N = 1,076) suggest good to very good psychometric properties and moderate to excellent internal consistencies. Confirmatory factor analysis (CFA) models suggest a very good model fit for the first-order, four factor models of the Carver-White BIS/BAS scales, Reinforcement Sensitivity Theory – Personality Questionnaire (RST-PQ), the two-factor model of revised Reinforcement Sensitivity Theory-Questionnaire (rRST-Q) and for the bifactor model of the Conflict Monitoring Questionnaire (CMQ-44). The CMQ-44 extends the psychometric measurement of previous trait-(r)BIS and trait-BAS scales. Factor scores of CMQ-44 cognitive demand correlate positively with factor scores of Carver-White BIS and all Carver-White BAS subfactors except RST-PQ-Impulsivity suggesting that CMQ-44 cognitive demand addresses Carver-White trait-BIS specifically and more generally the trait-BAS core. CMQ-44 anticipation of negative consequences and response adaptation correlate negatively with trait-BAS, whereas the second-order factor performance monitoring extends the rRST trait-space and correlates positively with trait-BAS.This study highlights psychometric properties and evidence of construct validity on parcel-level for questionnaires on the original and revised reinforcement sensitivity theory. Our data ( The reinforcement sensitivity theory RST,  and its a priori predicted convergent and discriminant construct validity RST-related questionnaires examined in this study, psychometric properties have been reported as a part of the construct validation . In termThe Carver and White BIS/BAS scales  with theThe factorial validity of the German Carver-White BIS/BAS scales, the RST-PQ, and the rRST-Q has been confirmed by means of CFAs . FurtherAs a new development, the conflict monitoring questionnaire CMQ,  investigEffects of measurement equivalence have been rarely addressed in previous CFA studies on (r)RST questionnaires. Beyond CFA modeling, effects of gender and/or age groups have been reported on the scale-level for the German version of the Carver-White BIS/BAS scales  and the Additionally, none of the (r)RST CFA studies investigated a hierarchical structure of the BIS/BAS sub-scales. As Previous studies revealed positive inter-correlations between trait-BIS scales of the Carver-White BIS/BAS scales , the RSTCognitive demand has been discussed in the context of the conflict-monitoring-theory  as a detThe CMQ-44 response adaptation scale is thought to be positively related to previous (r)RST-related trait-BIS scales because CMQ-44 response adaptation can serve to inhibit behavior especially when response adaptation occurs in a less adaptive manner. When CMQ-44 response adaptation is performed in a reactive, more flexible manner, higher scores of the CMQ-44 response adaptation scale could also correlate positively with trait-BAS scales and negatively with previous trait-(r)BIS scales. If the CMQ-44 response adaptation correlates negatively with previous trait-(r)BIS scales this would indicate that response adaptation extends previous trait-BIS scales by measuring a more flexible, reactive adaptation of responses instead of a fixed, proactive adaptation of responses .CMQ-44 uncertainty of reinforcement measures the tendency to be sensitive for situations that are ambiguously reinforcing because situations are rewarding as well as punishing or they are so complex for the decision process that the reinforcing value cannot be defined. CMQ-44 uncertainty of reinforcement should enhance behavioral inhibition tendencies and, therefore, correlates positively with (r)RST-related trait-BIS scales. Moreover, higher scores of CMQ-44 uncertainty of reinforcement should reduce behavioral approach tendencies and, therefore, -if at all- is negatively related to (r)RST trait-BAS scales. Presuming that people take the risk of errors into account, higher scores of CMQ-44 uncertainty of reinforcement could be positively related to approach behavior as measured with trait-BAS scales. The predictions of the CMQ-44 subscales with previous (r)RST-related trait-BIS and trait-BAS scales are summarized in a priori which items are thought to measure the latent constructs or at least parts of those constructs  because item misspecifications are ignored otherwise. The argument probably neglects the fact that items for the measurement of personality traits and intelligence have been sometimes constructed in an inductive, empirical manner rather than in a theory-driven approach as recommended by means of facet theory . To investigate construct validity in a test-fair manner for all (r)RST questionnaires in this study, items of all (r)RST questionnaires have been parceled with regard to their a priori defined construct content RST questionnaires – except the CMQ-44 – have been mainly investigated on the item-level. Parceling items  has beennstructs . In this critics . Marsh et theory . Thus, i content . This pra priori predicted convergent and discriminant validity (Based on prior findings we investigate the following research questions. (1) Are psychometric properties for the (r)RST-related questionnaires comparable to prior findings? (2) Can factorial validity of the four German (r)RST questionnaires  be confirmed based on the parcel level? (3) Are (r)RST latent factors equivalent across gender? (4) Do the factor scores for the best fitting CFA models provide evidence of validity ?N = 1,127 participants took part in a Unipark survey that was performed in collaboration with Respondi AG1 between November 2020 and January 2021 (n = 88 were assessed via Unipark by a research assistant in the team of the first author). The psychometric survey along with the research questions was approved in September 2020 by the Ethics committee of the Medical Faculty at the University of Kiel, Germany. Hypotheses in a priori . We recruited participants in three examination intervals via Respondi AG. The first examination was performed between 24-November-2020 and 13-December-2020 with n = 44 participants in a pre-test and n = 471 participants in the main test. The second examination interval included n = 2 participants in the pre-test and n = 523 in the main test lasting from 13-January-2021 until 25-January-2021. The third Unipark assessment started on 17-December-2020 and ended on 20-February-2021 with n = 5 participants in a pre-test and n = 83 participants who took part in the main test (n = 88 see above). Overall, of the N = 1,128 participants we excluded n = 51 pre-test participants because pre-tests included slight changes in the Unipark programming. One participant younger than 18 years was excluded.A total of N = 1,076 participants aged between 18 and 66 years  for statistical analysis. We planned a widely equal recruitment of four age groups between 18 and 28 years (n = 317), 29 and 39 years (n = 250), 40 and 50 years (n = 286), and 51 and 66 years (n = 223). A total of n = 514 female and n = 559 male participants took part in this study (for gender proportions in Germany2). Three participants classified their gender as diverse. Participants received a reimbursement credit via Respondi AG redirects of about 5 €. The study plan was pre-registered in Hogrefe Verlag, Germany . Data acquisition was funded by the University of Kiel, Germany.The final sample comprised Participants were asked to answer demographic variables . Afterward participants answered the items of four questionnaires in German language in the following sequence: (1) Conflict monitoring questionnaire CMQ-44 , (2) ReiThe CMQ originally includes 60 items with a 6-point Likert response scale: 1 = trifft überhaupt nicht zu , 2 = trifft überwiegend nicht zu (does mainly not correspond), 3 = trifft eher nicht zu (does rather not correspond), 4 = trifft eher zu (does rather correspond), 5 = trifft überwiegend zu (does mainly correspond), 6 = trifft vollständig zu (does completely correspond). The CMQ incorporates four latent factors named as structs in terms of facet theory . Two latThe German version of the RST-PQ  includesn = 88 who were recruited and reimbursed at the University of Kiel, Germany, in the team of the first author).At the start of the Unipark link, participants were informed about the study, duration per examination (about 30–40 min), and contact persons who were prepared to answer questions on the study. Participants were instructed to answer the items in a well-lit, quiet room with no disturbance during item answering and no participation of others. When participants gave written informed consent, they obtained demographic and questionnaire items for answering. Respondi AG handled the recruitment and reimbursement  of most participants  and for trait-BAS in the Carver-White BIS/BAS two factor model  with women (n = 514) and individuals who classified themselves as diverse (n = 3) showing higher trait-BIS and higher trait-BAS values than men (n = 559). In the Carver-White BIS/BAS four factor model, female and diverse individuals showed higher trait-BIS, trait-BAS-reward reactivity and trait-BAS-drive values than men .Effects of measurement equivalence across gender have not been predicted p < 0.01) and higher trait-BAS values  than men. Regarding the RST-PQ four-factor models for trait-BIS and trait-BAS, respectively, women and individuals who classified themselves as diverse scored higher than men for all four trait-BIS subscales . For the trait-BAS subfactors exclusively Goal-drive persistence and Reward reactivity were higher for female and diverse participants compared to men .For the RST-PQ two-factor model, women revealed higher trait-BIS values , whereas no gender differences were observed for trait-BAS . Finally, for the CMQ-44, women and participants who classified themselves as diverse reported higher Cognitive demand values than men . Men showed higher CMQ-44 anticipation of negative consequences values than women and individuals who classified themselves as diverse . Response adaptation was higher in female and diverse participants compared to male participants . Moreover, Performance monitoring (G) was higher in male individuals compared to female and diverse participants . No significant gender differences were observed for CMQ-44 uncertainty of reinforcement . For the CMQ-28, gender differences were not robust compared with CMQ-44 . In contrast to the CMQ-44, CMQ-28 uncertainty of reinforcement indicated higher factor scores for female and diverse participants compared to male participants . Comparable to the CMQ-44, CMQ-28 performance monitoring revealed higher path coefficient for men compared to women and diverse individuals .For the rRST-Q, women and individuals who classified themselves as diverse indicated higher trait-BIS values than men RST questionnaires that indicated the best model fit in terms of two or even three model fit indices see . We indiCognitive demand correlated positively exclusively with the Carver-White BIS factor score . ContrarWe observed positive and mainly significant inter-correlations of CMQ-44 cognitive demand with the factor scores of the other trait-BAS factors revealing that CMQ-44 cognitive demand facilitates reward-related behavior . NegativThe present study investigated psychometric properties (research question 1), evidence of factorial validity of (r)RST questionnaires (research question 2), effects of measurement equivalence for the latent (r)RST factors (research question 3), evidence of convergent and discriminant validity (research question 4). Our data reveal comparable and convincing evidence for the psychometric properties of the (r)RST questionnaires. Factorial validity has been confirmed for all (r)RST questionnaires. Best model fits have been observed for the four factor models of the Carver-White BIS/BAS scales , the four trait-BIS and four trait-BAS factors of the RST-PQ, the two-factor model of the RST-Q and for the CMQ-44 as well as CMQ-28 bifactor models. Gender effects were found for all inserted (r)RST questionnaires limiting measurement equivalence of the latent factors. Convergent validity for CMQ-44 cognitive demand has been exclusively observed with the Carver-White trait-BIS scales. Overall, the other CMQ-44 factors  rather extend the previous trait-BIS and trait-BAS space.Correlating positively with most of the previous trait-BAS factors, the CMQ-44 cognitive demand factor appeared to be a BAS-facilitating factor . A similExperimental studies investigating neural activations  will elucidate the contextual foundations and individual differences of the CMQ-44 factors to further our understanding on changes between checking and control mode of the BIS . For theThe present data motivate further research on emic and etic issues of (r)RST questionnaires in English-speaking samples. As (r)RST questionnaires have been applied in clinical samples , forensiThe present data suggest that the Carver-White BIS/BAS scales, the RST-PQ, the rRST-Q and the CMQ-44/28 are promising personality questionnaires for the (r)RST trait space with sufficient psychometric properties. Confirmatory factor models have been mainly confirmed for trait-BIS and trait-BAS. Gender effects matter for the assessment of trait-BIS and trait-BAS. We provide evidence that factor scores are a promising tool compared to unit-weighted sum scales to elucidate convergent and discriminant validity of the trait-BIS and trait-BAS factors. These data are promising to investigate changes of the BIS from checking to control , to predhttps://osf.io/9vu8e/?view_only=9655b511443c4c5e95f9393fcb15622c.As all inventories are part of an on-going construct validation process original data, code books, or program code will be made available in PsyArxiv upon request to the first author and depending on further validation studies: The studies involving human participants were reviewed and approved by Ethics Committee of the Medical Faculty, University of Kiel, Germany. The participants provided their written informed consent to participate in this study.AL: conceptualization, data curation and collection with team support and data processing, analysis, and wrote the manuscript. UE, MR, and PC: co-authors of the previous questionnaires for measuring the personality traits of (revised) reinforcement sensitivity theory, read, and commented on the manuscript prior to submission.


