Introduction: Diabetic ketoacidosis (DKA) is a life-threatening complication associated with significant morbidity and healthcare burden. Despite advances in diabetes care, recurrent DKA remains common, often reflecting gaps in treatment adherence and patient education. Identifying predictors of recurrence is crucial for risk stratification and targeted intervention. Methodology: We conducted a retrospective observational study of all adult DKA admissions to a tertiary centre between 2001 and 2025. Electronic medical records were reviewed for demographic data, biochemical parameters, precipitating factors, and clinical outcomes. DKA was defined using standard biochemical criteria. Recurrent DKA was defined as ≥2 admissions during the study period. Factors associated with recurrent DKA admissions were analyzed. Patients under the age of 18 years and those with missing vital information were excluded. Results: A total of 667 DKA admissions, comprising 566 patients, were identified, of which 101 admissions (15.1%) were recurrent, involving 65 patients. Among recurrent DKA episodes, the most common precipitating factors were infection (64.4%) and insulin omission (62.4%). After multivariate analyses, patients with type 1 diabetes mellitus (T1DM) were more likely to develop recurrent DKA compared to those with type 2 diabetes mellitus (aOR 4.16; 95% confidence interval [CI] 2.58–6.70; p <0.001). Insulin omission was strongly associated with recurrent DKA (aOR 2.29; 95% CI 1.46–3.60; p <0.001). In contrast, baseline glycated hemoglobin and chronic kidney disease were not significantly associated with recurrence. Diabetic counseling during the first DKA admission did not reduce recurrent DKA. There were no significant differences in mortality (3.9% vs 6.2%, p = 0.524) or critical care admission rates (40.6% vs 38.7%, p = 0.718) between recurrent and first DKA episodes. Conclusion Recurrent DKA accounts for a substantial proportion of DKA admissions and is strongly associated with insulin omission and T1DM. Our findings suggest that recurrent DKA is driven predominantly by behavioral and adherencerelated factors, indicating the need for multidisciplinary interventions beyond standard inpatient counseling.
Diabetic Ketoacidosis ; Retrospective Studies

Introduction: The rising incidence of diabetic ketoacidosis (DKA) in type 2 diabetes mellitus (T2DM) represents a paradigm shift from its traditional recognition as a hallmark complication of type 1 diabetes mellitus (T1DM). However, contemporary data comparing clinical presentation, precipitating factors, and outcomes between these two populations remain limited. Methodology: In this retrospective observational study, all adult DKA admissions with T1DM or T2DM at a tertiary centre between 2001 and 2025 were studied. DKA was defined according to standard biochemical criteria. Electronic medical records were reviewed to extract demographic data, biochemical parameters, precipitating factors, management details, and clinical outcomes of all adult DKA admission in T1DM and T2DM. Patients aged <18 years or those with incomplete data were excluded. Results: A total of 601 DKA episodes were analyzed, comprising 130 (21.6%) in patients with T1DM and 471 (78.4%) in those with T2DM. Mean age was 26.9 ± 0.71 years for T1DM and 52.1 ± 0.7 years for T2DM. Gender distribution was balanced (male 48.3%, female 51.7%). Mean hemoglobin A1c (HbA1c) was 11.3 ± 0.3% in T1DM and 12.1 ± 0.2% in T2DM. Infection was the most common precipitating factor overall (69.0%), occurring more frequently in T2DM than in T1DM (74.7% vs. 56.2%), followed by medication non-adherence (62.4% vs. 43.8%). Significant differences were observed between groups in admission pH, bicarbonate (both p <0.001), blood ketones (p = 0.028), and HbA1c (p = 0.010), whereas anion gap (p = 0.056) and blood glucose levels (p = 0.755) did not differ significantly. Clinical outcomes were comparable with respect to intensive care unit (ICU) admission rates (40.0% in T1DM vs. 39.0% in T2DM, p = 0.779) and median resolution time (p = 0.462). However, the median length of hospital stay was significantly longer in T2DM (8.2 ± 0.32 vs. 5.4 ± 0.4 days; p <0.001). Overall mortality was 6.0%, with substantially higher mortality in T2DM compared to T1DM (7.4% vs. 0.8%, p = 0.013). Conclusion In this large regional series of adult DKA, most episodes occurred in T2DM. Despite similar ICU admission rates and time to resolution, T2DM was associated with more frequent infection-related precipitants, longer hospital stays, and higher mortality, underscoring the need for targeted preventive strategies in this population.
