A Machine Learning Algorithm Improves the Diagnostic Accuracy of the Histologic Component of Antibody Mediated Rejection (AMR-H) in Cardiac Transplant Endomyocardial Biopsies.

BACKGROUND: Pathologic antibody mediated rejection (pAMR) remains a major driver of graft failure in cardiac transplant patients. The endomyocardial biopsy remains the primary diagnostic tool but presents with challenges, particularly in distinguishing the histologic component (pAMR-H) defined by 1) intravascular macrophage accumulation in capillaries and 2) activated endothelial cells that expand the cytoplasm to narrow or occlude the vascular lumen. Frequently, pAMR-H is difficult to distinguish from acute cellular rejection (ACR) and healing injury. With the advent of digital slide scanning and advances in machine deep learning, artificial intelligence technology is widely under investigation in the areas of oncologic pathology, but in its infancy in transplant pathology. For the first time, we determined if a machine learning algorithm could distinguish pAMR-H from normal myocardium, healing injury and ACR. MATERIALS AND METHODS: A total of 4,212 annotations (1,053 regions of normal, 1,053 pAMR-H, 1,053 healing injury and 1,053 ACR) were completed from 300 hematoxylin and eosin slides scanned using a Leica Aperio GT450 digital whole slide scanner at 40X magnification. All regions of pAMR-H were annotated from patients confirmed with a previous diagnosis of pAMR2 (>50% positive C4d immunofluorescence and/or >10% CD68 positive intravascular macrophages). Annotations were imported into a Python 3.7 development environment using the OpenSlide™ package and a convolutional neural network approach utilizing transfer learning was performed. RESULTS: The machine learning algorithm showed 98% overall validation accuracy and pAMR-H was correctly distinguished from specific categories with the following accuracies: normal myocardium (99.2%), healing injury (99.5%) and ACR (99.5%). CONCLUSION: Our novel deep learning algorithm can reach acceptable, and possibly surpass, performance of current diagnostic standards of identifying pAMR-H. Such a tool may serve as an adjunct diagnostic aid for improving the pathologist's accuracy and reproducibility, especially in difficult cases with high inter-observer variability. This is one of the first studies that provides evidence that an artificial intelligence machine learning algorithm can be trained and validated to diagnose pAMR-H in cardiac transplant patients. Ongoing studies include multi-institutional verification testing to ensure generalizability.

High-resolution Diffusion-weighted Imaging to Detect Changes in Tumor Size and ADC, and Predict Adverse Biopsy Histology during Prostate Cancer Active Surveillance.

PURPOSE: Majority of men with low-risk prostate cancer can be managed with active surveillance (AS). This study evaluates a high-resolution diffusion-weighted imaging (HR-DWI) technique to predict adverse biopsy histology (AH), defined as Gleason score ≥7 on any biopsy or ≥3 increase in number of positive biopsy cores on systematic biopsies. We test the hypothesis that high-grade disease and progressing disease undergo subtle changes during even short intervals that can be detected by HR-DWI. EXPERIMENTAL DESIGN: In a prospective clinical trial, serial multiparametric MRIs, incorporating HR-DWI and standard DWI (S-DWI) were performed approximately 12 months apart prior to prostate biopsy (n = 59). HR-DWI, which uses reduced field-of-view and motion compensation techniques, was compared with S-DWI. RESULTS: HR-DWI had a 3-fold improvement in spacial resolution compared with S-DWI as confirmed using imaging phantoms. For detecting AH, multiparametric MRI using HR-DWI had a sensitivity of 75% and specificity of 83.9%, and MRI using S-DWI had a sensitivity of 71.4% and specificity of 54.8%. The AUC for HR-DWI was significantly higher (0.794 vs. 0.631, P = 0.014). Secondary analyses of univariable predictors of AH showed tumor size increase [OR 16.8; 95% confidence interval (CI): 4.06-69.48; P < 0.001] and apparent diffusion coefficient (ADC) decrease (OR 5.06; 95% CI: 1.39-18.38; P = 0.014) on HR-DWI were significant predictors of AH. CONCLUSION: HR-DWI outperforms S-DWI in predicting AH. Patient with AH have tumors that change in size and ADC that could be detected using HR-DWI. Future studies with longer follow-up should assess HR-DWI for predicting disease progression during AS. SIGNIFICANCE: We report on a prospective clinical trial using a MRI that has three times the resolution of standard MRI. During AS for prostate cancer, two high-resolution MRIs performed approximately a year apart can detect tumor changes that predict the presence of aggressive cancers that should be considered for curative therapy such as prostatectomy or radiation.