The endocrine effects of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in the vasculature, and the autocrine effects of ANP and BNP in cardiomyocytes are mediated by the common guanylyl cyclase A receptor (GC-A) expressed in various tissues and cell types. C-type natriuretic peptide (CNP) has paracrine actions that regulate vascular resistance and moderate myocardial stiffness via guanylyl cyclase B receptor (GC-B). Genetically modified mice have revealed the physiological roles of ANP and BNP in blood pressure, cardiac remodeling, and acute myocardial infarction. Molecular pathways in GC-A signaling specifically in cardiomyocytes were also investigated. ANP and BNP via the GC-A signaling phosphorylate regulator of G-protein signaling subtype 4 (RGS4) result in the inhibition of Gαq signaling coupled with angiotensin II type 1A receptor, inhibit the activation of transient receptor potential C6 (TRPC6), and attenuate genomic actions of the cardiac mineralocorticoid receptor (MR). Moreover, recent studies showed the physiological roles of CNP via GC-B in blood pressure and cardiac stiffness. Since natriuretic peptides are degraded by neprilysin (NEP), inhibiting NEP activity is expected to enhance the actions of natriuretic peptides. Experimental studies and clinical trials have shown the effect of NEP inhibition on cardiac remodeling, acute myocardial infarction, and hypertension.Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) activate the guanylyl cyclase A receptor (GC-A), which synthesizes the second messenger cGMP in a wide variety of tissues and cells. C-type natriuretic peptide (CNP) activates the cGMP-producing guanylyl cyclase B receptor (GC-B) in chondrocytes, endothelial cells, and possibly smooth muscle cells, cardiomyocytes, and cardiac fibroblasts. The development of genetically modified mice has helped elucidate the physiological roles of natriuretic peptides via GC-A or GC-B. These include the hormonal effects of ANP/BNP in the vasculature, autocrine effects of ANP/BNP in cardiomyocytes, and paracrine effects of CNP in the vasculature and cardiomyocytes. Neprilysin (NEP) is a transmembrane neutral endopeptidase that degrades the three natriuretic peptides. Recently, mice overexpressing NEP, specifically in cardiomyocytes, revealed that local cardiac NEP plays a vital role in regulating natriuretic peptides in the heart tissue. Since NEP inhibition is a clinically accepted approach for heart failure treatment, the physiological roles of natriuretic peptides have regained attention. This article focuses on the physiological roles of natriuretic peptides elucidated in mice with GC-A or GC-B deletion, the significance of NEP in natriuretic peptide metabolism, and the long-term effects of angiotensin receptor-neprilysin inhibitor (ARNI) on cardiovascular diseases. The presence of granules in atrial myocytes observed by electron microscope similar to those in endocrine cells was reported in 1956 . Then, iThe metabolism of natriuretic peptides is affected by degradation by the natriuretic peptide clearance receptor (NPR-C), excretion from the kidney, and degradation by neprilysin (NEP). NEP is a neutral endopeptidase distributed throughout the body, including the kidneys, lungs, brain, endothelium, and heart, and degrades natriuretic peptides ,17,18. TANP knockout (KO) mice show salt-sensitive hypertension , whereasIntriguingly, smooth muscle cell (SMC)-specific GC-A KO mice have normal arterial blood pressure. Intravenous ANP administration caused a rapid decrease in blood pressure in floxed GC-A mice but not in SMC GC-A KO mice . This inIn contrast, endothelial cell (EC)-specific GC-A KO mice exhibit significantly increased systolic blood pressure (by approximately 12–15 mmHg), which is salt-resistant, compared with those of the control mice. Moreover, the total plasma volume was increased by 11–13% in EC-specific GC-A KO mice . In compRegarding CNP/GC-B signaling, vascular SMC-specific GC-B KO mice showed normal blood pressure similar to those of the control mice. CNP-induced acute vasorelaxation was nearly completely abolished in the mesenteric arteries of SMC-specific GC-B KO mice. In contrast, EC-specific CNP KO mice displayed significantly increased blood pressure values (by approximately 10 mmHg). The gene expression of endothelin-1 (ET-1) was enhanced in pulmonary vascular endothelial cells from EC-specific CNP KO mice. In EC-specific CNP KO mice, the plasma ET-1 concentrations were significantly higher and blood pressure was significantly reduced in response to an endothelin receptor antagonist than their control littermates. This suggests that, for the regulation of blood pressure in chronic conditions, CNP plays an important role in inhibiting ET-1 production through its actions on vascular endothelial cells . RecentlThe ANP concentration in the human heart tissue is extremely high . TherefoThe effect of endogenous ANP and BNP on cardiac GC-A receptor was more evident in cardiomyocyte (CM)-specific GC-A KO mice, which demonstrated an increased heart weight and cardiomyocyte hypertrophy compared with wild-type (WT) mice . Transve4080 site during the early phases of pressure overload in mice. The authors also observed that fibroblasts, endothelial cells, and pericytes might be local sources of CNP three days after TAC. However, TAC-induced hypertrophy and fibrosis did not differ between CM-specific GC-B KO and WT mice [Recently, a CM-specific GC-B KO mouse model was developed. The CNP-induced activation of GC-B/cGMP/PKGI signaling in cardiomyocytes prevented titin-based myocyte stiffening by phosphorylating titin springs at the specific Ser WT mice . It is iThe biological significance of natriuretic peptides following AMI has been studied in terms of their physiological and pathological actions. When GC-A KO and WT mice were applied to coronary ligation permanently, GCA KO mice exhibited more severe ventricular fibrosis in non-infarcted area and post-infarct hypertrophy than in WT mice four weeks after AMI . MoreoveA recent study showed that myocardial neutrophil activation and infiltration during the early phase post-AMI were significantly reduced in EC-specific GC-A KO mice. The AMI-dependent induction of endothelial adhesion molecules, such as E/P selectins, was significantly attenuated in EC-specific GC-A KO mice. Furthermore, the authors demonstrated that the expression of phosphodiesterase 2A (PDE2A) in human umbilical vein endothelial cells (HUVEC) was enhanced by tumor necrosis factor-α (TNF-α) and hypoxia, and they observed a significant induction of PDE2A expression in the heart after AMI. Using the cremaster model, in which TNF-α was pretreated to induce PDE2 expression, both ANP and BNP (100 nmol/L) had proinflammatory effects with leukocyte extravasation. The authors concluded that a high expression of PDE2 can mediate the hyperpermeability, which is induced by the effects of endothelial GC-A/cGMP signaling, and it may facilitate neutrophil extravasation during the sub-acute phase after AMI . In someCollectively, pathological plasma levels of natriuretic peptides may induce cardiac rupture at an early phase due to neutrophil invasion in the heart tissue, probably because they induce vascular hyperpermeability in the impaired endothelium. In contrast, natriuretic peptides prevent adverse cardiac remodeling in the chronic phase after AMI.NEP, also known as acute lymphoblastic leukemia antigen CD10 , was disIn clinical trials, treatment with NEP inhibitors showed limited effects on hypertension and heart failure, although the cardiovascular protective effects of elevated natriuretic peptides and bradykinin were expected. Elevation of angiotensin II and ET-1 levels in the plasma may partially contribute to the negative results. Omapatrilat, a molecule that inhibits angiotensin-converting enzyme (ACE), and NEP, was developed. Omapatrilat did not reduce mortality and hospitalization for heart failure compared with ACE inhibitors. Notably, the secondary endpoint  was significantly improved by 9% . HoweverLCZ696, which combines the angiotensin receptor blocker (ARB) valsartan with the NEP inhibitor sacubitril, was developed. As valsartan suppresses the action of angiotensin II enhanced by the NEP inhibitor, it can be expected that increased natriuretic peptides have protective effects on the cardiovascular system. ARNI is the first oral drug to enhance the action of natriuretic peptides through this mechanism.NEP presents a preferential degradation of human natriuretic peptides following the order CNP > ANP > BNP ,53. The The primary NEP cleavage sites in ANP and CNP are between cysteine and phenylalanine, breaking the ring and inactivating the peptide. In contrast, in BNP, it occurs between methionine and valine . NatriurIn a clinical trial, the plasma levels of ANP were measured after ARNI was administered to patients with heart failure with reduced ejection fraction (HFrEF). The mean ANP baseline level of 99 pg/mL increased to 203 pg/mL at three months . Since aA large clinical trial involving patients with heart failure  using LCZ696 reported that the LCZ696 group reduced the composite outcome of cardiovascular death and heart failure hospitalization by 20% compared to that in the enalapril group . IncreasIn the PROVE-HF study, in which ARNI was administered to patients with HFrEF, improvement in left ventricular contractility was observed at 12 months, demonstrating the effect of reverse remodeling by the ARNI . MoreoveSince global GC-A KO mice with permanent occlusion of coronary artery showed worse cardiac remodeling and prognosis than WT mice in the chronic phase , it was In an experimental study, LCZ696 was administered in rats 7 days after left coronary artery occlusion. LCZ696 prevented cardiac remodeling and the impaired left ventricular contraction compared with vehicle at 4 weeks . HoweverA randomized clinical trial (PARADISE-MI) was conducted to evaluate the long-term effects of LCZ696 on AMI. Patients with reduced ejection fraction (LVEF ≤ 40%) or pulmonary congestion were randomly assigned to receive the ARNI or the ACE inhibitor ramipril within 0.5 to 7 days after AMI. Patients were followed-up for an average of 22 months. The composite outcome of cardiovascular death, first hospitalization for heart failure, and first outpatient episodes of symptomatic heart failure was not significantly different between the ARNI and ACE inhibitor groups . HoweverThe hormonal effects of ANP and BNP and the paracrine effects of CNP via coordination between endothelial cells and pericytes are important for regulating blood pressure. As mentioned previously, ANP and BNP induce natriuresis, regulate circulating plasma volume via endothelial permeability effect, suppress aldosterone production, and inhibit sympathetic nervous activity. These hormonal effects enhanced by ARNI may contribute to reduction of blood pressure. Natriuresis by ARNI was confirmed in patients with salt-sensitive hypertension. ARNI significantly increased natriuresis at 6 and 24 h on day 1 after first dose administration compared with valsartan but not on day 28, leading to significant reduction of blood pressure on day 28 .The antihypertensive effects of LCZ696 on hypertension reported in clinical studies are consistent. In a study involving patients with mild or moderate essential hypertension, LCZ696 significantly reduced blood pressure after eight weeks compared with valsartan . In a phSince the structures of natriuretic peptides were determined, natriuretic peptides have been clinically used for treatment of acute heart failure and for biomarkers. The precise roles of natriuretic peptides in each tissue were revealed by genetically modified mice. Recent clinical application of ARNI has brought up the long-term beneficial effects of natriuretic peptides in patients with heart failure. However, the effects of ARNI on angiotensin II, endothelin, amyloid beta, and other substrates are needed to be elucidated in the future.


