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Acute myocarditis is an inflammatory condition that may herald the onset of dilated cardiomyopathy (DCM) or arrhythmogenic cardiomyopathy (ACM). We investigated the frequency and clinical consequences of DCM and ACM genetic variants in a population-based cohort of patients with acute myocarditis. This was a population-based cohort of 336 consecutive patients with acute myocarditis enrolled in London and Maastricht. All participants underwent targeted DNA sequencing for well-characterized cardiomyopathy-associated genes with comparison to healthy controls (n=1053) sequenced on the same platform. Case ascertainment in England was assessed against national hospital admission data. The primary outcome was all-cause mortality. Variants that would be considered pathogenic if found in a patient with DCM or ACM were identified in 8% of myocarditis cases compared with

The field of cardiac electrophysiology (EP) had adopted simple artificial intelligence (AI) methodologies for decades. Recent renewed interest in deep learning techniques has opened new frontiers in electrocardiography analysis including signature identification of diseased states. Artificial intelligence advances coupled with simultaneous rapid growth in computational power, sensor technology, and availability of web-based platforms have seen the rapid growth of AI-aided applications and big data research. Changing lifestyles with an expansion of the concept of internet of things and advancements in telecommunication technology have opened doors to population-based detection of atrial fibrillation in ways, which were previously unimaginable. Artificial intelligence-aided advances in 3D cardiac imaging heralded the concept of virtual hearts and the simulation of cardiac arrhythmias. Robotics, completely non-invasive ablation therapy, and the concept of extended realities show promise to revolutionize the future of EP. In this review, we discuss the impact of AI and recent technological advances in all aspects of arrhythmia care., Graphical Abstract Artificial intelligence-enhanced arrhythmia care.

AIMS Spontaneous coronary artery dissection (SCAD) is a cause of acute coronary syndromes and in rare cases sudden cardiac death (SCD). Connective tissue abnormalities, coronary inflammation, increased coronary vasa vasorum density and coronary fibromuscular dysplasia have all been implicated in the pathophysiology of SCAD but have not previously been systematically assessed. We designed a study to investigate the coronary histological and dermal collagen ultrastructural findings in SCAD. METHODS AND RESULTS 36 autopsy SCAD cases were compared with 359 SCAD survivors. Coronary and myocardial histology and immunohistochemistry were undertaken. Transmission electron microscopy (TEM) of dermal extracellular matrix components (ECM) of n = 31 SCAD survivors and n = 16 healthy volunteers were compared. Autopsy cases were more likely male (19% versus 5%; p = 0.0004) with greater proximal left coronary involvement (56% versus 18%; p

AIMS: Nuclear grade has been recently validated as a powerful prognostic tool in epithelioid malignant pleural mesothelioma (E-MPM). In other studies histological parameters including pleomorphic features and growth patterns were also shown to exert prognostic impact. The primary aims of our study are (1) externally validate the prognostic role of pleomorphic features in E-MPM and (2) investigate if evaluating growth pattern in addition to 2-tier nuclear grade improves prognostication. METHODS AND RESULTS: 614 consecutive cases of E-MPM from our institution over a period of 15 years were retrospectively reviewed, of which 51 showed pleomorphic features. E-MPM with pleomorphic features showed significantly worse overall survival compared those without (5.4 months vs 14.7 months). Tumours with predominantly micropapillary pattern showed the worst survival (6.2 months) followed by solid (10.5 months), microcystic (15.3 months), discohesive (16.1 months), trabecular (17.6 months) and tubulo-papillary (18.6 months). Sub-classification of growth patterns into high grade (solid, micropapillary) and low grade (all others) led to good separation of overall survival (10.5 months vs. 18.0 months) but did not predict survival independent of 2-tier nuclear grade. A composite score comprised of growth pattern and 2-tier nuclear grade did not improve prognostication compared with nuclear grade alone. Intra-tumoural heterogeneity in growth patterns is ubiquitous. CONCLUSIONS: Our findings support the incorporation of E-MPM with pleomorphic features in the epithelioid subtype as a highly aggressive variant distinct from 2-tier nuclear grade. E-MPM demonstrates extensive heterogeneity in growth pattern but its evaluation does not offer additional prognostic utility to 2-tier nuclear grade.

