Citations

ABSTRACT Background and Purpose Radiomics extracts imaging features that may not be detectable through conventional volumetric analyses. Given their role in multiple sclerosis (MS), we applied radiomics to thalamic nuclei and examined their associations with cognitive performance. Methods A total of 601 individuals were included (342 people with MS [PwMS] from two cohorts and 259 healthy controls [HC]). Radiomic features (RF) and volumes were extracted from the whole thalamus, five thalamic nuclei, and the putamen segmented on three‐dimensional T1‐weighted images. Cognitive performance was assessed using the Symbol Digit Modalities Test (SDMT) and Paced Auditory Serial Addition Test (PASAT) in PwMS and the Digit Symbol Substitution Test (DSST) in HC. In the first MS cohort, multivariate linear regression in a discovery set ( N = 103) identified thalamus‐derived RF associated with SDMT, which were retested in a replication set ( N = 63). Their associations with PASAT in a second MS cohort ( N = 176) and DSST in HC were also evaluated. We then tested whether the same RFs, when extracted from the putamen, was associated with SDMT. Least Absolute Shrinkage and Selection Operator (LASSO) models assessed the combined predictive value of RF and volumes. Results Twenty‐eight RF–region of interest (ROI) pairs were associated with SDMT in the replication set (false discovery rate [FDR] < 0.05). Of these, 24 were also associated with PASAT (FDR ≤ 0.03), and 2 with DSST. Only ventral nuclei volume showed replicated associations among volumetrics. Only four putamen‐derived pairs were associated with SDMT (FDR = 0.04). LASSO results confirmed RF outperformed volumes. Conclusion RF extracted from the thalamus is strongly associated with cognitive performance in PwMS, outperforming volumetric measures and supporting their potential as sensitive imaging biomarkers.

Abstract Nephrocalcinosis provides a nidus for stone formation and is strongly linked to renal injury and chronic kidney disease. Although the crucial role of macrophages in the formation and progression of calcium oxalate (CaOx) crystals has long been widely recognized, finding effective immunotherapies for nephrocalcinosis remains a challenge. In this study, we described an innovative macrophage‐based method that delivers interleukin‐10 (IL‐10) into the kidney, reduces the deposition of CaOx crystals, and alleviates renal injury in a mouse model of glyoxylate‐induced CaOx. Compared with recombinant IL‐10 direct injection, the macrophage‐based method has the advantages of biocompatibility and sustaining action. We found that the transplantation of engineered macrophages via the tail vein significantly reduced the volume of crystals in the kidney, thereby alleviating the kidney injury caused by crystal. In mechanistic studies, IL‐10‐secreting macrophages inhibited crystal formation and promoted crystal clearance by promoting macrophage M2 polarization, exerting a protective effect on renal tissue. Our data suggest that macrophage‐based delivery of IL‐10 to the kidney can be a potential treatment method for nephrocalcinosis.

