AIM:To evaluate the clinical efficacy of lamellar keratectomy and corneal collagen crosslinking(LKCCC)in treating superficial fungal keratitis.METHODS: Retrospective analysis. Totally 79 patients(79 eyes)with superficial fungal keratitis who underwent LKCCC in our hospital from January 2014 to October 2023 were included. After admission, routine antifungal drug treatment for 7 d showed no obvious improvement or progressive aggravation. The maximum diameter of corneal lesions in all patients was ≤7 mm, the maximum depth was no more than 50% of the corneal thickness at the location, and the remaining healthy corneal thickness was ≥300 μm. The follow-up time was 90 to 112 d.RESULTS:Among the included 79 eyes, the lesions were located in the central region of the cornea in 6 eyes, in the paracentral region in 61 eyes, and in the peripheral region in 12 eyes. Hypopyon was observed in 5 cases. LKCCC was successfully administered in 79 eyes, cured in 76 eyes(96%), and failed in 3 eyes(4%). The healing time of corneal epithelium in 76 cured eyes was 3-15 d, of which 51 eyes(67%)healed within 7 d and 24 eyes(32%)healed within 3 d. The uncorrected visual acuity(UCVA)and best corrected visual acuity(BCVA)of 76 eyes of cured patients were statistically significant compared with those preoperatively(P<0.0167). Two of the 3 failed eyes were located at the edge of the lesion and recovered after re-keratectomy. One eye was located in the center of the lesion and recovered after being covered by bulbar conjunctival flap. At the last follow-up, no other complications were observed in all patients except superficial cloud and thinning of cornea.CONCLUSION:LKCCC is a rapid and effective treatment for superficial fungal keratitis and can be considered a new treatment option.

AIM: To assess the impact of optimized pulsed technology(OPT)on the morphological and functional changes of meibomian glands in patients with meibomian gland dysfunction(MGD).METHODS: This prospective case-control study enrolled 60 MGD patients(60 right eyes)treated at Weifang Eye Hospital from September 2023 to February 2024. Patients were categorized into mild, moderate, and severe groups based on the extent of meibomian gland loss, with 20 cases(20 eyes)per group. Treatments consisted of bilateral OPT combined with meibomian gland massages, administered biweekly over four sessions. Ocular surface function indicators including the ocular surface disease index(OSDI), corneal fluorescein staining(CFS), non-invasive average tear break-up time(NIBUTav), and non-invasive tear meniscus height(NITMH), as well as meibomian gland function parameters such as meibomian gland expressibility score(MGES)and meibomian gland secretion score(MGYSS)were observed and recorded before treatment and at 3 mo after final treatment. Cellular-level assessments using in vivo confocal microscopy(IVCM)examined meibomian gland acinar unit density(MGAUD), inflammatory cell density(ICD), meibomian gland acinar longest diameter(MGALD)and meibomian gland acinar shortest diameter(MGASD).RESULTS: At baseline, no significant differences were found in NITMH across groups(P>0.05). Statistical significance were observed in NIBUTav, MGES, MGYSS, MGAUD, MGALD, and MGASD(all P<0.05). Compared to the mild group, the moderate and severe groups showed significant differences in OSDI, CFS, and ICD(all P<0.05), though no significant differences existed between moderate and severe groups(all P>0.05). At 3 mo after treatment, all groups showed no significant differences in NITMH(all P>0.05). All parameters improved significantly in the mild group(all P<0.05); all indicators improved in the moderate group(P>0.05), except for MGASD before and after treatment(all P<0.05); significant improvements were noted in OSDI, CFS, and NIBUTav in the severe group(all P<0.05), while MGES and MGYSS did not differ significantly(all P>0.05). IVCM parameters(MGAUD, ICD, MGALD, and MGASD)showed no significant change in the severe group(all P>0.05).CONCLUSION:OPT effectively enhances various ocular surface functions and improves gland expressibility and secretion quality in mild to moderate MGD cases, while also positively impacting certain cellular parameters. In severe cases, where most acinar functions are lost and structural reversibility is limited, OPT can still mitigate MGD symptoms and decelerate disease progression.

