Positron emission tomography (PET), typically combined with computed tomography (CT), has become a critical advanced imaging technique in oncology. With PET-CT, a radioactive molecule (radiotracer) is injected into the bloodstream and localizes to tumor sites because of specific cellular features of the tumor that accumulate the targeting radiotracer. The CT scan is performed at the same time, facilitating better visualization of radioactivity from deep or dense structures and providing detailed anatomic information. PET-CT has a variety of applications in oncology, including staging, therapeutic response assessment, restaging and surveillance. This series of six articles provides an overview of the value, applications, imaging and interpretive strategies of PET-CT in the more common adult malignancies. In the current and sixth report in this series, the application of PET-CT is reviewed for more aggressive skin cancers, sarcomas and neuroendocrine tumors.PET-CT is an advanced imaging modality with many oncologic applications, including staging, therapeutic assessment, restaging and surveillance for recurrence. The goal of this series of six review articles is to provide practical information to providers and imaging professionals regarding the best use of PET-CT for specific oncologic indications, the potential pitfalls and nuances that characterize these applications, and guidelines for image interpretation. Tumor-specific clinical information and representative PET-CT images are provided. The current, sixth article in this series addresses PET-CT in an evaluation of aggressive cutaneous malignancies, sarcomas and neuroendocrine tumors. A discussion of the role of FDG PET for all types of tumors in these categories is beyond the scope of this review. Rather, this article focuses on the most common malignancies in adult patients encountered in clinical practice. It also focuses on Food and Drug Agency (FDA)-approved and clinically available radiopharmaceuticals rather than research tracers or those requiring a local cyclotron. This information will serve as a guide to primary providers for the appropriate role of PET-CT in managing patients with cutaneous malignancies, sarcomas and neuroendocrine tumors. The nuances of PET-CT interpretation as a practical guide for imaging providers, including radiologists, nuclear medicine physicians and their trainees, are also addressed. The report also discusses the use of FDG PET-CT in some of the most common sarcomas encountered in clinical practice in adult patients. Finally, the article addresses PET-CT imaging in neuroendocrine tumors and includes both FDG PET-CT and somatostatin receptor (SSTR)-binding octreotide analogs, including NETSPOT®  and Detectnet® . These radiopharmaceuticals, combined with widespread availability, technological improvements in instrumentation, such as digital PET-CT, and acquired global experience, have placed PET-CT at the forefront of oncologic imaging for these tumors.This series of six review articles addresses the role of combined positron emission tomography–computed tomography (PET-CT) in adult clinical oncology. The sixth article in this series focuses on Ga-DOTA-TATE, have been reported to be effective in imaging Merkel cell carcinoma, with performances similar to that of FDG PET F-NaF PET-CT is extremely sensitive for areas of bone involvement in sarcomas. It has been proposed that a dual-tracer approach (simultaneous injection) of NaF and FDG PET may provide advantages when defining both soft tissue and bone sites of sarcoma involvement . Tr. Tr66]. Leiomyosarcomas arise from smooth muscle and are non-gastrointestinal mesenchymal stromal tumors. These tumors account for 7% of soft tissue sarcomas, with an average survival of 5 years . Non-uteSarcomas arise from vascular elements. Angiosarcomas include primary angiosarcomas of the aorta, great vessels and heart and are typically aggressive. Epithelioid and lymphangiosarcomas are slower-growing and less aggressive vascular sarcomas. In addition to the heart and large vessels, angiosarcomas can arise in many other organs, including the skin, lungs, bones, breasts, liver and spleen . AggressKaposi sarcoma (KS) is an angio-proliferative spindle cell tumor derived from immune and endothelial cells infected with human herpes virus type 8 (HHV-8). It occurs in conjunction with human immunodeficiency virus (HIV) infection and in immune-compromised patients. Sporadic  cases also occur which are more indolent and typically confined to the skin. The disease is endemic in parts of Africa. The treatment for acquired immunodeficiency syndrome (AIDS)-related KS, which can be aggressive and widespread, is highly active antiretroviral therapy (HAART), sometimes in combination with chemotherapy. There is evidence that FDG PET-CT can be used to monitor the effectiveness of treatment and human herpes virus (HHV)-8 viral load ,79. In aRhabdomyosarcoma arises from primitive mesenchymal tissue capable of differentiating into skeletal muscle. It is the most common soft tissue sarcoma. Ninety percent of cases occur in children and young adults. In older patients, rhabdomyosarcomas tend to be more aggressive. Treatment usually involves initial surgery and radiation, depending upon the extent of disease and the site of involvement. Chemotherapy may be utilized as well in high-risk patients. Metastatectomy or percutaneous ablative techniques may be performed for isolated pulmonary metastases. Sinonasal rhabdomyosarcoma is most common in children. Sinonasal plasmacytoid rhabdomyosarcoma in adults is in the category of small blue cell tumors and, although rare, can masquerade as other sinonasal tumors  81]. Rh. Rh81]. Liposarcoma is the most common soft tissue sarcoma in adults. Most cases arise de novo, although a small number may arise from preexisting lipomas. Liposarcoma exists as a well-differentiated subtype (occurring in soft tissues of both the limbs or retroperitoneum), a myxoid and/or round cell subtype (occurring predominantly in the limbs), and a pleomorphic, dedifferentiated subtype (primarily in the retroperitoneum). The latter is aggressive, with a poorer prognosis. Hibernomas, which are benign lipomas with brown fat characteristics, are often FDG-avid and found incidentally, but a distinction between these and low-grade liposarcomas cannot be made by FDG PET-CT . In geneSynovial sarcomas are rare soft tissue tumors. Advanced-stage synovial cell sarcomas have a poor prognosis, but lower-stage disease has a 70% 5-year survival. Over 90% of cases are associated with a fusion of the SYT/SSX genes t. Synovial cell sarcomas occur as spindle cell fibrous and glandular/epithelial forms. Synovial cell sarcomas tend to occur around the large joints, such as the knees, but also in other areas, including the hands, feet, neck, pericardium and pleura . TreatmeBenign nerve sheath tumors, including neurofibromas and schwannomas, can occur sporadically. Neurofibromatosis type-1 (NF1), which is caused by a deletion on chromosome 17q, is associated with multiple neurofibromas. Schwannomatosis is seen in NF2. Schwannomas are benign, as are most neurofibromas. Gangioneuromas arise from the sympathetic chain and are typically benign . HoweverThe most common bone sarcomas are chondrosarcoma, osteosarcoma and Ewing sarcoma. All can metastasize to bone and to soft tissues. Chondrosarcoma is an inclusive term for a variety of cartilage-containing tumors. They can be broadly classified as low- (grade I), intermediate- (grade II), or high-grade (grade III) or dedifferentiated (grade IV) tumors. Chondrosarcomas can arise de novo or by malignant degeneration of enchondromas or cartilage-capped exostoses. Malignant degeneration is often heralded by pain in the region. MRI may be utilized for evaluation. Intermediate and higher grade enchondromas are also painful and present as a large, expansile mass, sometimes with an accompanying soft tissue component. Myxoid chondrosarcomas arise from soft tissues rather than bone . Biopsy Enchondromas may have no activity or may be mildly metabolically active on FDG PET-CT, making distinction between these and low-grade chondrosarcomas difficult . The NCCOsteosarcoma is a potentially deadly form of bone cancer that typically arises in the distal femur, proximal tibia and proximal humerus of adolescents, and less commonly in the skull, jaw and pelvis. There are multiple variants of osteosarcoma, including conventional types and telangiectatic, multifocal, parosteal and periosteal subtypes. Most cases of osteosarcoma are without a known cause, although patients with certain conditions are at higher risk, including bone dysplasias such as Paget’s disease, fibrous dysplasia, enchondromatoses, multiple hereditary exostoses and the germ-line form of retinoblastoma. Five-year survival depends upon age—younger age being more favorable—with a value of 61.1% for age <25 years and a severe decline in disease-specific survival for elderly patients . DiagnosGuidelines for treatment of osteosarcoma are published by the NCCN and the European Society of Medical Oncology (ESMO) ,100. TreThe primary bone tumor, Ewing sarcoma, its soft tissue counterparts, peripheral primitive neuroendocrine tumor (PNET), and malignant small cell tumors of the thoracopulmonary region (Askin tumor) represent a related group of tumors (Ewing sarcoma family) with similar immunohistochemistry, genetic features and cellular origin. The bone tumors arise spontaneously with pain and swelling, typically involving the flat bones and the diaphyseal region of larger long bones. The age of occurrence of most tumors is the late teens and 20s. Most patients present with localized disease, which carries an overall survival rate of 60%. Patients with metastatic disease have an overall survival of <25%. Due to a high relapse rate with local treatment, such as surgery and radiation, systemic chemotherapy is typically utilized. Treatment guidelines have been published by NCCN and ESMO and are frequently revised with new medical evidence to support the revisions ,100. TheNeuroendocrine neoplasms or tumors (NETs) are a group of heterogeneous tumors that arise from the disseminated endocrine cell system, primarily from gastroenteropancreatic (GEP) organs. These tumors often produce and secrete biologically active peptides and amines which can induce clinical syndromes. Alternatively, they can be functionally inactive. The incidence and prevalence of NETs is rising in the United States. Based upon the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program data, the age-adjusted incidence rate has increased 6.4-fold from 1973  to 2012  and the age-adjusted incidence of NETs was 1.09 per 100,000 persons in 1973 and had increased to 6.98 per 100,000 persons by 2012. The precise etiology for this rise is not entirely clear but may in part be due to the increased diagnosis of early-stage disease and stage migration . Surviva1[77Lu]Lu-DOTA-TATE PRRT). For decades, SSTR imaging was performed with [111In]In-pentetreotide  [68Ga]Ga-DOTA-TATE , and [64Cu]Cu-DOTA-TATE  Cu-DOTA-TATE is a new somatostatin receptor-based radiotracer that was