The 2023 Duke-International Society for Cardiovascular Infectious Diseases Criteria for Infective Endocarditis: Updating the Modified Duke Criteria.

The microbiology, epidemiology, diagnostics, and treatment of infective endocarditis (IE) have changed significantly since the Duke Criteria were published in 1994 and modified in 2000. The International Society for Cardiovascular Infectious Diseases (ISCVID) convened a multidisciplinary Working Group to update the diagnostic criteria for IE. The resulting 2023 Duke-ISCVID IE Criteria propose significant changes, including new microbiology diagnostics (enzyme immunoassay for Bartonella species, polymerase chain reaction, amplicon/metagenomic sequencing, in situ hybridization), imaging (positron emission computed tomography with 18F-fluorodeoxyglucose, cardiac computed tomography), and inclusion of intraoperative inspection as a new Major Clinical Criterion. The list of "typical" microorganisms causing IE was expanded and includes pathogens to be considered as typical only in the presence of intracardiac prostheses. The requirements for timing and separate venipunctures for blood cultures were removed. Last, additional predisposing conditions (transcatheter valve implants, endovascular cardiac implantable electronic devices, prior IE) were clarified. These diagnostic criteria should be updated periodically by making the Duke-ISCVID Criteria available online as a "Living Document."

Angiopoietin 2 and hsCRP are associated with pulmonary hemodynamics and long-term mortality respectively in CTEPH-Results from a prospective discovery and validation biomarker study.

INTRODUCTION: Chronic thromboembolic pulmonary hypertension (CTEPH) is an underdiagnosed disease of uncertain etiology. Altered endothelial homeostasis, defective angiogenesis and inflammation are implicated. Angiopoietin 2 (Ang2) impairs acute thrombus resolution and is associated with vasculopathy in idiopathic pulmonary arterial hypertension. METHODS: We assessed circulating proteins associated with these processes in serum from patients with CTEPH (n = 71) before and after pulmonary endarterectomy (PEA), chronic thromboembolic pulmonary disease without pulmonary hypertension (CTEPD, n = 9) and healthy controls (n = 20) using Luminex multiplex arrays. Comparisons between groups were made using multivariable rank regression models. Ang2 and high-sensitivity C-reactive protein (hsCRP) were measured in a larger validation dataset (CTEPH = 277, CTEPD = 26). Cox proportional hazards models were used to identify markers predictive of survival. RESULTS: In CTEPH patients, Ang2, interleukin (IL) 8, tumor necrosis factor α, and hsCRP were elevated compared to controls, while vascular endothelial growth factor (VEGF) c was lower (p < 0.05). Ang2 fell post-PEA (p < 0.05) and was associated with both pre- and post-PEA pulmonary hemodynamic variables and functional assessments (p < 0.05). In the validation dataset, Ang2 was significantly higher in CTEPH compared to CTEPD. Pre-operative hsCRP was an independent predictor of mortality. CONCLUSIONS: We hypothesize that CTEPH patients have significant distal micro-vasculopathy and consequently high circulating Ang2. Patients with CTEPD without pulmonary hypertension have no discernible distal micro-vasculopathy and therefore have low circulating Ang2. This suggests Ang2 may be critical to CTEPH disease pathogenesis (impaired thrombus organization and disease severity).

A Case of Thrombotic Microangiopathy and Acute Sarcoidosis.

Although sarcoidosis is an established cause of multiorgan dysfunction, acute presentation with thrombotic microangiopathy resulting in severe renal and hematological sequelae has not been reported. We describe the case of a patient presenting with hypercalcemia, pancreatitis, and acute renal failure, followed by microangiopathic hemolytic anemia. Although there were no significant respiratory symptoms, thoracic radiology and mediastinal lymph node biopsy results were in keeping with sarcoidosis as the underlying cause of this multisystem presentation. Corticosteroids were commenced with clinical and biochemical improvement. This novel case highlights the need to consider sarcoidosis as part of the differential diagnosis for unusual multiorgan presentations and for early multidisciplinary involvement in such cases to permit optimal treatment.

