Thoracic Imaging

Quantitative Differentiation of Left Atrial Performance in Hypertrophic Cardiomyopathy: Comparison Between Nonobstruction and Occult Obstruction With 4-dimensional Volume-strain Objective: The objective of this study was to describe the different components of left atrial (LA) dysfunction predictors in nonobstructive and occult obstructive hypertrophy cardiomyopathy (HCM) patients especially with preserved left ventricular (LV) ejection fraction, particularly using LA 4-dimensional (D) longitudinal and circumferential strains. Methods: Twenty-eight nonobstructive HCM patients and 30 occult obstructive HCM patients according to LV outflow tract gradient at rest and after exercise were prospectively enrolled. 4D echocardiographic evaluation was performed in 58 HCM patients, both nonobstructive and occult obstructive, and 38 control subjects. LA reservoir, conduit, contractile functions were performed by 4D volume-strain with volumes and longitudinal, circumferential strains. Results: Optimal correlation coefficients obtained between LV 4D mass (index) and LA 4D longitudinal/circumferential strain (r=−0.860 to 0.518, all P<0.001). Both nonobstructive and occult obstructive HCM patients had increased volumes and significantly decreased longitudinal, circumferential strain values with lower reservoir, conduit, contractile functions than the controls (all P<0.001). Occult obstructive HCM patients presented incremented volumes compared with nonobstructive ones (P<0.001 to 0.003). Lower conduit function and higher contractile function indicated with lower reservoir function revealed by circumferential strain in occult obstructive HCM patients than nonobstructive ones (P<0.001 to 0.017). Interclass correlation coefficients of intraobserver and interobserver in the LV and LA 4D value evaluations were >0.75 and >0.85, respectively. Conclusions: LA volumes were significantly increased and LA reservoir, conduit, and contractile functions were significantly impaired in HCM patients. Furthermore, different performances of LA functional analyses in nonobstruction and occult obstruction patients with 4D volume-strain echocardiography may facilitate the recognition of subtle LA dysfunctional differentiation in HCM patients. M.S. is a co-first author and contributed equally as H.R. The research protocol was approved by the regional ethics committee, and all included patients provided written informed consent. H.R.: was involved in compilation of the data collected, drafting, and writing the manuscript. M.S. and P.-y.Z.: were the supervisors responsible for echocardiography and revision of the manuscript. L.-l.W., J.-y.R., and X.-w.M.: assisted in the measurement and monitoring the patients' examination. Supported by Nanjing Medical Science and Technique Development Foundation 2017(8). The authors declare no conflict of interest. Correspondence to: Ping-yang Zhang, MD, PhD, Department of Echocardiography, Nanjing First Hospital, Nanjing Medical University, Changle Road 68, Nanjing 210006, Jiangsu Province, China (e-mail: zhpy28@hotmail.com). This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/ Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved

Cardiac Magnetic Resonance Imaging in Coronavirus Disease 2019 (COVID-19): A Systematic Review of Cardiac Magnetic Resonance Imaging Findings in 199 Patients Objective: Cardiac magnetic resonance imaging (CMR) with its new quantitative mapping techniques has proved to be an essential diagnostic tool for detecting myocardial injury associated with coronavirus disease 2019 (COVID-19) infection. This systematic review sought to assess the important imaging features on CMR in patients diagnosed with COVID-19. Materials and Methods: We performed a systematic literature review within the PubMed, Embase, Google Scholar, and WHO databases for articles describing the CMR findings in COVID-19 patients. Results: A total of 34 studies comprising 199 patients were included in the final qualitative synthesis. Of the CMRs 21% were normal. Myocarditis (40.2%) was the most prevalent diagnosis. T1 (109/150; 73%) and T2 (91/144; 63%) mapping abnormalities, edema on T2/STIR (46/90; 51%), and late gadolinium enhancement (LGE) (85/199; 43%) were the most common imaging findings. Perfusion deficits (18/21; 85%) and extracellular volume mapping abnormalities (21/40; 52%), pericardial effusion (43/175; 24%), and pericardial LGE (22/100; 22%) were also seen. LGE was most commonly seen in the subepicardial location (81%) and in the basal-mid part of the left ventricle in inferior segments. In most of the patients, ventricular functions were normal. Kawasaki-like involvement with myocardial edema without necrosis/LGE (4/6; 67%) was seen in children. Conclusion: CMR is useful in assessing the prevalence, mechanism, and extent of myocardial injury in COVID-19 patients. Myocarditis is the most common imaging diagnosis, with the common imaging findings being mapping abnormalities and myocardial edema on T2, followed by LGE. As cardiovascular involvement is associated with poor prognosis, its detection warrants prompt attention and appropriate treatment. The authors declare no conflicts of interest. Correspondence to: Sanjiv Sharma, MD, Department of Cardiovascular Radiology & Endovascular Interventions, All India Institute of Medical Sciences, New Delhi 110029, India (e-mail: meetisv@yahoo.com). Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved

Smooth Muscle Conditions of the Chest: A Clinical, Radiologic, and Pathologic Review Smooth muscle conditions of the chest have diverse clinical and imaging manifestations and may involve nearly every thoracic structure. Differentiation among these conditions requires the integration of clinical, radiologic, and histopathologic data. Histologic examination in conjunction with immunohistochemistry is essential for differentiation from other spindle cell neoplastic mimics. Familiarity with these entities will ensure the inclusion of smooth muscle conditions in the differential diagnosis of thoracic soft tissue lesions and potentially guide the clinician in appropriate management. We review the clinical, imaging, and histopathologic features of thoracic smooth muscle-related conditions organized by the anatomic structures affected. The authors declare no conflicts of interest. Correspondence to: Justin T. Stowell, MD, Department of Radiology, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224 (e-mail: stowell.justin@mayo.edu). Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved

Influence of Asthma Onset on Airway Dimensions on Ultra–high-resolution Computed Tomography in Chronic Obstructive Pulmonary Disease Purpose: Asthma onset before the age of 40 years is associated with distinct clinical manifestations in chronic obstructive pulmonary disease (COPD) patients, but its morphologic features remain unestablished. This study aimed to explore airway morphology in COPD patients with asthma onset before 40 years of age using ultra–high-resolution computed tomography (U-HRCT), which allows a more accurate quantitation of the lumen and the wall in smaller airways than using conventional CT. Materials and Methods: Clinical data of 500 consecutive patients undergoing full inspiratory U-HRCT (1024×1024 matrix and 0.25 mm slice thickness) were retrospectively analyzed. COPD patients without asthma, COPD patients with asthma onset at age below or 40 years and above, and non-COPD smoker controls (N=137, 29, 34, and 22, respectively) were enrolled. The length, lumen area (LA), wall thickness and area (WA), and wall area percent (WA%) of the segmental (third-generation) to sub-subsegmental (fifth-generation) bronchus and the low attenuation volume percent (LAV%) were measured. Results: LA and WA were smaller in the fourth and fifth generation in COPD patients than in non-COPD controls, regardless of the age of asthma onset. LA was smaller and WA% was larger in the fourth-generation and fifth-generation airways in COPD with asthma onset before 40 years than COPD without asthma, whereas WA did not differ between them. In multivariate analyses, asthma onset before 40 years was associated with smaller LA in COPD patients independent of demographics, use of inhaled corticosteroids and long-acting bronchodilators, airflow limitation, and LAV%. Conclusions: Asthma onset before 40 years of age could be associated with greater lumen narrowing of the airways in COPD. This study was partially supported by the Japan Society for the Promotion of Science (JSPS) [Grants-in-Aid for Scientific Research 19K08624]. N.T., S.S, T.O., and T.H. were supported by a grant from FUJIFILM Co., Ltd. K.T. was supported by Canon Medical Systems Corporation. None of these companies had a role in the design or analysis of the study or in the writing of the manuscript. The authors declare no conflicts of interest. Correspondence to: Naoya Tanabe, MD, Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan (e-mail: ntana@kuhp.kyoto-u.ac.jp). Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved

Accessory and Incomplete Lung Fissures: Clinical and Histopathologic Implications Objective: This article reviews the anatomy, histology, and disease processes of pulmonary fissures, with emphasis on clinical implications of accessory and incomplete fissures. Conclusion: Accessory and incomplete pulmonary fissures are often overlooked during routine imaging but can have profound clinical importance. Knowledge of fissure anatomy could improve diagnostic accuracy and inform prognosis for oncologists, interventional pulmonologists, and thoracic surgeons. P.A.B.: primary manuscript author, retrieval and analysis of literature, design and production of tables, and editing and approval of the manuscript. R.A.G., G.M.L., and C.M.W.: data collection, critical review, and editing and approval of the manuscript. D.I.S.: pathologic data collection and analysis, pathologic slide preparation, literature analysis, and editing and approval of the manuscript. R.E.G.: critical review and editing and approval of the manuscript. M.D.G.: project supervision and editing and approval of the manuscript. M.L.: surgical data collection and analysis, surgical photography and video preparation, and editing and approval of the manuscript. J.T.S.: conception and design, senior manuscript author, study coordination, literature review; data collection and analysis, project oversight, and leadership. C.M.W. receives royalties from Amirsys and Elsevier. C.M.W. is a part of the speaker's bureau for Boehringer Ingelheim. The remaining authors declare no conflicts of interest. Correspondence to: Justin T. Stowell, MD, Department of Radiology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224 (e-mail: stowell.justin@mayo.edu). Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved

