Hypoglycemia is a major barrier to safe diabetes management. Although deep learning has been widely applied to blood glucose (BG) prediction, most studies provide limited hypoglycemia forewarning and are trained on small type 1 diabetes cohorts with restricted generalizability. We developed MT-HypoNet, a multitask neural network for real-time BG prediction and hypoglycemia forewarning from continuous glucose monitoring data. To improve detection near the hypoglycemia boundary, we introduce a statistically guided soft-label strategy. MT-HypoNet was validated on a multicenter cohort of 1,662 patients with type 1 and type 2 diabetes and prospectively evaluated in 36 perioperative patients with type 2 diabetes. In internal validation, MT-HypoNet achieved an AUC of 0.946 (95% CI: 0.946-0.947) for hypoglycemia forewarning and an RMSE of 19.84 ± 4.92 mg/dL for BG prediction. It generalized well to external datasets and maintained high prospective performance (AUC 0.966; RMSE 16.62 ± 4.01 mg/dL), supporting proactive management and improved safety.

Background: Evidence supports the effectiveness and safety of open-source automated insulin delivery (AID) in patients with type 1 diabetes. However, evidence regarding the clinical application of open-source AID in perioperative patients with type 2 diabetes remains limited. Methods: This was an open-label, single-center, exploratory pilot randomized controlled trial (RCT) with parallel groups. Patients with diabetes (excluding type 1 diabetes mellitus) scheduled for elective surgery were randomly assigned to the closed-loop group (open-source hybrid closed-loop AID system) or the control group (conventional insulin pump). The primary outcome was the percentage of time in the target glucose range (TIR, 3.9-10.0 mmol/L). Other efficacy and safety outcomes were also compared between the groups. Results: A total of 49 participants were included and randomized to the closed-loop group (n = 25) or the control group (n = 24). Participants underwent abdominal, orthopedic, thoracic surgery, or neurosurgery during hospitalization. Patients in the closed-loop group had significantly higher TIR than patients in the control group (76.4 ± 14.1% vs. 61.2 ± 20.0%, p = 0.005). Compared with the control group, the closed-loop group also exhibited a 15.6 percentage point reduction in time above range (TAR, >10 mmol/L) without increasing time below range (TBR, <3.9 mmol/L). There were no episodes of severe hypoglycemia (<2.2 mmol/L) or diabetic ketoacidosis in either group. Conclusions: This study demonstrates that in patients with diabetes undergoing elective surgery, the open-source hybrid closed-loop AID system provides better glycemic control than conventional insulin pump therapy.

Metabolic inflammation is closely linked to dynamic changes in circulating monocyte populations, yet how nutritional signals regulate this process remains unclear. ANGPTL8, a hepatokine rapidly induced by refeeding, emerged as a key regulator of postprandial monocyte dynamics. We examined ANGPTL8 expression in human and murine fasting-refeeding models and manipulated ANGPTL8 expression specifically in hepatocytes to assess its role in metabolic inflammation and insulin resistance in obese mice. ANGPTL8 overexpression elevated levels of circulating monocytes and proinflammatory cytokines, while its deletion reduced these parameters and conferred metabolic benefits. Mechanistically, recombinant ANGPTL8 stimulated CCL5 production in bone marrow-derived macrophages via P38 signaling activation, promoting monocyte recruitment and proinflammatory macrophage polarization. These effects were mitigated by CCR5 antagonism. Rescue experiments demonstrated that CCL5 supplementation in Angptl8-deficient mice restored monocyte levels and inflammatory responses. Functionally, ANGPTL8 worsened insulin resistance and glucose intolerance in obese mice, effects that were reversed by its deletion and recapitulated by CCL5 administration. These findings suggest that ANGPTL8 functions as a nutritional checkpoint that links feeding status to monocyte-mediated inflammation through the CCL5-CCR5 axis. By driving monocytosis and proinflammatory macrophage activation, ANGPTL8 exacerbates metabolic dysfunction. Targeting the ANGPTL8-CCL5-CCR5 pathway may therefore offer a promising therapeutic strategy for managing obesity-related metabolic diseases.

