Both reverse transcription-PCR (RT-PCR) and chest X-rays are used for the diagnosis of the coronavirus disease-2019 (COVID-19). However, COVID-19 pneumonia does not have a defined set of radiological findings. Our work aims to investigate radiomic features and classification models to differentiate chest X-ray images of COVID-19-based pneumonia and other types of lung patterns. The goal is to provide grounds for understanding the distinctive COVID-19 radiographic texture features using supervised ensemble machine learning methods based on trees through the interpretable Shapley Additive Explanations (SHAP) approach. We use 2,611 COVID-19 chest X-ray images and 2,611 non-COVID-19 chest X-rays. After segmenting the lung in three zones and laterally, a histogram normalization is applied, and radiomic features are extracted. SHAP recursive feature elimination with cross-validation is used to select features. Hyperparameter optimization of XGBoost and Random Forest ensemble tree models is applied using random search. The best classification model was XGBoost, with an accuracy of 0.82 and a sensitivity of 0.82. The explainable model showed the importance of the middle left and superior right lung zones in classifying COVID-19 pneumonia from other lung patterns. The coronavirus disease-2019 (COVID-19) is a viral respiratory disease with high rates of human-to-human contagious and transmission and was first reported in 27 patients with pneumonia of unknown etiology on December 31st, 2019, in Wuhan, China. The causative agent, a beta coronavirus 2b lineage . On JanuThe clinical aspects of COVID-19 are highly variable between individuals, varying in different levels of involvement from asymptomatic to lethal conditions. The incubation period goes from 2 to 14 days. A mildly symptomatic condition usually presents fever, dry cough, fatigue, muscle pain, and taste and smell changes, with few patients showing neurological and digestive symptoms . Severe The diagnosis of COVID-19 uses two approaches: reverse transcription-PCR (RT-PCR)  and chesThe interpretation of radiological lung patterns can reveal differences in lung diseases. For COVID-19-related pneumonia, the characteristic pattern in CXR includes a pleuropulmonary abnormality with the presence of bilateral irregular, confluent, or bandlike ground-glass opacity or consolidation in a peripheral and mid-to-lower lung zones distribution with less likely pleural effusion , 16. ForApart from typical visual interpretation, the lung disease patterns can be studied through texture-feature analysis and radiomic techniques. However, due to radiologists' unfamiliarity with COVID-19 patterns, computer-aided diagnosis (CAD) systems help to differentiate COVID-19-related and other lung patterns.Radiomics is a natural extension of CAD that converts the medical images into mineable high-dimensional data, allowing hypothesis generation, testing, or both . ComputeThe interpretability of results using medical images has been highly required. Therefore, explainable AI  predictions have been developed, such as the Shapley Additive Explanations (SHAP) framework . Our goaWe retrospectively used a public dataset of CXR images of COVID-19-related pneumonia and lung images of patients with no COVID-19 to investigate the radiomic features that can discriminate COVID-19 from other lung radiographic findings. We extracted first- and second-order radiomic features and divided our analysis into two main steps. First, we performed k-folds cross-validation to select the algorithm with the best performance classifying COVID-19 pneumonia and non-COVID-19. Second, we performed an explanatory approach to select the best set of radiomic features that characterize COVID-19 pneumonia.We used two public multi-institutional databases related to COVID-19 and non-COVID-19 to train and evaluate our model. BIMCV  is a large dataset, with annotated anonymized X-ray and CT images along with their radiographic findings, PCR, immunoglobulin G (IgG), and immunoglobulin M (IgM), with radiographic reports from Medical Imaging Databank in Valencian Region Medical Image Bank. BIMCV-COVID+  compriseWe used only CXR images of anteroposterior (AP) and posteroanterior (PA) projections of adult patients (≥18 years old). Some images from the dataset do not have information regarding projection  in the DICOM tag, and some projection tags are mislabeled. All images with missing the projection DICOM tag were discarded and, from the selected AP or PA projections, they were visually inspected and discarded if mislabeled.For COVID-19 positive patients, we selected only the first two images between the first and last positive PCRs. For non-COVID-19 participants with more than two X-ray acquisitions, only the first two images were selected. Therefore, we have 2,611 images from patients with COVID-19, and we randomly chose 2,611 images from non-COVID-19 to ensure a balanced dataset. Demographic information regarding selected patients is shown in Previous studies already used the BIMCV-COVID dataset to evaluate lung segmentation , data imWe applied a histogram equalization in each CXR image , 40 to nWe applied the opening morphological operator in each mask to remove background clusters and fill holes of the resulting lung mask, using a square structuring element, 8-connected neighborhood. The opening morphological operation smooths an object's contour, breaks narrow isthmuses, and eliminates thin protrusions. The mathematical details of opening morphological operation can be found in Gonzalez and Woods .We removed all clusters with <5 pixels and all connected regions with <75 pixels. The lung mask is stretched back to the original image size and applied to the original image before processing. We normalized all segmented lung images considering only pixels inside the lung mask, between 0 and 255.We split the image between the left and right side using the centroid of two areas; if the centroid is located within the first half of the matrix size (from left to right), it is considered as part of the right lung . Next, each lung's height is divided into upper, middle, and bottom zones, determined by the extremities' distance, divided into thirds. The segmentation workflow is shown in We used the PyRadiomics library to extract the first and second-order statistical texture-based features for each lung mask. The mathematical formulation of the features can be found in Zwanenburg, Leger, and Vallières . The radFirst-order features (18 features): These are based on the first-order histogram and related to the pixel intensity distribution.Gray-level co-occurrence matrix or GLCM (24 features): This gives information about the gray-level spatial distribution, considering the relationship between pixel pairs and the frequency of each intensity within an 8-connected neighborhood.Gray-level run length matrix or GLRLM (16 features): This is like GLCM; it is defined as the number of contiguous pixels with the same gray level considering a 4-connected neighborhood, indicating the pixel value homogeneity.Gray-level size zone matrix or GLSZM (16 features): This is used for texture characterization; it provides statistical representation by estimating a bivariate conditional probability density function of the image distribution values and is rotation-invariant.Gray-level dependence matrix or GLDM (14 features): This quantifies the dependence of gray image level by calculating the connectivity at a certain distance when its difference in pixel intensity is <1.We performed 10-folds cross-validation after radiomic feature extraction to guarantee unbiased metrics results and error generalization. We realized that a normalization between 0 and 1 and used SHAP- Recursive Feature Elimination with Cross-Validation (RFECV) feature selection in 9-folds of the dataset. Each machine learning model was trained using the selected features with the hyperparameter optimization method, and randomized search with cross-validation from the sci-kit learn library , 47. TheFeature selection is the process of selecting the most relevant features for a given task. The process reduces the computational cost regarding the training and evaluation of the machine learning model and improves the generalization . MoreoveWe used the SHAP-RFECV from the Probatus python library to perform the feature selection. Further information about the SHAP-RFECV algorithm and its applications can be found on the Probatus webpageWe trained two ensemble classification models based on tree-based models using the scikit-learn  library XGBoost is a scalable ensemble model based on an extreme gradient for tree boosting. It is based on regression trees, which in contrast to decision trees, contains a continuous score on each of the leaves. The input data is sorted into blocks of columns that are categorized by the corresponding feature value. The split search algorithm runs in the block seeking the split candidates' statistics in all leaf branches. It uses decision rules into trees to determine for each leaf the example will be placed. The final prediction is calculated by summing up the score in the corresponding leaves . The provia majority voting, one can achieve a robust classifier with enhanced generalization ability. The mathematical formulation of RF is described in Breiman   Breiman .Accuracy, sensitivity, precision, F1-Score, and the area under the curve (AUC) of the receiver operating characteristic (ROC) were used for model evaluation. The final model was selected based on the best sensitivity achieved in the cross-validation. Each metric is calculated as follows :where: TP = true positive, TN = true negative, FP = false positive, and FN = false negative.Despite their complexity, approaches to making AI models “interpretable” have gained attention to enhance the understanding of machine learning algorithms. Explaining tree models is particularly significant because the pattern that the model uncovers can be more important than the model's prediction itself. The SHAP approach is an additive feature attribution method that assigns an “importance value” to each feature for a particular prediction , 54. TheIn our work, we chose the SHAP approach with tree models because it is calculated in each tree leaf and gives interpretability for local explanations, which reveals the most informative features for each subset of samples. Local explanations allow the identification of global patterns on data and verify how the model depends on its input features. It also increases the signal-to-noise ratio to detect problematic data distribution shifts, making it possible to analyze the behavior of the entire dataset, which is composed of medical images from different databases .The SHAP approach uses an extension of Shapley values from the game theory to calculate the feature importance. The SHAP values are calculated based on the prediction difference when using all features and when using just a few ones. It addresses how the addition of one feature improves or not the prediction . In treeWe use the SHAP-RFECV approach on the final model to evaluate the most important features and how they affect the model's prediction.We extracted 88 features for each lung zone. Next, we applied RF and XGB models to analyze the performance with 10-fold cross-validation. The XGBoost model was selected for hyperparameters optimization and feature selection using SHAP due to its higher classification performance. The SHAP feature importance values are shown in f(x) = 2.207, is related to the model prediction identifying the CXR as a COVID-19. Similarly, the negative SHAP value in f(x) = −1.052, is related to the model prediction identifying the CRX as a patient with non-COVID-19.In the latest year, numerous studies have been developed applying different computer-aided methods to aid in diagnosing and in the prognosis COVID-19 , 57–75. The computer-aided methods using non-segmented images may lead to biases , 59 sincNowadays, COVID-l9 radiological studies are focused on CT findings, which have better sensitivity than CXR. However, CT is more expensive and scarcer than conventional X-rays, requiring complicated decontamination after scanning patients with COVID-19. Therefore, the American College of Radiology  recommenThe use of feature importance techniques can improve clinical practice in different medical fields. Hussain et al.  showed tThe main contribution of this study is the findings of a group of meaningful radiomic features in differentiating COVID-19 from other lung diseases using CXR using an explainable machine learning approach. The most relevant features are presented in As seen in In CXR images, the heart partially overlaps with the lungs in the left middle region, influencing feature importance. Despite being the most important feature, kurtosis was the only feature