Organ-specific lymphatics play distinct roles in regulating HDL trafficking and composition.

Recently, peripheral lymphatic vessels were found to transport high-density lipoprotein (HDL) from interstitial tissues to the blood circulation during reverse cholesterol transport. This function is thought to be critical to the clearance of cholesterol from atherosclerotic plaques. The role of organ-specific lymphatics in modulating HDL transport and composition is, however, incompletely understood. This study aimed to 1) determine the contribution of the lymphatics draining the intestine and liver (which are major sites of HDL synthesis) to total (thoracic) lymph HDL transport and 2) verify whether the HDLs in lymph are derived from specific organs and are modified during trafficking in lymph. The mesenteric, hepatic, or thoracic lymph duct was cannulated in nonfasted Sprague-Dawley rats, and lymph was collected over 5 h under anesthesia. Whole lymph and specific lymph lipoproteins (isolated by ultracentrifugation) were analyzed for protein and lipid composition. The majority of thoracic lymph fluid, protein, and lipid mass was sourced from the mesenteric, and to a lesser extent, hepatic lymph. Mesenteric and thoracic lymph were both rich in chylomicrons and very low-density lipoprotein, whereas hepatic lymph and plasma were HDL-rich. The protein and lipid mass in thoracic lymph HDL was mostly sourced from mesenteric lymph, whereas the cholesterol mass was equally sourced from mesenteric and hepatic lymph. HDLs were compositionally distinct across the lymph sources and plasma. The composition of HDL also appeared to be modified during passage from the mesenteric and hepatic to the thoracic lymph duct. Overall, this study demonstrates that the lipoproteins in lymph are organ specific in composition, and the intestine and liver appear to be the main source of HDL in the lymph.NEW & NOTEWORTHY High-density lipoprotein in lymph are organ-specific in composition and derive mostly from the intestine and liver. High-density lipoprotein also appears to be remodeled during transport through the lymphatics. These findings have implications to cardiometabolic diseases that involve perturbations in lipoprotein distribution and metabolism.

Inhibition of Niemann-Pick C1-Like 1 by Ezetimibe Reduces Dietary 5ß,6ß-Epoxycholesterol Absorption in Rats.

PURPOSE: Oxycholesterols (OCs) are produced from cholesterol by oxidation of the steroidal backbone and side-chain. OCs are present in blood and evidence suggests their involvement in disease development and progression. However, limited information is available regarding the absorption mechanisms and relative absorption rates of dietary OCs. Although ezetimibe is known to inhibit intestinal cholesterol absorption via Niemann-Pick C1-Like 1 (NPC1L1), whether it also inhibits dietary OC absorption is unclear. METHODS: We investigated the effects of ezetimibe on OC absorption in rats fed an OC-rich diet containing 10 different OCs. We collected lymphatic fluid using permanent cannulation of the thoracic duct and quantified OC levels. RESULTS: Ezetimibe treatment significantly reduced the apparent absorption of 5ß,6ß-epoxycholesterol (5,6ß-epoxy) and its levels in the proximal intestinal mucosa in OC-fed rats. Using in silico analyses, the binding energy of NPC1L1 N-terminal domain (NPC1L1-NTD) and 5,6ß-epoxy was found to be similar to that of NPC1L1-NTD and cholesterol, suggesting that polar uncharged amino acids located in the steroidal part of 5,6ß-epoxy were involved. CONCLUSION: Our results indicate that ezetimibe-mediated inhibition of dietary OC absorption varies depending on the specific OC, and only the absorption of 5,6ß-epoxy is significantly reduced.

Dual time point imaging for F18-FDG-PET/CT does not improve the accuracy of nodal staging in non-small cell lung cancer patients.

