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Aim: To compare the efficacy and safety of a fixed‐ratio combination of insulin glargine 100 U/mL plus lixisenatide (iGlarLixi) with premixed insulin, insulin degludec plus insulin aspart (IDegAsp), in Chinese people with type 2 diabetes (T2D) suboptimally controlled with oral antidiabetic drug(s) (OADs). Methods: In Soli‐D, a 24‐week, multicentre, open‐label, study, insulin‐naïve adults were randomized 1:1 to once‐daily injections of iGlarLixi (n = 291) or IDegAsp (n = 291), with continued metformin ± sodium‐glucose co‐transporter‐2 inhibitors. The primary endpoint was non‐inferiority in HbA1c change from baseline to week 24. Key secondary endpoints included superiority in HbA1c change and body weight (BW) change at week 24. Hypoglycaemia rates were also assessed. Results: At week 24, iGlarLixi showed non‐inferiority and superiority over IDegAsp in HbA1c reduction (least squares [LS] mean difference: −0.20 [95% confidence interval {CI}: –0.33, −0.07]; P <.001 for non‐inferiority; [97.5% CI: –0.35, −0.05]; P =.003 for superiority). iGlarLixi decreased BW and IDegAsp increased BW from baseline to week 24, with a statistically significant LS mean difference of −1.49 kg in favour of iGlarLixi (97.5% CI: –2.32, −0.66; P <.001). Event rates (per person‐year) for American Diabetes Association (ADA) Level 1, 2 or 3 hypoglycaemia were lower for iGlarLixi (1.90) versus IDegAsp (2.72) (relative risk: 0.71; 95% CI: 0.52, 0.98). No ADA Level 3 hypoglycaemia or unexpected safety findings were reported. Conclusions: In Chinese people with T2D suboptimally controlled with OADs, once‐daily iGlarLixi provided better glycaemic control with BW benefit and lower hypoglycaemia event rates versus IDegAsp. [ABSTRACT FROM AUTHOR]

Background: Cerebral autosomal-dominant arteriopathy with subcortical infarction and leukoencephalopathy (CADASIL) is an inherited small-vessel disease that affects the white matter of the brain. Recent studies have confirmed that the deposition of NOTCH3ECD is the main pathological basis of CADASIL; however, whether different mutations present the same pathological characteristics remains to be further studied. Some studies have found that mitochondrial dysfunction is related to CADASIL; however, the specific effects of NOTCH3ECD on mitochondrial remain to be determined. Objective: We aimed to explore the role of mitochondrial dysfunction in CADASIL. Methods: We established transgenic human embryonic kidney-293T cell models (involving alterations in cysteine and non-cysteine residues) via lentiviral transfection. Mitochondrial function and structure were assessed using flow cytometry and transmission electron microscopy, respectively. Mitophagy was assessed using western blotting and immunofluorescence. Results: We demonstrated that NOTCH3ECD deposition affects mitochondrial morphology and function, and that its protein levels are significantly correlated with mitochondrial quality and can directly bind to mitochondria. Moreover, NOTCH3ECD deposition promoted the induction of autophagy and mitophagy. However, these processes were impaired, leading to abnormal mitochondrial accumulation. Conclusions: This study revealed a common pathological feature of NOTCH3ECD deposition caused by different NOTCH3 mutations and provided new insights into the role of NOTCH3ECD in mitochondrial dysfunction and mitophagy. [ABSTRACT FROM AUTHOR]

Hostility towards women is a type of prejudice that can have adverse effects on women and society, but research on predictors of men's hostility towards women is limited. The present study primarily introduced predictors associated with misogynist involuntary celibates (incels), and then investigated whether loneliness, rejection, attractiveness, number of romantic and sexual partners, right‐wing authoritarianism, and gaming predicted hostility towards women among a more general sample of men. A total of 473 men (aged 18–35, single, heterosexual, UK residents) recruited via Prolific answered the hostile sexism subscale, the misogyny scale, the self‐perceived sexual attractiveness scale, the right‐wing authoritarianism scale, the game addiction scale for adolescents, the adult rejection‐sensitivity scale, the UCLA loneliness scale, and self‐developed questions regarding number of sexual and romantic partners, and time spent gaming. We found a strong positive relationship between right‐wing authoritarianism and hostility towards women, as well as a strong convex curvilinear relationship between attractiveness and hostility towards women. The number of sexual partners showed a moderate concave relationship with hostility towards women. We did not find sufficient support for a relationship between gaming and hostility towards women, and there was no support that loneliness, rejection, or romantic partners predicted hostility towards women among a general sample of men. Our study supports right‐wing authoritarianism and self‐perceived attractiveness as potential strong predictors in understanding men's hostility towards women in the wider community.Pre‐registration: https://osf.io/ms3a4. [ABSTRACT FROM AUTHOR]