Genomic evidence supports a clonal diaspora model for metastases of esophageal adenocarcinoma.

The poor outcomes in esophageal adenocarcinoma (EAC) prompted us to interrogate the pattern and timing of metastatic spread. Whole-genome sequencing and phylogenetic analysis of 388 samples across 18 individuals with EAC showed, in 90% of patients, that multiple subclones from the primary tumor spread very rapidly from the primary site to form multiple metastases, including lymph nodes and distant tissues-a mode of dissemination that we term 'clonal diaspora'. Metastatic subclones at autopsy were present in tissue and blood samples from earlier time points. These findings have implications for our understanding and clinical evaluation of EAC.

Diagnosis of myocardial infarction at autopsy: AECVP reappraisal in the light of the current clinical classification.

Ischemic heart disease is one of the leading causes of morbidity and death worldwide. Consequently, myocardial infarctions are often encountered in clinical and forensic autopsies, and diagnosis can be challenging, especially in the absence of an acute coronary occlusion. Precise histopathological identification and timing of myocardial infarction in humans often remains uncertain while it can be of crucial importance, especially in a forensic setting when third person involvement or medical responsibilities are in question. A proper post-mortem diagnosis requires not only up-to-date knowledge of the ischemic coronary and myocardial pathology, but also a correct interpretation of such findings in relation to the clinical scenario of the deceased. For these reasons, it is important for pathologists to be familiar with the different clinically defined types of myocardial infarction and to discriminate myocardial infarction from other forms of myocardial injury. This article reviews present knowledge and post-mortem diagnostic methods, including post-mortem imaging, to reveal the different types of myocardial injury and the clinical-pathological correlations with currently defined types of myocardial infarction.

Chronic thromboembolic pulmonary hypertension following long-term peripherally inserted central venous catheter use.

A 36-year-old woman presented with recurrent pulmonary emboli (PE) despite oral anticoagulation. She was a type I diabetic with severe gastroparesis requiring insertion of multiple long-term peripherally inserted central catheters (PICC) over a 10-year period. Imaging at presentation demonstrated a PICC-associated mobile mass in the right atrium and signs of pulmonary hypertension (PH). She was thrombolyzed and fully anticoagulated, and diabetic management without PICC strongly recommended. PH persisted, however, and she developed chronic thromboembolic pulmonary hypertension (CTEPH), for which successful pulmonary endarterectomy (PEA) surgery led to symptomatic and hemodynamic improvement. This was the first case of CTEPH reported related to long-term PICC use outside the setting of malignant disease, and a novel observation that the PEA specimen contained multiple plastic fragments. Long-term PICC placement increases the risk of CTEPH, a life-threatening, albeit treatable, complication.

A hypercoagulable state leading to venous limb gangrene associated with occult lung adenocarcinoma.

We report a case of lung adenocarcinoma-associated hypercoagulability leading to venous limb gangrene, managed successfully with argatroban and then dabigatran. Use of idarucizumab permitted diagnostic investigations, leading to targeted antineoplastic therapy with crizotinib, surgical resection with curative intent, and continued survival over 2 years after the index event.

Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. METHODS: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource-Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. RESULTS: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (Kco; 33% [interquartile range, 30%-35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23-38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. CONCLUSIONS: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low Kco and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation.

Consensus statement on surgical pathology of the aorta from the Society for Cardiovascular Pathology and the Association For European Cardiovascular Pathology: II. Noninflammatory degenerative diseases - nomenclature and diagnostic criteria.

Surgical aortic specimens are usually examined in Pathology Departments as a result of treatment of aneurysms or dissections. A number of diseases, genetic syndromes (Marfan syndrome, Loeys-Dietz syndrome, etc.), and vasculopathic aging processes involved in vascular injury can cause both distinct and nonspecific histopathologic changes with degeneration of the media as a common denominator. Terminology for these changes has varied over time leading to confusion and inconsistencies. This consensus document has established a revised, unified nomenclature for the variety of noninflammatory degenerative aortic histopathologies seen in such specimens. Older terms such as cystic medial necrosis and medionecrosis are replaced by more technically accurate terms such as mucoid extracellular matrix accumulation (MEMA), elastic fiber fragmentation and/or loss, and smooth muscle cell nuclei loss. A straightforward system of grading is presented to gauge the extent of medial degeneration and synoptic reporting tables are provided. Herein we present a standardized nomenclature that is accessible to general pathologists and useful for future publications describing these entities.

