Chemical reference material(CRM)is an important material basis in the process of chemical drug research and development and quality control.This paper introduces the definition and classification of CRMs;the domestic and international regulations and guidelines for the research and development,production,management and use of CRMs by pharmaceutical companies and authoritative CRM issuing organizations;the common preparation methods and key technologies of CRM raw materials;and the technical requirements for the selection of raw materials for different types of CRMs.In addition,this paper also introduces the routine development process and data requirements for the candidate raw material to become a CRM after chemical structure verification,physical and chemical property analysis,homogeneity assessment,stability monitoring,and assignment.It also introduces the classical assignment method,mass balance method,in detail,to provide users of CRMs and the developers of new drugs with some technical references related to the development,application and management of CRMs in China.

Objective:This study aimed to compare the audiological characteristics between children with unilateral auditory neuropathy (UAN) and single-sided deafness (SSD) to establish a valid basis for the differential diagnosis of children with UAN.Methods:A retrospective analysis was conducted on audiological and imaging evaluations of children with UAN and SSD who were treated at Beijing Children′s Hospital of Capital Medical University between May 2015 and June 2023. There were 17 children with UAN, comprising 10 males and 7 females, with an average age of 4.7 years. Additionally, there were 43 children with SSD, consisting of 27 males and 16 females, with an average age of 6.5 years. Audiological assessments included Auditory brainstem response (ABR), Steady-state auditory evoked potential (ASSR), Behavioural audiometry, Cochlear microphonic potential (CM), Distortino-product otoacoustic emission (DPOAE), and acoustic immittance test. The results of the audiological assessment and imaging phenotypic between the two groups of children were compared and analyzed by applying SPSS 27.0 statistical software.Results:(1) The UAN group (77.8%) had a significantly higher rate of ABR wave III L than the SSD group (20.9%) ( P<0.01). The PA thresholds at 500 Hz and 1 000 Hz of children with SSD were higher than those of children with UAN, while the ASSR thresholds at 500 Hz, 1000 Hz, 2 000 Hz, and 4 000 Hz of children with SSD were significantly higher than those of children with UAN ( P<0.05). (2) The degree of hearing loss in both UAN and SSD children was predominantly complete hearing loss. The percentage of complete hearing loss was significantly higher (χ2=4.353, P=0.037) in the SSD group (93.0%, 40/43) than in the UAN group (63.6%, 7/11). However, the percentage of profound hearing loss was significantly higher in the UAN group (27.3%, 3/11) than in the SSD group (2.3%, 1/43) ( Fisher′s exact test, P=0.023). In terms of hearing curve configuration, the percentage of flat type was significantly higher in the SSD group (76.7%, 33/43) than in the UAN group (36.4%, 4/11). The proportion of the UAN group (27.3%, 3/11) was significantly higher than that in the SSD group (2.3%, 1/43) in ascending type ( P<0.05). There were no statistically significant differences in the hearing curves of the declining type and other types between the two groups ( P>0.05). (3) The proportion of imaging assessment without abnormality was significantly more common in the UAN group (81.8%) than in the SSD group (37.1%) (χ2=6.695, P=0.015). Conclusions:Compared to children with SSD, the occurrence of wave III L on the ABR test was significantly more common in children with UAN. The percentage of ascending hearing curves was significantly higher in children with UAN than in children with SSD. ASSR thresholds were significantly lower in children with UAN. The normal imaging phenotype was significantly more common in children with UAN than in children with SSD.

Objective To investigate the effect of auditory brainstem response(ABR)in clinical detection and severity assessment of autism spectrum disorder(ASD)in children with normal hearing.Methods ① A total of 55 autistic children(110 ears)with normal hearing and 55 children(110 ears)with typical development(TD)who did not differ in sex composition ratio and average monthly age were divided into four sub-groups according to age:≤24 months group(22 ears),25～36 months group(40 ears),37～48 months group(28 ears)and＞48 months group(20 ears).The ABR latencies and interpeak latencies were compared between ASD children and age-matched TD children.② ASD children were graded by severity according to the Diagnostic and Statistical Manual of Mental Dis-orders(DSM-V),and the correlations between the ABR latencies and interpeak latencies in autistic children with normal hearing and the severity grading were studied.Results ① No statistically significant differences in ABR wave latencies and interpeak latencies were found in autistic children with normal hearing under 24 months of age compared to age-matched TD children(P＞0.05).② Compared with children with TD,autistic children with nor-mal hearing at 25～36 months of age had significantly longer wave Ⅲ latencies and the interpeak latencies of Ⅰ-Ⅲ andⅠ-Ⅴ;the significantly longer wave Ⅲ,Ⅴ latencies,the interpeak latencies of Ⅰ-Ⅲ,Ⅲ-Ⅴ and Ⅰ-Ⅴ in autistic chil-dren with normal hearing at 37～48 months of age.Autistic children with normal hearing in the＞48 months group had significantly longer wave Ⅴ latencies and interpeak latencies of Ⅲ-Ⅴ,Ⅰ-Ⅴ than age-matched TD children(P＜0.05).③ The higher the ASD severity grading the longer the wave Ⅲ and V latencies and the longer interpeak latencies of Ⅰ-Ⅲ,Ⅲ-Ⅴ,and Ⅰ-Ⅴ(P＜0.05).Conclusion Differences in the level of auditory brainstem pathway de-velopment emerged at 25 months of age,and autistic children with normal hearing had significantly lower levels of auditory brainstem development than age-matched TD children.There were correlations between the latencies and interpeak latencies of ABR in autistic children with normal hearing and the severity grading.