Background Coronavirus disease-19 (COVID-19) remains a public health crisis. The epidemiology of COVID-19-associated large- and medium-sized-vessel pathology is not well characterized. The aim of this study is to identify patients with possible COVID-19-associated large- and medium-sized-vessel pathology based on computed tomography (CT) imaging to provide insight into this rare, but potentially devastating, cardiovascular manifestation.Methods This is a single-center retrospective review of patients with CT chest, abdomen, and/or pelvis concerning for large- and medium-vessel pathology and confirmed COVID-19 infection from March 1, 2020 to October 31, 2020.Results During the study period, 6,553 CT reports were reviewed and pertinent imaging was identified in 139 patients. Of these, 8 patients  were COVID-19 positive. All patients had preexisting cardiovascular risk factors and three (37.5%) had an autoimmune disease. Four patients were never hospitalized for COVID-19. Among these, two presented to the hospital at a median of 39 days (range: 27–50) after their initial COVID-19 test with chest and back pain where imaging revealed extensive aortic pathology. One patient required surgical management for aortic pathology. All other patients were treated with expectant management and outpatient follow-up.Conclusion The clinical and radiological presentations of COVID-19-associated large- and medium-vessel pathology are heterogeneous and can be a late finding after COVID-19 recovery. Close clinical follow-up and surveillance imaging for large- and medium-sized-vessel pathology may be warranted in COVID-19 patients. Coronavirus disease-19 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) remains an ongoing global pandemic with a total of 94 million reported infections and over 2 million deaths worldwide as of January 16, 2021.Increasing clinical experience and research have highlighted that COVID-19-associated cardiovascular complications are not only challenging, but may ultimately be devastating. The cardiovascular effects of SARS-CoV-2 are not well understood and remain an area of ongoing investigation. There is a growing body of literature detailing a new condition in the pediatric population associated with COVID-19 termed multisystem inflammatory syndrome in children (MIS-C), which has been described as a Kawasaki-like illness.A retrospective search of the picture archiving and communication system was conducted for all CT examinations  involving the chest, abdomen, and/or pelvis in inpatient and outpatient adults ≥18 years old from March 1, 2020 to October 31, 2020 at New York University Langone Health (NYULH). The search terms “aortitis,” “penetrating ulcer,” “vasculitis,” “dissection,” “intramural hematoma,” and “pseudoaneurysm” were used. A total of 6,553 reports including at least one of these terms were identified. The full text of all imaging reports from the search was screened by a cardiovascular radiologist for positive findings of vascular pathology. Because large- and medium-sized-vessel vasculitis are general terms used to describe a heterogeneous group of infectious and noninfectious diseases, a broad definition was used to screen for positive CT findings. Large vessels were defined as involvement of the aorta and/or its major branches. CT images that qualified for positive vascular pathology included abnormal wall thickening surrounding a vessel lumen, periaortic wall thickening with or without associated fusiform vascular dilatation, and surrounding fat and/or soft tissue changes.Of the 6,553 reports, 139 relevant CT images were identified. Patients with positive radiologic findings were cross-referenced with review of their respective electronic medical records for a diagnosis of COVID-19, which was confirmed by a positive result on reverse transcriptase polymerase chain reaction (RT-PCR) assay of a specimen collected by nasopharyngeal swab. A total of eight patients with COVID-19 and pertinent imaging on CT were identified and their data were collected from direct electronic medical record review. This study was approved by the institutional review board at NYULH and because of its retrospective nature, informed patient consent was waived.From March 1, 2020 to October 31, 2020, eight patients  with confirmed COVID-19 by RT-PCR and CT imaging concerning for large- and medium-vessel pathology were identified. Patient demographics and clinical and laboratory information are presented inAmong the eight patients, four (50%) were not hospitalized and four (50%) were hospitalized for COVID-19. Of the patients who were hospitalized for COVID-19, all CT images were performed during admission. The indication for CT included assessment of pulmonary embolism (PE) in twopatients, abdominal pain in one patient, and to further evaluate an incidental finding of an ascending aortic dissection visualized on noncontrast head CT in one patient. Patients' COVID-19 treatments and overall outcomes are described inThree patients  had imaging concerning for large-vessel vasculitis, specifically aortitis, of COVID-19. Patients number 1 and 2 developed large-vessel vasculitis-associated symptoms and presented to the hospital at a median of 39 days (range: 27–50) after their initial COVID-19 test with chest and back pain where diagnostic CT demonstrated aortitis. At the time of presentation, both patients were hemodynamically stable and admitted to the hospital for treatment—one patient required surgical intervention while the other was treated medically.Laboratory results in the surgical patient (patient number 1) confirmed previous COVID-19 infection with negative COVID-19 RT-PCR and positive COVID-19 immunoglobulin G (IgG) antibodies. The patient's CT angiogram (CTA) chest, abdomen, and pelvis demonstrated multiple contained ruptures in the thoracic aorta including a 4.5-cm saccular pseudoaneurysm of the distal ascending aorta and proximal aortic arch –C. ThIn patient number 2 who was medically treated, laboratory results revealed persistent COVID-19 infection with positive COVID-19 RT-PCR. The patient's CTA chest, abdomen, and pelvis demonstrated aortitis involving the distal thoracic and proximal abdominal aorta extending to the origin of the celiac axis . This pDuring their hospitalization, both patients underwent infectious and immunologic workup for their aortitis, including antinuclear antibody (ANA), rapid plasma reagin, and antiphospholipid antibody panels, which were unremarkable.Both patients underwent interval CTA following treatment 3 months later, which demonstrated intact ascending and descending thoracic aortic aneurysm repairs  in the In patient number 3, who never developed large-vessel vasculitis-associated symptoms, the pertinent radiographic finding was incidentally discovered on CT abdomen and pelvis with contrast for evaluation of new-onset pancreatic insufficiency and weight loss. Imaging demonstrated soft tissue thickening around the infrarenal abdominal aorta consistent with acute vasculitis . Based 2/FiO2241), leukocytosis (white blood cell 18.3 × 103/µL), and rhabdomyolysis (creatinine kinase 47658 IU/L). Given concern for septic shock in the setting of COVID-19 pneumonia in conjunction with an underlying intra-abdominal pathology, CTA chest, abdomen, and pelvis was performed, which revealed vasculitis with decreased caliber of the celiac trunk branch vessels, proximal superior mesenteric artery, and bilateral renal arteries  with 2-week history of general malaise and worsening abdominal pain. The patient was hypothermic with body temperature of 35.5°C, hypotensive with mottled extremities, tachycardic with heart rate of 149 beats per minute, and tachypneic with respiratory rate of 30 breaths per minute. Oxygen supplementation and empiric treatment for sepsis were initiated. Laboratory evaluation indicated severe metabolic acidosis , mild acute respiratory distress syndrome (ARDS) (PaOrteries . The paTwo patients (25%) (patient numbers 5 and 6) had imaging concerning for penetrating aortic ulcer (PAU) involving the aortic arch. Patient number 5 presented to the ER with 4-day history of dyspnea, nonproductive cough, and general malaise. The patient was afebrile, tachycardic with heart rate of 114 beats per minute, and hypoxic with an oxygen saturation of 86% on room air. Chest radiograph (CXR) demonstrated bilateral multifocal airspace opacities with prominent interstitial markings . The paPatient number 6 was never hospitalized for COVID-19 and was recently diagnosed with severe aortic stenosis. As part of his preoperative evaluation for transcatheter aortic valve replacement (TAVR), he underwent CTA chest, abdomen, and pelvis, which revealed a linear flap in the proximal aortic arch suspicious for a previous penetrating ulcer . No addPatient number 7 had imaging concerning for right coronary artery (RCA) aneurysm. The patient presented to the ER with 1-day history of left-sided pleuritic chest pain. He was afebrile with an oxygen saturation of 95% on room air;however, he became tachypneic with a respiratory rate of 28 breaths per minute. Initial evaluation was concerning for acute coronary syndrome with ST-segment elevations in the inferior leads on electrocardiogram and troponin of 5.35 ng/mL. Additional laboratory tests revealed positive COVID-19 RT-PCR and COVID-19 IgG antibodies. CXR demonstrated mild left basilar opacity . In the2/FiO2164) with D-dimer 11272 ng/mL. The patient was not offered surgery and he expired in the hospital. Postmortem evaluation revealed organizing thrombi with neutrophils within the area of the dissection. There was no evidence of aortitis.Patient number 8 presented with an acute aortic dissection. He was initially brought to the ER due to acute onset chest pain and subsequently developed left-sided hemiplegia, left facial droop, right gaze deviation, and dysarthria. The patient underwent noncontrast CT head that did not reveal any acute intracranial findings. A CTA head, neck, chest, abdomen, and pelvis was performed, which demonstrated a Stanford Type A aortic dissection beginning at the proximal aortic arch with extension into the proximal portion of the innominate artery and extending to the infrarenal aorta with associated hemopericardium . The pa18F]FDG positron emission tomography/CT and compared with propensity-matched controls to evaluate for radiologic findings that would explain these symptoms. They reported that although the total vascular score was similar between the two groups, the target-to-blood pool was higher in the thoracic aorta, right iliac artery, and femoral arteries of recovered COVID-19 patients, highlighting that COVID-19 induces a persistent systemic vasculitis despite illness recovery.COVID-19-associated large- and/or medium-sized-vessel vasculitis is rare.The clinical presentation and radiological findings in our case series varied greatly. The two patients with PAU on imaging may be less likely associated with COVID-19 as isolated PAUs have been reported to occur in 2.3 to 7.6% of acute aortic syndromes and typically present in older patients with cardiovascular risk factors.Definitive diagnosis of COVID-19-associated large- and medium-vessel pathology in our case series is limited by the lack of confirmatory histopathology. Histopathology reports were available for two patients and in the patient with aortitis there was a predominance of neutrophilic infiltration as seen with Type 3 hypersensitivity-mediated COVID-19 vasculitis.COVID-19 remains a public health crisis. While significant advancements have been made regarding the medical management of this disease, the long-term ramifications of COVID-19 and its treatment remain to be seen. Thus far, we have identified several interesting vascular pathologies in patients with prior COVID-19 infection. It remains unclear how many recovered COVID-19 patients have undiagnosed large- and medium-sized vessel pathologies and the trajectory of their disease progression. We believe this association warrants further clinical and histopathologic investigation with a focus on identifying at-risk patients who would benefit from close surveillance.