selected from this region. The second and third most important features are both related to gray-level homogeneity. Higher values of Run Entropy in GLRLM, which were associated with COVID-19 in the upper left region, indicate more heterogeneity in the texture patterns. Higher values of gray-level non-uniformity in GLRLM in the upper right region, also associated with the disease, indicate lesser similarity between intensity values, corroborating the previous feature findings. COVID-19-induced consolidations tend to be diffuse or patchy, which may explain these features associations .We won't go over other features individually due to their decreasing and similar importance. However, it is important to note that from the 20 selected features, half are extracted from the upper right zone. Our previous study  showed sSaha et al.  created Cavallo et al.  made a tRasheed et al.  proposedBrunese et al.  developeKikkisetti et al.  used porYousefi et al.  proposedCasiraghi et al.  developeEven though the image characteristics are different in CT and CXR, they share the same physical interaction with tissues using X-rays. Caruso et al. study  used CT Similarly, Lin et al.  developeShiri et al.  made an One of the main limitations of AI studies is the currently available COVID-19 and non-COVID-19 CXR databases . Even thThe most important concern about some studies is that some databases of typical pneumonia CXR have images from pediatric and adult patients. They are primarily used due to the differentiation between viral and bacterial pneumonia. However, this may increase biases due to age-related characteristics . UsuallyOur model reached an accuracy of 0.82, a sensitivity of 0.82, a precision of 0.82, and F1-score metrics of 0.82 using CXR images and SHAP RFECV. Other COVID-19 studies using CXR images and machine learning models reached accuracy between 0.92 and 0.99, and sensibility between 0.91 and 0.99 , 63. HowThe main limitations of our study are the absence of clinical data to improve our models and the lack of statistical analysis to have more confidence about the importance of the features. Moreover, we limited the features extraction and other features that could be included, like the neighboring gray-tone difference matrix. Finally, we did not evaluate the effect of features' extraction applying different pre-processing filters.The sudden onset of COVID-19 generated a global task force to differentiate it from other lung diseases. With the main symptoms related to atypical pneumonia, the number of CXR and chest CT datasets has rapidly increased. More than 1 year and a half from the COVID-19 onset, the available datasets of chest images are more extensive, so it is possible to have confidence in classifying the disease from other pulmonary findings. However, before the 2020 pandemic, most lung radiomic signature analysis studies focused on identifying and classifying nodules and adenocarcinomas. Therefore, pneumonia radiomic signature is not well-established, even for typical pneumonia.We still do not know how COVID-19 affects the immune system and the lungs, but some cases do not have any CXR alterations, they have only parenchymal abnormalities . For furA big challenge in using large CXR image databases is maintaining label information such as projection . The further effort in global data curation could confirm projection without the need for visual confirmation.This article presents the SHAP approach to explain machine learning classification models based on hand-crafted radiomics texture features to provide grounds for understanding the characteristic radiographic findings on CXR images of patients with COVID-19. The XGB ML model is the best discriminant method between COVID-19 pneumonia and healthy and other lung pathologies using radiomic features extracted from lung CXR images divided into six zones. The explainable model shows the importance of the middle left and superior right lung zone in classifying COVID-19 pneumonia from other lung patterns. The method can potentially be clinically applied as a first-line triage tool for suspected individuals with COVID-19.The rapid increase of COVID-19 pneumonia cases shows the necessity of urgent solutions to differentiate individuals with and without COVID-19 due to its high spreadability and necessity of prompt management of ill individuals. Furthermore, the lack of knowledge about the disease made it necessary to find explainable radiological features to correlate with the biological mechanisms of COVID-19.https://bimcv.cipf.es/bimcv-projects/bimcv-covid19/.Publicly available datasets were analyzed in this study. This data can be found here: LM: study design, data mining and pre-processing, model development, writing, and analysis. CM and CD: study design, literature review, writing, and analysis. RB and AM: study design. All authors contributed to the article and approved the submitted version.This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nivel Superior – Brasil (CAPES) – Finance Code 001 and PUCRS by financial support with research scholarship.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.


Background: It is currently unknown whether results from intraoperative test stimulation of two types of Deep Brain Stimulation (DBS), either during awake pallidal (GPi) or thalamic (Vim), are comparable to the results generated by chronic stimulation through the definitive lead.Objective: To determine whether side-effects-thresholds from intraoperative test stimulation are indicative of postoperative stimulation findings.Methods: Records of consecutive patients who received GPi or Vim were analyzed. Thresholds for the induction of either capsular or non-capsular side-effects were compared at matched depths and at group-level.Results: Records of fifty-two patients were analyzed . The induction of side-effects was not significantly different between intraoperative and postoperative assessments at matched depths, although a large variability was observed ; non-capsular: GPi DBS: p = 0.20; and Vim DBS: p = 0.35). Linear mixed-effect models revealed no differences between intraoperative and postoperative assessments, although the Vim had significantly lower thresholds . Unpaired survival analyses demonstrated lower intraoperative than postoperative thresholds for capsular side-effects in patients under GPi DBS (p = 0.01), while higher intraoperative thresholds for non-capsular side-effects in patients under Vim DBS (p = 0.01).Conclusion: There were no significant differences between intraoperative and postoperative assessments of GPi and Vim DBS, although thresholds cannot be directly extrapolated at an individual level due to high variability. Deep Brain Stimulation (DBS) is an effective treatment to alleviate symptoms of various movement disorders, including Parkinson's disease (PD), dystonia, and Essential Tremor (ET), targeting either the subthalamic nucleus (STN), internal globus pallidus (GPi), or ventral intermediate nucleus of the thalamus (Vim) . CarefulIn a previous study on patients with PD, we demonstrated that lower stimulation intensities were intraoperatively required than post-operatively to induce both relief of rigidity and induction of capsular side-effects, during STN DBS . These rIn this study, we aimed to compare the thresholds for inducing side-effects between intraoperative test stimulation and postoperative chronic stimulation in Vim DBS and in GPi DBS. This knowledge could aid in clinical decision-making during the intraoperative choice of the best lead position and by potentially expediting the optimization of the postoperative DBS settings.A chart review was performed for all the consecutive patients receiving awake DBS for targets, other than STN (namely GPi and Vim), between September 2012 and February 2019 in the Haga/LUMC DBS center, and with available standard intraoperative and postoperative records. All patients were diagnosed with PD, dystonia, tremor, or a combination of these disorders. Given the retrospective nature of the study, a formal ethical evaluation was waived by the local medical ethics committee.The surgical procedure was performed with standard DBS techniques; a detailed description of the surgical procedure is provided elsewhere . Lead-imTest stimulation was performed in awake patients with the microelectrodes macrostimulation tip , using a pulse width of 60 μs and a frequency of 130 Hz, with constant current at two to five depths, along each trajectory with at least 2 mm distance. Stimulation intensity was increased with steps of 0.5 mA, starting at 0.5–1.0 mA, until the first appearance of debilitating side-effects. If no side-effects occurred, test stimulation was discontinued after maximal 6 mA.The position of the definitive lead was confirmed with intraoperative or postoperative CT-scans. The monopolar contact review was performed per clinical routine by the same neurologist who recorded the intraoperative results, ~10 days after surgery (range 9–10 days). Each of the four contact points of the definitive lead were tested in the same way as during intraoperative testing ; results of the intraoperative test stimulation were not used during the postoperative contact review. If no side-effects occurred, stimulation was usually discontinued after 6 mA, however higher stimulation intensities were occasionally tested at the neurologists' discretion. In case of directional leads, ring mode results were used for the purpose of this study.Side-effects were classified as either capsular or non-capsular. Capsular side-effects included muscle twitching and dysarthria; non-capsular side-effects included all other side-effects such as paresthesia, diplopia, phosphenes, nausea, and general discomfort. Paresthesia can arguably be considered as capsular as well, but were considered non-capsular given the stimulation in this particular region . BecauseThe therapeutic effect and the therapeutic window were not considered for this study, as therapeutic effect for dystonia is not evaluated during surgery. Intraoperatively tested depths, along with the finally chosen trajectory, were matched to corresponding postoperative contact points based on stereotactic target coordinates as previously described . For eact-tests were used to compare thresholds between targets. Given the non-normal distribution, non-parametric Wilcoxon-signed rank tests were used to study matched pairs of intraoperative and postoperative assessments. Results were stratified per combination of target and type of side-effect. Linear mixed models, using a restricted maximum likelihood (REML), were used to model whether there are differences between intraoperative and postoperative assessments. The threshold for induction of debilitating side-effects was used as an outcome, whilst the timing of the testing  was used as the “repeated” variable. Intra-individual variability was accounted for by modeling each individual as a random effect, whereas the influence of the anatomical target  was modeled as a fixed effect.Independent Comparisons at group-level were performed using Kaplan-Meier curves: an event was defined as the occurrence of a debilitating side-effect; censoring occurred if increasing the stimulation was discontinued without occurrence of side-effects. Separate curves were plotted for either intraoperative test stimulation or postoperative stimulation, as well as stratified per target. Log-rank (LR) tests were used to compare differences between the curves. Anonymized data may be shared upon request.Fifty-six patients received DBS in targets other than STN. Three patients had missing records and were excluded; one patient received zona incerta DBS and was excluded as well. Fifty-two patients were ultimately included for analysis: 95 definitive leads were placed . Patients' characteristics and targets are specified in p < 0.001) and non-capsular (p < 0.001) side-effects occurred at lower thresholds in patients under Vim DBS than those under GPi DBS. Intraoperatively, non-capsular side-effects occurred at lower thresholds in patients under Vim DBS (p < 0.001); no difference was seen for capsular side-effects (p = 0.215).Post-operatively, both capsular . Similarly, the induction of non-capsular side-effects was not significantly different either for both targets . Although the paired stimulation intensities did not significantly differ between the assessments, The threshold for induction of capsular side-effects was not significantly different between paired intraoperative and postoperative assessments for patients under GPi DBS and Vim DBS . The target significantly contributed to the threshold level-prediction , with thalamic stimulation having lower thresholds.For both capsular and non-capsular side-effects, linear mixed models showed that there was no significant difference between the