Purpose: The optimal sequencing of targeted therapies and the role of primary tumor resection (PTR) in KRAS wild-type metastatic colorectal cancer (mCRC) remain unclear. This study compared survival outcomes in patients treated with first-line cetuximab plus FOLFIRI (folinic acid, 5-fluorouracil, and irinotecan) versus bevacizumab plus FOLFIRI, followed by second-line oxaliplatin-based chemotherapy and later-line trifluridine/tipiracil or regorafenib. Methods: This retrospective cohort study used Taiwan’s National Health Insurance Research Database and the Taiwan Cancer Registry. Patients diagnosed with mCRC between 2013 and 2019 were included if they received first-line cetuximab or bevacizumab plus FOLFIRI, followed by later-line trifluridine/tipiracil or regorafenib. Patients were stratified by PTR status. Primary endpoints were overall survival and survival during trifluridine/tipiracil or regorafenib treatment. Secondary endpoints included time to treatment discontinuation (TTD) and TTD during trifluridine/tipiracil or regorafenib therapy. Stabilized inverse probability of treatment weighting was used for adjustment. Results: Among 559 patients, 278 were assigned to the non-PTR group and 281 to the PTR group. In the non-PTR group, the cetuximab cohort demonstrated significantly longer survival during trifluridine/tipiracil or regorafenib therapy (6.2 months vs. 4.9 months; hazard ratio [HR], 0.72) and longer TTD1 (the interval between initiation of first-line therapy and the start of second-line chemotherapy; 11.8 months vs. 9.5 months; HR, 0.67) than the bevacizumab cohort. Survival differences between regimens were less pronounced among patients who underwent PTR. Conclusion First-line cetuximab plus FOLFIRI may confer a survival advantage over bevacizumab in patients with KRAS wild-type mCRC without PTR, including during later-line therapy with trifluridine/tipiracil or regorafenib, whereas bevacizumab appears to provide more consistent benefits in those with PTR.

Objectives: . Idiopathic sudden sensorineural hearing loss (ISSNHL) is a significant cause of hearing loss. Intratympanic steroid injection (ITSI) is commonly used as an initial or salvage treatment; however, the lack of a standardized treatment protocol has resulted in variability in clinical practice. In addition, no efficient prediction model currently exists to support personalized management. Therefore, this study aimed to develop tailored management strategies for ISSNHL using a machine-learning model. Methods: . This retrospective multicenter cohort study was conducted between January 2015 and December 2020, with data analysis performed between January 2021 and March 2024. Patients were selected based on the International Classification of Diseases, 10th Revision criteria for ISSNHL, along with relevant medication and procedure codes. Patients with pure-tone audiogram results not meeting ISSNHL criteria, better initial hearing in the affected ear, an identifiable etiology, no post-treatment audiogram, or delayed treatment (>6 weeks) were excluded. We included 770 patients diagnosed with ISSNHL who received ITSI. The primary outcome was the area under the receiver operating characteristic curve for prediction performance. Recovery status was determined using the last pure-tone audiogram. Modeling was conducted on the Quanta for Medical Care AI platform using five machine-learning algorithms and a nested cross-validation framework, in which feature selection and hyperparameter tuning were performed in the inner folds and model performance was evaluated in the outer folds. Results: . A random forest classifier outperformed the other models in predicting hearing outcomes, achieving an area under the receiver operating characteristic curve of 0.788. Time to ITSI was the most influential treatment-related factor, with ITSI administered within 10 days of hearing loss being associated with better outcomes. This model can be used to provide personalized prognostic estimates under different treatment protocols. Conclusion . The machine-learning-based prediction model facilitates personalized treatment strategies and timely treatment adjustments for ISSNHL, thereby optimizing the likelihood of complete recovery.