Cardiovascular Risk Factors and Coronary Calcification in a Middle-aged Dutch Population: The ImaLife Study Purpose: To assess the presence of coronary artery calcium (CAC) and its association with cardiovascular risk factors and Systematic COronary Risk Evaluation (SCORE) risk in a middle-aged Dutch population. Methods: Classic cardiovascular risk factors and CAC were analyzed in 4083 participants aged 45 to 60 years (57.9% women) from the population-based ImaLife study. CAC scores were quantified on noncontrast cardiac CT scans. Age-specific and sex-specific distribution of CAC categories (0, 1 to 99, 100 to 299, ≥300) and percentiles were determined. SCORE risk categories (<1%, ≥1% to 5%, and ≥5%) were compared with CAC distribution. Population attributable fractions (PAFs) of classic risk factors for CAC were estimated. Results: CAC was present in 54.5% male and 26.5% female participants. The percentage of individuals with CAC increased with increasing age. Mean SCORE was 2.0% in men and 0.7% in women. In SCORE <1%, 32.7% of men and 17.1% of women had CAC. In men with SCORE ≥5%, 26.9% had no CAC. Only 0.1% of women had SCORE ≥5%. PAF of classic risk factors for CAC was 18.5% in men and 31.4% in women. PAF was highest for hypertension (in men 8.0%, 95% confidence interval, 4.2%-11.8%; in women 13.1%, 95% confidence interval, 7.9%-18.2%) followed by hypercholesterolemia and obesity. Conclusion: In this middle-aged cohort, more than half of the men and a quarter of the women had CAC. One out of 4 men at high risk (SCORE ≥5%) could be placed into a lower risk category owing to absence of CAC. Thus, adding CAC scoring to SCORE could have considerable effect on cardiovascular risk classification. Elimination of exposure to classic risk factors could reduce limited proportion of CAC in a middle-aged population. The PhD project of Congying Xia is part of the ImaLife project, which is funded by an institutional research grant from Siemens Healthineers and by the Ministry of Economic Affairs and Climate Policy by means of the PPP Allowance made available by the Top Sector Life Sciences & Health to stimulate public-private partnerships. M.O. is involved in the company iDNA BV. The authors declare no conflicts of interest. Correspondence to: Rozemarijn Vliegenthart, MD, PhD, Department of Radiology, University Medical Center Groningen, EB44, Hanzeplein 1, Groningen, 9713 GZ, The Netherlands (e-mail: r.vliegenthart@umcg.nl). This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/ Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved

Prevalence of Abnormal Coronary Findings on Coronary Computed Tomography Angiography Among Young Adults Presenting With Chest Pain Purpose: We evaluated the prevalence of coronary stenosis on coronary computed tomography angiography (CCTA) in patients aged 18 to 30 years, who presented to the emergency department with chest pain. We also examined the risk factors potentially associated with abnormal coronary findings on CCTA in this age group. Materials and Methods: A total of 884 patients were retrospectively evaluated. Indication for CCTA was guided by our hospital's chest pain protocol based on ACC/AHA guidelines. These were performed using the standard technique and interpreted based on CAD-RADS guidelines. Scans were identified as abnormal if atherosclerotic coronary artery disease (CAD), myocardial bridging (MB), or any anatomic coronary artery anomaly were present. Results: Twenty-two percent of patients had a coronary abnormality on CCTA. The most common abnormality was MB (17.3%), followed by CAD (4.4%) and coronary anomalies (1.5%). A small minority had stenosis (2.8%), most commonly caused by CAD. Most cases with stenosis were minimal to mild (72%) with 0.8% having coronary stenosis ≥50%. Age and male sex were risk factors for both coronary artery stenosis (odds ratio: 1.32 and 4.50, 95% confidence interval: 1.03-1.69, and 1.23-16.46, P=0.028 and 0.023, respectively) and CAD (odds ratio: 1.52 and 3.67, 95% confidence interval: 1.14-2.04, and 1.26-10.66, P=0.005 and 0.017, respectively). Conclusions: Epicardial coronary stenosis is rarely the cause of chest pain among young adult patients presenting to the emergency department. Age and male sex were both risk factors for coronary artery stenosis/disease in this age group. J.R.B.: concept, design, data collection, writing and editing manuscript, submission for publication. M.C.O.: concept, design, data collection. B.Y. and J.C.: writing and editing manuscript, statistical analysis. M.K., J.W., M.K., and A.A.: writing and editing manuscript. M.S., M.H., and A.G.: data collection. N.F.: data collection, writing and editing manuscript. C.W.: writing and editing manuscript, submission for publication. B.L.: concept, design, data collection, writing and editing manuscript. The authors declare no conflicts of interest. Correspondence to: Jeremy R. Burt, MD, Department of Radiology, MUSC, 96 Jonathan Lucas Street, MSC 323, Clinical Science Building, Room 210, Charleston, SC 29425 (e-mail: burtje@musc.edu). Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved

Blastomycosis: The Great Pretender Blastomycosis is an endemic fungal infection caused by Blastomyces, a soil-dwelling dimorphic fungus found predominantly in North America. In this pictorial essay, we illustrate the varied imaging features of blastomycosis along with a brief description of the epidemiology, clinical aspects, and differential diagnosis, emphasizing clues that can help radiologists arrive at this diagnosis. The authors declare no conflicts of interest. Correspondence to: Jeffrey P. Kanne, MD, Department of Radiology, University of Wisconsin School of Medicine and Public Health, 600 Highland Avenue MC 3252, Madison, WI 53792-3252 (e-mail: jkanne@uwhealth.org). Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved

Differentiating Nonischemic Dilated Cardiomyopathy With Incidental Infarction From Ischemic Cardiomyopathy by Geometric Indices Derived From Cardiovascular Magnetic Resonance Purpose: The purpose of this study was to differentiate nonischemic dilated cardiomyopathy with incidental myocardial infarction (NICM with incidental MI) from ischemic cardiomyopathy (ICM) by integrating left ventricular (LV) geometric indices and ischemic late gadolinium enhancement (LGE), obtained from cardiac magnetic resonance (CMR) imaging. Materials and Methods: All subjects were studied on a 1.5 Tesla magnetic resonance imaging scanner. All patients had an LV ejection fraction (LVEF) <50% with LV dilation. LV end-diastolic volume (LVEDV), LVEDV index (LVEDVi), LVEF, the number and distribution of ischemic LGE segments, and ratios of volumetric and functional indices to ischemic LGE segments were determined. Logistic regression was used to detect the independent predictor of ICM. Receiver operating characteristic analysis differentiated NICM with incidental MI from ICM. Results: Of a total of 63 patients enrolled, 45 patients had ICM, and 18 patients had NICM with incidental MI. Both groups had similar LVEF. Compared with ICM, NICM with incidental MI had more LV dilation, whereas ICM had more ischemic LGE segments. A higher number of ischamic LGE segments remained an independent predictor of ICM (odds ratio: 18.2, 95% confidence interval: 1.64-201.34, P=0.018). The optimal cut-off value for detecting NICM with incidental MI is the ratio of LVEDVi to the number of ischemic LGE segments over 25 mL/m2/segment (sensitivity 100%, specificity 91%, P<0.0001). Conclusion: Patients with NICM with incidental MI can be reliably distinguished from ICM using the ratio of LVEDVi divided by the number of ischemic LGE segments. This technique may improve diagnosis and help aid management of patients with cardiomyopathy and coexistent coronary artery disease. The authors declare no conflicts of interest. Correspondence to: Shihua Zhao, MD, FESC, Fuwai Hospital, No. 167 Beilishi Road, Beijing 100037, China (e-mail: cjrzhaoshihua2009@163.com). Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved

Radiologic Manifestations of Pulmonary Vein Ablation Complications: A Pictorial Review In patients with atrial fibrillation refractory to drug therapy and cardioversion, pulmonary vein ablation is an alternative treatment that eradicates arrhythmogenic activity originating in the muscles of the pulmonary veins. While this procedure has a low incidence of significant complications, iatrogenic injuries are possible. Through multimodality pictorial examples utilizing computed tomography, nuclear medicine, fluoroscopy, and chest radiographs, the complications associated with pulmonary vein ablation will be reviewed. Examples of pulmonary vein stenosis, right phrenic nerve injury with associated diaphragmatic paralysis, atrioesophageal fistula, and pericardioesophageal fistula will be illustrated. The authors declare no conflicts of interest. Correspondence to: Daniel T. Myers, MD, Department of Radiology, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI 48202 (e-mail: danielm@rad.hfh.edu). Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved

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Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com,

Telephone consultation 11855 int 1193,

Shock

Toll-Like Receptors, Associated Biochemical Signaling Networks, and S100 Ligands Host cells recognize molecules that signal danger using pattern recognition receptors (PRRs). Toll-Like Receptors (TLRs) are the most studied class of PRRs and detect pathogen associated molecular patterns and danger associated molecular patterns. Cellular TLR activation and signal transduction can therefore contain, combat and clear danger by enabling appropriate gene transcription. Here we review the expression, regulation and function of different TLRs, with an emphasis on TLR-4, and how TLR adaptor protein binding directs intracellular signaling resulting in activation or termination of an innate immune response. Finally, we highlight the recent progress of research on the involvement of S100 proteins as ligands for TLR-4 in inflammatory disease. Address reprint requests to John C. Marshall, MD, St. Michael's Hospital, 4th Floor Bond Wing, Room 4-007, 30 Bond Street, Toronto, Ontario, M5B 1W8, Canada. E-mail: john.marshall@unityhealth.to Received 25 October, 2020 Revised 12 November, 2020 Accepted 30 November, 2020 Conflicts of Interest: The authors have no conflicts of interest to declare. Grant Funding Source: Canadian Institutes of Health Research (MOP 129493) © 2020 by the Shock Society

Bone Marrow-Derived Mononuclear Cell Transplantation can Reduce Systemic Inflammation and Endothelial Glycocalyx Damage in Sepsis Bone marrow-derived mononuclear cells (BMMNCs) secrete anti-inflammatory mediators that protect against acute inflammation. Current evidence suggests that BMMNC transplantation can reduce acute tissue injury caused by systemic inflammation and lung dysfunction. This study evaluated the role of BMMNCs in reducing systemic inflammatory responses to vascular endothelial injury in sepsis. Bone marrow cells were harvested from the tibias and femurs of twelve-week-old male Wistar rats; BMMNCs were separated by density centrifugation. Additional rats underwent cecal ligation and puncture (CLP) or similar sham surgery. BMMNCs were injected intravenously 30 min after CLP. The Sham and CLP Control groups were administered PBS. The seven-day survival rate improved markedly in the CLP-BMMNC group compared with that in the Control group. BMMNCs markedly suppressed the serum levels of pro-inflammatory mediators such as tumor necrosis factor-alpha, interleukin-6, and histone H3 at 3, 6, and 12 h after CLP. In the CLP-BMMNC group, the serum levels of syndecan-1, the main component of the vascular endothelial glycocalyx layer, were notably lower than those in the Control group 6 h after CLP. Histological analysis revealed improvement of morphological damages in the CLP-BMMNC group. Ultrastructural analysis revealed that the glycocalyx structure was maintained and the continuity of the vascular endothelial glycocalyx layer was preserved in the BMMNC group, compared to the case for the Control group at 6 and 12 h. Therefore, BMMNC transplantation may provide reduced systemic inflammation and endothelial glycocalyx damage, dramatically improving the survival of rats. These findings provide insights into formulating potential therapeutic strategies against sepsis. Address reprint requests to Tsunehiro Matsubara, MD, Osaka University Graduate School of Medicine Department of Traumatology and Acute Critical Care Center, 2-15 Yamadaoka, Suita-city, Osaka 565-0871, Japan. E-mail: tsunehiro1231@live.jp Received 1 August, 2020 Revised 10 September, 2020 Accepted 9 December, 2020 Conflicts of Interest and Source of Funding: This study received a Grant-in-Aid for Young Scientists from The Ministry of Education, Culture, Sports, Science and Technology, Japan. The authors declare no conflicts of interest. © 2020 by the Shock Society