intraoperative and postoperative thresholds, while accounting for intra-individual variability and target  vs. 99 postoperative events (57 censored data points)], capsular side-effects were induced at a significant lower threshold during intraoperative stimulation than during postoperative stimulation in unpaired survival analyses (intraoperative mean (95%CI) 3.90 (3.54–4.27) mA vs. postoperative mean (95%CI) 4.58 (4.25–4.91) mA, χ2 = 0.03, p = 0.87, see 2 = 6.00, p = 0.01, see With patients in Vim DBS [98 intraoperative events (45 censored data points) vs. 119 postoperative events (72 censored data points)], capsular side-effects did not significantly differ between intraoperative and postoperative assessments in unpaired survival analyses [intraoperative mean (95%CI) 3.48 (3.31–3.66) mA vs. postoperative mean (95%CI) 3.49 (3.34–3.65) mA, χIn this study, we compared thresholds for inducing side-effects during intraoperative test stimulation to thresholds observed during the postoperative monopolar contact review with patients in both GPi and Vim DBS.Our results demonstrate no significant difference between intraoperative and postoperative assessments for the induction of both capsular and non-capsular side-effects, for both patients of GPi and Vim DBS, assessed with either Wilcoxon-signed rank tests for paired observations or linear mixed effect models accounting for intra-individual variability. However, although the results may not differ at group-level, individual variability in the range of 0.5–3.5 mA in either direction is evident, rendering the results from the intraoperative assessment inaccurate for the prediction of postoperative thresholds at the individual level. We therefore recommend maintaining the postoperative monopolar contact review in full, to record reliable thresholds for side-effects as reference point for chronic stimulation. Although intraoperative testing along the best trajectory appears inaccurate in predicting the threshold of postoperative effects in patients under Vim and GPi DBs, this is still relevant for target-positioning when comparing different trajectories. In this view, our results therefore do not disqualify the utility of intraoperative testing.Overall, in unpaired analyses, lower thresholds were observed in patients under GPi DBS during intraoperative test stimulation for the induction of both capsular and non-capsular side-effects than during postoperative stimulation, although the latter did not reach statistical significance. In contrast, no differences were seen in patients under Vim DBS in terms of capsular side-effects, whereas higher stimulation intensities were observed to induce non-capsular side-effects than during postoperative stimulation. This analysis was performed to compare our results with previous studies that adopted this method , 7, whicCombined with results from our previous study on patients under STN DBS, which demonstrated lower intensities during intraoperative stimulation for capsular side-effects , it appen = 6) has demonstrated a trend toward higher intraoperative stimulation intensities required for induction of side-effects. However, this study assessed intraoperative stimulation under general anesthesia, rendering the setting to study the induction of side-effects altogether different  constitutes a clear strength, although some bias about how side-effects were detected and recorded may have been introduced as well. Limitations include the retrospective design and inherent missing data. Despite the retrospective design, our method does reflect a systematic clinical approach which was consistent across involved neurologists. The number of missing data may have led to some bias, as both intraoperative and postoperative assessments at several depths and intensities were made at the physician's discretion, while data was, therefore, to be considered missing-not-at-random (MNAR). Inter-rater variability was not addressed as most of our patients was assessed by the same neurologist and the remaining data was insufficient to address this topic. Imputation of missing data was considered unfeasible given the large amount of missing data relative to observed data, and the missingness-structure being MNAR.Future research should apply prospective designs to avoid missing data. Exploration of the reasons behind the individual variability may provide further insight into the mechanisms behind the discrepancies between the various analyses. Studies focusing on prediction models, possibly applying automatic programming algorithms, should be performed to investigate whether prediction of optimal DBS settings for chronic stimulation can be performed based on intraoperative assessments.The raw data supporting the conclusions of this article will be made available by the authors, upon reasonable requestEthical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.VG and MFC designed and conducted the study. AM, CH, NG, and MFC performed patient recruitment and data collection. VG and RH performed data analysis and statistical analysis. VG and RH prepared the manuscript draft with important intellectual input from AM, CH, JH, NG, and MFC. VG, RH, and MFC had complete access to the study data. All authors critically reviewed the final manuscript and approved the final manuscript.Unrelated to this study, JH reports grants from The Netherlands Organisation for Health Research and Development, The Netherlands Organisation for Scientific Research, Hoffmann-La Roche, AbbVie, Lundbeck, Hersenstichting, Stichting Parkinson Fonds, Alkemade-Keuls Foundation, and Centre of Human Drug Research. AM reports travel support from Boston Scientific. CH reports travel support from Boston Scientific. NG reports travel support from Boston Scientific. MC reports support for advisory board from Medtronic (fees to institution), consultancy fees: Medtronic (fees to institution), CHDR (fees to institution), research support: Medtronic (to institution), AbbVie (to institution), research support in kind from Global Kinetics Corporation, travel support: Boston Scientific. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.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 the last decade, numerous circRNAs were discovered by virtue of the RNA-Seq technique. With the deepening of experimental research, circRNAs have brought to light the key biological functions and progression of human diseases. CircRNA ITCH has been demonstrated to be a tumor suppressor in numerous cancers, and recently it was found to play an important role in bone diseases, diabetes mellitus, and cardiovascular diseases. However, the functions of circ-ITCH have not been completely understood. In this review, we comprehensively provide a conceptual framework to elucidate circ-ITCH biological functions of cell proliferation, apoptosis and differentiation, and the pathological mechanisms of inflammation, drug resistance/toxicity, and tumorigenesis. Finally, we summarize its clinical applications in various diseases. This research aimed at clarifying the role of circ-ITCH, which could be a promising therapeutic target. In the past years, the human genome has been estimated by new technologies, and most of them were transcribed into RNAs. However, only 1–2% of the human transcriptome encodes for proteins .The circRNAs were discovered in 1976 after more than 30 years of being overlooked, and they have gradually become a new molecule of interest nearly a decade later ,5. The cBased on molecular origination, circRNAs can be divided into separate subtypes: exonic circRNAs (ecRNA), intronic circRNAs (ciRNA) and exon-intron circRNAs (ELciRNA) . Some of(a) Acting as a miRNA sponge. circRNAs function as competing endogenous RNAs (ceRNAs), which bind miRNAs and therefore inhibit the target genes. This is the most critical function of circRNA compared to other functions. The most classic research has been conducted upon circRNA ciRS-7, and it has been found to have more than 70 binding sites for miR-7; thus, it can strongly suppress the expression of miR-7 target gene CDR1 [ene CDR1   Regulating gene transcription. Although most circRNAs function in the cytoplasm, ciRNAs that remain in the nucleus also have a significant role, interacting with RNA polymerase II (Pol II) machinery and modulating host transcription. ElciRNAs promote parent gene transcription by binding to the small nuclear ribonucleoprotein U1 (snRNP U1) to form a complex and further interact with Pol II [h Pol II . For insh Pol II   Interacting with proteins. circRNAs can also act as protein scaffolds by interacting with RNA-binding proteins (RBP). For example, circ-Foxo3 can bind with p21 and CDK2 to form ternary complexes, thereby repressing cell cycle progression at the G1 and S phase [ S phase   Encoding function. Recent studies have shown that some ecRNAs can be effectively translated into proteins or peptides in a cap-independent manner. Both internal ribosome entry site (IRES)- and 5′ UTR N6-methyladenosine (m6A)-mediated translation initiation are considered potential translation mechanisms of circRNAs in cytoplasm [ytoplasm ,15. In 2ytoplasm   function of regulating protein stability was first discovered in non-agouti-lethal 18H mice . As a meCircular RNA itchy E3 ubiquitin protein ligase  was first reported by Memczak et al. . Circ-ITIn the past ten years, circ-ITCH has been demonstrated to play a crucial role in the progression of malignant cancers. Moreover, evidence that circ-ITCH contributes to non-neoplastic disease has gradually emerged. According to the existing research on circ-ITCH, we summarize biological and pathological processes that hope to provide vital clues about disease in the future.Circ-ITCH effects cell proliferation mainly through regulating target miRNAs and thus indirectly effecting the parental gene, ITCH. The Wnt signaling pathway is highly conserved in species’ evolution that plays a vital role in the development of cell proliferation, apoptosis, tissue regeneration, and other physiological processes . DisheveCirc-ITCH is involved in mediating cell apoptosis and the cell cycle by regulating the expression of apoptosis-related proteins and related signaling pathways. Circ-ITCH curbs myocardial cell apoptosis by decreasing levels of caspase 3, p53 and PARP via the miR-17-5p/Wnt/β-catenin signaling pathway . PTEN prRecently, circ-ITCH was found to participate in normal cell differentiation, especially within stem cells. Circ-ITCH was identified to differentially express during the osteogenic differentiation of periodontal ligament stem cells (PDLSCs) compared with normal PDLSCs. Further bioinformatic analysis revealed that circ-ITCH was predicted to interact with miR-34a and miR-146a to promote PDLSC osteogenic differentiation via the MAPK pathway . Thus, cInflammation is a complex process that is mediated by inflammatory cytokines and different immune cells . Out-of-Widely used chemotherapeutic drugs may produce serious drug resistance and systemic toxicity. Doxorubicin (DXR) is a classical anti-tumor antibiotic with a strong cytotoxic effect. Circ-ITCH has been demonstrated to elevate drug sensitivity and ameliorates drug toxicity in DXR. Zhou et al. found that circ-ITCH inhibits osteosarcoma resistance to DXR via the miR-524/RASSF6 pathway . The DXRA retrospective case analysis revealed that 324 prostate cancer patients with downregulated circ-ITCH expression showed a correlation with high lymph node metastasis . SeveralTo promote the rapid proliferation of cancer, tumor cells rely on the glycolytic pathway to obtain energy, which is a primitive metabolic pathway, called the Warburg effect. Circ-ITCH has been proven to regulate cellular metabolism-related factors by binding target miRNA. For example, circ-ITCH suppresses glycolysis of ovarian cancer cells by competitively sponging miR-106a to enhance the expression of E-cadherin (CDH1) . In addiDiabetes mellitus (DM) is a chronic metabolic disease characterized by insufficient insulin secretion from pancreatic β cells and leads to high blood glucose levels . CurrentDue to the unhealthy lifestyle and the increasing lifespan of the population, cardiovascular diseases (CVDs) are increasing consistently each year . As a leAn abundance of circRNAs is expressed in a bone disease-specific manner ,73. PresOsteosarcoma (OS) is a malignant bone tumor that often occurs in adolescents under the age of 20. In recent years, circ-ITCH has been identified to regulate the progression of osteosarcoma. Low levels of circ-ITCH were expressed in MG63, U2OS, OS732, and Saos-2 cells of osteosarcoma cell lines, and restrained proliferation and promoted apoptosis by sponging miR-22 in MG63 and Saos-2 cells . On the According to relevant studies, circ-ITCH mainly acts as a tumor suppressor in diverse cancer cell lines. Circ-ITCH effects tumorigenesis through