OBJECTIVES: To analyze the diagnostic performance of dual time point imaging (DTPI) for pre-therapeutic lymph node (LN) staging in non-small cell lung cancer (NSCLC). METHODS: This was a retrospective analysis of 47 patients with NSCLC who had undergone DTPI by PET (early + delayed) using F18-fluorodeoxyglucose (FDG). PET raw data were reconstructed iteratively (point spread function + time-of-flight). LN uptake in PET was assessed visually (four-step score) and semi-quantitatively (SUVmax, SUVmean, ratios LN/primary, LN/liver, and LN/mediastinal blood pool). DTPI analyses included retention indices (RIs), Δ-ratios and changes in visual score. Histology or cytology served as standards of reference. Accuracy was determined based on ROC analyses. RESULTS: Thirty-six of 155 LNs were malignant. DTPI accuracy was low for all measures (visual assessment, 24.5%; RI SUVmax, 68.4%; RI SUVmean, 65.8%; Δ-ratios, 63.9-76.1%) and significantly inferior to early PET. Accuracies of early (range, 86.5-92.9%) and delayed PET (range, 85.2-92.9%) were comparable. At early PET, accuracy of the visual score (92.9%) was similar or superior to semi-quantitative analyses (range, 86.5-92.3%). CONCLUSIONS: Using a modern PET/CT device and novel image reconstruction, neither additional delayed PET nor DTPI analyses improved the accuracy of PET-based LN staging. Dedicated visual assessment criteria performed very well. KEY POINTS: • DTPI did not improve accuracy of PET-based LN staging in NSCLC. • Analyzed SUV ratios were not superior to LN SUVmax or SUVmean. • A four-step visual score may allow highly accurate, standardized LN assessment.

Surgical anatomy of the internal thoracic lymph nodes in fresh human cadavers: basis for sentinel node biopsy.

BACKGROUND: While the optimal management of early breast cancer patients with sentinel lymph node (SLN) involvement mapped in the internal thoracic chain is still debated, biopsy may be performed when surgeons select patients who are most likely to benefit. The aim of this study is to examine anatomical aspects of internal thoracic nodes (ITNs) to orientate SLN biopsy in the parasternal area. METHODS: This study was based on dissections of 29 female cadavers. The parameters analyzed were the number of intercostal spaces (ICSs) containing at least one ITN, mean number of nodes in each ICS, position of the ITNs in relation to the internal thoracic artery (ITA), number of retrocostal spaces (RCSs) containing at least one ITN, and mean number of nodes in each RCS. RESULTS: The ICS that was most likely to have at least one ITN was the third, with 86.2% in the right side and 75.8% in the left side. In the second ICS, the rates were 69.2 and 73.6%, and in the fourth, the rates were 48.1 and 33.3%. In the third ICS, on both sides, the mean number of ITNs was the highest (1.2). A tendency of the nodes to be laterally located in the second ICS and medially located in the downward dissection was observed. Most of the RCSs did not present any nodes. CONCLUSIONS: This study indicates that most of the second and third ICSs presented at least one ITN, and the mean number of nodes in the third space was greater. There is a tendency to find nodes medial to the artery downwards from the second to the fourth ICS. ITNs are generally located in ICSs, and the majority of RCSs did not contain any nodes.

Impact of supradiaphragmatic lymphadenectomy on the survival of patients in stage IVB ovarian cancer with thoracic lymph node metastasis.

Introduction: To evaluate the survival impact of supradiaphragmatic lymphadenectomy as part of debulking surgery in stage IVB ovarian cancer with thoracic lymph node metastasis (LNM). Methods: We retrospectively enrolled patients diagnosed with stage IVB ovarian, fallopian or primary peritoneal cancer between 2010 and 2020, carrying cardiophrenic, parasternal, anterior mediastinal or supraclavicular lymph nodes ≥5 mm on axial chest computed tomography. All tumors were classified into the abdominal (abdominal tumors and cardiophrenic lymph nodes) and supradiaphragmatic (parasternal, anterior mediastinal or supraclavicular lymph nodes) categories depending on the area involved. Residual tumors were classified into <5 vs ≥5 mm in the abdominal and supradiaphragmatic areas. Based on the site of recurrence, they were divided into abdominal, supradiaphragmatic and other areas. Results: A total of 120 patients underwent primary debulking surgery (PDS, n=68) and interval debulking surgery after neoadjuvant chemotherapy (IDS/NAC, n=53). Residual tumors in the supradiaphragmatic area ≥5 mm adversely affected progression-free survival (PFS) and overall survival (OS) with marginal significance after PDS despite the lack of effect on survival after IDS/NAC (adjusted hazard ratios [HRs], 6.478 and 6.370; 95% confidence intervals [CIs], 2.224-18.864 and 0.953-42.598). Further, the size of residual tumors in the abdominal area measuring ≥5 mm diminished OS after IDS/NAC (adjusted HR, 9.330; 95% CIs, 1.386-62.800). Conclusion: Supradiaphragmatic lymphadenectomy during PDS may improve survival in patients diagnosed with stage IVB ovarian cancer manifesting thoracic LNM. Further, suboptimal debulking surgery in the abdominal area may be associated with poor OS after IDS/NAC. Trial registration: ClinicalTrials.gov (NCT05005650; https://clinicaltrials.gov/ct2/show/NCT05005650; first registration, 13/08/2021).Research Registry (Research Registry UIN, researchregistry7366; https://www.researchregistry.com/browse-the-registry#home/?view_2_search=researchregistry7366&view_2_page=1).