Neutrophil-To-Lymphocyte Ratio And Covid-19 No abstract available

Pharmacological and Genetic Inhibition of Translocator Protein 18 kDa Ameliorated Neuroinflammation in Murine Endotoxemia Model Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction associated with sepsis. The development of an effective strategy for early diagnosis and therapeutic intervention is essential for the prevention of poor prognosis of SAE. Translocator protein 18 kDa (TSPO) is a mitochondrial protein implicated in steroidogenesis and inflammatory responses. Despite accumulating evidence that implicates TSPO in the neuroinflammatory response of the central nervous system, the possible role of TSPO in SAE remains unclear. Aim of this study is to address a role of TSPO in neuroinflammation using mice 24 h after systemic injection of lipopolysaccharide (LPS), which consistently demonstrated microglial activation and behavioral inhibition. Quantitative polymerase chain reaction analysis revealed that hippocampal TSPO expression was induced following the systemic LPS injection, associated with an increase in pro-inflammatory cytokines such as tumor necrosis factor-α and interleukin-1β. Interestingly, pretreatment with the TSPO antagonist, ONO-2952, or germ-line deletion of the TSPO gene exhibited an anti-inflammatory effect with significant suppression of LPS-induced production of those cytokines. These effects demonstrated by the ONO-2952 or TSPO knockout were associated with significant recovery from behavioral inhibition, as shown by improved locomotor activity in the open field analysis. Histological analysis revealed that ONO-2952 pretreatment suppressed the LPS-induced activation of TSPO-expressing microglia in the hippocampus of mice. Collectively, these results suggest that TSPO plays a critical role in the SAE mouse model. Based on this finding, monitoring TSPO activity, as well as the progress of endotoxemia and its sequelae in the animal model, would deepen our understanding of the underlying molecular mechanism of SAE. Address reprint requests to Hidenori Aizawa, MD, PhD, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553 Japan. E-mail: haizawa@hiroshima-u.ac.jp Received 24 September, 2020 Revised 12 October, 2020 Accepted 23 November, 2020 Disclosure: The authors declare that they have no conflicts of interest. Funding: This research was supported by a Grant-in-Aid for Scientific Research on Innovative Areas (JP19H05723) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) to HA; a Grant-in-Aid for 'Integrated Research on Depression, Dementia and Development Disorders (20dm0107093)' carried out under the Strategic Research Program for Brain Sciences by AMED to SY and a Grant-in-Aid for Scientific Research C (18K08888) to KH. © 2020 by the Shock Society

HIF-1α and Hypoxia Responsive Genes are Differentially Expressed in Leukocytes from Survivors and Non-Survivors Patients during Clinical Sepsis Hypoxia inducible factor 1 alpha (HIF-1α) is linked to the metabolic and immune alterations in septic patients. Stabilization of HIF-1α by hypoxia or inflammation promotes the expression of several genes related to glycolytic metabolism, angiogenesis, coagulation, cell proliferation and apoptosis. Here we analyzed public available blood transcriptome datasets from septic patients and evaluated by PCR array the expression of HIF-1α and other hypoxia responsive genes in peripheral blood mononuclear cells (PBMC) from patients with sepsis secondary to community acquired infections. Samples were collected at ICU admission (D0, n=29) and after 7 days follow-up (D7, n = 18); healthy volunteers (n = 10) were included as controls. Hypoxia and glycolysis were among the top scored molecular signatures in the transcriptome datasets. PCR array showed that 24 out of 78 analyzed genes were modulated in septic patients compared to healthy volunteers; most of them (23/24) were downregulated at admission. This same pattern was observed in surviving patients, while non-survivors presented more upregulated genes. EGLN1, EGLN2 and HIF1AN, inhibitors of HIF-1α activation were downregulated in patients, regardless of the outcome, while HIF-1α and other target genes, such as PDK1 and HMOX1, expression were higher in non-survivors than in survivors, mainly at D7. Non-survivor patients also presented a higher SOFA score and lower PaO2/FiO2 ratio. Our results indicate a differential modulation of hypoxia pathway in leukocytes between septic patients who survived and those who did not survive with an increased intensity at D7, which is possibly influenced by disease severity and may affect the immune response in sepsis. Address reprint requests to Reinaldo Salomao, MD, PhD, Division of Infectious Diseases, Escola Paulista de Medicina, Hospital São Paulo, Universidade Federal de São Paulo, Rua Pedro de Toledo, 669, 10th Floor, Sao Paulo, SP, 04039-032, Brazil. E-mail: rsalomao@unifesp.br Received 25 September, 2020 Revised 19 October, 2020 Accepted 6 November, 2020 Funding: This work was supported by FAPESP (Grant 2017/21052-0). RS is the recipient of a Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) fellowship. BLF has a scholarship from FAPESP (2016/13855-2). Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (www.shockjournal.com). © 2020 by the Shock Society

The Value of Extracellular Cold-Inducible RNA-Binding Protein (eCIRP) in Predicting the Severity and Prognosis of Patients after Cardiac Arrest: A Preliminary Observational Study Background: Extracellular cold-inducible RNA-binding protein (eCIRP) acting as a novel damage-associated molecular pattern molecule promotes systemic inflammatory responses, including neuroinflammation in cerebral ischemia. We aimed to observe the changes of serum eCIRP and evaluate whether the increased serum eCIRP was associated with the severity and prognosis in patients with restoration of spontaneous circulation (ROSC). Methods: A total of 73 patients after ROSC were divided into non-survivor (n = 48) and survivor (n = 25) groups based on 28-day survival. Healthy volunteers (n = 25) were enrolled as controls. Serum eCIRP, procalcitonin (PCT), the pro-inflammatory mediators tumor necrosis factor (TNF)-α, interleukin-6 (IL)-6 and high mobility group protein (HMGB1), the neurological damage biomarkers neuron-specific enolase (NSE) and soluble protein 100β (S100β) were measured on days 1, 3 and 7 after ROSC. Clinical data and laboratory findings were collected, and the Sequential Organ Failure Assessment (SOFA) score and Acute Physiology and Chronic Health Evaluation (APACHE II) were calculated concurrently. Cerebral performance category (CPC) scores on day 28 after ROSC were recorded. Results: Serum eCIRP, IL-6, TNF-α, PCT and HMGB1, NSE and S100β were significantly increased within the first week after ROSC. The increased levels of eCIRP was positively correlated with IL-6, TNF-α, lactate, NSE, S100β, CPR time, SOFA score, APACHE II score and HMGB1 after ROSC. Serum eCIRP on days 1, 3 and 7 after ROSC could predict 28-day mortality and neurological prognosis. Serum eCIRP on day 3 after ROSC had a biggest AUC [0.862 (95%CI: 0.741–0.941)] for 28-day mortality and a biggest AUC [0.807 (95%CI: 0.630–0.981)] for neurological prognosis. Conclusions: Systemic inflammatory response with increased serum eCIRP occurred in patients after ROSC. Increased eCIRP level was positively correlated with the aggravation of systemic inflammatory response and the severity after ROSC. Serum eCIRP serves as a potential predictor for 28-day mortality and poor neurological prognosis after ROSC. Address reprint requests to Ping Gong, Emergency Department, First Affiliated Hospital of Dalian Medical University, No. 222 Zhongshan Road, Dalian 116023, Liaoning Province, China. E-mail: gongp828@sina.cn Received 10 October, 2020 Revised 27 October, 2020 Accepted 20 November, 2020 LW and R-FL contributed equally to this study and should be considered co-first authors. The authors report no conflicts of interest. Funding: This study was supported by the National Natural Science Foundation of China (81571869). Competing interests: The authors declare that they have no competing interests. © 2020 by the Shock Society

Endothelial NOX2 Limits Systemic Inflammation and Hypotension in Endotoxemia by Controlling Expression of Toll-Like Receptor 4 Leukocyte Nox2 is recognized to have a fundamental microbicidal function in sepsis but the specific role of Nox2 in endothelial cells (EC) remains poorly elucidated. Here, we tested the hypothesis that endothelial Nox2 participates in the pathogenesis of systemic inflammation and hypotension induced by lipopolysaccharide (LPS). LPS was injected intravenously in mice with Tie2-targeted deficiency or transgenic overexpression of Nox2. Mice with Tie2-targeted Nox2 deficiency had increased circulating levels of tumor necrosis factor alpha (TNF-α), enhanced numbers of neutrophils trapped in lungs and aggravated hypotension after LPS injection, as compared to control LPS-injected animals. In contrast, Tie2-driven Nox2 overexpression attenuated inflammation and prevented the hypotension induced by LPS. Because Tie2-Cre targets both EC and myeloid cells we generated bone marrow chimeric mice with Nox2 deletion restricted to leukocytes or ECs. Mice deficient in Nox2 either in leukocytes or ECs had reduced LPS-induced neutrophil trapping in the lungs and lower plasma TNF-α levels as compared to control LPS-injected mice. However, the pronounced hypotensive response to LPS was present only in mice with EC-specific Nox2 deletion. Experiments in vitro with human vein or aortic endothelial cells (HUVEC and HAEC, respectively) treated with LPS revealed that EC Nox2 controls NF-κB activation and the transcription of toll-like receptor 4 (TLR4), which is the recognition receptor for LPS. In conclusion, these results suggest that endothelial Nox2 limits NF-κB activation and TLR4 expression, which in turn attenuates the severity of hypotension and systemic inflammation induced by LPS. Address reprint requests to Prof. Ajay M. Shah, School of Cardiovascular Medicine and Sciences, James Black Centre, King's College London, 125 Coldharbour Lane SE5 9NU, London, United Kingdom. E-mail: ajay.shah@kcl.ac.uk. Received 9 September, 2020 Revised 29 September, 2020 Accepted 2 December, 2020 Sources of support: This research was supported by Sao Paulo Research Foundation (FAPESP) under grant agreement no 2012/24677-7 (S.C.T. Fellowship) and 2013/08216-2 (Center for Research of Inflammatory Disease (CRID), 2013/07937-8 (LRL as member of CEPID Redoxoma), the European Society of Cardiology (ESC, Basic Research Fellowship), and the British Heart Foundation (BHF CH/1999001/11735). Disclosure: The authors declare no financial conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (www.shockjournal.com). © 2020 by the Shock Society