Introduction: Repaglinide, a meglitinide analogue, has a rapid onset and short duration of action. It offers prandial glucose control while reducing hypoglycemia risk compared to sulfonylureas. We describe its use in our special cohorts of diabetic patients where repaglinide was prescribed to reduce hypoglycemia in vulnerable patients or to optimize glycemic control through pharmacotherapy intensification or deintensification. Cases: Cohort A comprised 12 elderly patients with multiple comorbidities (mean age: 70.3 years; mean DM duration: 18.3 years) characterized by high glucose variability and problematic hypoglycemia. In seven patients, low-dose gliclazide was replaced with repaglinide with reduction in hypoglycemic episodes. One patient on low-dose premixed insulin was successfully switched to preprandial repaglinide. Two patients on basal insulin were able to reduce their insulin requirements and stabilize their glucose levels. A younger patient with autonomic dysfunction had hypoglycemia while on insulin glulisine, while its omission led to severe hyperglycemia. Substituting glulisine with repaglinide resolved the glucose variability. Repaglinide effectively reduced hypoglycemic episodes while maintaining glycemic stability, with a mean hemoglobin A1c (HbA1c) reduction of 0.36% over 3–6 months. Cohort B consisted of six younger patients (mean age: 35.3 years) with focus on optimizing HbA1c and improving treatment adherence. Two patients on basal-bolus regimes success-fully transitioned off bolus insulin to repaglinide, significantly improving compliance. One patient on basal insulin was successfully transitioned to an all-oral regimen. Three patients on existing oral hypoglycemic agents were started on repaglinide to close the glycemic gap. Cohort B achieved a robust mean HbA1c reduction of 2.1% within 3–6 months. Conclusion Repaglinide remains an important armamentarium in personalized diabetes management. Its pharmacokinetics and flexible dosing allow intensification of glycemic control while minimizing the risk of hypoglycemia. It also offers a viable strategy for selected patients struggling with complex insulin regime.
Repaglinide

This study was aimed at investigating the effectiveness of various host nucleic acid removal and non-specific amplifica-tion techniques in animal tissue samples,to increase the accuracy of pathogen identification in tissue samples.Simulated samples were prepared with a mixture of mouse lung tissue homogenates and Klebsiella pneumoniae fluids,and processed with six host nucleic acid removal kits and three non-specific amplification techniques.The effectiveness of each method in removing host DNA and enriching nucleic acids of pathogenic microorganisms was evaluated through real-time fluorescence quantitative PCR and high-throughput se-quencing.For host nucleic acid removal techniques,the method of selective cleavage and quantitative degradation of host DNA(Com-plete5 kit)effectively decreased the host nucleic acid content in tissue samples and increased the relative abundance of pathogen nucleic acids.In contrast,the magnetic bead method for host DNA removal(Next microbiome DNA enrichment Kit kit)was less effec-tive.At lower pathogen concentrations(77 CFU/mL),the Vazyme kit was more effective than the other kits in removing host nucleic acids.Non-specific amplification techniques(MALBAC whole genome amplification,MDA isothermal amplification,and random primer amplification)were not applicable to tissue samples and were not effective in increasing the relative abundance of pathogen nucleic acids.Selective lysis and quantitative degradation of host DNA were suitable for processing tissue samples with high host back-ground and low pathogenic microorganism levels,whereas non-specific amplification methods were not applicable to tissue samples for pre-processing of macro-genome high-throughput sequencing.