Management of Isolated Thoracic Lymphadenopathy of Unclear Etiology: A Survey of Physicians and Literature Review.

Background After identifying incidental mediastinal lymph nodes, decisions need to be made regarding the required follow-up imaging, the intervals at which this imaging should be performed, the types of imaging and procedures needed, and when to discontinue the follow-up. The purpose of this study is to determine the majority opinion on the management of these findings and provide recommendations for future management of incidental mediastinal lymphadenopathy.  Methodology Sixty-two healthcare providers from a variety of specializations were surveyed on their preference for diagnostic workup and subsequent follow-up following the finding of incidental mediastinal lymphadenopathy on computed tomography (CT) of the chest. Results For thoracic lymphadenopathy of unclear etiology and patients who are not offered endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), most providers (47/62, 75.8%) initiate the CT scan follow-up at size 10 to 14 mm. Of those patients, 51.6% (32/62) of providers repeat the initial CT scan in three months and 41.9% (26/62) repeat the initial CT scan in six months. If the follow-up CT chest shows stable lymphadenopathy, 47.5% (29/62) repeat a CT chest every six months and 37% (23/62) repeat a CT chest every 12 months. The majority of providers (42/62, 67.7%) do not use positron emission tomography (PET)-CT for the initial evaluation of isolated thoracic lymphadenopathy and follow-up of lymphadenopathy with increasing size. For thoracic lymph nodes with a maximum diameter of 10 mm, only 4.8% (3/62) of providers continue CT screening after 24 months, while 24.6% (15/62) of providers continue CT screening after 24 months for sizes greater than 20 mm. Regarding the timing of EBUS-TBNA, 40.3% (25/62) of providers consider referring/performing this procedure at lymph nodes of size 11-15 mm, followed by 21% (13/62) of providers referring/performing the procedure at size 10 mm. Conclusions The majority of providers initiate CT scan follow-ups at 10 to 14 mm size for patients with isolated thoracic lymphadenopathy. The majority of providers do not use PET-CT for the initial evaluation of isolated thoracic lymphadenopathy. We found variable responses from providers regarding the timing of follow-up intervals and total duration. There is a need for consensus guidelines regarding the management of thoracic lymphadenopathy of unclear etiology.

Dietary lysophospholipids reduce lymphatic cholesterol transport compared with dietary phospholipids in thoracic lymph-duct cannulated rats.

Dietary phospholipids have been traditionally known to affect micelle formation. Egg yolk-derived lysophospholipids (LysoPL) are commercially available. We investigated the effects of dietary LysoPL on lymphatic lipid transport. We also compared sn-1 LysoPL and sn-2 LysoPL, which have different fatty acyl esterification positions. Thoracic lymph duct-cannulated rats were fed a diet supplemented with egg yolk-derived sn-1 LysoPL, sn-2 LysoPL, or phospholipids (PL). The amount of lymphatic lipid transport was also evaluated. Time courses of transport were applied to the one-compartment model as one of the pharmacokinetic analyses. The solubility of cholesterol in bile acid micelles was measured. Compared to the PL diet, the sn-1 and sn-2 LysoPL diets significantly reduced the lymphatic transport of cholesterol. There were no differences in the lymphatic PL and TAG transport. There was no difference in cholesterol transport between the sn-1 LysoPL group and the sn-2 LysoPL group; however, the transport rate constant at a decrease in lymphatic cholesterol was lower in the sn-1 LysoPL group than in the sn-2 LysoPL group. Cholesterol solubility in bile acid micelles was significantly decreased in the sn-1 LysoPL and sn-2 LysoPL groups compared to that in the PL group. Dietary LysoPL affects the behavior of intestinal cholesterol and suppresses lymphatic cholesterol transport.