approved by the FDA on 8 September 2020 for the localization of somatostatin receptor-positive neuroendocrine tumors (NETs) in adult patients [64Cu]Cu-DOTA-TATE attractive for widespread clinical adoption as it can be produced centrally and shipped to sites throughout the US. In a prospective study by Johnbeck et al., where [64Cu]Cu-DOTA-TATE and [68Ga]Ga-DOTA-TOC PET/CT were compared on a head-to-head basis, [64Cu]Cu-DOTA-TATE demonstrated the same per patient sensitivity as [68Ga]Ga-DOTA-TOC in detecting NETs, but significantly more lesions were detected with [64Cu]Cu-DOTA-TATE [64Cu]Cu-DOTA-TATE compared to [68Ga]Ga-DOTA-TATE and a scanning window of at least 3 h for [64Cu]Cu-DOTA-TATE has led to its increased adoption in multiple institutions. Beyond the physical differences that contribute to the detectability of lesions, the biodistributions of both DOTA-TATE constructs are essentially the same. We shall refer to PET-CT scans performed with these collective constructs as SSTR PET-CT scans.. T. T115]. Gastroenteropancreatic (GEP) neuroendocrine tumors or GEP NETs are NETs arising from the gastrointestinal tract and pancreas. GEP NETs are a heterogeneous group of malignancies with many different subtypes ranging from indolent, well-differentiated NETs to aggressive, poorly differentiated neuroendocrine carcinomas (NECs). All GEP NETs can metastasize, and even indolent tumors can lead to significant morbidity due to the secretion of bioactive hormones . NETs arMultiple studies have demonstrated improved diagnostic capabilities of SSTR PET-CT compared to conventional imaging, including contrast-enhanced CT, in the diagnosis of GEP NETs . For exa®). Typically, activity in the tumor that is greater than that in the liver is recommended in selection of patients who may best benefit by PRRT. SSTR PET-CT is excellent for well-differentiated NET imaging, with typically shows intense activity. Well-differentiated NETs characteristically are low in metabolic activity on FDG PET-CT (177Lu DOTATATE (Lutathera®). Poorly differentiated NETs are typically low in activity on SSTR-PET and are better imaged with FDG PET-CT  are less common than GEP NETs, accounting for approximately 1–2% of all lung malignancies and 20–25% of NETs ,129. PulKayani et al. reviewed the imaging findings of 18 consecutive patients with pulmonary NETs  who underwent SSTR as well as FDG PET-CT scans . They fo® imaging [131/123I]I–(3 Iodobenzyl)-guanidine (MIBG) was more commonly used for pheochromocytomas. Now, SSTR PET-CT imaging is becoming the functional imaging modality of choice at many centers for both paragangliomas and larger adrenal pheochromocytomas.Neuroectodermal tumors, including pheochromocytomas and paragangliomas (PPGLs), have demonstrated high uptake on SSTR imaging for decades, initially based upon early experience with Octreoscan imaging . [131/12131I-MIBG imaging . While [123I]I-MIBG, which has replaced [131I]I-MIBG, is still used, this study supported the improved diagnostic accuracy and image quality of SSTR PET-CT compared to MIBG SPECT-CT imaging  PET, FDG PET-CT and 123/131I-MIBG scintigraphy. These findings support the utilization of SSTR PET/CT imaging as a first-line imaging modality for the primary staging or restaging of PPGLs with unknown genetic status [Clinical PRRT therapeutic trials targeting SSTR are in development for metastatic PPGLs, which will require confirmation of SSTR expression by SSTR PET-CT. A recent meta-analysis by Han et al. assessed the performance of SSTR PET in the detection of PPGLs in thirteen studies for qualitative synthesis. The team found that, with the exception of polycythemia/paraganglioma syndrome, where the detection rate of SSTR PET-CT was only 35%, in other PPGLs, per-lesion detection rates of SSTR PET were consistently higher (92–100%) than other imaging modalities, including 18F-fluorohydroxyphenylalanine  . A discuIn addition to FDG, a number of other radiopharmaceuticals play either a current or potential role in the staging, therapeutic assessment and surveillance of neuroendocrine tumors. The imaging signatures of neoplasms, sometimes derived from a multi-tracer approach, have potential for characterizing tumors from a biological perspective and in the selection of patients for appropriate therapies. Many other types of tumors display variable degrees of neuroendocrine features. It is anticipated that, with time and additional data, the role of traditionally neuroendocrine-specific imaging tracers may be expanded to include a greater diversity of tumors and possibly targeted therapies based on imaging signatures.


Globally, with the COVID-19 pandemic, dental services were limited to emergency/ urgent conditions and were provided only after tele-triage referral for face-to-face management. However, no previous research explored whether the pain severity (PS) drives the tele-triage decisions. The current study examined the association between PS and tele-triage decision of whether to manage the condition remotely or refer the caller for face-to-face management.This retrospective cross-sectional study analyzed the PS reported by hotline callers, using numerical rating scale (NRS-11), during the first wave of COVID-19 lockdown (23 March–31 August 2020) and its association with tele-triage decision controlling for age, sex, history of chronic illness, and dental discipline needed. Binomial logistic regression assessed the association between the PS (exposure) and tele-triage decision (outcome). ANOVA compared PS across tele-triage categories, dental history and tentative diagnosis.p < 0.05). An increase in pain score by 1 unit was associated with 1.4 times increased odds of face-face referral (95% CI: 1.26–1.54). Pediatric/ adolescent patients (9–18 years) (odds ratio (OR) = 2.07; 95% CI: 1.07–4.02), history of chronic illness , need for surgical specialty  and orthodontic specialty  were independently associated with tele-triage decision. PS was highest for the emergency triage category , dental history of tooth with cavity or filling , and the tentative tele-diagnosis of cellulitis .PS was significantly associated with tele-triage decisions (During COVID-19 pandemic, tele-triage decisions were significantly influenced by patient-reported PS, adjusting for a range of variables. Despite this, referral for face-to-face management was individualized and driven by the tripartite considerations of the reported pain, clinical judgement, and the high transmission characteristics of COVID-19.The online version contains supplementary material available at 10.1186/s12903-022-02340-w. As COVID-19 affected the world, it was soon classified as a pandemic by the World Health Organization . This afAs part of the COVID-19 measures, the American Dental Association (ADA) published guidelines with definitions for different categories of dental conditions . Dental Pre-pandemic literature suggested that patients seek emergency appointments in dental practices, and to a certain extent in general medical practices and emergency departments because of ease of access, anxiety from dental intervention, or the notion that a course of antibiotics will treat the condition . COVID-1While TD offers acceptable reliability for the tentative diagnosis , the litTherefore, the current study assessed whether the severity of reported pain  affected the tele-triage decisions (binary outcome of whether the patient was managed remotely or referred for face-to-face management). PS was appraised across its associated tele-triage categories, dental history, and tentative tele-diagnosis to analyse their associations with tele-triage decisions. The emerging findings provide important information to a non-existent evidence base on the management of orofacial/dental pain during pandemics. The findings will provide practitioners and policy makers with information necessary to better manage reported orofacial/dental pain-related emergencies during situations like those experienced during the COVID-19 pandemic, or where resources are significantly limited for managing such emergencies.The institutional research board (IRB) at Hamad Medical Corporation (HMC) granted permission for this service evaluation project to proceed. This is a retrospective analysis of information routinely collected for clinical audit and service evaluation. We analyzed patient and triage data of all hotline calls during the first wave of COVID-19 lockdown . We excluded callers with incomplete records where outcomes were not reported (n = 389), as well as children ≤ 8 years old (n = 125) as the numeric pain scale is not applicable to patients of this age , 31. We We analyzed PS and its association with patient's age, sex, history of chronic illness, and dental discipline required. We also assessed the association between the PS and likelihood of the tele-triage decision of referral for face-to-face management, controlling for the same variables. Data were extracted from the electronic health records and the TD data collection form. The form was completed by each tele-dentist for every caller  and assist the team in the management of self-reported pain, swelling, bleeding, trauma, and oral-mucosal ulceration Fig. .Fig. 1ReThese guidelines were not binding but rather indicative, leaving some freedom of interpretation by the tele-dentists, who were trained to ensure consistency of the service in arriving at triage and management decisions while observing caller privacy. The recommended policy and guidelines, based on American Dental Association (ADA) , GeneralIn addition, as part of the service, dentists administered a TD data collection form  is a pain assessment tool that is simple and easy to score , consistTele-dentists categorized the condition into emergency, urgent or non-urgent and managed the condition accordingly. AAA strategy was utilized as appropriate, and medications were home delivered to patients using courier service. Callers who were referred to a hospital emergency department or dental facility to receive face-to-face interventions were tele-triaged for COVID-19 symptoms and directed accordingly to either HDC or COVID-19 dedicated facilities. The focus of the current study is the association between pain severity and the triage decision of whether the patient was managed remotely or referred for face-to-face management.Descriptive and inferential statistics characterized the sample. Categorical variables are reported as frequencies and percentages. Differences in tele-triage decisions were compared using Fisher’s Exact test (Monte Carlo test with 99% CI) due to relatively small sample size. Continuous variables are reported as mean ± standard deviation, and PS was compared using t test when comparisons were between two groups or Analysis of variance (ANOVA) when > 2 groups. Binomial logistic regression assessed the association between the PS (exposure) as a continuous variable and likelihood of being referred for face-to-face management, adjusted for age, sex, history of chronic illness, and dental discipline needed.In addition, sensitivity analysis was undertaken by including callers with pain score = 0 and comparing the emerging