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In the ischemic brain, hypoxia leads to mitochondrial dysfunction, insufficient energy production, and astrocyte activation. Yet, most studies investigating mitochondrial dysfunction in cerebral ischemia have focused exclusively on neurons. This review will highlight the importance of the morphological, molecular, and functional heterogeneity of astrocytes in their role in brain injuries and explore how activated astrocytes exhibit calcium imbalance, reactive oxygen species overproduction, and apoptosis. In addition, special focus will be given to the role of the mitochondrial protein frataxin in activated astrocytes during ischemia and its putative role in the pharmacological management of cerebral ischemia. Astrocytes interconnect cerebral microvessels with neurons. Mitochondrial function within the astrocytes regulates neuronal response during cerebrovascular ischemia. Astrocytic calcium influx may reduce frataxin (FXN) expression, thereby contributing to mitochondrial dysfunction. Targeted induction of astrocytic FXN may be an attractive therapeutic strategy for ischemic brain injury.

Metabolomics approaches, such as direct analysis in real time-high resolution mass spectrometry (DART-HRMS), allow characterising many polar and non-polar compounds useful as authentication biomarkers of dairy chains. By using both a partial least squares discriminant analysis (PLS-DA) and a linear discriminant analysis (LDA), this study aimed to assess the capability of DART-HRMS, coupled with a low-level data fusion, discriminate among milk samples from lowland (silages vs. hay) and Alpine (grazing; APS) systems and identify the most informative biomarkers associated with the main dietary forage. As confirmed also by the LDA performed against the test set, DART-HRMS analysis provided an accurate discrimination of Alpine samples; meanwhile, there was a limited capacity to correctly recognise silage- vs. hay-milks. Supervised multivariate statistics followed by metabolomics hierarchical cluster analysis allowed extrapolating the most significant metabolites. Lowland milk was characterised by a pool of energetic compounds, ketoacid derivates, amines and organic acids. Seven informative DART-HRMS molecular features, mainly monoacylglycerols, could strongly explain the metabolomic variation of Alpine grazing milk and contributed to its classification. The misclassification between the two lowland groups confirmed that the intensive dairy systems would be characterised by a small variation in milk composition.

Sickle cell disease (SCD) is an inherited blood disorder caused by a mutation in the beta‐globin gene, resulting in chronic complications, including cognitive decline—particularly in executive functions. Neuroimaging studies have identified structural and functional abnormalities associated with SCD; however, the directionality of information flow between brain networks and how disruptions in these interactions contribute to cognitive deficits remains poorly understood. This study employed Granger causality (GC) analysis to investigate effective connectivity and information flow between brain regions and resting‐state networks using ultra‐high‐field 7T MRI in adult patients with SCD (n = 51) and age‐, sex‐, and race‐matched controls (n = 44). We first performed a whole‐brain network analysis, followed by an examination of specific brain regions within the default mode network (DMN), executive control network (ECN), dorsal attention network (DAN), and ventral attention network (VAN). For each analysis, we computed both the magnitude and directionality of information flow to capture the strength and directional influence of connectivity between brain regions. While patients with SCD exhibited a higher magnitude of information flow compared to controls, this difference was only statistically significant when computed at the brain region level, not at the resting‐state network level. In terms of directionality, afferent flow from DAN and VAN to ECN was significantly greater in patients with SCD than in controls. Subtype analysis revealed that patients with severe SCD demonstrated significantly higher magnitude of information flow than those with mild SCD and controls. We also observed subtype‐specific differences in afferent flow to ECN: mild SCD patients showed significant flow from VAN, while severe SCD patients showed significant flow from DAN. Additionally, multiple regression analyzes assessing correlations between information flow and cognitive performance showed that controls had higher R2 values than patients with SCD, suggesting reduced network efficiency in SCD. This study is the first to apply GC‐based effective connectivity analysis in SCD, revealing unique pathways of information exchange in patients with SCD, potentially as compensatory mechanisms for disease‐related structural and functional disruptions. These findings provide novel insights into how SCD impacts brain network organization and cognitive function, emphasizing the importance of investigating network‐level dynamics in this population. Granger causality analysis of resting‐state data acquired using 7T fMRI shows that patients with sickle cell disease exhibit altered information flow to the executive control network. These directional changes—especially from attention networks—vary by disease subtype, revealing compensatory reorganization linked to cognitive function.

