Molecular Imaging最新文献

{"title":"Multiparametric CEST MRI for Time-Associated Characterization of Acute Ischemic Stroke: NOE (-3.5 ppm) Signal as a Potential Imaging Biomarker.","authors":"Zitong Min, Yupeng Wu, Hongjie Huang, Qifan Pang, Hui Xu, Mingyang Peng, Huiyou Chen, Xindao Yin, Jianqi Li, Liang Jiang","doi":"10.1177/15353508261477596","DOIUrl":"10.1177/15353508261477596","url":null,"abstract":"<p><p>This study investigated time-dependent group-level changes in chemical exchange saturation transfer (CEST) signals in a mouse model and explored utility in identifying stroke onset time. Multiparametric magnetic resonance imaging (diffusion weighted imaging, arterial spin labeling, and CEST) was conducted on 12 normal and 26 ischemic mice. Imaging findings were validated by immunohistochemical analysis. CEST parameters in infarct and penumbra were compared between strokes within 4.5 h and over 4.5 h. Correlations, regression, and receiver operating characteristic curves evaluated performance. Infarct guanidine, magnetization transfer (MT), nuclear Overhauser enhancement (NOE) (-3.5 ppm), and NOE (-1.6 ppm) significantly differed between groups and associated with onset time (<i>P</i> < .01). MT, NOE (-3.5 ppm), NOE (-1.6 ppm) showed significant associations with onset time in univariate logistic regression (<i>P</i> < .05). The NOE (-3.5 ppm) achieved an area under the curve of 0.848 (95% CI: 0.655-1.000), outperforming apparent diffusion coefficient (<i>z</i> = -2.397, <i>P</i> = .017) and cerebral blood flow (<i>z</i> = -2.271, <i>P</i> = .0271). NOE (-3.5 ppm) signals and lipid peroxidation both declined progressively with ischemic duration. These findings indicate that NOE (-3.5 ppm) signal attenuation parallels lipid peroxidation and may indicate progressive membrane lipid loss in ischemia.</p>","PeriodicalId":18855,"journal":{"name":"Molecular Imaging","volume":"25 ","pages":"15353508261477596"},"PeriodicalIF":2.4,"publicationDate":"2026-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13452940/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148701832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Review of Fluorophores for Fluorescence-Guided Surgery in Breast Cancer.","authors":"Naomi S Laskar, Aidan B Pidd, Dhurka Shanthakumar, Kimberly J C Tan, Edward W Tate, Daniel S Elson, Daniel R Leff","doi":"10.1177/15353508261471742","DOIUrl":"10.1177/15353508261471742","url":null,"abstract":"<p><p>Imprecision in breast-conserving surgery results in re-excision in 20% of cases, delaying adjuvant therapy and increasing patient anxiety and financial burden. Fluorescence-guided surgery (FGS) enables real-time tumor visualization and may improve surgical precision. This systematic review evaluates fluorophores investigated for intraoperative navigation in breast cancer. Medline, Embase, Scopus, and Web of Science were searched using \"breast cancer,\" \"surgery,\" \"fluorophore,\" and \"near-infrared.\" Eligible studies investigated in vivo fluorophores for invasive breast cancer in animals or humans. Of 1946 studies, 65 met the inclusion criteria. Extracted data included fluorophore administration, mechanism, optical properties, imaging systems, safety, and diagnostic accuracy. Dual-modality studies were excluded. 58 fluorophores were evaluated across 761 human and 520 animal subjects. Most agents emitted within the near-infrared-I (NIR-I) window (74.1%), while 11 utilized NIR-II imaging for deeper penetration. Indocyanine green (ICG) was the most widely studied fluorophore, demonstrating a pooled clinical tumor-to-background ratio (TBR) of 2.25 ± 0.74 (95% CI 2.10-2.39); sensitivity 80.8% (95% CI 72.5-89.2%); specificity 93.3% (95% CI 88.1-98.6%). IRDye800CW-trastuzumab demonstrated higher pooled TBRs of 4.83 ± 1.77 (95% CI 4.27-5.40). Nanoparticle-based fluorophores showed high contrast but remained preclinical. FGS is rapidly evolving, but no fluorophore has demonstrated optimal performance across translational endpoints; standardized reporting remains essential.</p>","PeriodicalId":18855,"journal":{"name":"Molecular Imaging","volume":"25 ","pages":"15353508261471742"},"PeriodicalIF":2.4,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13389200/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148562613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increased Brownian Motion of Water Molecules in Livers With Advanced Fibrosis: Preclinical and Clinical Observations With Magnetic Resonance Imaging (MRI).","authors":"Fan-Yi Xu, Gen-Wen Hu, Cun-Jing Zheng, Hua Huang, Jie-Qi Luo, Guang-Ping Zheng, Xiao-Hui Duan, Romaric Loffroy, Yì Xiáng J Wáng","doi":"10.1177/15353508261465601","DOIUrl":"10.1177/15353508261465601","url":null,"abstract":"<p><p>Despite the increased water content in fibrotic livers, numerous studies reported