findings to those of the main analysis  in order to explore the direction of any potential bias.P < 0.05 (two-tailed) was considered statistically significant.Dental discipline needed was included as a potential confounder in the regression analysis because some dental disciplines  are known to be associated with procedures that generate considerable aerosols with a higher risk of transmission of the COVID-19 virus, , hence dTable The mean PS for the whole sample was moderate/ high (6.05 ± 2.28), with adults reporting significantly more severe pain than other age groups. Callers who needed restorative and surgical specialties reported moderate/ high PS, while those who needed orthodontic procedures had significantly less PS. PS did not differ by caller sex or history of chronic illness.Table Section B of the Table We repeated the regression with and without adjusting for dental discipline. Not adjusting for discipline increased the significance and effect size of the child/ adolescent age group , concurring with the range of 22.5–46% pulpitis rates reported by other studies as the origin of orofacial/ dental pain during the pandemic , 19, 20.Hight levels of PS were observed with conditions that could precede a serious medical emergency or are caused by odontogenic infections. Our management decisions considered the risk of systemic life-threatening complications in tandem with PS, as recommended by the ADA . For insFor callers with low PS, the individualized approach after careful weighting of the reported pain and clinical picture was also evident. For instance, those with history of orthodontic appliance problems experienced the least pain, but the majority were referred. The majority of orthodontic patients typically fell in the pediatric/ adolescent group (9–18 years), and this could explain the 2.1 times increased odds of face-to-face referral for patients of this age group. Orthodontic appliance related problems may not be life threatening or severely painful; nevertheless, they challenge daily activities , quality of life, and could lead to significant consequences if left unattended.At the height of a rapidly changing pandemic, HDC management decisions provide positive lessons for future 'normal' times after the pandemic. On the one hand, during the pandemic, severe orofacial/ dental pain was the driver of urgent care . On the The current study has limitations. HDC is a tertiary dental services provider, and patients in the current study probably had previous dental experiences or persisting symptoms. Such patients are different than those who present at primary dental care centers experiencing their first dental pain encounter. The current cross sectional design does not allow any inferences of causal relationships between pain severity and triage decision decisions, rather only associations and should be interpreted as such. We encountered 40% missing data regarding the outcome during the early phase of the study when the dentists were home-working during the lockdown. This influenced the effective sample size used in the analysis. Others have similarly reported that the 'helpline was developed and implemented while many people were working from home during shelter-in-place restrictions, making training, calibration on information entry, and supervision more difficult. Despite conducting training sessions, initially there was inconsistent or incomplete recording of information in the spreadsheet for administrative calls and in the newly adopted Epic' , p. 833.The main public health implication of this study is that extending the application of teledentistry, tele-triage, tele-consultation, and tele-therapy to after the pandemic is over might offer a promising and useful approach if practiced with the same level of individualization and driven by considerations of both, the reported pain and clinical judgement. Such continuation of tele-services after the pandemic would lead to the freeing of healthcare resources that could be used elsewhere, shortening of long waiting lists, alleviation of over-crowded walk-in clinics, and reserving the chairside appointments to conditions that truly require such management.Future research should aim at larger sample sizes and less missing values. There is also a need for evidence premised on different demographic profiles and countries to better define dental characteristics that fall in the basic, urgent, or emergency categories of essential oral health care and the best route of action, in terms of remote or face-to-face management for each of these categories.During this phase of the pandemic, the most frequent symptom with most severe orofacial/ dental pain was decayed or filled tooth, and the most frequent tele-diagnosis was pulpitis. PS was significantly higher for emergency and urgent tele-triage categorizations. Tele-triage decisions were significantly influenced by severity of patient-reported orofacial/ dental pain, adjusting for a range of variables. However, acute dental conditions were not inevitably referred when they were judged to be manageable remotely; and conversely, less acute dental conditions were given the attention they required and referred when they were gauged to have potential life threating or quality of life implications. Such measured actions could lead to sizeable savings of healthcare resources which could, in future, be used to reduce pressure on clinics overcrowded with conditions that could be remotely managed. Hence, the continuation of such tele-approach later after the pandemic might be safe and useful for a range of scenarios and healthcare facilities if practiced with similar level of individualization and driven by careful considerations of the combination of reported pain and complaints on the one hand, and the meticulous clinical judgement on the other.Additional file 1. Fig. S1: Teledentistry data collection formAdditional file 2. Table S1: Regression analysis with and without adjusting for dental discipline required


Endobronchial ultrasound-guided transbronchial aspiration is a minimally invasive and highly accurate modality for the diagnosis of lymph node metastasis and is useful for pre-treatment biomarker test sampling in patients with lung cancer. Endobronchial ultrasound image analysis is useful for predicting nodal metastasis; however, it can only be used as a supplemental method to tissue sampling. In recent years, deep learning-based computer-aided diagnosis using artificial intelligence technology has been introduced in research and clinical medicine. This study investigated the feasibility of computer-aided diagnosis for the prediction of nodal metastasis in lung cancer using endobronchial ultrasound images. The outcome of this study may help improve diagnostic efficiency and reduce invasiveness of the procedure.Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a valid modality for nodal lung cancer staging. The sonographic features of EBUS helps determine suspicious lymph nodes (LNs). To facilitate this use of this method, machine-learning-based computer-aided diagnosis (CAD) of medical imaging has been introduced in clinical practice. This study investigated the feasibility of CAD for the prediction of nodal metastasis in lung cancer using endobronchial ultrasound images. Image data of patients who underwent EBUS-TBNA were collected from a video clip. Xception was used as a convolutional neural network to predict the nodal metastasis of lung cancer. The prediction accuracy of nodal metastasis through deep learning (DL) was evaluated using both the five-fold cross-validation and hold-out methods. Eighty percent of the collected images were used in five-fold cross-validation, and all the images were used for the hold-out method. Ninety-one patients (166 LNs) were enrolled in this study. A total of 5255 and 6444 extracted images from the video clip were analyzed using the five-fold cross-validation and hold-out methods, respectively. The prediction of LN metastasis by CAD using EBUS images showed high diagnostic accuracy with high specificity. CAD during EBUS-TBNA may help improve the diagnostic efficiency and reduce invasiveness of the procedure. Endobronchial ultrasound-guided transbronchial aspiration (EBUS-TBNA) is a minimally invasive and highly accurate modality for the diagnosis of lymph node (LN) metastasis and is useful for pre-treatment biomarker test sampling in patients with lung cancer . AccordiDuring EBUS-TBNA, multiple LNs are often encountered within the same nodal station. In this process, selecting the most suspicious LN for sampling is important, considering the difficulty of sampling all LNs using EBUS-TBNA under conscious sedation. Thus, EBUS image analysis is useful for predicting nodal metastasis; however, it can only be used as a supplemental method to tissue sampling . We haveIn recent years, deep learning (DL)-based computer-aided diagnosis (CAD) using artificial intelligence (AI) technology has been introduced in research and clinical medicine. CAD has been used for radiology, primarily in the areas of computed tomography (CT), positron emission tomography-CT (PET-CT), and ultrasound images, and for the diagnosis of several tumors, such as breast cancer and gastrointestinal tumors ,9,10,11.If real-time CAD-based prediction of nodal metastasis during EBUS-TBNA is made possible, the operator can easily identify the most suspicious node for diagnosis, thereby reducing the procedure time of EBUS-TBNA. The well-experienced EBUS operator could predict benign lymph nodes with approximately 90% accuracy by subjective categorization of EBUS ultrasound characters. The AI-CAD technology might make “the expert level prediction of nodal diagnosis” possible even for non-experts. The purpose of this study is to investigate the feasibility of CAD for the prediction of LN metastasis in lung cancer using endobronchial ultrasound images and DL technology. Patients with lung cancer or those suspected of suffering from lung cancer who underwent EBUS-TBNA for the diagnosis of LN metastasis were enrolled in this study. We prospectively collected clinical information and images related to bronchoscopy since April 2017 (registry ID: UMIN000026942), and the ethical committee allowed prospective case accumulation with written consent . The EBUS-TBNA video clips from April 2017 to December 2020 were retrospectively reviewed, and the patient’s clinical information was obtained from electronic medical records . This was a collaborative study between the Chiba University Graduate School of Medicine and Olympus Medical Systems Corp. . All patient identifiers were deleted, and the image data were sent to the Olympus Medical Systems Corp.’s laboratory and analyzed using DL technology . This study was conducted in accordance with the principles of the Declaration of Helsinki.The patients underwent EBUS-TBNA under local anesthesia with moderate conscious sedation using midazolam and pethidine hydrochloride. OLYMPUS BF-UC290F and EU-ME1 and EU-ME2 PREMIER PLUS were used to observe LNs. Systematic nodal observation starting from the N1, N2, and N3 stations using B-mode, Doppler mode, and elastography was first