Altered cellular metabolic pathway and epithelial cell maturation induced by MYO5B defects are partially reversible by LPAR5 activation.

Functional loss of the motor protein, Myosin Vb (MYO5B), induces various defects in intestinal epithelial function and causes a congenital diarrheal disorder, microvillus inclusion disease (MVID). Utilizing the MVID model mice, Vil1-Cre ERT2 ;Myo5b flox/flox (MYO5BΔIEC) and Vil1-Cre ERT2 ;Myo5b flox/G519R (MYO5B(G519R)), we previously reported that functional MYO5B loss disrupts progenitor cell differentiation and enterocyte maturation that result in villus blunting and deadly malabsorption symptoms. In this study, we determined that both absence and a point mutation of MYO5B impair lipid metabolism and alter mitochondrial structure, which may underlie the progenitor cell malfunction observed in MVID intestine. Along with a decrease in fatty acid oxidation, the lipogenesis pathway was enhanced in the MYO5BΔIEC small intestine. Consistent with these observations in vivo , RNA-sequencing of enteroids generated from two MVID mouse strains showed similar downregulation of energy metabolic enzymes, including mitochondrial oxidative phosphorylation genes. In our previous studies, lysophosphatidic acid (LPA) signaling ameliorates epithelial cell defects in MYO5BΔIEC tissues and enteroids. The present study demonstrates that the highly soluble LPAR5-preferred agonist, Compound-1, improved sodium transporter localization and absorptive function, and tuft cell differentiation in patient-modeled MVID animals that carry independent mutations in MYO5B. Body weight loss in male MYO5B(G519R) mice was ameliorated by Compound-1. These observations suggest that Compound-1 treatment has a trophic effect on intestine with MYO5B functional loss through epithelial cell-autonomous pathways that may improve the differentiation of progenitor cells and the maturation of enterocytes. Targeting LPAR5 may represent an effective therapeutic approach for treatment of MVID symptoms induced by different point mutations in MYO5B. NEW & NOTEWOTHY: This study demonstrates the importance of MYO5B for cellular lipid metabolism and mitochondria in intestinal epithelial cells, a previously unexplored function of MYO5B. Alterations in cellular metabolism may underlie the progenitor cell malfunction observed in microvillus inclusion disease (MVID). To examine the therapeutic potential of progenitor-targeted treatments, the effects of LPAR5-preferred agonist, Compound-1, was investigated utilizing several MVID model mice and enteroids. Our observations suggests that Compound-1 may provide a therapeutic approach for treating MVID.

Ipilimumab and nivolumab plus radioembolization as salvage therapy for atezolizumab and bevacizumab refractory hepatocellular carcinoma resulting in complete pathologic response.

Unresectable hepatocellular carcinoma unresponsive to first-line immunotherapy has a poor prognosis with modest response to tyrosine kinase inhibitors in the second line. In these patients, the benefit of local therapy with immunotherapy rechallenge is unknown. Radioembolization is a guideline-supported locoregional therapy for HCC that has shown the potential for synergy in combination with immunotherapy. This report describes a patient with veno-invasive HCC and extrahepatic invasion of the right kidney which progressed on atezolizumab and bevacizumab and was subsequently downstaged to resection with ipilimumab and nivolumab plus radioembolization yielding a complete pathologic response. The patient is currently more than 2 years since diagnosis without evidence of disease recurrence.

Acute tuft cell ablation induces malabsorption and alterations in secretory and immune cell lineages in small intestine.