Consensus statement on surgical pathology of the aorta from the Society for Cardiovascular Pathology and the Association for European Cardiovascular Pathology: I. Inflammatory diseases.

Inflammatory diseases of the aorta include routine atherosclerosis, aortitis, periaortitis, and atherosclerosis with excessive inflammatory responses, such as inflammatory atherosclerotic aneurysms. The nomenclature and histologic features of these disorders are reviewed and discussed. In addition, diagnostic criteria are provided to distinguish between these disorders in surgical pathology specimens. An initial classification scheme is provided for aortitis and periaortitis based on the pattern of the inflammatory infiltrate: granulomatous/giant cell pattern, lymphoplasmacytic pattern, mixed inflammatory pattern, and the suppurative pattern. These inflammatory patterns are discussed in relation to specific systemic diseases including giant cell arteritis, Takayasu arteritis, granulomatosis with polyangiitis (Wegener's), rheumatoid arthritis, sarcoidosis, ankylosing spondylitis, Cogan syndrome, Behçet's disease, relapsing polychondritis, syphilitic aortitis, and bacterial and fungal infections.

Cardiopulmonary exercise testing suggests a beneficial response to pulmonary endarterectomy in a patient with chronic thromboembolic obstruction and normal preoperative pulmonary hemodynamics.

Pulmonary endarterectomy offers a symptomatic and survival benefit in patients with chronic thromboembolic pulmonary hypertension through sustained improvement in right ventricular function. However, its role in patients with symptom limitation, chronic thrombotic obstruction, and a normal pulmonary hemodynamic profile is less clear. Cardiopulmonary exercise testing (CPET) stresses the cardiopulmonary system and has a characteristic response in pulmonary hypertension. CPET may therefore reveal abnormalities in patients with chronic thrombotic obstruction where hemodynamic investigations conducted at rest are reassuring. Using incremental CPET, we demonstrated improvements in right ventricular performance and ventilatory efficiency following pulmonary endarterecomy in a patient with preoperative exercise limitation and normal pulmonary hemodynamics. Careful evaluation of exercise responses may extend the potential benefit offered by pulmonary endarterectomy in patients with chronic thromboembolic obstruction irrespective of their resting hemodynamic profile.

Factors Affecting Stream Nutrient Loads: A Synthesis of Regional SPARROW Model Results for the Continental United States.

We compared the results of 12 recently calibrated regional SPARROW (SPAtially Referenced Regressions On Watershed attributes) models covering most of the continental United States to evaluate the consistency and regional differences in factors affecting stream nutrient loads. The models - 6 for total nitrogen and 6 for total phosphorus - all provide similar levels of prediction accuracy, but those for major river basins in the eastern half of the country were somewhat more accurate. The models simulate long-term mean annual stream nutrient loads as a function of a wide range of known sources and climatic (precipitation, temperature), landscape (e.g., soils, geology), and aquatic factors affecting nutrient fate and transport. The results confirm the dominant effects of urban and agricultural sources on stream nutrient loads nationally and regionally, but reveal considerable spatial variability in the specific types of sources that control water quality. These include regional differences in the relative importance of different types of urban (municipal and industrial point vs. diffuse urban runoff) and agriculture (crop cultivation vs. animal waste) sources, as well as the effects of atmospheric deposition, mining, and background (e.g., soil phosphorus) sources on stream nutrients. Overall, we found that the SPARROW model results provide a consistent set of information for identifying the major sources and environmental factors affecting nutrient fate and transport in United States watersheds at regional and subregional scales.

The Regionalization of National-Scale SPARROW Models for Stream Nutrients.