a sponge function, and further involves several signaling pathways, such as the Wnt/β-catenin and PI3K/AKT/mTOR signaling pathways. Next, we will summarize the following cancer mechanism and clinical significance of circ-ITCH.Prostate cancer (PCa) is one of the most common malignant tumors in the male genital system. There is an urgent need to develop new biomarkers and therapeutic targets with both sensitivity and specificity for the early screening and treatment of PCa . By condThe mortality of ovarian cancer ranks first among all kinds of gynecological tumors. Due to its high rate of mortality, it is urgent to seek promising treatment to improve overall survival rates . The abiMore and more studies have shown that circRNAs are abundant in neuronal tissues, which indicates that circRNAs are closely related to nervous system diseases. Glioma is the most common malignant tumor in the central nervous system, accounting for over 80% of all malignant brain tumors . As showcirc-ITCH within gastric cancer (GC) is in charge of the anti-cancer function through the ceRNA mechanism. Through the use of in vitro and in vivo tests, circ-ITCH was confirmed to be down-regulated in GC tissues and cell lines and also decreased GC growth by the miR-17/ITCH-Wnt/β-catenin pathway . MoreoveIn this review, we summarize the progress of recent research on the biological roles and pathological mechanisms of circ-ITCH. This review has provided evidence that circ-ITCH plays multiple roles in the development of solid cancer tumors, CVD, DM, and bone-related diseases. As we discussed above, circ-ITCH is an emerging multifunctional regulator and may be a useful biomarker for clinical therapy.However, the current studies of circ-ITCH are limited. For instance, the understanding of circ-ITCH in tumor types is comprehensive and extensive. However, this understanding remains at the cellular and animal levels and needs to be extended to human levels. There is an urgent need for these data to be translated for clinical application in the near future. Furthermore, based on the positive effects that circ-ITCH has on inflammatory diseases, we speculate that circ-ITCH may have an effect on senescence or fibrosis. In addition, the function of circ-ITCH is limited to the ceRNA mechanism. The online circRNA database shows that several RNA-binding proteins interact with circ-ITCH. These data imply that circ-ITCH has other mechanisms that have yet to be discovered but are necessary for the expansion of circ-ITCH research. Whether or not circ-ITCH can modulate immune responses through the ITCH pathway is another route of investigation that deserves to be explored. Besides, we found that the lack of standardized naming rules for circRNAs greatly increased the workload of collecting information. Thus, it is necessary to standardize the circRNA names.


In certain malignancies, patients with oligometastatic disease benefit from radical ablative or surgical treatment. The SABR-COMET trial demonstrated a survival benefit for oligometastatic patients randomized to local stereotactic ablative radiation (SABR) compared to patients receiving standard care (SC) alone. Our aim was to determine the cost-effectiveness of SABR.A decision model based on partitioned survival simulations estimated costs and quality-adjusted life years (QALY) associated with both strategies in a United States setting from a health care perspective. Analyses were performed over the trial duration of six years as well as a long-term horizon of 16 years. Model input parameters were based on the SABR-COMET trial data as well as best available and most recent data provided in the published literature. An annual discount of 3% for costs was implemented in the analysis. All costs were adjusted to 2019 US Dollars according to the United States Consumer Price Index. SABR costs were reported with an average of $11,700 per treatment. Deterministic and probabilistic sensitivity analyses were performed. Incremental costs, effectiveness, and cost-effectiveness ratios (ICER) were calculated. The willingness-to-pay (WTP) threshold was set to $100,000/QALY.Based on increased overall and progression-free survival, the SABR group showed 0.78 incremental QALYs over the trial duration and 1.34 incremental QALYs over the long-term analysis. Treatment with SABR led to a marginal increase in costs compared to SC alone . Therapy with SABR remained cost-effective until treatment costs of $88,969 over the trial duration (i.e. 7.6 times the average cost). Sensitivity analysis identified a strong model impact for ongoing annual costs of oligo- and polymetastatic disease states.Our analysis suggests that local treatment with SABR adds QALYs for patients with certain oligometastatic cancers and represents an intermediate- and long-term cost-effective treatment strategy. Metastatic cancers are considered incurable in a variety of tumor entities. The treatment of choice is systemic therapy. The state of oligometastatic disease (OMD) was introduced in the mid 90s as a subcategory of metastatic cancer. With only a limited number of metastases confined to a few organs, this state may represent a less aggressive tumor biology and open the possibility of treatment in a curative intent . HoweverTreatment options include ablative surgery, stereotactic ablative radiotherapy (SABR) and other local ablative procedures like thermal ablation and radioablation, which show different efficacy depending on anatomic location . ConsideThe SABR-COMET trial is one of the first phase II trials to compare treatment of patients with one to five metastases of varying tumor entities with standard care (SC) to additional SABR (SABR) . The triGiven this new local treatment option, our aim was to determine the cost-effectiveness of SABR compared to SC, taking into account PFS, OS and QoL.Our analysis followed recommendations of the Second Panel on Cost-Effectiveness in Health and Medicine . We deveAll individuals started in the oligometastatic state. Monthly overall and progression-free survival rates were derived from the Kaplan-Meier analysis of the SABR-COMET trial , calculated by multiplying years spent in OMD and PMD states by assigned utility weights. Utility weights for OMD were obtained from the FACT-G-Score used in the SABR-COMET trial and converted to EQ-5D according to Teckle et al. . UtilityTreatment strategies were compared in terms of net monetary benefits, incremental costs, incremental effectiveness, and incremental cost-effectiveness ratios (ICERs). The willingness-to-pay was set to $100,000 per QALY as in recent studies . Net monWe used comprehensive deterministic and probabilistic sensitivity analysis (PSA) to test the robustness of the model. Deterministic one-way sensitivity analysis was performed to identify variables that significantly influence the model outcomes. The ranges for deterministic sensitivity analysis were determined by the 95% confidence interval of the initial probabilities and by ±20% for costs. Moreover, PSA allows simultaneous alteration of multiple model input parameters using distributions according to probability density functions for second order Monte Carlo simulation runs  . The modIn the base case analysis of the total study population over the trial duration of 6 years, SABR led to an increased effectiveness of 0.78 QALY at increased costs of $1,133. The ICER was $1,446 per QALY. When additional long-term SEER data were applied, SABR led to an increased effectiveness of 1.34 QALY at additional costs of $52,180. The corresponding ICER was $38,874 per QALY. Adverse events only had a minor effect on our results with a loss of 0.002 QALYs for SABR and 0.0008 QALYs for SC. Incremental costs for treatment of adverse events amounted to $1,443 for the SABR group and $997 for the SC arm.The results of the deterministic one-way sensitivity analysis are presented in Overall, SABR was cost-effective in 100% of Monte Carlo simulation runs with an ICER of $1,105 per QALY during the trial duration and $38,740 per QALY for long-term survival in 99.95% of Monte Carlo simulation runs, indicating robustness of the model. In 47% of simulations, SABR was the dominant strategy when analyzed with SABR-COMET data, meaning that it provided better outcomes at lower costs.The mean incremental effectiveness was positive, meaning that SABR on average led to increased QALYs. Moreover, the mean values for the ICERs were below the willingness-to-pay threshold. The detailed results of the PSA are shown in This study evaluated the economic impact of SABR in the treatment of oligometastatic cancer patients. The analysis indicates that SABR is a cost-effective treatment option compared to SC alone. Additional costs of SABR were partly amortized due to longer progression-free survival in the OMD state, which was accompanied with lower treatment costs of systemic treatment. As expected, DSA demonstrated a relevant impact of treatment costs on the ICER. Yet even with an increase in SABR treatment costs up to about sevenfold, the SABR treatment strategy remained cost-effective.The SABR-COMET trial is the first basket study to prove survival benefits of SABR treatment in patients with OMD across different cancer entities. Previous cost-effectiveness analysis indicated cost-effectiveness for SABR in oligometastatic prostate cancer and NSCLC , 38. RecIn contrast to our study, Kumar et al. assumed treatment with SC for all patients and did not include costs for salvage or palliative radiotherapy. Qu et al. used data directly from the SABR-COMET trial, which is not publicly available in its entirety. Moreover, the discount rate was adapted according to Canadian guidelines for the Economic Evaluation of Health Technologies with 1.5% and not 3% as in Kumar et al. and our study. Qu et al. report a non-linear relationship between the number of lesions and the PFS hazard ratio (HR) with the need of decreasing the HR by 0.047 for each additional metastasis to maintain cost-effectiveness for SABR.Further studies including phase III trials are required to validate the results. Several studies are ongoing at the moment. These include the phase III of the SABR-COMET trial, namely SABR-COMET-3  and SABRThe study results should be interpreted with knowledge of the following limitations. First, the current state of evidence on SABR in OMD is still limited by the sample size of the underlying trial; current phase III trials are ongoing. Second, the FACT-G score was stated only for whole populations of study groups. No distinction was made between progression-free and progressive patients. Data on progression-related decrease in QoL were not publicly available from the SABR-COMET study. Third, no information was provided concerning which patients received systemic therapy. Therefore, in our analysis we used the same percentage for treatment with systemic therapy in the progression-free as well as the progressive patient group to avoid introducing any bias. Fourth, because of rapidly changing treatment regimens, specifying a cost for systemic treatment may remain a source of inaccuracy.Fifth, missing information on which treatment was administered and the inclusion of diverse tumor entities represents a challenge for precise estimation of costs for systemic cancer treatment. This may influence cost-effectiveness as one-dimensional sensitivity analysis demonstrated a great impact of costs for systemic treatment on the ICER. We therefore chose a restrictive approach for our cost-effectiveness analysis, which still indicated cost-effectiveness for the SABR group. Sixth, long-term survival data was obtained from SEER-Program with only OS being available. We deployed these data to also model PFS. Moreover, changes in systemic therapy with more efficient treatments , 47 as wIn conclusion, local treatment with SABR adds QALYs for patients with oligometastatic disease across selected cancer entities in SABR-COMET and represents an intermediate- and long-term cost-effective treatment strategy.https://pubmed.ncbi.nlm.nih.gov/32484754/ DOI: 10.1200/JCO.20.00818.Publicly available datasets were analyzed in this study. This data can be found here: DM: Investigation, Data Curation, Formal analysis, Writing - Original Draft, Software. MU: Validation, Writing - Review and Editing. SC: Validation, Writing - Review and Editing. K-MN Validation, Writing - Review and Editing. FM: Validation, Writing - Review and Editing. CW: Validation, Writing - Review and Editing. MF: Validation, Writing - Review and Editing. MW: Validation, Writing - Review and Editing. MS: Validation, Writing - Review and Editing. JeR: Validation, Writing - Review and Editing. JoR: Validation, Writing - Review and Editing. WK: Conceptualization, Methodology, Validation, Supervision, Project administration. 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.