The association between remnant cholesterol (RC) with obesity phenotypes remains unclear. This study designed to evaluate the association between RC and obesity phenotypes using data from the National Health and Nutrition Examination Survey (NHANES). The classification systems for obesity phenotypes encompassed both preclinical/clinical obesity and obesity stages, which were assessed based on two authoritative obesity guidelines: the 2025 clinical obesity guideline, and the 2016 obesity guideline established by the American Association of Clinical Endocrinologists and the American College of Endocrinology (AACE/ACE). Participants were selected according to the diagnostic criteria for obesity proposed in the 2025 clinical obesity guideline and were categorized into tertiles based on their RC levels. Their obesity phenotypes, obesity-related clinical manifestations, obesity-related comorbidities, and characteristics were then described. Logistic regression analyses and restricted cubic spline (RCS) models were used to analyze the relationship between RC and adverse obesity phenotypes. Sensitivity analyses were conducted in patients not receiving lipid-lowering drugs. This study comprised 3,207 adult participants, revealing distinct prevalence patterns: 47.80

Background and aims Angiopoietin-like protein 8 (ANGPTL8), an important regulator of glucose and lipid metabolism, has recently been shown to be associated with renal function decline in patients with diabetic kidney disease (DKD). However, the underlying molecular mechanisms remain unclear. This study aimed to elucidate the novel role of ANGPTL8 in DKD progression. Methods The renal expression of ANGPTL8 was measured in patients and murine models with DKD. Proximal tubule-specific Angptl8 knockout mice were generated to elucidate the role of ANGPTL8 in the pathogenesis of DKD. In vitro, ANGPTL8 was inhibited in human proximal tubular epithelial cells (PTECs) under high glucose plus palmitic acid (HGPA) stress. ANGPTL8 interacting proteins were screened using the human proteome microarray and validated by complementary interaction assays. Functional validation employed the Akt2 small interfering RNA and the specific Akt2 inhibitor in vitro and proximal tubule-specific Akt2 knockout mice in vivo. Results ANGPTL8 expression was significantly increased in renal proximal tubules during DKD. Proximal tubule-specific Angptl8 knockout ameliorated tubular injury and reduced tubular inflammation and fibrosis in DKD mice. In vitro, ANGPTL8 inhibition protected human PTECs against HGPA-induced inflammation and epithelial-mesenchymal transition (EMT). Mechanistically, intracellular ANGPTL8 directly binds to and activates Akt2, triggering downstream NF-κB pathway activation and GSK3β inhibition. Akt2 inhibition abolished ANGPTL8's pathogenic effects in vitro and in vivo. Conclusions Our findings demonstrate for the first time that elevated tubular ANGPTL8 promotes tubular inflammation and fibrosis during DKD by interacting with Akt2, highlighting the ANGPTL8-Akt2 axis as a promising target to prevent DKD progression.

The molecular mechanisms of early-onset multigenerational diabetes remain unknown. This study aimed to investigate the clinical and genetic characteristics of early-onset diabetes involving at least two consecutive generations. From 1296 inpatients with diabetes, we selected individuals who were ≤ 30 years of age and who were clinically suspected of having familial monogenic diabetes. Clinical data were collected from the probands and their family members. Whole-exome sequencing (WES) was used to identify possible causal variants for diabetes. Candidate pathogenic variants were verified by Sanger sequencing, assessed for cosegregation in family members, and evaluated on the basis of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines. Moreover, missense and synonymous variants were subjected to in silico pathogenicity prediction via MutationTaster and PolyPhen-2. RNAfold was used to predict RNA structural alterations for synonymous variants. Twenty-five early-onset diabetes patients with a history of familial diabetes were enrolled. Pathogenic/likely pathogenic variants (p.Gly292fs in HNF1A, p.Gly245Argfs*22 in PDX1, p.Asp329His in KCNJ11, p.Leu734Phe and p.Val606Gly in WFS1) were detected in four patients, who were diagnosed accurately and treated with reasonable hypoglycemic agents based on genetic testing results. The variants of uncertain significance (ABCC8 c.3039 G > A (p.Ser1013 = Ser), MAPK8IP1 p.Gln144_Gly145insSerGln, and TBC1D4 p.Arg1249Trp) were identified in three probands. Patients with early-onset diabetes involving at least two consecutive generations may harbor genetic variants. Genetic testing in this population enables precision diagnosis, informs individualized treatment, and facilitates genetic counseling.