Background & Aims: Intestinal tuft cells have recently been the interest of studies in several human gastrointestinal diseases. However, the impact of tuft cell deletion on intestinal physiological functions are not fully understood. This study investigated the effects of acute tuft cell loss on nutrient absorption and cell lineage differentiation. Methods: Tuft cell deletion was induced in DCLK1-IRES-GFP-CreERT2/+;Rosa-DTA (DCLK1-DTA) mice by a single tamoxifen injection concomitant with littermate controls. Intestinal tissues were analyzed two-, four-, or seven-days post tamoxifen injection. Results: DCLK1-DTA mice showed significantly shortened small intestinal length and body weight loss on day 4. Impaired activities of Na + -dependent glucose transporter 1 (SGLT1) and cystic fibrosis transmembrane regulator (CFTR) were observed in Ussing chamber experiments. Tissue immunostaining revealed a transient deletion of intestinal and biliary tuft cells, which was maximal on day 4 and recovered by day 7. On day 4 post tamoxifen, cholecystokinin (CCK)+ enteroendocrine cell numbers were increased particularly in the ileum. Correlated with the tuft cell reduction, the frequency of mislocalized Paneth cells, which were co-labeled by Paneth and goblet cell markers, was increased in the villus regions. In the lamina propria, fewer mast cells and leukocytes were found in the day 4 DCLK1-DTA mice than in controls. Conclusion: Ablation of intestinal tuft cells may induce nutrient malabsorption through alterations in epithelial cell proliferation and differentiation along with changes in mucosal defense response. These observations elucidate a new role for tuft cells in regulating intestinal absorption and mucosal regeneration.

Electrochemical Noise Analysis: An Approach to the Effectivity of Each Method in Different Materials.

Corrosion deterioration of materials is a major problem affecting economic, safety, and logistical issues, especially in the aeronautical sector. Detecting the correct corrosion type in metal alloys is very important to know how to mitigate the corrosion problem. Electrochemical noise (EN) is a corrosion technique used to characterize the behavior of different alloys and determine the type of corrosion in a system. The objective of this research is to characterize by EN technique different aeronautical alloys (Al, Ti, steels, and superalloys) using different analysis methods such as time domain (visual analysis, statistical), frequency domain (power spectral density (PSD)), and frequency-time domain (wavelet decomposition, Hilbert Huang analysis, and recurrence plots (RP)) related to the corrosion process. Optical microscopy (OM) is used to observe the surface of the tested samples. The alloys were exposed to 3.5 wt.% NaCl and H2SO4 solutions at room temperature. The results indicate that HHT and recurrence plots are the best options for determining the corrosion type compared with the other methods due to their ability to analyze dynamic and chaotic systems, such as corrosion. Corrosion processes such as passivation and localized corrosion can be differentiated when analyzed using HHT and RP methods when a passive system presents values of determinism between 0.5 and 0.8. Also, to differentiate the passive system from the localized system, it is necessary to see the recurrence plot due to the similarity of the determinism value. Noise impedance (Zn) is one of the best options for determining the corrosion kinetics of one system, showing that Ti CP2 and Ti-6Al-4V presented 742,824 and 939,575 Ω·cm2, while Rn presented 271,851 and 325,751 Ω·cm2, being the highest when exposed to H2SO4.

Histologic Findings of Sinusoidal Dilatation and Congestion in Liver Grafts Do Not Correlate with Hepatic Venous Anastomotic Gradients.

PURPOSE: Hepatic venous transplant anastomotic pressure gradient measurement and transjugular liver biopsy are commonly used in clinical decision-making in patients with suspected anastomotic hepatic venous outflow obstruction. This investigation aimed to determine if sinusoidal dilatation and congestion on histology are predictive of hepatic venous anastomotic outflow obstruction, and if it can help select patients for hepatic vein anastomosis stenting. MATERIALS AND METHODS: This is a single-center retrospective study of 166 transjugular liver biopsies in 139 patients obtained concurrently with transplant venous anastomotic pressure gradient measurement. Demographic characteristics, laboratory parameters, procedure and clinical data, and histology of time-zero allograft biopsies were analyzed. RESULTS: No relationship was found between transplant venous anastomotic pressure gradient and sinusoidal dilatation and congestion (P = 0.92). Logistic regression analysis for sinusoidal dilatation and congestion confirmed a significant relationship with reperfusion/preservation injury and/or necrosis of the allograft at time-zero biopsy (OR 6.6 [1.3-33.1], P = 0.02). CONCLUSION: There is no relationship between histologic sinusoidal dilatation and congestion and liver transplant hepatic vein anastomotic gradient. In this study group, sinusoidal dilatation and congestion is a nonspecific histopathologic finding that is not a reliable criterion to select patients for venous anastomosis stenting.

Can we screen opportunistically for low bone mineral density using CT scans of the shoulder and artificial intelligence?

