This study systematically collated and textual researched realgar from aspects such as name,origin,and quality by consulting ancient herbal texts,classic medical books,and modern literature.The textual research shows that current herbal works all take"realgar"as the official name,with aliases including"Huangshi shi","Shihuang","Tianyang shi","Jiguan shi","Xunhuang","Chouhuang",and"Mingxiong",etc.Ancient herbal records indicate that Xunhuang,Chouhuang,and Shuiku Realgar are all Realgar,while Orpiment is its associated mineral.In ancient times,the main production areas of Realgar were in Gansu,with outputs also seen in Shandong and Hunan.Nowadays,it is mainly produced in Hunan,Guizhou,Hubei,Gansu,Yunnan,Sichuan and other regions.Ancient herbal works mentioned characteristics like"cockscomb color","non-stinky","solid","red and bright"in their quality evaluation,while modern herbal works mostly evaluate its quality by color and texture,such as"red color","large blocks","brittle texture","glossy".The traditional efficacy of Realgar is to dry dampness,kill insects,detoxify various poisons,treat sores and activate blood.Modern studies have shown it also has anti-tumor,antibacterial and antiviral effects.Processing methods in past dynasties included water grinding,vinegar processing,refining,etc.,and currently,water grinding and acid water grinding are commonly used.This paper observed the properties of Realgar,detected the content of As?S?,and analyzed the microscopic characteristics and far-infrared spectral characteristics of qualified batches of Realgar.It was finally found that the As?S? content of qualified batches of Realgar was all more than 90%;under the scanning electron microscope,it showed massive shape,uniform distribution,obvious particles,and no agglomeration;a small amount of associated mineral Orpiment crystals were observed under the polarizing microscope;the characteristic peaks of Realgar(343-344 cm?1,224-225 cm?1,372-374 cm?1,367-369 cm?1,359 cm?1,207-208 cm?1,193-194 cm?1,168-170 cm?1)and Orpiment(390 cm?1,380 cm?1,347 cm?1,311 cm?1,300 cm?1,201 cm?1,182 cm?1,158 cm?1 and 139 cm?1)were determined."Red color and glossy"can be used as property references,"Realgar is a sulfide mineral of the Realgar family,with the main chemical component As?S?,associated with Orpiment"can be used as origin references,and"Shimen in Hunan,Wanshan in Guizhou,Yunnan,Gansu,Sichuan"can be used as production area references,which are consistent with the results of herbal textual research.This study provides a basis for the identification and analysis of Realgar,with a view to better guiding clinical medication and resource utilization.

Rare diseases are a collective term for diseases with extremely low prevalence and incidence rates.Up to now,China has released two lists identifying a total of 207 rare diseases.Given that most rare diseases do not have drugs with corresponding indications,physicians frequently resort to using off-label drugs when treating patients with rare diseases.However,there is currently no systematic guideline or expert consensus for the use of off-label medications in China.To comprehensively collect existing evidence of off-label drug use for rare diseases,fully analyze and evaluate the rationality of off-label drug use for rare diseases,and standardize the management of off-label drug use for rare diseases,the Rare Disease Branch of Beijing Medical Association,Chinese Pharmaceutical Association,Beijing Pharmaceutical Association,and the School of Public Health,Peking University have jointly initiated the drafting of the Expert Consensus on Off-label Use of Drugs for Rare Diseases.This consensus refer to the WHO Handbook for Guideline Development,the Guidelines for Developing/Revising Clinical Diagnostic and Treatment Guidelines in China(2022 Edition),the AGREE Ⅱ and the STAR tools.This protocol outlines the background and purpose of consensus,as well as the comprehensive framework for consensus development,encompassing panel formation,clinical issue identification,evidence retrieval,data extraction,and evidence-based recommendation formulation.

Photodynamic immunotherapy is a promising strategy for cancer treatment. However, the dysfunctional tumor vasculature results in tumor hypoxia and the low efficiency of drug delivery, which in turn restricts the anticancer effect of photodynamic immunotherapy. In this study, we designed photosensitive lipid nanoparticles. The synthesized PFBT@Rox Lip nanoparticles could produce type I/II reactive oxygen species (ROS) by electron or energy transfer through PFBT under light irradiation. Moreover, this nanosystem could alleviate tumor hypoxia and promote vascular normalization through Roxadustat. Upon irradiation with white light, the ROS produced by PFBT@Rox Lip nanoparticles in situ dysregulated calcium homeostasis and triggered endoplasmic reticulum stress, which further promoted the release of damage-associated molecular patterns, enhanced antigen presentation, and stimulated an effective adaptive immune response, ultimately priming the tumor microenvironment (TME) together with the hypoxia alleviation and vessel normalization by Roxadustat. Indeed, in vivo results indicated that PFBT@Rox Lip nanoparticles promoted M1 polarization of tumor-associated macrophages, recruited more natural killer cells, and augmented infiltration of T cells, thereby leading to efficient photodynamic immunotherapy and potentiating the anti-primary and metastatic tumor efficacy of PD-1 antibody. Collectively, photodynamic immunotherapy with PFBT@Rox Lip nanoparticles efficiently program TME through the induction of immunogenicity and oxygenation, and effectively suppress tumor growth through immunogenic cell death and enhanced anti-tumor immunity.

