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Ostechondritis dissecans (OCD) is an orthopaedic disease characterized by formation of osteochondral defects in developing joints. Epiphyseal cartilage necrosis (osteochondrosis [OC]) caused by focal failure of vascular supply is the known precursor lesion of OCD, but it remains to be established how the severity of vascular failure drives lesion healing or progression. In the current study we have implemented a novel piglet model of induced osteochondrosis of the lateral trochlear ridge of the femur to determine the role that the extent of ischemia plays in the development and progression of OC/OCD lesions. Ten 4-week-old Yorkshire piglets underwent surgical interruption of the vascular supply to the entirety (n = 4 pigs) or the distal half (n = 6 pigs) of the lateral trochlear ridge of the femur. At 2, 6, and 12 weeks postoperatively, distal femora were evaluated by magnetic resonance imaging (MRI) to determine the fate of induced OC lesions. At 12 weeks, piglets were euthanized, and the surgical sites were examined histologically. After complete devascularization, lesion size increased between the 6- and 12-week MRI by an average of 24.8 mm2 (95% CI: [-2.2, 51.7]; p = 0.071). During the same period, lesion size decreased by an average of 7.6 mm2 (95% CI: [-24.5, 19.4]; p = 0.83) in piglets receiving partial devascularization. At 12 weeks, average ± SD lesion size was larger (p<0.001) in piglets undergoing complete (73.5 ± 17.6 mm2) vs. partial (16.5 ± 9.8 mm2) devascularization. Our study demonstrates how the degree of vascular interruption determines lesion size and likelihood of healing in a large animal model of trochlear OC. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate organ at risk (OAR) auto-segmentation in the head and neck region of computed tomography images using two different commercially available deep-learning-based auto-segmentation (DLAS) tools in a single institutional clinical applications. Methods: Twenty-two OARs were manually contoured by clinicians according to published guidelines on planning computed tomography (pCT) images for 40 clinical head and neck cancer (HNC) cases. Automatic contours were generated for each patient using two deep-learning-based auto-segmentation models--Manteia AccuContour and MIM Prote'ge'AI. The accuracy and integrity of autocontours (ACs) were then compared to expert contours (ECs) using the Sørensen-Dice similarity coefficient (DSC) and Mean Distance (MD) metrics. Results: ACs were generated for 22 OARs using AccuContour and 17 OARs using Prote'ge'AI with average contour generation time of 1 min/patient and 5 min/patient respectively. EC and AC agreement was highest for the mandible (DSC 0.90 ± 0.16) and (DSC 0.91 ± 0.03), and lowest for the chiasm (DSC 0.28 ± 0.14) and (DSC 0.30 ± 0.14) for AccuContour and Prote'ge'AI respectively. Using AccuContour, the average MD was<1mm for 10 of the 22 OARs contoured, 1-2mm for 6 OARs, and 2-3mm for 6 OARs. For Prote'ge'AI, the average mean distance was<1mm for 8 out of 17 OARs, 1-2mm for 6 OARs, and 2-3mm for 3 OARs. Conclusions: Both DLAS programs were proven to be valuable tools to significantly reduce the time required to generate large amounts of OAR contours in the head and neck region, even though manual editing of ACs is likely needed prior to implementation into treatment planning. The DSCs and MDs achieved were similar to those reported in other studies that evaluated various other DLAS solutions. Still, small volume structures with nonideal contrast in CT images, such as nerves, are very challenging and will require additional solutions to achieve sufficient results. [ABSTRACT FROM AUTHOR]