a decrease in apparent diffusion coefficient (ADC) in liver fibrosis. We argue that the ADC decrease in fibrotic livers is due to the \"T2 shine-through\" of ADC, as the longer T2 in liver fibrosis leads to less signal decay between the low and high <i>b</i>-value images. The metric slow diffusion coefficient (SDC), predominantly measuring Brownian motion of water molecules, was proposed to mitigate the difficulties associated with this \"T2 shine-through\" of ADC. This study calculated ADC and SDC of 1 rat study with liver fibrosis induced by biliary duct ligation (BDL), and 3 sets of human liver fibrosis data. To tease out the menopausal effect on liver SDC, only the results of men's livers were analyzed for the human datasets. The rat study showed that liver ADC decreased stepwise (in weeks after BDL procedure) following fibrosis induction, and SDC increased stepwise. In human studies, all 3 datasets consistently showed that advanced fibrosis had a liver ADC lower than that of earlier stage fibrosis; advanced fibrosis had a liver SDC higher than that of earlier stage fibrosis.</p>","PeriodicalId":18855,"journal":{"name":"Molecular Imaging","volume":"25 ","pages":"15353508261465601"},"PeriodicalIF":2.4,"publicationDate":"2026-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13319571/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148369269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Carrier-Free Ce6&SR717 Nanomedicine Enables Abscopal Photoimmunotherapy via cGAS-STING Activation in Breast Cancer.","authors":"Xin Peng, Yi Sun, Yudong Guan, Tong Su, Xu Yang, Yanqiu Zhang, Youzhi Qi, Xiaoli Mai, Xuzhi Shi, Yongkang Dai, Guang Li, Yunmeng Bai, Pu Zhang, Xiaoyan Xin","doi":"10.1177/15353508261464127","DOIUrl":"10.1177/15353508261464127","url":null,"abstract":"<p><p>Potent STING agonists are among the most promising strategies for reversing immunosuppression in \"cold\" tumors, but <i>in vivo</i> antitumor efficacy is frequently limited by dose-limiting systemic toxicity and inadequate tumor selectivity. To achieve localized STING activation and robust systemic immunity, we combined STING agonism with photodynamic therapy (PDT), creating a carrier-free nanoplatform (Ce6&SR717 NPs) through self-assembly of SR717 (STING agonist) and Ce6 (chlorin e6, photosensitizer). This excipient-free design achieves maximum drug loading, alleviates carrier-related safety issues, and realizes the spatiotemporally synchronized activation of PDT-induced immunogenic cell death and STING signaling through irradiation, which establishes an auto-amplifying cycle of on-site antigen release and systemic immune priming. In the murine breast cancer model, Ce6&SR717 NPs plus laser irradiation dramatically increased CD8⁺ T-cell infiltration within the tumor, triggered strong systemic antitumor immunity, and suppressed both primary and distant tumors. Collectively, these results identify Ce6&SR717 NPs as a safe and efficient modality for synergistic photo-immunotherapy of immunologically cold tumors.</p>","PeriodicalId":18855,"journal":{"name":"Molecular Imaging","volume":"25 ","pages":"15353508261464127"},"PeriodicalIF":2.4,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13305515/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148345904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Radiomic Analysis of MRI for Assessing Response to Neoadjuvant Chemoradiotherapy in Rectal Adenocarcinoma: A Systematic Review and Metaanalysis.","authors":"Murat Jakipov, Amin Tamadon, Zhandos Burkitbayev, Bayram Kochiev, Aslan Karimov, Aigerim Temirbayeva, Yerbolat Iztleuov, Prashant Jamwal, Keivan Daneshvar, Nadiar M Mussin, Ramazon Safarzoda Sharoffidin","doi":"10.1177/15353508261462778","DOIUrl":"10.1177/15353508261462778","url":null,"abstract":"<p><strong>Background: </strong>This study aimed to evaluate the diagnostic performance of magnetic resonance imaging (MRI)-based radiomics for predicting pathological complete response (pCR) after neoadjuvant chemoradiotherapy in patients with locally advanced rectal adenocarcinoma.</p><p><strong>Methods: </strong>Eligible studies developed MRI-based radiomics or deep learning models to predict pCR and reported sufficient data to reconstruct 2 × 2 contingency tables. Only validation cohorts were included in the quantitative synthesis. Study quality was assessed using Quality Assessment of Diagnostic Accuracy Studies-2 and the Radiomics Quality Score. Pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio were estimated using a bivariate random-effects model. Hierarchical summary receiver operating characteristic (HSROC) analysis was performed.