Rare diseases are a collective term for diseases with extremely low prevalence and incidence rates.Up to now,China has released two lists identifying a total of 207 rare diseases.Given that most rare diseases do not have drugs with corresponding indications,physicians frequently resort to using off-label drugs when treating patients with rare diseases.However,there is currently no systematic guideline or expert consensus for the use of off-label medications in China.To comprehensively collect existing evidence of off-label drug use for rare diseases,fully analyze and evaluate the rationality of off-label drug use for rare diseases,and standardize the management of off-label drug use for rare diseases,the Rare Disease Branch of Beijing Medical Association,Chinese Pharmaceutical Association,Beijing Pharmaceutical Association,and the School of Public Health,Peking University have jointly initiated the drafting of the Expert Consensus on Off-label Use of Drugs for Rare Diseases.This consensus refer to the WHO Handbook for Guideline Development,the Guidelines for Developing/Revising Clinical Diagnostic and Treatment Guidelines in China(2022 Edition),the AGREE Ⅱ and the STAR tools.This protocol outlines the background and purpose of consensus,as well as the comprehensive framework for consensus development,encompassing panel formation,clinical issue identification,evidence retrieval,data extraction,and evidence-based recommendation formulation.

This study systematically collated and textual researched realgar from aspects such as name,origin,and quality by consulting ancient herbal texts,classic medical books,and modern literature.The textual research shows that current herbal works all take"realgar"as the official name,with aliases including"Huangshi shi","Shihuang","Tianyang shi","Jiguan shi","Xunhuang","Chouhuang",and"Mingxiong",etc.Ancient herbal records indicate that Xunhuang,Chouhuang,and Shuiku Realgar are all Realgar,while Orpiment is its associated mineral.In ancient times,the main production areas of Realgar were in Gansu,with outputs also seen in Shandong and Hunan.Nowadays,it is mainly produced in Hunan,Guizhou,Hubei,Gansu,Yunnan,Sichuan and other regions.Ancient herbal works mentioned characteristics like"cockscomb color","non-stinky","solid","red and bright"in their quality evaluation,while modern herbal works mostly evaluate its quality by color and texture,such as"red color","large blocks","brittle texture","glossy".The traditional efficacy of Realgar is to dry dampness,kill insects,detoxify various poisons,treat sores and activate blood.Modern studies have shown it also has anti-tumor,antibacterial and antiviral effects.Processing methods in past dynasties included water grinding,vinegar processing,refining,etc.,and currently,water grinding and acid water grinding are commonly used.This paper observed the properties of Realgar,detected the content of As?S?,and analyzed the microscopic characteristics and far-infrared spectral characteristics of qualified batches of Realgar.It was finally found that the As?S? content of qualified batches of Realgar was all more than 90%;under the scanning electron microscope,it showed massive shape,uniform distribution,obvious particles,and no agglomeration;a small amount of associated mineral Orpiment crystals were observed under the polarizing microscope;the characteristic peaks of Realgar(343-344 cm?1,224-225 cm?1,372-374 cm?1,367-369 cm?1,359 cm?1,207-208 cm?1,193-194 cm?1,168-170 cm?1)and Orpiment(390 cm?1,380 cm?1,347 cm?1,311 cm?1,300 cm?1,201 cm?1,182 cm?1,158 cm?1 and 139 cm?1)were determined."Red color and glossy"can be used as property references,"Realgar is a sulfide mineral of the Realgar family,with the main chemical component As?S?,associated with Orpiment"can be used as origin references,and"Shimen in Hunan,Wanshan in Guizhou,Yunnan,Gansu,Sichuan"can be used as production area references,which are consistent with the results of herbal textual research.This study provides a basis for the identification and analysis of Realgar,with a view to better guiding clinical medication and resource utilization.

