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Abstract For many years, the understanding of gastrointestinal stromal tumors (GISTs), which are the most common mesenchymal tumors of the gastrointestinal tract, has been very limited. However, it is now possible to provide a more precise definition through the use of pathology classification and molecular techniques. Coupled with the advancement of clinical practice, especially the development of targeted therapy, there is now a much better insight into its treatment. At present, organizations such as the National Comprehensive Cancer Network in the USA and the European Society for Medical Oncology in Europe have established a consensus and drawn up guidelines for the diagnosis, treatment, and follow-up of GISTs. With experts coming from various districts in Taiwan and combining the most recent clinical data and experiences, the Taiwan Surgical Society of Gastroenterology drafted the first national GIST treatment guidelines after a consensus meeting in 2007. Following subsequent advances in GIST diagnosis and treatment, further revisions and modifications have been made to the original guidelines. We present here the updated consensus and recommendations of the Taiwan Surgical Society of Gastroenterology for the diagnosis and treatment of GIST. We hope these guidelines can help enhance the quality of diagnosis, treatment, and care of patients with GIST in Taiwan.

Abstract Background Pancreatic adenocarcinoma (PCA) is one of the most lethal human malignancies, and radical surgery remains the cornerstone of treatment. After resection, the overall 5-year survival rate is only 10% to 29%. At the time of presentation, however, about 40% of patients generally have distant metastases and another 40% are usually diagnosed with locally advanced cancers. The remaining 20% of patients are indicated for surgery on the basis of the results of preoperative imaging studies; however, about half of these patients are found to be unsuitable for resection during surgical exploration. In the current study, we aimed to determine the clinicopathological characteristics that predict the resectability of PCA and to conduct a prognostic analysis of PCA after resection to identify favorable survival factors. Methods We retrospectively reviewed the medical files of 688 patients (422 men and 266 women) who had undergone surgery for histopathologically proven PCA in the Department of Surgery at Chang Gung Memorial Hospital in Taiwan from 1981 to 2006. We compared the clinical characteristics of patients who underwent resection and patients who did not undergo resection in order to identify the predictive factors for successful resectability of PCA, and we conducted prognostic analysis for PCA after resection. Results A carbohydrate antigen 19–9 (CA 19–9) level of 37 U/ml or greater and a tumor size of 3 cm or more independently predicted resectability of PCA. In terms of survival after resection, PCA patients with better nutritional status (measured as having an albumin level greater than 3.5 g/dl), radical resection, early tumor stage and better-differentiated tumors were associated with favorable survival. Conclusions Besides traditional imaging studies, preoperative CA 19–9 levels and tumor size can also be used to determine the resectability of PCA. Better nutritional status, curative resection, early tumor stage and well-differentiated tumors predict the favorable prognosis of PCA patients after resection.

Abstract Isolated pancreatic metastases from a non-pancreatic primary malignancy are very rare. Studies have shown that resection of metastases is of proven benefit in some types of tumors. We report a case of 76-year-old Taiwanese woman with rectal adenocarcinoma treated with neoadjuvant chemoradiotherapy and abdominoperineal resection 2 years ago presenting with an asymptomatic mass at the pancreatic tail on a routine follow up abdominal computed tomography scan. The patient underwent distal pancreatectomy and splenectomy under the preoperative impression of a primary pancreatic malignancy. Histological examination of the surgical specimen showed metastatic adenocarcinoma. Immunohistochemical studies confirmed the diagnosis of pancreatic metastasis from rectal adenocarcinoma. Postoperative chemotherapy in the form of oral capecitabine was given. The patient is alive and disease free 12 months after the surgery. In a patient presenting with a pancreatic mass with history of a non-pancreatic malignancy, a differential diagnosis of pancreatic metastasis should be considered. Surgical resection of a solitary pancreatic mass is justified not only to get the definitive diagnosis but also to improve the survival.

Abstract Background Pancreatic adenosquamous carcinoma (ASC) is a rare pancreatic malignancy subtype. We investigated the clinicopathological features and outcome of pancreatic ASC patients after surgery. Methods The medical records of 12 patients with pancreatic ASC undergoing surgical treatment (1993 to 2006) were retrospectively reviewed. Survival data of patients with stage IIB pancreatic adenocarcinoma and ASC undergoing surgical resection were compared. Results Symptoms included abdominal pain (91.7%), body weight loss (83.3%), anorexia (41.7%) and jaundice (25.0%). Tumors were located at pancreatic head in 5 (41.7%) patients, tail in 5 (41.7%), and body in 4 (33.3%). Median tumor size was 6.3 cm. Surgical resection was performed on 7 patients, bypass surgery on 3, and exploratory laparotomy with biopsy on 2. No surgical mortality was identified. Seven (58.3%) and 11 (91.7%) patients died within 6 and 12 months of operation, respectively. Median survival of 12 patients was 4.41 months. Seven patients receiving surgical resection had median survival of 6.51 months. Patients with stage IIB pancreatic ASC had shorter median survival compared to those with adenocarcinoma. Conclusion Aggressive surgical management does not appear effective in treating pancreatic ASC patients. Strategies involving non-surgical treatment such as chemotherapy, radiotherapy or target agents should be tested.

Abstract Background Gastrointestinal stromal tumors (GISTs), the most common type of mesenchymal tumors of the gastrointestinal (GI) tract, demonstrate positive kit staining. We report our surgical experience with 100 small intestine GIST patients and identify predictors for long-term disease-free survival (DFS) and overall survival (OS) to clarify the difference between high- and low-risk patients. Methods The clinicopathologic and follow-up records of 100 small intestine GIST patients who were treated at Chung Gung Memorial Hospital between 1983 and 2002 were retrospectively reviewed. Clinical and pathological factors were assessed for long-term DFS and OS by using a univariate log-rank test and a multivariate Cox proportional hazard model. Results The patients included 52 men and 48 women. Their ages ranged from 27 to 82 years. Among the 85 patients who underwent curative resection, 44 (51.8%) developed disease recurrence (liver metastasis was the most common form of recurrence). The follow-up period ranged from 5 to 202 months (median: 33.2 months). The 1-, 3-, and 5-year DFS and OS rates were 85.2%, 53.8%, and 43.7%, and 91.5%, 66.6%, and 50.5%, respectively. Using multivariate analysis, it was found that high tumor cellularity, mitotic count >5/50 high-power field, and a Ki-67 index ≧10% were three independent factors that were inversely associated with DFS. However, absence of tumor perforation, mitotic count < 5/50 high power field, and tumor with low cellularity were predictors of long-term favorable OS. Conclusion Tumors with low cellularity, low mitotic count, and low Ki-67 index, which indicate low risk, predict a more favorable DFS for small intestine GIST patients undergoing curative resection. Absence of tumor perforation with low mitotic count and low cellularity, which indicates low risk, can predict long-term OS for small intestine GIST patients who have undergone curative resection.

Abstract Background A bleeding pseudoaneurysm in patients with chronic pancreatitis is a rare and potentially lethal complication. Optimal treatment of bleeding peripancreatic pseudoaneurysm remains controversial. This study reports on experience at Chang Gung Memorial Hospital (CGMH) in managing of bleeding pseudoaneurysms associated with chronic pancreatitis. Methods The medical records of 9 patients (8 males and 1 female; age range, 28 – 71 years; median, 36 years) with bleeding pseudoaneurysms associated with chronic pancreatitis treated at CGMH between Aug. 1992 and Sep. 2004 were retrospectively reviewed. Alcohol abuse (n = 7;78%) was the predominant predisposing factor. Diagnoses of bleeding pseudoaneurysms were based on angiographic (7/7), computed tomographic (4/7), ultrasound (2/5), and surgical (2/2) findings. Whether surgery or angiographic embolization was performed was primarily based on patient clinical condition. Median follow-up was 38 months (range, 4 – 87 months). Results Abdominal computed tomography revealed bleeding pseudoaneurysms in 4 of 7 patients (57%). Angiography determined correct diagnosis in 7 patients (7/7, 100%). The splenic artery was involved in 5 cases, the pancreaticoduodenal artery in 2, the gastroduodenal artery in 1, and the middle colic artery in 1. Initial treatment was emergency (n = 4) or elective (n = 3) surgery in 7 patients and arterial embolization in 2. Rebleeding was detected after initial treatment in 3 patients. Overall, 5 arterial embolizations and 9 surgical interventions were performed; the respective rates of success of these treatments were 20% (1/5) and 89% (8/9). Five patients developed pseudocysts before treatment (n = 3) or following intervention (n = 2). Pseudocyst formation was identified in 2 of the 3 rebleeding patients. Five patients underwent surgical treatment for associated pseudocysts and bleeding did not recur. One patient died from angiography-related complications. Overall mortality rate was 11% (1/9). Surgery-related mortality was 0%. Conclusion Angiography is valuable in localizing bleeding pseudoaneurysms. In this limited series, patients with bleeding pseudoaneurysms associated with chronic pancreatitis treated surgically seemingly obtained good outcomes.

