Habitual use of glucosamine and adverse liver outcomes among patients with type 2 diabetes and MASLD.

BACKGROUND: Glucosamine is a dietary supplement commonly used to support joint health. However, there has been interest in exploring other effects of glucosamine on health outcomes due to its ant-inflammation effect. OBJECTIVE: This study compared the risks of major adverse liver outcomes (MALOs) between regular users and non-users of glucosamine among patients with type 2 diabetes and metabolic dysfunction associated steatotic liver disease (MASLD) using the data from a large prospective cohort study. METHODS: Demographic, anthropometric, laboratory and medication prescription information among 18 753 patients with type 2 diabetes and MASLD was obtained from the UK Biobank. MASLD was identified based on hepatic steatosis defined by fatty liver index ≥60 plus the presence of any clues of metabolic dysregulation and cardio-metabolic risk factors, excluding patients with moderate to severe alcohol consumption. RESULTS: During a mean follow-up of 11.4 years, 826 incident MALOs events were recorded. Patients not regularly using glucosamine compared with patients using glucosamine showed a significantly higher risk of the composite MALOs (HR 1.36, 95% confidence interval [CI] 1.09-1.69) as well as most individual MALOs except for ascites. The multivariable-adjusted HRs of MALOs within 3, 5 and 10 years among non-users of glucosamine compared with regular users were 1.79 (95% CI .69-2.03), 1.88 (95% CI 1.21-2.54) and 1.32 (95% CI 1.05-1.72), respectively. Further subgroup analyses in participants with different baseline characteristics and sensitivity analyses excluding participants who regularly took any other supplements and participants who used self-reports to diagnose diabetes confirmed the findings. CONCLUSIONS: The present study indicated that habitual use of glucosamine was associated with a low risk of individual and composite MALOs among patients with type 2 diabetes and MASLD.

Neutral or detrimental effects of TREM2 agonist antibodies in preclinical models of Alzheimer's Disease and Multiple Sclerosis.

Human genetics and preclinical studies have identified key contributions of TREM2 to several neurodegenerative conditions, inspiring efforts to modulate TREM2 therapeutically. Here, we characterize the activities of three TREM2 agonist antibodies in multiple mixed-sex mouse models of Alzheimer's Disease (AD) pathology and remyelination. Receptor activation and downstream signaling are explored in vitro, and active dose ranges are determined in vivo based on pharmacodynamic responses from microglia. For mice bearing amyloid-ß (Aß) pathology (PS2APP) or combined Aß and tau pathology (TauPS2APP), chronic TREM2 agonist antibody treatment had limited impact on microglia engagement with pathology, overall pathology burden, or downstream neuronal damage. For mice with demyelinating injuries triggered acutely with lysolecithin, TREM2 agonist antibodies unexpectedly disrupted injury resolution. Likewise, TREM2 agonist antibodies limited myelin recovery for mice experiencing chronic demyelination from cuprizone. We highlight the contributions of dose timing and frequency across models. These results introduce important considerations for future TREM2-targeting approaches.Significance Statement Multiple TREM2 agonist antibodies are investigated in mouse models of Alzheimer's Disease and Multiple Sclerosis. Despite agonism in culture models and after acute dosing in mice, antibodies do not show benefit in overall AD pathology and worsen recovery after demyelination.

Severe dawn phenomenon predicts long-term risk of all-cause mortality in patients with type 2 diabetes.

AIMS: The dawn phenomenon (DP) is an abnormal early morning blood glucose rise without nocturnal hypoglycaemia, which can be more easily and precisely assessed with continuous glucose monitoring (CGM). This prospective study aimed to explore the association between DP and the risk of all-cause mortality in patients with type 2 diabetes. MATERIALS AND METHODS: A total of 5542 adult inpatients with type 2 diabetes in a single centre were analysed. The magnitude of DP (ΔG) was defined as the increment in the CGM-determined glucose value from nocturnal nadir (after 24:00) to prebreakfast. Participants were stratified into four groups by ΔG: ≤1.11, 1.12-3.33, 3.34-5.55, and >5.55 mmol/L. Cox proportional hazard regression models were used to evaluate the impact of DP on all-cause mortality risk. RESULTS: During a median follow-up of 9.4 years, 1083 deaths were identified. The restricted cubic spline revealed a nonlinear (p for nonlinearity = 0.002) relationship between ΔG and the risk of all-cause mortality. A multivariate-adjusted Cox regression model including glycated haemoglobin A1c (HbA1c) showed that ΔG > 5.55 mmol/L was associated with 30% (95% CI, 1.01-1.66) higher risk of all-cause mortality, as compared with ΔG 1.12-3.33 mmol/L. CONCLUSIONS: Higher ΔG is significantly related to an increased risk of all-cause mortality in type 2 diabetes, suggesting that severe DP should be given more attention as a part of glucose management to reduce the risk of long-term adverse outcomes.