Objective To investigate the auditory effects of cochlear implantation in quiet and noisy environ-ments in children with different bilateral intervention modes,as well as the factors influencing these effects.Methods A total of 185 children with bilateral severe to profound sensorineural hearing loss were divided into three groups:bimodal hearing mode group(BIM,n=55),simultaneous bilateral cochlear implantation group(SCI,n=70),and sequential bilateral cochlear implantation group(SBCI,n=60).The Parents' Evaluation of Aural/Oral Performance of Children(PEACH)was used to assess the PEACH scores of the three groups in quiet and noisy environments one year after binaural hearing aid intervention.Additionally,the effects of cochlear implantation age,preoperative residual hearing,hearing aid usage,rehabilitation training mode,family system,and other factors on auditory per-formance in quiet and noisy environments were analyzed.Results The PEACH scores in quiet environments were higher than those in noisy environments for all three groups(all P＜0.05).The SCI group had higher PEACH scores in both quiet and noisy environments compared to the BIM group(P＜0.05).Multifactorial analysis revealed differences in factors influencing auditory performance in quiet and noisy environments among the three groups.First cochlear implantation before 3 years of age,preoperative hearing aid usage,and home-based rehabilitation training mode were common favourable influencing factors for auditory performance in both environments.Preopera-tive residual hearing below 95 dB HL was an favourable influencing factor for auditory performance in quiet environ-ments in the BIM group.The higher the level of parental education,the better auditory performance in both quiet and noisy environments for the SCI and SBCI groups.Implantation interval of 24 months or less and hearing aid usage during the inter-implantation period were favourable influencing factors for auditory performance in both envi-ronments for the SBCI group.Conclusion Children with severe to profound prelingual deafness after simultaneous bilateral CI implantation had better hearing performance than bimodal listening in quiet and noise environments.Ear-ly implantation,preoperative or inter-implantation hearing aid usage are recommended to improve auditory perform-ance in noisy environments,regardless of the bilateral intervention mode.The interval between bilateral cochlear im-plantations should be less than 12 months.

Objective:To compare the clinical effect of deproteinized calf blood extract (DCBE) eye drops and 0.3% sodium hyaluronate eye drops in the treatment of diabetic cataract patients with dry eye after phacoemulsification.Methods:A randomized controlled study was performed.A total of 112 patients (116 eyes) with type Ⅱ diabetes combined with cataract and dry eye who underwent phacoemulsification in the Eye Hospital of Shandong First Medical University from January 2022 to September 2022 were selected.Patients were divided into DCBE group (49 cases, 51 eyes) and sodium hyaluronate group (63 cases, 65 eyes) by the random number table method.Patients received DCBE eye drops and 0.3% sodium hyaluronate eye drops after surgery according to grouping.Preoperative and postoperative 1 week, 1 month subjective symptoms of dry eye, corneal edema grade, tear film breakup time (TBUT), corneal fluorescein staining (CFS) and Schirmer Ⅰ test (SⅠt) results were recorded and compared.This study adhered to the Declaration of Helsinki.The study protocol was approved by the Ethics Committee of Eye Hospital of Shandong First Medical University (No.SDSYKYY202112-1).Written informed consent was obtained from each subject.Results:There were significant differences in dry eye symptom score, TBUT and SⅠt at different time points between before and after surgery ( Ftime=323.202, 102.771, 151.876; all P<0.001).Dry eye symptom score decreased and SⅠt increased in the two groups at 1 week and 1 month after surgery compared with before surgery, and the differences were statistically significant (all P<0.017).TBUT was longer at 1 week and 1 month after surgery compared with before surgery in the DCBE group, and TBUT at 1 month after surgery was longer than that before surgery in the sodium hyaluronate group, and the differences were statistically significant (all P<0.017).There were statistically significant differences in CFS scores between the two groups at different time points before and after surgery ( Fgroup=5.391, P=0.022; Ftime=142.402, P<0.001).The CFS scores of both groups at 1 week and 1 month after surgery were lower than those before surgery, and CFS scores in the DCBE group were lower than those in the sodium hyaluronate group, with statistically significant differences (all P<0.017).One week after surgery, the proportion of patients with corneal edema in the DCBE group was 5.9%(3/51), which was significantly lower than 20.0%(13/65) in the sodium hyaluronate group ( χ2=4.790, P=0.029). Conclusions:DCBE eye drops can promote corneal repair, stabilize tear film and improve dry eye discomfort in early postoperative period in diabetic cataract, and its overall effect is better than 0.3% sodium hyaluronate eye drops.