Abstract Background This study uses cigarette price elasticity to evaluate the effect of a new excise tax increase on cigarette consumption and to investigate responses from various types of smokers. Methods Our sample consisted of current smokers between 17 and 69 years old interviewed during an annual face-to-face survey conducted by Taiwan National Health Research Institutes between 2000 to 2003. We used Ordinary Least Squares (OLS) procedure to estimate double logarithmic function of cigarette demand and cigarette price elasticity. Results In 2002, after Taiwan had enacted the new tax scheme, cigarette price elasticity in Taiwan was found to be -0.5274. The new tax scheme brought about an average annual 13.27 packs/person (10.5%) reduction in cigarette consumption. Using the cigarette price elasticity estimate from -0.309 in 2003, we calculated that if the Health and Welfare Tax were increased by another NT$ 3 per pack and cigarette producers shifted this increase to the consumers, cigarette consumption would be reduced by 2.47 packs/person (2.2%). The value of the estimated cigarette price elasticity is smaller than one, meaning that the tax will not only reduce cigarette consumption but it will also generate additional tax revenues. Male smokers who had no income or who smoked light cigarettes were found to be more responsive to changes in cigarette price. Conclusions An additional tax added to the cost of cigarettes would bring about a reduction in cigarette consumption and increased tax revenues. It would also help reduce incidents smoking-related illnesses. The additional tax revenues generated by the tax increase could be used to offset the current financial deficiency of Taiwan's National Health Insurance program and provide better public services.

Description of the subject. Alkaline phosphatases (APases) are commonly used as nonradioactive markers for detecting specific proteins or DNA targets in clinical medicine and molecular biology. However, their applications in the biotechnology industry require thermostability and storage stability. Our preliminary study revealed that APase from Thermus sp. NTU-237 (TsAPase) is thermostable and exhibits high activity. Therefore, it is desirable to establish the optimal conditions for its application. Objectives. To characterize APase from thermophile Thermus sp. NTU-237 and to evaluate its potential applications. Method. The APase gene of Thermus sp. NTU-237 was cloned and expressed in Escherichia coli. Subsequently, the effects of buffer, glycerol, sodium dodecyl sulfate (SDS), NaCl, and temperature on enzyme activity were studied to establish the optimal conditions for TsAPase assays. In addition, the potential for application of TsAPase was evaluated using the 5-bromo-4-chloro-3-indolyl phosphate/nitro blue tetrazolium (BCIP/NBT) active staining method. Results. Recombinant TsAPase was identified as having a dimeric structure and a molecular mass of 109 kDa. Sequence alignment analysis of known thermophilic APases with TsAPase and E. coli APase revealed that catalytic and binding residues were highly conserved. This finding suggested that the catalytic mechanism of TsAPase is the same as that of other APases. TsAPase activity was inhibited by glycerol and SDS but enhanced by NaCl and Tris-HCl buffer. The kinetic parameters Km, kcat, and Vmax were determined to be 81 µM, 6.08 s-1, and 6.76 U·mg-1, respectively. The optimum temperature of TsAPase was 80 °C, and TsAPase was stable at room temperature for more than 10 days. Moreover, TsAPase could catalyze the dephosphorylation of BCIP and could elicit blue color development by the BCIP/NBT reaction kit at room temperature. Conclusions. These results illustrate that TsAPase has potential for application in medical or basic research.

Purpose: To test the diagnostic performance of an artificial intelligence algorithm for detecting and segmenting macular neovascularization (MNV) with optical coherence tomography (OCT) and OCT angiography(OCTA) in eyes with macular edema from various diagnoses., Design: Prospective cross-sectional study., Participants: Study participants with macular edema due to either treatment-naïve exudative age-related macular degeneration (AMD), diabetic macular edema (DME), or retinal vein occlusion (RVO)., Methods: Study participants were imaged with macular 3x3-mm and 6x6-mm spectral-domain OCTA. Eyes with exudative AMD were required to have MNV in the central 3x3-mm area. A previously developed hybrid multi-task convolutional neural network for MNV detection (aiMNV) and segmentation was applied to all images, regardless of image quality., Main Outcome Measures: Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of detecting MNV; and intersection over union(IoU) score and F1 score for segmentation., Results: Of 114 eyes from 112 study participants, 56 eyes had MNV due to exudative AMD and 58 eyes with macular edema due to either DME or RVO. 3x3-mm OCTA scans with aiMNV detected MNV with 96.4% sensitivity, 98.3% specificity, 98.2% PPV, and 96.6% NPV. For segmentation, the average IoU score was 0.947 and the F1 score was 0.973. 6x6-mm scans performed well; however, sensitivity for MNV detection was lower than 3x3-mm scans due to lower scan sampling density., Conclusion: This novel aiMNV algorithm can accurately detect and segment MNV in eyes with exudative AMD from a control group of eyes that present with macular edema from either DME or RVO. Higher scan sampling density improved the aiMNV sensitivity for MNV detection., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: To evaluate the response of type 1 and type 2 macular neovascularization (MNV) components under anti-vascular endothelial growth factor (VEGF) treatment in age-related macular degeneration (AMD) using projection-resolved optical coherence tomography angiography (PR-OCTA)., Methods: This retrospective study included eyes with treatment-naïve exudative AMD treated with anti-VEGF injections under a pro re nata (PRN) protocol over 1 year. Two-dimensional MNV areas and three-dimensional MNV volumes were derived from macular PR-OCTA scans using an automated convolutional neural network. MNV was detected as flow signal within the outer retinal slab. Type 1 components and type 2 components were analyzed separately., Results: Of 17 enrolled eyes, 12 eyes were pure type 1 MNV and five eyes were type 2 MNV. In eyes with pure type 1, the total (sum of type 1 and type 2 components) MNV area and volume did not change from baseline to 6 months or 12 months (P > 0.05). In eyes with type 2 MNV, the total MNV area significantly decreased from the baseline to 6 months (P = 0.0074) and 12 months (P = 0.014). The total type 2 MNV volume also decreased from baseline visit to visits at 6 months and at 12 months, nearing statistical signifiicance (P = 0.061 and P = 0.074). In eyes with type 2 MNV, the type 1 component increased from 0.093 mm2 to 0.30 mm2 (P = 0.058), and the type 2 component decreased from 0.37 mm2 at 6 months to 0 at 12 months (P = 0.0087)., Conclusions: Type 1 and type 2 MNV may have different response under PRN anti-VEGF treatment over 1 year.

Radiation therapy is a crucial cancer treatment, but it can damage healthy tissues, leading to side effects like skin injuries and molecular alterations. This study aimed to elucidate histological and molecular changes in canine skin post-radiation therapy (post-RT) over nine weeks, focusing on inflammation, stem cell activity, angiogenesis, keratinocyte regeneration, and apoptosis. Four male beagles received a cumulative radiation dose of 48 Gy, followed by clinical observations, histological examinations, and an RT-qPCR analysis of skin biopsies. Histological changes correlated with clinical recovery from inflammation. A post-RT analysis revealed a notable decrease in the mRNA levels of Oct4, Sox2, and Nanog from weeks 1 to 9. VEGF 188 levels initially saw a slight increase at week 1, but they had significantly declined by week 9. Both mRNA and protein levels of COX-2 and Keratin 10 significantly decreased over the 9 weeks following RT, although COX-2 expression surged in the first 2 weeks, and Keratin 10 levels increased at weeks 4 to 5 compared to normal skin. Apoptosis peaked at 2 weeks and diminished, nearing normal by 9 weeks. These findings offer insights into the mechanisms of radiation-induced skin injury and provide guidance for managing side effects in canine radiation therapy.