Adult ; Diabetes Mellitus, Type 1 ; Diabetic Ketoacidosis ; Diabetes Mellitus, Type 2

Introduction: Diabetic ketoacidosis (DKA) in pregnancy is an uncommon yet life-threatening emergency, with disproportionate risks to both mother and fetus. Pregnancy-specific physiological changes predispose patients to rapid metabolic decompensation, often with atypical presentations. Despite this, local data remain limited. We describe the clinical profile, precipitating factors, and outcomes of DKA in pregnancy in a tertiary centre, with emphasis on potentially preventable triggers. Cases: Nine pregnant patients with DKA were identified from a retrospective review of all cases admitted for DKA from 2002 to 2025. Mean age was 31.67 ± 5.20 years; all were Malay. The majority had type 2 diabetes mellitus (55.6%), followed by type 1 diabetes (33.3%) and latent autoimmune diabetes in adults (11.1%). The mean period of amenorrhea was 19.67 ± 12.62 weeks. Infection was the leading precipitant (44.4%), with additional triggers including insulin omission (22.2%), hyperemesis gravidarum, preterm labor, steroid exposure, and perioperative fasting. Most diagnoses were made in the emergency department (55.6%). Biochemical parameters reflected significant severity (mean bicarbonate 7.89 ± 2.98 mmol/L; anion gap 25.00 ± 5.81), with 88.9% classified as severe DKA. Intensive Care Unit (ICU) care was required in 77.8% of cases. The majority (77.8%) were admitted to the ICU unit, with a median time to resolution of 13.00 ± 12.00 hours (interquartile range [IQR]), and the median hospital length of stay was 7.00 ± 5.00 days (IQR). Complications during treatment included hypokalemia (33.3%), acute kidney injury (22.2%), and hypoglycemia (11.1%). Rebound DKA occurred in one-third of patients. All patients were discharged clinically stable. Outcome data demonstrated pregnancy loss in three cases and one preterm birth. Conclusion DKA in pregnancy remains a severe and resource-intensive condition. This series highlights missed opportunities in prevention, with modifiable precipitants such as infection and insulin omission commonly identified. The high severity at presentation suggests delays in recognition. Early detection, optimized metabolic care, and targeted preventive strategies are crucial to improving maternal and fetal outcomes.
Female ; Pregnancy ; Diabetic Ketoacidosis

Background/Aims: Lenvatinib resistance remains a critical barrier in advanced hepatocellular carcinoma (HCC) therapy. However, the underlying mechanisms and strategies for reversing resistance remain incompletely understood. Methods: Integrated transcriptomics of lenvatinib-resistant patient tumors and an acquired-resistance murine model identified a novel macrophage subpopulation. Functional validation employed CRISPR-SAM screening, conditioned medium (CM) assays, subcutaneous/orthotopic xenografts, patient-derived organoids (PDOs), and patient-derived xenografts (PDXs). Mechanistic studies included ChIP-qPCR, co-immunoprecipitation, and pharmacologic targeting. Clinical relevance was assessed in a retrospective cohort. Results: Resistant HCC exhibited significant enrichment of a COLEC12high TAM subset , which correlated with poor survival and treatment response. These TAMs secreted neuregulin-1 (NRG1) , activating HER2/HER3-AKT signaling in tumor cells to drive cancer stemness and lenvatinib resistance. Mechanistically, in TAMs COLEC12 sequestered STAT1 in the cytoplasm, preventing its phosphorylation, and thereby derepressing STAT3-mediated NRG1 transcription. Depletion of NRG1 reversed the stemness phenotypes and resensitized tumors to lenvatinib both in vitro and in vivo. Clinically, high NRG1 expression predicted an inferior lenvatinib response and shorter survival. Crucially, the bispecific anti-HER2/HER3 antibody zenocutuzumab restored lenvatinib efficacy in PDOs, PDXs, and murine models. Conclusions Our work establishes the COLEC12high TAM/NRG1 axis as a master regulator of therapeutic resistance and identifies NRG1 as a predictive biomarker, providing a clinically actionable strategy to overcome lenvatinib resistance in HCC.

