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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.
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Modelos Animais de Doenças , Fêmur , Imageamento por Ressonância Magnética , Osteocondrose , Animais , Suínos , Fêmur/patologia , Fêmur/irrigação sanguínea , Osteocondrose/patologia , Osteocondrose/etiologia , Osteocondrose/cirurgia , Lesões do Sistema Vascular/patologia , Lesões do Sistema Vascular/etiologia , Osteocondrite Dissecante/patologia , Osteocondrite Dissecante/etiologia , Osteocondrite Dissecante/cirurgiaRESUMO
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 ProtégéAI. 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 ProtégéAI 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 ProtégéAI 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 ProtégéAI, 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.
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Legg-Calvé-Perthes disease (LCPD) is a childhood hip disorder characterized by ischemic injury to the epiphysis of the femoral head, but changes to the metaphysis have also been implicated in its pathogenesis. Quantitative magnetic resonance imaging (MRI) relaxation time mapping techniques are potentially useful to detect injury in LCPD, but studies to date have focused on the epiphysis. The purpose of this study was to assess whether T2, T1ρ, adiabatic T1ρ, and adiabatic T2ρ relaxation times can detect early metaphyseal changes in an LCPD piglet model. Complete epiphyseal ischemia of one femoral head was surgically induced and confirmed using contrast-enhanced MRI in n = 10 6-week-old piglets; the contralateral side was unoperated. The bilateral hips were imaged 1 week after surgery in vivo at 3T MRI using relaxation time mapping and contrast-enhanced MRI. Relaxation times and thicknesses of the metaphyseal primary and secondary spongiosa were measured and compared between the ischemic and contralateral-control femoral heads using paired t-tests. In the ischemic femoral heads, T2 relaxation times were significantly increased in the primary spongiosa (6.7 ± 9.8 ms, p = 0.029), and T2, T1ρ, adiabatic T1ρ, and adiabatic T2ρ relaxation times were significantly decreased in the secondary spongiosa (respectively: -13.3 ± 9.3 ms, p = 0.013; -32 ± 23 ms, p < 0.001; -43 ± 41 ms, p = 0.009; and -39 ± 13 ms, p < 0.001). The secondary spongiosa thickness was also significantly decreased in the ischemic femoral heads (p < 0.001). In conclusion, T2, T1ρ, adiabatic T1ρ, and adiabatic T2ρ relaxation time mapping techniques can detect early changes in the metaphysis following ischemic injury to the epiphysis of the femoral head in a piglet model of LCPD.
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Inter-organ communication is a vital process to maintain physiologic homeostasis, and its dysregulation contributes to many human diseases. Given that circulating bioactive factors are stable in serum, occur naturally, and are easily assayed from blood, they present obvious focal molecules for therapeutic intervention and biomarker development. Recently, studies have shown that secreted proteins mediating inter-tissue signaling could be identified by 'brute force' surveys of all genes within RNA-sequencing measures across tissues within a population. Expanding on this intuition, we reasoned that parallel strategies could be used to understand how individual genes mediate signaling across metabolic tissues through correlative analyses of gene variation between individuals. Thus, comparison of quantitative levels of gene expression relationships between organs in a population could aid in understanding cross-organ signaling. Here, we surveyed gene-gene correlation structure across 18 metabolic tissues in 310 human individuals and 7 tissues in 103 diverse strains of mice fed a normal chow or high-fat/high-sucrose (HFHS) diet. Variation of genes such as FGF21, ADIPOQ, GCG, and IL6 showed enrichments which recapitulate experimental observations. Further, similar analyses were applied to explore both within-tissue signaling mechanisms (liver PCSK9) and genes encoding enzymes producing metabolites (adipose PNPLA2), where inter-individual correlation structure aligned with known roles for these critical metabolic pathways. Examination of sex hormone receptor correlations in mice highlighted the difference of tissue-specific variation in relationships with metabolic traits. We refer to this resource as gene-derived correlations across tissues (GD-CAT) where all tools and data are built into a web portal enabling users to perform these analyses without a single line of code (gdcat.org). This resource enables querying of any gene in any tissue to find correlated patterns of genes, cell types, pathways, and network architectures across metabolic organs.