ImportanceSystemic antibiotic use for patients with a non–Clostridioides difficile infection (CDI) is a major risk factor for recurrent CDI. Increasing use of oral vancomycin for secondary prophylaxis against recurrent CDI in this context has uncertain efficacy.ObjectiveTo evaluate whether oral vancomycin prophylaxis compared with placebo is effective against recurrent CDI during and 8 weeks after the end of study treatment.Design, Setting, and ParticipantsThis phase 2, placebo-controlled, double-blind randomized clinical trial was conducted in 4 large health systems across the upper Midwest US. Adults who had completed treatment for CDI within the past 180 days and were taking a systemic antibiotic for a non-CDI indication were enrolled between May 21, 2018, and March 30, 2023, and followed up for 8 weeks after the end of study treatment.InterventionParticipants were randomized 1:1 to 125 mg of oral vancomycin or placebo once daily during antibiotic use for a non-CDI plus 5 days following cessation of those antibiotics.Main Outcomes and MeasuresThe primary outcome was recurrent CDI incidence during treatment and the 8-week follow-up period. The secondary outcome was vancomycin-resistant Enterococcus carriage in stool.ResultsAmong 81 randomized participants (median age, 59 years [IQR, 50-67 years]), all were included in the primary as-randomized analysis (39 in the vancomycin group; 42 in the placebo group). Sixty patients (74.1%) completed 8-week follow-up and were included in the secondary as–completed treatment analysis (31 in the vancomycin group; 29 in the placebo group). Recurrent CDI occurred in 17 of 39 participants in the oral vancomycin group (43.6%) and 24 of 42 in the placebo group (57.1%; absolute difference in percentage, −13.5% [95% CI, −35.1% to 8.0%]). Adverse events occurred in 27 of 39 participants in the oral vancomycin group (69.2%) and 27 of 42 in the placebo group (64.3%). Vancomycin-resistant Enterococcus carriage was found in 15 of 30 patients in the oral vancomycin group (50.0%) and 6 of 25 in the placebo group (24.0%) (P = .048) 8 weeks after treatment.Conclusions and RelevanceIn this randomized clinical trial, the incidence of recurrent CDI was lower (though did not reach significance) in participants taking oral vancomycin compared with those taking placebo. Because the study was underpowered, it was unable to reveal firm conclusions about the efficacy (or lack thereof) of vancomycin prophylaxis with respect to recurrent CDI.Trial RegistrationClinicalTrials.gov Identifier: NCT03462459

Abstract Cerium oxide (CeO 2 ) nanozymes have emerged as a novel class of nanozyme materials distinguished by their tunable valence states (Ce 3+ /Ce 4+ ) and abundant surface oxygen vacancies (OVs), demonstrating exceptional chemical stability, cost‐effectiveness, and scalable manufacturability. Precise control of reaction temperature or implementation of carrier‐mediated crystal growth strategies effectively enhances nanoparticle dispersion and mitigates aggregation. This review systematically summarizes recent advancements in CeO 2 nanozymes: First, it elaborates on cutting‐edge synthetic methodologies, encompassing self‐supported strategies (calcination, hydrothermal, and sol–gel) and carrier‐mediated approaches (small‐molecule compounds, macromolecular compounds, and nanomaterials), with comparative analysis of their respective merits and limitations. Second, the catalytic mechanism is comprehensively elucidated, particularly focusing on the modulation of electron transfer kinetics and surface adsorption energies in metal/nonmetal hybrid systems. By optimizing oxygen vacancy concentration to regulate Ce 3+ /Ce 4+ redox cycling dynamics, significant enhancement in redox efficiency and catalytic stability can be achieved, enabling precise enzyme‐like activity regulation. Furthermore, the review comprehensively summarizes breakthrough applications in multidimensional biomedical fields, including precision tumor therapy, intelligent antibacterial systems, inflammatory microenvironment regulation, and ultrasensitive biosensing. This work establishes a theoretical framework for structure‐activity relationship‐guided rational design of high‐performance CeO 2 nanozymes and delineates their potential translational applications in precision medicine.

Triple-negative breast cancer (TNBC) represents the most malignant subtype of breast cancer. The clinical application of PARP inhibitors (PARPi) is limited by the low frequency of BRCA1/2 mutations in TNBC. Here, we identified that MTAP deletion sensitized genotoxic agents in our clinical cohort of metastatic TNBC. Further study demonstrated that MTAP deficiency or inhibition rendered TNBC susceptibility to chemotherapeutic agents, particularly PARPi. Mechanistically, targeting MTAP that synergized with PARPi by disrupting the METTL16-MAT2A axis involved in methionine metabolism and depleting in vivo s-adenosylmethionine (SAM) levels. Exhausted SAM in turn impaired PARPi-induced DNA damage repair through attenuation of MRE11 recruitment and end resection by diminishing MRE11 methylation. Notably, brain metastatic TNBC markedly benefited from a lower dose of PARPi and MTAP deficiency/inhibition synergy due to the inherently limited methionine environment in the brain. Collectively, our findings revealed a feed-forward loop between methionine metabolism and DNA repair through SAM, highlighting a therapeutic strategy of PARPi combined with MTAP deficiency/inhibition for TNBC.