Methods: We model the DAR imaging process using a mixed Poisson–gaussian model and blindly restore the image by a penalized maximum-likelihood expectation-maximization algorithm (PG-PEM). PG-PEM implements a patch-based estimation algorithm with density-based spatial clustering of applications with noise to estimate noise parameters and uses L2 and Hessian Frebonius norms as regularization functions to improve performance. Results: First, PG-PEM outperformed other restoration algorithms at the denoising task (P < 0.01). Next, we implemented PG-PEM on preclinical DAR images  and clinical DAR images (bone biopsy sections from 223RaCl2-treated castration-resistant prostate cancer patients). DAR images restored by PG-PEM of all samples achieved a significantly higher effective resolution and contrast-to-noise ratio and a lower SD of background (P < 0.0001). Additionally, by comparing the registration results between the clinical DAR images and the segmented bone masks from the corresponding histologic images, we found that the radiopharmaceutical distribution was significantly improved (P < 0.0001). Conclusion: PG-PEM is able to increase resolution and contrast while robustly accounting for DAR noise and demonstrates the capacity to be widely implemented to improve preclinical and clinical DAR imaging of radiopharmaceutical distribution.Digital autoradiography (DAR) is a powerful tool to quantitatively determine the distribution of a radiopharmaceutical within a tissue section and is widely used in drug discovery and development. However, the low image resolution and significant background noise can result in poor correlation, even errors, between radiotracer distribution, anatomic structure, and molecular expression profiles. Differing from conventional optical systems, the point-spread function in DAR is determined by properties of radioisotope decay, phosphor, and digitizer. Calibration of an experimental point-spread function a priori is difficult, prone to error, and impractical. We have developed a content-adaptive restoration algorithm to address these problems.  Autoradiography is a powerful, high-resolution, and quantitative molecular imaging technique used to study the tissue distribution of radioisotopes in biologic systems and for analytic assays  results from isotropic emission and is dependent on a combination of energy dispersion in the phosphor, plate properties (lattice and grain size), and readout laser, and physical properties also make the PSF isotope-dependent. Additionally, replicating relevant features of the signal for DAR acquisitions in a phantom is difficult. In aggregate, it is thus not practical to calibrate the PSF beforehand.Apart from blurring effects caused by PSF, background signal caused by environmental radiation is always present in the imaging process. DAR noise can be attributed to multiple sources: Poisson noise exists in the photon-counting imaging system; gaussian noise comes from the imaging reader readout process, phosphor sheet inhomogeneities, and grain  algorithm, PG-PEM, is presented. We first describe this model in the context of the DAR imaging process along with a patch-based noise parameter estimation method. We incorporate a penalized MLEM algorithm to jointly estimate the restored specimen image and corresponding PSF. L2 and Hessian Frebonius norms are implemented for PSF and specimen signal separately, to improve the quality of the restored image. PG-PEM improves resolution, improves contrast, and suppresses noise more effectively than contemporary restoration approaches, using both preclinical and clinical applied diagnostic and therapeutic radiopharmaceuticals.18F-FDG or 18F-NaF, and harvested at 1 h. Tissues were embedded in optimal-cutting-temperature medium, frozen on dry ice, and sectioned at 8 μm by a cryostat . For all radiographic exposures, multisensitive phosphor plates were exposed at −20°C and read as digital light units using a Cyclone Plus (Perkin Elmer). We then used ImageJ . Male C57BL/6 mice (6–10 wk old) from Jackson Laboratory were administered approximately 7.4 MBq (200 μCi) of either 223RaCl2. The institutional review board approved this study (Human Research Protection Office protocol 201411135), and all subjects provided written informed consent. The biopsy sample was fixed in 4% paraformaldehyde for 24 h, transferred to 30% sucrose for 24 h, frozen, cut, and imaged.Bone biopsies were obtained from 7 metastatic castration-resistant prostate cancer patients under fluoroscopic guidance after a bone scan, 24 h after injection of Sections were stained with hematoxylin and eosin and scanned at ×10 .p is the pixel index, R the raw image, α the scaling factor corresponding to the gain of the imaging system, X the clean radioactive signal, h the PSF, b the mean of background, pb is invariant because of the homogeneous radiation around the tissue.According to the DAR imaging process, its physical model can be expressed as Equation 1:X, a careful modeling of gaussian noise b is necessary. We implement a noise model to jointly estimate parameters of the 2 components. This is based on the fact that Poisson distribution can be feasibly approximated by a gaussian distribution when b is greater than 3  , and the contrast-to-noise ratio (CNR) are set as the accuracy metrics because of the lack of ground truth. Full width at half maximum and STDB can evaluate the resolution and noise level separately, whereas CNR assesses overall performance.For DAR, it is difficult to measure full width at half maximum using microbeads. Alternatively, we use a recently published decorrelation-based method  , and structural similarity .Quantitative data are presented as box-and-whisker plots . We used paired 2-sided Student X (NP), and PG-PEM with total-variation regularization (TV). For comparison, we have applied our novel background reduction and blind restoration to all approaches and tuned h to be similar . PG-PEM, together with the 5 modified reference algorithms, was implemented on both simulated images  and experimental images. Regularization parameters are tuned , and comparisons on simulated data are analyzed .We benchmarked the performance of several restoration frameworks: Richardson–Lucy (RL) (n = 10) acquired from the mouse hindlimb after 18F-NaF PET imaging were used as experimental data and to evaluate the performance of image restoration approaches. As is standard for short-lived diagnostic radioisotopes and required tissue-processing, sectioning, and exposure times, the SNRs of the raw images are low, providing a model setting for comparison. Visual assessment and analyses , whereas that of RD has the lowest energy. The resolution of RD is the lowest because wavelet-denoising processes remove fine details. With an MLEM restoration framework (and the same regularization strategy for PSF h), RL, SP, NP, TV, and PG-PEM share similar resolutions. Notably, because of the lack of a regularization strategy for X, the resolution of NP may be slightly higher than those of the other methods, which can be neglected because of the impact of noise. The effective resolution improves at least 5-fold after restoration by PG-PEM (P < 0.0001). These data, along with the simulation results, demonstrate that PG-PEM is the best performer for blind restoration of DAR images.Next, we assessed the log-scale amplitude of the Fourier space. Because 18F-FDG, and the bone-seeking 18F-NaF, in tissue samples from mouse tumor, heart, and femur (n = 10 per group). We used PG-PEM to restore these data, and we calculated STDB, CNR, and effective resolution for comparison to the raw images . RL and SP algorithms were chosen as references to restore the same DAR images from tumors imaged with 18F-FDG . Compared with PG-PEM, the results of RL and SP, especially their background components, have more apparent noise. The corresponding STDB and CNR reveal that PG-PEM is superior to restore DAR images under extremely low-SNR conditions, with a P value of less than 0.0001.To determine whether PG-PEM could improve the quality of DAR images in diagnostic radiopharmaceuticals, we investigated the distribution of the widely used metabolic tracer w images . These r18F-FDG in the heart and 18F-NaF in the bone, could likewise be improved by PG-PEM. From the raw cardiac images, radioisotope signal is almost homogeneous. By contrast, the PG-PEM–restored data have a higher resolution and improved contrast, which may better reflect the spatial distribution of the tracer . We further compared the hematoxylin- and eosin-stained, raw, and restored DAR images of the murine femur . Consequently, PG-PEM can be of great use in personalized targeted α-particle radiotherapy assessment.After registration , raw and restored DAR images were fused with an anatomic bone mask . PG-PEM not only can improve the resolution and remove noise in these DAR images but also results in more accurate correlation with underlying anatomy. Quantitatively, line profiles, STDB, and CNR improve, and the effective resolution increases by approximately 1.7-fold over raw data . We thenAutoradiography is an important technique in drug development and evaluation of radiolabeled compounds for imaging and targeted therapy . Clearly, the kernel size of the PSF from the hindlimb is larger than that from the biopsy sample , consistent with the physics of α/positron travel, further validating the blind restoration approach.Interestingly, even though both SP and PG-PEM are based on the mixed Poisson–gaussian noise model, PG-PEM has lower noise and reduced background false-positive signal. This difference comes from the iteration process: PG-PEM first filters gaussian-distributed noise in the expectation step and then filters Poisson-distributed noise in the maximization step. In addition, we have also compared the PSFs estimated from different isotopes  and by the Society of Nuclear Medicine and Molecular Imaging Student Research Award (Peng Lu). No other potential conflict of interest relevant to this article was reported.


