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Deep venous valves are frequent sites of deep venous thrombosis initiation. However, the possible contribution of the valvular sinus endothelium has received little attention in studies of thrombosis risk. We hypothesized that the endothelium of valve sinus differs from that of vein lumen with up-regulation of anticoagulant and down-regulation of procoagulant activities in response to the local environment. In pursuit of this hypothesis, we quantified endothelial protein C receptor (EPCR), thrombomodulin (TM), and von Willebrand factor (VWF) by immunofluorescence in great saphenous veins harvested at cardiac bypass surgery. We found significantly increased expression of EPCR and TM in the valvular sinus endothelium as opposed to the vein lumenal endothelium, and the opposite pattern with VWF (paired t test for TM and EPCR, each P < .001; for VWF, P ‫؍‬ .01). These data support our hypothesis and suggest that variation in valvular sinus thromboresistance may be an important factor in venous thrombogenesis. (Blood. 2009; 114:1276-1279) IntroductionDirect evidence from autopsy studies and phlebography, as well as circumstantial evidence such as the correlation between frequency of deep venous thrombosis and the number of valves in individuals, have established the venous valvular sinus as a frequent location of thrombosis initiation. [1][2][3][4] This phenomenon has been attributed to stasis, one of the components of Virchow triad. In the 1960s, contrast media was shown to linger in valve sinuses an average of 27 minutes postvenography. 5 Valvular sinus stasis has also been associated with hypoxia and increased hematocrit, 6 as well as preventing the efflux of activated clotting factors and influx of clotting factor inhibitors, constituting a potentially hypercoagulable microenvironment, another component of Virchow triad. Stasis alone, however, is not a sufficient explanation for the propensity of thrombi to form in deep venous valve sinuses because, for example, prolonged periods of stasis associated with sleep are not associated with thrombus formation. Accordingly, there must be other factors interacting with stasis in the generation of venous valvular thrombi.In recent years, attention has been focused on the importance of endothelial heterogeneity in different vascular beds. 7,8 Venous endothelium manifests multiple distinct phenotypes in different organs such as the kidney and liver. Gene expression microarray studies have shown that endothelial cells from macro-versus microvascular beds, from arteries versus veins, and from different organs have distinctly different and characteristic gene expression profiles. 9 In response to local changes in flow, shear stress, or oxygenation, endothelial cells often adapt by increasing or decreasing expression of critical cell-surface and cytoplasmic proteins. 10 Thus, we hypothesized that valvular sinus endothelium would maintain a thromboresistant phenotype with the expression of the anticoagulant proteins thrombomodulin (TM) and endothelial protein C receptor (EPCR) u...

As a result of the 2019 novel human coronavirus (COVID-19) global spread, medical examiner/coroner offices will inevitably encounter increased numbers of COVID-19-infected decedents at autopsy. While in some cases a history of fever and/or respiratory distress (eg, cough or shortness of breath) may suggest the diagnosis, epidemiologic studies indicate that the majority of individuals infected with COVID-19 develop mild to no symptoms. Those dying with-but not of-COVID-19 may still be infectious, however. While multiple guidelines have been issued regarding autopsy protocol in cases of suspected COVID-19 deaths, there is some variability in the recommendations. Additionally, limited recommendations to date have been issued regarding scene investigative protocol, and there is a paucity of publications characterizing COVID-19 postmortem gross and histologic findings. A case of sudden unexpected death due to COVID-19 is presented as a means of illustrating common autopsy findings, as well as diagnostic and biosafety considerations. We also review and summarize the current COVID-19 literature in an effort to provide practical evidence-based biosafety guidance for medical examiner-coroner offices encountering COVID-19 at autopsy.

Giant cell myocarditis (GCM) is a rapidly progressive and frequently fatal disease that mainly affects young to middle-aged previously healthy individuals. Early diagnosis is critical, as recent studies have shown that rapidly instituted cyclosporine-based immunosuppression can reduce inflammation and improve transplant-free survival. Before the 1980s, GCM was mainly a diagnosis made at autopsy. Owing to advancements in diagnostic and therapeutic options, it is now increasingly diagnosed on the basis of endomyocardial biopsies, explanted hearts, or apical wedge sections removed at the time of ventricular assist device placement. Histologic examination remains the gold standard for diagnosis; however, there are many possible etiologies for cardiac giant cells. Having a working knowledge of the clinicopathologic features that distinguish GCM from other giant cell–containing lesions is essential, since such lesions can have widely divergent management and outcome.

