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 investigate the association of various polycyclic aromatic hydrocarbon (PAH) metabolites with diverse subtypes of cardiovascular disease (CVD) risk. METHODS: A novel predicting risk of cardiovascular disease EVENTs PREVENT equation was used to estimate the 10-year diverse subtypes of CVD risk, and their associations with PAH metabolites were analyzed using multiple logistic regression models, the weighted quantile sum (WQS) model, the quantile g-computation (qgcomp) model, and a stratified analysis of subgroups. RESULTS: For this study, six thousand seven hundred and forty-five participants were selected, and significant positive associations were observed between PAHs, naphthalene (NAP), and fluorene (FLU), and the risks of total CVD, atherosclerotic cardiovascular disease (ASCVD), and heart failure (HF). NAP and FLU were the primary contributors to the effects of PAH mixtures, and their associations with total CVD, ASCVD, and HF risk were significant in younger participants (30 ≤ age < 50 years); however, the associations of phenanthrene (PHEN) with ASCVD, HF, coronary heart disease (CHD), and stroke were dominant in aging participants (age ≥ 50 years). Notably, pyrene (PYR) was negatively associated with the risk of ASCVD, HF, CHD, and stroke. Similarly, negative associations of PYR with the four CVD subtypes were noticeable in aging participants. CONCLUSION Different PAHs metabolites had different impacts on each CVD subtype among different age groups. Notably, the protective effects of PYR on ASCVD, HF, CHD, and stroke were noticeable in aging individuals.
Humans ; Cardiovascular Diseases/chemically induced* ; Middle Aged ; Polycyclic Aromatic Hydrocarbons/metabolism* ; Male ; Female ; Adult ; Aged ; Risk Factors ; China/epidemiology*

Objective:To identify the gene mutation types of 4 suspected β-thalassemia patients in Yunnan Province,and to analyze the genotypes and hematological phenotypes.Methods:Whole genome sequencing was performed on the samples of 4 suspected β-thalassemia patients from the Dai ethnic group in a thalassemia endemic area of Yunnan Province,whose hematological phenotypes were not consistent with the results of common thalassemia gene mutations.The mutations of β-globin gene clusters were confirmed by polymerase chain reaction(PCR)and Sanger DNA sequencing technology.Results:The 3.5 kb deletion in β-globin gene cluster(NC_000011.10:g.5224302-5227791 del3490bp)was detected in 4 patients'samples,of which 1 case was also detected with HbE mutation and 1 case with CD17 mutation.These 2 patients displayed moderate anemia phenotype,while the two patients with only the 3.5 kb deletion presented with other mild anemia phenotype.Conclusion:Heterozygous carriers with rare 3.5 kb deletion of the β-globin gene cluster may develop mild anemia,compound mutations of the 3.5 kb deletion with other mutations may led to intermediate thalasemia with moderate to sever anemia.In areas with a high incidence of thalassemia,suspected patients should undergo genetic testing to avoid missing or misdiagnosing rare mutations.

Objective:To explore the application selection of preputial circular flap pedicle in the treatment of complex long segment urethral stricture.Methods:The data of 11 patients who underwent surgical reconstruction of the urethra for complex long segment urethral stricture between October 2019 and November 2022 in Xinhua Hospital Affiliated to Shanghai Jiaotong University, School of Medicine were retrospectively analyzed. The patients’ average age was 46(range 40-66) years old, with average urethral stricture length of 7 (range 6-13) cm and average maximum preoperative urinary flow rate of 5 (range 3-7) ml/s. They had a history of recurrent urinary tract infections and endoscopic treatment for urinary tract stones. Among the 11 cases, one patient had necrotizing fasciitis of the scrotum with complete destruction and loss of the scrotal urethra. This patient received acute bladder diversion, surgical debridement, vacuum sealing drainage, and negative pressure suction during the acute phase. And six months later, a circular preputial pedicle flap was used to reconstruct a 12 cm urethral defect in the scrotal region. The remaining 10 patients underwent preputial circular flap pedicle onlay urethral reconstruction. The changes in the patient's maximum urinary flow rate, and the signs of restenosis, urinary fistula, or urethral diverticulum were analyzed.Results:All 11 patients who underwent preputial circular flap pedicle urethral reconstruction had unobstructed urination after surgery. Surgical time ranged from 96 to 246 min, with an average of 121 min. The intraoperative blood loss ranged from 10 to 200 ml, with an average of 46 ml. The hospital stay ranged from 6 to 13 d, with an average of 9 d. The indwelling catheterisation time ranged from 18 to 28 d, with an average of 20 d. The patients were followed-up for 9 to 32 months, with an average of 24 months. All 11 cases had smooth urinary flow after surgery, and the maximum urinary flow rate ranged from 16.1 to 24.2 ml/s, with an average of 17.6 ml/s, which was significantly higher than that before surgery. Two patients had post-void dribbling after four weeks, and imaging showed the formation of a diverticulum in the reconstructed segment of the urethra.Conclusions:Urethral reconstruction with preputial circular flap pedicle is a viable treatment option for complex long segment urethral stricture. The surgical outcomes are satisfactory, and the choice of treatment should be based on the patient's own conditions and the surgeon's technical expertise.