Typical AFL was associated with graft rejection (p = 0.016), whereas atypical AFL was associated with coronary artery disease (p = 0.028) and stent implantation (p = 0.042). Patients with atypical AFL showed a higher all-cause 1-year mortality (p = 0.010) along with a higher rate of graft failure after diagnosis of AFL (p = 0.023). Recurrence of AFL was high (83.6%). Patients with catheter ablation after AFL recurrence had a higher 1-year freedom from AFL (p = 0.003). Conclusions: Patients with late-onset post-transplant AFL were younger at HTX, received more biatrial anastomosis, and showed a higher rate of moderate or severe tricuspid regurgitation. Typical AFL was associated with graft rejection, whereas atypical AFL was associated with myocardial ischemia, graft failure, and mortality. Catheter ablation represents a viable option to avoid further episodes of late-onset AFL after HTX.Aims: Atrial flutter (AFL) is a common late-onset complication after heart transplantation (HTX) and is associated with worse clinical outcomes. Methods: This study investigated the frequency, risk factors, and outcomes of late-onset post-transplant AFL. We analyzed 639 adult patients undergoing HTX at the Heidelberg Heart Center between 1989 and 2019. Patients were stratified by diagnosis and type of late-onset post-transplant AFL (>90 days after HTX). Results: A total of 55 patients (8.6%) were diagnosed with late-onset post-transplant AFL, 30 had typical AFL (54.5%) and 25 had atypical AFL (45.5%). Patients with AFL were younger at HTX ( Heart transplantation (HTX) has been considered the preferred treatment for patients with irreversible end-stage heart failure for more than 50 years ,2,3,4,5.Heart rhythm disorders after HTX may be especially amenable to promising therapeutic approaches to improve post-transplant survival and quality of life as they comprise a broad spectrum of cases ,18,19,20The traditional definition of AFL is based on 12-lead electrocardiogram (ECG) morphology and involves typical and atypical AFL . TypicalGiven the risk profile of HTX recipients with late-onset AFL, these patients are at high risk for post-transplant morbidity and mortality. However, data on the clinical management of patients with late-onset post-transplant AFL are limited and even less is known about the differences between typical and atypical late-onset AFL after HTX. We therefore sought to investigate the risk factors, treatment, and clinical outcomes of late-onset AFL after HTX with special focus on typical and atypical AFL.We performed this study in accordance with the ethical standards of the Declaration of Helsinki. The institutional review board (IRB) of Heidelberg University gave approval . We obtained written informed consent from patients for their inclusion in the Heidelberg HTX Registry and the clinical and scientific use of their data. The ethics approval does not require additional consent for this observational study as only routine clinical data were used ,17,18,19Our study included all adult patients (≥18 years) who received HTX at the Heidelberg Heart Center, Heidelberg, Germany, between 1989 and 2019, except for patients who had undergone repeat HTX. We initially stratified patients by diagnosis of late-onset post-transplant AFL (>90 days after HTX). Patients with late-onset post-transplant AFL were further divided into patients with typical and atypical AFL based on 12-lead ECG findings and electrophysiological study (EPS) data in case of performed ablation . The traPatient follow-up was performed in accordance with the Heidelberg Heart Center’s routine clinical protocol. After the initial hospital stay following HTX, patients were seen monthly as outpatients in the HTX clinic during the first six post-transplant months, then bimonthly until the end of the first year after HTX, and approximately three to four times per year thereafter  ,17,18,19Routine follow-up included medical history, physical examination, systolic and diastolic blood pressure measurement, blood and laboratory tests including immunosuppressive drug monitoring, resting 12-lead ECG, echocardiography, endomyocardial biopsy, annual chest X-ray as well as annual 24-h Holter monitoring. We were able to obtain complete follow-up data after HTX from all patients as no patient was lost to follow-up. In addition, we could record all causes of death within one year after diagnosis of late-onset AFL after HTX ,17,18,19Post-transplant medications including immunosuppressive drug therapy were administered as per the Heidelberg Heart Center’s standard of care. Perioperatively, patients received an anti-thymocyte globulin-based immunosuppression induction therapy. Cyclosporine A and azathioprine were applied as the initial immunosuppression until 2001. Mycophenolate mofetil consequently replaced azathioprine from 2001 onward, and tacrolimus subsequently replaced cyclosporine A since 2006. Steroids were tapered incrementally during the initial post-transplant months and were discontinued six months after HTX  ,17,18,19The primary outcome of this study was 1-year mortality after diagnosis of late-onset post-transplant AFL, which was further assessed by stratification into patients with typical and atypical late-onset post-transplant AFL. Causes of death within one year after diagnosis of late-onset post-transplant AFL were categorized into the following groups: graft failure, acute rejection, infection/sepsis, malignancy, and thromboembolic event/bleeding ,17,18,19Secondary outcomes included analysis of clinical findings, risks factors and treatment of patients with late-onset AFL after HTX. Our analysis comprised multiple univariate analyses in order to search for intergroup differences between patients with and without diagnosis of late-onset AFL after HTX as well as between patients with typical and atypical late-onset AFL after HTX. Parameters included recipient data, recipient previous open-heart surgery, recipient principal diagnosis for HTX, donor data, transplant sex mismatch, perioperative data, immunosuppressive drug therapy, and post-transplant concomitant medications ,17,18,19Patients with late-onset AFL after HTX were further analyzed with regard to clinical presentation and findings, echocardiographic features, and acute graft rejection (diagnosed ± 7 days at the time of AFL), as well as treatment modalities. Given the long study period of more than 30 years, we performed a sensitivity analysis to test the robustness of our results and to examine a possible era effect using a subgroup of patients with tacrolimus and mycophenolate mofetil, since the immunosuppressive drug regimen was changed from 2006 onward ,17,18,19n) with percentage (%). For measures of association, difference of mean or hazard ratio (HR) with 95% confidence interval (CI) were applied. Depending on the variable type and question, we used Student’s t-test, Mann–Whitney U-test, analysis of variance (ANOVA), Kruskal–Wallis test, chi-squared test, or Fisher’s exact test, as appropriate. The Kaplan–Meier estimator was used to graphically compare 1-year survival after diagnosis of late-onset post-transplant AFL in patients with typical and atypical AFL as well as to analyze 1-year freedom from further episodes of late-onset AFL after HTX between patients with and without catheter ablation after recurrence of late-onset post-transplant AFL. A p-value of <0.050 was considered statistically significant ) had typical late-onset AFL after HTX, and 25 HTX recipients (25 of 55 [45.5%]) had atypical late-onset AFL after HTX. The median interval from HTX to the initial diagnosis of late-onset post-transplant AFL was 8.8 years  and the median interval from diagnosis of late-onset post-transplant AFL until last follow-up was 2.3 years . Patients with late-onset AFL after HTX had a significantly lower recipient age at HTX , while atypical AFL was associated with a significantly higher percentage of arterial hypertension . Demographics stratified by typical and atypical late-onset AFL after HTX are presented in Analysis of demographics between patients with typical and atypical late-onset AFL after HTX showed that typical AFL was more present in male HTX recipients . We also observed no statistically significant differences between patients with and without diagnosis of late-onset AFL after HTX regarding the administration of acetylsalicylic acid, beta blockers, ivabradine, calcium channel blockers, angiotensin-converting-enzyme inhibitors/angiotensin II receptor blockers, or statins . Medications of study participants are given in In terms of the immunosuppressive drug therapy, we found no statistically significant differences between patients with and without diagnosis of late-onset AFL after HTX concerning the use of cyclosporine A, tacrolimus, azathioprine, or mycophenolate mofetil . Medications stratified by typical and atypical late-onset AFL after HTX are shown in Likewise, there were no statistically significant differences between patients with typical and atypical late-onset AFL after HTX concerning immunosuppressive drugs or concomitant medications . Patients with typical AFL had a higher percentage of palpitations  and AFL with 2:1 atrioventricular conduction , while patients with atypical AFL showed a higher percentage of chest pain  and peripheral edema . Late-onset post-transplant AFL was incidentally detected in 9 of 55 patients (16.4%), either on routine resting 12-lead ECG (7 of 55 [12.7%]) or on routine 24-h Holter monitoring (2 of 55 [3.6%]). Especially on routine resting 12-lead ECG, asymptomatic atypical AFL was significantly more often found than asymptomatic typical AFL . Regarding clinical findings, patients with atypical AFL suffered from a significantly higher percentage of coronary artery disease , acute myocardial ischemia with requirement for coronary stent implantation , acute infection , and chronic hemodialysis , whereas patients with typical AFL had a significantly higher percentage of acute graft rejection . Clinical presentation and findings of patients with late-onset AFL after HTX are presented in The majority of patients with late-onset post-transplant AFL were symptomatic (46 of 55 [83.6%]) but patients with typical AFL were more symptomatic than patients with atypical AFL , a higher rate of mitral regurgitation , a larger left atrial diameter , a larger left ventricular diameter , and a reduced mitral annular plane systolic excursion .Assessment of echocardiographic features showed that HTX recipients with late-onset post-transplant AFL had a high percentage of an enlarged right atrial (81.8%) and right ventricular diameter (70.9%) along with an elevated rate of reduced right ventricular function in more than half of all patients (52.7%). Comparison between patients with typical and atypical late-onset AFL after HTX indicated a higher rate of impaired left-sided heart function in patients with atypical late-onset AFL after HTX. They had a higher rate of a reduced left ventricular function , a higher early diastolic mitral inflow peak velocity (E) to early diastolic mitral annular velocity (e′) ratio , a lower deceleration time (DT) of the early diastolic mitral inflow peak (E) , a higher systolic pulmonary artery pressure , a higher right atrial pressure , and a more dilated inferior vena cava . Echocardiographic features of patients with late-onset AFL after HTX