Insulin resistance (IR) contributes to the development of the no-reflow phenomenon in acute myocardial infarction patients following coronary revascularization. However, the impact of IR on futile recanalization for anterior circulation large vessel occlusion (LVO) patients following endovascular treatment (EVT) remains unclear. This study was based on a multicenter cohort. Acute ischemic stroke patients with LVO who underwent successful EVT within 24 h of symptom onset were enrolled. IR was assessed by the triglyceride-glucose (TyG) index, obtained as ln [fasting TG (mg/dl) × FBG (mg/dl)/2]. The primary outcome was futile recanalization (90-day modified Rankin Scale [mRS] score 3–6 despite successful recanalization). Symptomatic intracranial hemorrhage was assessed as an independent short-term outcome and evaluated as a potential mediator between TyG and futile recanalization. Of 860 patients screened for eligibility, 608 patients who achieved recanalization were included. Enrolled patients were divided into three groups based on the TyG index levels (tertile [T] 1: 5.45–8.41; T2: 8.41–8.95; T3: 8.95–10.97). After adjustment for confounders, the T3 group had a higher proportion of futile recanalization than the T1 and T2 groups (T3 vs. T1: adjusted OR: 2.08, 95% CI 1.30–3.33, P = 0.002; T3 vs. T2: adjusted OR: 1.89, 95% CI 1.18–3.02, P = 0.008). The restricted cubic splines regression model revealed that the risk of futile recanalization and symptomatic intracranial hemorrhage (sICH) increased linearly with elevated TyG index. Mediation analysis showed that sICH partially mediated an estimated 17.4% (95% CI 1.3–58.0%) of the association between a higher TyG index and futile recanalization. The TyG index is a robust risk factor for symptomatic intracranial hemorrhage and futile recanalization in acute LVO patients who achieved successful recanalization.

Objective:Effectively managing postprandial blood glucose is significant for impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM). We developed a streamlined and real-world framework and evaluated how meal timing and staple food type affect postprandial glycemic responses (PPGRs) and the influencing factors on inter-individual differences of PPGR. Materials and methods:We conducted a prospective observational study involving 33 patients with IGT and T2DM. Over a 1-week free-living period, participants completed 7 standardized meal tests: glucose solutions at breakfast, lunch, and dinner; steamed bread, rice, noodles, and oats at lunch. Linear mixed-effects models were used to compare PPGR differences of meal timing and staple food type effects. Linear regression models were applied to explore factors influencing inter-individual heterogeneity in PPGRs. Results:Participants deemed the framework simple and well tolerated. Meal timing had no significant effect on PPGR at 120 minutes (time effect P = 0.110) or 180 minutes (time effect P = 0.097). HOMA-IR was positively associated with the meal timing variability index (adjusted: β = 9.10, 95% CI: 3.01-15.20, P = 0.005). Staple food types affected 120- and 180-minute incremental area under the curve (iAUC), relative peak glucose, and glucose fluctuation amplitude (staple food type effect P < 0.001), but had no significant effects on time to peak or coefficient of variation (staple food type effect P > 0.05). Those born in northern China had a significantly higher refined staple food sensitivity index (adjusted: β = 267.14, 95% CI: 59.18-475.09, P = 0.014). Conclusion:The framework enables convenient, outpatient-based assessment of PPGRs and is highly acceptable to patients. We need to focus not only on the group-level general characteristics of PPGRs but also analyze their individual-level heterogeneity; this emphasizes the critical role of personalized nutrition.

AIMS:To evaluate the platform-independent robustness of the continuous glucose monitoring (CGM)-derived High Blood Glucose Index (HBGI) and the predictive utility of a single day for progression to type 2 diabetes. METHODS:We analysed 365 valid CGM records from three devices across four independent cohorts. Linear mixed-effects modelling partitioned HBGI variance by device, dataset and metabolic status. Cross-sectional analyses, utilizing full monitoring periods to ensure biological robustness, evaluated HBGI gradients across glycaemic stages. Longitudinal analyses, utilizing single-day recordings, evaluated its predictive accuracy for progression to overt diabetes. RESULTS:Device type accounted for only 3.4% of total HBGI variance, compared with 31.8% for metabolic status. Cross-sectionally, HBGI demonstrated a robust stepwise increase from healthy through prediabetes to diabetes (p < 0.001). Longitudinally, baseline HBGI significantly differentiated metabolic progressors from non-progressors (p = 0.005) and showed moderate predictive accuracy (area under the curve = 0.74; 95% confidence interval: 0.61-0.85). Discriminative performance was comparable to mean glucose and superior to the M-value, time in range (70-180 mg/dL) and coefficient of variation. Notably, among prediabetic individuals with established glycaemic indices within recommended ranges, elevated HBGI (>0.174) identified an occult high-risk subgroup with a 5.39- to 6.13-fold higher progression risk. CONCLUSIONS:HBGI is a device-agnostic metric that effectively stratifies glycaemic severity. A single-day HBGI assessment provides complementary risk stratification by unmasking occult risk in prediabetes with established CGM indices within recommended ranges. However, given the limited progression events, its predictive threshold requires validation in larger, independent cohorts.