Background: Nosocomial meningitis with multidrug-resistant (MDR) or extensively drug-resistant (XDR) Acinetobacter baumannii is a life-threatening complication in neurosurgery. Treatment of these infections is challenging because of poor penetration of the available antibiotics into the cerebrospinal fluid (CSF). Intrathecal (ITH) or intraventricular (IVT) administration of antibiotics is increasingly used as the last treatment option against MDR/XDR Gram-negative bacteria meningitis not responding to intravenous (IV) regimens. However, pertinent data in pediatric patients is scarce.Case Presentation: A 14-year-old male patient developed meningitis from an MDR strain of A. baumannii following endoscopic endonasal resection of craniopharyngioma. Despite a combination therapy involving IV tigecycline, we observed clinical and bacteriologic failure. The patient was then successfully treated with an ITH and IV polymyxin B-based combination. Quantification of tigecycline and polymyxin B in CSF was performed with two-dimensional high-performance liquid chromatography (2D-HPLC) and HDLC coupled with tandem mass spectrometry (HPLC-MS/MS), respectively. Adverse drug reactions (neurotoxicity and skin hyperpigmentation), probably induced by polymyxin B, were acceptable and reversible.Conclusions: The case illustrates ITH and IV Polymyxin B-based combination is an optimal therapeutic option against MDR A. baumannii meningitis in this pediatric patient. In the future, real-time PK/PD data obtained from patients during ITH/IVT polymyxin B therapy should be required to optimize polymyxin use with maximal efficacy and minimal adverse effects. Acinetobacter baumannii has emerged as one of the major organisms isolated from the cerebrospinal fluid (CSF) cultures  or extensively drug-resistant (XDR) Gram-negative bacteria is a life-threatening complication in neurosurgery. cultures . Mortaliibiotics . This faibiotics . Consideibiotics –7. Furthibiotics , intrathibiotics . HoweverA. baumannii following endoscopic endonasal resection of craniopharyngioma. The patient has been successfully treated with ITH and IV Polymyxin B-based combination after a failed combined therapy involving IV tigecycline. In addition, concentrations of tigecycline and polymyxin B in CSF were retrospectively determined by two-dimensional high-performance liquid chromatography (2D-HPLC) and HPLC coupled with tandem mass spectrometry (HPLC-MS/MS), respectively  was administered. The intraoperative course of the patient was uneventful. However, the postoperative MRI examination showed an incomplete skull base reconstruction on the following day , the patient presented with remittent fever , IV polymyxin B , and cefoperazone/sulbactam (3 g every 6 h) on March 15, 2019. Polymyxin B was dissolved in saline up to a total volume of 1 mL and slowly injected into the CSF . After eAt the 12-months follow-up, the patient was in good clinical condition without signs of intracranial infection. Neurologically, vision in both his eyes was normal. Skin hyperpigmentation  and streA. baumannii meningitis following neurosurgical surgery and subsequent CSF rhinorrhoea. The risk factors such as CSF leakage, lumbar drainage placement, and repeated transnasal endoscopic repair may be significantly associated with subsequent A. baumannii meningitis of this patient  and 120,000 IU (divided into two doses) in children . The durtoxicity . HoweverThe present case enriched the PK information of polymyxin B in CSF, which may improve the clinical practice of polymyxins, especially in pediatric patients. However, it has limitations; for example, only one case has been reported. Additionally, the therapeutic drug monitoring (TDM) of tigecycline and polymyxin B in CSF were retrospectively performed after the end of treatment without TDM-based dosing optimization. In the future, real-time PK/PD data obtained from patients during ITH/IVT polymyxin B therapy should be required to optimize polymyxin use with maximal efficacy and minimal adverse effects.A. baumannii meningitis of pediatric patients. IV tigecycline should not be recommended for CNS infections of MDR Gram-negative pathogens because of the poor penetration into CSF. ITH administration of polymyxin B is a convenient route, especially in pediatric patients with lumbar drainage. Additionally, combined treatment with IV and ITH polymyxin B is vital for CSF sterilization. However, the efficacy and safety of tigecycline and polymyxins for pediatric CNS infections need to be clarified. Given the narrow therapeutic windows of polymyxin B, it is necessary to identify a practical PK/PD profile for optimizing dosage regimens of ITH/IVT polymyxin therapy.This case highlights the issues involved in treating life-threatening The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by the ethics committee of Daping Hospital. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin. Written informed consent was obtained from the individual(s), and minor(s)' legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.HX: conceptualization. CC: methodology. YZ: case presentation. YC: writing-original draft. XW: data analysis. DD: data collection. LX and MX: validation, writing-review, and editing. JC: supervision and project administration. All authors have read the last version of this manuscript and agree this submission.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.


Since late April 2020, a syndrome now termed Multisystem Inflammatory Syndrome in Children (MIS-C) has been seen in children and adolescents in association with COVID-19 infection. The definition of MIS-C involves fever, organ dysfunction and laboratory confirmation of inflammation in the context of laboratory or epidemiological evidence of SARS-CoV-2 infection in a patient under 21 years of age. Notably, cases are now being identified in adults termed Multisystem Inflammatory syndrome in Adults (MIS-A). Few cases have been reported in sub-Saharan Africa. We report a case of a young African male presenting with a maculopapular rash, persistent fever, elevation in inflammatory markers and a sudden, significant deterioration in cardiac function resulting in cardiogenic shock. The patient responded to intravenous steroids, intravenous immunoglobulin and background inotropic support. The recognition of this disease entity proves even more crucial now amidst the ongoing global wave of COVID-19 infection. It is paramount to identify these patients early, leading to prompt treatment avoiding further morbidity and mortality. The overall number of cases in this country has increased to 1,246,643 as of 12 January 2021, with case numbers on the rise due the second wave of the disease [The novel coronavirus disease 2019 (COVID-19) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first noted in December 2019 in Wuhan, China [th August 2020, a previously healthy, 17-year-old African male was transferred from a local hospital to the medical admission ward at Chris Hani Baragwanath Academic Hospital (CHBAH), Soweto, Johannesburg. The patient presented with a one week history of fever, generalized rash over the body and eyelids, intermittent headache with associated neck pain, sore throat and a dry cough, preceded by a day history of diarrhoea. There was no history of arthralgias, oral or nasal ulcers, or urethral discharge. There was no prior medical admission, no history of surgery and no significant medication or recreational drug use. He is currently a grade ten scholar. There was no known COVID-19 case contact, however recent travel to Kwa-Zulu Natal two weeks prior was noted  paracetamol with no clinical improvement. Blood investigations showed a rising C-reactive protein (CRP), procalcitonin (PCT), white cell count (WCC), ferritin, lactate dehydrogenase (LDH) and D-dimers . Blood aNeisseria meningitidis, other gram negative bacteria, rickettsia, leptospirosis or malaria. Non-infectious differential diagnoses were also considered: Kawasaki like disease (KD) as well as adult onset Still´s disease (AOSD) were considered in view of the rash, sore throat, elevated ferritin, CRP and erythrocyte sedimentation rate (ESR) in association with neutrophilia. Systemic lupus erythematosus (SLE) was considered on account of fever, rash and low complement  levels. An elevated temperature, rising CRP, PCT, LDH, D-Dimer and ferritin levels with deranged liver function tests (LFT), suggested a diagnosis of MIS-C.An initial wide differential diagnosis of infections was considered: viral infections such as human immunodeficiency virus (HIV) seroconversion, acute infection with Epstein-Barr virus (EBV), herpes simplex virus (HSV) or cytomegalovirus (CMV); and bacterial infections caused by Group A streptococci, On admission, the patient was tachycardic with a mean arterial pressure of 64mmHg, with no clinical or biochemical indicators of end organ hypoperfusion. Intravenous fluid boluses of crystalloid were administered with no significant response in haemodynamic parameters. Fluid boluses were ceased and urine output and serum lactate levels were monitored as markers of tissue hypoperfusion. Inotropes and vasopressors were not initiated as part of initial management. Doxycycline was added as empiric cover for rickettsial disease and ceftriaxone was continued on day two. Hydrocortisone was commenced on admission but discontinued on day three due to concern for infection. A transient resolution of the fever coincided with steroid initiation, and a subsequent elevation in temperature was noted when the steroids were interrupted . On day An IV methylprednisolone pulse of 500mg daily for three days was initiated with the IVIG on day five of admission. Serological testing for SARS-CoV-2 was performed at the National Institute for Communicable Diseases (NICD) and confirmed the presence of immunoglobulin (IgG) antibodies against the SARS-CoV-2 trimeric spike protein with in-house enzyme-linked immunosorbent assay (ELISA) testing. A bone marrow aspirate and trephine (BMAT) revealed increased macrophage activity, but did not meet criteria for macrophage activation syndrome (MAS). Doxycycline and ceftriaxone were discontinued after four and seven days, respectively. Colchicine was added to cover for possible associated myopericarditis. Defervescence was noted on day six , accompaMr. LN was reviewed 2 weeks later in the rheumatology outpatient clinic and was noted to have recovered fully with no residual symptoms. On examination there was complete resolution of the rash, with only few areas of residual hyperpigmentation. He had no tachycardia or signs of heart failure. A repeat ECHO showed an improvement in EF to 57%, without a pericardial effusion. The prednisone was weaned to 10mg daily and tapered down over the next four weeks. The treatment was well tolerated with no side effects noted. The patient returned to school and will be reviewed in the coming months.Informed consent was obtained from the patient to use historical and clinical information as well as images avoiding identifiable features.Our case study highlights a new disease phenomenon being increasingly recognized during the COVID-19 pandemic with clues to how it may present in our African population. This case report prompts further, larger studies of MIS-C in our setting. We have also included follow up findings and images illustrating the response to treatment. This was a single centre study and generalizations about this disease entity cannot be made.Similar to our patient, studies have noted a predominance of this condition in the African population with up to 52% of patients having had no associated comorbidities . PreviouRaised inflammatory markers