Objective:To investigate the correlation between macular cherry red spot (CS) and severity of neurological manifestations in Chinese children with sialidosis (SD) type I.Methods:A evidence-based medical study. "China", "Sialidosis" and "Sialidoses" were used as Chinese and English search terms. The literature was searched in CNKI, Wanfang and PubMed. The cases were all from China and matched the diagnostic criteria. According to the presence or absence of CS in the fundus, the SD children were divided into a group with CS (+) and a group without CS (-), and the correlation between the occurrence of ocular CS and neurological manifestations was compared with meta-analysis by RevMan 5.3 software.Results:Sixty-eight studies were initially retrieved according to the search strategy, and 17 studies were finally included, and 5 studies with CS+ and CS- were meta-analyzed. Among the 43 patients, 28 were male and 15 were female, with a median age of 12 years. Visual impairment was observed in 37 cases (90.2%, 37/41, 2 cases not recorded), and CS was present in 24 cases (55.8%, 24/43). The most common neurological manifestation was myoclonus (97.7%, 42/43), followed by cerebellar ataxia (95.1%, 39/41, 2 cases not recorded) and seizures (91.4%, 32/35, 8 cases not recorded). Pathogenic NEU1 gene mutations were detected in 42 cases and one case was undocumented. The incidence of seizure in group CS+ (100%, 20/20) was higher than that in group CS- (80%, 12/15). Meta-analysis showed that there was no statistically significant difference between the incidence of myoclonus or ataxia [relative risk ( RR)=1.13, 95% confidence interval ( CI) 0.79-1.63, P=0.49] and seizure ( RR=1.13, 95% CI 0.84-2.06, P=0.24) among the children in the CS+ and CS- groups. Conclusions:The incidence of ocular CS in Chinese children with type I SD was 55.8%. There was no correlation with neurological manifestations, however the incidence of seizure was significantly higher in patients with CS than in others without CS.

Objective:To observe the clinical features of eyes in children with methylmalonic acidemia (MMA).Methods:A retrospective clinical case study. From June 2019 to June 2022, 13 children with MMA visited on the Department of Ophthalmology of Henan Children's Hospital were included in the study. The anterior segment and fundus were examined under surface or general anesthesia. Best corrected visual acuity (BCVA) and refraction were performed in 9 cases; fluorescein fundus angiography (FFA) was performed in 3 cases; flash electroretinogram (FERG) was performed in 6 cases; flash visual evoked potential (FVEP) was detected in 6 cases; optical coherence tomography (OCT) was performed in 3 cases.Results:Among the 13 pediatric patients with methylmalonic acidemia, 6 cases were male and 7 cases were female. The average age at first visit was 45 months. All cases suffered from hyperhomocysteinemia; 9 cases were with epilepsy; 2 cases were with infantile spasms; 11 cases were with stunting, 13 cases were with repeated pulmonary infection during growth period; 4 cases were with hydrocephalus; 1 cases was with hypertension and renal insufficiency. Genetic dectection results of 8 cases were recorded, MMACHC:c.609G>A:p.W203* mutation site was found in all cases. One case was accompanied by corneal ulcer. There were 10 cases with nystagmus, 4 cases with macular degeneration, 3 cases with hyperopic refractive error and esotropia. Nine cases underwent BCVA examination, BCVA was light perception-0.6. In OCT, 2 cases of 3 cases showed retinal thinning and photoreceptor cell layer atrophy in the macular area. In FFA, 2 cases of 3 cases showed circular transparent fluorescence in the macular area. Five cases of 6 cases who with FVEP had different degrees of P100 peak time delay and decreased amplitude, and 4 cases of 6 cases with FERG had decrease of a and b wave in light and dark adaptation. Conclusions:The clinical phenotypes of eyes in children with MMA are various and the severity was different; most of them are accompanied by nystagmus, and the fundus lesions are common in the characteristic bovine eye like macular region. Those with macular disease have severe visual impairment.