are given in Analysis of diastolic parameters showed that patients with atypical late-onset AFL after HTX had a higher early diastolic mitral inflow peak velocity (E) to late diastolic mitral inflow peak velocity (A) ratio  or pharmacological cardioversion (9 of 55 [16.4%]) as treatment.p = 0.005), while patients with atypical AFL received significantly more often pharmacological cardioversion . No patient received catheter ablation at the initial occurrence of late-onset AFL after HTX, and spontaneous conversion of AFL only happened in a minority of patients (7 of 55 [12.7%]). Most patients with late-onset AFL after HTX had recurrence of AFL (46 of 55 [83.6%]). Preferred choice of treatment for patients with recurrence of late-onset AFL after HTX was catheter ablation which was performed in 20 patients . By contrast, 15 patients received electrical cardioversion  and 7 patients received pharmacological cardioversion .Patients with typical AFL received significantly more often electrical cardioversion . The Kaplan–Meier estimator of 1-year freedom from further episodes of post-transplant AFL stratified by patients with and without catheter ablation after recurrence of late-onset post-transplant AFL is presented in p = 0.022), 5 patients received electrical cardioversion , 2 patients received catheter ablation , and 2 further patients received repeat catheter ablation . Treatment of patients with late-onset AFL after HTX is summarized in Comparison between patients with and without catheter ablation after recurrence of late-onset post-transplant AFL showed a significantly lower 1-year rate of further episodes of post-transplant AFL in patients with catheter ablation (p = 0.010). The Kaplan–Meier estimator further showed a statistically significant inferior 1-year survival after diagnosis of late-onset post-transplant AFL in patients with atypical AFL (18 of 25 [72.0%]) in comparison to patients with typical AFL . The Kaplan–Meier survival curves are displayed in A total of 8 patients (14.5%) deceased within one year after diagnosis of late-onset post-transplant AFL. Patients with atypical AFL showed a significantly higher all-cause 1-year mortality than patients with typical AFL . Mortality and causes of death within one year after diagnosis of late-onset AFL after HTX are presented in Stratified by causes of death, patients with atypical AFL also had a significantly higher rate of graft failure within one year after diagnosis of late-onset post-transplant AFL ] in order to investigate a possible era effect and to examine the robustness of our results. This analysis showed similar findings supporting the robustness of our results and reducing the likelihood of a potential era effect.Late-onset post-transplant AFL is a common complication late after HTX and plays an important role in the clinical management of HTX recipients . PreviouAnother important finding of this study is the fact that patients with late-onset post-transplant AFL had a younger recipient age at the time of HTX. As the development of late-onset post-transplant AFL takes many years, older HTX recipients may not survive for such a long period and long-term survivors after HTX have a reported younger recipient age ,25,29,30To our knowledge, this is the largest study of HTX recipients with in-depth data analysis between patients with typical and atypical late-onset post-transplant AFL. Out of 55 HTX recipients with late-onset post-transplant AFL, 30 patients had typical AFL (54.5%) and 25 patients had atypical AFL (45.5%). Typical AFL was more common in male HTX recipients which is also the case in the general population ,35. PatiIn contrast, most HTX recipients with typical AFL were symptomatic in our study. The majority of these patients had palpitations which might result from a significantly higher percentage of AFL with 2:1 atrioventricular conduction in comparison to patients with atypical AFL. Palpitations as a main symptom of HTX recipients with typical AFL were also reported in smaller studies with AFL after HTX ,36,37. FClinical management of HTX recipients with late-onset post-transplant AFL involves electrical cardioversion, pharmacological cardioversion, catheter ablation, and in some cases conservative treatment due to spontaneous conversion of AFL ,40,41,42During the last two decades, treatment and clinical management of HTX recipients with late-onset post-transplant AFL has changed towards a more invasive approach focusing on radiofrequency catheter ablation with three-dimensional electroanatomical mapping systems in order to better understand the underlying mechanisms of post-transplant AFL ,40,41,42Rodríguez-Entem and colleagues  performep = 0.003). These findings are of high clinical relevance as there is a high risk of AFL recurrence in patients after HTX, and standard treatment of patients with AFL after HTX still consists of electrical or pharmacological cardioversion. Therefore, given the distinct cardiovascular risk profile of HTX recipients with late-onset post-transplant AFL, catheter ablation represents a viable option for HTX recipients in order to avoid further episodes of post-transplant AFL.In our study, 20 HTX recipients with recurrence of late-onset post-transplant AFL received catheter ablation . Only 2 of these 20 HTX recipients (10.0%) had a further episode of post-transplant AFL within one year after catheter ablation. In comparison to HTX recipients without catheter ablation after recurrence of late-onset post-transplant AFL, HTX recipients with catheter ablation after recurrence of late-onset post-transplant AFL showed a significantly lower 1-year rate of further episodes of post-transplant AFL (The results of our study were derived from a large single-center registry (Heidelberg HTX Registry) including the highly detailed data of 639 patients who received HTX at the Heidelberg Heart Center. In awareness of the known limitations of such a study design, our findings should be interpreted carefully and within the context of the existing literature. However, we would like to emphasize that our study was comparable to multicenter studies in sample size and our patients received standardized treatment and follow-up, reducing the likelihood of selection bias and potential confounders ,17,18,19Long-term follow-up is essential to detect late-onset post-transplant AFL. We therefore decided to analyze patients who received HTX at the Heidelberg Heart Center between 1989 and 2019 providing a minimum follow-up of two years after HTX. As a consequence of the long study period of more than 30 years, a possible era effect due to changes in surgical and medical care may have influenced our findings. In order to investigate a possible era effect, we performed a sensitivity analysis with HTX recipients who received tacrolimus and mycophenolate mofetil, since tacrolimus replaced cyclosporine A as the main immunosuppressive agent from 2006 onward. This analysis showed similar results supporting the robustness of our findings ,17,18,19Assessment of late-onset post-transplant AFL was based upon all available source files including resting 12-lead ECGs, monitor-telemetry, 24-h Holter monitoring, and EPS data in the case of performed ablation. The type of AFL was diagnosed on 12-lead ECG criteria  but an aPost-transplant AFL is a common and clinically relevant cardiac arrhythmia late after HTX. About one out of ten HTX recipients suffered from it and the median interval from HTX until the initial diagnosis of late-onset post-transplant AFL was around nine years. Patients with late-onset post-transplant AFL had a lower recipient age at HTX, received more biatrial anastomosis, and showed a higher rate of moderate or severe tricuspid regurgitation, all underlining the aspects of time, altered anatomy, and proarrhythmic substrate in the development of late-onset post-transplant AFL. Regarding the differences between typical and atypical AFL, typical AFL was associated with symptomatic palpitations and acute graft rejection, while atypical AFL was common in asymptomatic HTX recipients with coronary artery disease and requirement for coronary stent implantation. Impaired right-sided heart function was found in more than half of HTX recipients with late-onset post-transplant AFL, but a significant number of patients with atypical AFL also showed a reduced left-sided heart function and had a higher all-cause 1-year mortality along with a higher rate of graft failure after diagnosis of AFL. Initial standard treatment of patients with new-onset AFL after HTX mainly consists of electrical or pharmacological cardioversion, whereas catheter ablation is often only used in cases of recurrence. However, since most patients with late-onset AFL after HTX suffer from recurrence of AFL and the recurrence rate of AFL after catheter ablation is significantly lower, catheter ablation may not only represent a viable option for HTX recipients with recurrence of post-transplant AFL but also for HTX recipients with new-onset post-transplant AFL, especially in the light of the risk profile and vulnerability of these patients.


Low physical activity (PA) level and high sedentary time (SED) have been associated to cardiovascular (CVD) morbidity and mortality. Routinely assessing the PA-level of patients being admitted to hospital has been proposed. The aim was to explore PA-level and SED among patients prior to cardiac ward admission and whether this can predict all-cause mortality.A longitudinal observational study of patients with ischemic heart disease, heart failure, cardiac arrhythmia, valvular heart disorder and inflammatory heart diseases treated on cardiac wards (2015-2016) in Stockholm, Sweden. Data on PA-levels and SED prior to admission were collected by validated questionnaires during inpatient care. PA level a regular week was calculated by an index (3-19 points) including everyday PA and exercise. The cut-off of insufficiently physically active was set to > 9 points. Individuals' reporting ≥7 hours of sitting a normal day were categorised as high SED. Differences in PA-level and SED between different diagnose groups were explored by Benjamini-Hochberg procedure. The associations between PA-level and SED with all-cause mortality were analysed using cox regressions, adjusting for age, sex, diagnosis group, education level, disposable income, smoking status, alcohol consumption and eating habits.Among 1148 patients with CVD, approximately 56% were considered as insufficiently physically active (>9 points). In addition, approximately half the study population were categorized as high SED (≥7 hours per day). There were differences in PA-level and SED between the various cardiovascular diagnoses, with individuals with heart failure and valvular heart disorder being in general more inactive and having higher levels of SED. A total of 200 deaths occurred during a median follow-up time of 2.6 years. The mortality was higher among those categorised as insufficiently physically active  or high SED  compared to those reporting sufficient PA and low SED, respectively.A high amount reported insufficient PA and a high amount of SED preceding hospitalisation. There was an association between PA (negatively) and SED (positively) with all-cause mortality among patients with CVD. This highlights the prognostic value of assessing patients' PA-level and SED in clinical practice.