Total hip arthroplasty (THA) effectively treats various end-stage hip conditions, offering pain relief and improved joint function. However, surgical outcomes are influenced by multifaceted factors. This research aims to create a predictive model, incorporating radiomic and clinical information, to forecast post-surgery joint function in robot-assisted THA (RA-THA) patients. The study set comprised 136 patients who underwent unilateral RA-THA, which were subsequently partitioned into a training set (n = 95) and a test set (n = 41) for analysis. Preoperative CT imaging was employed to derive 851 radiomic characteristics, selecting those with an intra-class correlation coefficient > 0.75 for analysis. Least absolute shrinkage and selection operator regression reduced redundancy to six significant radiomic features. Clinical data including preoperative Visual Analog Scale (VAS), Harris Hip Score (HHS), and Western Ontario and McMaster University Osteoarthritis Index (WOMAC) score were collected. Logistic regression identified significant predictors, and three models were developed. Receiver operating characteristic and decision curves evaluated the models. Preoperative VAS, HHS, WOMAC score, and radiomics feature scores were significant predictors. In the training set, the AUCs were 0.835 (clinical model), 0.757 (radiomic model), and 0.891 (combined model). In the test set, the AUCs were 0.777 (clinical model), 0.824 (radiomic model), and 0.881 (combined model). The constructed nomogram prediction model combines radiological features with relevant clinical data to accurately predict functional outcomes 3 years after RA-THA. This model has significant prediction accuracy and broad clinical application prospects and can provide a valuable reference for formulating personalized treatment plans and optimizing patient management strategies., (© 2024. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

The impact of stroke on global health is profound, with both high mortality and morbidity rates. This condition can result from cerebral ischemia, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH). The pathophysiology of stroke involves secondary damage and irreversible loss of neuronal function. Post-translational modifications (PTMs) have been recognized as crucial regulatory mechanisms in ischemic and hemorrhagic stroke-induced brain injury. These PTMs include phosphorylation, glycosylation, ubiquitination, SUMOylation, acetylation, and succinylation. This comprehensive review delves into recent research on the PTMs landscape associated with neuroinflammation and neuronal death specific to cerebral ischemia, ICH, and SAH. This review aims to explain the role of PTMs in regulating pathologic mechanisms and present critical techniques and proteomic strategies for identifying PTMs. This knowledge helps us comprehend the underlying mechanisms of stroke injury and repair processes, leading to the development of innovative treatment strategies. Importantly, this review underscores the significance of exploring PTMs to understand the pathophysiology of stroke., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Dendritic cells (DCs) regulate the immune response associated with T lymphocytes, but their role in stroke remains unclear. In this study, we investigated the causal relationship between DCs and T-cell response in intracerebral hemorrhage (ICH) by focusing on TLRs (toll-like receptors) that may modulate the function of DCs., Methods: We studied the effects of TLR4, TLR2, and TLR9 on DC-mediated T-cell response and the outcomes of ICH using male C57BL/6 and CD11c-DTx (diphtheria toxin) receptor mice. We administered specific agents intraperitoneally or orally and evaluated the results using flow cytometry, real-time polymerase chain reaction, Western blotting, immunofluorescence staining, histopathology, and behavioral tests., Results: TLR4 and TLR2 activation induces DC maturation and reduces the ratio of regulatory T to T-helper 17 cells in the brain and periphery after ICH. When either of these receptors is activated, it can worsen neuroinflammation and exacerbate ICH outcomes. TLR9 also promotes DC maturation, stabilizing the number of DCs, particularly conventional DCs. TLR9 has the opposite effects on regulatory T/T-helper 17 balance, neuroinflammation, and ICH outcomes compared with TLR4 and TLR2. Upon stimulation, TLR4 and TLR9 may achieve these effects through the p38-MAPK (p38-mitogen-activated protein kinase)/MyD88 (myeloid differentiation primary response gene 88) and indoleamine 2,3-dioxygenase 1 (IDO1)/GCN2 (general control nonderepressible 2) signaling pathways, respectively. DCs act as intermediaries for TLR-mediated T-cell response., Conclusions: TLR-mediated opposing effects of DCs on T-cell response may provide novel strategies to treat ICH., Competing Interests: None.