Copyright: © Katopodis et al. Severe acute respiratory syndrome (SARS) coronavirus‑2 (SARS‑CoV‑2), the causative viral agent for the ongoing COVID‑19 pandemic, enters its host cells primarily via the binding of the SARS‑CoV‑2 spike (S) proteins to the angiotensin‑converting enzyme 2 (ACE2). A number of other cell entry mediators have also been identified, including neuropilin‑1 (NRP1) and transmembrane protease serine 2 (TMPRSS2). More recently, it has been demonstrated that transmembrane protease serine 4 (TMPRSS4) along with TMPRSS2 activate the SARS‑CoV‑2 S proteins, and enhance the viral infection of human small intestinal enterocytes. To date, a systematic analysis of TMPRSS4 in health and disease is lacking. In the present study, using in silico tools, the gene expression and genetic alteration of TMPRSS4 were analysed across numerous tumours and compared to controls. The observations were also expanded to the level of the central nervous system (CNS). The findings revealed that TMPRSS4 was overexpressed in 11 types of cancer, including lung adenocarcinoma, lung squamous cell carcinoma, cervical squamous cell carcinoma, thyroid carcinoma, ovarian cancer, cancer of the rectum, pancreatic cancer, colon and stomach adenocarcinoma, uterine carcinosarcoma and uterine corpus endometrial carcinoma, whilst it was significantly downregulated in kidney carcinomas, acute myeloid leukaemia, skin cutaneous melanoma and testicular germ cell tumours. Finally, a high TMPRSS4 expression was documented in the olfactory tubercle, paraolfactory gyrus and frontal operculum, all brain regions which are associated with the sense of smell and taste. Collectively, these data suggest that TMPRSS4 may play a role in COVID‑19 symptomatology as another SARS‑CoV‑2 host cell entry mediator responsible for the tropism of this coronavirus both in the periphery and the CNS.

Nuclear grading systems for epithelioid malignant pleural mesothelioma (MPM) have been proposed but it remains uncertain if they could be applied in a biopsy-heavy setting. Using the proposed system, we conducted an independent, external validation study using 563 consecutive cases of epithelioid MPM diagnosed at our institution between 2003 and 2017, of which 87% of patients underwent biopsies only. The median number of sites sampled was 1, with a median maximum tissue dimension of 17 mm (biopsy) and 150 mm (resection). The median overall survival (OS) was 14.7 months. The frequencies of grade I, II, and III tumors were 31% (132/563), 52% (292/563), and 17% (94/563). Grade I tumors were associated with the most favorable median OS (24.7 mo) followed by grades II (12.7 mo) and III (7.2 mo). The 2-tier nuclear grade separated tumors into low grade (19.3 mo) and high grade (8.9 mo). In multivariate analysis, 3-tier nuclear grade, 2-tier nuclear grade, and mitosis-necrosis score predicted OS independent of age, procedural type, solid-predominant growth pattern, necrosis, and atypical mitosis (all P

Objectives We present the initial 2-year results of CardioCel® patch (Admedus Regen Pty Ltd, Perth, WA, Australia) implantation in paediatric patients with congenital heart diseases. Methods This was a single-centre retrospective study with prospectively collected data of all patients aged 18 years and under operated for congenital heart disease. The patch was introduced in 2014, with clinical practice committee approval and a special consent in case of an Ozaki procedure. Standard follow-up was performed with systematic clinical exams and echocardiograms. In case of reoperation or graft failure, the patch was removed and sent for a histological examination. Results Between March 2014 and April 2016, 101 patients had surgical repair using a CardioCel patch. The mean age was 22 (±36.3) months, and the mean weight was 9.7 (±10.3) kg. No infections and no intraoperative implantation difficulties were associated with the patch. The median follow-up period was 212 (range 4-726) days. The overall 30-day postoperative mortality was 3.8% (n = 4), none of which were related to graft failure. Five children were reoperated because of graft failure, 4 of whom had the patch implanted for aortic and were aged less than 10 days. The indications for patch implantation in the aortic position were aortopulmonary window, truncus arteriosus, coarctation and aortic arch hypoplasia repair. The median time between the first and the second operation for graft failure was 245 (range 5-480) days. Conclusions Our experience shows that the patch is well tolerated in the septal, valvar and pulmonary artery positions. However, we experienced graft failures in infants in the aortic position.