performed. The size of each LN was measured, and EBUS-TBNA was performed for LNs > 3 mm along the short axis on the EBUS image. TBNA was initiated at N3, N2, and N1 stations to avoid overstating. For TBNA, a dedicated 22-gauge or 21-gauge needle  was used, and rapid on-site evaluation was performed during the procedure. All EBUS procedures were performed by skilled operators (T.N. and Y.Sakairi.) or under their supervision.Rapid on-site evaluation by DiffQick staining and conventional cytology by Papanicolaou staining were performed and diagnosed by a cytopathologist. The histological core was collected in CytoLyt solution and fixed in 10% neutral buffered formalin. The formalin-fixed paraffin-embedded specimens were stained with hematoxylin and eosin (H&E) and subjected to immunohistochemistry. Cytology as well as histology was evaluated by independent pathologists who provided pathological diagnosis . The refUltrasound images were recorded as video clips in the MP4 format; divided into shorter clips featuring each LN using video editing software, XMedia Recode 3.4.3.0 ; and subsequently anonymized using the dedicated software VideoRectFill . All patient information was manually masked on the software. An anonymized video clip was provided to Olympus Medical Systems Corp. with diagnostic information linked to each LN.In this study, we retrospectively and prospectively collected cases and investigated the detection of LN metastasis in each LN. The evaluation methods are illustrated in Prior to image analysis, the videos were decomposed into time-series images, from which images of different scenes were extracted. The areas in which the B-mode was drawn were cropped from the images and the cropped images were resized to the same size. To increase the generalizability of the DL algorithm, data augmentation was applied only to the training images, and the number of training images was increased. Scaling and horizontal flipping were used in the data augmentation process.The Convolutional Neural Network (CNN) structure used in this study for LN metastasis detection is shown in Initially, the ultrasound image was input to the feature CNN, and local features, such as edges and textures, were extracted from the input image in the first block. As it progressed through the network, its features were integrated and finally converted into features useful for detection.Subsequently, the features useful for metastasis detection were input into the detection CNN. The detection CNN outputs the probability and bounding box coordinates and sizes for both metastasis and nonmetastasis. The bounding box with the highest probability was selected from among all the metastatic and non-metastatic bounding boxes in the sequence. Finally, the metastasis or non-metastasis parameters, coordinates and size of the bounding box were obtained as the detection result.For the five-fold cross-validation method, 80% of all the images were used for training and validation. The images were divided into five sections: four sections were used for training, and the last section was used for validation. By changing the validation section, the training and validation were repeated five times. The prediction yield was calculated as the average of the results of each validation.In the hold-out method, all images were used for training and testing. All of the images comprising the 80% used for the five-fold cross-validation method were used for training. The remaining 20% of the images that were not used for the five-fold cross-validation method were used for testing, following which the prediction yield was calculated. The images of different sizes from the two ultrasound scanners (EU-ME1 and EU-ME2 PREMIER PLUS) were allocated proportionately in each section to avoid selection bias.The “Image” represents “per image” basis analysis and the “Lymph node” represents “per lymph node” basis analysis. The “per image” analysis was based on the accuracy of nodal metastasis prediction for each image. Due to limited number of still images, we used the video clips for analysis. However, in this case, multiple images with varying ultrasound features were included for each targeted lymph node, resulting in variation in the judgement of the AI-CAD system. Therefore, in addition to “per image” analysis, we included “per lymph node” analysis in which multiple images were evaluated for each lymph node. The “per lymph node” analysis included (1) calculation of the ratio between the number of images judged benign and malignant, (2) predicting as benign or malignant based on the ratio >50%, (3) analysis of the accuracy of nodal metastasis prediction for each lymph node. p < 0.05. Sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy were calculated using standard definitions. Statistical analysis was performed using Fisher’s exact test and chi-square test for categorical outcomes, and Student’s t-test for continuous variables. Data were analyzed using the JMP Pro 15 software . Statistical significance was set at Ninety-five cases with a total of 170 LNs were enrolled in the study. Two cases (two LNs) were excluded because of a history of malignant lymphoma. Cases of large-cell carcinoma and large-cell neuroendocrine carcinoma (one LN each) were also excluded because they could not be assigned to both the training and testing sets. Finally, 91 cases and 166 LNs were analyzed in this study . In thisPathological diagnosis including cytology and histology were performed for all lymph nodes. The success rate of each diagnosis was shown in First, we evaluated the ability of AI-CAD to detect LN metastasis using endobronchial ultrasound images. A total of 5255 and 6444 extracted images from the video clip were analyzed using the five-fold cross-validation and the hold-out methods, respectively . The repUsing the five-fold cross-validation method, the LN-based diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of the AI-CAD were measured to be 69.9% , 37.3% , 90.2% , 70.4%, and 69.8%, respectively . HoweverUsing the hold-out method, the LN-based diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of the AI-CAD were measured to be 87.9% , 76.9% , 95.0% , and 90.9% and 86.4%, respectively . Regarding the diagnostic yield by lung cancer subtypes, the diagnostic accuracy rates were 90.5% for no malignancy, 76.9% for adenocarcinoma, 61.1% for squamous cell carcinoma, and 93.9% for small cell lung cancer .The potential applications of AI technology are rapidly growing in the medical field and are expected to facilitate the demanding work of medical staff. The concept of AI, including such systems as machine learning and DL, has been growing in popularity since the evolution of graphics processing units. AI-CAD is one of the AI applications that has been actively developed in radiology. Significant work has been done in the area of combining radiomics and AI-CAD technology, which helps support the diagnosis of benign and malignant tumors, prediction of histology, stage, genetic mutations, and prediction of treatment response and recurrence using CT and PET-CT images ,16,17,18The comparison between the five-fold cross-validation and the hold-out methods, demonstrated that the hold-out method exhibited a superior diagnostic yield in this study setting. First, we evaluated using five-fold cross-validation, and then used hold-out method as the standard for developing AI-CAD technology. The number of evaluated images was increased by 20% for the hold-out method compared to five-fold cross-validation. The increased number of images helped with comprehensive covering of image variation and contributed toward better AI-CAD accuracy. The images used in this study were obtained using two different ultrasound image processors (EU-ME1 and EU-ME2 PREMIER PLUS). In addition, a certain amount of collected images  were of different sizes owing to the different screen sizes of the various video clips. These variations might affect the diagnostic yield of the five-fold cross-validation and the hold-out methods. Thus, for the analysis of different-size images the image had to be resized and then analyzed, which resulted in an adversarial example (AE). An AE is an event in which AI misrecognizes an image as completely different data owing to the addition of insignificant noises that are imperceptible to humans.  ThereforThe final diagnostic accuracy and specificity for the prediction of LN metastasis using AI-CAD in this study were 87.9% and 95.0%, respectively. Previous studies have reported comparable but lower values. For instance, Ozcelik et al. reported an accuracy rate of 82% and specificity of 72% for the diagnosis of lung cancer LN metastasis in 345 LNs by CNN using MATLAB . ChurchiFurthermore, we examined the diagnostic yield of lung cancer subtypes . The diaIn this study, the prediction rate for squamous cell carcinoma was relatively lower than other histology. One of the possible reasons of this phenomenon was that the squamous cell carcinoma often shows various histological characters, such as necrosis and fibrosis, and it reflects the characters on an EBUS ultrasound image, such as necrosis sign and heterogeneity of echogram. These various ultrasound image features might cause difficulties for learning and validation by AI-CAD, resulting in a lower prediction rate. Although better AI-CAD analysis required more numbers of squamous carcinoma cases for comprehensive coverage of the image variation of squamous cell carcinoma, the number of actual squamous cell carcinoma cases were relatively low in this study. If we could increase the number of squamous cell carcinoma cases, the diagnostic yield could be better in the future.This study has several limitations. First, the study population was limited, and we used video clips to overcome the limitations of the small sample size. Some cases underwent multiple LN assessments, and multiple LN images were obtained from a single case, which might show similar image characteristics. Second, we used only B-mode images in this study. Several reports have demonstrated the utility of other imaging modalities such as Doppler mode imaging and elastography ,6. FinalIn this study cohort, the prevalence of nodal metastasis was 38.5%, which was relatively low in comparison with the previous report. Most of the enrolled patients were referred to the surgical department as resectable lung cancer patients. In real clinical setting, the AI-CAD technology will be useful if the operator cannot decide which one to be sampled during EBUS-TBNA. The operator would not need the image analysis support for selecting the target when the lymph node is obviously enlarged. Thus, this study demonstrated that the AI-CAD can be used to support the nodal staging for surgically treatable patients.In this study, we found that AI-CAD (a combination of Xception and the hold-out method) for the prediction of LN metastasis using endobronchial ultrasound images is feasible and exhibits high diagnostic accuracy and specificity. AI-CAD for EBUS may reduce futile biopsies of LNs, shorten examination time, and make EBUS-TBNA a less invasive procedure, regardless of operator experience.