BACKGROUND:To assess the clinical benefits of Selenium (Se) supplementation in patients with Hashimoto thyroiditis (HT). METHODS:Eight databases were searched for randomized controlled trials. The outcomes of interest were thyroid peroxidase antibody (TPOAb), thyroglobulin antibody (TgAb), thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4). The study protocol is registered on INPLASY, DOI number is 10.37766/inplasy2022.10.0085. RESULTS:Twenty-one studies with a total of 1610 subjects were included. Serum TPOAb was significantly reduced after Se supplementation after 3 months (standardized mean difference [SMD] = -0.46, 95% confidence interval [CI]: -0.74 to -0.18, P = .001) and 6 months (SMD = -0.80, 95%CI: -1.38 to -0.21, P = .008). The serum TgAb levels decreased at 3 months (SMD = -0.46, 95%CI: -0.79 to -0.12, P = .007) but not at 6 months. Significant effects on declining the TSH titers were found after 6 months (SMD = -0.18, 95%CI = -0.35 to -0.01; P = .03). CONCLUSION:Se supplementation help reduce TPOAb and TSH levels in HT patients, leading to improvements in well-being or mood. Selenomethionine is more effective than NaSe and Se-yeast in the teatment of Hashimoto thyroid.

BACKGROUND:Cushing's syndrome (CS) is associated with increased risk for heart failure, which often initially manifests as left ventricular diastolic dysfunction (LVDD). In this study, we aimed to explore the potential risk factors of LVDD in CS by incorporating body composition parameters. METHODS:A retrospective study was conducted on patients diagnosed with endogenous CS no less than 18 years old. The control group consisted of healthy individuals who were matched to CS patients in terms of gender, age, and BMI. LIFEx software (version 7.3) was applied to measure epicardial adipose tissue volume (EATV) on non-contrast chest CT, as well as abdominal adipose tissue and skeletal muscle mass at the first lumbar vertebral level. Echocardiography was used to evaluate left ventricular (LV) diastolic function. Body compositions and clinical data were examined in relation to early LVDD. RESULTS:A total of 86 CS patients and 86 healthy controls were enrolled. EATV was significantly higher in CS patients compared to control subjects (150.33 cm3 [125.67, 189.41] vs 90.55 cm3 [66.80, 119.84], p < 0.001). CS patients had noticeably increased visceral fat but decreased skeletal muscle in comparison to their healthy counterparts. Higher prevalence of LVDD was found in CS patients based on LV diastolic function evaluated by E/A ratio (p < 0.001). EATV was proved to be an independent risk factor for LVDD in CS patients (OR = 1.015, 95%CI 1.003-1.026, p = 0.011). If the cut-point of EATV was set as 139.252 cm3 in CS patients, the diagnostic sensitivity and specificity of LVDD were 84.00% and 55.60%, respectively. CONCLUSION:CS was associated with marked accumulation of EAT and visceral fat, reduced skeletal muscle mass, and increased prevalence of LVDD. EATV was an independent risk factor for LVDD, suggesting the potential role of EAT in the development of LVDD in CS.

: Objective: This study seeks to analyze data from the United States (U.S.) Food and Drug Administration Adverse Event Reporting System (FAERS) to identify potential adverse drug event (ADE) signals associated with denosumab and provide valuable insights into the clinical safety of denosumab usage. Methods: Data on denosumabrelated ADEs reported from the FAERS between the second quarter of 2010 to the first quarter of 2022 were extracted using OpenVigil 2.1. The Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR) were calculated as measures to detect potential ADE signals. Results: The analysis of FAERS data uncovers potential ADE signals associated with the use of denosumab. These signals encompass a spectrum of adverse effects, including well- established risks such as musculoskeletal pain, hypocalcemia, and osteonecrosis of the jaw. Moreover, novel potential adverse events emerge, including oral diseases, fractures occurring in various locations, and signals indicating tumors beyond the drug's approved indications. Conclusions: This study highlights the significance of closely monitoring patients for potential adverse events during denosumab treatment. Healthcare professionals should exercise heightened vigilance for the development of oral diseases, fractures, and tumors in individuals receiving denosumab therapy. The identification of these additional ADE signals should inform clinical decision-making, patient risk assessments, and ongoing efforts in pharmacovigilance, thereby ensuring the safe and effective utilization of denosumab.