Purpose: Retinal ischemia is a major feature of diabetic retinopathy (DR). Traditional nonperfused areas measured by OCT angiography (OCTA) measure blood supply but not ischemia. We propose a novel 3-dimensional (3D) quantitative method to derive ischemia measurements from OCTA data., Design: Cross-sectional study., Participants: We acquired 223 macular OCTA volumes from 33 healthy eyes, 33 diabetic eyes without retinopathy, 7 eyes with nonreferable DR, 17 eyes with referable but nonvision-threatening DR, and 133 eyes with vision-threatening DR., Methods: Each eye was scanned using a spectral-domain OCTA system (Avanti RTVue-XR, Visionix/Optovue, Inc) with 1.6-mm scan depth in a 3 × 3-mm region (640 × 304 × 304 voxels) centered on the fovea. For each scanned OCTA volume, a custom algorithm removed flow projection artifacts. We then enhanced, binarized, and skeletonized the vasculature in each OCTA volume and generated a 3D oxygen tension map using a zero-order kinetics oxygen diffusion model. Each volume was scaled to the average retina thickness in healthy controls after foveal registration and flattening of the Bruch's membrane. Finally, we extracted 3D ischemia maps by comparison with a reference map established from scans of healthy eyes using the same processing. To assess the ability of the ischemia maps to grade DR severity, we constructed receiver operating characteristic curves for diagnosing diabetes, referable DR, and vision-threatening DR., Main Outcome Measures: Spearman correlation coefficient and area under receiver operating characteristic curve (AUC) were used to quantify the ability of the ischemia maps to DR., Results: The ischemia maps showed that the ischemic tissues were at or near pathologically nonperfused areas, but not the normally nonvascular tissue, such as the foveal avascular zone. We found multiple novel metrics, including inferred 3D-oxygen tension, ischemia index, and ischemic volume ratio, were strongly correlated with DR severity. The AUCs of ischemia index measured were 0.94 for diabetes, 0.89 for DR, 0.88 for referable DR, and 0.85 for vision-threatening DR., Conclusions: A quantitative method to infer 3D oxygen tension and ischemia using OCTA in diabetic eyes can identify ischemic tissue that are more specific to pathologic changes in DR., Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (© 2024 by the American Academy of Ophthalmology.)

Purpose: To train and validate a convolutional neural network to segment nonperfusion areas (NPAs) in multiple retinal vascular plexuses on widefield optical coherence tomography angiography (OCTA)., Methods: This cross-sectional study included 202 participants with a full range of diabetic retinopathy (DR) severities (diabetes mellitus without retinopathy, mild to moderate non-proliferative DR, severe non-proliferative DR, and proliferative DR) and 39 healthy participants. Consecutive 6 × 6-mm OCTA scans at the central macula, optic disc, and temporal region in one eye from 202 participants in a clinical DR study were acquired with a 70-kHz OCT commercial system (RTVue-XR). Widefield OCTA en face images were generated by montaging the scans from these three regions. A projection-resolved OCTA algorithm was applied to remove projection artifacts at the voxel scale. A deep convolutional neural network with a parallel U-Net module was designed to detect NPAs and distinguish signal reduction artifacts from flow deficits in the superficial vascular complex (SVC), intermediate capillary plexus (ICP), and deep capillary plexus (DCP). Expert graders manually labeled NPAs and signal reduction artifacts for the ground truth. Sixfold cross-validation was used to evaluate the proposed algorithm on the entire dataset., Results: The proposed algorithm showed high agreement with the manually delineated ground truth for NPA detection in three retinal vascular plexuses on widefield OCTA (mean ± SD F-score: SVC, 0.84 ± 0.05; ICP, 0.87 ± 0.04; DCP, 0.83 ± 0.07). The extrafoveal avascular area in the DCP showed the best sensitivity for differentiating eyes with diabetes but no retinopathy (77%) from healthy controls and for differentiating DR by severity: DR versus no DR, 77%; referable DR (rDR) versus non-referable DR (nrDR), 79%; vision-threatening DR (vtDR) versus non-vision-threatening DR (nvtDR), 60%. The DCP also showed the best area under the receiver operating characteristic curve for distinguishing diabetes from healthy controls (96%), DR versus no DR (95%), and rDR versus nrDR (96%). The three-plexus-combined OCTA achieved the best result in differentiating vtDR and nvtDR (81.0%)., Conclusions: A deep learning network can accurately segment NPAs in individual retinal vascular plexuses and improve DR diagnostic accuracy., Translational Relevance: Using a deep learning method to segment nonperfusion areas in widefield OCTA can potentially improve the diagnostic accuracy of diabetic retinopathy by OCT/OCTA systems.

Myxomatous mitral valve disease (MMVD) is the most common cardiovascular disorder in dogs with a high prevalence, accounting for approximately 75% of all canine heart disease cases. MMVD is a complex disease and shows variable progression from mild valve leakage to severe regurgitation, potentially leading to heart failure. However, the molecular mechanisms and age-related changes that govern disease progression, especially at the early stage (B1) before the development of discernable clinical signs, remain poorly understood. In this prospective study, we aimed to compare gene expression differences between blood samples of aged beagle dogs with stage B1 MMVD and those of healthy controls using RNA sequencing. Clinical evaluation was also conducted, which revealed minimal differences in radiographic and echocardiographic measurements despite distinct biomarker variations between the two groups. Comparative transcriptomics revealed differentially expressed genes associated with extracellular matrix remodeling, prostaglandin metabolism, immune modulation, and interferon-related pathways, which bear functional relevance for MMVD. In particular, the top 10 over- and under-expressed genes represent promising candidates for influencing pathogenic changes in MMVD stage B1. Our research findings, which include identified variations in clinical markers and gene expression, enhance our understanding of MMVD. Furthermore, they underscore the need for further research into early diagnosis and treatment strategies, as, to the best of our knowledge, no prior studies have explored the precise molecular mechanisms of stage B1 in MMVD through total RNA sequencing., Competing Interests: The authors have declared no conflicts of interest in relation to the research, authorship or publication of this article, (Copyright: © 2024 Kim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Importance: Best recruitment practices for increasing diversity are well established, but the adoption and impact of these practices in ophthalmology residency recruitment are unknown., Objective: To describe the adoption of bias reduction practices in groups underrepresented in ophthalmology (URiO) residency recruitment and determine which practices are effective for increasing URiO residents., Design, Setting, and Participants: This cross-sectional survey study used an 18-item questionnaire included in the online survey of the Association of University Professors in Ophthalmology (AUPO) Residency Program Directors. Data collection occurred from July 2022 to December 2022. The data were initially analyzed on January 16, 2023. Participants included residency program directors (PDs) in the AUPO PD listserv database., Main Outcomes and Measures: Descriptive analysis of resident selection committee approaches, evaluation of applicant traits, and use of bias reduction tools. Primary outcome was diversity assessed by presence of at least 1 resident in the last 5 classes who identified as URiO, including those underrepresented in medicine (URiM), lesbian, gay, bisexual, transgender, queer, intersex, and asexual plus, or another disadvantaged background (eg, low socioeconomic status). Multivariate analyses of recruitment practices were conducted to determine which practices were associated with increased URiO and URiM., Results: Among 106 PDs, 65 completed the survey (61.3%). Thirty-nine PDs used an interview rubric (60.0%), 28 used interview standardization (43.0%), 56 provided at least 1 bias reduction tool to their selection committee (86.2%), and 44 used postinterview metrics to assess diversity, equity, and inclusion efforts (67.7%). Application filters, interview standardization, and postinterview metrics were not associated with increased URiO. Multivariate logistic regression analysis showed larger residency class (odds ratio [OR], 1.34; 95% CI, 1.09-1.65; P = .01) and use of multiple selection committee bias reduction tools (OR, 1.47; 95% CI, 1.13-1.92; P = .01) were positively associated with increased URiO, whereas use of interview rubrics (OR, 0.72; 95% CI, 0.59-0.87; P = .001) and placing higher importance of applicant interest in a program (OR, 0.83; 95% CI, 0.75-0.92; P = .02) were negatively associated. URiM analyses showed similar associations., Conclusions and Relevance: Ophthalmology residency interviews are variably standardized. In this study, providing multiple bias reduction tools to selection committees was associated with increased URiO and URiM residents. Prioritizing applicant interest in a program may reduce resident diversity. Interview rubrics, while intended to reduce bias, may inadvertently increase inequity.