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Pró-Proteína Convertase 9 , Transdução de Sinais , Humanos , Animais , Camundongos , Homeostase , AdiposidadeRESUMO
To assess the performance of a knowledge-based planning (KBP) model for generating intensity-modulated proton therapy (IMPT) treatment plans as part of an adaptive radiotherapy (ART) strategy for patients with high-risk prostate cancer. A knowledge-based planning (KBP) model for proton adaptive treatment plan generation was developed based on thirty patient treatment plans utilizing RapidPlanTM PT (Varian Medical Systems, Palo Alto, CA). The model was subsequently validated using an additional eleven patient cases. All patients in the study were administered a prescribed dose of 70.2 Gy to the prostate and seminal vesicle (CTV70.2), along with 46.8 Gy to the pelvic lymph nodes (CTV46.8) through simultaneous integrated boost (SIB) technique. To assess the quality of the validation knowledge-based proton plans (KBPPs), target coverage and organ-at-risk (OAR) dose-volume constraints were compared against those of clinically used expert plans using paired t-tests. The KBP model training statistics (R2) (mean ± SD, 0.763 ± 0.167, range, 0.406 to 0.907) and χ² values (1.162 ± 0.0867, 1.039-1.253) indicate acceptable model training quality. Moreover, the average total treatment planning optimization and calculation time for adaptive plan generation is approximately 10 minutes. The CTV70.2 D98% for the KBPPs (mean ± SD, 69.1 ± 0.08 Gy) and expert plans (69.9 ± 0.04 Gy) shows a significant difference (p < 0.05) but are both within 1.1 Gy of the prescribed dose which is clinically acceptable. While the maximum dose for some organs-at-risk (OARs) such as the bladder and rectum is generally higher in the KBPPs, the doses still fall within clinical constraints. Among all the OARs, most of them received comparable results to the expert plan, except the cauda equina Dmax, which shows statistical significance and was lower in the KBPPs than in expert plans (48.5 ± 0.06 Gy vs 49.3 ± 0.05 Gy). The generated KBPPs were clinically comparable to manually crafted plans by expert treatment planners. The adaptive plan generation process was completed within an acceptable timeframe, offering a quick same-day adaptive treatment option. Our study supports the integration of KBP as a crucial component of an ART strategy, including maintaining plan consistency, improving quality, and enhancing efficiency. This advancement in speed and adaptability promises more precise treatment in proton ART.
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Neoplasias da Próstata , Terapia com Prótons , Radioterapia de Intensidade Modulada , Masculino , Humanos , Prótons , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador/métodos , Órgãos em Risco , Terapia com Prótons/métodos , Radioterapia de Intensidade Modulada/métodos , Neoplasias da Próstata/radioterapiaRESUMO
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.
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Cabeça do Fêmur , Doença de Legg-Calve-Perthes , Humanos , Animais , Criança , Suínos , Cabeça do Fêmur/diagnóstico por imagem , Cabeça do Fêmur/patologia , Doença de Legg-Calve-Perthes/diagnóstico por imagem , Doença de Legg-Calve-Perthes/patologia , Meios de Contraste , Imageamento por Ressonância Magnética , Isquemia/diagnóstico por imagem , Movimento (Física)RESUMO
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.
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Osteocondrite Dissecante , Osteocondrose , Osteonecrose , Animais , Suínos , Osteocondrite Dissecante/diagnóstico por imagem , Osteocondrite Dissecante/etiologia , Lâmina de Crescimento/patologia , Osteocondrose/patologia , Cartilagem/patologia , Osteonecrose/patologiaRESUMO
BACKGROUND CONTEXT: Etiology of adolescent idiopathic scoliosis (AIS) is still unknown. Prior in vitro research suggests intervertebral disc pathomorphology as a cause for the initiation and progression of the spinal deformity, however, this has not been well characterized in vivo. PURPOSE: To quantify and compare lumbar disc health and morphology in AIS to controls. STUDY DESIGN/SETTING: Cross-sectional study. METHODS: All lumbar discs were imaged using a 3T MRI scanner. T2-weighted and quantitative T2* maps were acquired. Axial slices of each disc were reconstructed, and customized scripts were used to extract outcome measurements: Nucleus pulposus (NP) signal intensity and location, disc signal volume, transition zone slope, and asymmetry index. Pearson's correlation analysis was performed between the NP location and disc wedge angle for AIS patients. ANOVAs were utilized to elucidate differences in disc health and morphology metrics between AIS patients and healthy controls. α=0.05. RESULTS: There were no significant differences in disc health metrics between controls and scoliotic discs. There was a significant shift in the NP location towards the convex side of the disc in AIS patients compared to healthy controls, with an associated increase of the transition zone slope on the convex side. Additionally, with increasing disc wedge angle, the NP center migrated towards the convex side of the disc. CONCLUSIONS: The present study elucidates morphological distinctions of intervertebral discs between healthy adolescents and those diagnosed with AIS. Discs in patients diagnosed with AIS are asymmetric, with the NP shifted towards the convex side, which was exacerbated by an increased disc wedge angle. CLINICAL SIGNIFICANCE: Investigation of the MRI signal distribution (T2w and T2* maps) within the disc suggests an asymmetric pressure gradient shifting the NP laterally towards the convexity. Quantifying the progression of these morphological alterations during maturation and in response to treatment will provide further insight into the mechanisms of curve progression and correction, respectively.
