherapy group was better than that of pharmacotherapy alone group ( OR=3.88,95% CI:1.57 to 9.58, P=0.003). Surgery rate in the body posture combined with pharmacotherapy group and pharmacotherapy alone group were 5.5% (3/55) and 21.6% (11/51) respectively. The result of Logistic regression showed that the pharmacotherapy alone group was more likely to be converted to surgery ( OR=0.21,95% CI:0.05 to 0.80, P=0.023). At the 6 months, no recurrence of cases was found in the body posture combined with pharmacotherapy group. However, the recurrence rate of pharmacotherapy alone group was 6.3% (3/48), there was no significant difference between the two groups ( P>0.05). Conclusion:The effect of body posture combined with pharmacotherapy for chronic subdural hematoma is better than that of pharmacotherapy alone.

Traditional development of small protein scaffolds has relied on display technologies and mutation-based engineering, which limit sequence and functional diversity, thereby constraining their therapeutic and application potential. Protein design tools have significantly advanced the creation of novel protein sequences, structures, and functions. However, further improvements in design strategies are still needed to more efficiently optimize the functional performance of protein-based drugs and enhance their druggability. Here, we extended an evolution-based design protocol to create a novel minibinder, BindHer, against the human epidermal growth factor receptor 2 (HER2). It not only exhibits super stability and binding selectivity but also demonstrates remarkable properties in tissue specificity. Radiolabeling experiments with ^99mTc, ⁶⁸Ga, and ¹⁸F revealed that BindHer efficiently targets tumors in HER2-positive breast cancer mouse models, with minimal nonspecific liver absorption, outperforming scaffolds designed through traditional engineering. These findings highlight a new rational approach to automated protein design, offering significant potential for large-scale applications in therapeutic mini-protein development.

Objective To investigate the proportion of Th17 cells,Th1-like Th17 cells and FoxP3+Th17 cells in bone marrow of patients with myelodysplastic syndrome(MDS),the expression of interleukin-17A(IL-17A)in bone marrow supernatant and its clinical significance.Methods Forty MDS patients(MDS group)and 18 patients with nutritional anemia(control group)were selected.MDS patients were classified into the low blast(MDS-LB)group(19 cases)and the increased blast(MDS-IB)group(21 cases,including 11 cases of type IB1 and 10 cases of type IB2)based on morphological definition.The MDS patients were scored according to the revised International Prognostic Scoring System(IPSS-R),with 18 cases in the low-risk group(≤4.5)and 22 cases in the high-risk group(>4.5).Flow cytometry was used to detect the proportion of Th17 cells,Th1-like Th17 cells and FoxP3+Th17 cells in bone marrow of the MDS group and the control group.Enzyme-linked immunosorbent assay(ELISA)was used to detect the level of IL-17A in bone marrow supernatant of the above samples.Results The proportion of Th17 cells and the level of IL-17A were higher in patients of the MDS group than those in the control group(P＜0.05).According to the median expression level of IL-17A,the MDS group was divided into the low-expression group(＜13.71 ng/L,20 cases)and the high-expression group(≥13.71 ng/L,20 cases).Compared with the low-expression group,there were higher proportion of patients with blast cells＜5%and low-risk patients(P＜0.05)in the high-expression group.Compared with the IL-17A low-expression group,the IL-17A high-expression group had a higher proportion of patients with blast cells＜5%and relatively low-risk patients(P＜0.05).Compared with the low-risk patients,high-risk patients had a lower proportion of Th17 cells,IL-17A levels and Th1-like Th17 cells,and a higher proportion of FoxP3+Th17 cells(P＜0.05).Compared with the MDS-LB group,the MDS-IB group had a lower proportion of Th17 cells,IL-17A levels and Th1-like Th17 cells,and a higher proportion of FoxP3+Th17 cells(P＜0.05).Conclusion The proportion of Th17 cells and the level of IL-17A are significantly increased in MDS patients.The decreased proportion of Th1-like Th17 cells and the increased proportion of FoxP3+Th17 cells may be related to the increased proportion of blast cells and higher risk stratification in patients.