Amide bond is formed by dehydration and condensation of amino and carboxyl groups in a molecule, which is used in structural design of drugs. The stability of the amide bond is affected by many factors, which make the pharmacokinetic behaviors of amide drugs complicated by metabolic heterogeneity. This review proposes that the expression and activity of hydrolase may be one of the important reasons for the obvious differences in the pharmacokinetics of amides among species, summarizes the common metabolic enzymes or proteins responsible for hydrolyzing amides so as to provide some reference for the structural design and further clinical study of amide drugs, and suggests that improper selection of in vitro evaluation systems may be an important cause for the inconsistency between between in vitro and in vivo pharmacokinetic characteristics of drugs, with a summary of the currently used in vitro drug metabolism systems for drug evaluation, aiming to provide a basis for preclinical evaluation of drugs.

ObjectiveThis study aims to examine the effect of Rhei Radix et Rhizoma-Coptidis Rhizoma on reducing insulin resistance in db/db mice by regulating the adenylate activated protein kinase （AMPK）/UNC-51-like kinase 1 （ULK1）/key molecule of autophagy， benzyl chloride 1 （Beclin1） pathway and elucidate the underlying mechanism. MethodSixty 6-week-old male db/db mice were studied. They were randomly divided into the model group， metformin group （0.26 g·kg^-1）， and low-， middle-， and high-dose groups （2.25， 4.5， 9 g·kg^-1） of Rhei Radix et Rhizoma-Coptidis Rhizoma. A blank group of db/m mice of the same age was set， with 12 mice in each group. After eight weeks of continuous intragastric administration， the blank group and model group received distilled water intragastrically once a day. The survival status of the mice was observed， and fasting blood glucose （FBG） was measured using a Roche blood glucose device. Fasting serum insulin （FINS） was measured using an enzyme-linked immunosorbent assay， and the insulin resistance index （HOMA-IR） was calculated. Hematoxylin-eosin （HE） staining was performed to observe the pathological changes in the liver of the mice. The protein expression levels of AMPK， Beclin1， autophagy associated protein 5 （Atg5）， and p62 in liver tissue were determined by using Western blot. The protein expression levels of autophagy associated protein 1 light chain 3B （LC3B） and ULK1 in liver tissue were determined using immunofluorescence. Real-time fluorescence quantitative PCR （Real-time PCR） was used to measure mRNA expression levels of AMPK， Beclin1， Atg5， ULK1， and p62. ResultCompared with the blank group， the model group exhibited a significant increase in body mass （P<0.01）. Additionally， the levels of FBG， FINS， and HOMA-IR significantly changed （P<0.01）. The structure of liver cells was disordered. The protein expression levels of AMPK， Beclin1， and Atg5 in liver tissue were significantly decreased （P<0.01）， while the expression level of p62 protein was significantly increased （P<0.01）. The expression levels of mRNA and proteins were consistent. Compared with the model group， the body mass of the metformin group and high and medium-dose groups of Rhei Radix et Rhizoma-Coptidis Rhizoma was significantly decreased （P<0.05）. FBG， FINS， and HOMA-IR were significantly decreased （P<0.05，P<0.01）. After treatment， the liver structure damage in each group was alleviated to varying degrees. The protein expressions of AMPK， Beclin1， Atg5， LC3B， and ULK1 were increased （P<0.05，P<0.01）， while the protein expression of p62 was decreased （P<0.01）. The expression levels of mRNA and proteins were generally consistent. ConclusionThe combination of Rhei Radix et Rhizoma-Coptidis Rhizoma can effectively improve liver insulin resistance， regulate the AMPK autophagy signaling pathway， alleviate insulin resistance in db/db mice， and effectively prevent the occurrence and development of type 2 diabetes.