ObjectiveTo investigate the impact of portal vein tumor thrombus （PVTT） classification on rebleeding in hepatocellular carcinoma （HCC） patients with different PVTT subtypes and esophagogastric variceal bleeding （EGVB）， and to provide a reference for formulating rational treatment regimens for such patients. MethodsA retrospective study was performed for 130 patients with HCC and PVTT who were treated due to EGVB in Beijing Ditan Hospital， Capital Medical University， from July 2020 to January 2025， and according to whether endoscopic treatment was performed， the patients were divided into endoscopic treatment group with 97 patients and conservative treatment group with 33 patients. Demographic and clinical data were collected from all patients， and the two groups were compared in terms of hemostasis success rate and rebleeding rate. The independent-samples t test was used for comparison of normally distributed continuous data between groups， and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between groups； the chi-square test or the Fisher’s exact test was used for comparison of categorical data between groups. The Kaplan-Meier method was used to estimate the cumulative incidence rate of rebleeding in patients with different subtypes of PVTT. Propensity score matching （PSM） was performed for the endoscopic treatment group and the conservative treatment group to balance the baseline data of the two groups. The Cox proportional hazards model was used to perform univariate and multivariate analyses and identify independent risk factors for rebleeding. ResultsThe endoscopic treatment group had a significantly lower cumulative rebleeding rate within 6 months than the conservative treatment group （35.1% vs 57.6%， hazard ratio ［HR］=0.480， 95% confidence interval ［CI］： 0.272—0.851， P=0.019）. The PVTT Ⅲ—Ⅳ group had a significantly higher cumulative rebleeding rate within 6 months than the PVTT Ⅱ group （52.2% vs 37.5%， HR=1.744， 95%CI： 1.008 — 3.018， P=0.022）. After PSM， there was no significant difference in rebleeding rate between the endoscopic treatment group and the conservative treatment group （38.1% vs 14.3%，HR=1.500，95%CI：0.125 — 2.002， P=0.588）， while the PVTT Ⅲ—Ⅳ group had a significantly higher cumulative rebleeding rate than the PVTT Ⅱ group （58.8% vs 12.5%，HR=1.561，95%CI：1.195 — 12.499，P=0.033）. The multivariate Cox regression analysis showed that PVTT subtype （HR=1.412， 95%CI： 0.998 — 1.997， P=0.049）， platelet count （HR=1.006， 95%CI： 1.001 — 1.010， P=0.021）， C-reactive protein （HR=1.011， 95%CI： 1.001 — 1.021， P=0.026）， and ascites （HR=1.803， 95%CI： 1.059 — 3.068， P=0.030） were independent risk factors for rebleeding. ConclusionFor HCC patients with PVTT and EGVB， endoscopic treatment can successfully achieve hemostasis， while it fails to significantly reduce rebleeding rates. PVTT classification can affect the risk of rebleeding， and patients with PVTT types Ⅲ—Ⅳ have a relatively high rebleeding rate.