OBJECTIVE: To evaluate whether the CT attenuation of bones seen on shoulder CT scans could be used to predict low bone mineral density (BMD) (osteopenia/osteoporosis), and to compare the performance of two machine learning models to predict low BMD. METHODS: In this study, we evaluated 194 patients aged 50 years or greater (69.2 ± 9.1 years; 170 females) who underwent unenhanced shoulder CT scans and dual-energy X-ray absorptiometry within 1 year of each other between January 1, 2010, and December 31, 2021. The CT attenuation of the humerus, glenoid, coracoid, acromion, clavicle, first, second, and third ribs was obtained using 3D-Slicer. Support vector machines (SVMs) and k-nearest neighbours (kNN) were used to predict low BMD. DeLong test was used to compare the areas under the curve (AUCs). RESULTS: A CT attenuation of 195.4 Hounsfield Units of the clavicle had a sensitivity of 0.577, specificity of 0.781, and AUC of 0.701 to predict low BMD. In the test dataset, the SVM had sensitivity of 0.686, specificity of 1.00, and AUC of 0.857, while the kNN model had sensitivity of 0.966, specificity of 0.200, and AUC of 0.583. The SVM was superior to the CT attenuation of the clavicle (P = .003) but not better than the kNN model (P = .098). CONCLUSION: The CT attenuation of the clavicle was best for predicting low BMD; however, a multivariable SVM was superior for predicting low BMD. ADVANCES IN KNOWLEDGE: SVM utilizing the CT attenuations at many sites was best for predicting low BMD.

Radiation Segmentectomy for the Treatment of Hepatocellular Carcinoma: A Practical Review of Evidence.

Radiation segmentectomy is a versatile, safe, and effective ablative therapy for early-stage hepatocellular carcinoma. Advances in radiation segmentectomy patient selection, procedural technique, and dosimetry have positioned this modality as a curative-intent and guideline-supported treatment for patients with solitary HCC. This review describes key radiation segmentectomy concepts and summarizes the existing literary knowledgebase.

Analysis of lncRNAs in Lupinus mutabilis (Tarwi) and Their Potential Role in Drought Response.

Lupinus mutabilis is a legume with high agronomic potential and available transcriptomic data for which lncRNAs have not been studied. Therefore, our objective was to identify, characterize, and validate the drought-responsive lncRNAs in L. mutabilis. To achieve this, we used a multilevel approach based on lncRNA prediction, annotation, subcellular location, thermodynamic characterization, structural conservation, and validation. Thus, 590 lncRNAs were identified by at least two algorithms of lncRNA identification. Annotation with the PLncDB database showed 571 lncRNAs unique to tarwi and 19 lncRNAs with homology in 28 botanical families including Solanaceae (19), Fabaceae (17), Brassicaceae (17), Rutaceae (17), Rosaceae (16), and Malvaceae (16), among others. In total, 12 lncRNAs had homology in more than 40 species. A total of 67% of lncRNAs were located in the cytoplasm and 33% in exosomes. Thermodynamic characterization of S03 showed a stable secondary structure with -105.67 kcal/mol. This structure included three regions, with a multibranch loop containing a hairpin with a SECIS-like element. Evaluation of the structural conservation by CROSSalign revealed partial similarities between L. mutabilis (S03) and S. lycopersicum (Solyc04r022210.1). RT-PCR validation demonstrated that S03 was upregulated in a drought-tolerant accession of L. mutabilis. Finally, these results highlighted the importance of lncRNAs in tarwi improvement under drought conditions.

[Basilar dolichoectasia and fusiform vertebral artery aneurysm: ischemic stroke of dual cause] / Dolicoectasia basilar y aneurisma fusiforme de arteria vertebral: accidente cerebrovascular isquémico de causa dual.

A 76-year-old woman arrived at the emergency department due to an ischemic stroke that affected the territory of the left anterior choroidal and basilar arteries. Imaging studies showed dolichoectasia basilar associated with a fusiform aneurysm with thrombi inside it in the left vertebral artery. Both anatomic abnormalities are associated with ischemic stroke.