are a hallmark of MIS-C including elevation in PCT, CRP, ferritin, and ESR, as seen in our patient. Interleukin 6 (IL-6) levels are also noted to be higher in this group . ElevateStudies have reported the onset of MIS-C occurring three to five weeks post SARS-CoV-2 infection with antibody testing playing a key role in diagnosis ,6. SerocFollowing a release by the CDC of the definition of MIS-C, guidelines have been formulated regarding assessment and management. According to local groups from the Western Cape. Features that should be noted on clinical examination include fever >38°C), rashes, headaches, conjunctivitis, oedema, mucositis and lymphadenopathy on general examination. System examination may reveal meningism, confusion, generalized abdominal pain as well as hypotension or shock, if significant cardiac involvement is present. Baseline investigations include full blood count (FBC), D-Dimer, ferritin, PCT, LDH, LFTs, international normalized ratio (INR), triglycerides and blood cultures. Other helpful bedside investigations include urine dipstick and electrocardiogram (ECG). Serology for SARS-CoV-2 should be drawn if MIS-C is suspected. Troponin and pro brain natriuretic peptide (pro-BNP) are recommended if clinically indicated or if any new abnormalities are noted on ECG. Further tests include lumbar puncture, ECHO, as well as chest radiograph and/or abdominal ultrasound if indicated [°C, rasheImportant differential diagnoses considered in this patient included infectious causes such as viral, (including HIV seroconversion), and bacterial infections. The viral panel on serum and cerebrospinal fluid was however negative and no organisms were cultured on repeated blood cultures and specific serological testing. HIV seroconversion may present as acute retroviral syndrome within two to four weeks of exposure with findings common to MIS-C being fever, rash, diarrhoea and headache . HoweverManagement guidelines have been drawn from the treatment of KD and other associated rheumatological diseases. The aims of treatment are to abate systemic inflammation and prevent further organ dysfunction. Currently there remains no set algorithm regarding treatment, with IVIG and glucocorticoids recommended alone or in combination ,8. StudiOur patient´s case along with others, illustrates the importance of early recognition and diagnosis of MIS-C due to the rapid clinical deterioration associated with the hyperinflammatory state. This condition is now increasingly seen in the adult and adolescent population highlighting the need for heightened awareness amongst those treating adults. Careful consideration is required due to the nonspecific nature of symptoms, clinical features and the wide differential which includes infection in our sub-Saharan African setting. Importantly, lack of access to serological testing for SARS-CoV-2 should not delay diagnosis and management of MIS-C, as early treatment is crucial in preventing further organ damage. This case also highlights the importance of collaboration between adult medical and paediatric specialists. Further studies are required in our setting to monitor the outcome and long-term sequelae in these patients with MIS-C.


This statement summarises basic settings in lung ultrasonography and best practice recommendations for lung ultrasonography in COVID-19, representing the agreed consensus of experts from the Ultrasound Subcommittee of the European Society of Radiology (ESR). Standard lung settings and artefacts in lung ultrasonography are explained for education and training, equipment settings, documentation and self-protection. Chest multislice-CT is still regarded as the gold-standard imaging technique for thoracic evaluation.Lung ultrasonography can show typical pattern for interstitial pneumonia.COVID-19 lesions mainly involve the peripheral pulmonary zones, which makes this disease accessible for pulmonary ultrasonography evaluation.Lung ultrasonography can make a substantial contribution, as it allows direct bedside examination of the lung and pleural space.Lung ultrasonography in experienced hands can give results that are comparable to chest MS-CT and superior to standard chest radiography for assessment of pneumonia and/or adult respiratory distress syndrome (ARDS).According to the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University (JHU), Coronavirus COVID-19 disease prevalence has increased globally day-to-day since early 2020, passing a total of more than 111 million infections worldwide in mid-February 2021, and more than 2.45 million deaths worldwide by this date. At the time of writing, the number of proven cases continues to rise, particularly in the USA, Russia, South America and Europe . The extSpreading mainly through the droplet route, the virus predominantly causes mild symptoms, the most common being temperature (80%), dry cough 56%), fatigue (22%) and muscle pain (7%); less common signs include a painful throat, a runny nose, diarrhoea, haemoptysis and chills . A life-6%, fatigDue to the continual development of their clinical condition, critically ill patients need thoracic imaging frequently . ThoraciMultislice-CT remains the gold standard imaging method for thoracic evaluation . As pulmLung ultrasonography in experienced hands can give results comparable to chest CT and superior to standard chest radiography for evaluation of pneumonia and/or adult respiratory distress syndrome (ARDS), with the additional benefit of ease of use, repeatability, absence of radiation exposure, and low cost , 24. TheThoracic and lung ultrasonography have increased in importance over the past decade –30, partA lung ultrasonography examination was first executed more than half century ago , 33. ExcSevere dyspnoea is a common presenting initial sign in the emergency room and the ICU. The variety of thinkable differential diagnoses is extensive; after history-taking, physical examination and determination of the vital parameters, prompt bedside emergency ultrasonography can be helpful. Focused pulmonary ultrasonography is a significant component of emergency ultrasonography beside dedicated ultrasonography of the abdomen and heart. While recommendations exist for elective chest ultrasonography , 39 and In the diagnosis of lung pathologies, ultrasonography artefacts arising from the chest wall and pleural surface can provide valuable information and may correlate with the existing lung pathophysiology. There are two major ultrasonographic artefact patterns that a clinician may detect: “A-lines” and “B-lines” in rare cases even “C-lines” are visible .A-lines are reverberation artefacts triggered by oscillating tissue with an air interface, causing the ultrasonography waves to be reflected strongly and to reverberate , 44. AmoIn 1982, Ziskin et al. first described the “comet-tail” ultrasonographic sign, seen when an intrahepatic shotgun pellet was detected to generate an artefact like to what is seen in celestial comets . On lungC-lines are small anterior lung consolidations suggest pneumonia; they are 18 times more often than pulmonary embolism  Fig. 3)3).Fig. 3For preoperative and postoperative transthoracic ultrasonography, most conventional US systems are suitable, using the "real-time B-mode" technique. There is a broad selection of different ultrasonography transducers which may be used for lung ultrasonography (LUS) , 48. EacPublished studies on lung ultrasonography have used a variety of transducers, including high-frequency linear, low-frequency curvilinear and low-frequency sector transducers. In most of the cases, the use of convex and linear transducer will be sufficient . Low-freThe most suitable transducer for bedside lung ultrasonography (BLUE) will be low-frequency convex transducers, because they can visualise the deep postero-lateral structures and can reveal consolidation and pleural effusion , 45. In High-frequency linear transducers, with more-shallow penetration, may be superior for identifying pneumothorax and examining the superficial anterior structures. They are suitable for children and thin adults .Specialised phased-array and microconvex transducers can be used to detect a broad variety of abnormalities, such as consolidation and pleural effusion .In order to evaluate vessels and the vascularisation of pathological findings, basic ultrasonography units should be equipped with pulsed and colour Doppler and M-mode .The diagnostic value of B-mode ultrasonography can be enhanced by using the dynamic M-mode. In the M-mode setting, a solitary vertical line of the ultrasonography image is selected. The detected ultrasonography signals of this line are displayed over time in a separate diagram. By using this M-mode setting, tissue movements will be represented as curves. Structures which are not moving appear as a horizontal line. By using the M-mode technique, the system displays a representation of tissue motion over time during the lung examination .In order to improve B-mode quality, most ultrasonography manufacturers use Compound Imaging and Harmonic Imaging. By disabling these modes, comet-tail artefacts or B-lines will be displayed more clearly , 44.Standard settings such as focal zone, image depth and overall gain should be adjusted to improve visualisation of the pleural line .Due to the extended exposure time of ultrasonography operators scanning COVID-19 patients, the risk of coronavirus transmission will be increased. Therefore adequate personal protective equipment should be worn while examination COVID-19 positive patients or patients with a high risk of being COVID-19 positive. According to Piscaglia et al., personal protective equipment should include FFP2 (N95) or FFP3 faces masks, gloves, disposable caps, shoe covers, protective glasses, goggles or face barriers in order to protect operators from potentially infectious patients, and also to protect patients from contracting COVID-19 from asymptomatic healthcare personal , 51, 52.Most ultrasonography systems are not designed for cleaning with liquid disinfectants. Extended disinfection with liquid disinfectant solutions will almost invariably damage the controls, knobs and keypad. To resolve this problem, the US machine should be covered entirely with transparent, thin, disposable nylon/plastic bags. This may interfere with cooling of the ultrasonography system, and potential overheating should be monitored. An additional option is to only cover the screen and the main keyboard/controls , 54. UnfUnder standard ultrasonography examination circumstances a cleaning tissue to wipe the probes might be adequate , 56. NevLung ultrasonography is used in emergency and ICU patients in recumbent  and—depending on the clinical situation—in a sitting position . In order to cover the complete lung, the examination should be performed in a systematic manner that investigates the entire anterolateral and posterior lung surfaces bilaterally; if necessary, selective regional lung ultrasonography can be performed with a patient-focused abbreviated approach .According to Lu et al., each hemithorax should be divided into six regions : anterioUsually, transthoracic scanning windows, using the intercostal spaces, will be used for the examination of the lung and pleura . In mostUltrasonography can be useful in addition to CT and CXR, or on its own, for the primary diagnosis and follow-up of COVID-19 disease . COVID-1The morphology and variations of subpleural lesions, changes of air and water content in consolidated peri-pulmonary tissues and air bronchograms, can be detected, using the low-frequency capability of curved transducers  Fig. 4)4).Fig. 4The findings and treatment of central lung diseases is currently limited in lung ultrasonography, due to the attenuation of sound waves by normal lung and bone tissues. The diagnosis of lung ultrasonography abnormalities relies on the artefacts created by peri-pulmonary lesions , 61. An The presence of B-lines artefacts  will vary among focal, multifocal and confluent patterns of involvement . The extIn COVID-19 lung disease, pleural effusions are uncommon; patients are generally more critically ill if pleural effusions are seen Fig. . An indiLung ultrasonography has substantial use in management of COVID-19 pneumonia in the ICU, due to its non-invasive assessment and dynamic observation of lung lesions , 64. Lun