To investigate the potential mediating effect of remnant cholesterol (RC) in the associations between angiopoietin-like 8 (ANGPTL8) and the risk of all-cause, cardiovascular disease (CVD), and cancer death. This prospective observational study included 3278 individuals from China. Binary logistic regression and mediation analyses were conducted to investigate the mediating effect of RC in the associations between ANGPTL8 and all-cause, CVD, and cancer death. During up to 5-year follow-up, a total of 265 deaths (8.08

Previous studies have been limited by their inability to differentiate between the effects of insulin sensitivity and β-cell function on the risk of kidney function decline, cardiovascular disease (CVD), and all-cause mortality. To address this knowledge gap, we aimed to investigate whether the physiological subtypes based on homeostasis model assessment-2 (HOMA2) indices of β-cell function (HOMA2-B) and insulin sensitivity (HOMA2-S) could be used to identify individuals with subsequently high or low of clinical outcome risk. This retrospective cohort study included 7,317 participants with a follow-up of up to 5 years. Based on HOMA2 indices, participants were categorized into four physiologic subtypes: the normal phenotype (high insulin sensitivity and high β-cell function), the insulinopenic phenotype (high insulin sensitivity and low β-cell function), the hyperinsulinaemic phenotype (low insulin sensitivity and high β-cell function), and the classical phenotype (low insulin sensitivity and low β-cell function). The outcomes included kidney function decline, CVD events (fatal and nonfatal), and all-cause mortality. Cox regression models were used to calculate hazard ratios (HRs) for outcomes, and spline models were used to examine the dose-dependent associations of HOMA2-B and HOMA2-S with outcomes. A total of 1,488 (20.3

Thyroid cancer is the most pervasive disease in the endocrine system and is getting extensive attention. The most prevalent method for an early check is ultrasound examination. Traditional research mainly concentrates on promoting the performance of processing a single ultrasound image using deep learning. However, the complex situation of patients and nodules often makes the model dissatisfactory in terms of accuracy and generalization. Imitating the diagnosis process in reality, a practical diagnosis-oriented computer-aided diagnosis (CAD) framework towards thyroid nodules is proposed, using collaborative deep learning and reinforcement learning. Under the framework, the deep learning model is trained collaboratively with multiparty data; afterward classification results are fused by a reinforcement learning agent to decide the final diagnosis result. Within the architecture, multiparty collaborative learning with privacy-preserving on large-scale medical data brings robustness and generalization, and diagnostic information is modeled as a Markov decision process (MDP) to get final precise diagnosis results. Moreover, the framework is scalable and capable of containing more diagnostic information and multiple sources to pursue a precise diagnosis. A practical dataset of two thousand thyroid ultrasound images is collected and labeled for collaborative training on classification tasks. The simulated experiments have shown the advancement of the framework in promising performance.