Background Unlike the vast amount of animal data available on the recellularization of allogenic decellularized heart valves (DHVs), there have only been sporadic histologic reports on such grafts in humans. Methods Two experienced cardiac pathologists independently evaluated human specimens obtained during reoperation between December 2010 and April 2017 DHVs in seven categories after automated staining (scores: 0 to 6) in comparison with published data. An optimal result of 42 points was classified as 100%. Results We found that 364 DHVs, 236 decellularized pulmonary homografts (DPHs), and 128 decellularized aortic homografts (DAHs) were implanted, and freedom from explantation was 96.1% (DAH) and 98.7% (DPH). Reoperations were because of (suspected) endocarditis in 5 of 11 patients, stenosis at the subvalvular or valvular or supravalvular level in 3 of 11 patients, planned staged reoperation in 2 of 11 patients, and 1 heart transplantation. Good reader agreement was reflected by an interagreement weighted κ of 0.783 (95% confidence interval: 0.707 to 0.859). The relative histologic score in nonendocarditis specimens was 76% ± 4.3% (maximum 81%). Intracellular procollagen type 1 production was found in recipient mesenchymal cells within the transplanted grafts. In endocarditis specimens the histologic score was significantly lower with 48% ± 7.3% (minimum 41%, p = 0.0004) because of leucocyte infiltration and matrix degradation. One DPH showed immune system-mediated graft failure. Grafts obtained during the first 12 months after implantation were not evenly repopulated with less recellularization in the inner parts; no difference was found between DAH and DPH with respect to extent of recellularization. Conclusions Substantial in vivo recellularization with noninflammatory cells was observed in this study. Spontaneous recellularization appears to require multiple months, which correspondingly has an impact on size selection for growing patients.

Following lung transplantation, fibrotic remodelling of the small airways has been recognized for almost 5 decades as the main correlate of chronic graft failure and a major obstacle to long-term survival. Mainly due to airway fibrosis, pulmonary allografts currently show the highest attrition rate of all solid organ transplants, with a 5-year survival rate of 58 % on a worldwide scale. The observation that these morphological changes are not just the hallmark of chronic rejection but rather represent a manifestation of a multitude of alloimmune-dependent and -independent injuries was made more recently, as was the discovery that chronic lung allograft dysfunction manifests in different clinical phenotypes of respiratory impairment and corresponding morphological subentities. Although recent years have seen considerable advances in identifying and categorizing these subgroups on the basis of clinical, functional and histomorphological changes, as well as susceptibility to medicinal treatment, this process is far from over. Since the actual pathophysiological mechanisms governing airway remodelling are still only poorly understood, diagnosis and therapy of chronic lung allograft dysfunction presents a major challenge to clinicians, radiologists and pathologists alike. Here, we review and discuss the current state of the literature on chronic lung allograft dysfunction and shed light on classification systems, corresponding clinical and morphological changes, key cellular players and underlying molecular pathways, as well as on emerging diagnostic and therapeutic approaches.

Background. Studies on the prognostic value of serial biomarker assays for future occurrence of allograft rejection (AR) are scarce. We examined whether repeated measurements of NT-pro-B-type natriuretic peptide (NT-proBNP), troponin T (TropT) and C-reactive protein (CRP) predict AR. Methods. From 2005 to 2010, 77 consecutive heart transplantation (HTx) recipients were included. The NT-proBNP, TropT, and CRP were measured at 16 +/- 4 (mean +/- standard deviation) consecutive routine endomyocardial biopsy surveillance visits during the first year of follow-up. Allograft rejection was defined as International Society for Heart and Lung Transplantation (ISHLT) grade 2R or higher at endomyocardial biopsy. Joint modeling was used to assess the association between repeated biomarker measurements and occurrence of future AR. Joint modeling accounts for dependence among repeated observations in individual patients. Results. The mean age of the patients at HTx was 49 +/- 9.2 years, and 68% were men. During the first year of follow-up, 1,136 biopsies and concurrent blood samples were obtained, and 56 patients (73%) experienced at least one episode of AR. All biomarkers were elevated directly after HTx and achieved steady-state after -12 weeks, both in patients with or without AR. No associations were present between the repeated measurements of NT-proBNP, TropT, or CRP and AR both early (weeks 0-12) and late (weeks 13-52) in the course after HTx (hazard ratios for weeks 13-52: 0.96 (95% confidence interval, 0.55-1.68), 0.67 (0.27-1.69), and 1.44 (0.90-2.30), respectively, per ln[unit]). Combining the three biomarkers in one model also rendered null results. Conclusion. The temporal evolution of NT-proBNP, TropT, and CRP before AR did not predict occurrence of acute AR both in the early and late course of the first year after HTx.