Abstract Background Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used due to their profound efficacy in glycemic control and weight management. Real-world observations have revealed potential neuropsychiatric adverse events (AEs) associated with GLP-1RAs. This study aimed to comprehensively investigate and characterize these neuropsychiatric AEs with GLP-1RAs. Methods We analyzed GLP-1RA adverse reaction reports using the FDA Adverse Event Reporting System database. Disproportionality analysis using reporting odds ratio (ROR) identified eight categories of neuropsychiatric AEs associated with GLP-1RAs. We conducted descriptive and time-to-onset (TTO) analyses and explored neuropsychiatric AE signals among individual GLP-1RAs for weight loss and diabetes mellitus (DM) indications. Results We identified 25,110 cases of GLP-1RA-related neuropsychiatric AEs. GLP-1RAs showed an association with headache (ROR 1.74, 95% confidence interval [CI] 1.65–1.84), migraine (ROR 1.28, 95%CI 1.06–1.55), and olfactory and sensory nerve abnormalities (ROR 2.44, 95%CI 1.83–3.25; ROR 1.69, 95%CI 1.54–1.85). Semaglutide showed a moderate suicide-related AEs signal in the weight loss population (ROR 2.55, 95%CI 1.97–3.31). The median TTO was 16 days (interquartile range: 3–66 days). Conclusions In this study, we identified eight potential neuropsychiatric adverse events (AEs) associated with GLP-1RAs and, for the first time, detected positive signals for migraine, olfactory abnormalities, and sensory abnormalities. We also observed positive suicide-related signals of semaglutide, in weight loss population. This study provides a reliable basis for further investigation of GLP-1RA-related neuropsychiatric AEs. However, as an exploratory study, our findings require confirmation through large-scale prospective studies.

To develop an accurate prediction system for gestational diabetes mellitus (GDM) in women adhering to Institute of Medicine (IOM) weight gain criteria by analyzing early-pregnancy metabolic kinetics and identifying independent risk factors. A prospective two-center cohort study enrolled 1,031 pregnant women meeting IOM guidelines. Clinical, anthropometric, and metabolic parameters (pre-pregnancy BMI, lipid profiles, inflammatory markers) were collected at 6–12 weeks of gestation. Machine learning models were trained on seven core variables identified via logistic regression, with performance evaluated by AUC, sensitivity, and specificity. The GDM group (n = 279) exhibited significantly higher pre-pregnancy weight, BMI, triglycerides (1.21 vs. 0.96 mmol/L, p < 0.001), and inflammatory markers. Multivariate analysis identified parity ≥ 2 (OR = 4.37), family diabetes history (OR = 1.64), third-trimester weight (OR = 1.13), and triglycerides (OR = 1.49) as independent predictors. A neural network model achieved the highest AUC (0.732) with 65.1

Objective:This two-center prospective cohort study aimed to evaluate the predictive value of the Metabolic Score for Insulin Resistance (METS-IR) for gestational diabetes mellitus (GDM) in Chinese women during early pregnancy and compare its performance with conventional insulin resistance (IR) indices. Methods:This prospective investigation evaluated 1450 Chinese gravidas (<12 gestational weeks) without pregestational diabetes from two obstetrical institutions. Baseline clinical-biochemical profiling occurred during the first trimester (6-12 weeks), with GDM confirmation via standardized 75g oral glucose tolerance testing at 24-28 weeks' gestation. Analytical methodologies incorporated multivariable regression modeling and ROC curve optimization to quantify the predictive validity of five metabolic indices (METS-IR, TyG index, TG/HDL-C ratio, HOMA-IR, TyG-BMI) for GDM risk stratification. Results:Among participants, 378 (26.1%) developed GDM. The GDM group (n=378, 26.1%) was older (median age 31.0 vs 30.0 years, p<0.0001) and had higher prepregnancy BMI (22.62 vs 21.32 kg/m², p<0.0001), fasting glucose (4.7 vs 4.5 mmol/L, p<0.0001) compared to NGT. The GDM group exhibited significantly higher METS-IR (31.14 vs 29.03, p <0.001) and other IR indices (p <0.001). In unadjusted models, METS-IR quartile 4 (Q4) was strongly associated with GDM (OR=3.33, 95% CI:2.38-4.70), but this association attenuated after adjusting for age, weight gain, lipids, and insulin (adjusted OR=1.56, 95% CI:1.04-2.35). Comparatively, the TyG index (adjusted OR=3.06, 95% CI:2.03-4.66) and TG/HDL-C ratio (adjusted OR=2.02, 95% CI:1.38-2.99) retained robust predictive power. ROC analysis revealed a moderate discriminative capacity for METS-IR (AUC=0.629 unadjusted; 0.676 fully adjusted), outperformed by HOMA-IR (AUC=0.699) and TyG (AUC=0.699). METS-IR demonstrated high specificity (76.2%) in unadjusted screening but showed dependency on metabolic confounders in adjusted models. Conclusion:METS-IR shows promise for early GDM screening and is outperformed by TyG and HOMA-IR in predictive value. METS-IR in early pregnancy reflects metabolic dysregulation linked to GDM risk, yet its predictive utility is partially mediated by lipid and insulin abnormalities. While METS-IR offers clinical feasibility through routine measurements, TyG and HOMA-IR exhibit superior independent predictive value. These findings highlight the importance of context-specific IR indices for early GDM risk stratification and underscore METS-IR's role as a composite marker of metabolically unhealthy obesity in pregnancy.

