OBJECTIVE To investigate the clinical characteristics of euglycemic diabetic ketoacidosis （euDKA） induced by empagliflozin， and provide references for safe medication. METHODS Case reports of euDKA induced by empagliflozin were retrieved and analyzed from PubMed， Web of Science， CNKI， and Wanfang Data. The Naranjo’s scale was adopted to assess the causal relationship between empagliflozin and euDKA. RESULTS A total of 29 patients were enrolled， including 16 males and 13 females，with a median age of 58 years. All patients were diagnosed with type 2 diabetes mellitus； 22 patients had at least one comorbidity. The median time to euDKA onset was 60 days after administration， and 7 cases occurred within 2 weeks of treatment. Perioperative periods，fasting，and low-carbohydrate or ketogenic diets were the main predisposing factors. Common presentations included nausea，vomiting， fatigue， tachypnea，and tachycardia. The causal relationship between empagliflozin and euDKA was assessed as “probable” in all cases. According to adverse reaction severity grading， 13 cases were grade 3 （severe） and 16 cases were grade 4 （life-threatening）. All patients discontinued empagliflozin and recovered after corresponding treatment. CONCLUSIONS euDKA is a serious adverse reaction to empagliflozin， which mostly occurs early in treatment. Perioperative periods， fasting， and ketogenic diets are prone to induce euDKA. Elderly patients and those with comorbidities are at higher risk. Risk assessment should be conducted before clinical administration； blood ketones and acid-base monitoring should be strengthened in the early medication period； withhold the drug before elective surgery， avoid prolonged fasting；upon diagnosis， discontinue empagliflozin and initiate intravenous insulin， provide fluid resuscitation promptly， and use other treatments to improve patient prognosis.

Objective: To investigate the effects of “Three Methods and Three Acupoints” (TMTP) Tuina therapy on spinal microcirculation in sciatic nerve injury (SNI). Methods: Thirty-six Sprague–Dawley rats were randomly assigned to four groups: normal, sham operation, model, and TMTP Tuina. Successful model induction was confirmed by observable hind limb lameness. After 20 sessions, hind limb grip strength and motor nerve conduction velocity (MNCV) were measured at baseline and following the 10th and 20th intervention. CD31 and α-SMA in the ventral horn of SNI model rats were detected using immunofluorescence. Motor neurons in the ventral horn were detected by Nissl staining. PTEN levels in the ventral horn were measured by ELISA, and PI3K, Akt, BDNF, VEGF, and HIF-1α expression was determined by RT-PCR. Spinal cord microcirculation was evaluated by western blotting analysis of the levels of Akt, p-Akt, BDNF, and VEGF. Results: Hind limb grip strength and MNCV significantly improved in the TMTP Tuina group compared to the model group (both P < .001). Morphology of ventral horn motor neurons in the TMTP Tuina group improved compared to the model group, with increased expressions of α-SMA (P = .002) and CD31 (P = .006). Western blot analysis indicated increased expression of VEGF (P = .005), p-Akt (P < .001), and BDNF (P = .008) in the ventral horn following Tuina treatment. RT-PCR analysis revealed increased expression of PI3K, Akt, BDNF, VEGF and HIF-1α (all P < .05). In contrast, expression of PTEN decreased compared to the model group (P < .001). Conclusion TMTP Tuina therapy may restore motor function in rats, enhance ventral horn motor neuron morphology, and promote angiogenesis and vascular smooth muscle proliferation. The mechanism may involve the activation of the PI3K/Akt signaling pathway.