Optical coherence tomography (OCT) and its extension OCT angiography (OCTA) have become essential clinical imaging modalities due to their ability to provide depth-resolved angiographic and tissue structural information non-invasively and at high resolution. Within a field of view, the anatomic detail available is sufficient to identify several structural and vascular pathologies that are clinically relevant for multiple prevalent blinding diseases, including age-related macular degeneration (AMD), diabetic retinopathy (DR), and vein occlusions. The main limitation in contemporary OCT devices is that this field of view is limited due to a fundamental trade-off between system resolution/sensitivity, sampling density, and imaging window dimensions. Here, we describe a swept-source OCT device that can capture up to a 12 × 23-mm field of view in a single shot and show that it can identify conventional pathologic features such as non-perfusion areas outside of conventional fields of view. We also show that our approach maintains sensitivity sufficient to visualize novel features, including choriocapillaris morphology beneath the macula and macrophage-like cells at the inner limiting membrane, both of which may have implications for disease.

Although three-dimensional (3D) printing techniques are used to mimic macro- and micro-structures as well as multi-structural human tissues in tissue engineering, efficient target tissue regeneration requires bioactive 3D printing scaffolds. In this study, we developed a bone morphogenetic protein-2 (BMP-2)-immobilized polycaprolactone (PCL) 3D printing scaffold with leaf-stacked structure (LSS) ( 3D-PLSS-BMP ) as a bioactive patient-tailored bone graft. The unique LSS was introduced on the strand surface of the scaffold via heating/cooling in tetraglycol without significant deterioration in physical properties. The BMP-2 adsorbed on 3D-PLSS-BMP was continuously released from LSS over a period of 32 d. The LSS can be a microtopographical cue for improved focal cell adhesion, proliferation, and osteogenic differentiation. In vitro cell culture and in vivo animal studies demonstrated the biological (bioactive BMP-2) and physical (microrough structure) mechanisms of 3D-PLSS-BMP for accelerated bone regeneration. Thus, bioactive molecule-immobilized 3D printing scaffold with LSS represents a promising physically and biologically activated bone graft as well as an advanced tool for widespread application in clinical and research fields., (© 2024 IOP Publishing Ltd.)

Purpose: Microaneurysms (MAs) have distinct, oval-shaped, hyperreflective walls on structural OCT, and inconsistent flow signal in the lumen with OCT angiography (OCTA). Their relationship to regional macular edema in diabetic retinopathy (DR) has not been quantitatively explored., Design: Retrospective, cross-sectional study., Participants: A total of 99 participants, including 23 with mild, nonproliferative DR (NPDR), 25 with moderate NPDR, 34 with severe NPDR, and 17 with proliferative DR., Methods: We obtained 3 × 3-mm scans with a commercial device (Solix, Visionix/Optovue) in 99 patients with DR. Trained graders manually identified MAs and their location relative to the anatomic layers from cross-sectional OCT. Microaneurysms were first classified as perfused if flow signal was present in the OCTA channel. Then, perfused MAs were further classified into fully and partially perfused MAs based on the flow characteristics in en face OCTA. The presence of retinal fluid based on OCT near MAs was compared between perfused and nonperfused types. We also compared OCT-based MA detection to fundus photography (FP)- and fluorescein angiography (FA)-based detection., Main Outcome Measures: OCT-identified MAs can be classified according to colocalized OCTA flow signal into fully perfused, partially perfused, and nonperfused types. Fully perfused MAs may be more likely to be associated with diabetic macular edema (DME) than those without flow., Results: We identified 308 MAs (166 fully perfused, 88 partially perfused, 54 nonperfused) in 42 eyes using OCT and OCTA. Nearly half of the MAs identified in this study straddle the inner nuclear layer and outer plexiform layer. Compared with partially perfused and nonperfused MAs, fully perfused MAs were more likely to be associated with local retinal fluid. The associated fluid volumes were larger with fully perfused MAs compared with other types. OCT/OCTA detected all MAs found on FP. Although not all MAs seen with FA were identified with OCT, some MAs seen with OCT were not visible with FA or FP., Conclusions: OCT-identified MAs with colocalized flow on OCTA are more likely to be associated with DME than those without flow., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Objective: Deep learning classifiers provide the most accurate means of automatically diagnosing diabetic retinopathy (DR) based on optical coherence tomography (OCT) and its angiography (OCTA). The power of these models is attributable in part to the inclusion of hidden layers that provide the complexity required to achieve a desired task. However, hidden layers also render algorithm outputs difficult to interpret. Here we introduce a novel biomarker activation map (BAM) framework based on generative adversarial learning that allows clinicians to verify and understand classifiers' decision-making., Methods: A data set including 456 macular scans were graded as non-referable or referable DR based on current clinical standards. A DR classifier that was used to evaluate our BAM was first trained based on this data set. The BAM generation framework was designed by combing two U-shaped generators to provide meaningful interpretability to this classifier. The main generator was trained to take referable scans as input and produce an output that would be classified by the classifier as non-referable. The BAM is then constructed as the difference image between the output and input of the main generator. To ensure that the BAM only highlights classifier-utilized biomarkers an assistant generator was trained to do the opposite, producing scans that would be classified as referable by the classifier from non-referable scans., Results: The generated BAMs highlighted known pathologic features including nonperfusion area and retinal fluid., Conclusion/significance: A fully interpretable classifier based on these highlights could help clinicians better utilize and verify automated DR diagnosis.

Purpose: Patients with rectal cancer without distant metastases are typically treated with radical surgery. Post curative resection, several factors can affect tumor recurrence. This study aimed to analyze factors related to rectal cancer recurrence after curative resection using different machine learning techniques., Methods: Consecutive patients who underwent curative surgery for rectal cancer between 2004 and 2018 at Gil Medical Center were included. Patients with stage IV disease, colon cancer, anal cancer, other recurrent cancer, emergency surgery, or hereditary malignancies were excluded from the study. The Synthetic Minority Oversampling Technique with Tomek link (SMOTETomek) technique was used to compensate for data imbalance between recurrent and no-recurrent groups. Four machine learning methods, logistic regression (LR), support vector machine (SVM), random forest (RF), and Extreme gradient boosting (XGBoost), were used to identify significant factors. To overfit and improve the model performance, feature importance was calculated using the permutation importance technique., Results: A total of 3320 patients were included in the study. After exclusion, the total sample size of the study was 961 patients. The median follow-up period was 60.8 months (range:1.2-192.4). The recurrence rate during follow-up was 13.2% (n = 127). After applying the SMOTETomek method, the number of patients in both groups, recurrent and non-recurrent group were equalized to 667 patients. After analyzing for 16 variables, the top eight ranked variables {pathologic Tumor stage (pT), sex, concurrent chemoradiotherapy, pathologic Node stage (pN), age, postoperative chemotherapy, pathologic Tumor-Node-Metastasis stage (pTNM), and perineural invasion} were selected based on the order of permutational importance. The highest area under the curve (AUC) was for the SVM method (0.831). The sensitivity, specificity, and accuracy were found to be 0.692, 0.814, and 0.798, respectively. The lowest AUC was obtained for the XGBoost method (0.804), with a sensitivity, specificity, and accuracy of 0.308, 0.928, and 0.845, respectively. The variable with highest importance was pT as assessed through SVM, RF, and XGBoost (0.06, 0.12, and 0.13, respectively), whereas pTNM had the highest importance when assessed by LR (0.05)., Conclusions: In the current study, SVM showed the best AUC, and the most influential factor across all machine learning methods except LR was found to be pT. The rectal cancer patients who have a high pT stage during postoperative follow-up are need to be more close surveillance., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Jeon et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Bone-subtraction computed tomography angiography (CTA) (BSCTA) is a new technique designed to overcome the limitation of three-dimensional CTA, where the vessels surrounded by bone and calcification can be obscured. An optimal contrast CT protocol for intracranial artery visualization with BSCTA has yet to be established in dogs., Objectives: The purpose of this study was to determine the optimal contrast protocol of CTA for visualizing intracranial artery using an automatic bone-subtraction technique in dogs., Methods: Brain CTA was performed four times for each of nine healthy beagle dogs to cover all the contrast protocols: two different contrast iodine concentrations (300 and 370 mgI/mL) and two different contrast media injection rates (2 and 4 mL/s). Bone removal post-processing was performed automatically by subtracting the non-enhanced CT data from the contrast CT data using a dedicated workstation. The bone-subtracted intracranial vessels were analysed for quantitative and qualitative evaluation., Results: Quantitative evaluation showed significantly higher CT attenuation values for the group with a 370 mgI/mL iodine content at a rate of 4 mL/s than the two groups with a 300 mgI/mL iodine content at the rates of 2 and 4 mL/s (p < 0.001). Qualitative assessment revealed significantly higher mean scores for the 370 mgI/mL groups than the 300 mgI/mL groups and significantly higher mean scores for the 4 mL/s groups than the 2 mL/s groups (p < 0.05)., Conclusions: The optimal contrast protocol for BSCTA suggests that high iodine material concentration and high injection rate should be used for strong arterial attenuation and great visualization of the intracranial arterial structure in dogs., (© 2023 The Authors. Veterinary Medicine and Science published by John Wiley & Sons Ltd.)