Effective interventions to manage postprandial glycemia are critical because postprandial glycemic response (PPGR) is strongly linked to cardiovascular and metabolic disease. Considering the interindividual variability in PPGR, the widespread application of dietary interventions has led to an increasing recognition that a universal, one-size-fits-all approach to dietary intervention is far from ideal. This highlights the need for personalized nutrition plans. In this context, we explored the potential benefits of leveraging machine learning to predict PPGR and guide personalized dietary interventions. We also critically examined the limitations of current approaches and outlined promising future directions for advancing this field.

ABSTRACT Objective To develop and validate an early second‐trimester predictive model integrating body mass index (BMI) trajectories and pathophysiological biomarkers for gestational diabetes mellitus (GDM) risk stratification, with the aim of reducing weight‐monitoring frequency while maintaining predictive accuracy. Methods In this prospective dual‐center cohort study, 1,450 pregnant women (<12 weeks gestation) without preexisting diabetes were enrolled from two Beijing maternal‐child hospitals. Serial anthropometric (BMI at 6–10, 12–14, 15–19, and 24–28 weeks) and metabolic biomarkers (fasting glucose, C‐peptide, lipids, uric acid) were analyzed. GDM was diagnosed via 75 g OGTT at 24–28 weeks. Multivariable logistic regression identified predictors using a 7:3 training‐test split. Model performance was assessed by area under the ROC curve (AUC), calibration, and decision curve analysis. Results GDM incidence was 26.1% (378/1,450). Significant weight/BMI disparities emerged as early as 6–10 weeks (GDM vs NGT: +2.3 kg, P < 0.0001), escalating through gestation. The final model incorporated age (OR = 1.07/year, 95% CI = 1.03–1.11), 12–14‐week BMI (OR = 1.06/kg/m2, 1.01–1.12), fasting glucose (OR = 1.86/mmol/L, 1.45–2.40), fasting C‐peptide (OR = 1.87/ng/mL, 1.28–2.73). The model demonstrated moderate discrimination (training AUC = 0.684; testing AUC = 0.685) with 63.7–67.2% sensitivity and 59.8–61.4% specificity at the optimal threshold (0.237). Negative predictive values exceeded 82%, enabling effective risk exclusion. Conclusions This dual‐center model pioneers GDM risk stratification by 12–14 weeks using clinically accessible metrics, reducing weight‐monitoring frequency without compromising prognostic value. While AUC limitations (0.68–0.69) suggest unmeasured contributors, its operational simplicity and robust negative predictive capacity support implementation in resource‐constrained settings. The findings redefine antenatal care paradigms by shifting focus to early metabolic dysregulation rather than late diagnostic thresholds.

OBJECTIVE:To assess the association between glycated haemoglobin (HbA1c) variability and risk of renal function decline in type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS:A comprehensive search was carried out in PubMed, Embase, Web of Science and the Cochrane Library (until 12 March 2024). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines were followed for this meta-analysis. HbA1c variability was presented as indices of the standard deviation (SD), coefficient of variation (CV), HbA1c variability score (HVS) and haemoglobin glycation index (HGI). This meta-analysis was performed using random-effect models. RESULTS:Eighteen studies met the objectives of this meta-analysis. The analyses showed positive associations between HbA1c variability and kidney function decline, with hazard ratio (HR) 1.26 (95% confidence interval [CI] 1.15-1.38) for high versus low SD groups, HR 1.47 (95% CI 1.30-1.65) for CV groups, HR 1.32 (95% CI 1.10-1.57) for HVS groups and HR 1.53 (95% CI 1.05-2.23) for HGI groups. In addition, each 1% increase in SD and CV was linked to kidney function decline, with HR 1.26 (95% CI 1.17-1.35), and 1.13 (95% CI 1.03-1.23), respectively. Also, each 1-SD increase in SD of HbA1c was associated with deterioration in renal function, with HR 1.17 (95% CI 1.07-1.29). CONCLUSIONS:The four HbA1c variability indicators were all positively associated with renal function decline progression; therefore, HbA1c variability might play an important and promising role in guiding glycaemic control targets and predicting kidney function decline progression in T2DM.

