Assessment of Small-bowel and Colonic Transit on Routine Gastric Emptying Scintigraphy: Establishment of Reference Values.

Purpose of the Study: The primary objective was to establish the reference values for small-bowel and colonic transit within the context of the routine standard solid meal gastric emptying scintigraphy (GES). The secondary objective was to compare the small-bowel and colonic transit between the anterior view and geometric mean methods. Materials and Methods: Twenty-nine healthy controls underwent routine GES, with additional imaging at 24 h if feasible. Small-bowel transit was assessed using the index of small-bowel transit (ISBT), calculated as the ratio of terminal ileal reservoir counts to total abdominal counts at 4 h. Colonic transit was evaluated using the colonic geometric center (CGC) by dividing the large bowel into four segments, with an additional fifth segment accounting for the eliminated counts. Reference values were established based on the fifth percentile or mean ± 1.96 standard deviations. Rapid small-bowel transit was visually determined. Paired Samples t-test or Wilcoxon signed-rank test, as applicable, was used to compare the small-bowel and colonic transit between the anterior view and geometric mean methods. For comparing small-bowel and colonic transit between females and males, the Independent samples t-test or Mann-Whitney U-test was applied, as appropriate. The correlation between age and small-bowel and colonic transit was assessed using Spearman's rank correlation analysis. Results: The reference value for small-bowel transit using the geometric mean method was established as ISBT >37% at 4 h, whereas rapid small-bowel transit was defined as the first visualization of activity in the cecum-ascending colon within 2 h. For colonic transit, the reference range was established as CGC 2.8-4.4 at 24 h. Comparing the anterior view and geometric mean methods, there were no significant differences in ISBT and CGC values (P ≥ 0.125). Gender did not affect small-bowel and colonic transit in both methods (P ≥ 0.378), and age showed no significant correlations (P ≥ 0.053). Conclusion: This study determined the reference values for small-bowel and colonic transit in the Indian population using routine GES, avoiding the need for additional complex procedures. The results may be generalized to the Indian population, emphasizing the importance of assessing small-bowel and colonic transit in patients with normal gastric emptying parameters to enhance gastrointestinal transit evaluation.

Early Outcomes in Patients With LVAD Undergoing Heart Transplant via Use of the SherpaPak Cardiac Transport System.

BACKGROUND: Heart transplant (HT) in recipients with left ventricular assist devices (LVADs) is associated with poor early post-HT outcomes, including primary graft dysfunction (PGD). As complicated heart explants in recipients with LVADs may produce longer ischemic times, innovations in donor heart preservation may yield improved post-HT outcomes. The SherpaPak Cardiac Transport System is an organ preservation technology that maintains donor heart temperatures between 4 °C and 8 °C, which may minimize ischemic and cold-induced graft injuries. This analysis sought to identify whether the use of SherpaPak versus traditional cold storage was associated with differential outcomes among patients with durable LVAD undergoing HT. METHODS: Global Utilization and Registry Database for Improved Heart Preservation-Heart (NCT04141605) is a multicenter registry assessing post-HT outcomes comparing 2 methods of donor heart preservation: SherpaPak versus traditional cold storage. A retrospective review of all patients with durable LVAD who underwent HT was performed. Outcomes assessed included rates of PGD, post-HT mechanical circulatory support use, and 30-day and 1-year survival. RESULTS: SherpaPak (n=149) and traditional cold storage (n=178) patients had similar baseline characteristics. SherpaPak use was associated with reduced PGD (adjusted odds ratio, 0.56 [95% CI, 0.32-0.99]; P=0.045) and severe PGD (adjusted odds ratio, 0.31 [95% CI, 0.13-0.75]; P=0.009), despite an increased total ischemic time in the SherpaPak group. Propensity matched analysis also noted a trend toward reduced intensive care unit (SherpaPak 7.5±6.4 days versus traditional cold storage 11.3±18.8 days; P=0.09) and hospital (SherpaPak 20.5±11.9 days versus traditional cold storage 28.7±37.0 days; P=0.06) lengths of stay. The 30-day and 1-year survival was similar between groups. CONCLUSIONS: SherpaPak use was associated with improved early post-HT outcomes among patients with LVAD undergoing HT. This innovation in preservation technology may be an option for HT candidates at increased risk for PGD. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04141605.

Increasing Utilization of Extended Criteria Donor Hearts for Transplantation: The OCS Heart EXPAND Trial.