Objective:To explore the association between serum selenium levels and total cancer risk in humans.Methods:A systematic search was conducted for Chinese and English literature on the association between selenium and cancer risk published up to December 2023 in the Chinese National Knowledge Infrastructure (CNKI), Wanfang, PubMed, EMbase, Web of Science, and Cochrane Central Register of Controlled Trials (CENTRAL) databases by using “neoplasms” “selenium” “prospective-studies” (both in English and Chinese) as keywords. The meta-analysis was performed using a random-effect model. The linear dose-response relationship was analyzed using a generalized least squares regression model, and the non-linear dose-response relationship was analyzed using a restricted cubic spline regression model. Publication bias was assessed by funnel plots and Egger′s regression asymmetry test.Results:A total of 12 prospective studies were included from 16 408 articles retrieved, including seven studies from Europe, four from America, and one from Asia, with a total of 4 586 cancer cases reported. Meta-analysis revealed an inverse association between baseline serum selenium levels and total cancer risk ( RR=0.68, 95% CI: 0.57-0.82, P=0.000). Furthermore, serum selenium was found to have a protective effect on both the incidence ( RR=0.66, 95% CI: 0.53-0.84, P=0.001) and mortality ( RR=0.70, 95% CI: 0.50-0.98, P=0.035) of total cancer. The inverse association between serum selenium and the incidence of total cancer was more pronounced in populations with low baseline serum selenium levels ( RR=0.65, 95% CI: 0.48-0.89, P=0.007). Additionally, dose-response meta-analysis showed that for every 10 μg/L increase in baseline serum selenium concentration, there was a 26% reduction in incidence of total cancer ( RR=0.74, 95% CI: 0.46-0.83, P=0.229) and a 6% reduction in mortality of total cancer ( RR=0.94, 95% CI: 0.86-0.96, P=0.229). Conclusion:Serum selenium is negatively associated with the incidence and mortality of total cancer.

Objective:Drug safety assessments based on real-world data are often challenged by both treatment switching and rare events. In this study, we used statistical simulations to investigate the effects of switching rates and treatment effects on the statistical performance of commonly used analytical strategies and methods under overlapping scenarios of treatment switching and rare events.Methods:The simulation scenario was set up as a bidirectional treatment switching (allowing the control group to switch to the treatment group and the treatment group to switch to the control group), and the event rates were set at approximately 2%, 5%, and 20%. Different simulation scenarios were generated with sufficient sample size to consider switching rate and relative treatment effect. The simulated datasets were analyzed using three types of analysis strategy, i.e. intention to treat (ITT), per protocol (PP), and as treated (AT). The performance of five indicators, namely percentage bias, mean square error, empirical standard error, coverage, and rejection rate, were compared among the different methods in different scenarios, and recommendations for method selection were given.Results:In terms of analytical strategies and methods, AT analysis were relatively optimal in terms of percentage bias and accuracy, followed by PP analysis and ITT analysis. When the relative treatment effects converged (e.g. HR=1.0), both the ITT analysis and the time-dependent AT approaches (marginal structural model, time-dependent Cox regression model or time-dependent propensity score matching) performed well; when the relative treatment effects were small (e.g. HR=0.8), the marginal structural model was the most optimal; when the relative treatment effects were large (e.g. HR=0.6 or 0.4), the approaches of using a censored treatment for switchers in the AT analysis were more accurate. In addition, the time-dependent AT approaches had the highest rejection rate when there was a difference in treatment effect between the two groups, and the ITT analysis had the lowest rejection rate. Conclusions:For the dual challenges of bidirectional switching and rare events in real-world drug safety evaluations, adequate sample size is a prerequisite for accurate estimation of treatment effects, while switching rates and effect sizes of switched drugs might also affect estimation accuracy. Appropriate strategies and methods should be selected for the analysis. It is necessary to consider whether the event is rare or not, the switching rate and the expected treatment effect size of the two types of treatment to select appropriate analysis strategies and methods.