ObjectiveAs a common lifestyle habit, alcohol consumption has a controversial association with the onset of Parkinson’s disease (PD). To demonstrate the correlation between alcohol consumption and PD and to identify associated genes, we integrated findings from clinical surveys, genomics, transcriptomics, and animal experiments. MethodsWe investigated the alcohol consumption rates (including both before and after disease onset) among 244 PD patients in China and 177 PD patients from the U.S. NHANES database. Mendelian randomization (MR) analysis was performed using genome-wide association study (GWAS) data for three alcohol-related traits and seven PD-related datasets from the MRC IEU OpenGWAS database. Transcriptomic data from the substantia nigra of PD patients were obtained from three GEO datasets (GSE7621, GSE20141, and GSE49036) to analyze RIT2 gene transcription. Finally, three groups of animal experiments (water/20% ethanol/20% liquor, with 4 C57BL/6J mice per group) were conducted to examine changes in brain RIT2 gene expression and transcriptomic profiles following alcohol consumption. ResultsThe alcohol consumption rates among PD patients in China and the U.S. (9%-18.87%) were significantly lower than the general population rates of 15%-45% in their respective regions (P<0.001), suggesting a possible negative association between alcohol consumption and PD. Subsequently, in 21 bidirectional MR analyses using 3 alcohol-related GWAS datasets and 7 PD-related GWAS datasets, the forward MR analyses (alcohol intake as exposure, PD as outcome) yielded 12 negative associations (OR_IVW<1) and 9 positive associations (OR_IVW>1). Among these, only two negative associations reached statistical significance: alcohol intake frequency (OR_IVW=0.75, 95% CI: 0.60-0.93, P=0.010) and alcohol consumption (OR_IVW=0.20, 95% CI: 0.05-0.83, P=0.026). The forward MR analysis (alcohol intake→PD) identified 235 SNPs, annotated to 316 genes, while the reverse MR analyses (PD→alcohol intake) identified 37 SNPs, annotated to 53 genes. Notably, only the RIT2 gene appeared in both the forward and reverse MR analyses (alcohol intake→PD: rs28597806, rs8083110; PD→alcohol intake: rs4588066). RIT2 is selectively expressed in the human brain (FPKM: 5.259±2.103), with low or no expression in peripheral tissues (FPKM: <1). Analysis of three human substantia nigra transcriptomic datasets revealed a decreasing trend in RIT2 gene expression in PD patients (GSE20141 array signal: 3.49±1.23 vs. 2.33±0.87, P=0.044). Animal experiments demonstrated that administration of 20% ethanol or 20% liquor (approximately 8% ethanol) stimulated a >2-fold upregulation of RIT2 gene expression in the mouse brain. Furthermore, transcriptomic sequencing revealed that the two alcohol-treated groups exhibited 96 (20% ethanol vs. water control) and 4 (20% liquor vs. water control) differentially expressed genes, respectively, indicating that low-dose alcohol consumption can achieve RIT2 upregulation while minimizing impact on other brain genes. In addition to its anti-infective effects, low-dose alcohol consumption primarily influences signaling pathways related to neurodegenerative diseases such as PD and Prion diseases. ConclusionAlcohol consumption is generally considered as a harmful lifestyle habit. However, some studies have also shown a lower risk of mortality among individuals who consume low doses of alcohol (100 g/week of ethanol) or drink occasionally. Currently, one of the research focuses on alcohol consumption is whether the human body can benefit from low-dose alcohol intake. This study provides new evidence supporting a negative association between alcohol consumption and PD, and for the first time, through MR analysis, identifies the RIT2 gene as a potential mediator of the effect of alcohol consumption on PD. RIT2 is selectively expressed in the human brain. Building upon existing evidence indicating downregulated RIT2 gene expression in PD pathogenesis, our experiments confirm that low-dose alcohol consumption can upregulate RIT2 expression in the brain. In brief, alcohol consumption may suppress the pathogenesis of PD by upregulating RIT2 expression in the substantia nigra. China is facing a serious problem of population aging. This study offers important insights for long-term PD prevention and treatment strategies, with the aim of benefiting more potential PD patients through lifestyle modifications, thereby improving the quality of life of the aging population and reducing the economic burden on healthcare.