Mujer de 76 años que acudió al servicio de urgencias por un accidente cerebro vascular isquémico que afectó el territorio de arteria coroidea anterior izquierda y basilar. Los estudios de imagen mostraron dolicoectasia basilar asociada a un aneurisma fusiforme con trombos en su interior en la arteria vertebral izquierda. Las dos anomalías anatómicas están asociadas a accidente cerebrovascular isquémico.

Effect of receiving a customizable brochure on breast cancer patients' knowledge about their diagnosis and treatment: A randomized clinical trial.

BACKGROUND: Patients' lack of knowledge about their own disease may function as a barrier to shared decision-making and well-being. This study aimed to evaluate the impact of written educational materials on breast cancer patients. METHODS: This multicenter, parallel, unblinded, randomized trial included Latin American women aged ≥18 years with a recent breast cancer diagnosis yet to start systemic therapy. Participants underwent randomization in a 1:1 ratio to receive a customizable or standard educational brochure. The primary objective was accurate identification of molecular subtype. Secondary objectives included identification of clinical stage, treatment options, participation in decision-making, perceived quality of information received, and illness uncertainty. Follow-up occurred at 7-21 and 30-51 days post-randomization. CLINICALTRIALS: gov identifier: NCT05798312. RESULTS: One hundred sixty-five breast cancer patients with a median age of 53 years and 61 days from diagnosis were included (customizable: 82; standard: 83). At first available assessment, 52%, 48%, and 30% identified their molecular subtype, disease stage, and guideline-endorsed systemic treatment strategy, respectively. Accurate molecular subtype and stage identification were similar between groups. Per multivariate analysis, customizable brochure recipients were more likely to identify their guideline-recommended treatment modalities (OR: 4.20,p = 0.001). There were no differences between groups in the perceived quality of information received or illness uncertainty. Customizable brochure recipients reported increased participation in decision-making (p = 0.042). CONCLUSIONS: Over one third of recently diagnosed breast cancer patients are incognizant of their disease characteristics and treatment options. This study demonstrates a need to improve patient education and shows that customizable educational materials increase patients' understanding of recommended systemic therapies according to individual breast cancer characteristics.

Outcomes of Radiation Segmentectomy for Hepatocellular Carcinoma in Patients with Non-Alcoholic Fatty Liver Disease versus Chronic Viral Hepatitis.

Purpose: To compare the outcomes of radiation segmentectomy for early-stage hepatocellular carcinoma (HCC) in patients with non-alcoholic fatty liver disease (NAFLD) versus hepatitis C virus (HCV). Materials and Methods: A retrospective analysis of consecutive patients with NAFLD- or HCV-related HCC treated with radiation segmentectomy from 01/2017-06/2022 was performed. Eligibility criteria included solitary tumor ≤8 cm or up to 3 HCC ≤3 cm, ECOG 0-1, and absence of vascular invasion or extrahepatic spread. Imaging best response was assessed per modified Response Evaluation Criteria in Solid Tumors. Target tumor and overall progression, time-to-progression (TTP), and overall survival (OS) were calculated. All outcomes were censored for liver transplantation (LT). Complete pathologic response (CPN) was assessed in patients who underwent LT. Results: Of 142 patients included (NAFLD: 61; HCV: 81), most had cirrhosis (NAFLD: 87%; HCV: 86%) and small tumors (median size NAFLD: 2.3 cm; HCV: 2.5 cm). Patients with NAFLD had higher BMI (p<0.001) and worse ALBI scores (p=0.003). Patients with HCV were younger (p<0.001) and had higher AFP levels (p=0.034). Median radiation dose (NAFLD: 508 Gy; HCV: 452 Gy) and specific activity (NAFLD: 700 Bq; HCV: 698 Bq) were similar between cohorts. Objective response was 100% and 97% in the NAFLD and HCV cohorts, respectively. Target tumor progression occurred in 1 (2%) NAFLD and 8 (10%) HCV patients. Target tumor TTP was not met for either cohort. Overall progression occurred in 23 (38%) NAFLD and 39 (48%) HCV patients. Overall TTP was 17.4 months (95% CI 13.5-22.2) in NAFLD and 13.5 months (95% CI 0.4-26.6) in HCV patients (p=0.86). LT was performed in 27 (44%) NAFLD and 33 (41%) HCV patients, with a CPN rate of 63% and 54%, respectively. OS was not met in the NAFLD cohort and was 53.9 months (95% CI 32.1-75.7) in the HCV cohort (p=0.15). Conclusion: Although NAFLD and HCV are associated with different mechanisms of liver injury, patients with early-stage HCC treated with radiation segmentectomy achieve comparable outcomes.