Low-dose IL-2 treatment confers anti-inflammatory effect against subarachnoid hemorrhage in mice.

Objective: Subarachnoid hemorrhage (SAH) was a stroke with high occurrence and mortality. At the early stage, SAH patients have severe cerebral injury which is contributed by inflammation. In this study, we aimed to explore the anti-inflammation effect of low-dose IL-2 in SAH mice. Methods: The 12-week-old C57BL/6J male mice were conducted with SAH surgery (Internal carotid artery puncture method). Different dose of IL-2 was injected intraperitoneally for 1 h, 1 day, and 2 days after SAH. Single-cell suspension and flow cytometry were used for the test of regulatory T (Treg) cells. Immunofluorescence staining was used to investigate the phenotypic polarization of microglia and inflammation response around neurons. Enzyme-Linked Immuno-sorbent Assay (ELISA) was applied to detect the level of pro-inflammatory factors. Results: Low-dose IL-2 could enrich the Treg cells and drive the microglia polarizing to M2. The level of pro-inflammatory factors, IL-1α, IL-6, and TNF-α decreased in the low-dose IL-2 group. The inflammation response around neurons was attenuated. Low-dose IL-2 could increase the number of Treg cells, which could exert a neuroprotective effect against inflammation after SAH. Conclusion: Low-dose IL-2 had the potential to be an effective clinical method to inhibit inflammation after SAH.

New Score Models for Predicting Bleeding and Ischemic of Ticagrelor Therapy in Patients with Diabetes Mellitus.

PURPOSE: Ticagrelor is an antiplatelet drug, and its use increases the risk of bleeding. Coronary artery disease is significantly influenced by the widespread occurrence of diabetes mellitus. In order to decrease the incidence of clinical adverse events, a novel bleeding and thrombosis score is developed in this research. METHODS: We conducted a retrospective analysis of patient data from two medical centers who were diagnosed with diabetes mellitus and treated with ticagrelor. We gathered information on every patient from the electronic database of the hospital and follow-up. The collected data were statistically analyzed to obtain risk factors for bleeding and ischemic events. RESULTS: A total of 851 patients with diabetes mellitus who have been administered ticagrelor are included in our investigation. A total of 76 patients have bleeding events and 80 patients have ischemic events. The analysis of multiple variables indicates that characteristics like the age of >65, having a previous occurrence of bleeding, experiencing anemia, using aspirin, and taking atorvastatin are linked to a higher likelihood of bleeding. Additionally, the age of >65, smoking, having a history of blood clots, and having a BMI ≥ 30 are found to increase the risk of ischemia. CONCLUSION: The A4B score established in this study was better than the HAS-BLED score，and the same is true for the ABST score to the CHA2DS-VASc score. This new risk assessment model can potentially detect patients who are at high risk for bleeding and ischemic events. For high-risk patients, the dose of ticagrelor can be adjusted appropriately or the medication can be adjusted.(2023-09-11, ChiCTR2300075627).

Clinical research progress of ridaforolimus (AP23573, MK8668) over the past decade: a systemic review.