BACKGROUND: Extended criteria donor (ECD) hearts available with donation after brain death (DBD) are underutilized for transplantation due to limitations of cold storage. OBJECTIVES: This study evaluated use of an extracorporeal perfusion system on donor heart utilization and post-transplant outcomes in ECD DBD hearts. METHODS: In this prospective, single-arm, multicenter study, adult heart transplant recipients received ECD hearts using an extracorporeal perfusion system if hearts met study criteria. The primary outcome was a composite of 30-day survival and absence of severe primary graft dysfunction (PGD). Secondary outcomes were donor heart utilization rate, 30-day survival, and incidence of severe PGD. The safety outcome was the mean number of heart graft-related serious adverse events within 30 days. Additional outcomes included survival through 2 years benchmarked to concurrent nonrandomized control subjects. RESULTS: A total of 173 ECD DBD hearts were perfused; 150 (87%) were successfully transplanted; 23 (13%) did not meet study transplantation criteria. At 30 days, 92% of patients had survived and had no severe PGD. The 30-day survival was 97%, and the incidence of severe PGD was 6.7%. The mean number of heart graft-related serious adverse events within 30 days was 0.17 (95% CI: 0.11-0.23). Patient survival was 93%, 89%, and 86% at 6, 12, and 24 months, respectively, and was comparable with concurrent nonrandomized control subjects. CONCLUSIONS: Use of an extracorporeal perfusion system resulted in successfully transplanting 87% of donor hearts with excellent patient survival to 2 years post-transplant and low rates of severe PGD. The ability to safely use ECD DBD hearts could substantially increase the number of heart transplants and expand access to patients in need. (International EXPAND Heart Pivotal Trial [EXPANDHeart]; NCT02323321; Heart EXPAND Continued Access Protocol; NCT03835754).

Donor Heart Recovery and Preservation Modalities in 2024.

Historically, heart transplantation (HT) has relied on the use of traditional cold storage for donor heart preservation. This organ preservation modality has several limitations, including the risk for ischemic and cold-induced graft injuries that may contribute to primary graft dysfunction and poor post-HT outcomes. In recent years, several novel donor heart preservation modalities have entered clinical practice, including the SherpaPak Cardiac Transport System of controlled hypothermic preservation, and the Transmedics Organ Care System of ex vivo perfusion. Such technologies are altering the landscape of HT by expanding the geographic reach of procurement teams and enabling both donation after cardiac death and the use of expanded criteria donor hearts. This paper will review the emerging evidence on the association of these modalities with improved post-HT outcomes, and will also suggest best practices for selecting between donor heart preservation techniques.

Near-lossless Compression of Tc-99 m DMSA Scan Images Using Discrete Cosine Transformation.

Aim and Objective: The objective of this study was to optimize the threshold for discrete cosine transform (DCT) coefficients for near-lossless compression of Tc-99 m Dimercaptosuccinic acid (DMSA) scan images using discrete cosine transformation. Materials and Methods: Two nuclear medicine (NM) Physicians after reviewing several Tc-99 m DMSA scan images provided 242 Tc-99 m DMSA scan images that had scar. These Digital imaging and communication in medicine (DICOM) images were converted in the Portable Network Graphics (PNG) format. DCT was applied on these PNG images, which resulted in DCT coefficients corresponding to each pixel of the image. Four different thresholds equal to 5, 10, 15, and 20 were applied and then inverse discrete cosine transformation was applied to get the compressed Tc-99 m DMSA scan images. Compression factor was calculated as the ratio of the number of nonzero elements after thresholding DCT coefficients to the number of nonzero elements before thresholding DCT coefficients. Two NM physicians who had provided the input images visually compared the compressed images with its input image, and categorized the compressed images as either acceptable or unacceptable. The quality of compressed images was also assessed objectively using the following eight image quality metrics: perception-based image quality evaluator, structural similarity index measure (SSIM), multiSSIM, feature similarity indexing method, blur, global contrast factor, contrast per pixel, and brightness. Pairwise Wilcoxon signed-rank sum tests were applied to find the statistically significant difference between the value of image quality metrics of the compressed images obtained at different thresholds and the value of the image quality metrics of its input images at the level of significance = 0.05. Results: At threshold 5, (1) all compressed images (242 out of 242 Tc-99 m DMSA scan images) were acceptable to both the NM Physicians, (2) Compressed image looks identical to its original image and no loss of clinical details was noticed in compressed images, (3) Up to 96.65% compression (average compression: 82.92%) was observed, and (4) Result of objective assessment supported the visual assessment. The quality of compressed images at thresholds 10, 15, and 20 was significantly better than that of input images at P < 0.0001. However, the number of unacceptable compressed images at thresholds 10, 15, and 20 was 6, 38, and 70, respectively. Conclusions: Up to 96.65%, near-losses compression of Tc-99 m DMSA images was found using DCT by thresholding DCT coefficients at a threshold value equal to 5.