Detecting whether L1 or other lumbar levels would be excluded from DXA bone mineral density analysis during opportunistic CT screening for osteoporosis using machine learning.

PURPOSE: One or more vertebrae are sometimes excluded from dual-energy X-ray absorptiometry (DXA) analysis if the bone mineral density (BMD) T-score estimates are not consistent with the other lumbar vertebrae BMD T-score estimates. The goal of this study was to build a machine learning framework to identify which vertebrae would be excluded from DXA analysis based on the computed tomography (CT) attenuation of the vertebrae. METHODS: Retrospective review of 995 patients (69.0% female) aged 50 years or greater with CT scans of the abdomen/pelvis and DXA within 1 year of each other. Volumetric semi-automated segmentation of each vertebral body was performed using 3D-Slicer to obtain the CT attenuation of each vertebra. Radiomic features based on the CT attenuation of the lumbar vertebrae were created. The data were randomly split into training/validation (90%) and test datasets (10%). We used two multivariate machine learning models: a support vector machine (SVM) and a neural net (NN) to predict which vertebra(e) were excluded from DXA analysis. RESULTS: L1, L2, L3, and L4 were excluded from DXA in 8.7% (87/995), 9.9% (99/995), 32.3% (321/995), and 42.6% (424/995) patients, respectively. The SVM had a higher area under the curve (AUC = 0.803) than the NN (AUC = 0.589) for predicting whether L1 would be excluded from DXA analysis (P = 0.015) in the test dataset. The SVM was better than the NN for predicting whether L2 (AUC = 0.757 compared to AUC = 0.478), L3 (AUC = 0.699 compared to AUC = 0.555), or L4 (AUC = 0.751 compared to AUC = 0.639) were excluded from DXA analysis. CONCLUSIONS: Machine learning algorithms could be used to identify which lumbar vertebrae would be excluded from DXA analysis and should not be used for opportunistic CT screening analysis. The SVM was better than the NN for identifying which lumbar vertebra should not be used for opportunistic CT screening analysis.

Opportunistic screening for osteoporosis and osteopenia from CT scans of the abdomen and pelvis using machine learning.

OBJECTIVES: To use multivariable machine learning using the computed tomography (CT) attenuation of each of the bones in the lumbar spine, pelvis, and sacrum, to predict osteoporosis/osteopenia. METHODS: This was a retrospective study of 394 patients aged 50 years or older with CT scans of the abdomen and pelvis and dual-energy x-ray absorptiometry (DXA) scans obtained within 6 months of each other. Volumetric segmentations were performed for each of the bones from L1-L4 vertebrae, pelvis, and sacrum to obtain the mean CT attenuation of each bone. The data was randomly split into training/validation (n = 274, 70%) and test (n = 120, 30%) datasets. The CT attenuation of the L1 vertebrae, univariate logistic regression, least absolute shrinkage and selection operator (LASSO), and support vector machines (SVM) with radial basis function (RBF) were used to predict osteoporosis/osteopenia. The performance of using the CT attenuation at L1 to the univariate logistic regression, LASSO, and SVM models were compared using DeLong's test in the test dataset. RESULTS: All CT attenuation measurements were predictive of osteoporosis/osteopenia (p < 0.001 for all). The SVM model (accuracy = 0.892, AUC = 0.886) outperformed the models using the CT attenuation of threshold of 173.9 Hounsfield units (HU) at L1 (accuracy = 0.725, AUC = 0.739, p = 0.010), the univariate logistic regression model (accuracy = 0.767, AUC = 0.533, p < 0.001) and the LASSO model (accuracy = 0.817, AUC = 0.711, p = 0.007) to predict osteoporosis/osteopenia. CONCLUSION: A SVM model using the CT attenuations of multiple bones within the lumbar spine and pelvis and clinical data has a better ability to predict osteoporosis/osteopenia than using the CT attenuation of L1 or a LASSO model. KEY POINTS: • Multivariable SVM model using the CT attenuation of multiple bones and clinical/demographic data was more predictive than using the CT attenuation at L1 only.