</p><p><strong>Results: </strong>Thirty-eight studies were included. The pooled sensitivity and specificity were 0.82 (95% CI, 0.71-0.90) and 0.86 (95% CI, 0.80-0.91), respectively. The pooled PLR and NLR were 6.0 (95% CI, 4.0-8.9) and 0.21 (95% CI, 0.12-0.35), corresponding to a diagnostic odds ratio of 29 (95% CI, 14-61). HSROC analysis showed an area under the curve of 0.846. Subgroup analyses suggested improved performance for deep learning and combined clinical-radiomic models.</p><p><strong>Conclusion: </strong>MRI-based radiomics demonstrates good diagnostic accuracy for predicting pCR after neoadjuvant chemoradiotherapy in rectal cancer, although methodological heterogeneity and limited prospective validation remain challenges.</p>","PeriodicalId":18855,"journal":{"name":"Molecular Imaging","volume":"25 ","pages":"15353508261462778"},"PeriodicalIF":2.4,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13276228/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148295767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Self-Supervised Learning Method for 3D Detection of Lung Cancer Based on PET Imaging.","authors":"Rui Zhang, Tie Cai, Shengyun Liang, Chao Cheng, Xuechen Li","doi":"10.1177/15353508261458538","DOIUrl":"10.1177/15353508261458538","url":null,"abstract":"<p><strong>Background: </strong>Positron emission tomography (PET) is one of the most effective imaging methods for detecting lung cancer, and artificial intelligence-based approaches are increasingly being applied to PET-based lung cancer detection. However, this typically requires a large amount of labeled data for training, while obtaining sufficient labeled PET imaging data remains challenging.</p><p><strong>Objective: </strong>To improve the accuracy of three-dimensional (3D) lung cancer detection in PET images and address the issue of scarce labeled data, this study aims to propose a novel self-supervised learning method based on the pseudo image generation.</p><p><strong>Methods: </strong>This method first uses a spatial tumor simulator to generate 3D images resembling real lung cancer lesions, and randomly implants them into the lung regions of PET images to construct pseudo-lung-cancer PET images. Subsequently, a restoration task based on pseudo-cancer images and normal images is designed as a self-supervised pretraining objective, using the 55 training cases to generate paired original and pseudo-lesion PET images, which are used to pretrain a Dual-Attention Hybrid Unet (DH-Unet) encoder-decoder integrated with a self-attention mechanism. Finally, the model is fine-tuned using real labeled PET data from these same 55 cases, along with 10 additional test cases, all pathologically confirmed as lung cancer, to complete the 3D lung cancer detection task.</p><p><strong>Results: </strong>Experimental results show that this method achieves significant performance in the lung cancer detection task, with an mAP@ 0.10 to 0.50 of 0.4616, which is 13.72% higher than that of the random initialization method and 11.1% higher than that of traditional self-supervised models.</p><p><strong>Conclusion: </strong>The proposed self-supervised learning framework, which combines pseudo image generation and a self-attention-equipped DH-Unet, provides an effective approach for improving lung cancer detection in PET imaging, especially in scenarios with limited labeled data.</p>","PeriodicalId":18855,"journal":{"name":"Molecular Imaging","volume":"25 ","pages":"15353508261458538"},"PeriodicalIF":2.4,"publicationDate":"2026-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13263499/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148252429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Low-Dose ¹²⁵I-Irradiation Enhances PRC1-Targeted NIS-CAR-T Cell Cytotoxicity Against Breast Cancer Cells.","authors":"Mengda Niu, Bai Yang, Xinxin Zhou, Jingjing Qin","doi":"10.1177/15353508261459491","DOIUrl":"10.1177/15353508261459491","url":null,"abstract":"<p><p>The efficacy of chimeric antigen receptor (CAR)-T therapy in solid tumors is limited by the immunosuppressive microenvironment and poor T-cell infiltration. Radiotherapy offers immunomodulatory potential, yet its synergy with CAR-T via targeted internal radionuclides remains unexplored. Here, we identified protein regulator of cytokinesis 1 (PRC1) as a novel immunotherapeutic target. Through bioinformatic analysis, we engineered PRC1-specific CAR-T cells coexpressing the sodium iodide symporter (NIS) and an shRNA targeting SLC26A4, enabling enhanced iodide uptake and retention. These NIS-CAR-T cells demonstrated potent, antigen-restricted cytotoxicity and cytokine secretion upon co-culture with breast cancer cells. Low-dose ¹²⁵I selectively induced cytolysis in tumor cells without impairing CAR-T function. At low effector-to-target ratios mimicking poorly infiltrated \"cold\" tumors, internal irradiation via ¹²⁵I significantly boosted CAR-T killing, even against low-antigen tumors. This study introduces a multifunctional CAR-T platform that integrates internal radiotherapy to overcome key barriers in solid tumors, thereby offering a radiosensitized cellular therapy designed for the hostile tumor microenvironment.