Rapamycin, an established mTOR inhibitor in clinical practice, is widely recognized for its therapeutic efficacy. Ridaforolimus, a non-prodrug rapalog, offers improved aqueous solubility, stability, and affinity compared to rapamycin. In recent years, there has been a surge in clinical trials involving ridaforolimus. We searched PubMed for ridaforolimus over the past decade and selected clinical trials of ridaforolimus to make a summary of the research progress of ridaforolimus in clinical trials. The majority of these trials explored the application of ridaforolimus in treating various tumors, including endometrial cancer, ovarian cancer, prostate cancer, breast cancer, renal cell carcinoma, and other solid tumors. These trials employed diverse drug combinations, incorporating agents such as ponatinib, bicalutamide, dalotuzumab, MK-2206, MK-0752, and taxanes. The outcomes of these trials unveiled the diverse potential applications of ridaforolimus in disease treatment. Our review encompassed analyses of signaling pathways, ridaforolimus as a single therapeutic agent, its compatibility in combination with other drugs, and an assessment of adverse events (AEs). We conclude by recommending further research to advance our understanding of ridaforolimus's clinical applications.

Ultralong-life and high-capacity magnesium/sodium hybrid-ion battery using a ternary CoSe/NiSe2/CuSe2 cathode and dual-ion electrolyte.

An ultrahigh-performance magnesium/sodium hybrid-ion battery (MNHB) is developed using ternary CoSe/NiSe2/CuSe2 (CNCS) "micro-flowers" as cathode materials, working with a coordinative [Mg2Cl2][AlCl4]2 and bis(trifluoroethylsulfonyl)imide anionic sodium salt in triglyme electrolyte. After 2000 cycles at 2.0 A g-1, the MNHB shows a stable capacity of 115.5 mA h g-1 and a high Coulombic efficiency exceeding 99.8%. The battery shows very rapid charging, and good stability in extreme environments, providing new opportunities to develop other hybrid-ion systems.

Iron overload in hypothalamic AgRP neurons contributes to obesity and related metabolic disorders.

Iron overload is closely associated with metabolic dysfunction. However, the role of iron in the hypothalamus remains unclear. Here, we find that hypothalamic iron levels are increased, particularly in agouti-related peptide (AgRP)-expressing neurons in high-fat-diet-fed mice. Using pharmacological or genetic approaches, we reduce iron overload in AgRP neurons by central deferoxamine administration or transferrin receptor 1 (Tfrc) deletion, ameliorating diet-induced obesity and related metabolic dysfunction. Conversely, Tfrc-mediated iron overload in AgRP neurons leads to overeating and adiposity. Mechanistically, the reduction of iron overload in AgRP neurons inhibits AgRP neuron activity; improves insulin and leptin sensitivity; and inhibits iron-induced oxidative stress, endoplasmic reticulum stress, nuclear factor κB signaling, and suppression of cytokine signaling 3 expression. These results highlight the critical role of hypothalamic iron in obesity development and suggest targets for treating obesity and related metabolic disorders.

The Alzheimer's disease risk gene BIN1 regulates activity-dependent gene expression in human-induced glutamatergic neurons.

Bridging Integrator 1 (BIN1) is the second most important Alzheimer's disease (AD) risk gene, but its physiological roles in neurons and its contribution to brain pathology remain largely elusive. In this work, we show that BIN1 plays a critical role in the regulation of calcium homeostasis, electrical activity, and gene expression of glutamatergic neurons. Using single-cell RNA-sequencing on cerebral organoids generated from isogenic BIN1 wild type (WT), heterozygous (HET) and homozygous knockout (KO) human-induced pluripotent stem cells (hiPSCs), we show that BIN1 is mainly expressed by oligodendrocytes and glutamatergic neurons, like in the human brain. Both BIN1 HET and KO cerebral organoids show specific transcriptional alterations, mainly associated with ion transport and synapses in glutamatergic neurons. We then demonstrate that BIN1 cell-autonomously regulates gene expression in glutamatergic neurons by using a novel protocol to generate pure culture of hiPSC-derived induced neurons (hiNs). Using this system, we also show that BIN1 plays a key role in the regulation of neuronal calcium transients and electrical activity via its interaction with the L-type voltage-gated calcium channel Cav1.2. BIN1 KO hiNs show reduced activity-dependent internalization and higher Cav1.2 expression compared to WT hiNs. Pharmacological blocking of this channel with clinically relevant doses of nifedipine, a calcium channel blocker, partly rescues electrical and gene expression alterations in BIN1 KO glutamatergic neurons. Further, we show that transcriptional alterations in BIN1 KO hiNs that affect biological processes related to calcium homeostasis are also present in glutamatergic neurons of the human brain at late stages of AD pathology. Together, these findings suggest that BIN1-dependent alterations in neuronal properties could contribute to AD pathophysiology and that treatment with low doses of clinically approved calcium blockers should be considered as an option to slow disease-onset and progression.