Utilizing machine learning for opportunistic screening for low BMD using CT scans of the cervical spine.

BACKGROUND: Computed Tomography (CT) scans of the cervical spine are often performed to evaluate patients for trauma and degenerative changes of the cervical spine. We hypothesized that the CT attenuation of the cervical vertebrae can be used to identify patients who should be screened for osteoporosis. METHODS: A retrospective study of 253 patients (177 training/validation and 76 test) with unenhanced CT scans of the cervical spine and Dual-energy x-ray Absorbtiometry (DXA) studies within 12 months of each other was performed. Volumetric segmentation of C1-T1, clivus, and first ribs was performed to obtain the CT attenuation of each bone. The correlations of the CT attenuations between the bones and with DXA measurements were evaluated. Univariate receiver operator characteristic (ROC) analyses, and multivariate classifiers (Random Forest (RF), XGBoost, Naïve Bayes (NB), and Support Vector Machines (SVM)) analyzing the CT attenuation of all bones, were utilized to predict patients with osteopenia/osteoporosis and femoral neck bone mineral density (BMD) T-scores <-1. RESULTS: There were positive correlations between the CT attenuation of each bone, and with the DXA measurements. A CT attenuation threshold of 305.2 Hounsfield Units (HU) at C3 had the highest accuracy (0.763, AUC=0.814) to detect femoral neck BMD T-scores ≤-1 and a CT attenuation threshold of 323.6 HU at C3 had the highest accuracy (0.774, AUC=0.843) to detect osteopenia/osteoporosis. The SVM classifier (AUC=0.756) had higher AUC than the RF (AUC=0.692, P=0.224), XGBoost (AUC=0.736; P=0.814), NB (AUC=0.622, P=0.133) and CT threshold of 305.2 HU at C3 (AUC=0.704, P=0.531) classifiers to identify patients with femoral neck BMD T-scores <-1. The SVM classifier (accuracy=0.816) was more accurate than using the CT threshold of 305.2 HU at C3 (accuracy=0.671) (McNemar's χ12=7.55, P=0.006). CONCLUSION: Opportunistic screening for low BMD can be done using cervical spine CT scans. A SVM classifier was more accurate than using the CT threshold of 305.2 HU at C3.

Statistically based nomograms for the minimal needle length required to achieve intra-articular fluoroscopic-guided injections of the shoulder, hip, and knee.

BACKGROUND: Image-guided intra-articular injections are commonly performed to reduce pain in patients with arthritis or other joint-related pathology. Utilizing a needle length that is too short could lead to increased patient discomfort, increased procedural time, and extra-articular injections. OBJECTIVE: To predict the minimum needle length required for fluoroscopic-guided intra-articular injections of the hips, knees, and shoulders based on patient age, gender, height and weight, or body mass index (BMI) and to evaluate whether this varies by gender. STUDY DESIGN: Cross-sectional study. SETTING: Tertiary care academic center. PARTICIPANTS: 600 consecutive patients with available magnetic resonance imaging (MRI) of the hips, knees, and shoulders (100 males and 100 females for each joint). METHODS: The distance from the skin to the joint (glenohumeral, hip and knee) and the thickness of the subcutaneous fat pad (distance from the skin to the muscle) along the injection path were measured. Multivariable linear ridge regression with 10-fold cross-validation was used to predict the distance from the skin to the hip, knee, and glenohumeral joints using age, gender, weight, and height or using age, gender, and BMI. RESULTS: The data show that the subcutaneous fat thickness and the distance from the skin to all joints increase with weight (p < .001) and BMI (p < .001). Subcutaneous fat pads around the anterior shoulder (p < .02) and knee (<.001) are thicker in women than in men. CONCLUSIONS: Patient habitus, in particular weight and BMI, are strong predictors of the thickness of the subcutaneous fat pads and consequently strong predictors of the distance from the skin to the joint. Subcutaneous fat pad thickness around the shoulders and knees varies by gender. Nomograms showing the minimal needle length required to achieve intra-articular injections of the hip, knee and glenohumeral joints are presented.