Metabolomic profiling during ex situ normothermic perfusion before heart transplantation defines patterns of substrate utilization and correlates with markers of allograft injury.

BACKGROUND: Cardiac metabolism is altered in heart failure and ischemia-reperfusion injury states. We hypothesized that metabolomic profiling during ex situ normothermic perfusion before heart transplantation (HT) would lend insight into myocardial substrate utilization and report on subclinical and clinical allograft dysfunction risk. METHODS: Metabolomic profiling was performed on serial samples of ex situ normothermic perfusate assaying biomarkers of myocardial injury in lactate and cardiac troponin I (TnI) as well as metabolites (66 acylcarnitines, 15 amino acids, nonesterified fatty acids [NEFA], ketones, and 3-hydroxybutyrate). We tested for change over time in injury biomarkers and metabolites, along with differential changes by recovery strategy (donation after circulatory death [DCD] vs donation after brain death [DBD]). We examined associations between metabolites, injury biomarkers, and primary graft dysfunction (PGD). Analyses were performed using linear mixed models adjusted for recovery strategy, assay batch, donor-predicted heart mass, and time. RESULTS: A total of 176 samples from 92 ex situ perfusion runs were taken from donors with a mean age of 35 (standard deviation 11.3) years and a median total ex situ perfusion time of 234 (interquartile range 84) minutes. Lactate trends over time differed significantly by recovery strategy, while TnI increased during ex situ perfusion regardless of DCD vs DBD status. We found fuel substrates were rapidly depleted during ex situ perfusion, most notably the branched-chain amino acids leucine/isoleucine, as well as ketones, 3-hydroxybutyrate, and NEFA (least squares [LS] mean difference from the first to last time point -1.7 to -4.5, false discovery rate q < 0.001). Several long-chain acylcarnitines (LCAC), including C16, C18, C18:1, C18:2, C18:3, C20:3, and C20:4, increased during the perfusion run (LS mean difference 0.42-0.67, q < 0.001). Many LCACs were strongly associated with lactate and TnI. The change over time of many LCACs was significantly different for DCD vs DBD, suggesting differential trends in fuel substrate utilization by ischemic injury pattern. Changes in leucine/isoleucine, arginine, C12:1-OH/C10:1-DC, and C16-OH/C14-DC were associated with increased odds of moderate-severe PGD. Neither end-of-run nor change in lactate or TnI was associated with PGD. CONCLUSIONS: Metabolomic profiling of ex situ normothermic perfusion solution reveals a pattern of fuel substrate utilization that correlates with subclinical and clinical allograft dysfunction. This study highlights a potential role for interventions focused on fuel substrate modification in allograft conditioning during ex situ perfusion to improve allograft outcomes.

Utility of 99mTc-Sulfur Colloid Lymphoscintigraphy and SPECT/CT in Chylothorax and Chylous Ascites.

Purpose: To assess the diagnostic efficacy of 99mTc-sulfur colloid lymphoscintigraphy in chylothorax and chylous ascites, and the utility of single-photon emission computed tomography-computed tomography (SPECT/CT) in localizing the sites of leaks. Methods: Data from patients who underwent lymphoscintigraphy for clinical suspicion of chylothorax or chylous ascites were retrospectively analyzed. Biochemical fluid analysis was taken as the reference standard. Pleural fluid triglyceride level > 110 mg/dL (with pleural fluid/serum ratio > 1) and a cholesterol level < 200 mg/dL (with pleural fluid/serum ratio < 1) were considered confirmatory for chylothorax. Ascitic fluid triglyceride level > 200 mg/dL with a low cholesterol level (ascites fluid/serum ratio < 1) was considered confirmatory for chylous ascites. Results: 26 patients (15 males, 57.7%) aged 9 months to 68 years were enrolled in the study. Based on the reference standard, 17 had chylothorax or chylous ascites (9 with surgical history). Lymphoscintigraphy was positive in 16 (with 1 false positive) and negative in 10 (with 2 false negatives). The sensitivity, specificity, negative predictive value, positive predictive value, and accuracy of lymphoscintigraphy were 88.2% (63.6-98.5%), 88.9% (51.8-99.7%), 80.0% (51.6-93.8%), 93.8% (70.1-99.0%), and 88.5% (69.9-97.6%), respectively. SPECT/CT could localize sites of leaks in 61.5% (8/13) with a localization rate of 77.8% (7/9) and 25.0% (1/4) in patients with surgical and nonsurgical causes, respectively. Conclusion: 99mTc-sulfur colloid lymphoscintigraphy is a highly efficacious noninvasive modality to diagnose chylothorax or chylous ascites with a high positive predictive value. SPECT/CT could localize the sites of leaks more frequently in patients with surgical causes.