Objective:To investigate the efficacy and safety of acute stent implantation during endovascular treatment for patients with emergent large vessel occlusion due to intracranial atherosclerotic stenosis.Methods:A retrospective analysis was carried out on 46 patients with emergent large vessel occlusion due to intracranial atherosclerotic stenosis who received endovascular treatment at the Strategic Support Force Medical Center from January 2015 to August 2022. Twenty-seven patients underwent balloon angioplasty alone and 19 patients underwent acute stent implantation. The baseline characteristics, modified thrombolysis in cerebral infarction (mTICI) score of the responsible vessels, modified Rankin scale (mRS) score 90 days after operation, incidence of symptomatic intracranial hemorrhage and mortality of the two groups were evaluated.Results:The proportion of effective recanalization of the offending vessels (mTICI≥2b) in the acute stenting group was slightly higher than that in the balloon angioplasty group (16/19 vs. 81.5%), but the difference was not statistically significant ( P>0.05). Besides, there was no significant difference in the median of mRS between the acute stenting group [3.0(0, 4.0)] and the balloon angioplasty group [4.0(1.0, 5.0)] 90 days after operation ( P>0.05). In terms of safety, the incidence of symptomatic intracranial hemorrhage and mortality were comparable between the two groups ( P>0.05). Conclusions:The effect of acute stent implantation during endovascular treatment for patients with emergent large vessel occlusion due to intracranial atherosclerotic stenosis is not inferior to that of balloon angioplasty, and it does not increase the risk of intracranial bleeding complications.

Clinical cases of necrotizing fasciitis and complete urethral defects in the scrotal region are rare. The diagnosis and treatment are very challenging. This article reports one case. The patient was admitted to the hospital after 1 week of poor urination and 2 days of scrotal swelling, and then underwent bladder diversion, surgical debridement, vacuum-sealing drainage, and wound closure. After four weeks, the wound healed and the patient was discharged. Six months later after surgery, scrotal urethral reconstruction was performed using a circular phimosis pedicled skin flap graft to repair the 12 cm urethral defect. The urethral catheter was removed after three weeks. The bladder fistula tube was removed after 5 weeks. During the follow-up of one year, there was no occurrence of urinary fistula and urinary obstruction.

Objective:To explore the application selection of preputial circular flap pedicle in the treatment of complex long segment urethral stricture.Methods:The data of 11 patients who underwent surgical reconstruction of the urethra for complex long segment urethral stricture between October 2019 and November 2022 in Xinhua Hospital Affiliated to Shanghai Jiaotong University, School of Medicine were retrospectively analyzed. The patients’ average age was 46(range 40-66) years old, with average urethral stricture length of 7 (range 6-13) cm and average maximum preoperative urinary flow rate of 5 (range 3-7) ml/s. They had a history of recurrent urinary tract infections and endoscopic treatment for urinary tract stones. Among the 11 cases, one patient had necrotizing fasciitis of the scrotum with complete destruction and loss of the scrotal urethra. This patient received acute bladder diversion, surgical debridement, vacuum sealing drainage, and negative pressure suction during the acute phase. And six months later, a circular preputial pedicle flap was used to reconstruct a 12 cm urethral defect in the scrotal region. The remaining 10 patients underwent preputial circular flap pedicle onlay urethral reconstruction. The changes in the patient's maximum urinary flow rate, and the signs of restenosis, urinary fistula, or urethral diverticulum were analyzed.Results:All 11 patients who underwent preputial circular flap pedicle urethral reconstruction had unobstructed urination after surgery. Surgical time ranged from 96 to 246 min, with an average of 121 min. The intraoperative blood loss ranged from 10 to 200 ml, with an average of 46 ml. The hospital stay ranged from 6 to 13 d, with an average of 9 d. The indwelling catheterisation time ranged from 18 to 28 d, with an average of 20 d. The patients were followed-up for 9 to 32 months, with an average of 24 months. All 11 cases had smooth urinary flow after surgery, and the maximum urinary flow rate ranged from 16.1 to 24.2 ml/s, with an average of 17.6 ml/s, which was significantly higher than that before surgery. Two patients had post-void dribbling after four weeks, and imaging showed the formation of a diverticulum in the reconstructed segment of the urethra.Conclusions:Urethral reconstruction with preputial circular flap pedicle is a viable treatment option for complex long segment urethral stricture. The surgical outcomes are satisfactory, and the choice of treatment should be based on the patient's own conditions and the surgeon's technical expertise.

