OBJECTIVE To determine the contents of N-nitroso impurities in raw materials/formulations of propranolol， metoprolol， atenolol， esmolol and bisoprolol， and clarify the attention threshold. METHODS Ultra-high performance liquid chromatography-quadrupole/electrostatic field orbitrap high-resolution mass spectrometry（UPLC-Q/Orbitrap HRMS）was adopted. An ACE Excel 3 C18-AR column was used for the separation and a mixture of 0.2% formic acid solution with 0.01 mol/L ammonium acetate and methanol was employed as the mobile phase by gradient elution， at a flow rate of 0.60 mL/min. The column temperature was set at 40 ℃ ， and the sample size was 5 μL. The heated electrospray ionization source was employed in the positive full mass spectra-selected ion monitoring mode. The contents of N-nitroso impurities in raw materials/formulations of 15 batches of β-blockers from 10 manufacturers were determined by this method. Discovery Studio software was applied to predict the toxicity of the impurities and estimate the attention threshold. RESULTS Among 5 kinds of β-blockers， the linear ranges of N-nitroso propranolol， N-nitroso metoprolol， N-nitroso atenolol， N-nitroso esmolol and N-nitroso bisoprolol were 1.01-503.38， 1.02-508.38， 0.97-483.63， 1.11-554.27 and 1.05-523.92 ng/mL， respectively （r＞0.999）. The limits of quantitation were 1.04， 0.25， 0.05， 0.55 and 1.05 ng/mL， and the limits of detection were 0.52， 0.08， 0.02， 0.17 and 0.52 ng/mL， respectively. RSDs of precision， reproducibility， recovery， stability and durability tests were all lower than 7.5% （n＝6 or n＝5）. Among the 15 batches of samples， except for 1 batch， N-nitroso propranolol （1.07-8.91 ng/mg）， N-nitroso metoprolol （1.43-3.37 ng/mg）， N-nitroso atenolol （1.33 ng/mg）， N-nitroso esmolol （0.19 ng/mg） and N-nitroso bisoprolol （1.27 ng/mg） were detected in all other batches. According to predictions， the above 5 impurities had varying degrees of reproductive toxicity， mutagenicity and carcinogenicity， with attention thresholds of 1.0， 0.4， 4.3， 0.2 and 46.7 ng/mg， respectively. CONCLUSIONS The established method is simple， rapid， sensitive and specific， the estimated attention thresholds are clear， which can be used for the control of N-nitroso impurities in various β-blockers.

Objective: To design the proficiency testing (PT) project (No. NIFDC-PT-183) for assays of bismuth potassium citrate capsules and organize to assess the proficiency of complexometric titration in laboratories, and provide some technical analyses and advices.
Methods: Two groups of samples with different concentration were prepared. The uniformity was evaluated with one-way analysis of variance and the stability was confirmed with t-test, whose results all conformed the requirements. The samples with three combinations were randomly distributed to 279 laboratories. The determination was performed according to the assays of bismuth potassium citrate capsules in Volume Ⅱ of the Chinese Pharmacopoeia 2015. The median value and normalized interquartile range (NIQR) of robust statistical analysis was adopted and Z-scores were used to evaluate the results from each of laboratories.
Results: Among 279 laboratories, 240 laboratories results were satisfactory, 23 were questionable, and the other 16 were unsatisfied. The satisfaction rate was 86.0%.
Conclusion: The overall capacity of national laboratories for assays of bismuth potassium citrate capsules is good while a portion of participants require further improvement.