Gastric cancer (GC) is the fifth commonest cancer and the third commonest reason of death causing by cancer worldwide. Currently, tumor immunology and ferropotosis develop rapidly that has made gastric cancer be treated in new directions. So, finding the potential targets and prognostic biomarkers for immunotherapy combined with ferropotosis is urgent.By mining TCGA, immune-related genes, ferropotosis-related genes and immune-ferropotosis-related differentially expressed genes (IFR-DEGs) were identified. The independent prognostic value of IFR-DEGs was determined by differential expression analysis, prognostic analysis, and univariate and lasso regression analysis. Then, based on the prognostic risk model, the correlation between IFR-DEGs and immune scores, immune checkpoints were evaluated. Besides, we predicted the response of high and low risk groups to drugs.A 15-gene prognostic feature was constructed. The high-risk group had a poorer prognosis than the low-risk group. High-risk group had higher level of Treg immune cell infiltration compared with that in the low-risk group, and the tumor purity, immune checkpoint PD-1 and CTLA4, and immunity in the high-risk group were higher than those in the low-risk group. These results indicate that immune ferropotosis-related genes migh be potential predictors of STAD’s response to ICI immunotherapy biomarkers. In addition, the response of small molecule drugs such as Nilotini, Sunitinib, Imatinib, etc. for high and low risk groups was predicted.IFRSig can be regarded as an independent prognostic feature and may estimate OS and clinical treatment response in patients with STAD. IFRSig also has important correlation with immune microenvironment. A new understanding of the immune-ferropotosis-related genes during the occurrence and development of STAD is provided in this study. Gastric cancer (GC) is the fifth commonest cancer and the third commonest reason of death causing by cancer worldwide , and is Ferroptosis, as a newly regulated cell death mode, differs from the molecular characteristics of other forms of regulatory cell death. Its genetic, biochemical and morphological characteristics are classified as iron-dependent cell death and superoxide lipids Accumulation . FerropoAs lots of ferropotosis-related genes regulating the relation between ferropotosis and tumor, the prognosis of patients can be evaluated by the expression of ferropotosis-related genes in tumor tissues. In this study, the STAD gene expression information was obtained by the analysis of Cancer Genome Atlas (TCGA) database, and then the differential expression of immune ferropotosis-related genes in the sample was analyzed, thus, the survival of STAD patients was predicted effectively by constructing a model containing multiple genes. The correlation between the risk scoring model and immune status was analyzed, the potential mechanisms were explored, diagnosis and treatment basis for clinical treatment were provided, and new therapeutic targets were found.https://www.immport.org./home) and the GeneCard database (https://www.genecards.org/) reached 17,500 in total, and the downloading of ferropotosis-related genes (FRGs) from the FerrDb database (http://www.datjar.com:40013/bt2104/) and previous literature  associated with immune ferropotosis in STAD, TCGA database was used for subsequent analysis. The downloading of human immune-related genes (IRGs) from the ImmPort database  was determined by performing a single factor Cox analysis of overall survival (OS). The predictive models of candidate immunity and ferropotosis-related IFR-DEGs were determined by performing minimum absolute contraction and selection operator LASSO proportional regression.A total of 352 STAD patients were randomly assigned to either the training cohort or the test cohort in a 1:1 ratio to construct and validate risk scores . For the training cohort, a linear combination of expression values for each prognostic gene was applied to construct the prognostic risk profile of our immune and ferropotosis-related genes (IFRSig). The establishment of profile was based on corresponding coefficients. Patients from the TCGA-STAD dataset were divided into low-risk group and high-risk group according to the median value of the risk score. Principal component analysis (PCA) was used to explore the distribution characteristics of different groups through the R package. Finally, the validity of prognostic indicators was evaluated by using the area under the curve (AUC) of the “time receiver operating characteristic curve (ROC) “.p < 0.05 indicating statistically evident differences.Functional enrichment analysis of differentially expressed genes related to immune Ferropotosis in gastric cancer Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed through the ClusterProfiler package, so that functional annotation and enrichment pathways were explored, where To assess the expression and prognostic value of IFR-DEGs in STAD further, a difference analysis and a prognostic analysis were performed through the “survival” package. According to the Cox proportional risk model and the Kaplan-Meier model, the risk ratio (HR) was calculated, Statistical significance was defined as p < 0.05 or <0.01.According to the “survival” package in the R software, with combination of clinicopathological features, the correlation between IFR-DEGs and clinicopathological features was analyzed. R package “rms” was used to obtain the column line diagram and calibration curve. The risk score related to the prognostic mode, as a prognostic factor, was used to assess the 1-year, 3-year and 5-year OS.SsGSEA and CIBERSORT R scripts were used to quantify the relative proportion of infiltrated immune cells. Spearman rank correlation analysis was used to explore the relationship between risk score values and immune-infiltrating cells. Furthermore, TIDE algorithm was used to evaluate two different tumor immune escape mechanisms using IFR-DEG markers.The R package of pRRophetic was applied for predicting the median maximum inhibitory concentration (IC50) of common small molecule drugs. IC50 represents the effectiveness of the substance in inhibiting specific biological or biochemical functions. Wilcoxon symbolic rank test was used for inter-group differences.p < 0.05, the difference was statistically evident.R software (version 4.0.2) was applied for statistical analysis. Perl programming language (version 5.30.2) was applied for data processing. Multivariate Cox regression analysis was applied to assess prognostic significance. PCA was also performed using R’s ggplot2 package. Kaplan-Meier curves and logrank tests were used to analyze survival differences between the two groups. Pearson correlation coefficient test was used for gene correlation analysis; Spearman correlation coefficient test was applied for risk score and correlation analysis of immune cells and immune genes. When The volcanogram showed 7180 up-regulated DEGs and 3772 down-regulated DEGs screened in the TCGA (p < 0.001). In the two groups of the test cohort, the same significant difference as OS was repeated (p < 0.05). As the results showed, the clinical prognosis of patients with low-risk scores was better than that of patients with high-risk scores, which was consistent with the two groups of results in each cohort. All results showed that IFRSig might have accurate pre-measurement capabilities for OS.According to the median risk score, high-risk group or low-risk group of patients were sorted for the training cohort and test (P < 0.001), tumor stage (P= 0.025), and risk score (P < 0.001) had significant correlation with OS (P = 8.802e -04), tumor stage (P = 0.017), and risk score (P < 0.001) had significant correlation with OS (In the TCGA cohort (training set), univariate Cox regression analysis showed age  were significantly increased in STAD patients in the high-risk group . In the p = 0.0023), PD-L1 (p = 0.15), CTLA-4 (p = 0.045) expression difference. These results suggested that the IF gene might be a potential predictive biomarker of STAD response to ICI immunotherapy.Regarding the TME score, high-risk patients had higher stromal scores, immune scores, and ESTIMATE score than low-risk patients  and Joint Funds for the innovation of science and Technology, Fujian province (Grant number: 2020Y9039).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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


In advanced stages of in Huntington's disease (HD) gait impairments and severe chorea are usually medication-refractory. The long-term effects on gait in HD of physiotherapy ICF-based management post- globus pallidus deep brain stimulation (GPi DBS) are not well-established. Physiotherapy has been recognized as an essential element in HD treatment. Here, we present a case report of a 56-year-old woman with HD on the advanced stage and severe chorea medication-refractory after GPi-DBS. We performed multidisciplinary motor assessments ICF-based to identify the disability at clinical and home-setting, including environmental and personal factors before and after GPi-DBS surgery and at 11-time points follow-up. The surgery was very successful and directly post GPi-DBS, there were a significant improvement in chorea and a substantial decrease in medication dose. A framework ICF- based physiotherapy protocol with external cues was developed to improve gait was delivered post-surgery and was continued three times/week during 18-months. Physiotherapy sessions consisted of a personalized protocol of exercises with functional movements, balance, and gait training with external cues. Improvements in gait were observed in 3-months post-intervention and were more expressive in 6-months follow-up. Our patient improved substantially HD motor symptoms and her quality of life after GPi-DBS intervention and a physiotherapy program ICF-based. The objective outcomes measures used to assess gait have served as endpoints to assessing the patient's motor profile during the pre-operative period. Assessments were helpful to verify the efficacy of the multidisciplinary intervention in long-term.Periodically assessing function and disability using outcome improvements may support clinicians' decisions about DBS, medication adjustments and guide physiotherapists to personalize the ICF-based intervention. Huntington's disease (HD) is a neurodegenerative disease characterized by chorea and cognitive and behavioral impairments . DespiteA starting point for gait rehabilitation management in HD can be functional assessment, and a model to use is the International Classification of Functioning, Disability, and Health (ICF) . HoweverThis case report describes a 56-year-old woman with a genetically confirmed diagnosed of HD . All motor tests were video-recorded for further analysis. Gait was assessed by Timed up and Go test (TUG) -months. , Mini-BEThe surgery was very successful, and directly post GPi DBS (50 Hz) there was a significant improvement in chorea (trunk and limbs) without ameliorating motor performances and a substantial decrease in medication dose was observed (olanzapine 2.5 mg) . DepressA ICF framework-based physiotherapy protocol with external cues was developed to improve gait post-surgery . After 2Regular physiotherapy treatment was crucial to improving axial motor symptoms, and functional mobility improvement was observed by the global impression of change. As shown in This case report shows that immediately after GPi DBS, the advanced stage HD patient with severe chorea and who was medication-refractory showed substantially improved motor symptoms and quality of life after GPi DBS intervention followed by an ICF-based physiotherapy program. The main findings from this case report are a sustained improvement of chorea after GPi DBS and significantly reduced medication dose, without significant change in depression and apathy. Besides several case reports, few small open-label and retrospective studies outlined the efficacy of haloperidol in the control of abnormal involuntary movements in HD without