Objective: To determine the impact of documentation workflow on the accuracy of coded diagnoses in electronic health records (EHRs)., Design: Cross-sectional study., Participants: All patients who completed visits at the Casey Eye Institute Retina Division faculty clinic between April 7, 2022 and April 13, 2022., Main Outcome Measures: Agreement between coded diagnoses and clinical notes., Methods: We assessed the rate of agreement between the diagnoses in the clinical notes and the coded diagnosis in the EHR using manual review and examined the impact of the documentation workflow on the rate of agreement in an academic retina practice., Results: In 202 visits by 8 physicians, 78% (range, 22%-100%) had an agreement between the coded diagnoses and the clinical notes. When physicians integrated the diagnosis code entry and note composition, the rate of agreement was 87.9% (range, 62%-100%). For those who entered the diagnosis codes separately from writing notes, the agreement was 44.4% (22%-50%, P < 0.0001)., Conclusion: The visit-specific agreement between the coded diagnosis and the progress note can vary widely by workflow. The workflow and EHR design may be an important part of understanding and improving the quality of EHR data., Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (© 2023 by the American Academy of Ophthalmology.)

Background: Osteoporotic vertebral compression fractures commonly involve the superior vertebral body; however, their associated causes have not yet been clearly established. This study aimed to determine the trabecular structural differences between the superior and inferior regions of the vertebral body using cadaveric and clinical studies., Materials and Methods: First, five vertebrae were collected from three human cadavers. The trabecular structures of the superior and inferior regions of each vertebral body were analyzed using micro-computed tomography (micro-CT), finite element analysis (FEA), and biomechanical test. Based on the results of the ex vivo study, we conducted a clinical study. Second, spine CT images were retrospectively collected. Bone volume and Hounsfield unit were analyzed for 192 vertebral bodies. Finally, after sample size calculation based on the pilot study, prospectively, 200 participants underwent dual-energy X-ray absorptiometry (DXA) of the lateral spine. The bone mineral densities (BMDs) of the superior and inferior regions of each lumbar vertebral body were measured. The paired t-test and Wilcoxon signed-rank test were used for the statistical analyses, and p-value < 0.05 was considered significant., Results: Cadaver studies revealed differences between the superior and inferior trabecular bone structures. The bone volume ratio, BMD, and various other trabecular parameters advocated for decreased strength of the superior region. Throughout the biomechanical study, the limitations of the compression force were 3.44 and 4.63 N/m 2 for the superior and inferior regions, respectively. In the FEA study, the inferior region had a lower average displacement and higher von Mises stress than the superior region. In the clinical spine CT-based bone volume and BMD study, the bone volume was significantly higher in the inferior region than in the superior region. In the lateral spine DXA, the mean BMD of the superior region of vertebral bodies was significantly lower compared with that of the inferior region., Conclusion: The superior trabecular structure of the lumbar vertebral bodies possesses more biomechanical susceptibility compared with the inferior trabecular structure, confirming its dominant role in causing osteoporotic vertebral fractures. Physicians should also focus on the BMD values of the superior region of the vertebral body using lateral spine DXA to evaluate osteoporosis., Competing Interests: Authors H-JA and SL was employed by SL Bio, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Shin, Lee, An, Hwang, Cho, Oh, Ahn, Lee, Hong, Lee and Lee.)

Background: Bone subtraction computed tomography angiography (BSCTA) is a useful alternative technique for improving visualization of vessels surrounded by skull bone. However, no studies have compared computed tomography angiography (CTA) and BSCTA for improving the visibility of canine cerebral blood vessels., Objectives: To evaluate the potential benefit of BSCTA for better delineation of brain arteries of the circle of Willis (CoW) in dogs by comparing BSCTA with non-subtraction computed tomography angiography (NSCTA)., Methods: Brain CTA was performed for nine healthy beagle dogs using a bolus tracking method with saline flushing. A total dose of 600 mgI/kg of contrast agent with an iodine content of 370 mgI/mL was injected at a rate of 4 ml/s. Bone removal was achieved automatically by subtracting non-enhanced computed tomography (CT) data from contrast CT data. Five main intracranial arteries of the CoW were analyzed and graded on a scale of five for qualitative evaluation., Results: Scores of basilar artery, middle cerebral artery, and rostral cerebral artery in the BSCTA group were significantly higher than those in the NSCTA group ( p = 0.001, p = 0.020, and p < 0.0001, respectively). Scores of rostral cerebellar artery (RcA) and caudal cerebral artery (CCA) did not differ significantly between the two groups. However, scores of RcA and CCA in the BSCTA group were higher than those in the NSCTA group., Conclusions: BSCTA improved visualization of intracranial arteries of the CoW with close contact to bone. Thus, it should be recommended as a routine scan method in dogs suspected of having brain vessel disease., Competing Interests: The authors declare no conflicts of interest., (© 2023 The Korean Society of Veterinary Science.)

Purpose: To assess whether the combination of en face OCT and OCT angiography (OCTA) can capture observable, but subtle, structural changes that precede clinically evident retinal neovascularization (RNV) in eyes with diabetic retinopathy (DR)., Design: Retrospective, longitudinal study., Participants: Patients with DR that had at least 2 visits., Methods: We obtained wide-field OCTA scans of 1 eye from each participant and generated en face OCT, en face OCTA, and cross-sectional OCTA. We identified eyes with RNV sprouts, defined as epiretinal hyperreflective materials on en face OCT with flow signals breaching the internal limiting membrane on the cross-sectional OCTA without recognizable RNV on en face OCTA and RNV fronds, defined as recognizable abnormal vascular structures on the en face OCTA. We examined the corresponding location from follow-up or previous visits for the presence or progression of the RNV., Main Outcome Measures: The characteristics and longitudinal observation of early signs of RNV., Results: From 71 eyes, we identified RNV in 20 eyes with the combination of OCT and OCTA, of which 13 (65%) were photographically graded as proliferative DR, 6 (30%) severe nonproliferative DR, and 1 (5%) moderate nonproliferative diabetic retinopathy. From these eyes, we identified 38 RNV sprouts and 26 RNV fronds at the baseline. Thirty-four RNVs (53%) originated from veins, 24 (38%) were from intraretinal microabnormalities, and 6 (9%) were from a nondilated capillary bed. At the final visit, 53 RNV sprouts and 30 RNV fronds were detected. Ten eyes (50%) showed progression, defined as having a new RNV lesion or the development of an RNV frond from an RNV sprout. Four (11%) RNV sprouts developed into RNV fronds with a mean interval of 7.0 months. Nineteen new RNV sprouts developed during the follow-up, whereas no new RNV frond was observed outside an identified RNV sprout. The eyes with progression were of younger age ( P  = 0.014) and tended to be treatment naive ( P  = 0.07) compared with eyes without progression., Conclusions: Longitudinal observation demonstrated that a combination of en face OCT and cross-sectional OCTA can identify an earlier form of RNV before it can be recognized on en face OCTA., Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (© 2023 by the American Academy of Ophthalmology.)

Coronary artery disease (CAD) is a prevalent cardiovascular condition characterized by the accumulation of plaque within coronary arteries. While distinct features of CAD have been reported, the association between genetic factors and CAD in terms of biomarkers was insufficient. This study aimed to investigate the connection between genetic factors and CAD, focusing on the thymidylate synthase ( TS ) gene, a gene involved in DNA synthesis and one-carbon metabolism. TS plays a critical role in maintaining the deoxythymidine monophosphate (dTMP) pool, which is essential for DNA replication and repair. Therefore, our research targeted single nucleotide polymorphisms that could potentially impact TS gene expression and lead to dysfunction. Our findings strongly associate the TS 1100T>C and 1170A>G genotypes with CAD susceptibility. We observed that TS 1100T>C polymorphisms increased disease susceptibility in several groups, while the TS 1170A>G polymorphism displayed a decreasing trend for disease risk when interacting with clinical factors. Furthermore, our results demonstrate the potential contribution of the TS 1100/1170 haplotypes to disease susceptibility, indicating a synergistic interaction with clinical factors in disease occurrence. Based on these findings, we propose that polymorphisms in the TS gene had the possibility of clinically useful biomarkers for the prevention, prognosis, and management of CAD in the Korean population.