Objective:To investigate the incidence and risk factors of coma in patients with hypoglycemia (≤3.9 mmol/L).Methods:A retrospective study was conducted. Patients aged 20 years and older with blood glucose levels ≤3.9 mmol/L, and measured by emergency physicians from January 2020 to December 2022 were collected. Baseline patient data, clinical values collected on-site, and treatment outcomes were analyzed. The Glasgow Coma Scale (GCS) was used to determine if patients were comatose, with GCS ≤8 classified as the coma group and GCS >8 as the non-coma group. Further analysis was conducted on the resuscitated coma group to identify factors affecting patient recovery. Patients were divided into eight age groups, seven time periods within 24 h, and six blood glucose level groups to calculate the incidence of coma. A multivariate logistic regression model was constructed to analyze independent risk factors for coma in hypoglycemic patients.Results:A total of 754 patients with blood glucose levels ≤3.9 mmol/L were collected, with 425 cases of coma and 329 non-coma cases, resulting in a coma probability of 56.37% (95% CI: 52.82%-59.91%). Patients in the coma group were older ( P<0.001) and had a higher prevalence of diabetes compared to the non-coma group (82.12% vs. 67.78%, P<0.001). The age of all patients was (73.05±15.20) years, with the 61-90 years age groups being the most prone to hypoglycemia and coma. In terms of time distribution, the high-incidence periods for hypoglycemia and coma were 0-6 o’clock, 6-9 o’clock, and 14-18 o’clock. The primary causes of hypoglycemia included reduced energy intake after insulin injection (12.07%), improper use of insulin (6.37%), and reduced energy intake (6.23%), with 71.09% of cases having unknown causes. Additionally, 18.44% of patients used insulin before the onset of hypoglycemia, with a higher proportion in the coma group compared to the non-coma group (22.12% vs. 13.68%, P=0.003). The initial blood glucose level of all patients was (2.13±0.85) mmol/L, with lower levels observed in the coma group compared to the non-coma group ( P<0.001). The probabilities of coma occurrence corresponding to blood glucose levels were: 1.1-1.5 mmol/L (72.97%), 1.6-2.0 mmol/L (68.90%), 2.1-2.5 mmol/L (54.10%), 2.6-3.0 mmol/L (38.20%), 3.1-3.5 mmol/L (37.50%), and 3.6-3.9 mmol/L (19.40%). Multivariate logistic regression analysis indicated that age ( OR=1.021, 95% CI: 1.010-1.033, P<0.001), insulin use before onset ( OR=1.948, 95% CI: 1.142-3.323, P=0.014), and blood glucose concentration ( OR=0.426, 95% CI: 0.347-0.522, P<0.001) were independent predictors of coma in hypoglycemic patients. The investigation revealed that after intravenous injection of 50% glucose solution, 215 of 425 coma patients regained consciousness (50.58%), and the recovery time was (18.43±9.09) min. Patients in the recovery group were younger and had lower initial blood glucose levels compared to the non-recovery group (both P<0.05), while recovery group re-measured blood glucose levels were higher than those in the non-recovery group ( P=0.002). Conclusions:The probability of coma in hypoglycemic patients was high, with insulin use being a common trigger. Proper use of insulin is essential to prevent hypoglycemia and coma.

We aimed to evaluate the effectiveness and safety of single-course initial regimens in patients with low-risk gestational trophoblastic neoplasia (GTN). In this trial (NCT01823315), 276 patients were analyzed. Patients were allocated to three initiated regimens: single-course methotrexate (MTX), single-course MTX + dactinomycin (ACTD), and multi-course MTX (control arm). The primary endpoint was the complete remission (CR) rate by initial drug(s). The primary CR rate was 64.4% with multi-course MTX in the control arm. For the single-course MTX arm, the CR rate was 35.8% by one course; it increased to 59.3% after subsequent multi-course MTX, with non-inferiority to the control (difference -5.1%,95% confidence interval (CI) -19.4% to 9.2%, P = 0.014). After further treatment with multi-course ACTD, the CR rate (93.3%) was similar to that of the control (95.2%, P = 0.577). For the single-course MTX + ACTD arm, the CR rate was 46.7% by one course, which increased to 89.1% after subsequent multi-course, with non-inferiority (difference 24.7%, 95% CI 12.8%-36.6%, P < 0.001) to the control. It was similar to the CR rate by MTX and further ACTD in the control arm (89.1% vs. 95.2%, P =0.135). Four patients experienced recurrence, with no death, during the 2-year follow-up. We demonstrated that chemotherapy initiation with single-course MTX may be an alternative regimen for patients with low-risk GTN.
Antineoplastic Combined Chemotherapy Protocols/adverse effects* ; Dactinomycin/adverse effects* ; Female ; Gestational Trophoblastic Disease/drug therapy* ; Humans ; Methotrexate/therapeutic use* ; Pregnancy ; Retrospective Studies