Abstract Apathy is a prevalent and persistent neuropsychiatric syndrome across many neurological disorders, significantly impacting both patients and caregivers. We systematically quantified discrepancies between self- and caregiver-reported apathy in 335 patients with a variety of diagnoses, such as frontotemporal dementia (behavioural variant and semantic dementia subtypes), Parkinson’s disease, Parkinson’s disease dementia, dementia with Lewy bodies, Alzheimer’s disease dementia, mild cognitive impairment, small vessel cerebrovascular disease, subjective cognitive decline and autoimmune encephalitis. Using the Apathy Motivation Index (AMI) and its analogous caregiver version (AMI-CG), we found that caregiver-reported apathy consistently exceeded self-reported levels across all conditions. Moreover, self-reported apathy accounted for only 14.1% of the variance in caregiver ratings. This apathy reporting discrepancy was most pronounced in conditions associated with impaired insight, such as behavioural variant frontotemporal dementia, and was significantly correlated with cognitive impairment. Deficits in memory and fluency explained an additional 11.2% of the variance in caregiver-reported apathy. Specifically, executive function deficits (e.g. indexed by fluency) and memory impairments may contribute to behavioural inertia or recall of it. These findings highlight the need to integrate patient and caregiver perspectives in apathy assessments, especially for conditions with prominent cognitive impairment. To improve diagnostic accuracy and deepen our understanding of apathy across neurological disorders, we highlight the need for adapted apathy assessment strategies that account for cognitive impairment particularly in individuals with insight or memory deficits. Understanding the cognitive mechanisms underpinning discordant apathy reporting in dementia might help inform targeted clinical interventions and reduce caregiver burden.

Intracerebral hemorrhage (ICH), caused by the rupture of small blood vessels, remains the least treatable subtype of stroke. The pathophysiology of ICH involves immediate mechanical compression from the hematoma, followed by secondary injuries such as cerebral edema, inflammation, and neuronal damage. Management aims to prevent hematoma expansion, enable safe and effective hematoma evacuation, and mitigate secondary injuries. Recent advancements in clinical management, including blood pressure control, hemostatic therapy, surgical and minimally invasive hematoma removal, and complication management, offer new hope. This review synthesizes these advancements, integrating insights from recent research and clinical trials, and highlights significant progress in evidence-based approaches that pave the way for precise and personalized treatment strategies. Nonetheless, further research is necessary to enhance our understanding of ICH mechanisms and develop more effective clinical interventions.

Abstract Background and Objectives Radiomics extracts imaging features that may not be detectable through conventional volumetric analyses. Given their role in multiple sclerosis (MS), we applied radiomics to thalamic nuclei and examined their associations with cognitive performance. Methods A total of 601 individuals were included (342 people with MS-PwMS from two cohorts, and 259 healthy controls-HC). Radiomic features (RF) and volumes were extracted from the whole thalamus, five thalamic nuclei, and the putamen segmented on 3D T1-weighted images. Cognitive performance was assessed using the Symbol Digit Modalities Test (SDMT) and Paced Auditory Serial Addition Test (PASAT) in PwMS, and the Digit Symbol Substitution Test (DSST) in HC. In the first MS cohort, multivariate linear regression in a discovery set (N=103) identified thalamus-derived RF associated with SDMT, which were retested in a replication set (N=63). Their associations with PASAT in a second MS cohort (N=176) and DSST in HC were also evaluated. We then tested whether the same RF, when extracted from the putamen, were associated with SDMT. LASSO models assessed the combined predictive value of RF and volumes. Figure 2 presents an overview of the involvement of different cohorts in the study, outlining the specific study objectives and the statistical analysis approaches employed. Results Twenty-eight RF–ROI pairs were associated with SDMT in the replication set (FDR<0.05). Of these, 24 were also associated with PASAT (FDR≤0.03), and 2 with DSST. Only ventral nuclei volume showed replicated associations among volumetrics. Only 4 putamen-derived pairs were associated with SDMT (FDR=0.04). LASSO results confirmed RF outperformed volumes. Discussion RF extracted from the thalamus are strongly associated with cognitive performance in PwMS, outperforming volumetric measures and supporting their potential as sensitive imaging biomarkers.