The effects of glycemic index on prostate cancer progression in a xenograft mouse model.

BACKGROUND: Previously, we found low-carbohydrate diets slowed prostate cancer (PC) growth and increased survival vs. a Western diet in mice, by inhibiting the insulin/IGF-1 axis. Thus, we tested whether modifying carbohydrate quality to lower glycemic index (GI) without changing quantity results in similar benefits as with reduced quantity. METHODS: Male SCID mice injected with LAPC-4 cells were single-housed and randomized when their tumors reached 200 mm3 on average to a LoGI (48% carbohydrate kcal, from Hylon-VII) or HiGI Western diet (48% carbohydrate kcal, from sucrose). Body weight and tumor volume were measured weekly. Body composition was assessed 35 days after randomization. Blood glucose and serum insulin, IGF-1 and IGFBP3 were measured at study end when tumor volumes reached 800 mm3. We analyzed gene expression of mice tumors by RNA-sequencing and human tumors using the Prostate Cancer Transcriptome Atlas. RESULTS: There were no significant differences in tumor volume (P > 0.05), tumor proliferation (P = 0.29), and overall survival (P = 0.15) between groups. At 35 days after randomization, the LoGI group had 30% lower body fat (P = 0.007) despite similar body weight (P = 0.58). At sacrifice, LoGI mice had smaller livers (P < 0.001) and lower glucose (P = 0.15), insulin (P = 0.11), IGF-1 (P = 0.07) and IGF-1:IGFBP3 ratio (P = 0.05), and higher IGFBP3 (P = 0.09) vs. HiGI, although none of these metabolic differences reached statistical significance. We observed differential gene expression and pathway enrichment in mice tumors by diet. The most upregulated and downregulated gene in the LoGI group showed expression patterns more closely resembling expression in human benign prostate tissue vs. PC. CONCLUSIONS: In this single mouse xenograft model, consuming a low GI diet did not delay PC growth or survival vs. a high GI diet despite suggestions of decreased activation of the insulin/IGF-1 pathway. These data suggest that improving carbohydrate quality alone while consuming a high carbohydrate diet may not effectively slow PC growth.

Wild-Type Transthyretin Cardiac Amyloidosis in a Transplanted Heart.

Wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) is more prevalent than appreciated in the elderly. We present the case of an 88-year-old woman who underwent heart transplantation for ischemic cardiomyopathy and then presented 21 years later with new onset atrial flutter, found on endomyocardial biopsy to have new ATTRwt-CM. (Level of Difficulty: Advanced.).

Macrophage angiotensin-converting enzyme reduces atherosclerosis by increasing peroxisome proliferator-activated receptor α and fundamentally changing lipid metabolism.