Pure red cell aplasia (PRCA) is a rare disease for which large controlled trials are challenging and as such recommendations are mostly based on retrospective studies or case accumulations. Cyclosporine A (CsA) provides the most effective treatment for PRCA with an overall response rate of 65%–87%,1 leaving approximately one-third of patients in need of an alternative agent. Moreover, responders typically take 2–3 months to achieve transfusion-independence (TI) from the start of therapy.1 As a result, large proportions of PRCA patients require regular blood transfusions, leading to decreased quality-of-life and substantial healthcare utilization. Novel treatment strategies are required to improve this dismal situation. Linperlisib is a highly selective and potent PI3Kδ inhibitor that received orphan drug designations by the Food and Drug Administration for the treatment of follicular lymphoma, chronic lymphocytic leukemia, and T cell lymphoma. For the first time, we evaluated the effects of Linperlisib on patients with acquired PRCA, including one idiopathic case and three cases secondary to T cell large granular lymphocyte leukemia (T-LGLL), and observed surprisingly rapid responses and manageable safety. Hereby, we retrospectively reported our preliminary experience in the hope of providing novel therapy idea for this rare condition. This study was approved by our institutional review board and all patients signed informed consents. Clinical courses and patients' characteristics are shown in Figure 1 and Supplemental Materials, and elaborated upon below. Case 1: A 48-year-old female diagnosed with PRCA associated with T-LGLL and monoclonal gammopathy of undetermined significance (MGUS) started on Linperlisib 80 mg daily 12 months ago after failing to respond to CsA along with prednisone taper (Table S1). Subsequently, Hb increased from 7.6 to 10.4 g/dL by the 10th day, and then normalized by the 21st day without transfusion. Bone marrow (BM) examination post-Linperlisib confirmed remarkable improved erythropoiesis (Figure S1). Linperlisib treatment was interrupted after 119 days due to colitis and replaced with a 42-day third-line treatment of Stanozolol (2 mg three times a day). Nevertheless, hemoglobin level decreased, and the patient had to resume regular transfusions. In response, Linperlisib was restarted at 40 mg per day, resulting in a second complete remission (CR, Hb > 11.0 g/dL in female and >12.0 g/dL in male without transfusion) after 22 days without any adverse effects being recorded subsequently (Figure 1 and Table S1). Case 2: A 63-year-old female was diagnosed with T-LGLL associated PRCA 5 years ago. Her Hb maintained normal for 4 years with CsA and steroid taper. Linperlisib 80 mg per day was orally administered due to relapsed anemia and Hb level was elevated from 6.3 to 7.7 g/dL in 1 week. After 30 days, CR was reached and continued for 155 days (Figure 1 and Table S1) until Linperlisib was terminated due to maculopapular (depicted in Figure S2), which disappeared within 4 weeks after stopping the medication. Case 3: A 79-year-old man was confirmed to have T-LGLL associated PRCA 5 months ago. He was intolerant to first-line therapy composed of CsA and methylprednisolone due to severe transaminase elevation. The attempt of Linperlisib 80 mg daily resulted in a progressive and rapid rise of Hb level, peaking at 11.1 g/dL, effectively eliminating the requirement for transfusions. The reticulocyte counts also displayed a noteworthy upsurge from 5.7 to 130.8 × 109/L within 2 weeks. A temporary rise in transaminase levels was resolved after 1 week of supportive care. Pneumonia occurred concomitantly with severe neutropenia (minimum count 0.02 × 109/L), resulting in a 2-week interruption in treatment and a decrease of Hb level to 9.2 g/dL. After that, Linperlisib was reintroduced at a dosage of 40 mg per day and the complete blood count (CBC) on day 141 revealed a Hb value above 10.0 g/dL and a neutrophil count within the normal range (Figure 1 and Table S1). Case 4: A 54-year-old male with anemia was diagnosed with PRCA associated with MGUS 1 year ago. Initial therapy composed of stanozolol, followed by CsA and prednisone did not decrease transfusion requirements and led to the therapy of Linperlisib 80 mg daily. Hb value elevated from 5.7 to 7.0 g/dL in 5 days, with a remarkable rise in reticulocyte count from 5.9 to 44 × 109/L. He has been received Linperlisib for 12 weeks without any adverse reactions to date, and the latest CBC on the 87th day showed a normal Hb of 12.6 g/dL (Figure 1 and Table S1). Bone marrow re-examination on Day 59 revealed improved erythropoiesis and unexpectedly unchanged plasma cell clone (Figure S3). The etiological diagnosis was accordingly revised as idiopathic PRCA with a coincidental MGUS, which has been described previously.2 With current therapies, responders typically take months, more specifically, 29 ± 45 days for LGLL-associated PRCA and 82 ± 200 days for idiopathic PRCA according to PRCA Collaborative Study Group of Japan,3, 4 to achieve TI from the start of therapy. In this study, all patients were heavily dependent on blood transfusions before starting Linperlisib treatment, with a requirement of 2–6 units per month. The initiation of Linperlisib (80 mg daily) promptly improved Hb values and reticulocyte counts and virtually eliminated the need for blood transfusions from the start of the therapy, with the exception of patient 4 having a planned transfusion that was delayed until after receiving Linperlisib due to resource constraints (Figure 1). Time for best response (three CR and one near CR) ranged from 21 to 46 days. Three patients had to discontinue due to adverse events of ≥grade 3 (detailed in Table S1), resulting in declines in Hb levels. Nevertheless, two patients resumed at the lower dose of 40 mg per day which promptly elevated Hb levels with good tolerance. In conclusion, Linperlisib demonstrated rapid response and manageable tolerability in refractory or relapsed patients with T-LGLL associated as well as idiopathic PRCA, which is impressive especially considering the cost and medical burden associated with blood transfusions. The precise mechanisms responsible for the rapid effect of Linperlisib in PRCA of different etiologies have yet to be investigated. Nevertheless, existing knowledge on PRCA and PI3K can provide valuable clues and implications. The dominant expression of p110δ on immune cells5 and the pathogenic role of abnormal immunity in PRCA,1 hints the possibility that Linperlisib inhibits abnormal immune responses against erythroid precursors, which at least partially contributes to Hb improvement. Theoretically, PI3Kδ participates in multiple processes of different lymphocyte subsets and the overall effect of PI3Kδ inhibition in vivo is subject to the balance between opposing actions of these subsets.5 In the context of PRCA, we speculate that Linperlisib's effectiveness may be primarily due to its suppression of T cell immune responses, which have been identified as the common pathogenesis in both idiopathic and LGLL-associated PRCA.6 In addition, the lack of reduction in LGLs (Table S2) may be explained by the viewpoint that PI3K/Akt pathway is essential for effector function of T cells rather than their survival or proliferation.7 An additional plausible explanation for the rapid remission of anemia is that Linperlisib enhances erythropoiesis and accelerates the recovery of reticulocytes and Hb. This remains speculative but feasible, as PI3K inhibition can down-express c-myc8 and potentially inhibit mTOR, both of which are known to contribute to erythropoiesis by promoting enucleation and autophagy.9, 10 Detailed explorations are required to fully understand the mechanisms behind the efficacy and to identify potential responders with different etiologies. As is common knowledge, integration of cases and accumulation of experiences greatly contribute to advancements in treating rare diseases. Despite the small sample size, limited follow-up, and only two subtypes included, this case series provides the first evidence of clinical benefit and manageable tolerability of PI3Kδ inhibitor treatment for idiopathic and LGLL-associated PRCA. To expedite the improvement of the dismal situation of this rare condition, we expeditiously reported our preliminary experiences, thereby encouraging more studies to further confirm the long-term efficacy and safety of PI3Kδ inhibitor for PRCA with different etiologies. Zhenzhen Wang devised the manuscript, reviewed the data, wrote and edited the manuscript. Bo Jiang devised the manuscript, reviewed the data, reviewed and edited the manuscript. Lin Song, Mingyuan Sun, Chunhong Li, Xiaoxia Li and Weiwei Zheng treated the patients and reviewed the manuscript. Junyuan Qi conceived and designed the study and reviewed and edited the manuscript. Yuan Tao and Qi Sun performed the review of bone marrow biopsies. This study was supported by a grant (NCRC-1-020, to Bo Jiang) from National Clinical Research Center for Blood Disease of China; Chinese Society of Clinical Oncology, Beijing Xisike Clinical Oncology Research Foundation (Y-HR2022ZD-0774, to Junyuan Qi). The authors declare no competing financial interests. The data that support the findings of this study are available from the corresponding author upon reasonable request. Data S1. Supporting information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Objective:Gestational diabetes mellitus (GDM) is a condition of glucose intolerance, which may be accompanied with inflammation. The levels of hematological parameters during pregnancy can reflect inflammatory conditions in pregnant women. This study aims to describe the dynamic change of blood cell parameters from the first trimester (6-12 weeks of gestation) to the second trimester (24-28 weeks of gestation) and to investigate the associations of these biomarkers with the risk of GDM.Methods:This study was a prospective double-center study conducted in Beijing, China (clinical trial number: NCT03246295). Hematological parameters were tested four times during the follow-up. Logistic regression analysis and Receiver Operating Characteristic (ROC) curve analysis were used to explore the association and predictive ability of hematological parameters for GDM.Results:There were 258 of 1027 pregnant women in our study developed GDM. Among the 1027 pregnant women, white blood cells (WBC) gradually increased, and red blood cells (RBC), hemoglobin (HGB), and platelet (PLT) tended to decrease from the first trimester to second trimester. After adjusting for confounding factors, higher levels of RBC, HGB, and PLT in both early and middle pregnancy were positively associated with GDM risk, whereas the level of WBC was associated with GDM risk only in early pregnancy. WBC, RBC, HGB, and PLT in early and middle pregnancy were all correlated with fasting insulin (FINS) in early pregnancy.Conclusion:Higher levels of hematological parameters in early and middle pregnancy were associated with glucose metabolism in early pregnancy and the subsequent risk of GDM.