Classification of Metastatic and Non-Metastatic Thoracic Lymph Nodes in Lung Cancer Patients Based on Dielectric Properties Using Adaptive Probabilistic Neural Networks.

OBJECTIVE: Dielectric properties can be used in normal and malignant tissue identification, which requires an effective classifier because of the high throughput nature of the data. With easy training and fast convergence, probabilistic neural networks (PNNs) are widely applied in pattern classification problems. This study aims to propose a classifier to identify metastatic and non-metastatic thoracic lymph nodes in lung cancer patients based on dielectric properties. METHODS: The dielectric properties (permittivity and conductivity) of lymph nodes were measured using an open-ended coaxial probe. The Synthetic Minority Oversampling Technique method was adopted to modify the dataset. Feature parameters were scored to select the appropriate feature vector using a Statistical Dependency algorithm. The dataset was classified using adaptive PNNs with an optimized smooth factor using the simulated annealing PNN (SA-PNN). The results were compared with traditional Probabilistic, Support Vector Machines, k-Nearest Neighbor and the Classify functions in MATLAB. RESULTS: The conductivity frequencies of 3959, 3958, 3960, 3978, 3510, 3889, 3888, and 3976 MHz were selected as the feature vectors for 219 lymph nodes (178 non-metastatic and 41 metastatic). Compared with the other methods, SA-PNN achieved the highest classification accuracy (92.92%) and the corresponding specificity and sensitivity were 94.72% and 91.11%, respectively. CONCLUSIONS: Compared with the other methods, the SA-PNN proposed in the present study achieved a higher classification accuracy, which provides a new scheme for classification of metastatic and non-metastatic thoracic lymph nodes in lung cancer patients based on dielectric properties.

Lymph Node Involvement in Oesophageal Carcinoma: A Single-Centre Observational Study From Western India.

Introduction Lymph node involvement is the most important predictor of prognosis in oesophageal cancer. The present study describes our single-centre experience of lymphadenopathy in oesophageal carcinoma cases at a tertiary care centre in the Marathwada region of Maharashtra state in western India. Methods This descriptive study included 31 patients who were operated for oesophageal carcinoma at the State Cancer Hospital in Marathwada from August 2015 to September 2017. Thirty patients underwent three-field lymph node dissections, and one patient underwent Ivor Lewis surgery with two-field lymph node dissections. Three-field lymph node dissections were through a thoracotomy, followed by laparotomy and left cervical incision. The lymphatic metastases were categorised as (a) adjacent node metastases, (b) multiple levels of lymph node metastases, and (c) skip node metastases. The histopathological assessment of the removed specimen and lymph nodes was done. Pathologists evaluated the character and depth of the primary tumour and its invasion and node involvement. The location and numbers of positive and negative nodes were recorded. Results A total of 31 patients were included in the study, of which 17 had lymph node involvement. A total of 946 lymph nodes were dissected and examined, and the average number of lymph nodes removed per patient was 30.51. Among the 28 squamous cell carcinoma cases, lymph node involvement was found in 14 cases (50%) whereas, in adenocarcinoma, all the three cases showed lymph node involvement. In 11 cases of squamous cell carcinoma, thoracic lymph nodes were involved, whereas abdominal lymph nodes were involved in nine and cervical lymph nodes in two cases. Thoracic lymph nodes were involved in two cases of adenocarcinoma and abdominal lymph nodes were involved in one case of adenocarcinoma. Conclusions Squamous cell carcinoma was the predominant type, and lymph node metastasis was observed in 50% of these cases. Thoracic lymph nodes were more commonly involved. Tumour staging T2 and T3 had an increasing percentage of lymph nodes involved. Lymph node involvement was more in moderately differentiated and undifferentiated oesophageal cancers.

Computed tomography of thoracic lymph nodes in 100 dogs with no abnormalities in the dominated area.

In dogs, reports on thoracic lymph nodes are lacking compared to abdominal lymph nodes. This report analyzed the position, number, size, shape, and homogeneity of thoracic lymph nodes (cranial sternal, cranial mediastinal, tracheobronchial, aortic thoracic, and pulmonary lymph nodes) using thoracic computed tomography (CT) images of 100 dogs without any lesions in the dominated areas of thoracic lymph nodes. The position and number of intrathoracic lymph nodes could be observed in CT, consistent with macroscopic anatomical studies. It was difficult to set a clinical index associated with size using CT scans. Image findings that indicated abnormalities, such as circular shapes and non-uniform, may be routinely found in dogs and may not be considered abnormal on CT scans.