Association between weight-adjusted-waist index and depression in US adults: A cross-sectional study.

BACKGROUND: Current evidence implicates a significant association between depression and obesity and related metabolic dysfunction. The weight-adjusted-waist index (WWI) was recently identified as an ideal index that integrates total body fat, muscle mass, and bone mass. This study investigated the relationship between WWI and depressive symptoms in adults. METHODS: Participants from the National Health and Nutrition Examination Survey (2005-2018) were enrolled. Depressive symptom severity was measured with the Patient Health Questionnaire-9 (PHQ-9). Survey-weighted multivariable logistic regression, subgroup analysis, and generalized additive models were used to determine the relationship between WWI and depressive symptoms. RESULTS: A total of 34,575 participants were included, with a mean WWI of 11.01; 2,979 participants were suspected of having depressive symptoms (PHQ-9 score ≥ 10). A significant positive association was identified between WWI and depressive symptoms (odds ratio = 1.416, 95 % confidence interval: 1.303-1.539, P < 0.0001). Subgroup analyses suggested that the association between WWI and depressive symptoms was stronger in individuals who were female, overweight, divorced, middle-aged or older (over 40 years old), and had diabetes. Furthermore, the non-linear multivariable regression revealed an inflection point for the WWI at 11.438, and the association was only significant when the WWI was higher than this point. LIMITATIONS: This study was retrospective and only included participants from the United States; therefore, further validation is needed from studies in other countries, especially middle-to-low-income countries, using longitudinal cohorts. CONCLUSIONS: This study identified a significant positive association between WWI and depressive symptoms.

Slow-wave sleep and REM sleep without atonia predict motor progression in Parkinson's disease.

BACKGROUND: Growing evidence supports the potential role of sleep in the motor progression of Parkinson's disease (PD). Slow-wave sleep (SWS) and rapid eye movement (REM) sleep without atonia (RWA) are important sleep parameters. The association between SWS and RWA with PD motor progression and their predictive value have not yet been elucidated. METHODS: We retro-prospectively analyzed clinical and polysomnographic data of 136 patients with PD. The motor symptoms were assessed using Unified Parkinson's Disease Rating Scale Part III (UPDRS III) at baseline and follow-up to determine its progression. Partial correlation analysis was used to explore the cross-sectional associations between slow-wave energy (SWE), RWA and clinical symptoms. Longitudinal analyses were performed using Cox regression and linear mixed-effects models. RESULTS: Among 136 PD participants, cross-sectional partial correlation analysis showed SWE decreased with the prolongation of the disease course (P = 0.046), RWA density was positively correlated with Hoehn & Yahr (H-Y) stage (tonic RWA, P < 0.001; phasic RWA, P = 0.002). Cox regression analysis confirmed that low SWE (HR = 1.739, 95% CI = 1.038-2.914; P = 0.036; FDR-P = 0.036) and high tonic RWA (HR = 0.575, 95% CI = 0.343-0.963; P = 0.032; FDR-P = 0.036) were predictors of motor symptom progression. Furthermore, we found that lower SWE predicted faster rate of axial motor progression (P < 0.001; FDR-P < 0.001) while higher tonic RWA density was associated with faster rate of rigidity progression (P = 0.006; FDR-P = 0.024) using linear mixed-effects models. CONCLUSIONS: These findings suggest that SWS and RWA might represent markers of different motor subtypes progression in PD.

Functional outcomes of different surgical treatments for common peroneal nerve injuries: a retrospective comparative study.