BackgroundGestational diabetes mellitus (GDM) is one of the most common medical complications of pregnancy, which increases the risk of other pregnant complications and adverse perinatal outcomes. Thyroid dysfunction is closely with the risk of diabetes mellitus. However, the relationship between euthyroid function in early pregnancy and GDM is still controversial.AimsThis study was to find the relationship between thyroid function within normal range during early pregnancy as well as glucose and lipids metabolisms as well as the risk of subsequent GDM.MethodsA total of 1486 pregnant women were included in this prospective double-center cohort study. Free thyroxine (FT4), thyroid stimulating hormone (TSH) and antithyroid peroxidase antibodies (TPOAb) were tested during 6-12 weeks of gestation and oral glucose tolerance test (OGTT) was conducted during 24-28 weeks to screen GDM. Relative risks (RR) with 95% confidence intervals (CI) for subsequent risk of GDM by thyroid function quartiles were assessed adjusting for major risk factors.ResultsThe incidence of GDM was 23.0% (342/1486). TSH, FT4 and the percentage of positive TPOAb were no significant difference between women with and without GDM, but FT4/TSH ratio was significantly higher in GDM group compared with NGT group [6.97(0.84,10.61) vs. 4.88(0.66,12.44), P=0.025)]. The linear trends of TC, TG, HDL-C, LDL-C, fasting glucose in the first trimester, insulin, C-peptide, HOMA-IR, fasting glucose during OGTT and incidence of GDM according to FT4/TSH ratio were all statistically significant. Further analysis based on fetal sex presented only the third quartile of FT4/TSH ratio in women carrying male fetus was associated with higher incidence of GDM statistically significant [RR (95% CI), 1.917 (1.143,3.216)], rather than in women carrying female fetus.ConclusionsThyroid function even in normal range is closely related to glucose and lipids metabolisms during the first trimester. Unappropriated FT4/TSH ratio in the first trimester is an independent risk factor of GDM in women carrying male fetus.