ameliorating motor performances , 3, 6, 7The UHDRS includes several scores assessing the primary features of HD  as well as the overall functional impact of these features; therefore, the bio-psycho-social view can also be accessed by UHDRS, which is as a “standard gold” outcome measure in HD. Furthermore, despite the expected neurodegenerative progression of HD, specialized clinical management after GPi DBS can improve gait impairments, effects which are sustained over the long term , 27. IntThe effects observed on TUG are significant and also higher than the minimal clinical change (2.58 points) proposed by Quinn et al. and the same trends were observed on BBS scores  .Despite growing evidence, no pharmacological or non-pharmacological disease-modifying therapy for HD has been identified to date . TherefoRecognition of gait impairments in HD is highly important in clinical practice for many reasons. First, although changes in gait and balance are frequently among the earliest signs of HD –33, manyAfter an initial assessment, we suggest that every patient with HD undergo regular screening for gait impairments using a test battery, which involves a review of the patient's history, a formal physical examination, and a cognitive assessment. The combination of outcomes that will determine the type of intervention and the type of training may involve many parameters  and an IRegardless of the evidence, the clinical implications and importance of referring DH people after GPi DBS to rehabilitation become evident in this case report. In our clinical experience with HD, gait and balance impairments are often formally assessed; however, formal ICF-based assessments are less frequent. We suspect that many practicing clinicians could further glean important insights from specialized multidisciplinary assessments of gait and balance than is routinely collected at present.Finally, the ICF-based objective outcomes measures used to assess gait served as endpoints for assessing the patient's motor profile during the pre-operative period. These measures also indicated the optimal time to refer the patient to surgical intervention. Assessments were helpful at verifying the efficacy of the multidisciplinary intervention immediately following the intervention and in the long term. Continuing specialized physiotherapy in high frequency (4 times/week) can help optimize gait improvements in HD in advanced stages after GPi DBS and maintain the results over long periods. The patient and family have considered the long-term treatment helpful, which improved her quality of life. This clinical management strategy can work as a good clinical implication. Work with a biopsychosocial model including formal assessments of the complete multidisciplinary team is important, and it was a limitation in this case report. It would be interesting to include formal speech therapist, occupational therapist, social worker, nurse specialist, and psychologist assessments in future studies.Periodical assessments of functioning and disability using outcome improvements may support neuromodulation parameter adjustments, pharmacological adjustments, and support physiotherapists at personalizing ICF-based interventions. Our strategy of continuing specialized physiotherapy interventions over a longer period has good potential for clinical implementation in HD therapy. Further research is needed to corroborate our findings.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by Comite de Etica e Pesquisa-USP-HOSPITAL DAS CLÍNICAS DA FACULDADE DE MEDICINA DA UNIVERSIDADE DE SÃO PAULO-HCFMUSP. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.TC and RC: research project—conception, organization, and execution, statistical analysis—design, execution, and review and critique, and manuscript—writing of the first draft and review and critique. RG, JT, and MH: research project—execution and statistical analysis—execution. EF: research project—conception and execution and statistical analysis— review and critique. MJ: manuscript—review and critique. EB: research project—execution and manuscript—review and critique. All authors contributed to the article and approved the submitted version.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Endothelial cell adhesion molecules have long been proposed as promising targets in many pathologies. Despite promising preclinical data, several efforts to develop small molecule inhibitors or monoclonal antibodies (mAbs) against cell adhesion molecules (CAMs) ended in clinical-stage failure. In parallel, many well-validated approaches for targeting CAMs with nanomedicine (NM) were reported over the years. A wide range of potential applications has been demonstrated in various preclinical studies, from drug delivery to the tumor vasculature, imaging of the inflamed endothelium, or blocking immune cells infiltration. However, no NM drug candidate emerged further into clinical development. In this review, we will summarize the most advanced examples of CAM-targeted NMs and juxtapose them with known traditional drugs against CAMs, in an attempt to identify important translational hurdles. Most importantly, we will summarize the proposed strategies to enhance endothelial CAM targeting by NMs, in an attempt to offer a catalog of tools for further development. Recent failures of advanced nanomedicine (NM) drug candidates (due to lack of efficacy or dose limiting toxicity)  inspire Structurally, CAMs like selectins , vascular cell adhesion molecule 1 (VCAM-1), intracellular adhesion molecule 1 (ICAM-1), and integrins are transmembrane glycoproteins, and their expression is correlated with the presence of inflammatory signaling via cytokines and chemokines in the proximity of tissue damage. Their main function is to facilitate the process of leukocyte infiltration from the blood stream into the inflamed tissues, by forming bonds with ligands on these circulating cells, allowing for rolling on the endothelium, adhesion and trans-endothelial migration , 9. ThisIn the present manuscript, we highlight the key studies in which endothelial CAM-targeted NM formulations were explored to improve drug delivery, to enhance vascular imaging or to disrupt CAM-mediated activity in pre-clinical settings, and we discuss how these approaches can be employed to enhance clinical translation. This mini-review will focus on the CAMs that are considered as early markers of endothelial activation and dysfunction, e.g., selectins , ICAM-1 and VCAM-1. Integrins, which are expressed on endothelial cells, but they are also present in a variety of tumor cells, are discussed as a separate group of vascular adhesion molecules.The major endothelial expressed CAMs can be divided into integrins, selectins (E- and P-selectin), and immunoglobulin superfamily members . L-selectin is expressed on the membranes of immune cells . The str4β1 also known as very late antigen-4 or VLA-4, and lymphocyte function-associated antigen-1, LFA-1), making them more adhesive to endothelial cells. Together these changes facilitate a multistep process of leukocyte transendothelial migration physiological events such as acute inflammation, immune response, wound repair, and hemostasis , 15, 19.The implications of CAMs in pathologies were extensively studied and confirmed on several levels. In some cases, CAMs show elevated plasma levels of their soluble forms in patients suffering from chronic diseases: soluble E-selectin in inflammatory bowel disease, bronchial asthma, atopic dermatitis  as well Secondly, tissue up-regulation of CAMs was confirmed in clinical samples taken from patients suffering from various inflammatory diseases. Elevated levels of E-selectin were detected in liver sections of patients with alcoholic liver disease, bronchial biopsies in chronic bronchitis, and synovium in rheumatoid arthritis . PatientFurthermore, animal disease models are providing valuable insight into CAM involvement in pathological processes. E-selectin was identified as a target in rodent models of asthma, myocardial infarction, stroke, and inflammatory bowel disease (IBD) , 32. VCAin vitro in TNFα activated HUVECs : natalizumab and vedolizumab, which target leukocyte expressed αt of IBD  and crizt of IBD . Table 1t of IBD . Aselizut of IBD , 46. Thet of IBD . Besidest of IBD , 49.in vitro inhibition of CAMs, however, no further clinical development can be identified (X). One of the first analogs of sLeX, pentasaccharide cylexin (CY-1053), was discontinued due to poor efficacy in CTs for reperfusion injury , a specific E-selectin inhibitor, is being investigated as an add-on therapy to standard chemotherapy in acute myeloid leukemia , or from microbial (efomycine M) or marine origin, have initially demonstrated entified . Employin injury , likely n injury . “Secondn injury –55. Evenn injury , 56. Rivn injury , howeverleukemia  and as aleukemia . Similarleukemia , 60.Interestingly, even though VCAM-1 is established as a viable target in immunological disorders and cancer , no humaResearch and development of these CAM inhibitors provided valuable insights on the complexity of future drug candidate development. Some of the lessons could be summarized as:Inhibition of leukocyte infiltration by blocking CAMs is a viable strategy for limiting inflammation, as validated by the success of natalizumab and vedolizumab.The clinical translation of several small molecule CAM inhibitors has stagnated either due to the insufficient binding affinity (glycomimetics), unfavorable pharmacokinetics (glycomimetics), lack of clinical efficacy  or potential immunogenicity (mAbs). Additionally, in the case of aselizumab it was postulated that even if the drug achieves the blockage of the majority of targeted CAMs, there is the possibility of compensatory activity of other CAMs that can diminish inhibitory effects on leukocyte infiltration.Choosing the right pathological process (indication) matters. Blocking P-selectin was not successful in CTs for cardiovascular diseases, but later it proved to be a good strategy in a specific niche: VOC in SCD.While the CAM-binding molecules alone showed insufficient efficacy, they could pose a functional part of a NM system. Using NM carriers with affinity ligands against CAMs could simultaneously provide both blocking of these leukocyte-anchors, which would potentially limit inflammation, and a possibility to deliver therapeutic cargo in a targeted manner right to the inflamed site. Attachment of multiple targeting ligands would improve the binding efficiency and the macromolecular nature of NM could improve the pharmacokinetic (PK) properties and stability, providing an answer to several issues that led to failure of mAbs and small molecule inhibitors of CAMs.In parallel with the development of mAbs and small molecule CAM inhibitors, many research groups aimed to develop CAM targeted NMs. Compared to small molecule CAM inhibitors and traditional small molecule anti-inflammatory or chemotherapeutic drugs, the advantages of NM are: a. better PK profile - prolonging half-life time in the circulation b. solubility enhancement of poorly water-soluble drugs c. improved stability d. delivery of the drug to the target site e. controlled release of the drug at the target tissue. Compared to mAbs, NMs that block CAM function possess: a. no/reduced immunogenicity b. multivalency c. the potential of steric shielding of cells. These goals can be achieved by the properties of NMs  and can be further improved in order to target selected cells in the desired tissue by constructing NMs bearing multiple targeting ligands.Targeting CAMs with affinity NMs can pursue several therapeutic goals :a. Targeted drug delivery to the inflamed endothelium - using CAM-targeted carriers bearing a. chemotherapeutic drugs to be delivered to the vicinity of tumors, or b. anti-inflammatory drugs for suppression of inflammation.b. Imaging - using NM imaging probes targeted toward CAMs for imaging of a. cancer vasculature or b. inflamed vasculature.c. Functional blocking - using “drug-free” NM (without cargo) to