Objective:To observe the changes of macular visual function after myopic foveoschisis (MF) and pars plana vitrectomy (PPV) combined with internal limiting membrane peeling and air filling.Methods:A single-center, retrospective study. From October 2018 to October 2019, 29 MF inpatients (32 eyes) in Tianjin Eye Hospital were included in this study. There were 3 males (4 eyes) and 26 females (28 eyes). The age was 63.00±3.45 years old. Equivalent spherical lens degree was -14.16±2.54 D, and axial length was 29.14±1.04 mm. Among them, 3 patients (3 eyes) had lamellar macular holes. All eyes underwent standard pars plana three-channel 25G PPV combined with internal limiting membrane peeling and air filling. Before surgery and at 1, 3, and 6 months after surgery, macular microperimetry was performed with a macular integrity assessment instrument, and the mean retinal sensitivitie (MS) within 10° of the macula, fovea 2° and 4° fixation rates (P1, P2), 63% and 95% bivariate contour ellipse area (BCEA) were recorded. The comparison of MS, P1, P2, 63%BCEA and 95%BCEA at different times before and after surgery was performed by paired t test; the comparison of fixation stability rate was performed by χ 2 test. Results:Compared with before surgery, there were significant differences in the improvement of MS in affected eyes at 1, 3 and 6 months after surgery ( t=-2.208, -3.435,-4.919; P=0.038, 0.002, 0.000). In the pairwise comparison at different times after surgery, only 6 months after surgery and 1 month after surgery were significantly different ( P=0.036). Compared with the preoperative P1, P2, 63%BCEA and 95%BCEA, the P1 and P2 of the eyes gradually increased after surgery, while the 63%BCEA and 95%BCEA gradually decreased, however, the difference was not statistically significant (P1: t=-1.595,-1.698,-1.966; P=0.125, 0.104, 0.062. P2: t=-1.622,-1.654,-1.707; P=0.119, 0.112, 0.102. 63%BCEA: t=1.410, 1.409, 1.553; P=0.172, 0.173, 0.135. 95%BCEA: t=1.412, 1.408, 1.564; P=0.172, 0.173, 0.132). Six months after surgery, all the eyes underwent anatomical repositioning of the macular area, and no serious complications such as full-thickness macular hole and macular hole retinal detachment were found. Conclusions:PPV with internal limiting membrane peeling and air filling is an effective and safe method for MF, and the macular function improved significantly within 6 months postoperatively.

Synthetic polymer hydrogel nanoparticles(NPs)were developed to function as abiotic affinity reagents for fibrinogen.These NPs were made using both temperature-sensitive N-isopropyl acrylamide(NIPAm)and L-amino acid monomers.Five kinds of L-amino acids were acryloylated to obtain functional mono-mers:L-phenylalanine(Phe)and L-leucine(Leu)with hydrophobic side chains,L-glutamic acid(Glu)with negative charges,and L-lysine(Lys)and L-arginine(Arg)with positive charges.After incubating the NPs with fibrinogen,y-globulin,and human serum albumin(HSA)respectively,the NPs that incorporated N-acryloyl-Arg monomers(AArg@NPs)showed the strongest and most specific binding affinity to fibrin-ogen,when compared with y-globulin and HSA.Additionally,the fibrinogen-AArg binding model had the best docking scores,and this may be due to the interaction of positively charged AArg@NPs and the negatively charged fibrinogen D domain and the hydrophobic interaction between them.The specific adsorption of AArg@NPs to fibrinogen was also confirmed by the immunoprecipitation assay,as the AArg@NPs selectively trapped the fibrinogen from a human plasma protein mixture.AArg@NPs had a strong selectivity for,and specificity to,fibrinogen and may be developed as a potential human fibrinogen-specific affinity reagent.