Humans ; Aged ; Lung Diseases ; Pneumonia/drug therapy* ; Adrenal Cortex Hormones/therapeutic use* ; Pulmonary Disease, Chronic Obstructive/drug therapy* ; Administration, Inhalation ; Community-Acquired Infections/drug therapy*

Background and purpose:For patients with human epidermal growth factor receptor 2(HER2)-positive metastatic breast cancer,trastuzumab treatment can prolong the overall survival and significantly improve the prognosis of patients.However,the reference original research trastuzumab(Herceptin?)is more expensive.Biosimilars have comparable efficacy and safety profiles while increasing patient access to treatment.This clinical trial aimed to evaluate the efficacy,pharmacokinetics,safety and immunogenicity of the trastuzumab biosimilar AK-HER2 compared to trastuzumab(Herceptin?)in patients with HER2-positive metastatic breast cancer.Methods:This multi-center,randomised,double-blind phase Ⅲ clinical trial was conducted in 43 subcenters in China.This study complied with the research protocol,the ethical principles stated in the Declaration of Helsinki and the quality management standards for drug clinical trials.It was approved by the hospital's medical ethics committee.The clinical trial registration agency is the State Food and Drug Administration(clinical trial approval number:2015L04224;clinical trial registration number:CTR20170516).Written informed consent was obtained from subjects before enrollment.Enrolled patients were randomly assigned to the AK-HER2 group and the control group,respectively receiving AK-HER2 or trastuzumab(initial loading dose 8 mg/kg,maintenance dose 6 mg/kg,every 3 weeks as a treatment cycle,total treatment time is 16 cycles)in combination with docetaxel(75 mg/m2,treatment duration is at least 9 cycles).The primary endpoint of this clinical trial was the objective response rate(ORR9)between the AK-HER2 group and the control group in the 9th cycle.Secondary efficacy endpoints included ORR16,disease control rate(DCR),clinical benefit rate(CBR),progression-free survival(PFS)and 1-year survival rate.In this study,100 subjects(AK-HER2 group to control group=1:1)were randomly selected for blood sample collection after the 6th cycle of medication,The collection time points were 45 minutes after infusion(the end of administration),4,8,24,72,120,168,336,and 504 hours after the end of administration.After collection,blood samples were analyzed by PK parameter set(PKPS).Other evaluation parameters included safety and immunogenicity assessment.Results:A total of 550 patients with HER2-positive metastatic breast cancer were enrolled in this clinical trial between Sep.2017 and Mar.2021.In the AK-HER2 group(n=237),129 subjects in the experimental group achieved complete response(CR)or partial response(PR),and the ORR9 was 54.4%.There were 134 subjects in the control group(n=241)who achieved CR or PR,and the ORR9 was 55.6%.The ORR9 ratio between the AK-HER2 group and the control group was 97.9%[90%confidence interval(CI):85.4%-112.2%,P=0.784],which was not statistically significant.In all secondary efficacy endpoints,no statistically significant differences were observed between the two groups.We conducted a mean ratio analysis of pharmacokinetics(PK)parameters between the AK-HER2 group and the control group,and the results suggested that the pharmacokinetic characteristics of the two drugs are similar.The incidence of treatment emergent adverse event(TEAE)leading to drug reduction or suspension during trastuzumab treatment was 3.6%(10 cases)in the AK-HER2 group and 8.1%(22 cases)in the control group.There was statistically significant difference between the two groups(P=0.027).The incidence rate was significantly lower in the AK-HER2 group than in the control group,and there was no statistically significant difference among the other groups.The differences in the positive rates of anti-drug antibodies(ADA)and neutralizing antibodies(NAB)between groups were of no statistical significance(P=0.385 and P=0.752).Conclusion:In patients with HER2-positive metastatic breast cancer,AK-HER2 was comparable to the trastuzumab(Herceptin?)in terms of drug efficacy,pharmacokinetics,safety and immunogenicity.