There is a clinical need for alternatives to gadolinium contrast‐enhanced magnetic resonance imaging (MRI) to facilitate early detection and assessment of femoral head ischemia in pediatric patients with Legg‐Calvé‐Perthes disease (LCPD), a juvenile form of idiopathic osteonecrosis of the femoral head. The purpose of this study was to determine if intravoxel incoherent motion (IVIM), a noncontrast‐enhanced MRI method to simultaneously measure tissue perfusion and diffusion, can detect femoral head ischemia using a piglet model of LCPD. Twelve 6‐week‐old piglets underwent unilateral hip surgery to induce complete femoral head ischemia. The unoperated, contralateral femoral head served as a perfused control. The bilateral hips of the piglets were imaged in vivo at 3T MRI using IVIM and contrast‐enhanced MRI 1 week after surgery. Median apparent diffusion coefficient (ADC) and IVIM parameters (diffusion coefficient: Ds; perfusion coefficient: Df; perfusion fraction: f; and perfusion flux: f*Df) were compared between regions of interest comprising the epiphyseal bone marrow of the ischemic and control femoral heads. Contrast‐enhanced MRI confirmed complete femoral head ischemia in 11/12 piglets. IVIM perfusion fraction (f) and flux (f*Df) were significantly decreased in the ischemic versus control femoral heads: on average, f decreased 47 ± 27% (Δf = −0.055 ± 0.034; p = 0.0003) and f*Df decreased 50 ± 27% (Δf*Df = −0.59 ± 0.49 × 10−3 mm2/s; p = 0.0026). In contrast, IVIM diffusion coefficient (Ds) and ADC were significantly increased in the ischemic versus control femoral heads: on average, Ds increased 78 ± 21% (ΔDs = 0.60 ± 0.14 × 10−3 mm2/s; p < 0.0001) and ADC increased 60 ± 36% (ΔADC = 0.50 ± 0.23 × 10−3 mm2/s; p < 0.0001). In conclusion, IVIM is sensitive in detecting bone marrow ischemia in a piglet model of LCPD. [ABSTRACT FROM AUTHOR]

Failure of endochondral ossification due to interruption of the vascular supply to the epiphyseal cartilage is a critical step in the development of osteochondritis dissecans (OCD). Herein we describe the vascular architecture of the distal humeral epiphyseal cartilage in pigs and identify characteristic features that have been associated with sites predisposed to OCD development across species. Distal humeral specimens were harvested from pigs (n = 5, ages = 1, 10, 18, 30, and, 42 days old) and imaged at 9.4T magnetic resonance imaging (MRI) using a 3D gradient recalled echo sequence. The MRI data were processed using a quantitative susceptibility mapping (QSM) pipeline to visualize the vascular architecture. Specimens were also evaluated histologically to identify the presence of ischemic epiphyseal cartilage necrosis (osteochondrosis [OC]‐latens) and associated failure of endochondral ossification (OC‐manifesta). The QSM data enabled visualization of two distinct vascular beds arising from the perichondrium at the lateral and medial aspects of the distal humeral epiphysis. Elongated vessels originating from these beds coursed axially to supply the lateral and medial thirds of epiphyseal cartilage. At 18 days of age and older, a shift from perichondrial to transosseous blood supply was noted axially, which appeared more pronounced on the lateral side. This shift coincided with histologic identification of OC‐latens (30‐ and 42‐day‐old specimens) and OC‐manifesta (18‐ and 42‐day‐old specimens) lesions in the corresponding regions. The vascular anatomy and its evolution at the distal humeral epiphysis closely resembles that previously reported at predilection sites of knee OCD, suggesting a shared pathophysiology between the knee and elbow joints. [ABSTRACT FROM AUTHOR]

Persistent, unresolved inflammation in the liver represents a key trigger for hepatic injury and fibrosis in various liver diseases and is controlled by classically activated proinflammatory macrophages, while restorative macrophages of the liver are capable of reversing inflammation once the injury trigger ceases. Here we exhibit neutrophils as key contributors to resolving the inflammatory response in the liver using two models of liver inflammation resolution. Using two models of liver inflammatory resolution, we found that mice undergoing neutrophil depletion during the resolution phase exhibited unresolved hepatic inflammation, activation of the fibrogenic machinery, and early fibrosis. These findings were associated with an impairment of the phenotypic switch of proinflammatory macrophages into a restorative stage after removal of the cause of injury and an increased NLRP3/miR-223 ratio. Mice with a deletion of the granulocyte-specific miR-223 gene showed a similarly impaired resolution profile that could be reversed by replacing miR-223 levels using a miR-223 3p mimic or by infusion of neutrophils from wild-type animals. Collectively, our findings reveal hepatic neutrophils as resolving effector cells that induce proinflammatory macrophages into a restorative phenotype, potentially via miR-223., Introduction Liver inflammation constitutes a central contributor to liver pathology during chronic injury from varying etiologies (1, 2). While it is self-limiting, liver inflammation is considered beneficial and contributes to [...]