Mesenchymal stem cells (MSCs) and macrophages collaboratively contribute to bone regeneration after injury. However, detailed mechanisms underlying the interaction between MSCs and inflammatory macrophages (M1) remain unclear. A macrophage-depleted tooth extraction model was generated in 5-wk-old female C57BL/6J mice using clodronate liposome (12.5 mg/kg/mouse, intraperitoneally) or saline injection (control) before maxillary first molar extraction. Mice were sacrificed on days 1, 3, 5, 7, and 10 after tooth extraction ( n  = 4). Regenerated bone volume evaluation of tooth extraction socket (TES) and histochemical analysis of CD80 + M1, CD206 + M2 (anti-inflammatory macrophages), PDGFRα + MSC, and TNF-α + cells were performed. In vitro, isolated MSCs with or without TNF-α stimulation (10 ng/mL, 24 h, n  = 3) were bulk RNA-sequenced (RNA-Seq) to identify TNF-α stimulation-specific MSC transcriptomes. Day 7 micro-CT and HE staining revealed significantly lower mean bone volume (clodronate vs control: 0.01 mm 3 vs 0.02 mm 3 , p <.0001) and mean percentage of regenerated bone area per total TES in clodronate group (41.97% vs 54.03%, p <.0001). Clodronate group showed significant reduction in mean number of CD80 + , TNF-α + , PDGFRα + , and CD80 + TNF-α + cells on day 5 (306.5 vs 558.8, p <.0001; 280.5 vs 543.8, p <.0001; 365.0 vs 633.0, p <.0001, 29.0 vs 42.5, p <.0001), while these cells recovered significantly on day 7 (493.3 vs 396.0, p =.0004; 479.3 vs 384.5, p =.0008; 593.0 vs 473.0, p =.0010, 41.0 vs 32.5, p =.0003). RNA-Seq analysis showed that 15 genes (|log2FC| > 5.0, log2TPM > 5) after TNF-α stimulation were candidates for regulating MSC's immunomodulatory capacity. In vivo, Clec4e and Gbp6 are involved in inflammation and bone formation. Clec4e , Gbp6 , and Cxcl10 knockdown increased osteogenic differentiation of MSCs in vitro. Temporal reduction followed by apparent recovery of TNF-α-producing M1 macrophages and MSCs after temporal macrophage depletion suggests that TNF-α activated MSCs during TES healing. In vitro mimicking the effect of TNF-α on MSCs indicated that there are 15 candidate MSC genes for regulation of immunomodulatory capacity., Competing Interests: The authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Venetoclax is a standard treatment for patients with chronic lymphocytic leukemia (CLL) following covalent Bruton tyrosine kinase inhibitor (cBTKi) therapy, despite relatively limited prospective data in this setting. Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi that was designed to overcome the pharmacologic limitations of cBTKi and re-establish BTK inhibition. An unanchored matching-adjusted indirect comparison (MAIC) was conducted to estimate the treatment effect of pirtobrutinib versus venetoclax monotherapy in patients with cBTKi-pretreated CLL. Data from patients with CLL who were venetoclax-naïve and pretreated with cBTKi received pirtobrutinib (N=146) in the phase I/II BRUIN study were compared with the only identified trial of patients with CLL receiving venetoclax after a cBTKi (N=91), as administered as monotherapy until progression. Outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and treatment-emergent adverse events. Both unweighted and weighted analyses were conducted. PFS and OS of pirtobrutinib and venetoclax were comparable in both unweighted and weighted analyses (weighted hazard ratios for PFS: 1.01, 95% confidence interval [CI]: 0.58-1.73, P=0.98 and OS: 0.64, 95% CI: 0.25-1.67, P=0.34). ORR was significantly higher for pirtobrutinib (80.2% vs. 64.8%, P=0.01). Grade ≥3 treatment-emergent adverse events were lower in weighted analyses for pirtobrutinib versus venetoclax (all P<0.01), except for pneumonia, which was similar. These results suggest that pirtobrutinib may also be considered as an effective and well-tolerated treatment for patients with relapsed CLL following cBTKi.