Driven by policy initiatives promoting the integration of digital-intelligent technologies with primary healthcare and the digital transformation of traditional Chinese medicine (TCM), Smart TCM has emerged as a pivotal strategy for enhancing primary healthcare services for major chronic diseases. This paper reviews the current status, challenges, and feasible pathways of Smart TCM in community-level management of cardiovascular–cerebrovascular diseases and tumors, which represent major chronic disease burdens. Our findings indicate that Smart TCM demonstrates emerging potential in primary healthcare for chronic diseases across the entire continuum of “prevention-screening-diagnosis-treatment-management.” However, several significant challenges persist, including data silos and security vulnerabilities, limited applicability of existing models to real-world clinical needs, and insufficient digital literacy among primary healthcare physicians and elderly patients. To address these constraints, this paper proposes a multidimensional strategy encompassing the development of secure and interoperable regional data platforms, lightweight intelligent devices and support services aligned with primary care capacity, unified technical and data standards with corresponding quality control systems, adaptive and dynamically updated artificial intelligent models, interdisciplinary workforce training and patient education programs, and enhanced policy and health insurance support. Overall, Smart TCM shows great promise for improving the efficiency of primary healthcare delivery and establishing innovative TCM-based chronic disease management paradigms.

OBJECTIVE To investigate the mechanism by which Shenfukang capsule （SFK） ameliorates renal interstitial fibrosis （RIF） by regulating macrophage-fibroblast crosstalk via the signal transducer and activator of transcription 3 （STAT3）/Yes-associated protein （YAP） pathway. METHODS RAW264.7 macrophages were induced to polarize with transforming growth factor-β 1 （TGF-β 1 ）. Subsequently， a non-contact co-culture system of macrophages with renal fibroblasts NRK-49F， as well as a non-contact co-culture system of macrophages with YAP-knockdown renal fibroblasts， were established. Cells were treated with low， medium， and high concentrations （4， 8， 16 μg/mL） of SFK， as well as a STAT3 inhibitor （STAT3-I，1.64 μg/mL） and losartan potassium tablets （positive control， 0.28 μg/mL）， for 48 h. After intervention， the protein and mRNA expression levels of CD86， CD163， and STAT3 in macrophages， as well as CD86， F4/80， and STAT3 mRNA， were detected. In co-cultured renal fibroblasts， the protein and mRNA expression levels of α -smooth muscle actin （ α -SMA）， Vimentin， collagen type Ⅰ （Col-Ⅰ）， matrix metalloproteinase-1 （MMP-1）， and YAP were detected. In co-cultured YAP-knockdown renal fibroblasts， the protein and mRNA expression levels of α -SMA， Vimentin， and MMP-1 were also detected. RESULTS Following TGF-β 1 induction， the protein expression levels of CD86， CD163， and STAT3， as well as the mRNA expression levels of CD86， F4/80， and STAT3 in macrophages were significantly increased （ P ＜0.05）. The conditioned medium from polarized macrophages activated renal fibroblasts， as evidenced by significantly increased protein and mRNA expression levels of α -SMA， Vimentin， Col-Ⅰ， and YAP， and significantly decreased protein and mRNA expression levels of MMP-1 in renal fibroblasts （ P ＜0.05）. Treatment with SFK and STAT3-I reversed the changes in the above indicators， with the medium concentration SFK group showing stronge r effects on some indicators than the low and high concentration groups. In the non-contact co-culture experiment of macrophages and YAP-knockdown renal fibroblasts， there were no statistically significant differences in the protein and mRNA expression of α-SMA， Vimentin， and MMP-1 among the groups. CONCLUSIONS SFK can inhibit macrophage-renal fibroblast crosstalk by blocking the STAT3/YAP pathway， thereby delaying the progression of RIF.