Intervertebral disc (IVD) degeneration is a common pathological condition associated with low back pain. Recent evidence suggests that mesenchymal signaling cells (MSCs) promote IVD regeneration, but underlying mechanisms remain poorly defined. One postulated mechanism is via modulation of macrophage phenotypes. In this manuscript, we tested the hypothesis that MSCs produce trophic factors that alter macrophage subsets. To this end, we collected conditioned medium from human, bone marrow-derived STRO3+ MSCs. We then cultured human bone marrow-derived macrophages in MSC conditioned medium (CM) and performed single cell RNA-sequencing. Comparative analyses between macrophages cultured in hypoxic and normoxic MSC CM showed large overlap between macrophage subsets; however, we identified a unique hypoxic MSC CM-induced macrophage cluster. To determine if factors from MSC CM simulated effects of the antiinflammatory cytokine IL-4, we integrated the data from macrophages cultured in hypoxic MSC CM with and without IL-4 addition. Integration of these data sets showed considerable overlap, demonstrating that hypoxic MSC CM simulates the effects of IL-4. Interestingly, macrophages cultured in normoxic MSC CM in the absence of IL-4 did not significantly contribute to the unique cluster within our comparison analyses and showed differential TGF-ß signaling; thus, normoxic conditions did not approximate IL-4. In addition, TGF-ß neutralization partially limited the effects of MSC CM. In conclusion, our study identified a unique macrophage subset induced by MSCs within hypoxic conditions and supports that MSCs alter macrophage phenotypes through TGF-ß-dependent mechanisms. [ABSTRACT FROM AUTHOR]

The U.S. education system often functions as an adverse developmental context for Black students. Discriminatory policies and racist ideologies contribute to a series of cascading inequities in students' learning experiences. For example, years of data indicate an overrepresentation of Black students suspended and/or expelled from school. Moreover, Black Americans' experiences and contributions to U.S. society are often left out of curricula, compounding the physical exclusion of Black students from classrooms with the exclusion of their experiences. While such contexts inhibit learning and growth at critical developmental stages, the out-of-school time (OST) context can amplify the voices of Black students and support their learning and development in ways that address these exclusionary practices. Specifically, youth participatory action research (YPAR) during OST is an important critical pedagogical approach that provides a safe context for Black students to engage in challenging oppressive policies and practices within schools. The current study engages four Black/African American youth (aged 15–18 years old) in YPAR and positions youth as active learners and experts in their learning and developmental growth. Findings suggest an equitable OST context can contribute to our understanding of Black students' experiences in school and the co-creation of solutions for a more just learning environment. [ABSTRACT FROM AUTHOR]

Vitamin D plays an active role beyond mineral metabolism and skeletal health, including regulation of the immune system. Vitamin D deficiency is widely prevalent, and observational studies link low vitamin D status to a risk of infections and auto-immune disorders. Reports indicate an inverse relationship between vitamin D status and such conditions. This review details vitamin D signalling interactions with the immune system and provides experimental and clinical evidence evaluating vitamin D status, vitamin D supplementation and host susceptibility to infections, inflammation and auto-immunity. The published literature including related reviews, systematic reviews, meta-analyses, randomised controlled trials (RCTs), observational studies and basic science reports have been synthesised. Meta-analyses of observational studies have demonstrated a link between low vitamin D status and risk of acute respiratory infections, COVID-19 disorders, multiple sclerosis, type 1 diabetes (T1DM), inflammatory bowel disease (IBD), systemic lupus erythematosus and other auto-immune disorders. Observational studies suggest that vitamin D supplementation may protect against several infectious and auto-immune conditions. Meta-analyses of RCTs had mixed results, demonstrating a small protective role for vitamin D supplementation against acute respiratory infections, especially in those with vitamin D deficiency and children, and providing modest benefits for the management of T1DM and IBD. Vitamin D status is inversely associated with the incidence of several infectious and auto-immune conditions. Supplementation is recommended for those with vitamin D deficiency or at high risk of deficiency, and it might provide additional benefit in acute respiratory infections and certain auto-immune conditions. [ABSTRACT FROM AUTHOR]

Thiamine (vitamin B1) is available in common foods such as the outer husk of rice and is necessary for normal cardiovascular, neurological and metabolic processes. Thiamine deficiency is common in many parts of Asia and Africa, affecting up to a third or more of children and women of child-bearing age. The diagnosis is based on clinical suspicion, especially when noting heart failure in infants, encephalopathy in patients of any age, and peripheral neuropathy in older children and adults. Blood tests for whole-blood thiamine diphosphate (the quantity of biologically active thiamine present) and erythrocyte transketolase activity (the functional impact of thiamine) are not always readily available in areas where thiamine deficiency is common. Treatment is safe and effective, although dosing guidelines vary widely; 50 mg daily for 5 days is probably effective for treating acute thiamine deficiency disorders, and ongoing adequate thiamine intake is also needed. Prevention efforts depend on local and regional circumstances, including dietary diversification, food fortification, and/or supplementation of children and women at risk.Abbreviations: HIC: high-income countries; LMIC: low- and middle-income countries; MRI: magnetic resonance imaging; TDD: thiamine deficiency disorders. [ABSTRACT FROM AUTHOR]