bind CAMs and block their function, in order to: a. inhibit leukocyte trafficking into the inflamed tissues or b. Inhibit cancer cells homing to the pre-metastatic niche and metastasis formation.An array of different nanocarriers  block copolymers and poly (PLA) nanoparticles ethyl (3'-CE)) or quinic acid (Qa)-based mimetics were used to decorate the surface of liposomes or were conjugated to an N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer, respectively, as selectin targeting ligands, and exhibited higher uptake into activated endothelial cells  to the inflamed kidneys in a murine model . SimilarD(KLAKLAK)2, KLAK) to tumor vasculature. The hydrophilic HPMA-based copolymer bearing multiple copies of Esbp showed high binding affinity (at low nanomolar range) and selectivity to activated endothelial cells  decreased the rate of tumor growth and prolonged the survival of mice bearing primary Lewis lung carcinoma, or established melanoma (B16-F10) lung metastases  and cyclic FLDVRK ) reviewed in ], P-seleSimilar to short peptides, short sequences of nucleotides, commonly referred to as DNA or RNA aptamers were also developed for targeting CAMs. A thioaptamer targeting E-selectin (ESTA-1)  demonstrCAM-targeting of NM can also be achieved through usage of cell-membrane fragments of cells known to engage with CAMs. Liang et al.  used the1 integrin, and modified it to express integrin α4, which together form a complex, VLA-4, a ligand for VCAM-1. This NM was loaded with DEX and used for drug delivery to inflamed lungs and suppressing inflammation.Recently, a new approach for generating targeting ligands on NMs emerged from the advances in genetical engineering. Park et al.  developeTargeting of imaging probes to endothelial CAMs in cancerous and inflammation sites holds promise to improve management of these conditions. Nano-sized imaging probes of diverse shape, materials and physical properties have been developed over the years to improve the visualization of pathological sites by intravital microscopy (IVM), positron emission tomography (PET), magnetic resonance imaging (MRI) and ultrasound (US) modality in pre-clinical settings . Selecte4), a counterpart of VCAM-1. In vitro, the peptide was shown to bind to VCAM-1 with 12-fold higher target-to-background ratios comparing to anti-VCAM-1 mAb. Magneto-fluorescent NPs modified with this peptide were tested in vivo. Interestingly, in their following work, the authors conducted further phage-display studies with in vivo atherosclerotic plaques, and identified a linear sequence VHPKQHR (VINP), with even higher binding affinity. In direct comparison of VNP and VINP, the latter was shown to bind VCAM-1 with 20 times higher affinity  or HPMA, compared to monovalent sLeX/sLea, illustrates the potential of multivalent systems to target CAM-expressing cells more efficiently than their monovalent counterparts , 85X or Besides higher binding affinity, the use of NMs for functional blockade reveals another advantage over non-polymeric inhibitors, which is the shielding from cell-cell interactions by nanosized inhibitors. The binding of CAMs to ligands on flexible polymeric carriers sterically hinders the interaction of surrounding adhesion molecules with their ligands and therefore increases the inhibitory potential of the NM , 149. ThX- or other glycomimetic ligand-bearing polymer treatment reduces neutrophil and/or macrophage infiltration in rodent models of inflammation, such as peritoneal inflammation  mice. P-Esbp reduced atherosclerotic lesions in these mice, stabilized atherosclerotic plaques and reduced the total leukocyte count in the blood stream, as a response to less inflammation . Binding of PLGA NPs decorated with cLABL decreased T-cells conjugation to DCs, inhibiting the activation of T-cells, much more effectively than the free cLABL peptide .X positive cells to endothelium  with various functions in cell-cell and cell-extracellular matrix interactions. This family of receptors can be divided into several groups, based on their ligand specificity: endothelial specific receptors, leukocyte-specific receptors, laminin-binding receptors, and collagen-binding receptors . In contvβ3 and αvβ5 integrins  and are present at elevated levels on a variety of different cancer cells . Their bntegrins . Integriacizumab , several imaging  or utiliothelium . Throughothelium .vβ3 and αvβ5, were developed for imaging and imaging-guided phototherapy  peptides have been investigated as DDS for cancer therapy, which bind to vascular integrins and additionally to neuropilin-1 . iRGD-deotherapy .vβ5 via RGD-peptide have demonstrated therapeutic antiangiogenic efficacy for the treatment of choroidal neovascularization  or are insufficiently up-regulated at the desired site , 11. IncIf we consider the physiological functions of CAMs in leukocyte adhesion and tissue transmigration, it is intuitively apparent that binding multiple CAMs can ensure better affinity of NMs, leading to superior efficacy. The notion of potential binding synergism mainly was investigated in molecular ultrasound imaging by targeted microbubbles (MBs) , 170.X) with the aim to improve imaging of inflamed vasculature. These dual-targeted MBs demonstrated 20 % higher adhesion to activated endothelial cells under flow, than MBs bearing either anti-ICAM-1 Ab or sLeX alone  and selectins , yielding NMs which bind to E- and P-selectin . To inveApart from radiation, other physical agents, such as heat were shown to induce up-regulation of CAMs mostly in the tumor vasculature , withoutConsidering the inflammation-inducible nature of CAMs, the most obvious intervention that could enhance their presence on the blood vessel endothelium is administration of pro-inflammatory cytokines. However, systemic administration of such cytokines would lead to overall inflammation and, given their complex effects on many receptors and multiple tissues, unpredictable adverse effects. For example, TNFα, although named for its ability to shrink certain tumors in animal models, turned out to have a rather complex effect on tumor growth and a potential for supporting tumor progression . FurtherA more tailored approach includes using known drugs, with defined safety profiles that have been shown to up-regulate CAMs at the sites of inflammation. Imiquimod, an agonist of toll-like receptor 7 (TLR-7) was shown to induce E-selectin expression on previously negative human squamous cell carcinomas (SCC) , 192, whAnother pharmacological intervention exploits the connection between CAM expression and angiogenesis. As it is known that angiogenic factors inhibit the expression of CAMs (ICAM-1 and VCAM-1) , some stUpregulation of ICAM-1 in cervical cancer cell lines can be achieved by irradiation alone, however combining gamma irradiation with the pharmacological agent retinoic acid leads to an additive effect, superior to either agent alone . PossiblAlthough CAM-targeted NMs have shown promising therapeutic results in pre-clinical settings, there are challenges that hamper their clinical translation. Targeting success depends on several parameters, including relative expression of CAMs in diseased and normal tissues, binding affinity and avidity, and target trafficking and turnover. Moreover, the properties of the carrier molecule itself or ligand determine the stability, biodistribution, general toxicity, and safety of the vascular-targeted system, making it difficult to predict the feasibility and clinical efficacy of endothelial CAM-targeted NM formulations for the treatment of cancer or inflammatory disorders.Since pathological factors modulate CAM expression in the disease site, it is important to pre-determine the target-CAM's expression level, both in the diseased tissue and in normal tissues, as this ratio may play a significant role in the success of drug delivery. In case the CAM is almost exclusively expressed on the inflamed endothelium at high density , a system with high binding affinity may give better outcomes. Moreover, if the target is expressed at low levels on vascular endothelium under physiological conditions, and upregulated in disease  - a system with “marginal” avidity might be sufficient to anchor only to cells with pathological levels of the marker. Indeed, a controlled reduction of the ligand surface density on the carrier enhanced the selectivity of targeting to inflamed pulmonary vasculature in animal models, as determined by PET imaging , 198.in vitro) has shown promise as potential therapeutic for human diseases, albeit the success was limited, and its development appears to be discontinued. Since bimosiamose functions primarily by blocking E-selectin-mediated adhesion, it probably did not fully block L- and P-selectin activity and the remaining selectins could still be sufficient to mediate adhesion. Alternatively, it's possible that the other CAMs  could compensate for selectin blockage. Thus, a Pan-selectin antagonist in combination with blocking other CAMs should be considered for effective therapies for the prevention of leukocyte infiltration in inflammatory conditions.Targeting only one CAM alone may be insufficient in controlling disease as observed in a clinical trial of L-selectin neutralizing Ab (aselizumab), mentioned above. In these patients, the lack of efficacy was reported, even though very high level of L-selectin blockade on neutrophils was achieved . A possiGiven that CAMs play an essential role in leukocyte traffic into inflamed tissues, interfering with CAM functions by blocking their mediated activity may pose a risk. Neutrophils play a crucial role in the resolution of inflammation and blocking their activity might delay the healing process , 199. A Lβ2 , reached the market for psoriasis treatment. In consistence with the mechanism of action, this mAb induced a marked increase in peripheral WBC count, due to blocking their migration into tissues. Additionally, it precipitated T-cells hyporesponsivness, through an effect on α4β1 integrin, which correlated with reduced ability to produce an immune response  natalizumab. Soon after being approved for treatment of multiple sclerosis in 2004, it was withdrawn from the market due to cases of PML. Following further risk-benefit analysis, natalizumab was re-introduced under a special prescription program. Since then, this drug was approved for the treatment of Crohn's disease by FDA (not by EMA). Interestingly, another integrin-blocking mAb, Vedolizumab, which binds to α4β7 integrins did not show potential to induce PML , which negatively correlates with cancer severity, can also be decreased and this in turn may hamper the antitumor immune response  .To date, a vast number of NM targeting CAMs has been developed and tested preclinically with various theranostic goals. No such system is close to regulatory approval, even though several non-NM drugs targeting CAMs have successfully found their therapeutic niche. We highlighted potential strategies that could help to maximize the potential advantages of NM and help clinical translation .A close reading of up-to-date literature signals us that future successful CAM-targeting NMs will be systems with a biocompatible carrier, have multivalent display of low Mw high-affinity ligands (peptide or aptamer), target two or several CAMs, with or without a conventional drug payload, depending on their therapeutic purpose. All of the critical elements  should be investigated in order to find the optimal conditions to assure enhanced binding avidity, with minimal off-target effects, optimal PK properties, and avoid immune clearance. Furthermore, this NM could be combined with a pharmacological or physical agent that could potentiate the expression of the target CAM at the disease site, leading to improved targeting.Choosing the relevant indication is another level of complexity. The roles of target CAMs should be well established and close attention should be paid to the possibility of compensatory up-regulation of other non-target CAMs as a result of successful targeting. We believe that NM translation should be directed first at diseases of those organs where NMs tend to accumulate , as this increases the chance of good clinical outcomes. Alternatively, CAM targeting could be combined with the local administration of NMs.New inspiration comes from an array of “drug-free” macromolecular therapeutics for CAM targeting as an alternative to unsuccessful low-Mw drug inhibitors. These systems lack the presence of drug payload, which eliminates the potential for inducing drug-related adverse effects.All of the building elements for CAM-targeted NM are well studied and an array of systems confirmed their preclinical efficacy. We are looking forward to seeing their clinical translation in the following years.NM and MR were involved with drafting and writing the review manuscript, and including tables and figures. AD was involved in planning and writing this manuscript. All authors contributed to the article and approved the submitted version.The laboratory of AD is supported by Grant No. 1115/19 from the Israel Science Foundation (ISF), Grant No. 2017200 given by the United States–Israel Binational Science Foundation (BSF), by Grant No. 3-15008 from the Israeli Ministry of Health (MOH) and Grant No. 85698 from the Israeli Ministry of Science and Technology (MOS). MR is grateful to the Minerva fellowship for financial support.