Aims There were some studies reported inconsistent results on the associations between fetal sex and maternal metabolism. This study aimed to examine the effect of fetal sex on maternal glucose and lipid metabolism and perinatal outcomes in women with gestational diabetes mellitus (GDM) during pregnancy in Chinese population. Methods This was a retrospective cohort study including 134 women diagnosed as GDM. All of them accepted 100g oral glucose tolerance test(OGTT) during 26–29 gestational week because of positive 50g glucose challenge test(GCT) and then had a regular follow-up. The clinical and laboratory data as well as perinatal outcomes were collected from Electronic Medical Record. Results Of 134 pregnant women with GDM, 64(47.76%) delivered a girl and 70(52.24%) delivered a boy. Homeostasis model assessment of β-cell function (HOMA-β) in women carrying a male fetus was significantly lower than in those carrying a female fetus [176(129.09,245.56) vs. 212(150.00,307.5), p = 0.029]. There was no difference between two groups in maternal lipid metabolism. Large-for-gestational-age(LGA) fetus was more likely to happen on male fetus (14.8% vs. 3.1%, p = 0.033), but there were no difference between two groups of the other perinatal outcomes. Higher maternal fasting blood glucose(OR 5.256, 95% CI 1.318,14.469) and lower HDL-C/LDL-C in women carrying male fetus suggested higher risk of LGA. Conclusions Women carrying a male fetus suggested decreased maternal β-cell function and increased percentage of LGA. The different management strategy of women with GDM between male and female fetus during pregnancy is necessary.