Aims Restrictive Allograft Syndrome (RAS) and idiopathic pleuroparenchymal fibroelastosis (IPPFE) are two different diseases reported to share the same histology. RAS relates to chronic allograft dysfunction in lung transplantation with IPPFE being a rare condition in native lungs. Our aim is to compare their histologies, alongside biopsies of usual interstitial pneumonia (UIP), to determine if there are differences that might help to elucidate the pathogenesis. Methods and Results We selected 4 post-mortem allograft lungs from patients who developed clear clinical RAS pattern, 5 biopsies diagnosed as IPPFE, 5 UIP biopsies and 5 sections of normal lung. Histopathologic features were described without knowledge of clinical and radiological features. Both RAS allografts and IPPFE biopsies showed intra-alveolar fibrosis and elastosis (IAFE), but RAS allografts also showed concomitant obliterative bronchiolitis, vascular lymphoplasmacytic inflammation within fibro-intimal thickening, less fibroblastic foci at the advancing edge of the fibrosis (1 against 14.4 FF in 2mm2) and a slight reduction of the capillary network compared to UIP (p=0.07) and controls (p=0.06). The main differences seen in UIP were the lack of IAFE and the presence of honeycomb change. Conclusions RAS and PPFE histopathology both show IAFE, but display various differences, particularly in their vascular morphology that may allow further understanding of pathogenesis. This article is protected by copyright. All rights reserved.

Accurate knowledge of causes of sudden cardiac death (SCD) in athletes and its precipitating factors is necessary to establish preventative strategies.This study investigated causes of SCD and their association with intensive physical activity in a large cohort of athletes.Between 1994 and 2014, 357 consecutive cases of athletes who died suddenly (mean 29 ± 11 years of age, 92% males, 76% Caucasian, 69% competitive) were referred to our cardiac pathology center. All subjects underwent detailed post-mortem evaluation, including histological analysis by an expert cardiac pathologist. Clinical information was obtained from referring coroners.Sudden arrhythmic death syndrome (SADS) was the most prevalent cause of death (n = 149 [42%]). Myocardial disease was detected in 40% of cases, including idiopathic left ventricular hypertrophy (LVH) and/or fibrosis (n = 59, 16%); arrhythmogenic right ventricular cardiomyopathy (ARVC) (13%); and hypertrophic cardiomyopathy (HCM) (6%). Coronary artery anomalies occurred in 5% of cases. SADS and coronary artery anomalies affected predominantly young athletes (≤ 35 years of age), whereas myocardial disease was more common in older individuals. SCD during intense exertion occurred in 61% of cases; ARVC and left ventricular fibrosis most strongly predicted SCD during exertion.Conditions predisposing to SCD in sports demonstrate a significant age predilection. The strong association of ARVC and left ventricular fibrosis with exercise-induced SCD reinforces the need for early detection and abstinence from intense exercise. However, almost 40% of athletes die at rest, highlighting the need for complementary preventive strategies.

Objectives: In patients with malignant pleural mesothelioma (MPM), local tumor outgrowth (LTO) after invasive procedures is a well-known complication. Currently, no biomarker is available to predict the occurrence of LTO. This study aims to investigate whether the tumor macrophage infiltration and phenotype of and/or the infiltration of CD8(+) T-cells predicts LTO. Materials and methods: Ten mesothelioma patients who developed LTO were clinically and pathologically matched with 10 non-LTO mesothelioma patients. Immunohistochemistry was performed on diagnostic biopsies to determine the total TAM (CD68), the M2 TAM (CD163) and CD8(+) T-cell count (CD8). Results: The mean M2/total TAM ratio differed between the two groups: 0.90 +/- 0.09 in the LTO group versus 0.63 +/- 0.09 in patients without LTO (p < 0.001). In addition, the mean CD8(+) T-cell count was significantly different between the two groups: 30 per 0.025 cm(2) (range 2-60) in the LTO group and 140 per 0.025 cm(2) (range 23-314) in the patients without LTO (p < 0.01). Conclusion: This study shows that patients who develop LTO after a local intervention have a higher M2/total TAM ratio and lower CD8(+) cell count at diagnosis compared to patients who did not develop this outgrowth. We propose that the M2/total TAM ratio and the CD8(+) T-cell amount are potential tools to predict which MPM patients are prone to develop LTO. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

We present a case of a patient with intramyocardial metastases from a carcinoid tumor. These findings were detected using cardiovascular magnetic resonance imaging, with functional metabolic activity analyzed using nuclear imaging and confirmed by histologic findings at surgical biopsy. This case highlights the value of cardiovascular magnetic resonance imaging and the importance of multimodality imaging.