Objective:To compare the efficacy of body posture combined with pharmacotherapy and pharmacotherapy alone in the treatment of chronic subdural hematoma(CSDH).Methods:Firstly, retrospective case series study was conducted. Thirty cases of CSDH that had received body posture combined with pharmacotherapy at Department of Neurosurgery, Huashan Hospital Affiliated to Fudan University from December 2016 to October 2020 were studied retrospectively. Twenty-seven patients were male, and 3 patients were female. The age of patients ( M(IQR)) was 66(16) years (range:28 to 84). Nineteen patients had unilateral hematoma, and 11 patients had bilateral hematoma. All patients received pharmacotherapy and body posture therapy that was to raise their lower limbs 20 to 30 cm with leg lift pad and get abdominal compressed with customized abdominal belt in supine position. Patients were required to maintain the body posture as much as possible, with the maximum to 16 to 18 hours per day. Patients with unilateral hematoma should tilt the head to the affected side and avoid tilting it to the opposite side. For patients with bilateral hematoma, there was no need for head lateralization. Patient were treated with oral dexamethasone and atorvastatin simultaneously. The preliminary efficacy of body posture combined with pharmacotherapy was determined by hematoma improvement rate which was analyzed by Clopper-Pearson method. Then, the multi-center, prospective, randomized controlled trial had carried out in 9 medical centers from August 2020 to November 2021. The stratified block randomization method was adopted. Patients were randomized in a ratio of 1∶1 to either receive pharmacotherapy alone(the control group) or body posture combined with pharmacotherapy(the experiment group) for 3 months and followed up for 6 months. Effective treatment was defined as complete absorption of hematoma, or the hematoma volume decreased by more than 10 ml and Markwalder grading scale score had improved by more than 1 point compared to the baseline. The efficacy rate and surgery conversion rate at 3 months and recurrence at 6 months were observed. Comparison between groups was performed with paired sample t test, Mann-Whitney U test, χ2 test, corrected χ2 test, or Fisher exact probability method. Logistic regression was used to compare the effective rate and operation rate between the two groups. Results:In the respective study, 30 patients completed follow-up 13 to 353 days after treatment. At the last follow-up, the incidence of almost complete absorption or significantly absorption of hematoma (hematoma volume was significantly reduced accompanied by symptom improvement) was 93.3%. The 95% CI for the incidence that analyzed by the Clopper-Pearson method was 77.9% to 99.2%. One hundred and six patients were enrolled in the multicenter study. Fifty-five patients underwent body posture combined with pharmacotherapy. The age was 74(17) years (range:26 to 92). Thirty-nine patients were males and 16 were females. Fifty-one patients underwent pharmacotherapy alone. The age was 69(12) years (range:48 to 84). Thirty-seven patients were males and 14 were females. The length of body posture recorded in diary card was (15.7±2.3) hours(range:7.6 to 19.3 hours). The efficacy rate in the body posture combined with pharmacotherapy group and pharmacotherapy alone group were 83.6% (46/55) and 56.9% (29/51), respectively at 3 months. The result of the logistic regression analysis showed that the efficacy of body posture combined with pharmacotherapy group was better than that of pharmacotherapy alone group ( OR=3.88,95% CI:1.57 to 9.58, P=0.003). Surgery rate in the body posture combined with pharmacotherapy group and pharmacotherapy alone group were 5.5% (3/55) and 21.6% (11/51) respectively. The result of Logistic regression showed that the pharmacotherapy alone group was more likely to be converted to surgery ( OR=0.21,95% CI:0.05 to 0.80, P=0.023). At the 6 months, no recurrence of cases was found in the body posture combined with pharmacotherapy group. However, the recurrence rate of pharmacotherapy alone group was 6.3% (3/48), there was no significant difference between the two groups ( P>0.05). Conclusion:The effect of body posture combined with pharmacotherapy for chronic subdural hematoma is better than that of pharmacotherapy alone.