The purpose of this exploratory study was to describe associations between NIH Toolbox-Cognition Battery subtests and legacy measures of neurocognitive function in two samples with neurological conditions (stroke and sickle cell disease (SCD)). This exploratory secondary analysis uses data from two studies that assessed cognition at one time point using the NIH Toolbox-Cognition Battery, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and subtests from the Delis-Kaplan Executive Functions System (DKEFS). People with stroke ( = 26) and SCD ( = 64) were included. Associations between the NIH Toolbox-Cognition Battery subtests and corresponding legacy measures were examined using linear correlations, Bland-Altman analysis, and Lin's Concordance Correlation Coefficient. Linear correlations and Lin's Concordance Correlation Coefficient were poor to strong in both samples on NIH Toolbox-CB subtests: Flanker Inhibitory Control and Attention ( = .35 to .48, Lin CCC = .27 to .37), Pattern Comparison Processing Speed ( = .40 to .65, Lin CCC = .37 to .62), Picture Sequence Memory ( = .19 to .55, Lin CCC = .18 to .48), Dimensional Change Card Sort ( = .39 to .77, Lin CCC = .38 to .63), Fluid Cognition Composite ( = .88 to .90, Lin CCC = .60 to .79), and Total Cognition Composite ( = .64 to .83, Lin CCC = .60 to .78). Bland-Altman analyses demonstrated wide limits of agreement across all subtests (-3.17 to 3.78). The NIH Toolbox-Cognition Battery subtests may behave similarly to legacy measures as an overall assessment of cognition across samples at risk for neurological impairment. Findings should be replicated across additional clinical samples.

Red blood cells (RBCs) contain the highest purine nucleoside phosphorylase (PNP) level per cell volume, yet the role of PNP in the pathogenesis of sickle cell disease (SCD) is incompletely understood, highlighting an important gap in our knowledge of the disease. Previously, we reported increased PNP release by RBCs and accelerated purine nucleoside metabolism with increased production of pro‐oxidant, pro‐inflammatory and vasculotoxic byproducts in children with SCD and animal models of hemolytic injury. Thus, we hypothesized that PNP inhibition would reduce hemolysis and attenuate end‐organ damage in SCD. In adult patients with SCD (n = 63), plasma PNP levels were markedly elevated compared to controls (n = 27; p < 0.001) and correlated positively with LDH (r = 0.6032, p < 0.0001) and negatively with haemoglobin (r = −0.4523, p = 0.0002). SCD mice also showed accelerated purine metabolism compared to controls. Treatment with the PNP inhibitor 8‐aminoguanosine (8‐AG) increased inosine and guanosine and reduced downstream vasculotoxic byproducts hypoxanthine (p = 0.036), xanthine (p = 0.004) and guanine (p = 0.047), indicating efficient PNP inhibition. 8‐AG treatment rebalanced the purine metabolome in SCD mice to favour protective over harmful purine metabolites without negatively affecting haematological parameters. This was associated with reduced hemolysis and decreased splenomegaly, hepatomegaly, and hepatic and renal injury. This study suggests that PNP is an important erythrocytic damage‐associated molecular pattern molecule involved in the complex pathophysiology of SCD and proposes PNP inhibitors as a new therapeutic option for SCD and other hemolytic diseases.

Several international registries have reported on the efficacy of caplacizumab for the treatment of immune thrombotic thrombocytopenic purpura (iTTP). Similar real-world data from the United States (US) are limited. In this single center retrospective study, we sought to describe caplacizumab prescribing patterns and review clinical outcomes for US patients with iTTP. Subjects were eligible for inclusion if they were diagnosed with acute iTTP and received care at University of Pittsburgh Medical Center-affiliated hospitals from 2012 to 2022. Subjects were divided into an historical cohort who received standard of care therapy alone, and early and late administration cohorts (EA and LA) who received caplacizumab within and greater than 72 h of admission, respectively, plus standard of care. Clinical data were collected from the electronic record. Thirty-two subjects were included: 16 historical, 12 EA, and 4 LA subjects. Refractoriness occurred more frequently in the LA and historical cohorts as compared to the EA cohort (4 (100%) vs. 6 (38%) vs. 3 (25%), p = 0.02). The LA cohort also experienced longer lengths of hospital stay, required more TPE procedures, and were exposed to the greatest amount of donor plasma (p < 0.05 for all) as compared to the other cohorts. Time to platelet count normalization was longest in the LA cohort (p = 0.013). There were no significant between-group differences in bleeding events. Because we are unable to predict which patients will develop refractoriness, we recommend frontline administration of caplacizumab to all patients with iTTP.