Neurological and psychiatric manifestations related to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection are widely recognised. Standard magnetic resonance imaging (MRI) investigations are normal in 40–80% of symptomatic patients, eventually delaying appropriate treatment when MRI is unrevealing any structural changes. The aim of this study is to investigate white matter abnormalities during an early stage of post-COVID-19 (coronavirus disease 2019) encephalitis while conventional MRI was normal.A patient with post-COVID-19 autoimmune encephalitis was investigated by serial MRIs and diffusion tensor imaging (DTI). Ten healthy control individuals (HC) were utilised as a control group for the DTI analysis. Major projection, commissural and association white matter pathways were reconstructed, and multiple diffusion parameters were analysed and then compared to the HC average using a z-test for serial examinations.Eleven days after the onset of neurological symptoms, DTI revealed early white matter changes, compared with HC, when standard MRI was normal. On day 68, DTI showed multiple white matter lesions compared with HC, visible at this time also by the MRI images, indicating inflammatory changes in different association and projection white matter pathways.We confirm a limitation in the sensitivity of conventional MRI at the acute setting of post-COVID-19 autoimmune encephalitis. A complementary DTI investigation could be a valuable diagnostic tool in early therapeutic decisions concerning COVID-19-related neurological symptoms. Coronavirus disease 2019 (COVID-19) is an on-going viral pandemic caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Neurological and psychiatric manifestations related to SARS-CoV-2 infection are widely reported . The neuA previously healthy 40-year-old man developed mild respiratory symptoms without requiring hospitalisation. He had a positive nasopharyngeal swab for SARS-CoV-2. After 22 days, he developed acute psychotic symptoms, and within 1 day, he became mutistic and then unresponsive. Once admitted to the hospital, he showed a decorticated posture, rowing-eye-movements and bilateral corticospinal tract involvement with hyperreflexia and Babinski sign bilaterally as previously described . StandarTen healthy control individuals (HC)  with no previous traumatic brain injury and neurological or neuropsychiatric conditions were included as a control group as previously reported , 19. TheThe patient was examined three times with the same protocol using a 3.0 Tesla scanner . High-resolution 3D-T1-weighted (T1w), 3D-T2 fluid attenuated inversion recovery (3D-FLAIR), Diffusion-Weighed Imaging (DWI) and Susceptibility weighted imaging (SWI) were acquired for standard evaluation. The second and third scans included diffusion-weighted tensor images (DTI). Details about DTI acquisition, data processing and tracking technique are provided in Electronic supporting material 1 (ESM1).White matter pathways from the patient were then compared to the HC average using a z-test for both examinations. Indices where the z-test reached a significance level of <0.05 are highlighted with red (day 11) and green (day 68) in The first two MRI scans  were negative , top rowIn this report, we present two main results. First, we confirm a limitation in the sensitivity of conventional MRI at the acute setting of SARS-CoV-2-related autoimmune encephalitis. As described by other reports, neuroimaging in COVID-19 is important to find haemorrhagic and thromboembolic lesions but is frequently negative despite neurological symptoms , 8, 20. Second, we detected early focal white matter changes using DTI while the conventional MRI was negative. DTI has been shown to be sensitive to even minor tissue changes not yet visible on conventional MR , 15. We We formulate a pathophysiological hypothesis based on the clinical features, laboratory analyses and structural radiological investigations combining MRI and DTI. Our results suggest that the combination of conventional MRI and DTI could be a more sensitive diagnostic tool with high value for clinical neurologists in early therapeutic decisions of COVID-19-related neurological symptoms. In fact, in the modern era of neurology, clinicians are often reluctant to treat when standard morphological imaging does not reveal any structural lesions. This can lead to treatment delay, thus more severe symptoms and risk for sustained disability.To improve our understanding of the pathophysiology of cerebral COVID-19 manifestations, only studies with larger cohorts of patients analysed with early and longitudinal MRI and DTI investigations would be able to better characterise lesion topography, temporal evolution of the lesions, development of symptoms and treatment response.


This report describes the unique case of an intra-articular lipoma in a 34-year-old male. The patient presented with a history of chronic knee pain associated with an intermittent sensation of the knee giving way. Physical examination and initial radiographic imaging were unremarkable. Magnetic resonance imaging (MRI) revealed a 9.2 x 6.7 mm ovoid mass posterior to the posterior cruciate ligament (PCL) exhibiting hyperintense signals on T1-weighted images and intermediate-to-high intensity signals on T2. On subsequent proton density fat suppression sequences, the mass demonstrated homogenous signal suppression and was confirmed as being a lipoma. To the best of our knowledge, this is only the second reported case of an intra-articular lipoma arising posterior to the PCL. Intra-articular lipomas, albeit rare, should be considered in the differential diagnosis for chronic knee pain with associated joint motion abnormalities. MRI remains the gold standard in imaging intra-articular soft tissue pathology and should be the study of choice in differentiating intra-articular lipomas from similar conditions such as pigmented villonodular synovitis and lipoma arborescens. Lipomas, benign tumors of fat, are common soft tissue tumors. They commonly affect middle-aged individuals between 40 and 60 and usually occur just under the skin . Deeper True intra-articular lipomas are solitary round or ovoid masses of fat contained within a fibrous capsule. True intra-articular lipomas most often occur in the knee joint, commonly in the anterior compartment on Hoffa’s fat pad or the suprapatellar pouch, although they occasionally affect the hip, spine, shoulders, elbows, and wrists . Rarely We report a 34-year-old male with a true intra-articular lipoma posterior to the PCL. Through a literature review, we discuss the appropriate differentials and imaging features that radiologists must be acquainted with.A 34-year-old male, otherwise healthy, presented complaining of chronic right knee pain and a feeling of the knee giving way. Meniscal degeneration or tear was suspected, and the patient was referred to us for radiological evaluation.The initial X-ray of the right knee was normal and revealed no soft tissue swelling or degenerative changes Figures -2.Subsequent magnetic resonance imaging (MRI) of the right knee demonstrated a small ovoid area of abnormal signal intensity was noted posterior to the PCL. It measured 9.2 x 6.7 mm and exhibited hyperintense signals on T1-weighted images and intermediate-to-high intensity signals on T2 Figures -4 and siMinimal associated effusion was observed in the tibiofemoral joint, mild edematous changes were seen in the prepatellar soft tissues, and no additional findings were noted. A diagnosis of small intra-articular lipoma posterior to the PCL was made on this basis. Unfortunately, we could not procure a biopsy specimen for histopathologic confirmation of lipoma, but the signal suppression on PDFS sequences confirms a lipomatous nature, and the imaging evaluation strongly suggested probable intra-articular lipoma.We managed the patient symptomatically and advised him for regular follow-ups because we lack an arthroscopic facility at our hospital.Intra-articular lipomas are exceedingly rare. They are space-occupying lesions and present clinically with symptoms of mass effect, most commonly pain and limited range of movement. They can alternatively manifest with locking of the knee -6 - by gThe role of plain X-ray in the diagnosis of intra-articular lipoma is limited. Small lipomas may not be detected, whereas larger lesions may feature isolated soft-tissue swelling with no other joint changes -11. In tMRI is the diagnostic tool of choice because it offers a more soft tissue definition than other modalities such as computed tomography (CT). Intra-articular lipomas exhibit high-intensity signals on T1- and T2-weighted images, which suppress fat suppression sequences . HoweverSheldon et al. classified the differential diagnosis of intra-articular mass lesions based on underlying pathogenesis . The mosPigmented villonodular synovitis (PVNS), a benign but locally aggressive monoarticular synovial disease characterized by villous or nodular synovial expansion and hemosiderin deposition, is another important differential . This leLastly, peri-cruciate fat pad inflammation is another lipomatous cause of non-specific posterior knee pain, occurring mainly in young, physically active adults, similar to our patient. The peri-cruciate fat pad situates in the intercondylar fossa between the cruciate ligaments. MRI reveals increased signals on PDFS sequences and post-contrast enhancement .A PCL ganglion cyst is another common differential to consider. Like intra-articular lipomas, ganglion cysts are more common in the anterior compartment and present non-specifically with knee pain, limited ROM, and/or snapping and locking of the knee. On imaging, they classically appear as well-defined cystic masses adjacent to the PCL, which display hypointense signals on T1 and T2-weighted sequences and do not suppress on PDFS, differentiating them from lipomas .Lastly, liposarcomas are the second most common soft-tissue sarcomas and can rarely develop in the knee joint. Like intra-articular lipomas, they affect middle-aged individuals. However, they are locally aggressive tumors, manifested clinically as a rapidly growing painless soft-tissue swelling around the knee joint and a requirement for radical amputation if diagnosis and intervention are delayed . FurtherIn summary, a myriad of conditions - both benign and malignant - can involve the knee joint all of which present similarly on clinical evaluation. Imaging, particularly MRI, is essential in the diagnostic workup of intra-articular masses, but a biopsy is essential when imaging evaluation is uncertain to exclude rare etiologies like intra-articular liposarcoma before surgical intervention. Surgical consultations are curative. Both arthroscopy and arthrotomy are viable treatment options in the literature. However, arthroscopic resection may not be feasible for larger lesions, favoring arthrotomy .We report the second case of intra-articular lipoma in the knee joint posterior to the PCL. Intra-articular lipomas have a non-specific clinical presentation, making a thorough radiologic evaluation essential. MRI is the imaging modality of choice in diagnosing intra-articular mass lesions while plain radiographs have a relatively limited utility. Key differentials of intra-articular lipoma to rule out include lipoma arborescens and PVNS. Rare etiologies to consider include intra-articular liposarcoma, ganglion cyst, and peri-cruciate fat pad inflammation. When imaging evaluation is uncertain, a biopsy should be done to carry out a histopathological diagnosis. The major limitation of the present study was us being unable to confirm our diagnosis histologically after surgical resection. Nevertheless, the imaging findings were strongly suggestive of lipoma, and we hope that practicing radiologists familiarize themselves with the aforementioned differential imaging findings of these lesions to prevent complications of misdiagnosis.


Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressively debilitating, rare disease associated with high mortality. ATTR-CM occurs when TTR amyloid protein builds up in the myocardium along with different organs, most commonly the peripheral and the autonomic nervous systems. Managing the cardiac complications with standard heart failure medications is difficult due to the challenge to maintain a balance between the high filling pressure associated with restricted ventricular volume and the low cardiac output. To date, tafamidis is the only agent approved for ATTR-CM treatment. Besides, several agents, including green tea, tolcapone, and diflunisal, are used off-label in ATTR-CM patients. Novel therapies using RNA interference also offer clinical promise. Patisiran and inotersen are currently approved for ATTR-polyneuropathy of hereditary origin and are under investigation for ATTR-CM. Monoclonal antibodies in the early development phases carry hope for amyloid deposit clearance. Despite several drug candidates in the clinical development pipeline, the small ATTR-CM patient population raises several challenges. This review describes current and future therapies for ATTR-CM and sheds light on the clinical development hurdles facing them. TTR gene, located on the long arm of chromosome 18 [Amyloidosis is a rare disease in which amyloid fibrils misfold and aggregate into toxic oligomers that build up extracellularly in the tissue . It can osome 18 ,14. The osome 18 . The preosome 18 ,17. Bothosome 18 ,20. Lateosome 18 . Howeverosome 18 . For manosome 18 . After tosome 18 , the UniThe distinctive pathophysiology of ATTR-CM, characterized by both restrictive ventricular filling and reduced stroke volume, renders the use of standard heart failure medications difficult , summariEpigallocatechin-3-gallate (EGCG) is a polyphenolic natural compound most abundant in green tea . EGCG isFor many decades, liver transplantation has been considered the only approach to halt the progression of ATTRv-CM. Although liver transplantation removes the main source of aberrant amyloid protein, it does not provide a complete cure for the disease. In a large collective of 2127 liver transplant patients who were included in Familial Amyloidotic Polyneuropathy World Transplant Registry (FAPWTR), the overall 20-year survival rate was 55.3%. The largest benefit was observed in ATTRv patients carrying the most common pVal50Met variant . The reaDissociation of the TTR tetramer is considered the rate-limiting step in the amyloidogenesis . The binTolcapone is an orally available catechol-O-methyltransferase inhibitor used for the treatment of Parkinson’s disease, usually in combination with levodopa and carbidopa. It has a high binding affinity to the TTR binding pockets, stabilizing the tetramer . TolcapoDiflunisal is an FDA-approved non-steroidal anti-inflammatory agent (NSAID). Due to its structural match to T4, diflunisal can bind and stabilize the TTR tetramer . A randoTafamidis meglumine (20 mg) was approved in 2011 by the EMA for stage I ATTRv polyneuropathy following the results of an 18-month phase III clinical trial (NCT00409175) where it was able to stop the disease progression in 60% of the treated compared to 38% of the placebo group ,56. The Acoramidis (AG10) is an orally active TTR stabilizer under investigation. The small molecule mimics the protective TTR mutation Thr119Met by forming hydrogen bonds with the serine residues at position 117 . In humaMds84 is a bivalent TTR ligand that simultaneously binds both binding pockets. This property overcomes the monovalent agent’s negative cooperativity binding effect . In vitrReplacing the source of aberrant TTR protein via liver transplantation has been the only effective treatment strategy for decades. ATTRv patients could only benefit from liver transplantation reaching a one-year survival rate of 74.3% and three- and five-year survival rates of 60.0% and 52.5%, respectively . A paradPatisiran is a siRNA encapsulated in lipid-based nanoparticles enabling hepatic uptake via micropinocytosis . It is tInotersen is a subcutaneously administered ASO, approved by the FDA and EMA for hereditary ATTR-polyneuropathy following the results of the NEURO-ATTR study. The approval of inotersen came two months after that of patisiran. The NEURO-ATTR study enrolled 172 patients who were randomized in a 2:1 ratio to inotrasine (300 mg every week) or placebo. Compared to placebo, the treatment group showed improved neurological manifestation, improved quality of life, and reduced mean serum TTR level by 75% from baseline . Recentln = 140) or placebo (n = 66) for five days over a week followed by weekly doses. The study was prematurely terminated after 6.71 months due to high mortality in the revusiran-treated arm (18 deaths) compared to the placebo-treated arm (two deaths). The subsequent analysis did not reveal any causality [Revusiran is the first N-acetylgalactosamine  conjugated siRNA to enter clinical trials. GalNAc is a galactose derivative that binds to the asialoglycoprotein receptor (ASGPR) on hepatocytes leading to clathrin-mediated uptake. This advancement allows dose-reduction and enables subcutaneous administration . The Phaausality .Molecular modifications known as enhanced stabilization chemistry (ESC) patterns characterize second-generation RNA interference agents. ESC remarkably enhances the pharmacodynamic and pharmacokinetic properties of the RNA interference agents, allowing a significantly lower dose, with a markedly reduced dosing frequency compared to the first-generation agents .Vutrisiran, formerly known as ALN-TTRsc02, is a long-acting, subcutaneously administered successor of patisiran. In a phase I, randomized, single-blind, placebo-controlled trial on 80 healthy subjects, vutrisiran demonstrated a favourable safety profile and sustained TTR plasma level reduction in a dose-dependent manner . The druEplontersen, formerly known as AKCEA-TTR-LRx or IONIS-TTR-LRx, is the GalNAc-conjugated successor of inotersen. The global phase III NEURO-TTRansform study (NCT04136184) is currently evaluating eplontersen subcutaneous injections 45 mg every four weeks against inotersen 284 mg weekly in patients with hereditary ATTR-polyneuropathy . In paraThe recently introduced clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease (CRISPR-Cas9) gene-editing system has revolutionized biomedical research via allowing one-time treatment for deadly diseases including ATTR-CM . NTLA-20Doxycycline is an FDA-approved broad-spectrum antibiotic that belongs to the tetracyclines family. Tetracyclines can bind to the ribosomal subunits disrupting the synthesis of aggregation-prone proteins ,89. PrecTargeting pathological TTR amyloid deposits while sparing physiological TTR tetramers is conceivable via antibodies designed to recognize prefibrillar and fibrillar TTR-specific epitopes . AntibodATTR-CM is an orphan disease characterized by a small patient population. The clinical development of therapies for ATTR-CM faces several challenges, as shown in


We report a case of a patient double-seropositive for anti-glomerular basement membrane (anti-GBM) and anti-neutrophil cytoplasmic antibodies (ANCA) who reported retrosternal chest pain during a regular hemodialysis session associated with ST-segment depression in electrocardiogram and an increase of serum high-sensitivity troponin T. Urgent coronary angiography excluded obstructive coronary artery disease, suggesting the diagnosis of ischemia with non-obstructive coronary arteries. This case illustrates an unusual presentation of cardiovascular involvement in a patient with double-positive ANCA/anti-GBM disease, emphasizing the possible relevance of coronary microvascular dysfunction and the need for close cardiovascular follow-up in this patient population. Anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV) and anti-glomerular basement membrane (GBM) disease are rare entities , 2. The A 61-year-old Caucasian man presented to our university clinic with acute kidney injury. He was diagnosed with scleritis of the right eye approximately 13 years before current admission and had received azathioprine (AZA) for immunosuppression due to suspected myeloperoxidase (MPO)-ANCA positive granulomatosis with polyangiitis (GPA) without evidence of further organ involvements. Besides, he had arterial hypertension treated with angiotensin-converting enzyme inhibitor/hydrochlorothiazide and had been diagnosed with prostate cancer 2 years before current admission . The AZA therapy had been discontinued 19 months prior to presentation due to an influenza infection. Thereafter, on admission, a nephritic syndrome was present. Laboratory investigations revealed an increase of MPO-ANCA and anti-glomerular basement membrane (anti-GBM) antibody titers . Thus, a kidney biopsy was performed, and the diagnosis of double-positive disease was made .Plasma exchange (14 sessions), high-dose corticosteroids, and cyclophosphamide (CYC – cumulative dose of 3.3 g) were initiated. However, he progressed to end-stage kidney disease and required hemodialysis (HD). In addition, 2 doses of rituximab (RTX) 500 mg each 2 weeks apart were given followed by 500 mg every 6 months as maintenance immunosuppressive therapy.After 4 weeks of HD initiation, during a regular HD session, the patient reported retrosternal chest pain. Electrocardiogram (ECG) showed ST depressions in leads II, III, aVF, and V4 to V6 , which cDouble-positive disease is a life-threatening disorder characterized by small vessel vasculitis affecting the kidneys and the lungs with a coincidence of anti-GBM disease and AAV . CardiacMyocardial infarction with non-obstructive coronary arteries represents a major health problem and is often misdiagnosed, leading to possible undertreatment . PatientA study by Pugnet et al. analyzed patients with GPA who underwent CMR . In pativia decreased coronary flow and perfusion pressure. Moreover, similar to patients with systemic lupus erythematosus, systemic inflammation in AAV patients might also contribute to coronary vasomotor abnormalities  for the publication of any potentially identifiable images or data included in this article.MaK and BO wrote the first draft of the manuscript. JG described the coronary angiography and ECG. CR evaluated and interpreted the cardiac MRI findings. MP performed the histological work-up. MaK, AKi, AKr, KE, and AR contributed to the data acquisition and drafting of the manuscript. All authors contributed to the article and approved the submitted version.