Objective:To observe the healing morphology, macular microstructure and visual function of idiopathic macular hole (IMH) after pars plana vitrectomy (PPV) combined with internal limiting membrane (ILM) flap.Methods:Retrospective case study. From 2016 to 2018, 39 eyes of 39 patients with IMH diagnosed in Tianjin Eye Hospital were included in the study. Among them, there were 4 eyes in 4 males and 35 eyes in 35 females, with an average age of 64.56±7.2 years. BCVA, OCT, OCT angiography (OCTA) and MAIA microperimetry examination were performed in all patients. BCVA examination was performed with the international standard visual acuity chart, which was converted to logMAR visual acuity when recording. All patients underwent PPV combined with ILM flap covering and air tamponade. According to the characteristics of OCT images postoperatively, the eyes were divided into U-shaped closed group, V-shaped closed group, irregular closed group and flat closed group, with 26, 5, 7 and 1 eyes respectively. There was a significant difference in the minimum hole diameter ( F=5.118, P=0.005) and macular hole classification ( F=3.608, P=0.024). The shallow capillary layer (SCP) blood flow density in the U-shaped closure group was significantly higher than that in the V-shaped closure group, the irregular closure group and the flat closure group (t=2.079, 2.368; P=0.047, 0.025). At 1, 3, 6 months after the operation, the same equipment and methods were used for relevant examination. The blood flow density of BCVA, SCP, perimeter of foveal avascular zone (PERIM) and mean sensitivity (MS) were compared before and after operation. Independent sample t-test was used for quantitative data comparison between different groups, and χ2 test was used for counting data comparison. Results:Six months after operation, the logMAR of the eyes in the U-shaped closure group was -0.75±0.29 higher than that before operation, and was better than that in the V-shaped closure group, the irregular closure group and the flat closure group ( t=-2.974, -2.518; P=0.006, 0.018). The integrity of external limiting membrane (ELM) and ellipsoid in U-shaped closed group was significantly higher than that in V-shaped closed group, irregular closed group and flat closed group ( χ2=15.229, 10.809; P=0.020, 0.013). The percentage of macular central fovea reflex mass in the U-shaped closed group was significantly lower than that in the V-shaped closed group, irregular closed group and flat closed group ( χ2=20.107, P=0.000). PERIM in U-shaped closure group was smaller than that in V-shaped closure group, irregular closure group and flat closure group, and the difference was statistically significant ( t=-3.391, -2.427; P=0.002, 0.022). The total MS of macular area 10° in the U-shaped closure group was significantly higher than that in the other V-shaped closure group, irregular closure group and flat closure group ( t=2.939, 2.811; P=0.001, 0.001). Conclusion:After IMH operation, the U-shaped closure showed better BCVA and macular light sensitivity, the proportion of ELM and ellipsoid to restore structural integrity are higher, PERIM is smaller, and there are fewer macular fovea strong reflex masses.

Objective:To observe the changes of microperimeter and OCT angiography (OCTA) in idiopathic macular hole (IMH) before and after operation, and to explore the correlation between the changes and visual acuity.Methods:From January 2018 to January 2019, 41 patients (41 eyes) with IMH who underwent pars plana vitrectomy (PPV) with or without internal limiting membrane (ILM) flap surgery in Tianjin Eye Hospital were included in this study. Among them, 8 patients (8 eyes) were male and 33 patients (33 eyes) were female. The average age was 64.02±6.46 years. The average course of disease was 7.00±8.85 months. BCVA, microperimeter and OCTA were performed. The retinal mean sensitivity (RMS) at 10 ° and fovea 2 ° fixation rate (P1) and binary contour ellipse area (63% BCEA) were measured by macular integrity assessment instrument. The central retinal thickness (CRT), choroidal blood flow area (CFA), superficial and deep retinal blood flow density (FAVD, FDVD), foveal avascular zone (FAZ) and blood flow densitywithin the width of FAZ 300 μm (FD-300) were measured by OCTA. Twenty one and 19 eyes with or without ILM flap operation were treated with 25G standard three incision PPV. The follow-up time was more than 6 months. Paired t-test was used to compare the indexes before and after operation. Pearson correlation analysis was performed for the correlation between logMAR visual acuity and microperimeter variables and OCTA variables. Nonparametric test was performed for paired comparison between affected eyes and contralateral eyes before and after operation.Results:At 6 months after operation, logMAR visual acuity ( t=-12.33), RMS ( t=7.94), P1 ( t=3.21), 63% BCEA ( t=-3.98), CRT ( t=-9.17), CFA ( t=8.14), FSVD ( t=3.75), FDVD ( t=3.88) were significantly improved compared with those before operation ( P<0.001). The difference of FAZ area ( t=-1.40) and FD-300 ( t=1.95) before and after operation were not statistically significant ( P>0.05). The results of correlation analysis showed that logMAR visual acuity 6 months after surgery was correlated with preoperative logMAR visual acuity, MIN, RMS, P1, 63% BCEA, FSVD, FDVD and FAZ ( r=0.432、0.527、-0.410、-0.383、0.349、-0.406、-0.373、0.407; P<0.05). At 6 months after operation, the indexes of the affected eyes were significantly improved compared with those before operation, but worse than those of the contralateral eyes ( P<0.05). Conclusions:PPV for IMH can effectively improve the visual acuity, retinal function and foveal microvascular circulation. Retinal function and blood circulation changes have a significant impact on postoperative visual acuity.