Objective:To analyze the optimal dose of urokinase (UK) for intravenous thrombolysis in Chinese patients with acute ischemic stroke within 4.5 hours of onset.Methods:Based on the intravenous thrombolysis registry for Chinese ischemic stroke within 4.5 hours of onset (INTRECIS) cohort, consecutive patients who received intravenous UK from April 1, 2017 to July 1,2019 were retrospectively collected . According to the tertile dose of UK per body weight, eligible patients were divided into low dose group [(1.00-1.67)×10 4 international unit per kilogram], moderate dose group [(1.68-2.33)×10 4 international unit per kilogram] and high dose group (2.34-3.00)×10 4 international unit per kilogram]. Furthermore, subgroups were analyzed according to age, gender, and baseline National Institutes of Health Stroke Scale (NIHSS) scores. The primary efficacy outcome was excellent functional outcome, defined as a 90-day modified Rankin Scale (mRS) score of 0-1. The secondary efficacy outcomes included favorable functional outcome (mRS score of 0-2 at 90 days), mRS score distribution at 90 days and changes in NIHSS score at 1 day and 14 days, compared with the baseline. The primary safety outcome was symptomatic intracranial hemorrhage (sICH), and the secondary safety outcomes included recurrence of stroke within 90 days, all-cause mortality and any random bleeding events. Results:A total of 1 144 patients were included in the analysis: 549 in the low dose group, 509 in the moderate dose group and 86 in the high dose group. The proportion of excellent functional outcome was higher in the high dose group, compared with the low dose group [79.07% (68/86) vs 67.03% (368/549), OR=2.427, 95% CI 1.280-4.587, P=0.007] and the moderate dose group [79.07%(68/86) vs 70.53%(359/509), OR=1.942, 95% CI 1.023-3.690, P=0.043]. The incidence of sICH was similar among the 3 groups [high dose group vs low dose group: 1.16% (1/86) vs 2.00% (11/549), OR=0.607, 95% CI 0.071-5.153, P=0.648; high dose group vs moderate dose group: 1.16%(1/86) vs 0.79% (4/509), OR=0.330, 95% CI 0.101-1.074, P=0.596]. The subgroup analysis showed that higher proportion of excellent functional outcome was found in the high dose group patients with senior citizens (≥60 years old) [high dose group vs low dose group: 80.70% (46/57) vs 63.07% (222/352), OR=3.401, 95% CI 1.500-7.752, P=0.003; high dose group vs moderate dose group: 80.70% (46/57) vs 69.63% (227/326), OR=2.381, 95% CI 1.074-5.291, P=0.033], moderate neurologic deficit (NIHSS score 4-16) [high dose group vs low dose group:79.07% (34/43) vs 62.61% (211/337), OR=2.604, 95% CI 1.190-5.682, P=0.017; high dose group vs moderate dose group:79.07% (34/43) vs 65.02% (184/283), OR=2.315, 95% CI 1.055-5.097, P=0.036], and large artery atherosclerosis [high dose group vs low dose group: 81.40% (35/43) vs 62.32% (177/284), OR=3.584, 95% CI 1.416-9.009, P=0.007; high dose group vs moderate dose group: 81.40% (35/43) vs 66.06% (144/218), OR=2.793, 95% CI 1.090-7.143, P=0.032]. Conclusions:Intravenous UK dose calculated according to body weight may be reasonable for treating acute ischemic stroke. Intravenous UK with dose of (2.34-3.00)×10 4 international unit per kilogram may favor better benefit for acute ischemic stroke, which warrants further confirmation.

Objective To summarize experience of anti-cancer drug management for clinical trials,and to explore a more efficient and standardized management model of anti-cancer drugs used in clinical trials.Methods Based on our current work in central pharmacy,the particularity and complexity of anti-cancer drug management for clinical trials were analyzed.In the meantime,we identified high-risk parts in the drug management process.Based on those risks,feasible measures were taken and presented in detail.Results Management of anti-cancer drugs used in clinical trials has its characteristics,such as long cycle,low error-tolerant rate,closed-loop model,etc.Recognizing these representative high-risk parts during the trials and making responses,including standardization of drug management records and disposition of drugs and packaging returned by subjects,should be achieved as soon as possible.Conclusion Establishing and observing strict rules and regulations,improving the hardware and software performance of the central pharmacy as well as implementing risk-based drug management is beneficial to conduct clinical trials normatively.