AAR-LN-DQ: Automatic anatomy recognition based disease quantification in thoracic lymph node zones via FDG PET/CT images without Nodal Delineation.

PURPOSE: The derivation of quantitative information from medical images in a practical manner is essential for quantitative radiology (QR) to become a clinical reality, but still faces a major hurdle because of image segmentation challenges. With the goal of performing disease quantification in lymph node (LN) stations without explicit nodal delineation, this paper presents a novel approach for disease quantification (DQ) by automatic recognition of LN zones and detection of malignant lymph nodes within thoracic LN zones via positron emission tomography/computed tomography (PET/CT) images. Named AAR-LN-DQ, this approach decouples DQ methods from explicit nodal segmentation via an LN recognition strategy involving a novel globular filter and a deep neural network called SegNet. METHOD: The methodology consists of four main steps: (a) Building lymph node zone models by automatic anatomy recognition (AAR) method. It incorporates novel aspects of model building that relate to finding an optimal hierarchy for organs and lymph node zones in the thorax. (b) Recognizing lymph node zones by the built lymph node models. (c) Detecting pathologic LNs in the recognized zones by using a novel globular filter (g-filter) and a multi-level support vector machine (SVM) classifier. Here, we make use of the general globular shape of LNs to first localize them and then use a multi-level SVM classifier to identify pathologic LNs from among the LNs localized by the g-filter. Alternatively, we designed a deep neural network called SegNet which is trained to directly recognize pathologic nodes within AAR localized LN zones. (d) Disease quantification based on identified pathologic LNs within localized zones. A fuzzy disease map is devised to express the degree of disease burden at each voxel within the identified LNs to simultaneously handle several uncertain phenomena such as PET partial volume effects, uncertainty in localization of LNs, and gradation of disease content at the voxel level. We focused on the task of disease quantification in patients with lymphoma based on PET/CT acquisitions and devised a method of evaluation. Model building was carried out using 42 near-normal patient datasets via contrast-enhanced CT examinations of their thorax. PET/CT datasets from an additional 63 lymphoma patients were utilized for evaluating the AAR-LN-DQ methodology. We assess the accuracy of the three main processes involved in AAR-LN-DQ via fivefold cross validation: lymph node zone recognition, abnormal lymph node localization, and disease quantification. RESULTS: The recognition and scale error for LN zones were 12.28 mm ± 1.99 and 0.94 ± 0.02, respectively, on normal CT datasets. On abnormal PET/CT datasets, the sensitivity and specificity of pathologic LN recognition were 84.1% ± 0.115 and 98.5% ± 0.003, respectively, for the g-filter-SVM strategy, and 91.3% ± 0.110 and 96.1% ± 0.016, respectively, for the SegNet method. Finally, the mean absolute percent errors for disease quantification of the recognized abnormal LNs were 8% ± 0.09 and 14% ± 0.10 for the g-filter-SVM method and the best SegNet strategy, respectively. CONCLUSIONS: Accurate disease quantification on PET/CT images without performing explicit delineation of lymph nodes is feasible following lymph node zone and pathologic LN localization. It is very useful to perform LN zone recognition by AAR as this step can cover most (95.8%) of the abnormal LNs and drastically reduce the regions to search for abnormal LNs. This also improves the specificity of deep networks such as SegNet significantly. It is possible to utilize general shape information about LNs such as their globular nature via g-filter and to arrive at high recognition rates for abnormal LNs in conjunction with a traditional classifier such as SVM. Finally, the disease map concept is effective for estimating disease burden, irrespective of how the LNs are identified, to handle various uncertainties without having to address them explicitly one by one.

Thoracic lymph node station recognition on CT images based on automatic anatomy recognition with an optimal parent strategy.