Virulence factor genes (VFGs) play pivotal roles in bacterial infections and have been identified within the human gut microbiota. However, their involvement in chronic diseases remains poorly understood. Here, we establish an expanded VFG database (VFDB 2.0) consisting of 62,332 nonredundant orthologues and alleles of VFGs using species-specific average nucleotide identity ( https://github.com/Wanting-Dong/MetaVF_toolkit/tree/main/databases ). We further develop the MetaVF toolkit, facilitating the precise identification of pathobiont-carried VFGs at the species level. A thorough characterization of VFGs for 5452 commensal isolates from healthy individuals reveals that only 11 of 301 species harbour these factors. Further analyses of VFGs within the gut microbiomes of nine chronic diseases reveal both common and disease-specific VFG features. Notably, in type 2 diabetes patients, long HiFi sequencing confirms that shared VF features are carried by pathobiont strains of Escherichia coli and Klebsiella pneumoniae. These findings underscore the critical importance of identifying and understanding VFGs in microbiome-associated diseases. Here, by mining 18,521 complete bacterial genomes, the authors construct VFDB 2.0, an expanded database of virulence factor genes, consisting of 62,332 nonredundant orthologues and alleles with annotated host taxa using species-specific average nucleotide identity, and present MetaVF, a toolkit that facilitates precise identification and quantification of virulence factor genes carried by specific pathobionts in human gut metagenomes.

The influence of the microbiota on hypoglycemic agents is becoming more apparent. The effects of metformin, a primary anti-diabetes drug, on gut microbiota are still not fully understood. This prospective cohort study aims to investigate the longitudinal effects of metformin on the gut microbiota of 25 treatment-naïve diabetes patients, each receiving a daily dose of 1500 mg. Microbiota compositions were analyzed at baseline, and at 1, 3, and 6 months of medication using 16S rRNA gene sequencing. Prior to the 3-month period of metformin treatment, significant improvements were noted in body mass index (BMI) and glycemic-related parameters, such as fasting blood glucose (FPG) and hemoglobin A1c (HbA1c), alongside homeostasis model assessment indices of insulin resistance (HOMA-IR). At the 3-month mark of medication, a significant reduction in the α-diversity of the gut microbiota was noted, while β-diversity exhibited no marked variances throughout the treatment duration. The Firmicutes to Bacteroidetes ratio. markedly decreased. Metformin treatment consistently increased Escherichia-Shigella and decreased Romboutsia, while Pseudomonas decreased at 3 months. Fuzzy c-means clustering identified three longitudinal trajectory clusters for microbial fluctuations: (i) genera temporarily changing, (ii) genera continuing to decrease (Bacteroides), and (iii) genera continuing to increase(Lachnospiraceae ND3007 group, [Eubacterium] xylanophilum group, Romboutsia, Faecalibacterium and Ruminococcaceae UCG-014). The correlation matrix revealed associations between specific fecal taxa and metformin-related clinical parameters HbA1c, FPG, Uric Acid (UA), high-density lipoproteincholesterol (HDL-C), alanine aminotransferase (ALT), hypersensitive C-reactive protein (hs-CRP), triglyceride (TG) (P < 0.05). Metacyc database showed that metformin significantly altered 17 functional pathways. Amino acid metabolism pathways such as isoleucine biosynthesis predominated in the post-treatment group. Metformin’s role in glucose metabolism regulation may primarily involve specific alterations in certain gut microbial species rather than an overall increase in microbial species diversity. This may suggest gut microbiota targets in future studies on metabolic abnormalities caused by metformin.

The sulfhydryl group of clopidogrel metabolite could induce insulin autoimmune syndrome (IAS) with hypoglycemia as the major symptom. For patients with cardiovascular disease taking clopidogrel for vascular protection, this adverse event hypoglycemia increases the risk of cardiovascular events. However, discontinuing clopidogrel leaves patients without appropriate antiplatelet therapy. Treating IAS with glucocorticoids is also risky for these patients' primary cardiovascular diseases. Early recognition and appropriate treatment of clopidogrel-induced IAS (CIAS) would be beneficial for patients. This research aimed to discover the clinical features and investigate optimal therapeutic management of CIAS. We systematically searched for cases of CIAS in PubMed and Embase and performed data mining in Food and Drug Administration Adverse Event Reporting System (FAERS). In the CIAS series, clinical features were summarized and compared to 287 IAS cases, including demographic information, HLA alleles, onset, and symptoms. The therapeutic effect of glucocorticoids was compared between the receiving group and the not-receiving group. The possibilities of common antiplatelet drugs to induce hypoglycemia/IAS were investigated with chemical structure and FAERS reports. A CIAS series of 51 patients was established. CIAS had an onset age of 74.8±8.6 years old, 92.2% male, and a balanced proportion of East Asians and non-East Asians. Confusion occurred more frequently in CIAS than in IAS from various causes, while the other symptoms and hypoglycemia types were similar. The recovery time was approximately the same whether using glucocorticoids/immunotherapy in CIAS or not. Among common antiplatelet drugs, ticagrelor and rivaroxaban were unlikely to induce hypoglycemia/IAS. Clopidogrel is a distinctive cause of IAS featuring an elderly male presenting confusion as the symptom of hypoglycemia. Glucocorticoids/immunotherapy might not be necessary for the long-term recovery of CIAS. To balance the risks of hypoglycemia and cardiovascular events, substituting clopidogrel with ticagrelor and rivaroxaban might be considered.