Introduction: Vitamin D deficiency affects from 10% to 50% in various pediatric population groups and causes life-threatening hypocalcemia in infants, crippling rickets in infants and children, and increased risk of subsequent adult metabolic and neurologic problems. Areas covered: An English language literature search of PubMed was performed since 1940 as were the authors’ personal literature collections. References identified in the reviewed literature are considered. Diagnosis: The diagnosis of vitamin D deficiency is based on serum 25-hydroxyvitamin D levels. Clinical features of rickets include bone deformities and elevated alkaline phosphatase. Most children and adolescents who are biochemically vitamin D deficient do not have specific symptoms or signs of deficiency. Prevention: Prevention of vitamin D deficiency is via exposure to sunshine, food and beverage fortification, and dietary supplementation. Treatment: Effective treatment of vitamin D deficiency is via oral or injectable administration of vitamin D. Dosing and duration of vitamin D therapy have been described for healthy children and for children with underlying medical conditions, but recommendations vary. Expert opinion: Further investigation is needed to determine long-term non-skeletal effects of childhood vitamin D deficiency, benefits of supplementation in asymptomatic individuals with biochemical vitamin D deficiency, and appropriate screening for vitamin D deficiency in asymptomatic children and adolescents. [ABSTRACT FROM AUTHOR]

The NLRP3 inflammasome is a protein complex responsible for caspase-1-dependent maturation of the proinflammatory cytokines IL-1[beta] and IL-18. Gain-of-function missense mutations in NLRP3 cause the disease spectrum known as the cryopyrin-associated periodic syndromes (CAPS). In this study, we generated Nlrp3-knockin mice on various KO backgrounds including Il1b/Il18-, caspase-1-, caspase-11- (Casp1/11-), and 7nf-deficient strains. The [Nlrp3.sup.L351P] [Il1b.sup.-/-] [Il18.sup.-/-] mutant mice survived and grew normally until adulthood and, at 6 months of age, exhibited marked splenomegaly and leukophilia. Injection of these mice with low-dose LPS resulted in elevated serum TNF levels compared with [Nlrp3.sup.L351P] [Casp1/11.sup.-/-] mice and [Il1b.sup.-/-] [Il18.sup.-/-] littermates. Treatment of [Nlrp3.sup.A350V] mice with the TNF inhibitor etanercept resulted in all pups surviving to adulthood, with normal body and spleen/body weight ratios. [Nlrp3.sup.A350V] [Tnf.sup.-/-] mice showed a similar phenotypic rescue, with marked reductions in serum IL-1[beta] and IL-18, reduced myeloid inflammatory infiltrate in the skin and spleen, and substantial decreases in splenic mRNA expression of both inflammasome components (Nlrp3, Pycard, pro-Caspf) and pro-cytokines (Il1b, Il18). Likewise, we observed a reduction in the expression of both pro-Casp1 and pro-Il1b in cultured [Nlrp3.sup.A350V] [Tnf.sup.-/-] BM-derived DCs. Our data show that TNF is an important transcriptional regulator of NLRP3 inflammasome components in murine inflammasomopathies. Moreover, these results may have therapeutic implications for CAPS patients with partial responses to IL-1-targeted therapies., Introduction The inflammasome complex is formed by NLRP3, along with the adaptor protein pycard (ASC) and pro-caspase-1, which, when activated by various endogenous and microbe-derived danger signals, directs the autocleavage [...]