AIMS: The metabolic failure of macrophages to adequately process lipid is central to the aetiology of atherosclerosis. Here, we examine the role of macrophage angiotensin-converting enzyme (ACE) in a mouse model of PCSK9-induced atherosclerosis. METHODS AND RESULTS: Atherosclerosis in mice was induced with AAV-PCSK9 and a high-fat diet. Animals with increased macrophage ACE (ACE 10/10 mice) have a marked reduction in atherosclerosis vs. WT mice. Macrophages from both the aorta and peritoneum of ACE 10/10 express increased PPARα and have a profoundly altered phenotype to process lipids characterized by higher levels of the surface scavenger receptor CD36, increased uptake of lipid, increased capacity to transport long chain fatty acids into mitochondria, higher oxidative metabolism and lipid ß-oxidation as determined using 13C isotope tracing, increased cell ATP, increased capacity for efferocytosis, increased concentrations of the lipid transporters ABCA1 and ABCG1, and increased cholesterol efflux. These effects are mostly independent of angiotensin II. Human THP-1 cells, when modified to express more ACE, increase expression of PPARα, increase cell ATP and acetyl-CoA, and increase cell efferocytosis. CONCLUSION: Increased macrophage ACE expression enhances macrophage lipid metabolism, cholesterol efflux, efferocytosis, and it reduces atherosclerosis. This has implications for the treatment of cardiovascular disease with angiotensin II receptor antagonists vs. ACE inhibitors.

Atypical cardiac amyloidosis phenotypes identified at transplant: a case series.

Background: Transthyretin amyloidosis (TTR) is increasingly implicated as an aetiology of advanced cardiomyopathy. Typically, both genetic variant (TTRv) and wild-type (TTRwt) amyloidosis present with a restrictive phenotype. We present a series of three patients who were found to have cardiac amyloidosis on explant following heart transplant (HT) who had atypical, non-restrictive phenotypes. Case Summary: All three patients were men, three were Black, and only one had an alternative pre-HT explanation for their advanced, dilated cardiomyopathy. Pre-HT transthoracic echocardiograms were notable for left ventricular (LV) dilation (>95th percentile for height and gender), low EF, and normal LV wall thickness. Explants showed varying amounts of amyloid deposition, ranging from diffuse biventricular patterns to perivascular involvement. Mass spectrometry confirmed the presence of TTRv (two cases) and TTRwt (one case). Discussion: Patients with dilated cardiomyopathy may harbour cardiac amyloidosis. Uncertainty remains regarding the contribution of amyloidosis to the development of a dilated phenotype. The pathogenic Val142Ile variant seen in two of these patients, a variant common in Black patients, suggests a need for further investigation into the potential relationship between TTRv amyloidosis and dilated cardiomyopathy.

Prostate cancer extracellular vesicle digital scoring assay - a rapid noninvasive approach for quantification of disease-relevant mRNAs.

Optimizing outcomes in prostate cancer (PCa) requires precision in characterization of disease status. This effort was directed at developing a PCa extracellular vesicle (EV) Digital Scoring Assay (DSA) for detecting metastasis and monitoring progression of PCa. PCa EV DSA is comprised of an EV purification device (i.e., EV Click Chip) and reverse-transcription droplet digital PCR that quantifies 11 PCa-relevant mRNA in purified PCa-derived EVs. A Met score was computed for each plasma sample based on the expression of the 11-gene panel using the weighted Z score method. Under optimized conditions, the EV Click Chips outperformed the ultracentrifugation or precipitation method of purifying PCa-derived EVs from artificial plasma samples. Using PCa EV DSA, the Met score distinguished metastatic (n = 20) from localized PCa (n = 20) with an area under the receiver operating characteristic curve of 0.88 (95% CI:0.78-0.98). Furthermore, longitudinal analysis of three PCa patients showed the dynamics of the Met scores reflected clinical behavior even when disease was undetectable by imaging. Overall, a sensitive PCa EV DSA was developed to identify metastatic PCa and reveal dynamic disease states noninvasively. This assay may complement current imaging tools and blood-based tests for timely detection of metastatic progression that can improve care for PCa patients.

Reporting Trends, Practices, and Resource Utilization in Neuroendocrine Tumors of the Prostate Gland: A Survey among Thirty-Nine Genitourinary Pathologists.