Red Blood Cells Elicit Platelet-Dependent Neutrophil Recruitment into Lung Airspaces Haemolysis that occurs in intravascular haemolytic disorders, such as sickle cell disease and malaria, is associated with inflammation and platelet activation. Alveolar haemorrhage, for example following primary blast lung injury (PBLI) or acute respiratory distress syndrome (ARDS), results in the escape of erythrocytes (RBCs) into alveolar spaces, where they subsequently lyse and release their intracellular contents. However, the inflammatory effects of RBCs in the airways are not fully understood. We hypothesized that RBCs in the airway induce an inflammatory response, associated with platelet activation. By instilling whole RBCs or lysed RBCs into the airways of mice, we have demonstrated that whole RBCs elicit macrophage accumulation in the lung. However, lysed RBCs induce significant inflammatory cell recruitment, particularly neutrophils and this was associated with a 50% increase in circulating platelet neutrophil complexes (PNCs). Platelet depletion prior to lysed RBC exposure in the lung resulted in reduced neutrophil recruitment, suggesting that the presence of intracellular RBC components in the airways can elicit inflammation that is platelet dependent. To identify specific platelet dependent signalling pathways involved in neutrophil recruitment, anti-P-selectin ligand and anti-PSGL1 blocking antibodies were tested, however neither affected neutrophil recruitment. These findings implicate an involvement for other, as yet unidentified platelet-dependent signalling and adhesion mechanisms. Further understanding of how platelets contribute to lung inflammation induced by the presence of RBCs could offer novel therapeutic approaches to attenuate inflammation that occurs in conditions associated with alveolar haemorrhage. Address reprint requests to Simon C. Pitchford, Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London, UK. E-mail: simon.pitchford@kcl.ac.uk Received 23 September, 2020 Revised 13 October, 2020 Accepted 2 December, 2020 Authorship: S.A. designed and performed the research, analyzed the data, and wrote the paper. S.A.S., S.J.C., B.G.O'S., R.T.A., and K.A contributed to assay development and performed in vivo procedures. S.C.P., and C.P.P proposed the project, designed research and wrote the paper. Conflicts of interest. No author has a conflicts of interest to disclose. © 2020 by the Shock Society

Burn Injury Impairs Neutrophil Chemotaxis through Increased Ceramide Infection is a common and often deadly complication after burn injury. A major underlying factor is burn-induced immune dysfunction, particularly with respect to neutrophils as the primary responders to infection. Temporally after murine scald injury, we demonstrate impaired bone marrow neutrophil chemotaxis towards CXCL1 ex vivo. Additionally, we observed a reduced recruitment of neutrophils to the peritoneal after elicitation seven days after injury. We demonstrate that neutrophil ceramide levels increase after burn injury, and this is associated with decreased expression of CXCR2 and blunted chemotaxis. A major signaling event upon CXCR2 activation is Akt phosphorylation and this was reduced when ceramide was elevated. In contrast, PTEN levels were elevated and PTEN-inhibition elevated phospho-Akt levels and mitigated the burn-induced neutrophil chemotaxis defect. Altogether, this study identifies a newly described pathway of ceramide-mediated suppression of neutrophil chemotaxis after burn injury and introduces potential targets to mitigate this defect and reduce infection-related morbidity and mortality after burn. Address reprint requests to Charles C. Caldwell, Department of Surgery, University of Cincinnati College of Medicine, MSB SRU G479, 231 Albert Sabin Way, Cincinnati, OH 45267-0558. E-mail: Charles.caldwell@uc.edu Received 17 September, 2020 Revised 7 October, 2020 Accepted 5 November, 2020 Conflict of Interest: None Authorship: NB, VN, CCC: Conception and study design. NB, FS: Data acquisition and analysis, drafting of the article. NB, FS, BK, EG, VN, CCC: Data interpretation, revision of the article, final approval of the version to be submitted. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (www.shockjournal.com). © 2020 by the Shock Society

Findings and Prognostic Value of Lung Ultrasonography in Coronal Virus Disease 2019(COVID-19) Pneumonia Purpose: We used lung ultrasonography to identify features of COVID-19 pneumonia and to evaluate the prognostic value. Materials and Methods: We performed lung ultrasonography on 48 COVID-19 patients in an ICU (Wuhan, China) using a 12-zone method. The associations between lung ultrasonography score, PaO2/FiO2, APACHE II, SOFA, and PaCO2 with 28-day mortality were analyzed and the receiver operator characteristic curve was plotted. Results: 25.9% areas in all scanning zones presented with B7 lines and 23.5% with B3 lines(B-pattern) on lung ultrasonography; 13% areas with confluent B lines(B-pattern), 24.9% in areas with consolidations, and 9.9% in areas with A lines. Pleural effusion was observed in 2.8% of areas. Lung ultrasonography score was negatively correlated with PaO2/FiO2 (n = 48, r = -0.498, P < 0.05) andpositively correlated with APACHE II (n = 48, r = 0.435, P < 0.05). Lung ultrasonography score was independently associated with 28-day mortality. The areas under ROC curves of lung ultrasonography score was 0.735 (95% CI: 0.586–0.844). The sensitivity, specificity, and cutoff values were 0.833, 0.722, and 22.5, respectively. Conclusions: Lung ultrasonography could be used to assess the severity of COVID-19 pneumonia, and it could also reveal the pathological signs of the disease. The lung ultrasonography score on ICU admission was independently related to the ICU 28-day mortality. Address reprint requests to Zhiyong Peng, and Shuhan Cai, Wuhan University Zhongnan Hospital, China. e-mails:pengzy5@hotmail.com,caishuhan@163.com Received 12 September, 2020 Revised 1 October, 2020 Accepted 18 November, 2020 Lu Li and Aihua Qin: Authors contributed equally to this study and therefore shared the first authorship. Declaration of Conflicting Interests' statement: The authors have no conflicts of interest to declare relevant to this publication. Funding: This work was supported by the National Natural Science Fund (grants 81772046 and 81971816 to Dr Peng) and the Special Project for Significant New Drug Research and Development in the Major National Science and Technology Projects of China (2020ZX09201007 to Dr Peng). Ethics approval and consent to participate: This study was approved by the institutional ethics board of Zhongnan Hospital of Wuhan University (No. 2020088K). Informed consent was waived as it was a retrospective study. Consent for publication: Not applicable. Availability of data and materials: The datasets analyzed during the current study are available from the corresponding author on reasonable request. Authors' contributions: LL and AQ collected the data and wrote the manuscript. XY did the statistical analysis. SZ, YL, and FZ collected the data. JL, BH, and SC revised the manuscript. ZP designed and finalized the manuscript.{Citation} © 2020 by the Shock Society

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Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com,

Telephone consultation 11855 int 1193,

Pediatric Critical Care Medicine

Organ Donation Authorization After Brain Death Among Patients Admitted to PICUs in the United States, 2009–2018 Objectives: To identify trends in and factors associated with pediatric organ donation authorization after brain death. Design: Retrospective cohort study of data from Virtual Pediatric Systems, LLC (Los Angeles, CA). Setting: Data from 123 PICUs reporting to Virtual Pediatric Systems from 2009 to 2018. Patients: Patients less than 19 years old eligible for organ donation after brain death. Measurements and Main Results: Of 2,777 eligible patients, 1,935 (70%) were authorized for organ donation; the authorization rate remained unchanged over time (ptrend = 0.22). In a multivariable logistic regression model, hospitalizations lasting greater than 7 days had lower odds of authorization (adjusted odds ratio, 0.5; p < 0.001 vs ≤ 1 d) and White patients had higher odds than other race/ethnicity groups. Authorization was higher for trauma-related encounters (adjusted odds ratio, 1.5; p < 0.001) and when donation was discussed with an organ procurement organization coordinator (adjusted odds ratio, 1.7; p < 0.001). Of 123 hospitals, 35 (28%) met or exceeded a 75% organ donation authorization target threshold; these hospitals more often had an organ procurement organization coordinator discussing organ donation (85% vs 72% of encounters; p < 0.001), but no difference was observed by PICU bed size. Conclusions: Organ donation authorization after brain death among PICU patients was associated with length of stay, race/ethnicity, and trauma-related encounter, and authorization rates were higher when an organ procurement organization coordinator was involved in the donation discussion. This study identified factors that could inform initiatives to improve the authorization process and increase pediatric organ donation rates. No endorsement or editorial restriction of the interpretation of these data or opinions of the authors has been implied or stated. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://journals.lww.com/pccmjournal). Virtual Pediatric Systems (VPS) data were provided by VPS, LLC (Los Angeles, CA). The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: alicen.spaulding@childrensmn.org ©2020The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