Currently, there are many papers that have been published on the detection and segmentation of lymph nodes from medical images. However, it is still a challenging problem owing to low contrast with surrounding soft tissues and the variations of lymph node size and shape on computed tomography (CT) images. This is particularly very difficult on low-dose CT of PET/CT acquisitions. In this study, we utilize our previous automatic anatomy recognition (AAR) framework to recognize the thoracic-lymph node stations defined by the International Association for the Study of Lung Cancer (IASLC) lymph node map. The lymph node stations themselves are viewed as anatomic objects and are localized by using a one-shot method in the AAR framework. Two strategies have been taken in this paper for integration into AAR framework. The first is to combine some lymph node stations into composite lymph node stations according to their geometrical nearness. The other is to find the optimal parent (organ or union of organs) as an anchor for each lymph node station based on the recognition error and thereby find an overall optimal hierarchy to arrange anchor organs and lymph node stations. Based on 28 contrast-enhanced thoracic CT image data sets for model building, 12 independent data sets for testing, our results show that thoracic lymph node stations can be localized within 2-3 voxels compared to the ground truth.

The intrathoracic lymph node ratio seems to be a better prognostic factor than the level of lymph node involvement in lung metastasectomy of colorectal carcinoma.

OBJECTIVES: Data on thoracic lymph node involvement (LNI) in lung metastasis of colorectal cancer (CRC) are conflicting, with a 5-year overall survival (OS) ranging from 6 to 40%. We aimed to evaluate whether there are subgroups of patients according to the lymph node ratio (LNR). METHODS: We retrospectively reviewed the data from 106 patients who underwent a thoracic procedure for CRC lung metastasis with pathologically proven thoracic LNI. RESULTS: In the univariate analysis, the median OS was significantly poorer for a pN2 location of LNI (26 vs 16 months, P = 0.04), LNR ≥50% (30 vs 17 months, P = 0.005), high preoperative CEA (32 vs 16 months, P = 0.02), hepatic metastases (27 vs 11 months, P <0.0001) and disease-free survival < 24 months (32 vs 17 months, P = 0.05). When pN1 and pN2 patients were staged according to the LNR, the median OS was significantly better for an LNR <50% (27 vs 17 months for pN1, 32 vs 12 months for pN2, P = 0.01). In the multivariate analysis, a high preoperative CEA [hazard ratio (HR): 2.256 (1.051-4.841), P = 0.04], pN1 status [HR: 0.337 (0.162-0.7), P = 0.004] and the absence of hepatic metastases [HR: 0.395 (0.180-0.687), P = 0.02] remained significant prognostic factors. There was an upward trend for patients with LNR <50% [HR: 0.565 (0.296-1.082), P = 0.08]. Otherwise, low LNR was significantly associated with a decreased risk of loco-regional recurrence (HR: 0.36, 95% confidence intervals: 0.14-0.96, P = 0.04). CONCLUSIONS: The LNR seems to be a more reliable prognostic factor than LNI for CRC lung metastasis. Prospective studies are necessary.

Dietary egg white protein inhibits lymphatic lipid transport in thoracic lymph duct-cannulated rats.

Dietary egg white protein (EWP) decreases serum cholesterol levels. We previously showed that EWP decreased cholesterol absorption in the intestine. Rats subjected to permanent lymph duct cannulation were used to investigate the effects of dietary EWP on lipid transport. They were fed diets with 20% EWP and casein, and their lymph was collected to quantify lymphatic lipid levels. Dietary EWP decreased lymphatic cholesterol transport compared with casein. It was previously shown that EWP excluded cholesterol from bile acid micelles. Therefore, pepsin-hydrolyzed EWP and casein were prepared. EWP was not completely digested. Ovalbumin, which is the most abundant protein in EWP, showed resistance to digestion by pepsin. This study investigated the effects of EWP pepsin hydrolysate (EWP-ph) on cholesterol micellar solubility, cholesterol transfer from the micellar to the oil phase, water-holding capacity (WHC), settling volume in water (SV), and relative viscosity and compared them with the effects of casein pepsin hydrolysate (C-ph). EWP-ph significantly decreased the micellar solubility and transfer rate and increased the WHC, SV, and relative viscosity compared with C-ph. Moreover, the pepsin hydrolysate of ovalbumin, a major protein in EWP, played a role in decreasing cholesterol micellar solubility, leading to the inhibition of cholesterol absorption. In conclusion, dietary EWP decreased cholesterol intestinal absorption by exerting combined effects of these physicochemical properties in the gut.