Objective To investigate the proportion of Th17 cells,Th1-like Th17 cells and FoxP3+Th17 cells in bone marrow of patients with myelodysplastic syndrome(MDS),the expression of interleukin-17A(IL-17A)in bone marrow supernatant and its clinical significance.Methods Forty MDS patients(MDS group)and 18 patients with nutritional anemia(control group)were selected.MDS patients were classified into the low blast(MDS-LB)group(19 cases)and the increased blast(MDS-IB)group(21 cases,including 11 cases of type IB1 and 10 cases of type IB2)based on morphological definition.The MDS patients were scored according to the revised International Prognostic Scoring System(IPSS-R),with 18 cases in the low-risk group(≤4.5)and 22 cases in the high-risk group(>4.5).Flow cytometry was used to detect the proportion of Th17 cells,Th1-like Th17 cells and FoxP3+Th17 cells in bone marrow of the MDS group and the control group.Enzyme-linked immunosorbent assay(ELISA)was used to detect the level of IL-17A in bone marrow supernatant of the above samples.Results The proportion of Th17 cells and the level of IL-17A were higher in patients of the MDS group than those in the control group(P＜0.05).According to the median expression level of IL-17A,the MDS group was divided into the low-expression group(＜13.71 ng/L,20 cases)and the high-expression group(≥13.71 ng/L,20 cases).Compared with the low-expression group,there were higher proportion of patients with blast cells＜5%and low-risk patients(P＜0.05)in the high-expression group.Compared with the IL-17A low-expression group,the IL-17A high-expression group had a higher proportion of patients with blast cells＜5%and relatively low-risk patients(P＜0.05).Compared with the low-risk patients,high-risk patients had a lower proportion of Th17 cells,IL-17A levels and Th1-like Th17 cells,and a higher proportion of FoxP3+Th17 cells(P＜0.05).Compared with the MDS-LB group,the MDS-IB group had a lower proportion of Th17 cells,IL-17A levels and Th1-like Th17 cells,and a higher proportion of FoxP3+Th17 cells(P＜0.05).Conclusion The proportion of Th17 cells and the level of IL-17A are significantly increased in MDS patients.The decreased proportion of Th1-like Th17 cells and the increased proportion of FoxP3+Th17 cells may be related to the increased proportion of blast cells and higher risk stratification in patients.

Congenital heart disease（CHD）is a common congenital anomaly that is the leading cause of death among children under the age of five years with birth defects in both developed and developing countries. With the increasing prevalence of CHD，the importance of early diagnosis and intervention of CHD is well accepted. Prenatal ultrasonography is routinely applied for the screening of CHD but many factors influence its diagnostic accuracy. Biomarker testing is a simple and rapid method that can be used as an adjunct to prenatal screening for CHD. This review aims to provide new ideas for the early diagnosis of children with CHD by exploring the pathogenesis of biomarkers in CHD. In recent years，many studies have been devoted to the exploration of biomarkers related to CHD，and the studies on biomarkers in CHD are summarized from three aspects：epigenetics，proteomics and environmental factors.

Threatened abortion is a common disease of obstetrics and gynecology and one of the diseases responding specifically to traditional Chinese medicine （TCM）. The China Association of Chinese Medicine organized experts in TCM obstetrics and gynecology， Western medicine obstetrics and gynecology， and pharmacology to deeply discuss the advantages of TCM and integrated Chinese and Western medicine treatment as well as the medication plans for threatened abortion. After discussion， the experts concluded that chromosome， endocrine， and immune abnormalities were the key factors for the occurrence of threatened abortion， and the Qi and blood disorders in thoroughfare and conception vessels were the core pathogenesis. In the treatment of threatened abortion， TCM has advantages in preventing miscarriages， alleviating clinical symptoms and TCM syndromes， relieving anxiety， regulating reproductive endocrine and immune abnormalities， personalized and diversified treatment， enhancing efficiency and reducing toxicity， and preventing the disease before occurrence. The difficulty in diagnosis and treatment of threatened abortion with traditional Chinese and Western medicine lies in identifying the predictors of abortion caused by maternal factors and the treatment of thrombophilia. Recurrent abortion is the breakthrough point of treatment with integrated traditional Chinese and Western medicine. It is urgent to carry out high-quality evidence-based medicine research in the future to improve the modern diagnosis and treatment of threatened abortion with TCM.