Avoidable Serum Potassium Testing in the Cardiac ICU: Development and Testing of a Machine-Learning Model Objectives: To create a machine-learning model identifying potentially avoidable blood draws for serum potassium among pediatric patients following cardiac surgery. Design: Retrospective cohort study. Setting: Tertiary-care center. Patients: All patients admitted to the cardiac ICU at Boston Children's Hospital between January 2010 and December 2018 with a length of stay greater than or equal to 4 days and greater than or equal to two recorded serum potassium measurements. Interventions: None. Measurements and Main Results: We collected variables related to potassium homeostasis, including serum chemistry, hourly potassium intake, diuretics, and urine output. Using established machine-learning techniques, including random forest classifiers, and hyperparameter tuning, we created models predicting whether a patient's potassium would be normal or abnormal based on the most recent potassium level, medications administered, urine output, and markers of renal function. We developed multiple models based on different age-categories and temporal proximity of the most recent potassium measurement. We assessed the predictive performance of the models using an independent test set. Of the 7,269 admissions (6,196 patients) included, serum potassium was measured on average of 1 (interquartile range, 0–1) time per day. Approximately 96% of patients received at least one dose of IV diuretic and 83% received a form of potassium supplementation. Our models predicted a normal potassium value with a median positive predictive value of 0.900. A median percentage of 2.1% measurements (mean 2.5%; interquartile range, 1.3–3.7%) was incorrectly predicted as normal when they were abnormal. A median percentage of 0.0% (interquartile range, 0.0–0.4%) critically low or high measurements was incorrectly predicted as normal. A median of 27.2% (interquartile range, 7.8–32.4%) of samples was correctly predicted to be normal and could have been potentially avoided. Conclusions: Machine-learning methods can be used to predict avoidable blood tests accurately for serum potassium in critically ill pediatric patients. A median of 27.2% of samples could have been saved, with decreased costs and risk of infection or anemia. Mr. Patel, Dr. Sperotto, and Mr. Molina contributed equally. Drs. Santillana and Kheir jointly supervised this research. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://journals.lww.com/pccmjournal). Supported, in part, by the Gerber Foundation and, in part, by the Joyful Heart Fund. The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: msantill@fas.harvard.edu; john.kheir@childrens.harvard.edu ©2020The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

Early Mobilization in a PICU: A Qualitative Sustainability Analysis of PICU Up! Objectives: To identify staff-reported factors and perceptions that influenced implementation and sustainability of an early mobilization program (PICU Up!) in the PICU. Design: A qualitative study using semistructured phone interviews to characterize interprofessional staff perspectives of the PICU Up! program. Following data saturation, thematic analysis was performed on interview transcripts. Setting: Tertiary-care PICU in the Johns Hopkins Hospital, Baltimore, MD. Subjects: Interprofessional PICU staff. Interventions: None. Measurements and Main Results: Fifty-two staff members involved in PICU mobilization across multiple disciplines were interviewed. Three constructs emerged that reflected the different stages of PICU Up! program execution: 1) factors influencing the implementation process, 2) staff perceptions of PICU Up!, and 3) improvements in program integration. Themes were developed within these constructs, addressing facilitators for PICU Up! implementation, cultural changes for unitwide integration, positive impressions toward early mobility, barriers to program sustainability, and refinements for more robust staff and family engagement. Conclusions: Three years after implementation, PICU Up! remains well-received by staff, positively influencing role satisfaction and PICU team dynamics. Furthermore, patients and family members are perceived to be enthusiastic about mobility efforts, driving staff support. Through an ongoing focus on stakeholder buy-in, interprofessional engagement, and bundled care to promote mobility, the program has become part of the culture in the Johns Hopkins Hospital PICU. However, several barriers remain that prevent consistent execution of early mobility, including challenges with resource management, sedation decisions, and patient heterogeneity. Characterizing these staff perceptions can facilitate the development of solutions that use institutional strengths to grow and sustain PICU mobility initiatives. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://journals.lww.com/pccmjournal). Mr. Patel was funded by the Johns Hopkins University Provost's Undergraduate Research Award. Dr. Kudchadkar was supported by the Johns Hopkins Clinical and Translational Science Awards Award Number 5KL2RR025006 from the National Center for Advancing Translational Sciences of the National Institutes of Health and the Johns Hopkins Bloomberg School of Public Health Sommer Scholars Program. Dr. Eakin's institution received funding from the National Heart Lung and Blood Institute (NHLBI). Dr. Balas's institution received funding from NHLBI 1 R01 HL146781-01, American Association of Critical Care Nurses Research Grant, and she received funding from the Society of Critical Care Medicine and H3C. Dr. Needham's institution received funding from Baxter Pharma and Reck Medical Devices, and he received funding from Haisco USA. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: sapna@jhmi.edu ©2020The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

Respiratory Variation in Aortic Blood Flow Velocity in Hemodynamically Unstable, Ventilated Neonates: A Pilot Study of Fluid Responsiveness Objectives: To assess whether respiratory variation in aortic blood flow peak velocity can predict preload responsiveness in mechanically ventilated and hemodynamically unstable neonates. Design: Prospective observational diagnostic accuracy study. Setting: Third-level neonatal ICU. Patients: Hemodynamically unstable neonates under mechanical ventilation. Interventions: Fluid challenge with 10 mL/kg of normal saline over 20 minutes. Measurements and Main Results: Respiratory variation in aortic blood flow peak velocity and superior vena cava flow were measured at baseline (T0), immediately upon completion of the fluid infusion (T1), and at 1 hour after fluid administration (T2). Our main outcome was preload responsiveness which was defined as an increase in superior vena cava flow of at least 10% from T0 to T1. Forty-six infants with a median (interquartile range) gestational age of 30.5 weeks (28–36 wk) were included. Twenty-nine infants (63%) were fluid responders, and 17 (37%) were nonresponders Fluid responders had a higher baseline (T0) respiratory variation in aortic blood flow peak velocity than nonresponders (9% [8.2–10.8] vs 5.5% [3.7–6.6]; p < 0.001). Baseline respiratory variation in aortic blood flow peak velocity was correlated with the increase in superior vena cava flow from T0 to T1 (rho = 0.841; p < 0.001). The area under the receiver operating characteristic curve of respiratory variation in aortic blood flow peak velocity to predict preload responsiveness was 0.912 (95% CI, 0.82–1). A respiratory variation in aortic blood flow peak velocity cut-off point of 7.8% provided a 90% sensitivity (95% CI, 71–97), 88% specificity (95% CI, 62–98), 7.6 positive likelihood ratio (95% CI, 2–28), and 0.11 negative likelihood ratio (95% CI, 0.03–0.34) to predict preload responsiveness. Conclusions: Respiratory variation in aortic blood flow velocity may be useful to predict the immediate response to a fluid challenge in hemodynamically unstable neonates under mechanical ventilation. If our results are confirmed, this measurement could be used to guide safe and individualized fluid resuscitation in critically ill neonates. Dr. Oulego-Erroz, guarantor, takes full responsibility of the content of the article, including data and analysis, and he conceived and designed the study, analyzed data, and drafted the article. Dr. Terroba-Seara acquired and analyzed data and critically reviewed the article. Dr. Alonso-Quintela conceived the study, acquired data, and critically reviewed the article. Dr. Rodríguez-Núñez conceived and designed the study and critically reviewed the article. All authors gave their approval for the final version of the article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://journals.lww.com/pccmjournal). The authors have disclosed that they do not have any potential conflicts of interest. Address requests for reprints to: Ignacio Oulego-Erroz, Complejo Asistencial Universitario de León, Altos de Nava s/n 24002, León, Spain. E-mail: ignacio.oulego@gmail.com. ©2020The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

Spillover of Early Extubation Practices From the Pediatric Heart Network Collaborative Learning Study Objectives: The Pediatric Heart Network Collaborative Learning Study used collaborative learning strategies to implement a clinical practice guideline that increased rates of early extubation after infant repair of tetralogy of Fallot and coarctation of the aorta. We assessed early extubation rates for infants undergoing cardiac surgeries not targeted by the clinical practice guideline to determine whether changes in extubation practices spilled over to care of other infants. Design: Observational analyses of site's local Society of Thoracic Surgeons Congenital Heart Surgery Database and Pediatric Cardiac Critical Care Consortium Registry. Setting: Four Pediatric Heart Network Collaborative Learning Study active-site hospitals. Patients: Infants undergoing ventricular septal defect repair, atrioventricular septal defect repair, or superior cavopulmonary anastomosis (lower complexity), and arterial switch operation or isolated aortopulmonary shunt (higher complexity). Interventions: None. Measurements and Main Results: Aggregate outcomes were compared between the 12 month pre-clinical practice guideline and 12 months after study completion (Follow Up). In infants undergoing lower complexity surgeries, early extubation increased during Follow Up compared with Pre-Clinical Practice Guideline (30.2% vs 18.8%, p = 0.006), and hours to initial postoperative extubation decreased. We observed variation in these outcomes by surgery type, with only ventricular septal defect repair associated with a significant increase in early extubation during Follow Up compared with Pre-Clinical Practice Guideline (47% vs 26%, p = 0.006). Variation by study site was also seen, with only one hospital showing an increase in early extubation. In patients undergoing higher complexity surgeries, there was no difference in early extubation or hours to initial extubation between the study eras. Conclusions: We observed spillover of extubation practices promoted by the Collaborative Learning Study clinical practice guideline to lower complexity operations not included in the original study that was sustainable 1 year after study completion, though this effect differed across sites and operation subtypes. No changes in postoperative extubation outcomes following higher complexity surgeries were seen. The significant variation in outcomes by site suggests that center-specific factors may have influenced spillover of clinical practice guideline practices. Supported, in part, by funding from the National Heart, Lung, and Blood Institute, NIH5U10HL109781 and K08HL116639 (principal investigator Gailes). The Pediatric Cardiac Critical Care Consortium Data Coordinating Center receives funding from the University of Michigan Congenital Heart Center, CHAMPS for Mott, and the Michigan Institute for Clinical & Health Research (National Institutes of Health/National Center for Advancing Translational Sciences UL1TR002240), all University of Michigan, Ann Arbor, MI. Dr. Witte's institution received funding from the Pediatric Heart Network/National Heart, Lung, and Blood Institute. Drs. Witte, Mahle, Pasquali, and Gaies received support for article research from the National Institutes of Health (NIH). Dr. Pasquali's institution received funding from the NIH. Dr. Zhang disclosed work for hire. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: madolin.witte@hsc.utah.edu ©2020The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