Purpose: To assess the value of en face OCT for detecting clinically unsuspected retinal neovascularization (RNV) in patients with nonproliferative diabetic retinopathy (NPDR)., Design: A retrospective, cross-sectional study., Participants: Treatment-naïve patients clinically graded as NPDR in an ongoing prospective observational OCT angiography (OCTA) study at a tertiary care center., Methods: Each patient underwent imaging of 1 eye with a spectral-domain OCTA, generating a 17 × 17-mm widefield image by montaging four 9 × 9-mm scans. Two independent graders examined a combination of en face OCT, en face OCTA with a custom vitreoretinal interface slab, and cross-sectional OCTA to determine the presence of RNV. We measured the area of RNV flow within RNV lesions on en face OCTA., Main Outcome Measures: Detection rate of clinically occult RNV with OCT and OCTA., Results: Of 63 enrolled eyes, 27 (43%) were clinically graded as severe NPDR, 16 (25%) as moderate NPDR, and 20 (32%) as mild NPDR. Using the combination of en face OCT, en face OCTA, and cross-sectional OCTA, the graders detected 42 RNV lesions in 12 (19%) eyes, of which 8 (67%) were graded as severe NPDR, 2 (17%) as moderate NPDR, and 2 (17%) as mild NPDR. The sensitivity of en face OCT alone for detecting eyes with RNV was similar to that of en face OCTA alone (100% vs. 92%; P = 0.32), whereas the specificity of en face OCT alone was significantly lower than that of en face OCTA alone (32% vs. 73%; P < 0.001). For detecting individual RNV lesions, the en face OCT was 100% sensitive, compared with 67% sensitivity for the en face OCTA (P < 0.001). The area of RNV lesions that manual grading with en face OCTA alone missed was significantly smaller than that of manually detectable RNV (Mean [standard deviation] RNV flow area, 0.015 [0.020] mm 2 vs. 0.16 [0.36] mm 2 ; P < 0.001)., Conclusion: The combination of en face OCT and OCTA can detect clinically occult RNV with high sensitivity. For screening these small lesions, en face OCT may be a useful imaging modality., Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Brain computed tomography (CT) perfusion is a technique that allows for the fast evaluation of cerebral hemodynamics. However, quantitative studies of brain CT perfusion in veterinary medicine are lacking. The purpose of this study was to investigate the normal range of perfusion determined via CT in brains of healthy dogs and to compare values between white matter and gray matter, differences in aging, and each hemisphere. Nine intact male beagle dogs were prospectively examined using dynamic CT scanning and post-processing for brain perfusion. Regional cerebral blood volume (rCBV), regional cerebral blood flow (rCBF), mean transit time, and time to peak were calculated. Tissue ROIs were drawn in the gray matter and white matter of the frontal, temporal, parietal, and occipital lobes; caudate nucleus; thalamus; piriform lobe; hippocampus; and cerebellum. Significant differences were observed between the white matter regions and gray matter regions for rCBV and rCBF ( p < 0.05). However, no significant differences were identified between hemispheres and between young and old groups in brain regions. The findings obtained in this study involving healthy beagle dogs might serve as a reference for regional CT perfusion values in specific brain regions. These results may aid in the characterization of various brain diseases in dogs.

Projection artifacts are a significant limitation of optical coherence tomographic angiography (OCTA). Existing techniques to suppress these artifacts are sensitive to image quality, becoming less reliable on low-quality images. In this study, we propose a novel signal attenuation-compensated projection-resolved OCTA (sacPR-OCTA) algorithm. In addition to removing projection artifacts, our method compensates for shadows beneath large vessels. The proposed sacPR-OCTA algorithm improves vascular continuity, reduces the similarity of vascular patterns in different plexuses, and removes more residual artifacts compared to existing methods. In addition, the sacPR-OCTA algorithm better preserves flow signal in choroidal neovascular lesions and shadow-affected areas. Because sacPR-OCTA processes the data along normalized A-lines, it provides a general solution for removing projection artifacts agnostic to the platform., Competing Interests: Jie Wang: Optovue/Visionix, Inc (P, R); David Huang: Optovue/Visionix, Inc. (F, P, R), Boeringer Ingelheim Inc. (C); Yali Jia: Optovue/Visionix, Inc. (P, R), Optos Inc. (P)., (© 2023 Optica Publishing Group under the terms of the Optica Open Access Publishing Agreement.)

Introduction: To assess the diagnostic accuracy of automatically quantified macular fluid volume (MFV) for treatment-required diabetic macular edema (DME). Methods : This retrospective cross-sectional study included eyes with DME. The commercial software on optical coherence tomography (OCT) produced the central subfield thickness (CST), and a custom deep-learning algorithm automatically segmented the fluid cysts and quantified the MFV from the volumetric scans of an OCT angiography system. Retina specialists treated patients per standard of care based on clinical and OCT findings without access to the MFV. The main outcome measures were the area under the receiver operating characteristic curve (AUROC), sensitivity, and specificity of the CST, MFV, and visual acuity (VA) for treatment indication. Results : Of 139 eyes, 39 (28%) were treated for DME during the study period and 101 (72%) were previously treated. The algorithm detected fluid in all eyes; however, only 54 eyes (39%) met the DRCR.net criteria for center-involved ME. The AUROC of MFV predicting a treatment decision of 0.81 was greater than that of CST (0.67) ( P  = .0048). Untreated eyes that met the optimal threshold for treatment-required DME based on MFV (>0.031 mm 3 ) had better VA than treated eyes ( P  = .0053). A multivariate logistic regression model showed that MFV ( P  = .0008) and VA ( P  = .0061) were significantly associated with a treatment decision, but CST was not. Conclusions : MFV had a higher correlation with the need for treatment for DME than CST and may be especially useful for ongoing management of DME., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Oregon Health & Science University (OHSU) and Drs. Jia and Huang have a significant financial interest in Optovue Inc, a company that may have a commercial interest in the results of this research and technology. These potential conflicts of interest have been reviewed and managed by OHSU. Dr. Tsuboi has a financial interest unrelated to the current manuscript from Alcon Japan Ltd, Abbott Medical Optics, Santen Co, Ltd, Novartis Pharma KK, and Bayer. No other disclosures were reported., (© The Author(s) 2023.)

Despite the minimized puncture sizes and high efficiency, microneedle (MN) patches have not been used to inject hemostatic drugs into bleeding wounds because they easily destroy capillaries when a tissue is pierced. In this study, a shelf-stable dissolving MN patch is developed to prevent rebleeding during an emergency treatment. A minimally and site-selectively invasive hemostatic drug delivery system is established by using a peripheral MN (p-MN) patch that does not directly intrude the wound site but enables topical drug absorption in the damaged capillaries. The invasiveness of MNs is histologically examined by using a bleeding liver of a Sprague-Dawley (SD) rat as an extreme wound model in vivo. The skin penetration force is quantified to demonstrate that the administration of the p-MN patch is milder than that of the conventional MN patch. Hemostatic performance is systematically studied by analyzing bleeding weight and time and comparing them with that of conventional hemostasis methods. The superior performance of a p-MN for the heparin-pretreated SD rat model is demonstrated by intravenous injection in vivo., (© 2023 Wiley-VCH GmbH.)