This analysis modifies the parsimonious specification of recently published total nitrogen (TN) and total phosphorus (TP) national-scale SPAtially Referenced Regressions On Watershed attributes models to allow each model coefficient to vary geographically among three major river basins of the conterminous United States. Regionalization of the national models reduces the standard errors in the prediction of TN and TP loads, expressed as a percentage of the predicted load, by about 6 and 7%. We develop and apply a method for combining national-scale and regional-scale information to estimate a hybrid model that imposes cross-region constraints that limit regional variation in model coefficients, effectively reducing the number of free model parameters as compared to a collection of independent regional models. The hybrid TN and TP regional models have improved model fit relative to the respective national models, reducing the standard error in the prediction of loads, expressed as a percentage of load, by about 5 and 4%. Only 19% of the TN hybrid model coefficients and just 2% of the TP hybrid model coefficients show evidence of substantial regional specificity (more than ±100% deviation from the national model estimate). The hybrid models have much greater precision in the estimated coefficients than do the unconstrained regional models, demonstrating the efficacy of pooling information across regions to improve regional models.

Cerebral amyloid angiopathy in the aetiology and immunotherapy of Alzheimer disease.

Amyloid is deposited in the walls of arteries and capillaries as cerebral amyloid angiopathy (CAA) in the brains of older individuals and of those with Alzheimer disease (AD). CAA in AD reflects an age-related failure of elimination of amyloid-beta (Abeta) from the brain along perivascular lymphatic drainage pathways. In the absence of conventional lymphatic vessel in the brain, interstitial fluid and solutes drain from the brain to cervical lymph nodes along narrow basement membranes in the walls of capillaries and arteries, a pathway that is largely separate from the cerebrospinal fluid. In this review we focus on the pathology and pathogenesis of CAA, its role in the aetiology of AD and its impact on immunotherapy for AD. The motive force for lymphatic drainage of the brain appears to be generated by arterial pulsations. Failure of elimination of Abeta along perivascular pathways coincides with a reduction in enzymic degradation of Abeta, reduced absorption of Abeta into the blood and age-related stiffening of artery walls that appears to reduce the motive force for lymphatic drainage. Reduced clearances of Abeta and CAA are associated with the accumulation of insoluble and soluble Abetas in the brain in AD and the probable loss of homeostasis of the neuronal environment due to retention of soluble metabolites within the brain. Tau metabolism may also be affected. Immunotherapy has been successful in removing insoluble plaques of Abeta from the brain in AD but with little effect on cognitive decline. One major problem is the increase in CAA in immunised patients that probably prevents the complete removal of Abeta from the brain. Increased knowledge of the physiology and structural and genetic aspects of the lymphatic drainage of Abeta from the brain will stimulate the development of therapeutic strategies for the prevention and treatment of AD.

Geriatric surgery is about disease, not age.

Maintaining life span and quality of life remains a valid aim of surgery in elderly people. Surgery can be an effective way of restoring both length and quality of life to older people. Minimally invasive techniques and surgery under local anaesthesia make fewer demands on geriatric physiology; given that co-morbidity is a stronger predictor of outcome from surgery than age, this is a significant consideration.

Perivascular drainage of amyloid-beta peptides from the brain and its failure in cerebral amyloid angiopathy and Alzheimer's disease.

Alzheimer's disease is the commonest dementia. One major characteristic of its pathology is accumulation of amyloid-beta (Abeta) as insoluble deposits in brain parenchyma and in blood vessel walls [cerebral amyloid angiopathy (CAA)]. The distribution of Abeta deposits in the basement membranes of cerebral capillaries and arteries corresponds to the perivascular drainage pathways by which interstitial fluid (ISF) and solutes are eliminated from the brain--effectively the lymphatic drainage of the brain. Theoretical models suggest that vessel pulsations supply the motive force for perivascular drainage of ISF and solutes. As arteries stiffen with age, the amplitude of pulsations is reduced and insoluble Abeta is deposited in ISF drainage pathways as CAA, thus, further impeding the drainage of soluble Abeta. Failure of perivascular drainage of Abeta and deposition of Abeta in the walls of arteries has two major consequences: (i) intracerebral hemorrhage associated with rupture of Abeta-laden arteries in CAA; and (ii) Alzheimer's disease in which failure of elimination of ISF, Abeta and other soluble metabolites from the brain alters homeostasis and the neuronal environment resulting in cognitive decline and dementia. Therapeutic strategies that improve elimination of Abeta and other soluble metabolites from the brain may prevent cognitive decline in Alzheimer's disease.