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Degeneração do Disco Intervertebral , Disco Intervertebral , Cifose , Escoliose , Humanos , Adolescente , Escoliose/diagnóstico por imagem , Estudos Transversais , Disco Intervertebral/diagnóstico por imagem , Degeneração do Disco Intervertebral/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Vértebras Lombares/diagnóstico por imagemRESUMO
Purpose: To develop an extension to locally low rank (LLR) denoising techniques based on transform domain processing that reduces the number of images required in the MR image series for high-quality denoising. Theory and Methods: LLR methods with random matrix theory-based thresholds are successfully used in the denoising of MR image series in a number of applications. The performance of these methods depend on how well the LLR assumption is satisfied, which deteriorates with few numbers of images, as is commonly encountered in quantitative MRI applications. We propose a transform-domain approach for denoising of MR image series to represent the underlying signal with higher fidelity when using a locally low rank approximation. The efficacy of the method is demonstrated for fully-sampled k-space, undersampled k-space, DICOM images, and complex-valued SENSE-1 images in quantitative MRI applications with as few as 4 images. Results: For both MSK and brain applications, the transform domain denoising preserves local subtle variability, whereas the quantitative maps based on image domain LLR methods tend to be locally more homogeneous. Conclusion: A transform domain extension to LLR denoising produces high quality images and is compatible with both raw k-space data and vendor reconstructed data. This allows for improved imaging and more accurate quantitative analyses and parameters obtained therefrom.
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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.
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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.
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Hipocalcemia , Raquitismo , Deficiência de Vitamina D , Lactente , Adolescente , Criança , Humanos , Deficiência de Vitamina D/tratamento farmacológico , Raquitismo/diagnóstico , Raquitismo/tratamento farmacológico , Raquitismo/etiologia , Vitamina D/uso terapêutico , Resultado do TratamentoRESUMO
The NLRP3 inflammasome is an intracellular, multiprotein complex that promotes the auto-catalytic activation of caspase-1 and the subsequent maturation and secretion of the pro-inflammatory cytokines, IL-1ß and IL-18. Persistent activation of the NLRP3 inflammasome has been implicated in the pathophysiology of a number of inflammatory and autoimmune diseases, including neuroinflammation, cardiovascular disease, non-alcoholic steatohepatitis, lupus nephritis and severe asthma. Here we describe the preclinical profile of JT002, a novel small molecule inhibitor of the NLRP3 inflammasome. JT002 potently reduced NLRP3-dependent proinflammatory cytokine production across a number of cellular assays and prevented pyroptosis, an inflammatory form of cell death triggered by active caspase-1. JT002 demonstrated in vivo target engagement at therapeutically relevant concentrations when orally dosed in mice and prevented body weight loss and improved inflammatory and fibrotic endpoints in a model of Muckle-Wells syndrome (MWS). In two distinct models of neutrophilic airway inflammation, JT002 treatment significantly reduced airway hyperresponsiveness and airway neutrophilia. These results provide a rationale for the therapeutic targeting of the NLRP3 inflammasome in severe asthma and point to the use of JT002 in a variety of inflammatory disorders.
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Doenças Cardiovasculares , Nefrite Lúpica , Animais , Camundongos , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Caspase 1RESUMO
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.