Objective To explore the effects of drug therapy combined with multi-dimensional psychological intervention on the insomnia of shift medical staff in"sunshine hospital"mode,and to provide a reference for improving the physical and mental health of shift medical staff.Methods A total of 140 cases of medical staff with insomnia in shifts in Wuhan were included and divided into study group and control group by random number table method,70 cases in each group.The control group was given drug treatment,and the study group was treated combined with multi-dimensional psychological intervention.based on"sunshine hospital"model.The scale and questionnaire of PSQI,ISI,ESS and FAS were used to evaluate sleep status and HAMD,HAMA,PHQ-9 and SAS were used to evaluate psychological status,at baseline,visit 1(baseline+intervention for 1 month)and visit 2(baseline+intervention for 3 months),respectively.Results(1)Sleep status:There were differences in 7 dimensions of PSQI score,ISI,ESS,and FAS score between the study group and the control group at different periods(P<0.05);Among them,the PSQI scores of the two groups showed significant difference between the two groups at interview 2(P<0.05);There were significant differences in sleep quality,sleep efficiency scores,ESS and FAS between the two groups at visit 1 and visit 2(P<0.05).(2)Psychological status:HAMD,HAMA,PHQ-9 and SAS scores of the study group and the control group were different in different periods(P<0.05).At interview 2,there were significant differences in HAMA and SAS scores between the two groups(P<0.05).Conclusion Based on the"sunshine hospital"model of drug therapy combined with multi-dimensional psychological intervention,it can significantly improve sleepiness,fatigue symptoms,sleep quality,sleep efficiency,and anxiety and depression of first-line shift medical staff in the short term,and significantly alleviate overall insomnia and anxiety in the long term.

Objective:To explore the effect of transitional care led by special disease nurses in patients with venous thromboembolism (VTE) after intervention.Methods:From February 2020 to April 2021, 124 patients undergoing VTE intervention in Vascular Surgery of Xinxiang Central Hospital were selected by convenient sampling. According to the propensity matching score of 1∶1, the patients were divided into the control group and the observation group, with 62 cases each. The control group was given routine nursing, and the observation group received transitional care led by special disease nurses on the basis of the control group. The follow-up lasted for 12 months. The severity of post-venous thrombosis syndrome (Villalta Scale score), medication compliance, follow-up compliance and quality of life score were compared between the two groups.Results:The completion rates of follow-up at the end of 3, 6 and 12 months in the control group were 95.16% (59/62), 82.26% (51/62) and 70.97% (44/62), respectively. The completion rates of follow-up at the end of 3, 6 and 12 months in the observation group were 100.00% (62/62), 96.77% (60/62) and 91.94% (57/62), respectively. The completion rate of follow-up at each time point in the observation group was higher than that in the control group, and the differences were statistically significant at the end of 6 and 12 months ( P<0.05). The Villalta score of the control group and the observation group increased gradually. The Villalta scores of the observation group at the end of 3, 6 and 12 months were lower than that of the control group, with statistically significant differences ( P<0.05). The score of medication compliance in the control group decreased gradually, while the score of medication compliance in the observation group increased gradually. The scores of medication compliance in the observation group at the end of 3, 6 and 12 months were higher than that in the control group, with statistically significant differences ( P<0.05). The quality of life score of the observation group gradually increased, and the quality of life scores of the observation group at the end of 6 and 12 months were higher than those of the control group, the differences were statistically significant ( P<0.05) . Conclusions:The transitional care led by special disease nurses can effectively increase the postoperative follow-up and medication compliance of VTE patients, reduce the severity of post-venous thrombosis syndrome and improve the quality of life.

Objective : To evaluate the effects of low temperature plasma modification on the surface morphology and bonding durability of zirconia ceramics. Methods: 180 pieces of zirconia ceramic(Y-TZP) were randomly divided into 5 groups(n= 36). Group A:blank group; Group B:sandblast group; Group C:nitrogen( N2) plasma group; Group D:oxygen(O2) plasma group; Group E:argon(Ar) plasma group. The surface hydrophilicity and microstructure of zirconia ceramics were observed,and the changes of surface elements and functional groups were detected. Each group of bonded specimens was randomly divided into two subgroups(n= 15). After receiving 0 and10 000 cycles of heat and cold,the shear strength was measured. The measured results were statistically analyzed and the fracture mode was analyzed. Results: The surface contact angles of groups B,C,D and E were significantly lower than those of group A,with statistically significant differences(P<0. 001). Compared with group A,the surface morphology of group C,D and E did not significantly change,while that of group B significantly changed. XPS showed that the surface carbon decreased,oxygen increased and carbon/oxygen ratio decreased after plasma treatment. SBS results showed that the immediate shear bonding strength of group A was lower than that of the other four groups(P<0. 001),and there was no significant difference in the immediate shear bonding strength of groups B,C,D and E(P>0. 05);After artificial aging,the shear bonding strength of group A was significantly lower than that of the other four groups,and the difference of shear bonding strength between groups A and B before and after artificial aging was statistically significant(P<0. 001). Conclusion The zirconia ceramics achieves better bonding strength and durability with resin cement through three kinds of low temperature plasmas,without changing the surface morphology.