Background Thrombocytopenia and poor prognosis in severe conditions are associated. However, the clinical significance of thrombocytopenia in pyogenic liver abscess (PLA) has not been evaluated. Objective To evaluate the association between thrombocytopenia and the prognosis of patients with PLA. Methods A consecutive case series of 458 adult patients with PLA hospitalized at Tongji Hospital (Wuhan, China) between October 2011 and June 2021 was included in this cross-sectional analysis. Patient data were compared between the thrombocytopenia and non-thrombocytopenia groups. Multivariate logistic regression, receiver operating characteristic (ROC) curve and propensity score -matched analyses (PSM) were performed. Results Of the 458 patients with PLA, 94 (20.5%) developed thrombocytopenia, 19 (4.1%) developed septic shock, 14 (3.1%) were admitted to the ICU, and 15 (3.3%) died during hospitalization. Thrombocytopenia was independently associated with shock (95%CI = 3.529–57.944, P < 0.001), ICU admission (95%CI = 1.286–25.733, P = 0.022), and mortality (95%CI = 1.947–34.223, P = 0.004) in multivariate regression analysis. ROC analysis showed that thrombocytopenia may be an identified marker of shock [area under the ROC curve (AUC), 0.8119; cut-off, 92.50; P < 0.0001], ICU admission (AUC, 0.7484; cut-off, 82.50; P < 0.0015), and mortality (AUC, 0.7827; cut-off, 122.50; P < 0.002). These findings remained consistent across 86 pairs of patients analyzed for PSM analyses. Conclusions Thrombocytopenia is an independent risk factor for poor prognosis in PLA and patients may be more prone to adverse outcomes.

Inhibition of immunocyte infiltration and activation has been suggested to effectively ameliorate nonalcoholic steatohepatitis (NASH). Paired immunoglobulin-like receptor B (PirB) and its human ortholog receptor, leukocyte immunoglobulin-like receptor B (LILRB2), are immune-inhibitory receptors. However, their role in NASH pathogenesis is still unclear. Here, we demonstrate that PirB/LILRB2 regulates the migration of macrophages during NASH by binding with its ligand angiopoietin-like protein 8 (ANGPTL8). Hepatocyte-specific ANGPTL8 knockout reduces MDM infiltration and resolves lipid accumulation and fibrosis progression in the livers of NASH mice. In addition, PirB −/− bone marrow (BM) chimeras abrogate ANGPTL8-induced MDM migration to the liver. And yet, PirB ectodomain protein could ameliorate NASH by sequestering ANGPTL8. Furthermore, LILRB2-ANGPTL8 binding-promoted MDM migration and inflammatory activation are also observed in human peripheral blood monocytes. Taken together, our findings reveal the role of PirB/LILRB2 in NASH pathogenesis and identify PirB/LILRB2-ANGPTL8 signaling as a potential target for the management or treatment of NASH.

Background: Stickler syndrome (SS) is a group of hereditary collagenopathies caused by a variety of collagen and non-collagen genes. Affected patients have characteristic manifestations involving ophthalmic, articular, craniofacial and auditory disorders. SS is classified into several subtypes according to clinical and molecular features. Type 3 SS is an ultra-rare disease, known as non-ocular SS or otospondylomegaepiphyseal dysplasia (OSMED) with only a few pathogenic COL11A2 variants reported to date. Case presentation: A 29-year-old Chinese male was referred to our hospital for hearing loss and multiple joint pain. He presented a phenotype highly suggestive of OSMED, including progressive sensorineural deafness, spondyloepiphyseal dysplasia with large epiphyses, platyspondyly, degenerative osteoarthritis, and sunken nasal bridge. We detected compound heterozygous mutations in COL11A2, both of which were predicted to be splicing mutations. One is synonymous mutation c.3774C>T (p.Gly1258Gly) supposed to be a splice site mutation, the other is a novel intron mutation c.4750 + 5 G>A, which is a highly conservative site across several species. We also present a review of the current known pathogenic mutation spectrum of COL11A2 in patients with type 3 SS. Conclusion: Both synonymous extonic and intronic variants are easily overlooked by whole-exome sequencing. For patients with clinical manifestations suspected of SS syndrome, next-generation whole-genome sequencing is necessary for precision diagnosis and genetic counseling.