Objective:To explore the association between serum selenium levels and total cancer risk in humans.Methods:A systematic search was conducted for Chinese and English literature on the association between selenium and cancer risk published up to December 2023 in the Chinese National Knowledge Infrastructure (CNKI), Wanfang, PubMed, EMbase, Web of Science, and Cochrane Central Register of Controlled Trials (CENTRAL) databases by using “neoplasms” “selenium” “prospective-studies” (both in English and Chinese) as keywords. The meta-analysis was performed using a random-effect model. The linear dose-response relationship was analyzed using a generalized least squares regression model, and the non-linear dose-response relationship was analyzed using a restricted cubic spline regression model. Publication bias was assessed by funnel plots and Egger′s regression asymmetry test.Results:A total of 12 prospective studies were included from 16 408 articles retrieved, including seven studies from Europe, four from America, and one from Asia, with a total of 4 586 cancer cases reported. Meta-analysis revealed an inverse association between baseline serum selenium levels and total cancer risk ( RR=0.68, 95% CI: 0.57-0.82, P=0.000). Furthermore, serum selenium was found to have a protective effect on both the incidence ( RR=0.66, 95% CI: 0.53-0.84, P=0.001) and mortality ( RR=0.70, 95% CI: 0.50-0.98, P=0.035) of total cancer. The inverse association between serum selenium and the incidence of total cancer was more pronounced in populations with low baseline serum selenium levels ( RR=0.65, 95% CI: 0.48-0.89, P=0.007). Additionally, dose-response meta-analysis showed that for every 10 μg/L increase in baseline serum selenium concentration, there was a 26% reduction in incidence of total cancer ( RR=0.74, 95% CI: 0.46-0.83, P=0.229) and a 6% reduction in mortality of total cancer ( RR=0.94, 95% CI: 0.86-0.96, P=0.229). Conclusion:Serum selenium is negatively associated with the incidence and mortality of total cancer.

Objectives:To systemically evaluate the efficacy and safety of His-Purkinje conduction system pacing(HPCSP,including His bundle pacing[HBP]and left bundle branch area pacing[LBBAP])combined with atrioventricular node ablation for the treatment of atrial fibrillation combined with heart failure.Methods:The PubMed,Cochrane Library,Web of Science,Embase,China National Knowledge Infrastructure(CNKI),Wanfang Data,VIP,and Yiigle were searched for studies on HPCSP combined with atrioventricular node ablation for the treatment of atrial fibrillation combined with heart failure since the established until July 31,2024.Meta-analysis was performed using RevMan 5.4 and Stata 15.1.Results:A total of 13 studies were included with 1 071 patients,the success rate of HPCSP combined with atrioventricular node ablation was 93.1%.The meta-analysis results revealed that,in terms of effectiveness outcomes,compared with baseline,left ventricular end-diastolic diameter(mean difference[MD]=-3.11,95%CI:-4.16 to-2.06,P<0.000 01)was significantly reduced,New York Heart Association(NYHA)cardiac function classification(MD=-1.36,95%CI:-1.48 to-1.24,P<0.000 01)was significantly decreased,and left ventricular ejection fraction(MD=9.86,95%CI:7.02 to 12.69,P<0.000 01)was significantly increased during follow-up.The pacing QRS duration was prolonged from baseline after atrioventricular node ablation(MD=7.83,95%CI:2.79 to 12.87,P=0.002);In terms of safety outcomes,HPCSP pacing thresholds remained stable(MD=0.07,95%CI:-0.01 to 0.15,P=0.11)and impedance was decreased(MD=-78.84,95%CI:-120.21 to-37.47,P=0.000 2)during operation and follow-up.The complication rate was 7.9%,the heart failure rehospitalization rate was 4.5%and the mortality rate was 5.8%.Compared with biventricular pacing(BVP),HPCSP was correlated with shorter pacing QRS duration(MD=-39.08,95%CI:-62.35 to-15.80,P=0.001)and higher left ventricular ejection fraction(MD=4.38,95%CI:0.37 to 8.40,P=0.03),there was no significant difference in left ventricular end-diastolic diameter(MD=-9.11,95%CI:-19.93 to 1.72,P=0.100).During follow-up,LBBAP exhibited a lower pacing threshold than HBP(MD=0.61,95%CI:0.23 to 1.00,P=0.002);Endpoint event rates were similar between HBP and LBBP(RR=1.47,95%CI:0.83 to 2.60,P=0.190).Conclusions:Results of this meta-analysis demonstrate that HPCSP combined with atrioventricular node ablation for the treatment of atrial fibrillation combined with heart failure is effective and safe.HPCSP is associated with better ventricular electro-mechanical synchronization and cardiac function compared with BVP,and LBBAP pacing parameters are superior to HBP.