Objective: Osteonecrosis of the femoral head (ONFH) is a common orthopedic condition that will prompt joint dysfunction, significantly impacting patients' quality of life. However, the specific pathogenic mechanisms underlying this disease remain elusive. The objective of this study is to examine the differentially expressed messenger RNAs (DE mRNAs) and key genes linked to ONFH, concurrently investigating the immune cell infiltration features in ONFH patients through the application of the CIBERSORT algorithm., Methods: Microarray was applied to scrutinize mRNA expression profiles in both ONFH patients and healthy controls, with data integration sourced from the GEO database. DE mRNAs were screened using the Limma method. The biological functions of DE mRNAs were explored through the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, Gene Ontology (GO) functional analysis, and Gene Set Enrichment Analysis (GSEA). Additionally, support vector machine-recursive feature elimination (SVM-RFE) and the least absolute shrinkage and selection operator (LASSO) were employed to discern diagnostic biomarkers associated with the disease. Receiver operating characteristic (ROC) analysis was utilized to assess the statistical performance of the feature genes. The validation of key genes was performed using qRT-PCR in bone tissues obtained from ONFH patients and healthy controls. Osteogenic differentiation of BMSC was then performed and detected by alkaline phosphatase staining (ALP) and qRT-PCR to verify the correlation between key genes and osteogenic differentiation. Finally, immune cell infiltration analysis was executed to evaluate immune cell dysregulation in ONFH, concurrently exploring the correlation between the infiltration of immune cells and key genes., Results: After consolidating the datasets, the Limma method revealed 107 DEGs, comprising 76 downregulated and 31 upregulated genes. Enrichment analysis revealed close associations of these DE mRNAs with functions such as cell migration, osteoblast differentiation, cartilage development and extracellular region. Machine learning algorithms further identified APOD, FBXO43 and LRP12 as key genes. ROC curves demonstrated the high diagnostic efficacy of these genes. The results of qRT-PCR showed that the expression levels of key genes were consistent with those of microarray analysis. In addition, the results of in vitro experiments showed that APOD was closely related to osteogenic differentiation of BMSC. Immune infiltration analysis suggested a close correlation between ONFH and imbalances in levels of Neutrophils, Monocytes, Macrophages M2, Dendritic cells activated and Dendritic cells resting., Conclusion: APOD is closely related to osteogenic differentiation of BMSCs and can be used as a diagnostic marker of ONFH. Immune cell infiltration significantly differs between controls and ONFH patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Duan, Xing, Zhang, Li, Chen, Lei, Zhao, Cao, Guan, Kong, Li, Wu, Wang, Tian and Yang.)

Aim: Red blood cell distribution width-to-albumin ratio (RAR) is a combined new indicator reflecting immunology and has been reported to predict the prognosis of inflammation-related diseases and brain diseases. However, the association and predictive value of RAR in the prognosis of patients with autoimmune encephalitis (AE) has not been reported., Methods: This was a retrospective cohort study, and data were collected from the Henan Provincial People's Hospital. RAR was categorized according to quartile. The prognosis was assessed using the modified Rankin Scale (mRS), and an mRS score of ≥3 was defined as a poor prognosis. The logistical regression model was used to explore the association between RAR and the prognosis, with results reported as odds ratio (OR) and 95% confidence interval (CI). The predictive value of RAR was evaluated by calculating the area under the receiving operating curve (AUC), sensitivity, specificity, and accuracy., Results: A total of 175 eligible patients were included for analysis, and 51 patients were identified as having poor prognosis. After adjusting age, cancer, other diseases, histological subtype, antiepileptic therapy, anti-tumor treatment, ICU treatment, and length of stay, RAR in the highest quartile (Q4) was found to be significantly associated with the high odds of poor prognosis (OR = 5.63, 95%CI: 1.98-16.02) compared to RAR in the lowest quartile (Q1). In addition, RAR was identified as a predictor for the prognosis of AE patients (AUC = 0.660, 95%CI: 0.574-0.746)., Conclusion: This study found the close association and predictive value of RAR for the prognosis of AE patients, indicating that RAR might help clinicians identify high-risk populations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Yang, Xia, Ma, Zhang, Guo and Zang.)

Background: Cerebral autosomal-dominant arteriopathy with subcortical infarction and leukoencephalopathy (CADASIL) is an inherited small-vessel disease that affects the white matter of the brain. Recent studies have confirmed that the deposition of NOTCH3ECD is the main pathological basis of CADASIL; however, whether different mutations present the same pathological characteristics remains to be further studied. Some studies have found that mitochondrial dysfunction is related to CADASIL; however, the specific effects of NOTCH3ECD on mitochondrial remain to be determined., Objective: We aimed to explore the role of mitochondrial dysfunction in CADASIL., Methods: We established transgenic human embryonic kidney-293T cell models (involving alterations in cysteine and non-cysteine residues) via lentiviral transfection. Mitochondrial function and structure were assessed using flow cytometry and transmission electron microscopy, respectively. Mitophagy was assessed using western blotting and immunofluorescence., Results: We demonstrated that NOTCH3ECD deposition affects mitochondrial morphology and function, and that its protein levels are significantly correlated with mitochondrial quality and can directly bind to mitochondria. Moreover, NOTCH3ECD deposition promoted the induction of autophagy and mitophagy. However, these processes were impaired, leading to abnormal mitochondrial accumulation., Conclusions: This study revealed a common pathological feature of NOTCH3ECD deposition caused by different NOTCH3 mutations and provided new insights into the role of NOTCH3ECD in mitochondrial dysfunction and mitophagy.