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Reading Indian scene texts is complex due to the use of regional vocabulary, multiple fonts/scripts, and text size. This work investigates the significant differences in Indian and Latin Scene Text Recognition (STR) systems. Recent STR works rely on synthetic generators that involve diverse fonts to ensure robust reading solutions. We present utilizing additional non-Unicode fonts with generally employed Unicode fonts to cover font diversity in such synthesizers for Indian languages. We also perform experiments on transfer learning among six different Indian languages. Our transfer learning experiments on synthetic images with common backgrounds provide an exciting insight that Indian scripts can benefit from each other than from the extensive English datasets. Our evaluations for the real settings help us achieve significant improvements over previous methods on four Indian languages from standard datasets like IIIT-ILST, MLT-17, and the new dataset (we release) containing 440 scene images with 500 Gujarati and 2535 Tamil words. Further enriching the synthetic dataset with non-Unicode fonts and multiple augmentations helps us achieve a remarkable Word Recognition Rate gain of over  Multiple computer vision tasks rely on Scene Text Recognition (STR), and several commercial applications also benefit from it . STR hasWe investigate the transfer learning of complete scene-text recognition models—(i) from English to two Indian languages (Hindi and Gujarati) and (ii) among the six Indian languages, i.e., Gujarati, Hindi, Bangla, Telugu, Tamil, and Malayalam.We also contribute two datasets of around 500 word images in Gujarati and 2535 word images in Tamil from a total of 440 Indian scenes.On IIIT-ILST Hindi, Telugu, and Malayalam datasets, we achieve gains of or works ,15. We oWe are the first to use over 500 Hindi fonts with an existing synthesizer and show that the font diversity can significantly improve non-Latin STR. Specifically, on the IIIT-ILST Hindi dataset, we achieve a remarkable WRR gain of over Human civilizations often involve reading multi-lingual text in scenes. The growth in non-Latin STR systems is gradual despite tremendous improvements in recognition models ,7,8,9,10We now discuss datasets and associated works in the field of photo-OCR.Works of Photo-OCR on Latin Datasets: As stated earlier, the process of Photo-OCR conventionally includes two steps: (i) Text detection and (ii) text recognition. With the success of Convolutional Neural Networks (CNN) for object detection, the works have been extended to text detection, treating words or lines as the objects [ objects ,17,18. L objects  extend s objects  and Bušt objects  present  objects  propose  objects  propose  objects  introduc objects  propose  objects . The ima objects  recently objects . Ghosh e objects  proposesWorks of Photo-OCR on Non-Latin Datasets: Recently, there has been an increasing interest in scene-text recognition for non-Latin languages such as Chinese, Korean, Hindi, Japanese, etc. Several datasets like RCTW (12 K scene images), ReCTS-25k (25 K signboard images), CTW (32 K scene images), and RRC-LSVT (450 K scene images) from ICDAR’19 Robust Reading Competition (RRC) exist for Chinese [ Chinese ,30,31,32 Chinese ,34. Kore Chinese ,36. The  Chinese . The RRC Chinese  propose  Marathi . Around  Marathi  for vide Marathi  for imag Marathi  propose Transfer Learning in Photo-OCR: With the advent of deep learning in the last decade, transfer learning became an essential part of vision models for tasks such as detection and segmentation [entation ,42. The entation . The sceentation ,23,24. Gentation  proposesWe now discuss the motivation for our work.Transfer Learning amongst Indian scripts: As discussed earlier in It is essential to note the differences between the n-grams of English and Indian languages. Many of the top-5 n-grams in English are the complete word forms, which is not the case with Indian languages owing to their richness in inflections (or fusions) . AdditioSignificance of the variety of fonts: To study the effect of fonts and training examples, we extend the analysis in Gunna et al. [a et al.  on Englia et al. ,47 for HFor the IIIT-ILST Hindi dataset, we use three settings for our experiment: 2 M samples with 97 fonts, 7 M samples with 552 fonts, and augmented 20 M samples with 552 Fonts for our analysis. The results are shown in the green plot in Synthetic Datasets: As shown in w et al. .) with tw et al. . For eacSample images of our synthetic data are shown in Additionally, the number of Unicode fonts available in Gujarati is fewer than those available in other Indian languages. Next, we choose Hindi, as Hindi characters are similar to Gujarati characters and the average word length of Hindi is higher than Gujarati. Bangla has comparable word length statistics with Hindi and shares the property of the top-connector line with Hindi. Still, we keep it after Hindi in the list as its characters are visually dissimilar and more complicated than Gujarati and Hindi. We use less than 100 for fonts in Hindi, Bangla, and Telugu. We list Tamil after Bangla because these languages share similar vowels’ appearance : The first baseline model we train is Convolutional-Recurrent Neural Network (CRNN), which is the combination of CNN and RNN as shown in i et al. .STAR-Net (Baseline 2): As shown in Transfer Learning: We initially train individual models for each language to analyze the performance and the features learned by the models for further transfers. For the transfer learning experiments among languages, we finetune all network layers.Correction BiLSTM: After training the STAR-Net model on a real dataset, we add a correction BiLSTM layer  individual models for each language, (ii) the transfer learning from English to two Indian languages, (iii) the transfer learning among six Indian languages, (iv) correction BiLSTM, (v) increasing font diversity with augmentations, and (vi) lexicon-based transcription approaches.Performance on Synthetic Datasets: It is essential to compare the results on synthetic datasets of different languages sharing common backgrounds, as it provides a good intuition about the difficulty in reading different scripts. In We present the results of our transfer learning experiments on the synthetic datasets in Performance on Real Datasets: Performance with Correction BiLSTM: Since we observe the highest gain of  dataset , we furt dataset  to the b dataset . The resa et al. .Features Visualization: In Incorporating more fonts and augmentation techniques: We present results of the baseline 2 experiments with 552 fonts in s row 2, . Similars row 4, . Hence, Further, using 2 M synthetic images, we generate 8 M training samples  by incorporating the augmentation pipeline described in Performance with lexicon-based transcription: Lexicon-based transcriptions achieve better results on the datasets [datasets ,48,54. Wdatasets , a metriError Analysis: We analyze the quantitative results using two tools of evaluation, i.e, WA-ECR plots (Word-Averaged Erroneous Character Rate) and histogram plots [am plots . We presx. As we observe in The histogram plots are plotted against the edit distance of the predicted label and ground truth of the test image. Meanwhile, WA-ECR plots are a normalized way of presenting the total number of errors per label length. Both of these are useful in inspecting the overall performance of STR systems. The bars at We now substantiate how our proposed models, with transfer learning and data diversity improve the detection for top character confusions. We present the example of such confusions in We created over 2 million synthetic images in six different languages with varying scripts and vocabulary characteristics to improve Scene Text Recognition (STR) for low-resource Indian languages. We analyzed the language transfers for two different baselines via several controlled experiments. The transfer of image and text features seems intuitively relevant for text recognition models in deep learning. However, in this study, we observe that transferring English STR models to Indian languages turned out to be inefficient and, in most cases, resulted in lower-quality models than those trained on individual languages. Our experiments show that transfer learning across the six languages that share a resemblance in terms of glyphs structure and n-gram distributions results in a performance boost compared to the individual baselines. Our STR models performed better than the previous works in all Indian languages, and we have established new standards for recognizing scene-text in low-resource Indian languages. When plugged into the STAR-Net model, the proposed end-to-end trainable Correction BiLSTM improves the Bangla results further while finetuning. For the IIIT-ILST Hindi dataset, we have achieved WRRs similar to English STR by incorporating font diversity and augmentation into our recognition network. We also accomplish the CRRs of above


Extracorporeal membrane oxygenation (ECMO) is frequently used in critically ill children and, even if the reported results are good, it remains a challenge encompassing numerous risks. There are two types of ECMO: veno-arterial ECMO (VA-ECMO) which can be used for heart and lung support, while veno-venous (VV-ECMO) is used for lung support only. Indications for VA-ECMO, even if they must be carefully considered, peculiarly if respiratory failure is predominant, remain frequent in infants because there are several specific problems with the use of VV-ECMO. Various types of perforations have been reported with the use of a dual-lumen cannula in VV-ECMO . In a suOn bifemoral VA-ECMO in the adult population, when left ventricle (LV) recovery coexists with respiratory failure, an antegrade ejection by the LV of relatively deoxygenated blood hinders the retrograde oxygenated blood flow of the VA-ECMO in the aortic arch resulting in cerebral hypoxemia. This has been described as Harlequin syndrome (HS) . In adulThe diagnosis of this HS must be suspected (and therefore prevented) with clinical, biological, blood gas and echocardiographic signs (Additional file The best prevention of HS is to carefully consider VA-ECMO indications. Moreover, to prevent and/or treat a HS, several options can be proposed in function of LV function (Additional file In conclusion, HS must be suspected and prevented in all VA-ECMO patients in order to avoid a prolongated or a secondary/recurrent cardiac dysfunction.Additional file 1. Diagnosis elements during the successive stages in the Harlequin syndrome and elements of discussion for ECMO management.Additional file 2. Blood gas according to sample site.