Objective:Drug safety assessments based on real-world data are often challenged by both treatment switching and rare events. In this study, we used statistical simulations to investigate the effects of switching rates and treatment effects on the statistical performance of commonly used analytical strategies and methods under overlapping scenarios of treatment switching and rare events.Methods:The simulation scenario was set up as a bidirectional treatment switching (allowing the control group to switch to the treatment group and the treatment group to switch to the control group), and the event rates were set at approximately 2%, 5%, and 20%. Different simulation scenarios were generated with sufficient sample size to consider switching rate and relative treatment effect. The simulated datasets were analyzed using three types of analysis strategy, i.e. intention to treat (ITT), per protocol (PP), and as treated (AT). The performance of five indicators, namely percentage bias, mean square error, empirical standard error, coverage, and rejection rate, were compared among the different methods in different scenarios, and recommendations for method selection were given.Results:In terms of analytical strategies and methods, AT analysis were relatively optimal in terms of percentage bias and accuracy, followed by PP analysis and ITT analysis. When the relative treatment effects converged (e.g. HR=1.0), both the ITT analysis and the time-dependent AT approaches (marginal structural model, time-dependent Cox regression model or time-dependent propensity score matching) performed well; when the relative treatment effects were small (e.g. HR=0.8), the marginal structural model was the most optimal; when the relative treatment effects were large (e.g. HR=0.6 or 0.4), the approaches of using a censored treatment for switchers in the AT analysis were more accurate. In addition, the time-dependent AT approaches had the highest rejection rate when there was a difference in treatment effect between the two groups, and the ITT analysis had the lowest rejection rate. Conclusions:For the dual challenges of bidirectional switching and rare events in real-world drug safety evaluations, adequate sample size is a prerequisite for accurate estimation of treatment effects, while switching rates and effect sizes of switched drugs might also affect estimation accuracy. Appropriate strategies and methods should be selected for the analysis. It is necessary to consider whether the event is rare or not, the switching rate and the expected treatment effect size of the two types of treatment to select appropriate analysis strategies and methods.

The cellular and molecular components of the tumor immune microenvironment (TIME) and their information exchange processes significantly influence the trends of anti-tumor immunity. In recent years, numerous studies have begun to evaluate TIME in the context of previous cancer treatment strategies. This review will systematically summarize the compositional characteristics of TIME and, based on this foundation, explore the impact of current cancer therapies on the remodeling of TIME, aiming to provide new insights for the development of innovative immune combination therapies that can convert TIME into an anti-tumor profile.
Tumor Microenvironment/immunology* ; Humans ; Neoplasms/therapy* ; Immunotherapy/methods* ; Animals

To describe the incidence and mortality of adult head and neck cancer (HNC) in different regions worldwide and their temporal trends.

Elemene is widely recognized as an effective anti-cancer compound and is routinely administered in Chinese clinical settings for the management of several solid tumors, including non-small cell lung cancer (NSCLC). However, its detailed molecular mechanism has not been adequately demonstrated. In this research, it was demonstrated that elemene effectively curtailed NSCLC growth in the patient-derived xenograft (PDX) model. Mechanistically, employing high-throughput screening techniques and subsequent biochemical validations such as microscale thermophoresis (MST), microRNA-145-5p (miR-145-5p) was pinpointed as a critical target through which elemene exerts its anti-tumor effects. Interestingly, elemene serves as a binding stabilizer for miR-145-5p, demonstrating a strong binding affinity (dissociation constant (K _D) = 0.39 ± 0.17 μg/mL) and preventing its degradation both in vitro and in vivo, while not interfering with the synthesis of the primary microRNA transcripts (pri-miRNAs) and precursor miRNAs (pre-miRNAs). The stabilization of miR-145-5p by elemene resulted in an increased level of this miRNA, subsequently suppressing NSCLC progression through the miR-145-5p/mitogen-activated protein kinase kinase kinase 3 (MAP3K3)/nuclear factor kappaB (NF-κB) pathway. Our findings provide a new perspective on revealing the interaction patterns between clinical anti-tumor drugs and miRNAs.