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.

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.

Objective To explore the effect and mechanism of massage on skeletal muscle overuse injury in rats.Methods Thirty-two male Sprague-Dawley rats were randomly assigned to the blank(8 rats)and modeling groups(24 rats)using a random number table method.A model of skeletal muscle overuse injury was induced in the modeling group using downhill running centrifugal contraction exercise for 4 weeks.The successfully modeled rats were divided into a model group,a massage group,and a Yunnan Baiyao Aerosol group,with 8 rats in each group.The 4 groups of rats were subjucted to balance beam test.After 24 h of completing the modeling,the massage group was treated with a self-made massager,while the Yunnan Baiyao Aerosol group was treated with Yunnan Baiyao Aerosol twice a day for 3 consecutive days.Twenty-four hours after the end of treatment,the four groups of rats underwent behavioral evaluation again using the beam balance test.Hematoxylin-eosin staining was used to observe damage to the gastrocnemius muscle.The enzyme-linked immunosorbent assay was used to measure the concentrations of tumor necrosis factor-α(TNF-α),interleukin-6(IL-6),and 5-hydroxytryptamine(5-HT)in plasma.Western blotting was used to detect the protein expression levels of phosphorylated p38 mitogen-activated protein kinase(p-p38 MAPK),phosphorylated c-Jun N-terminal kinase(p-JNK),and phosphorylated extracellular signal-regulated kinase 1/2(p-ERK1/2)proteins in the MAPK signaling pathway.Results Before treatment,compared to the blank group,the rats in the model group,massage group,and Yunnan Baiyao Aerosol group had a longer walking time on the balance beam and a higher number of sliding claws(P<0.05).After treatment,compared with the blank group,the model group showed longer walking time on the balance beam,increased number of sliding claws,significant infiltration of inflammatory cells in gastrocnemius muscle,increased levels of TNF-α,IL-6,5-HT,and p-p38 MAPK,p-JNK,and p-ERK1/2(P<0.05).Compared to the model group,the walking time of the balance beam in the massage group was shortened,the number of sliding claws was reduced,the number of inflammatory cells was reduced,TNF-α,IL-6,and 5-HT indices decreased,and p-p38 MAPK,p-JNK,p-ERK1/2 indices decreased(P<0.05).The Yunnan Baiyao Aerosol group showed a decrease in the number of sliding claws,fewer inflammatory cells,reduced IL-6 levels,and decreased p-JNK and p-ERK1/2(P<0.05).Compared to the massage group,the Yunnan Baiyao Aerosol group had more inflammatory cells,increased IL-6 levels,and elevated p-JNK and p-ERK1/2 levels(P<0.05).Conclusion Massage can improve chronic skeletal muscle fatigue injury,and its mechanism of action may be through inhibiting the MAPK signaling pathway,downregulating the p-ERK1/2,p-p38 MAPK,and p-JNK proteins in this pathway,indirectly affecting the release of inflammatory factors,thus reducing skeletal muscle cell damage,inhibiting the release of inflammatory mediators,and promoting skeletal muscle repair.

Objective To explore the effect and mechanism of massage on skeletal muscle overuse injury in rats.Methods Thirty-two male Sprague-Dawley rats were randomly assigned to the blank(8 rats)and modeling groups(24 rats)using a random number table method.A model of skeletal muscle overuse injury was induced in the modeling group using downhill running centrifugal contraction exercise for 4 weeks.The successfully modeled rats were divided into a model group,a massage group,and a Yunnan Baiyao Aerosol group,with 8 rats in each group.The 4 groups of rats were subjucted to balance beam test.After 24 h of completing the modeling,the massage group was treated with a self-made massager,while the Yunnan Baiyao Aerosol group was treated with Yunnan Baiyao Aerosol twice a day for 3 consecutive days.Twenty-four hours after the end of treatment,the four groups of rats underwent behavioral evaluation again using the beam balance test.Hematoxylin-eosin staining was used to observe damage to the gastrocnemius muscle.The enzyme-linked immunosorbent assay was used to measure the concentrations of tumor necrosis factor-α(TNF-α),interleukin-6(IL-6),and 5-hydroxytryptamine(5-HT)in plasma.Western blotting was used to detect the protein expression levels of phosphorylated p38 mitogen-activated protein kinase(p-p38 MAPK),phosphorylated c-Jun N-terminal kinase(p-JNK),and phosphorylated extracellular signal-regulated kinase 1/2(p-ERK1/2)proteins in the MAPK signaling pathway.Results Before treatment,compared to the blank group,the rats in the model group,massage group,and Yunnan Baiyao Aerosol group had a longer walking time on the balance beam and a higher number of sliding claws(P<0.05).After treatment,compared with the blank group,the model group showed longer walking time on the balance beam,increased number of sliding claws,significant infiltration of inflammatory cells in gastrocnemius muscle,increased levels of TNF-α,IL-6,5-HT,and p-p38 MAPK,p-JNK,and p-ERK1/2(P<0.05).Compared to the model group,the walking time of the balance beam in the massage group was shortened,the number of sliding claws was reduced,the number of inflammatory cells was reduced,TNF-α,IL-6,and 5-HT indices decreased,and p-p38 MAPK,p-JNK,p-ERK1/2 indices decreased(P<0.05).The Yunnan Baiyao Aerosol group showed a decrease in the number of sliding claws,fewer inflammatory cells,reduced IL-6 levels,and decreased p-JNK and p-ERK1/2(P<0.05).Compared to the massage group,the Yunnan Baiyao Aerosol group had more inflammatory cells,increased IL-6 levels,and elevated p-JNK and p-ERK1/2 levels(P<0.05).Conclusion Massage can improve chronic skeletal muscle fatigue injury,and its mechanism of action may be through inhibiting the MAPK signaling pathway,downregulating the p-ERK1/2,p-p38 MAPK,and p-JNK proteins in this pathway,indirectly affecting the release of inflammatory factors,thus reducing skeletal muscle cell damage,inhibiting the release of inflammatory mediators,and promoting skeletal muscle repair.