Simple Summary: For proton therapy, verification CT (vCT) scans are routinely acquired to ensure the accuracy and precision of treatment delivery, as this approach allows clinicians to monitor and adapt treatment plans based on potential changes to the patient's anatomy and tumor. This study investigates synthetic CT's (sCT) potential as an alternative to vCT scans, focusing on its reliability across various treatment sites. Synthetic CT could offer a more efficient approach and possibly enhance patient experience by reducing the necessity for frequent vCT scans. The consistency between sCT and vCT in terms of image quality and dosimetric impact is crucial. It will allow clinicians to monitor and adjust treatment plans promptly and more accurately based on patients' anatomical changes, potentially optimizing treatment processes and outcomes. The insights from this study are pivotal for refining clinical practices and fostering advancements in treatment strategies, ultimately aiming at precision and accuracy in adaptive treatment. Purpose: The study evaluates the efficacy of cone-beam computed tomography (CBCT)-based synthetic CTs (sCT) as a potential alternative to verification CT (vCT) for enhanced treatment monitoring and early adaptation in proton therapy. Methods: Seven common treatment sites were studied. Two sets of sCT per case were generated: direct-deformed (DD) sCT and image-correction (IC) sCT. The image qualities and dosimetric impact of the sCT were compared to the same-day vCT. Results: The sCT agreed with vCT in regions of homogeneous tissues such as the brain and breast; however, notable discrepancies were observed in the thorax and abdomen. The sCT outliers existed for DD sCT when there was an anatomy change and for IC sCT in low-density regions. The target coverage exhibited less than a 5% variance in most DD and IC sCT cases when compared to vCT. The Dmax of serial organ-at-risk (OAR) in sCT plans shows greater deviation from vCT than small-volume dose metrics (D0.1cc). The parallel OAR volumetric and mean doses remained consistent, with average deviations below 1.5%. Conclusion: The use of sCT enables precise treatment and prompt early adaptation for proton therapy. The quality assurance of sCT is mandatory in the early stage of clinical implementation. [ABSTRACT FROM AUTHOR]

To address noise inherent in electronic data acquisition systems and real-world sources, Araki et al. [Phys. D, 417 (2021), 132819] demonstrated a grid-based nonlinear technique to remove noise from a chaotic signal, leveraging a clean high-fidelity signal from the same dynamical system and ensemble averaging in multidimensional phase space. This method achieved denoising of a time series data with 100\% added noise but suffered in regions of low data density. To improve this grid-based method, here an unstructured mesh based on triangulations and Voronoi diagrams is used to accomplish the same task. The unstructured mesh more uniformly distributes data samples over mesh cells to improve the accuracy of the reconstructed signal. By empirically balancing bias and variance errors in selecting the number of unstructured cells as a function of the number of available samples, the method achieves asymptotic statistical convergence with known test data and reduces synthetic noise on experimental signals from Hall effect thrusters with greater success than the original grid-based strategy. [ABSTRACT FROM AUTHOR]

The article discusses the potential of artificial intelligence (AI) in clinical care, specifically in the field of cardiovascular imaging. The authors highlight the challenges of identifying AI applications with real-world impact and emphasize the importance of evidence-based research for clinical implementation. They present a study by Pieszko et al. that developed an AI model to predict the likelihood of left atrial appendage thrombus in patients undergoing cardioversion. The model showed promising results, outperforming traditional diagnostic methods. The authors suggest that further research, including randomized controlled trials, is needed to assess the true value and impact of AI models in clinical practice. [Extracted from the article]

Salmonella enterica is a group of facultative, gram-negative bacteria. Recently, new evidence indicated that Salmonella could reprogram the host metabolism to increase energy or metabolites available for intracellular replication. In this study, using a chicken-specific kinomic immunometabolism peptide array analysis, we found that infection by S. Enteritidis induced significant phosphorylation changes in many key proteins of the glycolytic pathway in chicken macrophage HD-11 cells, indicating a shift in glycolysis caused by Salmonella infection. Nitric oxide production and changes of glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) represented by extracellular acidification rate (ECAR) and oxygen consumption rate (OCR), respectively, were measured in chicken macrophages infected with three Salmonella strains (S. Enteritidis, S. Heidelberg, and S. Senftenberg). The infection reduced glycolysis and enhanced OXPHOS in chicken macrophages as indicated by changes of ECAR and OCR. Salmonella strains differentially affected macrophage polarization and glycolysis. Among three strains tested, S. Enteritidis was most effective in downregulating glycolysis and promoting M2 polarization as measured by ECAR, ORC, and NO production; while S. Senftenberg did not alter glycolysis and may promote M1 polarization. Our results suggested that downregulation of host cell glycolysis and increase of M2 polarization of macrophages may contribute to increased intracellular survival of S. Enteritidis. [ABSTRACT FROM AUTHOR]