Objective To compare the efficacy of precut over a pancreatic duct stent(PPDS)and transpancreatic precut sphincterotomy(TPS)for difficult biliary cannulation in endoscopic retrograde cholangiopancreatography(ERCP).Methods A retrospective analysis was conducted on the clinical data of all consecutive patients underwent ERCP by the same doctor in our hospital between April 2019 and March 2023.According to the selected method during difficult biliary cannulation when guidewire entered pancreatic duct unintendedly,the patients were divided into two groups,1)PPDS group:placing a pancreatic duct stent first,then using a needle knife to cut bile duct sphincter on the surface of the pancreatic duct stent,preserving pancreatic duct sphincter,and then selectively cannulate bile duct;2)TPS group:precut through pancreatic duct sphincter first,then a pancreatic duct stent was placed,and bile duct was selectively cannulated.The success rate of biliary cannulation and ERCP-related complication between the two groups were compared.Results Among 762 ERCP patients,84 patients were enrolled in this study,44 patients in PPDS group,and 40 patients in TPS group.In PPDS group,42 patients(95.4%,42/44)had successful biliary cannulation.No post-ERCP pancreatitis(PEP),bleeding,perforation occurred in PPDS group.In TPS group,39 patients(97.5%,39/40)had successful biliary cannulation.Four patients(10.0%,4/40)had PEP in PPDS group,no bleeding or perforation occurred.All patients were cured.The success rate of biliary cannulation between two groups had no significant difference(P>0.05),while the rate of PEP had significant difference(P<0.05).Conclusions Both PPDS and TPS are good choice for difficult biliary cannulation with high success rate of biliary cannulation.PPDS is more suitable for patients with high-risk factors for PEP,while TPS is a simple technique.

Objective To compare the efficacy of precut over a pancreatic duct stent(PPDS)and transpancreatic precut sphincterotomy(TPS)for difficult biliary cannulation in endoscopic retrograde cholangiopancreatography(ERCP).Methods A retrospective analysis was conducted on the clinical data of all consecutive patients underwent ERCP by the same doctor in our hospital between April 2019 and March 2023.According to the selected method during difficult biliary cannulation when guidewire entered pancreatic duct unintendedly,the patients were divided into two groups,1)PPDS group:placing a pancreatic duct stent first,then using a needle knife to cut bile duct sphincter on the surface of the pancreatic duct stent,preserving pancreatic duct sphincter,and then selectively cannulate bile duct;2)TPS group:precut through pancreatic duct sphincter first,then a pancreatic duct stent was placed,and bile duct was selectively cannulated.The success rate of biliary cannulation and ERCP-related complication between the two groups were compared.Results Among 762 ERCP patients,84 patients were enrolled in this study,44 patients in PPDS group,and 40 patients in TPS group.In PPDS group,42 patients(95.4%,42/44)had successful biliary cannulation.No post-ERCP pancreatitis(PEP),bleeding,perforation occurred in PPDS group.In TPS group,39 patients(97.5%,39/40)had successful biliary cannulation.Four patients(10.0%,4/40)had PEP in PPDS group,no bleeding or perforation occurred.All patients were cured.The success rate of biliary cannulation between two groups had no significant difference(P>0.05),while the rate of PEP had significant difference(P<0.05).Conclusions Both PPDS and TPS are good choice for difficult biliary cannulation with high success rate of biliary cannulation.PPDS is more suitable for patients with high-risk factors for PEP,while TPS is a simple technique.