目的 利用大样本数据对依洛尤单抗和阿利西尤单抗的不良事件(ADE)进行信号挖掘分析,为临床合理安全用药提供参考.方法 收集美国食品药品管理局不良事件报告系统(FAERS)中2015年第3季度—2021年第2季度共24季度的依洛尤单抗和阿利西尤单抗的ADE报告,采用报告比值比(ROR)法和比例报告比值(PRR)法对其进行数据挖掘.利用《国际医学用语词典》(MedDRA)对药物不良事件信号进行标准化分析.结果 共收集不良事件报告8 024 207份,筛选出相关的ADE报告73 797份,其中依洛尤单抗报告61 883例,阿利西尤单抗报告11 914例,男女比例0.74∶1,年龄集中在45～74岁.挖掘到依洛尤单抗和阿利西尤单抗相关ADE信号主要集中在注射部位反应、骨骼肌肉系统疾病以及呼吸系统疾病等方面,且依洛尤单抗在骨骼肌肉系统疾病及呼吸系统疾病相关ADE具有更高风险.将信号进行规整比对,还挖掘出了神经系统疾病等药品说明书中尚未收录的关联较强的ADE信号.结论 利用FAERS数据库可较深入挖掘分析依洛尤单抗和阿利西尤单抗的安全警示信号,为临床安全合理选择用药提供参考.

Background Skeletal muscle mass is an essential parameter for diagnosing sarcopenia. The gold standard for assessing skeletal muscle mass is using computed tomography (CT) to measure skeletal muscle area at the third lumbar vertebra (L3) level. This study aims to investigate whether skeletal muscle mass could be evaluated at the first lumbar vertebra (L1) level using images obtained from routine chest CT scans. Methods Skeletal muscle index (SMI, cm2/m2) and skeletal muscle density (SMD, HU) are commonly used to measure relative muscle mass and the degree of fat infiltration. This study used CT images at the L1 level to measure the skeletal muscle area (SMA, cm2) in 815 subjects from the health examination center. Linear regression analysis was used to explore the association between L1 and L3 measurements. The receiver operating characteristic (ROC) analysis was used to assess the predictive performance of L1 SMI for sarcopenia. The sex-specific cut-off values for low skeletal muscle mass in patients under the age of 60 were determined using the following formula: “mean − 1.28 × standard deviation.” A multivariate linear regression model was established. Results A significantly higher SMI at the L1 level was found in males than in females (43.88 ± 6.33 cm2/m2 vs 33.68 ± 5.03 cm2/m2; P < 0.001). There were strong correlations between measures at the L1 and L3 levels in both the total subject and sex-specific analyses. A negative association was found between age and L3 SMI in males (r = −0.231, P = 0.038). Both body mass index (BMI) and body surface area (BSA) were positively associated with L1 SMI in both males and females. A multivariate analysis was used to establish a prediction rule to predict SMI at the L3 level. The assessment of consistency and interchangeability between predicted and actual SMI at the L3 level yielded moderately good results. Considering the significant differences observed between male and female participants, the sex-specific cut-off values of the L1 SMI for defining low skeletal muscle mass were 36.52 cm2/m2 in males and 27.29 cm2/m2 in females. Conclusions Based on a population from central China, the correlated indicators obtained at the L1 level from routine chest CT scans may serve as effective surrogate markers for those at the L3 level in assessing overall skeletal muscle mass.

Background Low muscle mass/sarcopenia has been associated with poor prognosis in many diseases, but its clinical significance in pyogenic liver abscess (PLA) remains unclear. The purpose of this study is to investigate the relationship between muscle mass and prognosis of patients with PLA. Methods A total of 154 adult patients with PLA hospitalized at Tongji Hospital (Wuhan, Hubei, China) between October 2011 and June 2021 were included in this retrospective analysis. Muscle-fat related indicators were measured by computed tomography (CT) images at the third lumbar vertebra (L3) level. The data of patients between the sarcopenia group and non-sarcopenia group were compared. Multivariate logistic regression and receiver operating characteristic (ROC) curve analyses were performed. Results The skeletal muscle index (SMI) was independently associated with adverse outcomes (95% CI [0.649–0.954], P = 0.015) of PLA in multivariate logistic regression analysis. This conclusion held true in sex-specific subgroup analysis. ROC analysis indicated that SMI may predict adverse outcomes in both male (area under the ROC curve [AUC], 0.718; cut-off, 52.59; P < 0.001) and female (AUC, 0.714; cut-off, 38.39; P = 0.017) patient populations. Conclusions Sarcopenia serves as an independent risk factor for poor prognosis in PLA and patients with sarcopenia may be more prone to adverse outcomes.