BACKGROUND: This study aims to assess the recovery patterns and factors influencing outcomes in patients with common peroneal nerve (CPN) injury. METHODS: This retrospective study included 45 patients with CPN injuries treated between 2009 and 2019 in Jing'an District Central Hospital. The surgical interventions were categorized into three groups: neurolysis (group A; n = 34 patients), nerve repair (group B; n = 5 patients) and tendon transfer (group C; n = 6 patients). Preoperative and postoperative sensorimotor functions were evaluated using the British Medical Research Council grading system. The outcome of measures included the numeric rating scale, walking ability, numbness and satisfaction. Receiver operating characteristic (ROC) curve analysis was utilized to determine the optimal time interval between injury and surgery for predicting postoperative foot dorsiflexion function, toe dorsiflexion function, and sensory function. RESULTS: Surgical interventions led to improvements in foot dorsiflexion strength in all patient groups, enabling most to regain independent walking ability. Group A (underwent neurolysis) had significant sensory function restoration (P < 0.001), and three patients in Group B (underwent nerve repair) had sensory improvements. ROC analysis revealed that the optimal time interval for achieving M3 foot dorsiflexion recovery was 9.5 months, with an area under the curve (AUC) of 0.871 (95% CI = 0.661-1.000, P = 0.040). For M4 foot dorsiflexion recovery, the optimal cut-off was 5.5 months, with an AUC of 0.785 (95% CI = 0.575-0.995, P = 0.020). When using M3 toe dorsiflexion recovery or S4 sensory function recovery as the gold standard, the optimal cut-off remained at 5.5 months, with AUCs of 0.768 (95% CI = 0.582-0.953, P = 0.025) and 0.853 (95% CI = 0.693-1.000, P = 0.001), respectively. CONCLUSIONS: Our study highlights the importance of early surgical intervention in CPN injury recovery, with optimal outcomes achieved when surgery is performed within 5.5 to 9.5 months post-injury. These findings provide guidance for clinicians in tailoring treatment plans to the specific characteristics and requirements of CPN injury patients.

Higher cortical excitability to negative emotions involved in musculoskeletal pain in Parkinson's disease.

OBJECTIVE: Changes in brain structure and neurotransmitter systems are involved in pain in Parkinson's disease (PD), and emotional factors are closely related to pain. Our study applied electroencephalography (EEG) to investigate the role of emotion in PD patients with chronic musculoskeletal pain. METHODS: Forty-two PD patients with chronic musculoskeletal pain and 38 without were enrolled. EEG data were recorded under resting conditions, and while viewing pictures with neutral, positive, and negative content. We compared spectrum power, functional connectivity, and late positive potential (LPP), an event-related potential (ERP), between the groups. RESULTS: PD patients with pain tended to have higher scores for the Hamilton Rating Scale for Depression (HRSD). In the resting EEG, mean ß-band amplitude was significantly higher in patients with pain than in those without. Logistic regression analysis showed that higher HRSD scores and higher mean ß-band amplitude were associated with pain. ERP analysis revealed that the amplitudes of LPP difference waves (the absolute difference between positive and negative condition LPP and neutral condition LPP) at the central-parietal region were significantly reduced in patients with pain (P = 0.029). Spearman correlation analysis showed that the amplitudes of late (700-1000 ms) negative versus neutral condition LPP difference waves were negatively correlated with pain intensity, assessed by visual analogue scale, (r = -0.393, P = 0.010) and HRSD scores (r = -0.366, P = 0.017). CONCLUSION: Dopaminergic and non-dopaminergic systems may be involved in musculoskeletal pain in PD by increasing ß-band activity and weakening the connection of the θ-band at the central-parietal region. PD patients with musculoskeletal pain have higher cortical excitability to negative emotions. The changes in pain-related EEG may be used as electrophysiological markers and therapeutic targets in PD patients with chronic pain.

Supporting cognitive catch-up: The effects of cluster-randomized psychosocial stimulation interventions on preterm low birthweight children in rural China.

Improved survival of preterm low birthweight (LBW) infants due to advances in neonatal care has brought issues such as postnatal development trajectories to the foreground. This study pools evidence from three cluster-randomized experiments evaluating community-based psychosocial stimulation programs conducted from 2014 to 2017 that included 3571 rural Chinese children aged 6-24 months (51.1% male, 96.2% Han Chinese). The risk of severe cognitive delay was found to be 26.5 percentage points higher for preterm LBW children than for their peers at age 2.5, with a prevalence rate of 48.3%. Results show that psychosocial stimulation interventions can improve child cognitive development at scale, with beneficial impacts on child cognition disproportionately larger for preterm LBW children, helping them to catch up developmentally.