Backgrounds::GALLIUM is a global phase III study that demonstrated significant improvements in progression-free survival (PFS) for obinutuzumab plus chemotherapy (G-chemo) vs. rituximab plus chemotherapy (R-chemo) in previously untreated patients with follicular lymphoma (FL). This study aimed to report the results of a subgroup of patients in China. Methods::Patients were randomized to G-chemo or R-chemo. Responders received maintenance therapy for 2 years or until disease progression. The primary endpoint was investigator (INV)-assessed PFS. Secondary endpoints included the overall response rate (ORR) and complete response rate (CRR) at the end of induction chemotherapy, overall survival (OS), and safety.Results::Overall, 58 patients with FL were randomized to the G-chemo ( n = 25) and R-chemo arms ( n = 33). The INV-assessed PFS rate at 3 years was 81.8% in the G-chemo arm, vs. 70.2% in the R-chemo arm (hazard ratio 0.35; 95% confidence interval: 0.09-1.34; P = 0.1120). The INV-assessed CRRs (without positron emission tomography [PET]) in these arms were 24.0% and 21.2%, respectively, whereas the ORRs were 80.0% and 90.9%, respectively. INV-assessed CRR-PET was 52.6% in the G-chemo, vs. 60.9% in the R-chemo. Median OS was not reached in either arm. Grade 3 to 5 adverse events were more frequent in the R-chemo arm (97.0% vs. 88.0%). Conclusions::The results of this subgroup analysis were consistent with those of the global population, and they suggest that G-chemo has a positive benefit-risk profile in patients from China with FL.Trial registration::ClinicalTrials.gov, No. NCT01332968.

Objective To identify the effectiveness of physical therapy on neuromuscular control dysfunction of chronic ankle instability (CAI). Methods CAI physiotherapy-related systematic reviews, meta-analysis, randomized controlled studies and case-controlled studies were systematically searched in PubMed, Web of Science, Cochrane, PEDro, EBSCO and CNKI from October 1st, 2010 to October 1st, 2020. After quality assessment, the research evidence regarding certain intervention was then graded according to the Oxford Center for Evidence-based Medicine. Results A total of 20 articles were included. Intervention based on unstable plane exercise training could significantly improve lower limb balance control ability (Ⅰ A) and muscle strength (Ⅱ A) for CAI patients. The efficiency of exercise-based intervention could be further raised (Ⅱ C) with the aid of external equipment, but either the benefits in muscle reaction (Ⅲ C) or proprioception (Ⅱ D) was limited. Six sessions or more of manual therapy could be used to enhance the balance ability of the lower limbs (Ⅱ B), while taping failed to provide improvements in ankle proprioception in short period or immediately (Ⅰ A). Conclusion Unstable plane training-based therapeutic exercise and manual therapy could effectively enhance the neuromuscular control with high-quality evidence supporting, which can be primary interventions for CAI patients. Meanwhile, taping and other external devices could be used as adjunct methods to improve the efficiency of physiotherapy program, while there is currently no evidence to support the application of modality treatment in neuromuscular control of CAI.

ObjectiveTo investigate the tolerance, pharmacokinetics, and antiviral activity of coblopasvir hydrochloride capsules in patients with hepatitis C. MethodsA total of 36 patients with hepatitis C who were admitted to The First Hospital of Jilin University from November 2016 to January 2017 were enrolled as subjects, and four dose groups (30 mg, 60 mg, 90 mg, and 120 mg) and one placebo group were established. The subjects were administered once daily for 3 consecutive days; tolerance was evaluated on D2 and D6, and follow-up was performed on D8 and D10. The subjects were enrolled based on single dose escalation, and a multiple-dose study was conducted under the premise of good tolerance to single dose. Liquid chromatography-tandem mass spectrometry was used to measure the plasma concentration of coblopasvir hydrochloride in human body, and WinNonlin 6.4 software was used to calculate main pharmacokinetic parameters. HCV RNA load was used to evaluate antiviral activity at different time points; a one-way analysis of variance was used for comparison between multiple groups, and the LSD t-test was used for further comparison between two groups. ResultsAfter coblopasvir hydrochloride capsules were administered orally once a day at a dose of 30-120 mg, the plasma concentration and exposure of coblopasvir hydrochloride increased with the increase in dose. There were no significant differences in plasma concentration and exposure between multiple-dose administration and single-dose administration in a fasting state, without accumulation in human body. After the oral administration of coblopasvir hydrochloride capsules once a day, the subjects with HCV genotype 1b had a reduction in HCV RNA load since baseline, with the lowest level at 120 hours, and there was a significant difference in antiviral activity between different dose groups (F=14.621, P＜0.000 1), among which the 60 mg group had a significantly greater reduction than the 30 mg group (P=0.025), while there was no significant difference between the 60 mg group and the 90/120 mg group (P＞0.05). There was no significant difference in HCV RNA load between different groups of patients with HCV genotype 2a (P＞0.05). Of all 36 subjects, 20 reported 34 cases of treatment-emergent adverse events, among which 19 cases were associated with coblopasvir hydrochloride, and no significant adverse events or serious adverse events were observed. ConclusionOral administration of coblopasvir hydrochloride capsules in a fasting state at a dose of 30-120 mg/d (for 3 consecutive days) has good safety and antiviral activity. Therefore, it has good application prospect in the treatment of HCV infection and provides a basis for dose selection in phrase 2 study.