Background. Neuroendocrine differentiation in the prostate gland ranges from clinically insignificant neuroendocrine differentiation detected with markers in an otherwise conventional prostatic adenocarcinoma to a lethal high-grade small/large cell neuroendocrine carcinoma. The concept of neuroendocrine differentiation in prostatic adenocarcinoma has gained considerable importance due to its prognostic and therapeutic ramifications and pathologists play a pivotal role in its recognition. However, its awareness, reporting, and resource utilization practice patterns among pathologists are largely unknown. Methods. Representative examples of different spectrums of neuroendocrine differentiation along with a detailed questionnaire were shared among 39 urologic pathologists using the survey monkey software. Participants were specifically questioned about the use and awareness of the 2016 WHO classification of neuroendocrine tumors of the prostate, understanding of the clinical significance of each entity, and use of different immunohistochemical (IHC) markers. De-identified respondent data were analyzed. Results. A vast majority (90%) of the participants utilize IHC markers to confirm the diagnosis of small cell neuroendocrine carcinoma. A majority (87%) of the respondents were in agreement regarding the utilization of type of IHC markers for small cell neuroendocrine carcinoma for which 85% of the pathologists agreed that determination of the site of origin of a high-grade neuroendocrine carcinoma is not critical, as these are treated similarly. In the setting of mixed carcinomas, 62% of respondents indicated that they provide quantification and grading of the acinar component. There were varied responses regarding the prognostic implication of focal neuroendocrine cells in an otherwise conventional acinar adenocarcinoma and for Paneth cell-like differentiation. The classification of large cell neuroendocrine carcinoma was highly varied, with only 38% agreement in the illustrated case. Finally, despite the recommendation not to perform neuroendocrine markers in the absence of morphologic evidence of neuroendocrine differentiation, 62% would routinely utilize IHC in the work-up of a Gleason score 5 + 5 = 10 acinar adenocarcinoma and its differentiation from high-grade neuroendocrine carcinoma. Conclusion. There is a disparity in the practice utilization patterns among the urologic pathologists with regard to diagnosing high-grade neuroendocrine carcinoma and in understanding the clinical significance of focal neuroendocrine cells in an otherwise conventional acinar adenocarcinoma and Paneth cell-like neuroendocrine differentiation. There seems to have a trend towards overutilization of IHC to determine neuroendocrine differentiation in the absence of neuroendocrine features on morphology. The survey results suggest a need for further refinement and development of standardized guidelines for the classification and reporting of neuroendocrine differentiation in the prostate gland.

Case series - COVID-19 is unlikely to affect male fertility: Results of histopathological and reverse transcriptase polymerase chain reaction analysis.

INTRODUCTION: We aimed to analyze the testicular histopathology of men who died with active COVID-19 infection. METHODS: We performed autopsy of eight consecutive men who died of COVID-19 pneumonia. Lung and testis tissue of all men were stained for SARS-CoV-2 nucleocapsid, angiotensin-converting enzyme 2 (ACE-2) receptor immunohistochemistry (IHC). H&E was performed to assess for spermatogenesis and evidence of testicle tissue damage. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis for SARS-CoV-2 was performed on matched lung and bilateral testicular tissue samples from all men. RESULTS: Patient age ranged from 50-79 years. SARS-CoV-2 viral RNA was detected by RTPCR in testis tissue in one man. All eight testicle specimens that underwent IHC for ACE2 receptor showed uniformly strong immunoreactivity against all testicle cell populations. By H&E, all testis specimens showed no inflammation, vascular thrombosis, vasculitis, or morphological evidence of viral changes. One case showed diminished but not absent spermatogenesis, consistent with patient age. CONCLUSIONS: Our results suggest that SARS-CoV-2 is unlikely to affect male fertility. Contrary to all prior histological studies, our results showed no evidence of damage to reproductive tissues that might impair fertility.

Feminising hormone therapy reduces testicular ACE-2 receptor expression: Implications for treatment or prevention of COVID-19 infection in men.