Brain Death Evaluation in Children With Suspected or Confirmed Coronavirus Disease 2019 Objectives: To discuss the challenges of conducting a death by neurologic criteria or brain death evaluation in the coronavirus disease 2019 era and provide guidance to mitigate viral transmission risk and maintain patient safety during testing. Design: Not applicable. Setting: Not applicable. Patients: Children with suspected or confirmed coronavirus disease 2019 who suffer catastrophic brain injury due to one of numerous neurologic complications or from an unrelated process and require evaluation for death by neurologic criteria. Interventions: Not applicable. Measurements and Main Results: There is a risk to healthcare providers from aerosol generation during the neurologic examination and apnea test for determination of death by neurologic criteria. In this technical note, we provide guidance to mitigate transmission risk and maintain patient safety during each step of the death by neurologic criteria evaluation. Clinicians should put on appropriate personal protective equipment before performing the death by neurologic criteria evaluation. Risk of aerosol generation and viral transmission during the apnea test can be mitigated by using continuous positive airway pressure delivered via the ventilator as a means of apneic oxygenation. Physicians should assess the risk of transporting coronavirus disease 2019 patients to the nuclear medicine suite to perform a radionucleotide cerebral blood flow study, as disconnections to and from the ventilator for transport and inadvertent ventilator disconnections during transport can increase transmission risk. Conclusions: When conducting the neurologic examination and apnea test required for death by neurologic criteria determination in patients with suspected or confirmed coronavirus disease 2019, appropriate modifications are needed to mitigate the risk of viral transmission and ensure patient safety. The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: kirschenm@chop.edu ©2020The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

Echocardiographic Parameters and Mortality in Pediatric Sepsis: A Systematic Review and Meta-Analysis Objective: We conducted a systematic review and meta-analysis to investigate the prognostic value of echocardiographic parameters in pediatric septic patients. Data Sources: MEDLINE, PubMed, and EMBASE (last update April 5, 2020). Study Selection: Observational studies of pediatric sepsis providing echocardiographic parameters in relation to mortality. Data Extraction: Echocardiography data were categorized as those describing left ventricular systolic or diastolic function, right ventricular function, and strain echocardiography parameters. Data from neonates and children were considered separately. Analysis is reported as standardized mean difference and 95% CI. Data Synthesis: We included data from 14 articles (n = 5 neonates, n = 9 children). The fractional shortening was the most commonly reported variable (11 studies, n = 555 patients) and we did not identify an association with mortality (standardized mean difference 0.22, 95% CI [–0.02 to 0.47]; p = 0.07, I2 = 28%). In addition, we did not find any association with mortality also for left ventricular ejection fraction (nine studies, n = 417; standardized mean difference 0.06, 95% CI [–0.27 to 0.40]; p = 0.72, I2 = 51%), peak velocity of systolic mitral annular motion determined by tissue Doppler imaging wave (four studies, n = 178; standardized mean difference –0.01, 95% CI [–0.34 to 0.33]; p = 0.97, I2 = 0%), and myocardial performance index (five studies, n = 219; standardized mean difference –0.51, 95% CI [–1.10 to 0.08]; p = 0.09, I2 = 63%). However, in regard to left ventricular diastolic function, there was an association with mortality for higher early wave of transmitral flow/peak velocity of early diastolic mitral annular motion determined by tissue Doppler imaging ratio (four studies, n = 189, standardized mean difference –0.45, 95% CI [–0.80 to –0.10]; p = 0.01, I2 = 0%) or lower peak velocity of early diastolic mitral annular motion determined by tissue Doppler imaging wave (three studies, n = 159; standardized mean difference 0.49, 95% CI [0.13–0.85]; p = 0.008, I2 = 0%). We did not find any association with mortality for early wave of transmitral flow/late (atrial) wave of trans-mitral flow ratio (six studies, n = 273; standardized mean difference 0.28, 95% CI [–0.42 to 0.99]; p = 0.43, I2 = 81%) and peak velocity of systolic mitral annular motion determined by tissue Doppler imaging wave measured at the tricuspid annulus (three studies, n = 148; standardized mean difference –0.18, 95% CI [–0.53 to 0.17]; p = 0.32, I2 = 0%). Only a few studies were conducted with strain echocardiography. Conclusions: This meta-analysis of echocardiography parameters in pediatric sepsis failed to find any association between the measures of left ventricular systolic or right ventricular function and mortality. However, mortality was associated with higher early wave of transmitral flow/peak velocity of early diastolic mitral annular motion determined by tissue Doppler imaging or lower peak velocity of early diastolic mitral annular motion determined by tissue Doppler imaging, indicating possible importance of left ventricular diastolic dysfunction. These are preliminary findings because of high clinical heterogeneity in the studies to date. Drs. La Rosa and Grasso contributed equally. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://journals.lww.com/pccmjournal). The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: filipposanfi@yahoo.it ©2020The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

Intracranial and Cerebral Perfusion Pressure Thresholds Associated With Inhospital Mortality Across Pediatric Neurocritical Care Objectives: Targets for treatment of raised intracranial pressure or decreased cerebral perfusion pressure in pediatric neurocritical care are not well defined. Current pediatric guidelines, based on traumatic brain injury, suggest an intracranial pressure target of less than 20 mm Hg and cerebral perfusion pressure minimum of 40–50 mm Hg, with possible age dependence of cerebral perfusion pressure . We sought to define intracranial pressure and cerebral perfusion pressure thresholds associated with inhospital mortality across a large single-center pediatric neurocritical care cohort. Design: Retrospective chart review. Setting: PICU, single quaternary-care center. Patients: Individuals receiving intracranial pressure monitoring from January 2012 to December 2016. Interventions: None. Measurements and Main Results: Intracranial pressure and cerebral perfusion pressure measurements from 262 neurocritical care patients (87 traumatic brain injury and 175 nontraumatic brain injury; 63% male; 8.3 ± 5.8 yr; mortality 11.1%). Mean intracranial pressure and cerebral perfusion pressure had area under the receiver operating characteristic curves of 0.75 and 0.64, respectively, for association of inhospital mortality. Cerebral perfusion pressure cut points increased with age (< 2 yr = 47, 2 to < 8 yr = 58 mm Hg, ≥ 8 yr = 73 mm Hg). In the traumatic brain injury subset, mean intracranial pressure and cerebral perfusion pressure had area under the receiver operating characteristic curves of 0.70 and 0.78, respectively, for association of inhospital mortality. Traumatic brain injury cerebral perfusion pressure cut points increased with age (< 2 yr = 45, 2 to < 8 yr = 57, ≥ 8 yr = 68 mm Hg). Mean intracranial pressure greater than 15 mm Hg, male sex, and traumatic brain injury status were independently associated with inhospital mortality (odds ratio, 14.23 [5.55–36.46], 2.77 [1.04–7.39], and 2.57 [1.03–6.38], respectively; all p < 0.05). Mean cerebral perfusion pressure less than 67 mm Hg and traumatic brain injury status were independently associated with inhospital mortality (odds ratio, 5.16 [2.05–12.98] and 3.71 [1.55–8.91], respectively; both p < 0.01). In the nontraumatic brain injury subset, mean intracranial pressure had an area under the receiver operating characteristic curve 0.77 with an intracranial pressure cut point of 15 mm Hg, whereas mean cerebral perfusion pressure was not predictive of inhospital mortality. Conclusions: We identified mean intracranial pressure thresholds, utilizing receiver operating characteristic and regression analyses, associated with inhospital mortality that is below current guidelines-based treatment targets in both traumatic brain injury and nontraumatic brain injury patients, and age-dependent cerebral perfusion pressure thresholds associated with inhospital mortality that were above current guidelines-based targets in traumatic brain injury patients. Further study is warranted to identify data-driven intracranial pressure and cerebral perfusion pressure targets in children undergoing intracranial pressure monitoring, whether for traumatic brain injury or other indications. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://journals.lww.com/pccmjournal). Supported, in part, by K23 NS104133 (to Dr. Au), 1K23 HD099331-01A1 (to Dr. Horvat), T32 HD040686 (to Dr. Rakkar), R21 NS115174 (to Dr. Clark), The Children's Trust Fund (to Drs. Horvat and Simon), and the UPMC Children's Hospital of Pittsburgh Scientific Program. Drs. Clark and Au are funded by the National Institute of Neurological Disorders and Stroke. Drs. Horvat and Rakkar are funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The work was performed at the UPMC Children's Hospital of Pittsburgh. For information regarding this article, E-mail: auak@upmc.edu ©2020The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

Influence of Cardiopulmonary Resuscitation Coaching on Interruptions in Chest Compressions During Simulated Pediatric Cardiac Arrest Objectives: To determine the impact of a cardiopulmonary resuscitation coach on the frequency and duration of pauses during simulated pediatric cardiac arrest. Design: This is a secondary analysis of video data collected from a prospective multicenter trial. Forty simulated pediatric cardiac arrest scenarios (20 noncoach and 20 coach teams), each lasting 18 minutes in duration, were reviewed by three clinical experts to document events surrounding each pause in chest compressions. Setting: Four pediatric academic medical centers from Canada and the United States. Subjects: Two-hundred healthcare providers in five-member interprofessional resuscitation teams that included either a cardiopulmonary resuscitation coach or a noncoach clinical provider. Interventions: Teams were randomized to include either a trained cardiopulmonary resuscitation coach or an additional noncoach clinical provider. Measurements and Main Results: The frequency, duration, and associated factors with each interruption in chest compressions were recorded and compared between the groups with and without a cardiopulmonary resuscitation coach, using t tests, Wilcoxon rank-sum tests, or chi-squared tests, depending on the distribution and types of outcome variables. Mixed-effect linear models were used to explore the effect of cardiopulmonary resuscitation coaching on pause durations, accounting for multiple measures of pause duration within teams. A total of 655 pauses were identified (noncoach n = 304 and coach n = 351). Cardiopulmonary resuscitation-coached teams had decreased total mean pause duration (98.6 vs 120.85 s, p = 0.04), decreased intubation pause duration (median 4.0 vs 15.5 s, p = 0.002), and similar mean frequency of pauses (17.6 vs 15.2, p = 0.33) when compared with noncoach teams. Teams with cardiopulmonary resuscitation coaches are more likely to verbalize the need for pause (86.5% vs 73.7%, p < 0.001) and coordinate change of the compressors, rhythm check, and pulse check (31.7% vs 23.2%, p = 0.05). Teams with cardiopulmonary resuscitation coach have a shorter pause duration than non-coach teams, adjusting for number and types of tasks performed during the pause. Conclusions: When compared with teams without a cardiopulmonary resuscitation coach, the inclusion of a trained cardiopulmonary resuscitation coach leads to improved verbalization before pauses, decreased pause duration, shorter pauses during intubation, and better coordination of key tasks during chest compression pauses. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http:journals.lww.com/pccmjournal). Drs. Kessler and Cheng conceptualized and designed the study. Dr. Kessler, Dr. Grabinski, Dr. Shepard, Ms. Jones, and Dr. Cheng designed the data collection instruments. Dr. Grabinski, Dr. Shepard, and Ms. Jones reviewed videos and coordinated data collection. Drs. Kessler and Lin contributed to the statistical analysis and the interpretation of data. Dr. Kessler takes overall responsibility for the article. All authors contributed to the drafting and meaningful review of the article and approved the final article as submitted. Ms. Nye, Ms. Gaither, Dr. Hunt, Ms. Davidson, and Ms. Chatfield (International Network for Simulation-based Pediatric Innovation, Research, and Education Cardiopulmonary Resuscitation Group byline authors) contributed to the conceptualization and design of the study, coordinated and supervised data collection at one site, and approved the final article as submitted. Findings from this study were presented in poster format at the International Pediatric Simulation Society annual meeting in Toronto on May 20, 2019. Dr. Cheng reports that the parent study for this project was funded through a research grant from the Heart and Stroke Foundation of Alberta, Alberta Health Services, and the University of Calgary. He also reports additional research infrastructure support provided by the Alberta Children's Research Institute, the Alberta Children's Hospital Foundation, and the Department of Pediatrics, Cumming School of Medicine, University of Calgary, to support investigator initiated research conducted in concert with the Kid Simulation Research Program, Alberta Children's Hospital. Dr. Hunt was responsible for the initial description of the cardiopulmonary resuscitation (CPR) coach. She reports funding from International Network for Simulation-Based Innovation, Research, & Education to investigate further the impact of the CPR Coach on compliance with CPR guidelines. She also reports that unrelated to this study she and her research partners do have nonexclusive agreement with Zoll Medical Corporation licensing educational technology on which they hold patents with the potential for revenue. She has also received reimbursement for travel expenses and honoraria for speaking about the CPR Coach role she created. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: dk2592@cumc.columbia.edu ©2020The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