Objective:To explore the effectiveness, safety and cost between urinary follicle stimulating hormone (uFSH) and recombinant follicle stimulating hormone (rFSH) in controlled ovarian stimulation (COS) in China.Methods:Data were collected from 16 reproductive centers in China covering oocytes collection time from May 1, 2015 to June 30, 2018. Eligible patients were over 18 years old, adopting COS with uFSH (uFSH group) or rFSH (rFSH group) as start gonadotropins (Gn), and using in vitro fertilization (IVF) and (or) intracytoplasmic sperm injection for fertilisation, excluding frozen embryo recovery cycle. Generalised estimating equation was used to address the violation of independency assumption between cycles due to multiple IVF cycles for one person and clustering nature of cycles carried out within one center. Controlling variables included age, body mass index, anti-Müllerian hormone level, cause of infertility, ovulation protocol, type of fertilisation, number of embryos transferred, number of days of Gn use.Results:Totally 102 061 cycles met eligibility criteria and were included in the analyses. In terms of effectiveness, after controlling relevant unbalanced baseline characteristics, compared with rFSH group, the high oocyte retrieval (>15 oocytes was considered high retrieval) rate of uFSH group significantly decreased in gonadotropin-releasing hormone agonist protocol ( OR=0.642, P<0.01) and in gonadotropin-releasing hormone antagonist protocol ( OR=0.556, P=0.001), but the clinical pregnancy rate per transfer cycle and the live birth rate per transfer cycle significantly increased ( OR=1.179, OR=1.169, both P<0.01) in both agonist and antagonist protocols. For safety, multiple analysis result demonstrated that in the agonist protocol, compared with rFSH group, the incidence of moderate to severe ovarian hyperstimulation syndrome of uFSH group significantly decreased ( OR=0.644, P=0.002). The differences in ectopic pregnancy rate and multiple pregnancy rate between the uFSH and rFSH groups were not significant ( P=0.890, P=0.470) in all patients. In terms of cost, compared with rFSH group, the uFSH group had lower total Gn costs for each patient ( P<0.01). Conclusion:For patients who underwent COS, uFSH has better safety, and economic profiles over rFSH in China.

Objective:To study the clinical characteristics of children with adenovirus pneumonia complicated with liver injury and the understanding of clinicians.Methods:The children diagnosed with community-acquired adenovirus pneumonia were enrolled from January 1, 2013 to December 31, 2020. The clinical characteristics of the normal liver function group and the liver injured group were compared, and multivariate regression was applied.Results:Among the 3 294 enrolled children, 1 704 children had elevated alanine aminotransferase and/or aspartate aminotransferase on admission, and the liver function impairment rate was 51.7% (1 704/3 294), of which 1 671 cases were mildly injured (98.06%, 1 671/1 704), 28 cases were moderately injured (1.64%, 28/1 704), and 5 cases were severely injured (0.29%, 5/1 704). Compared with the normal liver function group, the proportion of male children in the liver injured group was higher (68.1% vs. 64.2%, P=0.017), and the age was younger[16(9, 30) months vs. 38(19, 53) months, P<0.001]. Children with liver injury were more likely to have wheezing (32.9% vs. 18.7%, P<0.001), shortness of breath (13.7% vs. 9.1%, P<0.001), and diarrhea (11.0% vs. 4.7%, P<0.001). The white blood cell counts, neutrophil counts and hemoglobin in the liver injured group were lower than those in the normal group, while the lymphocyte counts were higher than those in the normal group. The levels of creatine kinase, cardiac creatine kinase and lactate dehydrogenase were higher. The proportion of severe pneumonia in the liver injured group (26.9% vs. 11.2%, P<0.001) was higher than that in the normal liver function group, and the case fatality rate was significantly higher (1.47% vs. 0.25%, P<0.001). Comparing the probability of liver injury in children with mild and severe adenovirus pneumonia, it was found that the severe pneumonia group had more frequent liver injury (73.0% vs 46.6%, P<0.001), and both moderate and severe liver injury groups were higher than in the mild group. Further multivariate logistic regression analysis did not find a significant factor associated with the incidence of liver injury. Conclusions:The incidence of adenovirus pneumonia in children with liver injury was high, and mild injury is more common. Children with liver injury were younger, had more severe clinical symptoms such as wheezing and shortness of breath, and higher proportion of severe pneumonia and mortality. Among them, children with severe pneumonia had a higher proportion of liver injury, and moderate to severe injury was more common. The monitoring of children with different degrees of liver injury should be strengthened.