Symptomatic COVID-19 screening has been a cornerstone of case identification during the pandemic. Despite the myriad of COVID-19 symptoms, screens have focused on fever, cough, and dyspnea. It is unknown how well these symptoms identify cases in a healthy military population. This study aims to evaluate the utility of symptom-based screening in identifying COVID-19 through different COVID-19 waves.A convenience sample of 600 active-duty service members who arrived at JBSA in 2021 and 2022 was included in this study. We compared 200 symptomatic service members who tested positive for COVID-19 in each of FEB-APR 2021 (prior to the emergence of the Delta variant), JUN-AUG 2021 (Delta variant was predominant), and JAN 2022 (Omicron variant was predominant). Collected data included test date, reported symptoms, and vaccination status. Comparisons were conducted via Chi-Square or Fisher’s Exact test.Of the 600 symptomatic active-duty service members who tested positive for COVID-19, the most common symptoms were sore throat , headache , and cough . While sore throat was the most prominent symptom during Delta  and Omicron , headache was the most common prior to Delta . There were significant differences in symptoms by vaccination status (Table 2). Overall, screening for fever, cough, and dyspnea had a 65.1% sensitivity in this cohort (Table 3) with its lowest sensitivity in the pre-Delta cohort (53.5%) and highest sensitivity in the fully vaccinated Omicron cohort (78.3%).In this descriptive cross-sectional study evaluating symptomatic military members with COVID-19, symptom prevalence varied based on the predominant COVID-19 variant as well as patients’ vaccination status. As screening strategies evolve with the pandemic, changing symptom prevalence should be considered.All Authors: No reported disclosures.


Of particular translational relevance, our findings support a model whereby upregulation of COX-2 expression and activity post-chemotherapy impairs the efficacy of the combination of PD-1 blockade and chemotherapy. Accordingly, pharmacological inhibition of COX-2 with celecoxib, an anti-inflammatory drug already used clinically, unleashed tumour control in preclinical models when given alongside chemoimmunotherapy combinations.Cytotoxic therapies, such as chemotherapy and radiotherapy, are mainstays of cancer treatment for both early and unresectable, advanced disease. In addition to debulking the tumour mass through direct killing of proliferating tumour cells, these treatments can promote tumour control via immune-stimulating effects. Nonetheless, chemoresistance and tumour relapse remain huge clinical problems, suggesting that induction of anti-cancer immunity post-cytotoxic therapy is often weak, not durable and/or overcome by immune evasive mechanisms. In our recent study (Nat Commun 13:2063), we demonstrate that cancer cell-intrinsic activation of the cyclooxygenase (COX)-2/prostaglandin E Immune checkpoint blockade (ICB) therapies have transformed cancer treatment but only a fraction of patients experience benefit, especially long-term. Combinations with other treatment modalities are therefore actively being evaluated to improve patient outcomes. In particular, the combination of ICB with standard of care chemotherapy regimens has shown promise for multiple indications, leading to approvals for first-line treatment in different cancer types including non-small cell lung cancer, triple negative breast cancer (TNBC) and bladder cancer. However, clinical trial results have been mixed, with chemoimmunotherapy combinations in some cases failing to provide a benefit above standard of care chemotherapy. The design of more effective rational combinations requires a better understanding of the underlying basis for intrinsic and acquired therapy resistance.2 (PGE2) axis as a nodal protumourigenic inflammatory pathway often co-opted by cancer cells to drive immune evasion and resistance to ICB. In this latest study, we set out to investigate its contribution to inflammation and tumour immunity during chemotherapy treatment. Of interest, previous studies had already implicated PGE2 release from dying cancer cells post-cytotoxic therapy in stimulating cancer cell proliferation and tumour repopulation. We sought to establish the prevalence, underlying mechanisms, and consequence of PGE2 upregulation for the inflammatory properties of cancer cells post-cytotoxic therapy.Cancer-associated inflammation can play a dual role in tumour progression, with the potential to foster or restrain tumour growth. Therapeutic strategies that modulate the inflammatory tumour microenvironment (TME) to facilitate immune-mediated tumour control could therefore be valuable partners to chemoimmunotherapy combinations. Our previous work has underscored the cyclooxygenase (COX)-2/prostaglandin E2 pathway in chemotherapy-treated cancer cells and showed that transcriptional upregulation of the COX-2 gene and downstream PGE2 release occurs across multiple murine cancer cell lines, but notably only in cancer cells with basal COX-2 expression. By analysing a publicly available dataset of 60 human cancer cell lines treated with different chemotherapy drugs, we confirmed this phenomenon is conserved in mice and man regardless of the tumour tissue of origin. Chemotherapy-driven PGE2 release strictly relied on the enzymatic activity of COX-2, as it was fully prevented by addition of the selective COX-2 inhibitor celecoxib. Furthermore, transcriptional upregulation of Ptgs2 (encoding COX-2) post-chemotherapy was essential for enhanced PGE2 production. Thus, cancer cells genetically engineered to express COX-2 from an unrelated constitutive promoter were unable to upregulate the pathway in response to chemotherapy. These findings have important clinical implications, as measuring baseline activity of the COX-2/PGE2 pathway in tumours pan-cancer type could help identify patients most likely to benefit from the addition of a COX-2 inhibitor to chemoimmunotherapy regimens.We first characterised activation of the COX-2/PGEPtgs2 promoter. After confirming the increase in GFP fluorescence by these reporter cells post-chemotherapy closely reflected upregulation of COX-2 mRNA transcription, we utilised them to screen a library of 1280 market-approved drugs. Remarkably, all classes of chemotherapeutic agents led to increased COX-2 transcription when used at concentrations that induced cancer cell growth arrest, indicating that activation of the COX-2/PGE2 pathway happens independently of the drug mechanism of action. Noteworthy, both chemotherapy drugs reported to stimulate, and not stimulate, immunogenic cell death (ICD) similarly increased COX-2 expression and PGE2 synthesis, excluding this phenomenon as major contributor to the differential ability of ICD and non-ICD inducers to stimulate cancer immunity.We generated a reporter cell line to study the kinetics of COX-2 transcriptional upregulation alongside treatment effects on cancer cell growth by live cell imaging. The reporter cells express destabilised GFP, a short half-life version of GFP, under the control of the endogenous 2 upregulation post-chemotherapy through inhibitor and siRNA-based approaches, we excluded a major role for caspase activity, reactive oxygen species or various transcription factors known to bind to the Ptgs2 promoter region, including NF-κB, C/EBPβ, Sp1 and AP-1. Furthermore, we demonstrated that this response occurs prior to activation of the apoptosis executioners caspase-3/-7 but coincides with the halt in cancer cell proliferation. Indeed, no transcriptional COX-2 upregulation was observed for any of the diverse compounds tested in the library screen unless they also concomitantly promoted cancer cell arrest. Accordingly, analysis of an available transcriptome dataset of multiple human cancer cell lines treated with different chemotherapy agents indicated that the increase in COX-2 transcription correlates with the level of growth inhibition induced by the drug. Given how prevalent the increase in COX-2 expression post-chemotherapy was across mouse and human cancer cells and the variety of treatments that could trigger it, we speculate that there is a widely conserved, yet unidentified, cell stress response pathway that underlies the acute upregulation of Ptgs2 transcription. The full characterisation of this pathway and whether it also contributes to COX-2 upregulation post-cytotoxic treatment in non-tumour cells warrants further investigation.Interrogating the mechanism underlying COX-2/PGE2 pathway activity on the inflammatory properties of cancer cells post-chemotherapy in vivo, we assessed the recruitment of immune cells and production of soluble inflammatory mediators after injecting chemotherapy-treated cells into the peritoneum of mice. This experimental system, previously used to study the inflammatory response to dying cells, allowed us to delineate the response driven by the treated cancer cells, without the confounding effects that systemic chemotherapy would have on non-tumour cells. Using this approach, we showed that cancer cells which upregulate COX-2 expression post-chemotherapy stimulate markedly enhanced recruitment of neutrophils and monocytes or production of soluble factors compared with control untreated cancer cells. Notably, cancer cells which lacked or expressed basal levels of COX-2 but could not upregulate its transcription post-chemotherapy behaved similar to untreated cells, uncovering the increase in COX-2 as a major determinant of the inflammatory properties of chemotherapy-treated cancer cells.To determine the impact of increased COX-2/PGE2 activity to immune escape, we next evaluated whether pharmacological inhibition of COX-2 would alter the efficacy of chemoimmunotherapy combinations. Clinical trials evaluating the addition of COX-2 inhibitors to cytotoxic therapy regimens have historically produced mixed results. Since inhibition of the COX-2/PGE2 pathway can efficiently enhance responses to ICB in multiple pre-clinical tumour models, it may be that additional stimulation of the immune system is required to observe a therapeutic benefit from chemotherapy and COX-2 inhibitor combinations in certain contexts. Our findings are in line with this speculation, as mice bearing poorly immunogenic tumours formed by 4T1 breast cancer cells failed to respond unless treated with the triple drug combination of chemotherapy, PD-1 blockade and COX-2 inhibition. The triple combination reduced the accumulation of neutrophils and monocytes, often associated with immunosuppression and ICB resistance, and increased the proportion of tumour-infiltrating IFNγ-producing T cells, indicating mobilisation of an enhanced anti-cancer immune response. Likewise, in a colorectal cancer model partially sensitive to chemoimmunotherapy, COX-2 inhibition further improved tumour control, indicating that pharmacologically targeting the COX-2/PGE2 pathway could benefit tumours both sensitive or refractory to chemoimmunotherapy.Given these findings and our previous work highlighting a crucial contribution for cancer cell-intrinsic COX-2/PGEMetastatic spread remains a major clinical challenge and multiple trials are examining the benefit of chemoimmunotherapy combinations for the prevention and treatment of cancer metastasis. We utilised the metastatic orthotopic 4T1 model of TNBC to explore whether the addition of a COX-2 inhibitor could improve the efficacy of chemoimmunotherapy in an adjuvant therapy preclinical model. Mammary tumours were surgically removed prior to the initiation of therapy, and the rate of local tumour reoccurrence and lung metastasis monitored. In this experimental setting, the addition of a COX-2 inhibitor alongside chemoimmunotherapy was again essential to limit tumour relapse and spontaneous metastasis after surgery.2 synthesis, by modulating the inflammatory features of cancer cells post-cytotoxic treatment, limit T cell-mediated tumour immunity . Therefore, pharmacologically targeting the COX-2/PGE2 axis could represent a viable strategy to unleash the efficacy of combinations of cytotoxic therapy and immunotherapy.In conclusion, our findings support a model whereby increased COX-2 expression and the resulting augmented PGE