Objective:To observe and analyze the clinical characteristics and correlation between the eye and nervous system in children with infantile gangliosideosis.Methods:From November 2018 to January 2021, 3 children with infantile ganglion lipidosis diagnosed by genetic examination in the Department of Ophthalmology and Neurology, Beijing Children's Hospital of Capital Medical University, and through China National Knowledge Infrastructure and Wanfang database and The National Library of Medicine of the United States (PubMed) were searched, and 53 cases of Chinese infantile gangliosideosis diagnosed by gene, enzyme activity or pathological examination were selected and a total of 56 cases were included in the study. The searching time was from the establishment of the database to February 2021, and the search keywords are"gangliosideosis", "cherry-spot" macula and "Chinese". The demographic characteristics of 56 cases of children and other system manifestations were analyzed such as eyes, nervous system, skin, bones. According to the presence or absence of cherry-spot (CS) on the fundus examination, the children were divided into a fundus CS group (group A) and a fundus without CS group (group B), with 20 and 27 cases, respectively. The age of onset, gender, different types and neurological manifestations of the two groups of children were compared and analyzed. The non-parametric rank sum test was used for age comparison between groups; the χ2 test or Fisher's exact test were used for the comparison of gender, disease type and incidence between groups. Results:Among the 56 children, 27 were males and 29 were females; the median age of onset was 7.0 months. There were 33 and 23 cases of GM1 and GM2, respectively. Among 44 children with visual function examination records, 41 cases (93.2%, 41/44) were unable to follow the visual object. Of 47 children who underwent ocular fundus examination, 20 cases (42.6%, 20/47) had CS on the fundus. The main manifestations of the nervous system are neuromotor development regression or retardation (100%, 56/56), convulsions (58.1%, 25/43), and "startle" phenomena (89.7%, 26/29). Among 42 patients with brain magnetic resonance imaging examination records, 39 cases (92.9%) were abnormal. The incidence of "startle" and seizures in group A was higher than that in group B, and the difference was statistically significant ( χ2=5.815, 6.182, P=0.021, 0.013). Conclusios:Chinese infantile gangliosideosis is more common in GM1 type. Ocular visual impairment is the visual object as the main manifestation, the incidence of fundus CS is 42.6%, and the symptoms of neurological damage in children with CS are more severe.

Objective:To analyze the characteristics and prognosis of hearing loss in children with bacterial meningitis.Methods:This was a single-center retrospective cohort study. Patients diagnosed with bacterial meningitis who were hospitalized in Beijing Children′s Hospital between 2010 and 2016 and older than 28 days and younger than 18 years at symptom onset were included in this study ( n=573). All clinical information including hearing assessment results during hospitalization were reviewed. All patients with hearing loss were followed up to repeat their hearing test and assess their hearing condition with parents′ evaluation of aural and (or) oral performance of children (PEACH). Patients were grouped according to their hearing assessment results, and Logistic regression analysis was used to analyze the risk factors for hearing loss in patients with bacterial meningitis. Results:Five hundred and seventy-three patients were enrolled in this study, including 347 males and 226 females. The onset age ranged from 29 days to 15.8 years. Two hundred and forty-six patients had identified causative pathogens, among whom 92 cases (37.4%) were pneumococcal meningitis cases. Hearing loss was found in 160 cases (27.9%) during hospitalization, involving 240 ears. Permanent hearing loss was found in 20 cases (16.9%), involving 32 ears. In the patients with permanent hearing loss, 87.5% (28/32) of ears were identified as severe or profound hearing loss during hospitalization. Logistic regression analysis showed that dystonia, the protein concentration level in cerebrospinal fluid>1 g/L, glucose concentration level lower than 1 mmol/L and subdural effusion were independent risk factors for hearing loss ( OR=2.426 (1.450-4.059), 1.865 (1.186-2.932), 1.544 (1.002-2.381) and 1.904 (1.291-2.809)). Conclusions:Hearing loss is a common sequela of bacterial meningitis in children. Most patients have transient hearing loss, but patients with severe or profound hearing impairment have a higher risk of developing permanent hearing loss.