Objective To investigate the auditory effects of cochlear implantation in quiet and noisy environ-ments in children with different bilateral intervention modes,as well as the factors influencing these effects.Methods A total of 185 children with bilateral severe to profound sensorineural hearing loss were divided into three groups:bimodal hearing mode group(BIM,n=55),simultaneous bilateral cochlear implantation group(SCI,n=70),and sequential bilateral cochlear implantation group(SBCI,n=60).The Parents' Evaluation of Aural/Oral Performance of Children(PEACH)was used to assess the PEACH scores of the three groups in quiet and noisy environments one year after binaural hearing aid intervention.Additionally,the effects of cochlear implantation age,preoperative residual hearing,hearing aid usage,rehabilitation training mode,family system,and other factors on auditory per-formance in quiet and noisy environments were analyzed.Results The PEACH scores in quiet environments were higher than those in noisy environments for all three groups(all P＜0.05).The SCI group had higher PEACH scores in both quiet and noisy environments compared to the BIM group(P＜0.05).Multifactorial analysis revealed differences in factors influencing auditory performance in quiet and noisy environments among the three groups.First cochlear implantation before 3 years of age,preoperative hearing aid usage,and home-based rehabilitation training mode were common favourable influencing factors for auditory performance in both environments.Preopera-tive residual hearing below 95 dB HL was an favourable influencing factor for auditory performance in quiet environ-ments in the BIM group.The higher the level of parental education,the better auditory performance in both quiet and noisy environments for the SCI and SBCI groups.Implantation interval of 24 months or less and hearing aid usage during the inter-implantation period were favourable influencing factors for auditory performance in both envi-ronments for the SBCI group.Conclusion Children with severe to profound prelingual deafness after simultaneous bilateral CI implantation had better hearing performance than bimodal listening in quiet and noise environments.Ear-ly implantation,preoperative or inter-implantation hearing aid usage are recommended to improve auditory perform-ance in noisy environments,regardless of the bilateral intervention mode.The interval between bilateral cochlear im-plantations should be less than 12 months.

Objective:To compare the clinical effect of deproteinized calf blood extract (DCBE) eye drops and 0.3% sodium hyaluronate eye drops in the treatment of diabetic cataract patients with dry eye after phacoemulsification.Methods:A randomized controlled study was performed.A total of 112 patients (116 eyes) with type Ⅱ diabetes combined with cataract and dry eye who underwent phacoemulsification in the Eye Hospital of Shandong First Medical University from January 2022 to September 2022 were selected.Patients were divided into DCBE group (49 cases, 51 eyes) and sodium hyaluronate group (63 cases, 65 eyes) by the random number table method.Patients received DCBE eye drops and 0.3% sodium hyaluronate eye drops after surgery according to grouping.Preoperative and postoperative 1 week, 1 month subjective symptoms of dry eye, corneal edema grade, tear film breakup time (TBUT), corneal fluorescein staining (CFS) and Schirmer Ⅰ test (SⅠt) results were recorded and compared.This study adhered to the Declaration of Helsinki.The study protocol was approved by the Ethics Committee of Eye Hospital of Shandong First Medical University (No.SDSYKYY202112-1).Written informed consent was obtained from each subject.Results:There were significant differences in dry eye symptom score, TBUT and SⅠt at different time points between before and after surgery ( Ftime=323.202, 102.771, 151.876; all P<0.001).Dry eye symptom score decreased and SⅠt increased in the two groups at 1 week and 1 month after surgery compared with before surgery, and the differences were statistically significant (all P<0.017).TBUT was longer at 1 week and 1 month after surgery compared with before surgery in the DCBE group, and TBUT at 1 month after surgery was longer than that before surgery in the sodium hyaluronate group, and the differences were statistically significant (all P<0.017).There were statistically significant differences in CFS scores between the two groups at different time points before and after surgery ( Fgroup=5.391, P=0.022; Ftime=142.402, P<0.001).The CFS scores of both groups at 1 week and 1 month after surgery were lower than those before surgery, and CFS scores in the DCBE group were lower than those in the sodium hyaluronate group, with statistically significant differences (all P<0.017).One week after surgery, the proportion of patients with corneal edema in the DCBE group was 5.9%(3/51), which was significantly lower than 20.0%(13/65) in the sodium hyaluronate group ( χ2=4.790, P=0.029). Conclusions:DCBE eye drops can promote corneal repair, stabilize tear film and improve dry eye discomfort in early postoperative period in diabetic cataract, and its overall effect is better than 0.3% sodium hyaluronate eye drops.