Background: Although with the application of etanercept biosimilars in the field of rheumatoid arthritis, the evidences of their efficacy, safety, and immunogenicity are still limited. We conducted this meta-analysis to evaluate the efficacy, safety and immunogenicity of etanercept biosimilars for treating active rheumatoid arthritis compared to reference biologics (Enbrel®). Methods: PubMed, Embase, Central, and ClinicalTrials.gov were searched for randomized controlled trials of etanercept biosimilars treated in adult patients diagnosed with rheumatoid arthritis from their earliest records to 15 August 2022. The outcomes included ACR20, ACR50, and ACR70 response rate at different time points from FAS or PPS, adverse events, and proportion of patients developed anti-drug antibodies. The risk of bias of each included study was assessed using the revised Cochrane Risk of Bias in Randomised Trials tool, and the certainty of evidence was rated according to the Grading of Recommendation Assessment, Development, and Evaluation. Results: Six RCTs with 2432 patients were included in this meta-analysis. Etanercept biosimilars showed more benefits in ACR50 at 24 weeks from PPS [5 RCTs, OR = 1.22 (1.01, 1.47), p = 0.04, I2 = 49%, high certainty], ACR50 at 1 year from PPS [3 RCTs, OR = 1.43 (1.10, 1.86), p < 0.01, I2 = 0%, high certainty] or FAS [2 RCTs, OR = 1.36 (1.04, 1.78), p = 0.03, I2 = 0%, high certainty], and ACR70 at 1 year from PPS [3 RCTs, OR = 1.32 (1.01, 1.71), p = 0.04, I2 = 0%, high certainty]. In terms of other outcomes about efficacy, safety, and immunogenicity, the results showed that there was no significant difference between etanercept biosimilars and reference biologics, and the certainty of evidences ranged from low to moderate. Conclusion: Etanercept biosimilars showed more benefits in ACR50 response rate at 1 year than reference biologics (Enbrel®), other outcomes for clinical efficacy, safety, and immunogenicity of etanercept biosimilars were comparable with originator in patients with rheumatoid arthritis. Systematic Review Registration: PROSPERO, identifier CRD42022358709.

We aimed to explore the medium- and long-term (≥12 weeks) effects of dapagliflozin on serum uric acid (SUA) level in patients with type 2 diabetes mellitus (T2DM) in the real world study and to explore the influencing factors of dapagliflozin on reducing SUA level. This observational, prospective cohort study was based on the real world. There were 77 patients included in this study. They were divided into two groups. Patients in treatment group (n = 38) were treated as dapagliflozin 10 mg/d combined with therapy of routine glucose-lowering drugs (GLDs), and patients in the control group (n = 39) were treated with their routine GLDs. All measurements of physical examinations, blood, and urine samples, including age, sex, weight, height, systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting blood glucose (FBG), glycosylated hemoglobin (HbA1c), and SUA, were collected at baseline for all patients in these two groups and repeated after 12, 24, and 48 weeks of therapy. We compared the changes of metabolic indicators including SUA in these two groups to evaluate the effects of dapagliflozin and analyzed its influencing factors. In the dapagliflozin group, mean SUA levels significantly decreased from 334.2 ± 99.1 μmol/L at baseline to 301.9 ± 73.2 μmol/L after 12 weeks therapy (t = 2.378, p = 0.023). There was no significant statistical difference of SUA levels after 24 weeks treatment of dapagliflozin compared with 12-week and 48-week treatment with dapagliflozin (p > 0.05). We found that baseline SUA had a significant impact on the effect of dapagliflozin on reducing SUA (OR 1.014, 95%CI 1.003–1.025, p = 0.014) by logistic regression analysis. Receiver operating characteristic (ROC) curve showed that T2DM patients with SUA level ≥ 314.5 μmol/L had relative accuracy in recognizing the good effects of dapagliflozin on reducing SUA (sensitivity 76.9%, specificity 76.2%). Combination therapy of dapagliflozin with routine blood-glucose-lowering drugs in T2DM patients showed the significant and sustained stable effect of lowering SUA level in this real-world study.

This study aimed to develop a simplified screening model to identify pregnant Chinese women at risk of gestational diabetes mellitus (GDM) in the first trimester. This prospective study included 1289 pregnant women in their first trimester (6–12 weeks of gestation) with clinical parameters and laboratory data. Logistic regression was performed to extract coefficients and select predictors. The performance of the prediction model was assessed in terms of discrimination and calibration. Internal validation was performed through bootstrapping (1000 random samples). The prevalence of GDM in our study cohort was 21.1