Synopsis: A deep-learning-based macular extrafoveal avascular area (EAA) on a 6×6 mm optical coherence tomography (OCT) angiogram is less dependent on the signal strength and shadow artefacts, providing better diagnostic accuracy for diabetic retinopathy (DR) severity than the commercial software measured extrafoveal vessel density (EVD)., Aims: To compare a deep-learning-based EAA to commercial output EVD in the diagnostic accuracy of determining DR severity levels from 6×6 mm OCT angiography (OCTA) scans., Methods: The 6×6 mm macular OCTA scans were acquired on one eye of each participant with a spectral-domain OCTA system. After excluding the central 1 mm diameter circle, the EAA on superficial vascular complex was measured with a deep-learning-based algorithm, and the EVD was obtained with commercial software., Results: The study included 34 healthy controls and 118 diabetic patients. EAA and EVD were highly correlated with DR severity (ρ=0.812 and -0.577, respectively, both p<0.001) and visual acuity (r=-0.357 and 0.420, respectively, both p<0.001). EAA had a significantly (p<0.001) higher correlation with DR severity than EVD. With the specificity at 95%, the sensitivities of EAA for differentiating diabetes mellitus (DM), DR and severe DR from control were 80.5%, 92.0% and 100.0%, respectively, significantly higher than those of EVD 11.9% (p=0.001), 13.6% (p<0.001) and 15.8% (p<0.001), respectively. EVD was significantly correlated with signal strength index (SSI) (r=0.607, p<0.001) and shadow area (r=-0.530, p<0.001), but EAA was not (r=-0.044, p=0.805 and r=-0.046, p=0.796, respectively). Adjustment of EVD with SSI and shadow area lowered sensitivities for detection of DM, DR and severe DR., Conclusion: Macular EAA on 6×6 mm OCTA measured with a deep learning-based algorithm is less dependent on the signal strength and shadow artefacts, and provides better diagnostic accuracy for DR severity than EVD measured with the instrument-embedded software., Competing Interests: Competing interests: YJ and STB (financial support) have a significant financial interest in Optovue Inc. These potential conflicts of interest have been reviewed and are managed by OHSU. The other authors do not have any potential financial conflicts of interest., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To evaluate intraretinal cystoid spaces in patients with idiopathic macular hole (MH)., Methods: Retrospective cohort study included consecutive patients with full-thickness MH who underwent successful MH surgery and 12 months of follow-up. Custom software was applied to preoperative optical coherence tomography scans to generate fluid volume. Inner fluid volume was defined as cystoid spaces in the inner nuclear layer, and outer fluid volume was defined as cystoid spaces in Henle fiber layer of the outer nuclear layer., Results: Thirty-nine eyes from 39 participants were included. Postoperative 12-month visual acuity correlated with both inner fluid volume and minimum MH size (both P < 0.05) but not outer fluid volume. Inner fluid volume positively correlated with minimum MH size ( P = 0.0003). After accounting for minimum MH size with multivariable analysis, inner fluid volume effect on VA remained significant ( P = 0.025). After dividing inner fluid volume into tertiles, mean baseline visual acuity was 20/50 in eyes with small inner fluid volume, and was 20/125 in eyes with large inner fluid volume ( P = 0.0039). Mean postoperative 12-month visual acuity was 20/20 in eyes with small inner fluid volume compared with 20/32 in eyes with large inner fluid volume ( P = 0.019)., Conclusion: Increased inner fluid volume was associated with worse postoperative VA., Competing Interests: Oregon Health & Science University (OHSU) and Drs. Jia, Huang, and Bailey have a significant financial interest in Optovue Inc, a company that may have a commercial interest in the results of this research and technology. These potential conflicts of interest have been reviewed and managed by the OHSU. Dr Tsuboi reported receiving personal fees from Bayer, Novartis Pharma, Santen, and Alcon Japan outside the submitted work. Dr. Kamei has a financial interest (to institution) in HOYA Surgical Optics, Abbott Medical Optics, Novartis Pharma KK, Pfizer Japan, Inc., HANDAYA Co., Ltd., TOMEY Co., Ltd., Kowa Co., Ltd, Santen Co., Ltd., Senju Co., Ltd., Otsuka Co., Ltd., and Alcon Japan Ltd. outside the submitted work. No other disclosures were reported.

Bacillus amyloliquefaciens is a gram-positive bacterial species that is utilised as a probiotic in humans and animals. There are no reports of infective endocarditis (IE) in dogs. An 8-year-old, spayed, female Maltese presented with a 1-month history of fever, depression, weight loss, and hindlimb lameness. Laboratory test results indicated non-regenerative anaemia, neutrophilia, hyperglobulinemia, and proteinuria. Echocardiography revealed vegetation on the septal leaflet of the mitral valve and thromboemboli in the left atrium. Consecutive blood culture results revealed that the blood samples were consistently positive for Bacillus amyloliquefaciens, which is generally considered a probiotic bacterial species for animals. Broad-spectrum antibiotics (amoxicillin-clavulanic acid and cefotaxime) and anticoagulants (clopidogrel and rivaroxaban) were administered for 4 months. The clinical signs were responsive to antibiotic treatment. After 4 months, the dog was no longer febrile and the size of the thromboemboli in the left atrium had decreased. Bacteria were no longer isolated in blood cultures after antibiotic therapy. To the best of our knowledge, this is the first case report of canine IE caused by bactaeremic infection with Bacillus amyloliquefaciens.

Purpose: Timely diagnosis of eye diseases is paramount to obtaining the best treatment outcomes. OCT and OCT angiography (OCTA) have several advantages that lend themselves to early detection of ocular pathology; furthermore, the techniques produce large, feature-rich data volumes. However, the full clinical potential of both OCT and OCTA is stymied when complex data acquired using the techniques must be manually processed. Here, we propose an automated diagnostic framework based on structural OCT and OCTA data volumes that could substantially support the clinical application of these technologies., Design: Cross sectional study., Participants: Five hundred twenty-six OCT and OCTA volumes were scanned from the eyes of 91 healthy participants, 161 patients with diabetic retinopathy (DR), 95 patients with age-related macular degeneration (AMD), and 108 patients with glaucoma., Methods: The diagnosis framework was constructed based on semisequential 3-dimensional (3D) convolutional neural networks. The trained framework classifies combined structural OCT and OCTA scans as normal, DR, AMD, or glaucoma. Fivefold cross-validation was performed, with 60% of the data reserved for training, 20% for validation, and 20% for testing. The training, validation, and test data sets were independent, with no shared patients. For scans diagnosed as DR, AMD, or glaucoma, 3D class activation maps were generated to highlight subregions that were considered important by the framework for automated diagnosis., Main Outcome Measures: The area under the curve (AUC) of the receiver operating characteristic curve and quadratic-weighted kappa were used to quantify the diagnostic performance of the framework., Results: For the diagnosis of DR, the framework achieved an AUC of 0.95 ± 0.01. For the diagnosis of AMD, the framework achieved an AUC of 0.98 ± 0.01. For the diagnosis of glaucoma, the framework achieved an AUC of 0.91 ± 0.02., Conclusions: Deep learning frameworks can provide reliable, sensitive, interpretable, and fully automated diagnosis of eye diseases., Financial Disclosures: Proprietary or commercial disclosure may be found after the references., (© 2022 Published by Elsevier Inc. on behalf of American Academy of Ophthalmology.)

Reference genes are crucial in molecular biological studies as an internal control for gene re-search as they exhibit consistent expression patterns across many tissue types. In canines, radiation therapy is the most important therapeutic tool to cure various diseases like cancer. However, when using radiation for therapeutic strategy, radiation exposure to healthy tissues leads to some possible side effects such as acute radiation-induced skin injury and alters gene expression. Therefore, the analysis of a change in reference gene expression during the skin recovery process after radiation therapy is essential in healthy canine tissue. In the present study, we analyzed eight reference genes ( ACTB, GAPDH, YWHAZ, GUSB, HPRT1, RPL4, RPS5, and TBP ) in canine dermal tissues at 0, 1, 2, 3, 4, 5, 7, and 9 weeks of radiation exposure that affected the skin condition of canines. The stability of reference genes is determined by evaluating radiation therapy's effect on healthy canine dermal tissue. Epidermal marker, Keratin 10 expression varies each week after irradiation, and HPRT1 is found to be the most suitable for normalization of mRNA expression in radiation-exposed canine dermal tissues. Changes in the gene expression level were evaluated by using a reliable tool such as quantitative real-time polymerase chain reaction (qRT-PCR). In order to achieve a valid qRT-PCR result, the most stable reference genes used for normalization after the radiation exposure process are important. Therefore, the current study was designed to evaluate the most stable reference gene for the post-irradiation canine tissues. After radiation exposure, the alternation of reference gene expression was estimated by three algorithms (geNorm, Normfinder, and Bestkeeper). The RG validation programs (GeNorm and NormFinder) suggested that HPRT1 , RPL4 , and TBP were suitable for normalization in qRT-PCR. Furthermore, three algorithms suggested that HPRT1 was the most stable reference gene for normalization with qRT-PCR results, regardless of before and after radiation exposure. Whereas GAPDH was found to be the most unstable reference gene. In addition, the use of stable or unstable reference genes for the normalization of Keratin 10 expression showed statistical differences. Therefore, we observed that, to obtain accurate and suitable PCR results of the canine tissues with and without radiation exposure, the HPRT1 reference gene is recommended for normalization with its high stability. Additionally, the use of RGs such as HPRT1, RPL4 , and TBP for normalization in qRT-PCR experiments is recommended for post-radiation canine tissues to generate more accurate and reliable data. These results will provide fundamental information regarding internal controls for gene expression studies and can be used for the analysis of gene patterns in regenerative medicine.