Background and Purpose:The early prediction of local tumor progression-free survival(LTPFS)after radiofrequency ablation(RFA)for colorectal cancer(CRC)lung metastases has significant clinical importance.The application of radiomics in the prediction of tumor prognosis has been explored.This study aimed to construct a radiomics-based nomogram for predicting LTPFS after RFA in CRC patients with lung metastases.Methods:This study retrospectively analyzed 172 CRC patients with 401 lung metastases admitted to Department of Interventional Radiology,Fudan University Shanghai Cancer Center from August 2016 to January 2019.This study was reviewed by the medical ethics committee of Fudan University Shanghai Cancer Center(ethics number:2402291-24).After augmentation of pre-ablation and immediate post-ablation computed tomography(CT)images,the target metastases and ablation regions were segmented manually to extract the radiomic features.Maximum relevance and minimum redundancy algorithm(MRMRA)and least absolute shrinkage and selection operator(LASSO)regression models were applied for feature selection.The clinical model,the radiomics model,and the fusion model were constructed based on the selected radiomic features and clinical variables screened by the multivariate analysis.The Harrell concordance index(C-index)and area under receiver operating characteristic(ROC)curves(AUC)were calculated to evaluate the prediction performance.Finally,the corresponding nomogram of the best model was drawn.Results:Among all the lung metastases,102(25.4%)had final recurrence,and 299(74.6%)had complete response(CR).The median follow-up time was 21 months(95%CI:19.466-22.534),and the LTPFS rates at 1,2,and 3 years after RFA were 76.5%(95%CI:72.0-80.4),72.1%(95%CI:66.6-76.9)and 69.9%(95%CI:64.0-75.1).In both the training and test dataset,the fusion model based on the final 12 radiomic features through the LASSO regression and 4 clinical variables screened by multivariate analysis achieved the highest AUC values for LTPFS,with C-index values of 0.890(95%CI:0.854-0.927)and 0.843(95%CI:0.768-0.916),respectively.Conclusion:The fusion model based on radiomic features and clinical variables is feasible for predicting LTPFS after RFA of CRC patients with lung metastases,whose performance is superior to the single radiomic and clinical model.At the same time,the nomogram of the fusion model can intuitively predict the prognosis of CRC patients with lung metastases after RFA,thus assisting clinicians in developing individualized follow-up review plans for patients and adjusting treatment strategies flexibly.

Objective:To explore the genetic etiology for a patient with Alstr?m syndrome (ALMS) presenting as dilated cardiomyopathy.Methods:A 41-year-old male patient who had presented at the Sixth Medical Center of PLA General Hospital on October 20, 2021 was selected as the study subject. Clinical and laboratory examinations were carried out. Whole exome sequencing (WES) was employed for genetic testing, and candidate variants were validated by Sanger sequencing and pathogenicity analysis.Results:The patient had a 14-year medical history characterized by dilated cardiomyopathy, complete atrioventricular block, visual impairment, sensorineural hearing loss, truncal obesity, insulin resistance, type 2 diabetes, hypertension, renal dysfunction, and paranoid delusions. Genetic testing revealed that he has harbored compound heterozygous variants of the ALMS1 gene, namely c. 6823C>T (p.Arg2275Ter) and c. 9442_9445dup (p.Ser3149LysfsTer2). Sanger sequencing confirmed that they were inherited from his father and mother, respectively. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were predicted to be pathogenic (PVS1_VeryStrong+ PM2_Supporting+ PM3+ PP3, PVS1_VeryStrong+ PM2_Supporting+ PM3). Literature review indicated that the complete atrioventricular block in the patient was a phenotype unreported previously. Conclusion:The c. 6823C>T (p.Arg2275Ter) and c. 9442_9445dup (p.Ser3149LysfsTer2) compound heterozygous variants of the ALMS1 gene probably underlay the pathogenesis in this patient. Above findings have expanded the phenotypic spectrum of ALMS and provided insights for clinicians dealing with similar cases.

Objective:To construct a risk model of liver injury related to parenteral nutrition (PNALD) in patients with severe acute pancreatitis (SAP).Methods:The clinical data of 176 SAP patients admitted to the 971 Hospital of Navy from January 2019 to August 2021 were retrospectively collected. According to whether PNALD occurred or not, the patients were divided into liver injury group ( n=33) and non-liver injury group ( n=143). Multivariate logistic regression was used to analyze the influencing factors of PNALD in SAP patients. Then decision tree model and multivariate logistic regression model were established based on the screened risk factors. Hosmer and Lemeshow Test calibration curves were used to calibrate the two models, and receiver operating characteristic curve (ROC) was drawn and area under the curve (AUC) was calculated to compare the prediction efficiency of the two models. Results:Drinking history (history of alcohol intake), serum albumin / globulin ratio ≤1.45, prothrombin time (PT)≥18.52 s, PT activity ≤48.96, activated partial thromboplastin time (APTT) ≥45.91 s were all risk factors for PNALD. The ROC curve of the multivariate logistic regression model and the decision tree model was drawn, and calculated AUC of the two models was 0.851 and 0.906, respectively; the sensitivity was 79.6% and 80.8%, respectively; the specificity was 80.5% and 79.6%, respectively; and the Youden index was 0.601 and 0.604, respectively, with good consistency.Conclusions:Low serum albumin/globulin ratio and PT activity, high PT and APTT are all risk factors for PNALD. The PNALD prediction model based on the above risk factors has high specificity and sensitivity.