When macular diseases involves the fovea, patients' central vision is significantly reduced. A central dark spot appears in the visual field, and their visual function indicators, such as reading speed and fixation stability, are significantly impaired, which seriously affects the patients' quality of life. The human body's response to the damage of the fovea region is a spontaneous adaptation strategy adopted by the brain. The brain will select the paracentral region as the pseudo fovea to serve as the fixation site of the eye, however, the development of patient's own residual vision is not maximized by this adaptation behavior. In recent years, through continuous research, it has been discovered that the automatic eye position recognition and automatic eye tracking system in the microperimeter can accurately detect specific retinal sites, combined with the biofeedback training mode, and can combine fundus examination with biofeedback training. It can help patients with age-related macular degeneration, pathological myopia macular degeneration, Stargardt's disease, macular hole and other macular diseases to choose the best retinal site as an eye movement benchmark, maximize the patient's residual vision and improve the patient's visual function.

Objective: To observe the effect of 25G pars plana vitrectomy (PPV) combined with or without internal limiting membrane (ILM) flap and sterile air or perfluoropropane (C₃F₈) tamponade in the treatment of idiopathic macular hole (IMH). Methods: A retrospective case analysis. From December 2015 to December 2016 in Tianjin Eye Hospital, 101 eyes of 98 consecutive IMH patients who underwent 25G PPV combined with or without ILM flap and sterile air or C₃F₈ tamponade, were included in this study. All patients underwent BCVA and OCT examination. The BCVA examination was performed using the international standard visual acuity chart, which was converted into logMAR visual acuity. The patients were divided into three groups according to preoperative minimum liner diameter of Hole (MLD) and surgical methods: MLD<400 μm for the group A, 41 eyes of 39 patients, MLD more than 400 μm without ILM flap surgery as the group B, 39 eyes of 38 patients, including 16 eyes tamponaded with air and 23 eyes tamponaded with C₃F₈, MLD more than 400 μm with ILM flap as the group C, a total of 21 patients of 21 eyes, including 7 eyes tamponaded with air and 14 eyes tamponaded with C₃F₈. The logMAR BCVA of group A, B and C were 0.82±0.39, 1.11±0.42, 1.25±0.50, respectively. The follow-up times were 1 week, 1 month, 3 month, 6 month and 1 year post operation, BCVA and OCT were performed at each follow-up time. The hole closure rate and BCVA improvement were observed. Results: The postoperative BCVA of group A, B and C was improved obviously,the differences were statistically significant (t=−11.66, −7.52, −4.99; P<0.01). There was no significant difference in improvement of visual acuity between the three groups (A and B, A and C, B and C group: t=0.77, −0.41, 0.28; P=0.44, 0.72, 0.76). 96.94% macular hole closure occurred in 7 days post operation. The postoperative visual acuity improved significantly in 3 mouth after operation, Conclusions The macular hole closure occurred mainly in 1 week after operation, postoperative visual acuity increased mostly in the 3rd month post operation. There is no advantage of ILM flap in improve postoperative visual acuity of IMH patients with MLD more than 400 μm.