This paper reports 3 cases of acute hepatitis of unknown cause in children who met the case definition of WHO. Human adenovirus group C was detected in case 3, and the quantity of viral DNA was relatively high, which may be related to the liver function damage in the patient, but its role in pathogenesis needs further study to confirm.

Objective:To analyze the effects of noise exposure on the hearing at different frequencies in workers from the automobile manufacturing industry.Methods:A total of 4723 noise workers in a large automobile manufacturing company in Guangzhou were chosen as the research object by using judgment sampling method between April and July, 2018, and carried out 0.5, 1.0, 2.0, 3.0, 4.0 and 6.0 kHz pure tone audiometry threshold to analyze the characteristics of the status of hearing loss at different frequencies and its relationship with the noise exposure time.Results:The detection rate of hearing loss in noise-exposed workers was 29.8% (1406/4723) . Among them, the binaural hearing loss was 21.2% (999/4723) , and single unilateral hearing loss accounted for 8.6% (407/4723) . The hearing loss detection rate of right ear was higher than that of the left ear ( P<0.05) , especially in the 6.0 kHz ( P<0.001) . The detection rate of increased speech frequency hearing threshold was 1.9% (90/4723) , and the detection rate of increased high-frequency hearing threshold was 28.9% (1366/4723) . The detection rate of increased threshold in both the left and the right ear increased with the increase of frequency ( P<0.001) , the increased hearing threshold was the highest at the frequency of 6.0 kHz. The auditory threshold of left ear in 0.5 kHz were higher than that of right ear at the same frequency ( P<0.05) . The detection rate of hearing loss increased with the increase of noise exposure time ( P<0.001) , and the increased threshold of 3.0, 4.0 and 6.0 kHz from workers increased with the increase of noise exposure time ( P<0.001) . Conclusion:There is a significant increased threshold in workers exposed to noise frequency of 6.0 kHz, right ear is more easily damaged than left ear, there is a dose-response relationship for the noise exposure time and high-frequency hearing loss.

Objective:To analyze the effects of noise exposure on the hearing at different frequencies in workers from the automobile manufacturing industry.Methods:A total of 4723 noise workers in a large automobile manufacturing company in Guangzhou were chosen as the research object by using judgment sampling method between April and July, 2018, and carried out 0.5, 1.0, 2.0, 3.0, 4.0 and 6.0 kHz pure tone audiometry threshold to analyze the characteristics of the status of hearing loss at different frequencies and its relationship with the noise exposure time.Results:The detection rate of hearing loss in noise-exposed workers was 29.8% (1406/4723) . Among them, the binaural hearing loss was 21.2% (999/4723) , and single unilateral hearing loss accounted for 8.6% (407/4723) . The hearing loss detection rate of right ear was higher than that of the left ear ( P<0.05) , especially in the 6.0 kHz ( P<0.001) . The detection rate of increased speech frequency hearing threshold was 1.9% (90/4723) , and the detection rate of increased high-frequency hearing threshold was 28.9% (1366/4723) . The detection rate of increased threshold in both the left and the right ear increased with the increase of frequency ( P<0.001) , the increased hearing threshold was the highest at the frequency of 6.0 kHz. The auditory threshold of left ear in 0.5 kHz were higher than that of right ear at the same frequency ( P<0.05) . The detection rate of hearing loss increased with the increase of noise exposure time ( P<0.001) , and the increased threshold of 3.0, 4.0 and 6.0 kHz from workers increased with the increase of noise exposure time ( P<0.001) . Conclusion:There is a significant increased threshold in workers exposed to noise frequency of 6.0 kHz, right ear is more easily damaged than left ear, there is a dose-response relationship for the noise exposure time and high-frequency hearing loss.