An abdominal aortic aneurysm (AAA) is a localized dilatation of the aorta related to the regional weakening of the wall structure, resulting in substantial morbidity and mortality with the aortic ruptures as complications. Ruptured AAA is a dramatic catastrophe, and aortic emergencies constitute one of the leading causes of acute death in older adults. AAA management has been centered on surgical repair of larger aneurysms to mitigate the risks of rupture, and curative early diagnosis and effective pharmacological treatments for this condition are still lacking. Nanoscience provided a possibility of more targeted imaging and drug delivery system. Multifunctional nanoparticles (NPs) may be modified with ligands or biomembranes to target agents' delivery to the lesion site, thus reducing systemic toxicity. Furthermore, NPs can improve drug solubility, circulation time, bioavailability, and efficacy after systemic administration. The varied judiciously engineered nano-biomaterials can exist stably in the blood vessels for a long time without being taken up by cells. Here, in this review, we focused on the NP application in the imaging and treatment of AAA. We hope to make an overview of NP-assisted diagnoses and therapy in AAA and discussed the potential of NP-assisted treatment. An abdominal aortic aneurysm (AAA) is a localized dilatation of the aorta related to the regional weakening of the wall structure, resulting in substantial morbidity and mortality with the aortic ruptures as complications. The disease's prevalence depends on the population studied, with reported prevalence varying between 1.4 and 12.4% , 4, possvia targeted delivery.Nanoscience provided a possibility of more targeted imaging and drug delivery system. Nanoparticles (NPs) are particles in the nanometer range (1–100 nm), which are more than 100 times smaller than human cells, and have biological activity and fluidity in both the internal and external blood vessel systems . MultifuHere in this review, we focused on the NP application in AAA. We summarized the NP-assisted imaging and treatment of AAA to overview the value of NP in AAA diagnosis and treatment and discuss the potential use in AAA.Most AAAs are asymptomatic until severe complications such as rupture occur, leading to patients' sudden death . On the in vivo tracking of therapeutic cells (in vivo targeting of AuNPs conjugated with elastin (EL-AuNPs) of damaged aortic elastin in AAA lesions, and a correlation between micro-CT-based signal intensities and burst pressures was found. Lane et al. also used EL-AuNPs as a diagnostic tool for evaluating unruptured AAAs. Electron dense EL-AuNPs were visualized by micro-CT, and the corresponding gold-to-tissue volume ratios quantified. The gold-to-tissue volume ratios correlated strongly with the concentration of infused porcine pancreatic elastase and therefore the degree of elastin damage . There have been studies exploring the application of CT in the diagnosis of AAA. For example, CT signal heterogeneity measurements in small AAAs have been revealed as a useful risk stratification tool to identify aneurysms with a high risk of significant expansion . Gold NPic cells . Using aic cells  revealedn damage . These f18F-FDG) uptake in patients with AAA, suggesting a possible association between increased 18F-FDG uptake and AAA expansion and rupture , MRI can obtain three-dimensional tomographical information with high temporal–spatial resolution in whole tissue samples. The protons' alignment was generated in the body by a powerful magnetic field and then excited by a radiofrequency pulse (RF pulse), causing proton resonance. The energy is released, and the proton spins back to the equilibrium state after being removed from the RF pulse, which can be detected by MRI sensors without involving harmful radioactivity . T1-weig*-weighted gradient-echo images showed areas of hypointense signal within the aortic wall immediately and up to 1 month after cell therapy, indicating that MRI with magnetic cell labeling can be used to document endovascular cell delivery , which were used to identify further magnetic cell labeling's ability in assessing the success of endovascular cell therapy for AAA. T2delivery . Kitagawdiseases .Since collagen is a significant AAA component, NPs targeting collagen could be beneficial in AAA imaging . In a pr18F-FDG PET-CT and USPIO-enhanced MRI, both 18F-FDG PET-CT and USPIO-MRI uptake identify vascular inflammation associated with AAA  activation contributes to AAA growth and rupture. Yao et al. conducted a study to evaluate the ability of a novel activatable MRI nanoprobe to target MMPs in an ANG II-induced AAA model . This na99mTc-NC100692) to investigate integrin-targeted imaging for detecting vessel wall inflammation  (PLA) nanoparticles (EL-PEG-PLA NPs) binding in the elastic laminae in elastase perfusion model and CaCl2 model  degradation, represent a promising drug class for AAA treatment. However, thus far, none of them has reached clinic success. The main limiting factors are low efficacy at low dosages but high toxicity at high dosages, quick activity loss in blood circulation, and low water solubility , 69. Resvia mini-osmotic pumps or peri-aortic foams, the doxycycline dosage sufficient to inhibit MMP activities in vivo could be lowered (co-glycolic acid) (PLGA) NPs for elastin-targeted delivery of doxycycline to AAA sites (via a double-emulsion solvent evaporation technique using a di-dodecyl dimethyl ammonium bromide (DMAB), a cationic surfactant, followed by PEGylation to prolong the blood circulation time and increase the water solubility  (PEG-b-PBLG) that was synthesized and formed a micellar NP via self-assembly -assembly . Shirasuuate AAA . Later iuate AAA . They geuate AAA , 80. Rapin vitro experiments, this unique design proved responsive  to the H2O2 condition and inhibitory to oxidative stress and VSMC apoptosis by acting as a ROS scavenger. When administered to a CaCl2-induced AAA rat model, this NP conjugated with c (RGDfK) demonstrated the outstanding aneurysm-targeting ability. Furthermore, the rapamycin-loaded formulation exhibited clear therapeutic benefits, as indicated by reduced AAA size, MMP activity, macrophage infiltration, and endothelial deterioration -responsive and targeted nanoplatforms to deliver rapamycin. In the ioration .Hyaluronic acid or hyaluronan (HA), a glycosaminoglycan (GAG) in the ECM , was repin vitro, the authors accumulated that NP-assisted delivery holds the promise for TGF-β1-based therapy in AAA management (Transforming growth factor-beta 1 (TGF-β1), a polypeptide that regulates cell growth, differentiation, proliferation, and apoptosis , is alsonagement .in vivo. The system was composed of a targeted graft labeled with a small target molecule and the target-recognizing nanocarrier, which contained suitable drugs. The drug released from this drug delivery system reduced the expression of MMP-9 in mouse aortas  (PCL) bi-layered vascular graft consisting of an internal layer with circumferentially aligned microfibers and an external layer with random nanofibers. The circumferentially oriented VSMCs were successfully regenerated after the grafts were implanted in the rat abdominal aorta for 3 months. Then they investigated the long-term (18 months) performance of the bi-layered grafts in the same model. They found that most of the grafts' luminal surface circumferentially oriented VSMCs migrated to the grafts' luminal surface to form a neointima with uniform thickness. Accordingly, ECM including collagen, elastin, and GAG displayed high density in the neointima layer while low density in the walls of the graft because of the incomplete degradation of PCL. However, the contraction and relaxation function of regenerated neoartery almost disappeared. Other factors of grafts should be considered to achieve the regenerated artery similar to the native vessels after long-term implantation, but this is still a potential orientation in AAA graft . What is2-induced AAA model, and elastase-induced AAA model, but none of these models can accurately reproduce the pathogenic environment and disease progression of AAA patients. For instance, the complex hemodynamic changes in AAA are hard to achieve in these models. Second, the extended timing and costs, as well as potential immunogenic response, are also significant challenges to translate preclinical findings from animal models to human settings. Third, although, NPs conjugated with antibodies  have high selectivity of AAA lesions, they are unstable in the organic solvent and are easy to denature during the conjugation process  in AAA. In order to better understand the basic hemodynamic features in AAA imaging and seek potential treatment, many investigations have been made –102. JucIn further research, more drug-coated NP delivery systems will be developed to get an AAA-targeted local treatment. Moreover, NPs in stent graft coated with therapeutic agents or targeted components have a promising prospect in AAA treatment.LY and KZ wrote this manuscript. ZL provided the topic of this review and performed the critical revision of the manuscript. ZL and YS contributed to the concept of this manuscript. All authors read and approved the final manuscript.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.


Recommendations to improve older adults' health and well-being focus on enhancing meaning in life through social interaction. Research studies have suggested that a tablet-based intervention can create opportunities to enhance meaning in life, thus reducing social isolation and loneliness. The purpose of this study was to examine the feasibility of using a tablet-based intervention to enhance meaning in life among older adults. Senior Meaning in Life Enhancement (SMiLE) is a tablet-based application developed and implemented based on person-centered counseling, logotherapy, and Acceptance Commitment Therapy (ACT). Thirty-one participants (adults aged over 65 years) were randomized for intervention (n = 15) or waitlist control (n = 16). The intervention group received a tablet with our embedded app. Participants were invited to participate in the app-based 2-month program for 30-minutes each day with the tablet. We evaluated pre-and post-semi-structured interviews, meaning in life scales, and usability tests. Data were analyzed using thematic analyses, descriptive statistics, and Mann–Whitney and Wilcoxon tests. Findings confirmed that at two months after the intervention, there was a statistically significant difference in the gap between pre-and post-meaning in life scores between the two groups . Furthermore, qualitative findings included positive changes in behavior, relationships, and usability. This pilot study suggests the feasibility of a tablet-based intervention in older adults and demonstrates its potential benefit for meaning in life. These findings are valuable to researchers, practitioners, and designers interested in technological interventions for older adults.