Background Cutaneous leiomyosarcoma (CLM) is a very rare smooth muscle tumour that accounts for about 2–3% of all superficial soft tissue sarcomas. Although the development of various malignancies in scar tissue is well known, we report the first case of a CLM developing in a small pox scar. Case presentation A 66-year-old man presented with a painless, slow-growing lump in a small pox scar on his left shoulder. Histological biopsies showed the lesion to be a primary, well-differentiated cutaneous leiomyosarcoma. A CT scan of the thorax was conducted, which showed no signs of metastases. The complete lesion was then surgically excised, and histopathological examination revealed a radically excised cutaneous type leiomyosarcoma After 13 months’ review the patient was doing well with no evidence of tumour recurrence. Conclusions This is the first report of a CLM arising in a small pox scar. Although the extended time interval between scarring and malignant changes makes it difficult to advise strict follow-up for patients with small pox scars, one should be aware that atypical changes and/or symptoms occurring in a small pox scar could potentially mean malignant transformation.

Recent studies have shown that certain non-coding short RNAs, called miRNAs, play an important role in diffuse large B-cell lymphomas. Patients with diffuse large B-cell lymphoma have great diversity in both clinical characteristics, site of presentation and outcome. The aim of our study is to validate the differential expression in germinal center and non-germinal center diffuse large B-cell lymphoma,s and to study to the extent to which the primary site of differentiation is associated with the miRNA expression profile. We studied 50 cases of de novo diffuse large B-cell lymphoma for the expression of 15 miRNAs (miR-15a, miR-15b, miR-16, miR-17-3p, miR-17-5p, miR-18a, miR-19a, miR-19b, miR-20a, miR-21, miR-92, miR-127, miR-155, miR-181a and miR-221). Apart from 19 nodal cases without extranodal dissemination (stages I and II), we selected two groups with unambiguous stages I and II extranodal presentation; 9 cases of primary central nervous system, II cases of primary testicular and II cases of other primary extranodal diffuse large B-cell lymphomas. All cases were analyzed with qRT-PCR. In situ hybridization for the most differentially expressed miRNAs was performed to show miRNA expression in tumor cells, but not in background cells. MiR-21 and miR-19b showed the highest expression levels. No significant differences were seen between germinal center and non- germinal center diffuse large B-cell lymphomas in either the total or the nodal group for any of the 15 miRNAs. Two miRNAs showed significant differences in expression levels for diffuse large B-cell lymphoma subgroups according to the site of presentation. MiR-17-5p showed a significant higher expression level in the central nervous system compared with testicular and nodal diffuse large B-cell lymphomas (P

MicroRNAs ( miRNAs) are an important class of small RNAs that regulate gene expression at the post-transcriptional level. It has become evident that miRNAs are involved in hematopoiesis, and that deregulation of miRNAs may give rise to hematopoietic malignancies. The aim of our study was to establish miRNA profiles of naive, germinal center ( GC) and memory B cells, and validate their expression patterns in normal lymphoid tissues. Quantitative (q) RT-PCR profiling revealed that several miRNAs were elevated in GC B cells, including miR-17-5p, miR-106a and miR-181b. One of the most abundant miRNAs in all three B-cell subsets analyzed was miR-150, with a more than 10-fold lower level in GC B cell as compared with the other two subsets. miRNA in situ hybridization ( ISH) in tonsil tissue sections confirmed the findings from the profiling work. Interestingly, gradual decrease of miR-17-5p, miR-106a and miR-181b staining intensity from the dark to the light zone was observed in GC. A strong cytoplasmic staining of miR-150 was observed in a minority of the centroblasts in the dark zone of the GC. Inverse staining pattern of miR-150 against c-Myb and Survivin was observed in tonsil tissue sections, suggesting possible targeting of these genes by miR-150. In line with this, the experimental induction of miR-150 lead to reduced c-Myb, Survivin and Foxp1 expression levels in the Burkitt's lymphoma cell line, DG75. In conclusion, miRNA profiles of naive, GC and memory B cells were established and validated by miRNA ISH. Within the GC cells, a marked difference was observed between the light and the dark zone. Laboratory Investigation (2009) 89, 708-716; doi:10.1038/labinvest.2009.26; published online 6 April 2009

We introduce a method for photoacoustic imaging of the carotid artery, tailored toward detection of lipid-rich atherosclerotic lesions. A common human carotid artery was obtained at autopsy, embedded in a neck mimicking phantom and imaged with a multimodality imaging system using interstitial illumination. Light was delivered through a 1.25-mm-diameter optical probe that can be placed in the pharynx, allowing the carotid artery to be illuminated from within the body. Ultrasound imaging and photoacoustic signal detection is achieved by an external 8-MHz linear array coupled to an ultrasound imaging system. Spectroscopic analysis of photoacoustic images obtained in the wavelength range from 1130 to 1250 nm revealed plaque-specific lipid accumulation in the collagen structure of the artery wall. These spectroscopic findings were confirmed by histology. (C) The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License.