Sodium Alginate Aerogel as a Carrier of Organogelators for Effective Oil Spill Solidification and Recovery.

Marine oil spills pose a serious threat to the marine ecological environment. Phase-selective organogelators (PSOGs) are ideal candidates for oil spill gelation when used in combination with a mechanical recovery method. However, the toxicity of an organic solvent carrier has become a key problem when it is applied in the remediation of marine oil pollution. In this study, through an inexpensive and nontoxic ionic cross-linking and freeze-drying method, we successfully developed composite oil gelling agents that used a biomass sodium alginate aerogel as the carrier of 12-hydroxystearic acid (12-HSA). Simultaneously, carboxylated cellulose nanofibers (CNF-C) with large specific surface area and graphene oxide (GO) with excellent mechanical properties as reinforcing fillers were combined with an alginate matrix. 12-HSA, as a green and inexpensive organic gelator, was uniformly loaded on the aerogels by vacuum impregnation. The sodium alginate aerogel was capable of absorbing and storing oil due to its three-dimensional network skeleton and high porosity. Rheological studies have demonstrated that the organic gelator 12-HSA can be released from the aerogel substrate and self-assemble to form an oleogel with the absorbed oil quickly. The synergistic effect between absorption and congelation endows the composite oil gelling agent with efficient oil spill recovery capability. Based on eco-friendly, biodegradable, and simple synthesis methods, this composite oil gelling agent shows great potential for application in marine oil spill recovery.

Nomogram for predicting bleeding events in nonvalvular atrial fibrillation patients receiving rivaroxaban: A retrospective study.

Background and Aims: To construct a bleeding events prediction model of nonvalvular atrial fibrillation (NVAF) patients receiving rivaroxaban. Methods: We conducted a retrospective cohort study in patients with NVAF who received rivaroxaban from June 2017 to March 2019. Demographic information and clinical characteristics were obtained from the electronic medical system. Univariate analysis was used to find the primary predictive factors of bleeding events in patients receiving rivaroxaban. Multiple analysis was conducted to screen the primary independent predictive factors selected from the univariate analysis. Finally, the independent influencing factors were applied to build a prediction model by using R software; then, a nomogram was established according to the selected variables visually, and the sensitivity and specificity of the model was evaluated. Results: Twelve primary predictive factors were selected by univariate analysis from 46 variables, and multivariate analysis showed that older age, higher prothrombin time (PT) values, history of heart failure and stroke were independent risk factors of bleeding events. The area under curve (AUC) for this novel nomogram model was 0.828 (95% CI: 0.763-0.894). The mean AUC over 10-fold stratified cross-validation was 0.787, and subgroup analysis validation also showed a satisfied AUC. In addition, the decision curve analysis showed that the PT in combination with CHA2DS2-VASc and HASBLED was more practical and accurate for predicting bleeding events than using CHA2DS2-VASc and HASBLED alone. Conclusions: PT in combination with CHA2DS2-VASc and HASBLED could be considered as a more practical and accurate method for predicting bleeding events in patients taking rivaroxaban.

Thymoma with immunodeficiency, combined diffuse panbronchiolitis, and latent autoimmune diabetes in adults- case report and systematic review.

Thymoma with Immunodeficiency (Good's Syndrome, GS) is a rare association between thymoma and immunodeficiency, first described over 60 years ago. Patients with GS typically present with thymomas, reduced or absent B cells in the peripheral blood, hypogammaglobulinemia, and defects in cell-mediated immunity. We report the case of a 67-year-old woman diagnosed with GS following the development of a progressive, severe, refractory pulmonary infection and diffuse panbronchiolitis (DPB). She also had diabetes, characterized by anti-glutamic acid decarboxylase antibody positivity, leading to a diagnosis of latent autoimmune diabetes in adults (LADA). A thorough review of existing literature revealed that GS is often confirmed after multiple episodes of opportunistic infections or autoimmune diseases post-thymoma surgery. Due to their immunodeficiency, GS patients frequently suffer from recurrent infections over extended periods, and some succumb to severe infections. Regular immunoglobulin infusions may be effective in treating GS.