The Role of Recipient Thyroid Hormone Supplementation in Primary Graft Dysfunction After Heart Transplantation: A Propensity-Adjusted Analysis.

OBJECTIVES: To investigate whether recipient administration of thyroid hormone (liothyronine [T3]) is associated with reduced rates of primary graft dysfunction (PGD) after orthotopic heart transplantation. DESIGN: Retrospective cohort study. SETTING: Single-center, university hospital. PARTICIPANTS: Adult patients undergoing orthotopic heart transplantation. INTERVENTIONS: A total of 609 adult heart transplant recipients were divided into 2 cohorts: patients who did not receive T3 (no T3 group, from 2009 to 2014), and patients who received T3 (T3 group, from 2015 to 2019). Propensity-adjusted logistic regression was performed to assess the association between T3 supplementation and PGD. MEASUREMENTS AND MAIN RESULTS: After applying exclusion criteria and propensity-score analysis, the final cohort included 461 patients. The incidence of PGD was not significantly different between the groups (33.9% no T3 group v 40.8% T3 group; p = 0.32). Mortality at 30 days (3% no T3 group v 2% T3 group; p = 0.53) and 1 year (10% no T3 group v 12% T3 group; p = 0.26) were also not significantly different. When assessing the severity of PGD, there were no differences in the groups' rates of moderate PGD (not requiring mechanical circulatory support other than an intra-aortic balloon pump) or severe PGD (requiring mechanical circulatory support other than an intra-aortic balloon pump). However, segmented time regression analysis revealed that patients in the T3 group were less likely to develop severe PGD. CONCLUSIONS: These findings indicated that recipient single-dose thyroid hormone administration may not protect against the development of PGD, but may attenuate the severity of PGD.

99m-Tc TRODAT Single-Photon Emission Computerized Tomography Scan Image Compression using Singular Value Decomposition.

Introduction: The objective of the study was to compress 99m-Tc TRODAT single-photon emission computerized tomography (SPECT) scan image using Singular Value Decomposition (SVD) into an acceptable compressed image and then calculate the compression factor. Materials and Methods: The SVD of every image from the image dataset of 2256 images (of forty-eight 99m-Tc TRODAT SPECT studies [48 studies X 47 trans-axial images = 2256 trans-axial images]) was computed and after truncating singular values smaller than a threshold, the compressed image was reconstructed. The SVD computation time and percentage compression achieved were calculated for each image. Two nuclear medicine physicians visually compared compressed image with its original image, and labeled it as either acceptable or unacceptable. Compressed image having loss of clinical details or presence of compression artifact was labeled unacceptable. The quality of compressed image was also assessed objectively using the following image quality metrics: Error, structural similarity (SSIM), brightness, global contrast factor (GCF), contrast per pixel (CPP), and blur. We also compared the TRODAT uptake in basal ganglia estimated from the compressed image and original image. Results: Nuclear Medicine Physician labeled each image acceptable, as they found compressed image identical to its original image. The values of brightness, GCF, CPP, and blur metrics show that compressed images are less noisy, brighter, and sharper than its original image. The median values of error (0.0006) and SSIM (0.93) indicate that the compressed images were approximately identical to its original image. In 39 out of 48 studies, the percentage difference in TRODAT uptake (in basal ganglia from compressed and original image) was negligible (approximately equal to zero). In remaining 9 studies, the maximum percentage difference was 13%. The SVD computation time and percentage compression achieved for a TRODAT study were 0.17398 s and up to 54.61%, respectively. Conclusions: The compression factor up to 54.61% was achieved during 99m-Tc TRODAT SPECT scan image compression using SVD, for an acceptable compressed image.

Utility of 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Cardiac Infections.