ObjectiveTo reveal the intervention effect of Dahuang Mudantang on pancreatic injury in rats with acute pancreatitis （AP） of dampness-heat in large intestine syndrome and explore its possible mechanism based on network pharmacology. MethodNinety-six SPF-grade Wistar rats were randomly divided into the following six groups： a blank group， a model group， low-， medium-， and high-dose Dahuang Mudantang groups （3.5， 7， and 14 g·kg^-1）， and a Qingyi Lidan granules group （3 g·kg^-1）， with 16 rats in each group. The AP model of dampness-heat in large intestine syndrome was induced in rats except for those in the blank group by "high-temperature and high-humidity environment + high-sugar and high-fat diet + retrograde injection of 5% sodium taurocholate into the pancreaticobiliary duct". The blank and model groups received equal volumes of distilled water by gavage， while the treatment groups were administered Dahuang Mudantang or Qingyi Lidan granules 1 hour before modeling， and 12 and 24 hours after modeling. Samples were collected 1 hour after the last administration. The general conditions of the rats were observed. The AP model of dampness-heat in large intestine syndrome was evaluated. Serum amylase （AMS） and C-reactive protein （CRP） levels were determined using biochemical methods. Pancreatic tissue morphology was observed using hematoxylin-eosin （HE） staining. Network pharmacology was employed to predict potential targets of Dahuang Mudantang in the intervention in AP， and molecular biology technique was used to verify relevant targets. ResultCompared with the blank group， the model group exhibited lethargy， unkempt fur， loose and foul-smelling stools， elevated anal temperature with arching and twisting reactions， significantly increased serum levels of AMS and CRP （P<0.05）， abnormal pancreatic ductules， disordered interlobular spaces， and inflammatory cell infiltration in histopathological examination， as well as pathological changes including pancreatic acinar cell swelling， congestion， and necrosis. Compared with the model group， the treatment groups showed varying degrees of improvement in general survival conditions， reduced twisting reactions， visibly improved stool characteristics， reduced pancreatic tissue edema and necrosis， decreased serum AMS and CRP levels （P<0.05）， with the high-dose Dahuang Mudantang group showing the most pronounced effects （P<0.05）. Network pharmacology prediction indicated that hederagenin， β-sitosterol， and quercetin were the most widely connected active compounds with disease targets. Protein-protein interaction （PPI） network analysis revealed that protein kinase B （Akt）， tumor protein P53 （TP53）， tumor necrosis factor （TNF）， interleukin-6 （IL-6）， transcription factor （JUN）， vascular endothelial growth factor α （VEGFα）， interleukin-1β （IL-1β）， and vascular cell adhesion molecule-1 （VCAM1） were key targets in the "drug-disease" interaction. KEGG enrichment analysis suggested that the response of the mitogen activated protein kinase （MAPK） signaling pathway might be a core mechanism for DHMDT in the intervention in AP. Molecular biology analysis showed that compared with the blank group， the model group had significantly increased levels of TNF-α， IL-6， and VCAM-1 in pancreatic tissue （P<0.05）， as well as significantly elevated expression levels of p38 mitogen-activated protein kinase （p38 MAPK）， mitogen-activated protein kinase-activated protein kinase 2 （MK2）， and human antigen R （HUR） genes and proteins （P<0.05）. Compared with the model group， the treatment groups exhibited decreased levels of TNF-α， IL-6， and VCAM-1 in pancreatic tissue （P<0.05）， reduced expression levels of p38 MAPK， MK2， and HUR genes and proteins， with the high-dose Dahuang Mudantang group showing the most pronounced effects （P<0.05）. ConclusionDahuang Mudantang activates and regulates the p38 MAPK/MK2/HUR signaling pathway to suppress the release of inflammatory factors， thereby improving pancreatic injury.