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The NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome is a multiprotein complex and component of the innate immune system that is activated by exogenous and endogenous danger signals to promote activation of caspase-1 and the maturation and release of the proinflammatory cytokines interleukin (IL)-1ß and IL-18. Inappropriate activation of NLRP3 has been implicated in the pathophysiology of multiple inflammatory and autoimmune diseases, including cardiovascular disease, neurodegenerative diseases, and nonalcoholic steatohepatitis (NASH), thus increasing the clinical interest of this target. We describe in this study the preclinical pharmacologic, pharmacokinetic, and pharmacodynamic properties of a novel and highly specific NLRP3 inhibitor, JT001 (6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonylurea). In cell-based assays, JT001 potently and selectively inhibited NLRP3 inflammasome assembly, resulting in the inhibition of cytokine release and the prevention of pyroptosis, a form of inflammatory cell death triggered by active caspase-1. Oral administration of JT001 to mice inhibited IL-1ß production in peritoneal lavage fluid at plasma concentrations that correlated with mouse in vitro whole blood potency. Orally administered JT001 was effective in reducing hepatic inflammation in three different murine models, including the Nlrp3A350V /+CreT model of Muckle-Wells syndrome (MWS), a diet-induced obesity NASH model, and a choline-deficient diet-induced NASH model. Significant reductions in hepatic fibrosis and cell damage were also observed in the MWS and choline-deficient models. Our findings demonstrate that blockade of NLRP3 attenuates hepatic inflammation and fibrosis and support the use of JT001 to investigate the role of NLRP3 in other inflammatory disease models. SIGNIFICANCE STATEMENT: Persistent inflammasome activation is the consequence of inherited mutations of NLRP3 and results in the development of cryopyrin-associated periodic syndromes associated with severe systemic inflammation. NLRP3 is also upregulated in nonalcoholic steatohepatitis, a metabolic chronic liver disease currently missing a cure. Selective and potent inhibitors of NLRP3 hold great promise and have the potential to overcome an urgent unmet need.
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Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas NLR , Domínio Pirina , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/prevenção & controle , Caspase 1/metabolismo , Inflamação , Colina/efeitos adversos , Interleucina-1beta/metabolismoRESUMO
BACKGROUND: Stress echocardiography (SE) is one of the most commonly used diagnostic imaging tests for coronary artery disease (CAD) but requires clinicians to visually assess scans to identify patients who may benefit from invasive investigation and treatment. EchoGo Pro provides an automated interpretation of SE based on artificial intelligence (AI) image analysis. In reader studies, use of EchoGo Pro when making clinical decisions improves diagnostic accuracy and confidence. Prospective evaluation in real world practice is now important to understand the impact of EchoGo Pro on the patient pathway and outcome. METHODS: PROTEUS is a randomized, multicenter, 2-armed, noninferiority study aiming to recruit 2,500 participants from National Health Service (NHS) hospitals in the UK referred to SE clinics for investigation of suspected CAD. All participants will undergo a stress echocardiogram protocol as per local hospital policy. Participants will be randomized 1:1 to a control group, representing current practice, or an intervention group, in which clinicians will receive an AI image analysis report (EchoGo Pro, Ultromics Ltd, Oxford, UK) to use during image interpretation, indicating the likelihood of severe CAD. The primary outcome will be appropriateness of clinician decision to refer for coronary angiography. Secondary outcomes will assess other health impacts including appropriate use of other clinical management approaches, impact on variability in decision making, patient and clinician qualitative experience and a health economic analysis. DISCUSSION: This will be the first study to assess the impact of introducing an AI medical diagnostic aid into the standard care pathway of patients with suspected CAD being investigated with SE. TRIAL REGISTRATION: Clinicaltrials.gov registration number NCT05028179, registered on 31 August 2021; ISRCTN: ISRCTN15113915; IRAS ref: 293515; REC ref: 21/NW/0199.
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Doença da Artéria Coronariana , Ecocardiografia sob Estresse , Humanos , Inteligência Artificial , Medicina Estatal , Doença da Artéria Coronariana/diagnóstico por imagem , Angiografia Coronária/métodosRESUMO
Previously, the supplementation of a microencapsulated blend of organic acids and botanicals improved the health and performance of broiler breeders under non-challenged conditions. This study aimed to determine if the microencapsulated blend impacted dysbiosis and necrotic enteritis (NE) in broiler breeders. Day-of-hatch chicks were assigned to non-challenge and challenge groups, provided a basal diet supplemented with 0 or 500 g/MT of the blend, and subjected to a laboratory model for NE. On d 20-21, jejunum/ileum content were collected for microbiome sequencing (n = 10; V4 region of 16S rRNA gene). The experiment was repeated (n = 3), and data were analyzed in QIIME2 and R. Alpha and beta diversity, core microbiome, and compositional differences were determined (significance at p ≤ 0.05; Q ≤ 0.05). There was no difference between richness and evenness of those fed diets containing 0 and 500 g/MT microencapsulated blend, but differences were seen between the non-challenged and challenged groups. Beta diversity of the 0 and 500 g/MT non-challenged groups differed, but no differences existed between the NE-challenged groups. The core microbiome of those fed 500 g/MT similarly consisted of Lactobacillus and Clostridiaceae. Furthermore, challenged birds fed diets containing 500 g/MT had a higher abundance of significantly different phyla, namely, Actinobacteriota, Bacteroidota, and Verrucomicrobiota, than the 0 g/MT challenged group. Dietary supplementation of a microencapsulated blend shifted the microbiome by supporting beneficial and core taxa.