A seeming paradox of sickle cell disease is that patients do not suffer from a high prevalence of systemic hypertension in spite of endothelial dysfunction, chronic inflammation and vasculopathy. However, some patients do develop systolic hypertension and increased pulse pressure, an increasingly recognized major cardiovascular risk factor in other populations. Hence, we hypothesized that pulse pressure, unlike other blood pressure parameters, is independently associated with markers of hemolytic anemia and cardiovascular risk in sickle cell disease. We analyzed the correlates of pulse pressure in patients (n  =  661) enrolled in a multicenter international sickle cell trial. Markers of hemolysis were analyzed as independent variables and as a previously validated hemolytic index that includes multiple variables. We found that pulse pressure, not systolic, diastolic or mean arterial pressure, independently correlated with high reticulocyte count (beta  =  2.37, p  =  0.02) and high hemolytic index (beta  =  1.53, p = 0.002) in patients with homozygous sickle cell disease in two multiple linear regression models which include the markers of hemolysis as independent variables or the hemolytic index, respectively. Pulse pressure was also independently associated with elevated serum creatinine (beta  =  3.21, p  =  0.02), and with proteinuria (beta  =  2.52, p  =  0.04). These results from the largest sickle cell disease cohort to date since the Cooperative Study of Sickle Cell Disease show that pulse pressure is independently associated with hemolysis, proteinuria and chronic kidney disease. We propose that high pulse pressure may be a risk factor for clinical complications of vascular dysfunction in sickle cell disease. Longitudinal and mechanistic studies should be conducted to confirm these hypotheses.

Key Clinical Message Warm Autoimmune Hemolytic Anemia (WAHA) is the most common form of autoimmune hemolysis and there is a growing body of evidence of an association between SARS‐CoV‐2 infection, WAHA and a hyperinflammatory state, including hemophagocytic lymphohistiocytosis/macrophage activation syndrome. However, there is no literature to date of WAHA or hyperinflammatory state following administration of anti‐SARS‐CoV‐2 monoclonal antibody treatment. This report documents a case of a patient with history of WAHA who developed brisk hemolysis and a hyperinflammatory state consistent with hemophagocytic lymphohistiocytosis/macrophage activation syndrome after COVID‐19 infection and treatment with an anti‐SARS‐CoV‐2 monoclonal antibody. He was successfully treated with multimodal treatment involving steroids, intravenous immunoglobulins, rituximab, anakinra, and vincristine with resolution of the hemolysis. Evidence of hemophagocytosis in the peripheral smear of a patient with warm autoimmune hemolytic anemia after COVID‐19 and anti‐SARS‐CoV‐2 monoclonal antibodies.

Clay minerals are naturally occurring rock and soil materials primarily composed of fine-grained aluminosilicate minerals, characterized by high hygroscopicity. In animal production, clays are often mixed with feed and, due to their high binding capacity towards organic molecules, used to limit animal absorption of feed contaminants, such as mycotoxins and other toxicants. Binding capacity of clays is not specific and these minerals can form complexes with different compounds, such as nutrients and pharmaceuticals, thus possibly affecting the intestinal absorption of important substances. Indeed, clays cannot be considered a completely inert feed additive, as they can interfere with gastro-intestinal (GI) metabolism, with possible consequences on animal physiology. Moreover, clays may contain impurities, constituted of inorganic micronutrients and/or toxic trace elements, and their ingestion can affect animal health. Furthermore, clays may also have effects on the GI mucosa, possibly modifying nutrient digestibility and animal microbiome. Finally, clays may directly interact with GI cells and, depending on their mineral grain size, shape, superficial charge and hydrophilicity, can elicit an inflammatory response. As in the near future due to climate change the presence of mycotoxins in feedstuffs will probably become a major problem, the use of clays in feedstuff, given their physico-chemical properties, low cost, apparent low toxicity and eco-compatibility, is expected to increase. The present review focuses on the characteristics and properties of clays as feed additives, evidencing pros and cons. Aims of future studies are suggested, evidencing that, in particular, possible interferences of these minerals with animal microbiome, nutrient absorption and drug delivery should be assessed. Finally, the fate of clay particles during their transit within the GI system and their long-term administration/accumulation should be clarified.

Food fraud, corresponding to any intentional action to deceive purchasers and gain an undue economical advantage, is estimated to result in a 10 to 65 billion US dollars/year economical cost worldwide. Dairy products, such as cheese, in particular cheeses with protected land- and tradition-related labels, have been listed as among the most impacted as consumers are ready to pay a premium price for traditional and typical products. In this context, efficient food authentication methods are needed to counteract current and emerging frauds. This review reports the available authentication methods, either chemical, physical, or DNA-based methods, currently used for origin authentication, highlighting their principle, reported application to cheese geographical origin authentication, performance, and respective advantages and limits. Isotope and elemental fingerprinting showed consistent accuracy in origin authentication. Other chemical and physical methods, such as near-infrared spectroscopy and nuclear magnetic resonance, require more studies and larger sampling to assess their discriminative power. Emerging DNA-based methods, such as metabarcoding, showed good potential for origin authentication. However, metagenomics, providing a more in-depth view of the cheese microbiota (up to the strain level), but also the combination of methods relying on different targets, can be of interest for this field.