Use of Honey Versus Standard Care for Hospital-Acquired Pressure Injury in Critically Ill Children: A Multicenter Randomized Controlled Trial Objectives: To examine if the use of honey (medicated) for dressing is superior to standard care in terms of time to complete wound healing in stages 1–3 of pressure injuries in children admitted to the PICU. Design: Multicenter, open-label, parallel-group, randomized trial. Setting: Tertiary-care PICU from August 2017 to January 2019. Patients: Critically ill children, 2 months to 17 years old, who developed pressure injury (stages 1–3) were included; those on more than two inotropes or with signs of acute wound infection or wounds with greater than 5 cm diameter or known allergy to honey were excluded. Interventions: Children were randomized to receive either medicated honey dressing or standard (routine) wound care for the management of their pressure injury. Measurements and Main Results: The primary outcome was the time to complete wound healing. Manuka or active Leptospermum honey dressing/gel was used in the intervention group. Enrolled children were followed up until death or discharge from the hospital. A total of 99 children were enrolled: 51 in the intervention group and 48 in the standard care group. Baseline characteristics, including the nutritional status, were comparable between the groups. The most common sites of injury were bony prominences at face mask contact points. The median time to complete healing was 7 days (95% CI, 6–7 d) versus 9 days (7–10 d) in the intervention and standard care groups, respectively (p = 0.002; log-rank test). At any random time, children in the intervention group were about 1.9-fold more likely to have their pressure injury completely healed than those in the standard care group (hazard ratio 1.86; 95% CI, 1.21–2.87). There were no allergic reactions or secondary wound infections in the intervention group. Conclusions: The use of medicated honey dressings decreased the time to wound healing in critically ill children with pressure injuries. There were no allergic reactions or secondary bacterial infections in any of these children. ClinicalTrials.gov ID: NCT03391310 Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://journals.lww.com/pccmjournal). Supported, in part, by HARD Manufacturing-WFPICCS Pediatric Critical Care Research Grant'-10000 USD. Drs. Sankar's, AV's, Rameshkumar's, Mahadevan's, and Kabra's institutions received funding from WFPICCS HARD Manufacturing Pediatric Critical Care Research Grant. Dr. Sankar's institution also received funding from the Department of Science and Technology and the Indian Council of Medical Research. Dr. Lodha disclosed off-label product use of medicated honey dressings for pressure ulcers in critically ill children For information regarding this article, E-mail: jhumaji@gmail.com ©2020The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

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Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com,

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Clinical Nuclear Medicine

Solitary Vulvar Involvement of Ovarian Non-Hodgkin Lymphoma Mimicking Bartholin's Abscess on 18F-FDG PET/CT A 49-year-old woman was diagnosed with diffuse large B-cell lymphoma of the left ovary. Two months after the hysterectomy and bilateral salpingo-oophorectomy operation, the patient was referred to 18F-FDG PET/CT for staging. A mass lesion measuring 2.8 × 3 cm with intense 18F-FDG uptake was observed at right labium majus, which could be considered as a Bartholin's cyst or abscess. The lesion was excised, and non-Hodgkin lymphoma involvement of vulva was revealed by histopathology. Received for publication October 2, 2020; revision accepted November 15, 2020. Conflicts of interest and sources of funding: none declared. Correspondence to: Nurhan Ergül, MD, Clinic of Nuclear Medicine, Istanbul Training and Research Hospital, Kasap İlyas Mah. Org. Abdurrahman Nafiz Gürman Cd. 34098 Fatih, Istanbul, Turkey. E-mail: nurhanergul@yahoo.com. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Prospective Correlation of Prognostic Immunohistochemical Markers With SUV and ADC Derived From Dedicated Hybrid Breast 18F-FDG PET/MRI in Women With Newly Diagnosed Breast Cancer Purpose The aim of this study was to correlate prognostically relevant immunohistochemical parameters of breast cancer with simultaneously acquired SUVs and apparent diffusion coefficient (ADC) values derived from hybrid breast PET/MRI. Patients and Methods Fifty-six women with newly diagnosed, therapy-naive, histologically proven breast cancer (mean age, 54.1 ± 12.0 years) underwent dedicated prone 18F-FDG breast PET/MRI. Diffusion-weighted imaging (b-values: 0, 500, 1000 s/mm2) was performed simultaneously with the PET acquisition. A region of interest encompassing the entire primary tumor on each patient's PET/MRI scan was used to determine the glucose metabolism represented by maximum and mean SUV as well as into corresponding ADC maps to assess tumor cellularity represented by mean and minimum ADC values. Histopathological tumor grading and prognostically relevant immunohistochemical markers, that is, Ki67, progesterone receptor, estrogen receptor, and human epidermal growth factor receptor 2 (HER2), were assessed. Pearson correlation coefficients were calculated to compare SUV and ADC values as well as the immunohistochemically markers and molecular subtype. For the comparison with the tumor grading, a Wilcoxon test was used. Results A significant inverse correlation between SUV and ADC values derived from breast PET/MRI (r = −0.49 for SUVmean vs ADCmean; r = −0.43 for SUVmax vs ADCmin; both P's < 0.001) was found. Tumor grading and Ki67 both showed a positive correlation with SUVmean from breast PET/MRI (r = 0.37 and r = 0.32, P < 0.01). For immunohistochemical markers, HER2 showed an inverse correlation with ADC values from breast PET/MRI (r = −0.35, P < 0.01). Molecular subtypes significantly correlate with SUVmax and SUVmean (r = 0.52 and r = 0.42, both P's < 0.05). In addition, estrogen receptor expression showed an inverse correlation with SUVmax and SUVmean from breast PET/MRI (r = −0.45 and r = −0.42, P < 0.001). Conclusions The present data show a correlation between increased glucose metabolism, cellularity, tumor grading, estrogen and HER2 expression, as well as molecular subtype of breast cancer primaries. Hence, simultaneous 18F-FDG PET and diffusion-weighted imaging from hybrid breast PET/MRI may serve as a predictive tool for identifying high-risk breast cancer patients in initial staging and guide-targeted therapy. Received for publication August 23, 2020; revision accepted November 12, 2020. J.M. and J.K. contributed equally to this study. Conflicts of interest and sources of funding: The authors declare no conflict of interest. The study is funded by Deutsche Forschungsgemeinschaft, a German research foundation (BU3075/2-1). The funding foundation was not involved in the trial design, patient recruitment, data collection, analysis, interpretation or presentation, writing or editing of the reports, or the decision to submit for publication. The corresponding author had full access to all data in the study and had all the responsibility for the decision to submit for publication. Ethical approval: All procedures performed were in accordance with the ethical standards of the institutional research committee and with the principles of the 1964 Declaration of Helsinki and its later amendments. Informed consent: Informed consent was obtained from all individual participants included in the study. Correspondence to: Julian Kirchner, MD, Department of Diagnostic and Interventional Radiology, Medical Faculty, University Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany. E-mail: Julian.Kirchner@med.uni-duesseldorf.de. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Intense Diffuse Uptake of 68Ga-FAPI-04 in the Breasts Found by PET/CT in a Patient With Advanced Nasopharyngeal Carcinoma The physiological uptake of 68Ga-FAPI-04 due to the change of the internal environment is little known. We report the case of a 45-year-old woman who was highly suspected to have advanced nasopharyngeal carcinoma. 18F-FDG and 68Ga-FAPI-04 PET/CT was performed for evaluating the disease. Both PET and CT with different tracers detected the primary nasopharyngeal carcinoma and metastases in right neck lymph nodes, liver, and bones. To our surprise, intense diffuse uptake of 68Ga-FAPI-04 was found in both breasts, which might be due to the hormone stimulation because the patient received 68Ga-FAPi-04 PET/CT just at the period of ovulation. Received for publication October 6, 2020; revision accepted November 12, 2020. Conflicts of interest and sources of funding: none declared. Correspondence to: Hu-bing Wu, MD, PET Center, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Avenue North, Guangzhou, Guangdong 510515, China. E-mail: wuhbym@163.com. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Fibroblast Activation Protein Inhibitor PET/CT: A Promising Molecular Imaging Tool Purpose Fibroblast activation protein (FAP) is a cell membrane–bound serine peptidase, overexpressed in cancer-associated fibroblasts and activated fibroblasts at wound healing/inflammatory sites. Recently, molecular PET/CT imaging with radiolabeled FAP inhibitor (FAPI) has been evaluated in different diseases. We aimed to assess its potential role based on the available literature. Patients and Methods We conducted a comprehensive review of the available preclinical and clinical data on FAPI PET/CT in an attempt to summarize its current status and potential future role. Based on that, we have discussed the pathophysiology behind FAP-based imaging, followed by a discussion of FAPI radiopharmaceuticals including their synthesis, biodistribution, and dosimetry. Next, we have discussed studies evaluating FAPI PET/CT in different oncological and nononcological pathologies. The potential of FAPI PET/CT in theranostics has also been addressed. Results Based on the early scientific evidence available, including preclinical and clinical studies, FAPI PET/CT seems to be a promising molecular imaging tool, especially in oncology. It can be used for imaging different types of cancers and outperforms 18F-FDG PET/CT in some of these. Its potential as a theranostic tool warrants special attention. Conclusions Fibroblast activation protein inhibitor PET/CT has the potential to emerge as a powerful molecular imaging tool in the future. However, as of yet, the available evidence is limited, warranting further research and trials in this field. Received for publication September 8, 2020; revision accepted November 12, 2020. Conflicts of interest and sources of funding: none declared. Correspondence to: Punit Sharma, MD, FEBNM, FANMB, Department of Nuclear Medicine and PET/CT, Apollo Gleneagles Hospital, 58, Canal Circular Rd, Kolkata 700054, India. E-mail: dr_punitsharma@yahoo.com. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