Colorectal cancer (CRC) is a common malignant tumor. The treatment of patients with advanced disease still faces severe challenges. Among patients with metastatic colorectal cancer (mCRC), most of those with microsatellite stable (MSS)/proficient mismatch repair (pMMR) tumors are highly insensitive to monotherapy with immune checkpoint inhibitors. With in-depth investigations into the mechanisms of the tumor immune microenvironment in MSS/pMMR CRC, the combination strategies of immunotherapy and targeted therapy have become a key direction to break through the treatment bottleneck in this population. These strategies include combinations of immunotherapy with antiangiogenic agents, epidermal growth factor receptor inhibitors, histone deacetylase inhibitors, and MAPK pathway inhibitors. Although the current relevant evidence is mainly derived from early-phase clinical trials, a number of studies demonstrated that immunotherapy combined with targeted therapy can improve the objective response rate and survival benefit in patients with MSS/pMMR mCRC and shows remarkable efficacy advantages in specific subgroups. This article systematically reviews the biological basis and clinical research progress of relevant combination therapeutic strategies, discusses potential beneficiary subgroups, and prospects future research directions. It aims to provide theoretical evidence and clinical references for optimizing the individualized treatment paradigm for this large patient population.

ObjectiveTo clarify whether METTL14 mediates the core role of acupuncture at Neiguan (PC6) in promoting myelination and improving behavior in young autistic rats through gene intervention technology. MethodsThe ASD model was established by intraperitoneal injection of valproic acid (VPA) in pregnant rats. Male offspring were intracerebroventricularly injected with adenovirus-packaged METTL14 shRNA (sh-METTL14) or its control (sh-NC) on postnatal day 1, with a model group set as well. Subsequently, the juvenile rats were divided into model group, acupuncture group, acupuncture+sh-NC group, and acupuncture+sh-METTL14 group. The acupuncture group received acupuncture at Neiguan (PC6) from postnatal day 7, once daily for 21 consecutive days. Neurobehavioral changes were evaluated by behavioral tests; METTL14 knockdown efficiency and the expression of METTL14, METTL3, and PTEN were detected by quantitative real-time PCR (qRT-PCR) and Western blot (WB); PTEN m⁶A levels were measured by RNA immunoprecipitation-qPCR (RIP-qPCR); myelin ultrastructure, expression of myelin basic protein (MBP) and neurofascin 155 (NF155), and dendritic spine density were observed using transmission electron microscopy (TEM), enzyme-linked immunosorbent assay (ELISA), immunofluorescence, qRT-PCR, and primary neuron culture. ResultsBehaviorally, knockdown of METTL14 significantly counteracted the beneficial effects of acupuncture in improving self-grooming, open field exploration, three-chamber social interaction, and Morris water maze learning and memory (P<0.05, P<0.01). Compared with the acupuncture+sh-NC group, the acupuncture+sh-METTL14 group showed significantly decreased mRNA and protein expression of hippocampal METTL14 (P<0.01), and the upregulating effects of acupuncture on METTL3 and PTEN expression were reversed (P<0.01). Meanwhile, knockdown of METTL14 significantly inhibited the acupuncture-induced increase in PTEN m⁶A levels (P<0.01). Morphologically, knockdown of METTL14 attenuated the improvement of myelin structure by acupuncture, reversed the downregulation of MBP and upregulation of NF155 induced by acupuncture, and blocked the increase in dendritic spine density (P<0.05, P<0.01). ConclusionMETTL14 is a key molecule mediating the therapeutic effect of acupuncture at Neiguan. Acupuncture at Neiguan upregulates METTL14, thereby enhancing m⁶A methylation modification of PTEN mRNA to stabilize its expression, ultimately promoting myelin development and improving behavioral symptoms in ASD juvenile rats. This preliminarily reveals the modern biological connotation of “opening Xuanfu and dredging myelin”.