A hydrologic network supporting spatially referenced regression modeling in the Chesapeake Bay Watershed.

The U.S. Geological Survey has developed a methodology for statistically relating nutrient sources and land-surface characteristics to nutrient loads of streams. The methodology is referred to as SPAtially Referenced Regressions On Watershed attributes (SPARROW), and relates measured stream nutrient loads to nutrient sources using nonlinear statistical regression models. A spatially detailed digital hydrologic network of stream reaches, stream-reach characteristics such as mean streamflow, water velocity, reach length, and travel time, and their associated watersheds supports the regression models. This network serves as the primary framework for spatially referencing potential nutrient source information such as atmospheric deposition, septic systems, point-sources, land use, land cover, and agricultural sources and land-surface characteristics such as land use, land cover, average-annual precipitation and temperature, slope, and soil permeability. In the Chesapeake Bay watershed that covers parts of Delaware, Maryland, Pennsylvania, New York, Virginia, West Virginia, and Washington D.C., SPARROW was used to generate models estimating loads of total nitrogen and total phosphorus representing 1987 and 1992 land-surface conditions. The 1987 models used a hydrologic network derived from an enhanced version of the U.S. Environmental Protection Agency's digital River Reach File, and course resolution Digital Elevation Models (DEMs). A new hydrologic network was created to support the 1992 models by generating stream reaches representing surface-water pathways defined by flow direction and flow accumulation algorithms from higher resolution DEMs. On a reach-by-reach basis, stream reach characteristics essential to the modeling were transferred to the newly generated pathways or reaches from the enhanced River Reach File used to support the 1987 models. To complete the new network, watersheds for each reach were generated using the direction of surface-water flow derived from the DEMs. This network improves upon existing digital stream data by increasing the level of spatial detail and providing consistency between the reach locations and topography. The hydrologic network also aids in illustrating the spatial patterns of predicted nutrient loads and sources contributed locally to each stream, and the percentages of nutrient load that reach Chesapeake Bay.

Cerebrovascular disease is a major factor in the failure of elimination of Abeta from the aging human brain: implications for therapy of Alzheimer's disease.

Alzheimer's disease (AD) is characterized by the intracellular deposition of ubiquitinated tau and by the extracellular accumulation of soluble, insoluble, and fibrillary Abeta. Previous studies suggest that Abeta is normally eliminated from the brain along perivascular pathways that may become blocked in the aging brain, resulting in cerebral amyloid angiopathy. As age is a major risk factor for AD and for cerebrovascular disease (CVD), we test the hypothesis that CVD inhibits the elimination of Abeta from the aging human brain. Sections from 100 aged and AD brains were stained for Abeta by immunohistochemistry and by reticulin and Masson trichrome techniques. Early deposition of Abeta in brain parenchyma was related to individual arterial territories in the cortex. In areas of more extensive accumulation of Abeta, there was an inverse relationship between capillary amyloid angiopathy and plaques of Abeta. Thus, arterial territories with extensive capillary amyloid angiopathy were devoid of Abeta plaques, whereas in areas with abundant diffuse plaques there was no capillary amyloid angiopathy. Serial sections showed that cortical arteries feeding capillary beds with Abeta angiopathy were occluded by thrombus. We conclude that CVD inhibits the elimination of Abeta along capillary walls and changes the distribution of Abeta in the cerebral cortex. Loss of pulsations in thrombosed or arteriosclerotic arteries may thus abolish the motive force necessary for the drainage of Abeta and inhibit the elimination of Abeta. Therapies to increase elimination of Abeta in AD need to consider the effects of CVD on the elimination of Abeta from the aging human brain.