Reactive oxygen species are a fatal challenge to the plant pathogenic bacterium Pseudomonas syringae. In this study, we reveal that the global regulatory protein RsmA3 from the RetS-Gac/Rsm signalling pathway modulates RpoS in the early-log growth phase in the P. syringae wild-type strain MB03, thereby regulating oxidative tolerance to H 2 O 2 and ultimately affecting pathogenicity to the host plant. Following increased H 2 O 2 by external addition or endogenous induction by menadione, the resistance of the mutant strain ΔretS to H 2 O 2 is significantly enhanced due to rapid increases in the transcription of Rsm-related non-coding small RNAs (nc sRNAs), a sigma factor RpoS, and H 2 O 2 -detoxifying enzymes. Moreover, the ΔretS mutant is significantly less pathogenic in cucumber leaves. Seven Rsm-related nc sRNAs (namely, rsmZ, rsmY and rsmX 1-5 ) show functional redundancy in the RetS-Gac-Rsm signalling pathway. External addition of H 2 O 2 stimulates increases in the transcription of both rsmY and rsmZ. Thus, we propose a regulatory model of the RetS-Gac-Rsm signalling pathway in P. syringae MB03 for the regulation of H 2 O 2 tolerance and phytopathogenicity in the host plant., (© 2022 Society for Applied Microbiology and John Wiley & Sons Ltd.)

Optical coherence tomography (OCT) is widely used in ophthalmic practice because it can visualize retinal structure and vasculature in vivo and 3-dimensionally (3D). Even though OCT procedures yield data volumes, clinicians typically interpret the 3D images using two-dimensional (2D) data subsets, such as cross-sectional scans or en face projections. Since a single OCT volume can contain hundreds of cross-sections (each of which must be processed with retinal layer segmentation to produce en face images), a thorough manual analysis of the complete OCT volume can be prohibitively time-consuming. Furthermore, 2D reductions of the full OCT volume may obscure relationships between disease progression and the (volumetric) location of pathology within the retina and can be prone to mis-segmentation artifacts. In this work, we propose a novel framework that can detect several retinal pathologies in three dimensions using structural and angiographic OCT. Our framework operates by detecting deviations in reflectance, angiography, and simulated perfusion from a percent depth normalized standard retina created by merging and averaging scans from healthy subjects. We show that these deviations from the standard retina can highlight multiple key features, while the depth normalization obviates the need to segment several retinal layers. We also construct a composite pathology index that measures average deviation from the standard retina in several categories (hypo- and hyper-reflectance, nonperfusion, presence of choroidal neovascularization, and thickness change) and show that this index correlates with DR severity. Requiring minimal retinal layer segmentation and being fully automated, this 3D framework has a strong potential to be integrated into commercial OCT systems and to benefit ophthalmology research and clinical care., Competing Interests: Oregon Health & Science University (OHSU), Dr. David Huang and Dr. Yali Jia have a significant financial interest in Optovue, Inc. These potential conflicts of interest have been reviewed and managed by OHSU. Other authors do not have financial interest to the disclosure of this article., (© 2022 Optica Publishing Group under the terms of the Optica Open Access Publishing Agreement.)

Purpose: T stage plays an important role in the classification of subgroups in stage II colon cancer. Patients with pathologic T4 are at high risk of recurrence and it is recommended to include adjuvant chemotherapy in the treatment plan, while this is not necessary in pathologic T3. There is a discrepancy between the surgical T stage (sT), as determined by the surgeon in the operative field, and pathologic T stage (pT). The pathologic stage is considered a standard prognostic factor, but it has not been established whether the surgical stage has an oncologic impact. The aim of this study was to compare oncologic outcomes between sT4 and sT3 in pathologic stage IIA right colon cancer., Methods: Between January 2005 and December 2018, there were 354 patients who underwent right hemicolectomy performed by a single surgeon (JHB) at a tertiary hospital. The data from these patients were retrospectively collected and analyzed. Only those patients with pathologic stage IIA (pT3N0M0) right colon adenocarcinomas were included in this study. Patients with mucinous carcinoma, signet ring cell carcinoma, squamous cell carcinoma, or hereditary colon cancer, and who had emergent surgery were excluded. Finally, 86 patients were included in this study. The patients were categorized, according to their surgical records, into either the sT4 group (n=28) or the sT3 group (n=58)., Results: There were no statistical differences between the two groups in terms of age, sex, body mass index, comorbidities, cancer location, histologic grade, lymphovascular invasion, perineural invasion, number of harvested lymph nodes, and adjuvant chemotherapy. The 5-year overall survival rate was significantly different between the sT4 and sT3 groups (92.6% vs. 97.7%, p=0.024). In addition, the 5-year disease-free survival rate was significantly different between the sT4 and sT3 groups (88.6% vs. 97.7%, p=0.017). In the multivariate Cox regression analysis, a classification of sT4 was a significant independent predictive factor for recurrence ( p = 0.023)., Conclusions: Long-term oncologic outcomes have shown significant differences between surgical T4 and T3 in pathologic stage IIA right colon cancer patients. Further large-scale, multicenter studies are required to verify the clinical impact of the surgical staging., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jeon, Nam, Choi, Hwang and Baek.)

Purpose: Reliable classification of referable and vision threatening diabetic retinopathy (DR) is essential for patients with diabetes to prevent blindness. Optical coherence tomography (OCT) and its angiography (OCTA) have several advantages over fundus photographs. We evaluated a deep-learning-aided DR classification framework using volumetric OCT and OCTA., Methods: Four hundred fifty-six OCT and OCTA volumes were scanned from eyes of 50 healthy participants and 305 patients with diabetes. Retina specialists labeled the eyes as non-referable (nrDR), referable (rDR), or vision threatening DR (vtDR). Each eye underwent a 3 × 3-mm scan using a commercial 70 kHz spectral-domain OCT system. We developed a DR classification framework and trained it using volumetric OCT and OCTA to classify eyes into rDR and vtDR. For the scans identified as rDR or vtDR, 3D class activation maps were generated to highlight the subregions which were considered important by the framework for DR classification., Results: For rDR classification, the framework achieved a 0.96 ± 0.01 area under the receiver operating characteristic curve (AUC) and 0.83 ± 0.04 quadratic-weighted kappa. For vtDR classification, the framework achieved a 0.92 ± 0.02 AUC and 0.73 ± 0.04 quadratic-weighted kappa. In addition, the multiple DR classification (non-rDR, rDR but non-vtDR, or vtDR) achieved a 0.83 ± 0.03 quadratic-weighted kappa., Conclusions: A deep learning framework only based on OCT and OCTA can provide specialist-level DR classification using only a single imaging modality., Translational Relevance: The proposed framework can be used to develop clinically valuable automated DR diagnosis system because of the specialist-level performance showed in this study.

Mn(II)-oxidizing microorganisms are generally considered the primary driving forces in the biological formation of Mn oxides. However, the mechanistic elucidation of the actuation and regulation of Mn oxidation in soilborne bacteria remains elusive. Here, we performed joint multiple gene-knockout analyses and comparative morphological and physiological determinations to characterize the influence of carbon metabolism on the Mn oxide deposit amount (MnODA) and the Mn oxide formation of a soilborne bacterium, Escherichia coli MB266. Different carbon source substances exhibited significantly varied effects on the MnODA of MB266. A total of 16 carbon metabolism-related genes with significant variant expression levels under Mn supplementation conditions were knocked out in the MB266 genome accordingly, but only little effect on the MnODA of each mutant strain was accounted for. However, a simultaneous four-gene-knockout mutant (namely, MB801) showed an overall remarkable MnODA reduction and an initially delayed Mn oxide formation compared with the wild-type MB266. The assays using scanning/transmission electron microscopy verified that MB801 exhibited not only a delayed Mn-oxide aggregate processing, but also relatively smaller microspherical agglomerations, and presented flocculent deposit Mn oxides compared with normal fibrous and crystalline Mn oxides formed by MB266. Moreover, the Mn oxide aggregate formation was highly related to the intracellular ROS level. Thus, this study demonstrates that carbon metabolism acts as a pronounced modulator of MnODA in MB266, which will provide new insights into the occurrence of Mn oxidation and Mn oxide formation by soilborne bacteria in habitats where Mn(II) naturally occurs.