It has been proposed that men hospitalised with COVID-19 be treated with oestrogen or progesterone to improve COVID-19 outcomes. Transgender women (male-to-female) are routinely treated with oestrogen or oestrogen +progesterone for feminisation which provides a model for the effect of feminising hormones on testicular tissue. Our goal was to analyse differences in ACE-2 expression in testicles of trans-women taking oestrogen or oestrogen +progesterone. Orchiectomy specimens were collected from trans-women undergoing gender-affirming surgery, who were taking oestrogen or oestrogen+progesterone preoperatively. For controls, we used benign orchiectomy specimens from cis-gender men. All specimens were stained with H&E, Trichrome (fibrosis), insulin-like 3 antibody (Leydig cell) and ACE-2 IHC. Cells per high-powered field were counted by cell type (Leydig, Sertoli and Germ). Stain intensity was rated on a 0-2 scale. On immunohistochemistry staining for Leydig cells and ACE-2 staining, the oestrogen+progesterone cohort had fewer Leydig cells compared with controls. The oestrogen+progesterone cohort also had greater degree of tissue fibrosis compared with controls and the oestrogen cohort. This work supports the hopeful possibility that a short course of progesterone (or oestrogen+progesterone) could downregulate ACE-2 to protect men from COVID-19 infection.

Improvement in plasma D-dimer level in severe SARS-CoV-2 infection can be an indicator of fibrinolysis suppression: Case reports.

RATIONALE: Fibrinolysis shutdown associated with severe thrombotic complications is a recently recognized syndrome that was previously seldom investigated in patients with severe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. It presents a unique therapeutic dilemma, as anticoagulation with heparin alone is insufficient to address the imbalance in fibrinolysis. And while the use of fibrinolytic agents could limit the disease severity, it is often associated with bleeding complications. There is a need for biomarkers that will guide the timely stratification of patients into those who may benefit from both anticoagulant and fibrinolytic therapies. PATIENT CONCERNS: All 3 patients presented with shortness of breath along with comorbidities predisposing them to severe SARS-CoV-2 infection. One patient (Patient 3) also suffered from bilateral deep venous thrombosis. DIAGNOSES: All 3 patients tested positive for SARS-CoV-2 RNA by reverse transcription polymerase chain reaction (RT-PCR) and were eventually diagnosed with respiratory failure necessitating intubation. INTERVENTIONS: All 3 patients required mechanical ventilation support, 2 of which also required renal replacement therapy. All 3 patients were also placed on anticoagulation therapy. OUTCOMES: In Patients 1 and 2, the initial D-dimer levels of 0.97 µg/ml fibrinogen equivalent units (FEU) and 0.83 µg/ml FEU were only slightly elevated (normal <0.50 µg/ml FEU). They developed rising D-dimer levels to a peak of 13.21 µg/ml FEU and >20.0 µg/ml FEU, respectively, which dropped to 1.34 µg/ml FEU 8 days later in Patient 1 and to 2.94 µg/ml on hospital day 13 in Patient 2. In Patient 3, the D-dimer level on admission was found to be elevated to >20.00 µg/ml FEU together with imaging evidence of thrombosis. And although he received therapeutic heparin infusion, he still developed pulmonary embolism (PE) and his D-dimer level declined to 5.91 µg/ml FEU. Despite "improvement" in their D-dimer levels, all 3 patients succumbed to multi-system organ failure. On postmortem examination, numerous arterial and venous thromboses of varying ages, many consisting primarily of fibrin, were identified in the lungs of all patients. LESSONS: High D-dimer levels, with subsequent downtrend correlating with clinical deterioration, seems to be an indicator of fibrinolysis suppression. These findings can help form a hypothesis, as larger cohorts are necessary to demonstrate their reproducibility.

Heart Transplantation for Giant Cell Myocarditis: A Case Series.