Objective:To analyze the prospective associations between liver biomarkers and mortality among Chinese middle-aged and elderly populations and to evaluate the mortality risk predictive value.Methods:A total of 22 758 participants from the 3 rd resurvey of the China Kadoorie Biobank were included. Cox proportional hazard models were used to analyze the prospective associations of 5 liver biomarkers with mortality. These liver biomarkers included two liver imaging biomarkers (liver fat attenuation parameter, liver stiffness measurement) and three serum liver enzyme biomarkers [gamma-glutamyl transferase (GGT), ALT, and AST]. Restricted cubic spline was used to assess the nonlinear associations between biomarkers and mortality. The area used the receiver operating characteristic curve (AUC) to evaluate the predictive ability of the models after incorporating liver biomarkers into traditional prediction models for mortality. Results:The mean age of the participants was (65.2±9.1) years, with a median follow-up of 1.5 years, during which 307 deaths occurred. Compared to individuals without hepatic steatosis, those with severe hepatic steatosis had a 79% higher risk of mortality, with a HR of 1.79 (95% CI: 1.06-3.03). Compared to individuals without hepatic fibrosis, those with advanced fibrosis and cirrhosis had higher mortality risks of 48% and 91%, respectively (both P<0.05). For each standard deviation increase in GGT, the mortality risk increased by 10% ( HR=1.10, 95% CI: 1.05-1.15), with the positive association plateauing at higher GGT levels. AST exhibited a U-shaped association with mortality risk. The AUC of the prediction model adding liver biomarkers into traditional prediction factors was 0.718 (95% CI: 0.679-0.757), with an increase of 0.030 ( P<0.001) compared with the traditional model. Conclusions:Severe hepatic steatosis, higher levels of hepatic fibrosis, and elevated GGT levels are significantly associated with higher mortality risk. AST shows a U-shaped nonlinear association with mortality risk. Incorporating liver biomarkers into traditional risk prediction models enhance the ability to predict mortality.

Objective:To investigate the prospective associations between plasma metabolites and the risks of all-cause and cause-specific mortality among Chinese adults.Methods:This study analyzed plasma metabolomics data from 2 183 healthy adults in the China Kadoorie Biobank (CKB), measured using targeted mass spectrometry. Cox proportional hazards regression models were used to examine the associations between 630 metabolites and the risk of all-cause mortality. Cause-specific hazard regression models evaluated the associations between metabolites and cardiovascular disease (CVD) risks, cancer, and other-cause mortality. Stepwise regression was used to identify key metabolites independently associated with all-cause mortality, and the area under the receiver operating characteristic curve (AUC) was calculated to assess the improvement in predictive performance when these metabolites were added to traditional risk prediction models.Results:The mean age of the participants was (53.2±9.8) years, 65.1% of whom were female. During a median follow-up of 14.5 years, 231 deaths occurred. A total of 44 metabolites were significantly associated with the risk of all-cause mortality [false discovery rate (FDR)-adjusted P<0.05], primarily including triglycerides, ceramides, and amino acids. Additionally, 29 and 15 metabolites were found to be associated with cancer and other-cause mortality, respectively, but no metabolites were significantly associated with CVD mortality after FDR corrections. Adding 14 metabolites independently associated with all-cause mortality into the traditional prediction model significantly improved its predictive performance. Specifically, incorporating metabolites into the traditional model, which already included laboratory biomarkers, increased the AUC to 0.798 (95% CI: 0.755-0.843), an improvement of 0.088 compared to the traditional model ( P<0.001). Conclusions:Multiple metabolites are significantly associated with mortality risk and can substantially improve the accuracy of mortality risk prediction models. These findings provide new insights into the physiological mechanisms of aging and offer valuable clues for personalized health risk assessment.