</p>","PeriodicalId":18855,"journal":{"name":"Molecular Imaging","volume":"25 ","pages":"15353508261459491"},"PeriodicalIF":2.4,"publicationDate":"2026-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13250420/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148226711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to \"Positron Emission Tomography (PET) with ¹⁸F-FGA for Diagnosis of Myocardial Infarction in a Coronary Artery Ligation Model\".","authors":"","doi":"10.1177/15353508261438968","DOIUrl":"https://doi.org/10.1177/15353508261438968","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.1155/2022/9147379.].</p>","PeriodicalId":18855,"journal":{"name":"Molecular Imaging","volume":"25 ","pages":"15353508261438968"},"PeriodicalIF":2.4,"publicationDate":"2026-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13198643/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148016418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Imaging Sphingosine-1-Phosphate Receptor: A Promising Strategy to Neuroinflammation of Epilepsy.","authors":"Shuxian Xu, Yanbo Yu, Matthew R Brier, Tammie L S Benzinger, Zhude Tu","doi":"10.1177/15353508261451369","DOIUrl":"10.1177/15353508261451369","url":null,"abstract":"<p><p>Epilepsy is a complex neurological disorder characterized by recurrent, unprovoked seizures. Emerging evidence indicates that the sphingosine-1-phosphate receptor (S1PR) family plays a significant and multifaceted role in the pathological processes underlying epileptogenesis and blood-brain barrier integrity. This review comprehensively explores the intricate role of S1PR signaling in epilepsy, with a particular focus on the integration of neuroimaging findings. In this review, we summarize recent advances in Positron Emission Tomography techniques that offer invaluable insights into S1PR-related pathophysiological changes in the epileptic brain. Furthermore, we discuss the substantial potential of S1PRs as novel therapeutic targets. By integrating these cutting-edge neuroimaging biomarkers with our evolving understanding of the underlying molecular pathways, this review aims to highlight promising new diagnostic tools and innovative treatment strategies for epilepsy.</p>","PeriodicalId":18855,"journal":{"name":"Molecular Imaging","volume":"25 ","pages":"15353508261451369"},"PeriodicalIF":2.4,"publicationDate":"2026-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13176574/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147964321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bone Tracers for Transthyretin Amyloid Cardiomyopathy: Are [^99mTc]Tc-DPD and [^99mTc]Tc-HMDP Equivalent?","authors":"Julien Dubois, Florentin Kucharczak, Denis Mariano-Goulart, Tom Paunet","doi":"10.1177/15353508261430506","DOIUrl":"10.1177/15353508261430506","url":null,"abstract":"<p><p>The management of transthyretin amyloid cardiomyopathy (ATTR-CM) has revolved around the scintigraphic diagnosis since the introduction of a specific treatment; however, the equivalency of the bone radiotracers remains unclear. This retrospective monocentric observational study compared [^99mTc]Tc-3,3-diphosphono-1,2-propanodicarboxylic acid ([^99mTc]Tc-DPD) and [^99mTc]Tc-hydroxy-methylene diphosphonate ([^99mTc]Tc-HMDP) intensity of myocardial uptake compared with background noise for ATTR-CM suspicion. Two hundred and seventy-four patients who underwent planar scintigraphy after intravenous injection of [^99mTc]Tc-DPD or [^99mTc]Tc-HMDP for ATTR-CM were included. The patients' current visual Perugini grades were retrieved. Regions of interest were measured on the heart (H) and on the contralateral mediastinum (CM), and H/CM ratios were calculated. Although the distribution of quantitative assessments of heart to contralateral mediastinum ratios is wider with [^99mTc]Tc-DPD, no difference in Perugini grades was found between [^99mTc]Tc-DPD and [^99mTc]Tc-HMDP for the diagnosis of ATTR-CM in evocative/non-evocative conditions. There was no difference in ATTR-CM diagnosis between the 2 tracers with a threshold of 1.5 (<i>p</i>-value <0.001 for [^99mTc]Tc-HMDP and for [^99mTc]Tc-DPD). We show in our local cohort that [^99mTc]Tc-DPD and [^99mTc]Tc-HMDP for amyloidosis diagnosis are equivalent for ATTR-CM diagnosis based on the Perugini grading scale.</p>","PeriodicalId":18855,"journal":{"name":"Molecular Imaging","volume":"25 ","pages":"15353508261430506"},"PeriodicalIF":2.4,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13158494/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147931478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}