BACKGROUND: Giant cell myocarditis (GCM) has a poor prognosis without heart transplant, but post-transplant survival is unknown. PURPOSE: To describe the post-transplant survival of patients with GCM at a large transplant center. METHODS: Seven patients underwent heart transplant for histologically confirmed GCM of the explanted heart. The median age was 59 years, and 43% (3 of 7) were female. All patients had cardiogenic shock, multiorgan failure, elevated troponin, and recurrent ventricular tachycardia, and some required mechanical circulatory support. All patients received rabbit antithymocyte globulin (rATG) in the perioperative period at a dose of 1.5 mg/kg daily for 1 to 5 days and 4 received intravenous immunoglobulin 1 g/kg daily for 2 days after rATG. All patients had early initiation of tacrolimus by first to third postoperative day depending on renal function, early mycophenolate, and high dose steroid. All were maintained using tacrolimus, mycophenolate, and prednisone. RESULTS: One patient had asymptomatic recurrence of GCM at 3 months, managed by up-titration of tacrolimus, and had asymptomatic 2R cellular rejection at 4 months, managed with steroid bolus. No patient had high-grade rejection. One patient died at 267 days, possibly of GCM. Six of 7 (86%) remain alive at a median of 842 days (2.3 years) post transplant. CONCLUSIONS: Patients with GCM have excellent post-transplant survival with use of rATG and triple drug immunosuppressive therapy; however, some patients remain at risk for GCM recurrence after transplant, which may respond to augmented immunosuppression.

Pulmonary capillary hemangiomatosis: a lesson learned.

Pulmonary capillary hemangiomatosis (PCH) is a rare and controversial entity that is known to be a cause of pulmonary hypertension and is microscopically characterized by proliferation of dilated capillary-sized channels along and in the alveolar walls. Clinically, it is mostly seen in adults. Clinical features are characterized by nonspecific findings such as shortness of breath, cough, chest pain, and fatigue. It can be clinically indistinguishable from pre-capillary pulmonary arterial hypertension disorders such as primary pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension. However, the diagnostic distinction, which usually requires a multidisciplinary approach, is crucial in order to avoid inappropriate treatment with vasodilator medications usually used for PAH treatment. Prognosis of PCH remains poor with lung transplant being the only definitive treatment. We report an autopsy case of pulmonary capillary hemangiomatosis unmasked at autopsy that was treated with a prostacyclin analog, usually contraindicated in such patients. We emphasize that this entity should always be on the differential diagnosis in a patient with pulmonary hypertension and requires great vigilance on the part of the clinician, radiologist and pathologist to make the diagnosis and guide appropriate management.

Pulmonary capillary hemangiomatosis: a lesson learned

Pulmonary capillary hemangiomatosis (PCH) is a rare and controversial entity that is known to be a cause of pulmonary hypertension and is microscopically characterized by proliferation of dilated capillary-sized channels along and in the alveolar walls. Clinically, it is mostly seen in adults. Clinical features are characterized by nonspecific findings such as shortness of breath, cough, chest pain, and fatigue. It can be clinically indistinguishable from pre-capillary pulmonary arterial hypertension disorders such as primary pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension. However, the diagnostic distinction, which usually requires a multidisciplinary approach, is crucial in order to avoid inappropriate treatment with vasodilator medications usually used for PAH treatment. Prognosis of PCH remains poor with lung transplant being the only definitive treatment. We report an autopsy case of pulmonary capillary hemangiomatosis unmasked at autopsy that was treated with a prostacyclin analog, usually contraindicated in such patients. We emphasize that this entity should always be on the differential diagnosis in a patient with pulmonary hypertension and requires great vigilance on the part of the clinician, radiologist and pathologist to make the diagnosis and guide appropriate management.

Amyloidosis of the bladder and association with urothelial carcinoma: report of 29 cases.