Death certificates are legal documents containing critical information. Despite the importance of accurate certification, errors remain common. Estimates of error prevalence vary between studies, and error classification systems are often unclear. Relatively few studies have assessed the frequency at which death certification errors occur in US hospitals, and even fewer have attempted a standardized classification of errors based on their severity. In the current study, our objective was to evaluate the frequency of death certification errors at an academic center, implement a standardized method of categorizing error severity, and analyze sources of error to better identify ways to improve death certification accuracy. Design: We retrospectively reviewed the accuracy of cause and manner of death certification at our regional academic institution for 179 cases in which autopsy was performed between 2013-2016. We compared non-pathologist physician completed death certificates with the cause and manner of death ultimately determined at autopsy. Methods: Errors were classified via a 5-point scale of increasing error severity. Grades I-IIc were considered minor errors, while III-V were considered severe. Sources of error were analyzed. Results: In the majority of cases (85%), death certificates contained ≥ one error, with multiple errors (51%) being more common than single (33%). The most frequent error type was Grade 1 (53%), followed by Grade III (30%), and Grade IIb (18%). The more severe Grade IV errors were seen in 23% of cases; no Grade V errors were found. No amendments were made to any death certificates following finalization of autopsy results during the study period. Conclusion: This study reaffirms the importance of autopsy and autopsy pathologists in ensuring accurate and complete death certification. It also suggests that death certification errors may be more frequent than previously reported. We propose a method by which death certification errors can be classified in terms of increasing severity. By understanding the types of errors occurring on death certificates, academic institutions can work to improve certification accuracy. Better clinician education, coordination with autopsy pathologists, and implementation of a systematic approach to ensuring concordance of death certificates with autopsy results is recommended.

e Among the most fascinating virulence attributes of Candida is the ability to transition to a biofilm lifestyle. As a biofilm, Candida cells adhere to a surface, such as a vascular catheter, and become encased in an extracellular matrix. During this mode of growth, Candida resists the normal immune response, often causing devastating disease. Based on scanning electron microscopy images, we hypothesized that host cells and proteins become incorporated into clinical biofilms. As a means to gain an understanding of these host-biofilm interactions, we explored biofilm-associated host components by using microscopy and liquid chromatography-mass spectrometry. Here we characterize the host proteins associated with several in vivo rat Candida albicans biofilms, including those from vascular catheter, denture, and urinary catheter models as well as uninfected devices. A conserved group of 14 host proteins were found to be more abundant during infection at each of the niches. The host proteins were leukocyte and erythrocyte associated and included proteins involved in inflammation, such as C-reactive protein, myeloperoxidase, and alarmin S100-A9. A group of 59 proteins were associated with both infected and uninfected devices, and these included matricellular and inflammatory proteins. In addition, site-specific proteins were identified, such as amylase in association with the denture device. Cellular analysis revealed neutrophils as the predominant leukocytes associating with biofilms. These experiments demonstrate that host cells and proteins are key components of in vivo Candida biofilms, likely with one subset associating with the device and another being recruited by the proliferating biofilm.

Multinucleated giant cells (MGCs) are often detected in cases of papillary thyroid carcinoma (PTC). Their origin and significance, however, has not been established. One possibility is that they form in response to injury induced by fine needle aspiration biopsy (FNAB). Other hypotheses are that the chemically-altered colloid produced by PTC induces MGCs to act as colloidophages, or else MGCs are a non-specific immune response ingesting neoplastic follicle cells. We assigned 172 cases of PTC a semi-quantitative score for MGCs. Cases with “many” MGCs were immunohistochemically stained for AEI/AEIII, CD68, and CD163 to assess for epithelial vs histiocytic differentiation, and for thyroglobulin and TTF-1 to assess for MGC ingestion of colloid or thyroid follicle cells respectively. Overall, we identified MGCs in 100/172 (58.1%) PTC specimens; in 45 (26.2%), “many” MGCs were found, while in 55 (31.9%) MGCs were “few.” The mean sizes of PTC in cases with many as opposed to rare/no MGCs was 2.50 cm vs 1.8 [P = 0.003]. The cases of PTC with many MGCs had higher multifocality (26/45 vs 51/127 [P = 0.06]), extrathyroidal extension (21/45 vs 36/127 [P = 0.03]), and recurrence (8/45 vs 9/127 [P = 0.08]), than did cases with rare or no MGCs. The majority of patients both with and without numerous MGCs had previous histories of FNA or hemilobectomy: 40/45 and 99/127 respectively (P = 0.062). The majority of MGCs were positive for CD68 (45/45), CD163 (44/45), thyroglobulin (34/45) and negative for AEI/AEIII (44/45) and TTF-1 (44/45). These results indicate that MGCs in PTC are of histiocytic origin. Cases of PTC with many MGCs have a significantly greater likelihood of extrathyroidal extension and greater tumor size than cases with few/no MGCs. MGCs appear to be functioning largely as colloidophages.