68Ga-FAPI PET/CT Versus 68Ga-DOTATATE PET/CT in the Evaluation of a Patient With Neuroendocrine Tumor 68Ga-FAPI (fibroblast activation protein-specific inhibitor) PET/CT was performed in a 56-year-old man with multiple liver masses, which were confirmed grade 2 well-differentiated neuroendocrine tumors with liver Tru-Cut biopsy. With 68Ga-DOTATE PET/CT, primary tumor in the pancreas, multiple metastases in the liver and metastatic portocaval lymph node were detected. In 68Ga-FAPI PET/CT imaging performed for comparison, it was seen that metastatic lesions in the liver were distinguished much better because of low background activity, and the primary tumor and metastatic lymph node were clearly selected. This case suggested that FAPI-bounded radionuclides may be useful in the evaluation and targeted therapy of neuroendocrine tumors. Received for publication September 25, 2020; revision accepted November 12, 2020. Conflicts of interest and sources of funding: none declared. Correspondence to: Cihan Gündoğan, MD, Department of Nuclear Medicine, Gazi Yaşargil Training and Research Hospital, University of Health Sciences, Üçkuyular mevki, 21070, Kayapınar, Diyarbakır, Turkey. E-mail: cihangd@hotmail.com. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Inferior Vena Cava Tumor Thrombus From Thyroid Cancer Detected by 68Ga-PSMA-617 PET/CT A 61-year-old woman was diagnosed with progressive metastatic radioactive iodine refractory differentiated thyroid cancer and underwent multitargeted tyrosine kinase inhibitor (TKI) Donafenib therapy. After 12 months of therapy, she developed resistance to TKI. Considering the limited treatment options available, a 68Ga–prostate-specific membrane antigen (PSMA)–617 PET/CT was conducted for potential therapeutic target. 68Ga-PSMA-617 PET/CT showed an intense radiotracer uptake in inferior vena cava, which was subsequently confirmed as tumor thrombus. Thus, this patient is a rare case in which the tumor thrombus from thyroid cancer was discovered in inferior vena cava via 68Ga-PSMA-617 PET/CT. Received for publication October 28, 2020; revision accepted November 13, 2020. Conflicts of interest and sources of funding: This work was supported by the National Natural Science Foundation of China (no. 81771875). None declared to all authors. Correspondence to: Zhi Yang, PhD, Department of Nuclear Medicine, Peking University Cancer Hospital and Institute, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), 52 Fucheng Rd, Haidian District, Beijing100142, China. E-mail: pekyz@163.com; and Yansong Lin, MD, PhD, Department of Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing St, Dongcheng District, Beijing 100730, China. E-mail: linyansong1968@163.com. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

FDG PET/CT of Benign Psammomatous Meningioma Effacing the Medulla A 62-year-old woman had progressively developing throbbing right neck pain for 1 year. The pain radiated to the right suboccipital area, sometimes accompanied by breathlessness. To rule out cancer, patient received FDG PET/CT, which showed an intraspinal cord intense FDG-avid calcified mass at the level of the first cervical spine, mimicking malignancy. MRI showed it effacing the medulla; surgery is probably a challenge. She received laminectomy with tumor removal; pathology showed psammomatous meningioma, World Health Organization grade I. This case suggests that benign spinal cord psammomatous meningioma with calcification may show high FDG uptake, mimicking malignancy. Received for publication September 23, 2020; revision accepted November 5, 2020. Conflicts of interest and sources of funding: none declared. Correspondence to: Yuh-Feng Wang, MD, PhD, Department of Nuclear Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, No. 2, Minsheng Rd, Dalin Township, Chiayi 622, Taiwan, Republic of China. E-mail: yuhfeng@gmail.com. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Ovarian Inflammation Mass Mimicking Recurrent Rectal Cancer 17 Years After Surgery: PET/CT and MRI Findings A 58-year-old woman diagnosed with rectal cancer received surgery and chemotherapy 17 years ago, and since then, she has been tumor-free. However, 1 month ago, she complained of progressive abdominal and pelvic pain. MRI scans revealed a soft-tissue ovarian mass with heterogeneous signals in the right pelvis, showing obvious enhancement after contrast injection. On PET/CT images, the lesion presented with intense FDG accumulation. Above imaging findings raised the possibility of tumor recurrence, and thus exploratory laparotomy was performed. Pathological results confirmed the diagnosis of active inflammation with fibrous tissue hyperplasia. Received for publication October 15, 2020; revision accepted November 1, 2020. Conflicts of interest and sources of funding: This study was supported by the National Natural Science Foundation of China (grants 81471692 and 81901776), project funded by the China Postdoctoral Science Foundation (grant 2019M650245), and Post-Doctor Research Project, West China Hospital, Sichuan University (grant 18HXBH070). None declared to both authors. Correspondence to: Anren Kuang, MD, Department of Nuclear Medicine, Laboratory of Clinical Nuclear Medicine, West China Hospital of Sichuan University, No. 37 Guoxue Alley, Chengdu 610041, China. E-mail: kuanganren@263.net. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Prognostic Value of Positive Presurgical FDG PET/CT in the Evaluation of Tumor-Induced Osteomalacia Objectives Tumor-induced osteomalacia (TIO), a rare paraneoplastic syndrome, is curable by excision or destruction of the causative tumor. However, occasionally, TIO may relapse after surgical intervention. We aimed to investigate the roles of 18F-FDG PET/CT in the prognosis of TIOs. Methods Seventy-six patients who had surgically removed tumors that caused osteomalacia were included in this retrospective investigation. All patients underwent both 18F-FDG and 68Ga-DOTATATE PET/CT prior to surgery. The prognostic value of presurgical FDG PET/CT study was determined with 5-year follow-up. Results In the presurgical evaluation, 68Ga-DOTATATE detected lesions in all 76 patients. However, FDG PET/CT was positive in only 25 among all 76 patients. Following surgical removal of the causative tumor, all 76 patients had symptomatic relief and normalization of the serum phosphate level initially. However, 15 of 76 cases (19.7%) had recurrent hypophosphatemia and became symptomatic again during the follow-up. Among these 15 patients with recurrence, 11 (73.3%) had recurrent lesions at the original location of the resected causative tumors, whereas 4 were in other locations due to malignant nature of the primary tumor. Interestingly, 14 of these 15 patients with recurrent disease had positive presurgical FDG PET/CT findings with an incident ratio of 56.0% (14 of 25). In contrast, only 1 patient with recurrent disease had negative presurgical FDG PET/CT scan with an incident ratio of 1.9% (1 of 51), significantly less than the positive presurgical FDG PET/CT group (P < 0.05). Conclusions A positive presurgical FDG PET/CT suggests increased likelihood for possible recurrence of TIO after surgical resection. In contrast, when a causative tumor detected by 68Ga-DOTATATE PET/CT does not have elevated activity on FDG PET/CT, the chance of recurrence is very small. Received for publication October 26, 2020; revision accepted November 2, 2020. Conflicts of interest and sources of funding: The authors declare that they have no conflict of interest. This report was funded by CAMS Innovation Fund for Medical Sciences (CAMS-2017-I2M-1-001). The requirement for informed consent was waived because this retrospective study used existing patient data and images. Correspondence to: Hongli Jing, MD, PhD, Department of Nuclear Medicine, Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Wangfujing, Dongcheng District, Beijing 100730, China. E-mail: annsmile1976@sina.com; or Fang Li, MD, Department of Nuclear Medicine, Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Wangfujing, Dongcheng District, Beijing 100730, China. E-mail: lifang@pumch.cn. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Reduced Myocardial Uptake of 123I-MIBG in Congenital Insensitivity to Pain With Anhidrosis A 30-year-old man presented with repeated episodes of painless injuries in his feet and abnormally high body temperature. He was diagnosed with congenital insensitivity to pain with anhidrosis—a rare hereditary peripheral neuropathy characterized by decreased pain, reduced sweating, and autonomic neuropathy. Congenital insensitivity to pain with anhidrosis is also called hereditary sensory and autonomic neuropathy type IV. 123I-MIBG myocardial scintigraphy showed reduced myocardial uptake (heart-to-mediastinum ratio: 1.56 and 1.42 in the early and late phases, respectively; washout ratio, 49%), indicating autonomic dysfunction. This finding may contribute to the diagnosis of congenital insensitivity to pain with anhidrosis and the semiquantitative evaluation of an autonomic dysfunction. Received for publication July 7, 2020; revision accepted October 29, 2020. Conflicts of interest and sources of funding: none declared. Correspondence to: Mihoko Sasahara, MD, Department of Radiology, Tokushima University Graduate School of Biomedical Sciences, 2-50-1 Kuramoto-cho, Tokushima 770-8503, Japan. E-mail: k.mihoko.928@gmail.com. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

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Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com,

Telephone consultation 11855 int 1193,