The association of amyloidosis with certain neoplastic processes is well known. Amyloid uncommonly occurs in relationship with other epithelial neoplasms including urothelial carcinoma. Herein, we report 29 cases of amyloidosis in the bladder, 14 of which were found in relationship to urothelial carcinoma. With institutional review board approval. We searched pathology archives for cases of amyloidosis in the bladder. Clinical, laboratory, and surgical pathology records were reviewed, and data were recorded for all cases. Diagnosis of amyloid was made by Congo red stain showing apple-green birefringence on polarization microscopy and special studies in some cases. Twenty-nine cases of amyloid were identified in bladder specimens. Presentation as a mass lesion was the most common (n = 18). Immunohistochemical subtyping done in 17 cases showed transthyretin-type (n = 10), AL (n = 3), AA (n = 1), amyloid P (n = 1), and undetermined (n = 2) types of amyloid. Eighteen (62%) cases were classified as localized primary amyloidosis and 11 (38%) as secondary manifestation of systemic amyloidosis. In 14 (48%) cases, there was an associated urothelial carcinoma: 5 urothelial carcinoma in situ, 4 low-grade noninvasive papillary urothelial carcinoma, 2 high-grade noninvasive papillary urothelial carcinoma, and 3 high-grade invasive urothelial carcinoma. Associated urothelial carcinoma was present in 4 of 7 patients with systemic amyloidosis and 10 of 18 patients with localized amyloidosis, with the difference not being statistically significant (P = .45). Amyloidosis of the bladder is rare and presents as a mucosal mass or hematuria that may mimic urothelial carcinoma. In this study, we found urothelial carcinoma occurring in 48% of the cases in association with amyloidosis, a finding not previously reported. The relationship of amyloid in the bladder and urothelial carcinoma, although likely not causal, appears to be a unique finding not frequently seen with other solid tumors.

Pathology and Pathogenesis of Chagas Heart Disease.

Chagas heart disease is an inflammatory cardiomyopathy that develops in approximately one-third of people infected with the protozoan parasite Trypanosoma cruzi. One way T. cruzi is transmitted to people is through contact with infected kissing bugs, which are found in much of the Western Hemisphere, including in vast areas of the United States. The epidemiology of T. cruzi and Chagas heart disease and the varied mechanisms leading to myocyte destruction, mononuclear cell infiltration, fibrosis, and edema in the heart have been extensively studied by hundreds of scientists for more than 100 years. Despite this wealth of knowledge, it is still impossible to predict what will happen in an individual infected with T. cruzi because of the tremendous variability in clonal parasite virulence and human susceptibility to infection and the lack of definitive molecular predictors of outcome from either side of the host-parasite equation. Further, while several distinct mechanisms of pathogenesis have been studied in isolation, it is certain that multiple coincident mechanisms combine to determine the ultimate outcome. For these reasons, Chagas disease is best considered a collection of related but distinct illnesses. This review highlights the pathology and pathogenesis of the most common adverse sequela of T. cruzi infection-Chagas heart disease-and concludes with a discussion of key unanswered questions and a view to the future.

Accelerated Cardiac Diffusion Tensor Imaging Using Joint Low-Rank and Sparsity Constraints.

OBJECTIVE: The purpose of this paper is to accelerate cardiac diffusion tensor imaging (CDTI) by integrating low-rankness and compressed sensing. METHODS: Diffusion-weighted images exhibit both transform sparsity and low-rankness. These properties can jointly be exploited to accelerate CDTI, especially when a phase map is applied to correct for the phase inconsistency across diffusion directions, thereby enhancing low-rankness. The proposed method is evaluated both ex vivo and in vivo, and is compared to methods using either a low-rank or sparsity constraint alone. RESULTS: Compared to using a low-rank or sparsity constraint alone, the proposed method preserves more accurate helix angle features, the transmural continuum across the myocardium wall, and mean diffusivity at higher acceleration, while yielding significantly lower bias and higher intraclass correlation coefficient. CONCLUSION: Low-rankness and compressed sensing together facilitate acceleration for both ex vivo and in vivo CDTI, improving reconstruction accuracy compared to employing either constraint alone. SIGNIFICANCE: Compared to previous methods for accelerating CDTI, the proposed method has the potential to reach higher acceleration while preserving myofiber architecture features, which may allow more spatial coverage, higher spatial resolution, and shorter temporal footprint in the future.