Diagnosis of cardiac infections, which includes infective endocarditis (IE) and cardiac device infections, despite having a high death rate, is still challenging. Frequently used modalities such as echocardiography, computed tomography (CT), and magnetic resonance imaging cannot confirm the presence of an active infection or extracardiac findings. Taking these things to consideration, newer guidelines have suggested the inclusion of 18F fluorodeoxyglucose positron emission tomography/CT (18F FDG PET/CT) in the workup of patients with suspected prosthetic valve IE. In this pictorial essay, we are demonstrating the utility of 18F-FDG PET/CT in varied cases of IE, cardiac implantable electronic devices, and coronary stent infection and how they helped in solving diagnostic dilemmas.

Inhaled Epoprostenol Compared With Nitric Oxide for Right Ventricular Support After Major Cardiac Surgery.

BACKGROUND: Right ventricular failure (RVF) is a leading driver of morbidity and death after major cardiac surgery for advanced heart failure, including orthotopic heart transplantation and left ventricular assist device implantation. Inhaled pulmonary-selective vasodilators, such as inhaled epoprostenol (iEPO) and nitric oxide (iNO), are essential therapeutics for the prevention and medical management of postoperative RVF. However, there is limited evidence from clinical trials to guide agent selection despite the significant cost considerations of iNO therapy. METHODS: In this double-blind trial, participants were stratified by assigned surgery and key preoperative prognostic features, then randomized to continuously receive either iEPO or iNO beginning at the time of separation from cardiopulmonary bypass with the continuation of treatment into the intensive care unit stay. The primary outcome was the composite RVF rate after both operations, defined after transplantation by the initiation of mechanical circulatory support for isolated RVF, and defined after left ventricular assist device implantation by moderate or severe right heart failure according to criteria from the Interagency Registry for Mechanically Assisted Circulatory Support. An equivalence margin of 15 percentage points was prespecified for between-group RVF risk difference. Secondary postoperative outcomes were assessed for treatment differences and included: mechanical ventilation duration; hospital and intensive care unit length of stay during the index hospitalization; acute kidney injury development including renal replacement therapy initiation; and death at 30 days, 90 days, and 1 year after surgery. RESULTS: Of 231 randomized participants who met eligibility at the time of surgery, 120 received iEPO, and 111 received iNO. Primary outcome occurred in 30 participants (25.0%) in the iEPO group and 25 participants (22.5%) in the iNO group, for a risk difference of 2.5 percentage points (two one-sided test 90% CI, -6.6% to 11.6%) in support of equivalence. There were no significant between-group differences for any of the measured postoperative secondary outcomes. CONCLUSIONS: Among patients undergoing major cardiac surgery for advanced heart failure, inhaled pulmonary-selective vasodilator treatment using iEPO was associated with similar risks for RVF development and development of other postoperative secondary outcomes compared with treatment using iNO. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03081052.

Transplantation Outcomes with Donor Hearts after Circulatory Death.

BACKGROUND: Data showing the efficacy and safety of the transplantation of hearts obtained from donors after circulatory death as compared with hearts obtained from donors after brain death are limited. METHODS: We conducted a randomized, noninferiority trial in which adult candidates for heart transplantation were assigned in a 3:1 ratio to receive a heart after the circulatory death of the donor or a heart from a donor after brain death if that heart was available first (circulatory-death group) or to receive only a heart that had been preserved with the use of traditional cold storage after the brain death of the donor (brain-death group). The primary end point was the risk-adjusted survival at 6 months in the as-treated circulatory-death group as compared with the brain-death group. The primary safety end point was serious adverse events associated with the heart graft at 30 days after transplantation. RESULTS: A total of 180 patients underwent transplantation; 90 (assigned to the circulatory-death group) received a heart donated after circulatory death and 90 (regardless of group assignment) received a heart donated after brain death. A total of 166 transplant recipients were included in the as-treated primary analysis (80 who received a heart from a circulatory-death donor and 86 who received a heart from a brain-death donor). The risk-adjusted 6-month survival in the as-treated population was 94% (95% confidence interval [CI], 88 to 99) among recipients of a heart from a circulatory-death donor, as compared with 90% (95% CI, 84 to 97) among recipients of a heart from a brain-death donor (least-squares mean difference, -3 percentage points; 90% CI, -10 to 3; P<0.001 for noninferiority [margin, 20 percentage points]). There were no substantial between-group differences in the mean per-patient number of serious adverse events associated with the heart graft at 30 days after transplantation. CONCLUSIONS: In this trial, risk-adjusted survival at 6 months after transplantation with a donor heart that had been reanimated and assessed with the use of extracorporeal nonischemic perfusion after circulatory death was not inferior to that after standard-care transplantation with a donor heart that had been preserved with the use of cold storage after brain death. (Funded by TransMedics; ClinicalTrials.gov number, NCT03831048.).