Objective To investigate the improvement effect of 18kD translocator protein(TSPO)ligand YL-IPA08 on lipopolysaccharide(LPS)-induced depressive,anxiety-like behaviors and cognitive dysfunction in mice and the related anti-inflammatory mechanism.Methods(1)50 male C57BL/6J mice were randomly divided into control group,LPS model group,LPS+YL-IPA08(1.0 or 3.0 mg/kg)group and YL-IPA08(3.0 mg/kg)group,with 10 mice in each group.Mice in LPS model group were intraperitoneally injected with LPS(0.5 mg/kg)once on day 1 and day 8.Mice in LPS+YL-IPA08(1 or 3 mg/kg)and YL-IPA08(3.0 mg/kg)groups were intragastrically administered YL-IPA08(1.0 or 3.0 mg/kg)for 13 consecutive days,once a day.From the 9th to 12th day,the open field test,tail suspension test,forced swimming test,novel object recognition test and elevated-plus maze test were used to evaluate the depressive,anxiety-like behaviors and cognitive function of mice.Western blotting was used to detect the expression levels of postsynaptic density protein 95(PSD95)and brain-derived neurotrophic factor(BDNF)in the prefrontal cortex of mice.(2)BV2 mouse microglia cells were divided into control group(phosphate buffered saline incubation for 1 h),LPS model group(incubated with 1.0 mg/L LPS for 6 h),LPS+YL-IPA08(0.5 or 1.0 μmol/L)group(incubated with 0.5 or 1.0 μmol/L YL-IPA08 for 1 h and then incubated with 1 mg/L LPS for 6 h),and YL-IPA08 group(incubated with 1.0 μmol/L YL-IPA08 for 1 h).ELISA was used to detect the expression levels of inflammatory factors interleukin-1β(IL-1β),interferon-γ(IFN-γ),IL-4,IL-10 and transforming growth factor-β1(TGF-β1).Western blotting was used to detect the expression levels of the members of Smad protein family(Smad2,Smad3)mediating signal transduction of TGF-β.Results(1)The results of behavioral experiments showed that there was no significant difference in the total movement distance of mice in each group in the open field test(P>0.05).Compared with the control group,the number of entries and duration time in the central area of mice in LPS model group were significantly decreased(P<0.05);the immobility time in the tail suspension test and the forced swimming test was significantly prolonged(P<0.05);the recognition index in the novel object recognition test,the percentage of entries into the open arms and the percentage of duration time in the open arm in the elevated-plus maze test were significantly decreased(P<0.05),and the expression levels of PSD95 and BDNF in the prefrontal cortex were significantly decreased(P<0.05).Compared with LPS model group,above behavioral and expression changes in LPS+YL-IPA08(3.0 mg/kg)group were significantly reversed(P<0.05).(2)Compared with control group,the expression levels of pro-inflammatory factors IL-1β and IFN-γ in BV2 cells in LPS model group were significantly increased(P<0.05),and the expressions of anti-inflammatory factors IL-4,IL-10 and TGF-β1 were significantly decreased(P<0.05),and the expression levels of Smad2 and Smad3 were significantly decreased(P<0.05).Compared with LPS model group,the expression level of IFN-γ in BV2 cells in LPS+YL-IPA08(0.5 μmol/L)group was significantly decreased,and the expression levels of IL-4 and TGF-β1 were significantly increased(P<0.05);the above changes were significantly reversed in LPS+YL-IPA08(1.0 μmol/L)group(P<0.05).Conclusion YL-IPA08 can significantly attenuate LPS-induced depressive and anxiety-like behaviors in mice and alleviate the decline in cognitive dysfunction,which mechanism may be related to improving neuroinflammation and regulating the TGF-β/Smad pathway.