Multimodality hemodynamic evaluation for optimizing management of anomalous origin of the right pulmonary artery from the aorta in an adolescent.

The hemodynamics of anomalous origin of the pulmonary artery (PA) from the aorta is challenging. Different sources of blood supply to the lungs lead to a unique state of differential flow, pressure, and pulmonary vascular resistance in each lung. The decision for surgical reimplantation of the anomalous PA during infancy is easy. The assessment of operability beyond infancy, however, is perplexing. In this report, we describe stepwise multimodal hemodynamic evaluation and successful surgical management in a 15-year-old boy with an isolated anomalous origin of the right PA from the aorta. We also report 5-year hemodynamic data confirming sustained benefit over the long term, thus providing much-needed clinical validation of often cited Poiseuille's and Ohm's laws.

Denoising Tc-99m DMSA images using Denoising Convolutional Neural Network with comparison to a Block Matching Filter.

INTRODUCTION: A DnCNN for image denoising trained with natural images is available in MATLAB. For Tc-99m DMSA images, any loss of clinical details during the denoising process will have serious consequences since denoised image is to be used for diagnosis. The objective of the study was to find whether this pre-trained DnCNN can be used for denoising Tc-99m DMSA images and compare its performance with block matching 3D (BM3D) filter. MATERIALS AND METHODS: Two hundred forty-two Tc-99m DMSA images were denoised using BM3D filter (at sigma = 5, 10, 15, 20, and 25) and DnCNN. The original and denoised images were reviewed by two nuclear medicine physicians and also assessed objectively using the image quality metrics: SSIM, FSIM, MultiSSIM, PIQE, Blur, GCF, and Brightness. Wilcoxon signed-rank test was applied to find the statistically significant difference between the value of image quality metrics of the denoised images and the corresponding original images. RESULTS: Nuclear medicine physicians observed no loss of clinical information in DnCNN denoised image and superior image quality compared to its original and BM3D denoised images. Edges/boundaries of the scar were found to be well preserved, and doubtful scar became obvious in the denoised image. Objective assessment also showed that the quality of DnCNN denoised images was significantly better than that of original images at P -value <0.0001. CONCLUSION: The pre-trained DnCNN available with MATLAB Deep Learning Toolbox can be used for denoising Tc-99m DMSA images, and the performance of DnCNN was found to be superior in comparison with BM3D filter.

A Carrier Female Manifesting an Unusual X-Linked Retinoschisis Phenotype Associated with the Pathogenic Variant c.266delA, p.(Tyr89LeufsTer37) in RS1, and Skewed X-Inactivation.

X-linked retinoschisis (XLRS) is the most common juvenile macular degeneration in males. Unlike most other X-linked retinal dystrophies, carrier heterozygous females are very rarely reported to show clinical features of the disease. Herein, we describe unusual retinal features in a 2-year-old female infant with family history and genetic testing consistent with XLRS.

Binding, Neutralization and Internalization of the Interleukin-13 Antibody, Lebrikizumab.

INTRODUCTION: IL-13 is the primary upregulated cytokine in atopic dermatitis (AD) skin and is the pathogenic mediator driving AD pathophysiology. Lebrikizumab, tralokinumab and cendakimab are therapeutic monoclonal antibodies (mAb) that target IL-13. METHODS: We undertook studies to compare in vitro binding affinities and cell-based functional activities of lebrikizumab, tralokinumab and cendakimab. RESULTS: Lebrikizumab bound IL-13 with higher affinity (as determined using surface plasma resonance) and slower off-rate. It was more potent in neutralizing IL-13-induced effects in STAT6 reporter and primary dermal fibroblast periostin secretion assays than either tralokinumab or cendakimab. Live imaging confocal microscopy was employed to determine the mAb effects on IL-13 internalization into cells via the decoy receptor IL-13Rα2, using A375 and HaCaT cells. The results showed that only the IL-13/lebrikizumab complex was internalized and co-localized with lysosomes, whereas IL-13/tralokinumab or IL-13/cendakimab complexes did not internalize. CONCLUSION: Lebrikizumab is a potent, neutralizing high-affinity antibody with a slow disassociation rate from IL-13. Additionally, lebrikizumab does not interfere with IL-13 clearance. Lebrikizumab has a different mode of action to both tralokinumab and cendakimab, possibly contributing to the clinical efficacy observed by lebrikizumab in Ph2b/3 AD studies.