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Primary prevention of venous thromboembolism with apixaban for multiple myeloma patients receiving immunomodulatory agents.
Cornell RF, Goldhaber SZ, Engelhardt BG, Moslehi J, Jagasia M, Harrell S, Rubinstein SM, Hall R, Wyatt H, Piazza G
(2020) Br J Haematol 190: 555-561
MeSH Terms: Aged, Comorbidity, Consolidation Chemotherapy, Factor Xa Inhibitors, Female, Hemorrhage, Humans, Immunologic Factors, Lenalidomide, Maintenance Chemotherapy, Male, Middle Aged, Multiple Myeloma, Myocardial Infarction, Pilot Projects, Proof of Concept Study, Prospective Studies, Pulmonary Embolism, Pyrazoles, Pyridones, Stroke, Thalidomide, Thrombophilia, Venous Thromboembolism, Venous Thrombosis
Show Abstract · Added May 29, 2020
Immunomodulatory drugs (IMiDs) have improved survival of patients with multiple myeloma (MM) and comprise the therapeutic backbone at all phases of therapy. Although well-tolerated, IMiDs increase rates of venous thromboembolism (VTE). In this phase IV, single-arm pilot study, fifty patients with MM on IMiDs received apixaban 2·5 mg orally twice daily for primary prevention of VTE and were prospectively monitored for six months. The primary safety outcomes were rates of major haemorrhage and clinically relevant non-major haemorrhage over six months. The primary efficacy outcome was the rate of symptomatic VTE over six months. IMiDs used were lenalidomide (58%) or pomalidomide (42%). During the six-month evaluation period, no patients experienced major haemorrhage or VTE. Three patients experienced clinically relevant, non-major haemorrhage which was managed medically, and all were able to resume apixaban. One patient stopped therapy shortly after initiation due to an allergic reaction to apixaban. No patients experienced stroke, myocardial infarction, or death. In this pilot study, low-dose apixaban was safe and well-tolerated as a primary prevention therapy of VTE for patients with MM receiving IMiDs. Further studies are needed to validate low-dose apixaban as a standard primary prevention anti-thrombotic strategy for patients with MM receiving IMiDs.
© 2020 British Society for Haematology and John Wiley & Sons Ltd.
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25 MeSH Terms
Distributed deep learning across multisite datasets for generalized CT hemorrhage segmentation.
Remedios SW, Roy S, Bermudez C, Patel MB, Butman JA, Landman BA, Pham DL
(2020) Med Phys 47: 89-98
MeSH Terms: Deep Learning, Hemorrhage, Humans, Image Processing, Computer-Assisted, Tomography, X-Ray Computed
Show Abstract · Added October 30, 2019
PURPOSE - As deep neural networks achieve more success in the wide field of computer vision, greater emphasis is being placed on the generalizations of these models for production deployment. With sufficiently large training datasets, models can typically avoid overfitting their data; however, for medical imaging it is often difficult to obtain enough data from a single site. Sharing data between institutions is also frequently nonviable or prohibited due to security measures and research compliance constraints, enforced to guard protected health information (PHI) and patient anonymity.
METHODS - In this paper, we implement cyclic weight transfer with independent datasets from multiple geographically disparate sites without compromising PHI. We compare results between single-site learning (SSL) and multisite learning (MSL) models on testing data drawn from each of the training sites as well as two other institutions.
RESULTS - The MSL model attains an average dice similarity coefficient (DSC) of 0.690 on the holdout institution datasets with a volume correlation of 0.914, respectively corresponding to a 7% and 5% statistically significant improvement over the average of both SSL models, which attained an average DSC of 0.646 and average correlation of 0.871.
CONCLUSIONS - We show that a neural network can be efficiently trained on data from two physically remote sites without consolidating patient data to a single location. The resulting network improves model generalization and achieves higher average DSCs on external datasets than neural networks trained on data from a single source.
© 2019 American Association of Physicists in Medicine.
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5 MeSH Terms
Atypical Clinical Manifestations of Cerebral Amyloid Angiopathy.
Akers C, Acosta LMY, Considine C, Claassen D, Kirshner H, Schrag M
(2019) Curr Neurol Neurosci Rep 19: 64
MeSH Terms: Aged, Alzheimer Disease, Brain, Cerebral Amyloid Angiopathy, Cerebral Hemorrhage, Cognitive Dysfunction, Diagnosis, Differential, Female, Humans, Lewy Body Disease, Male, Neuroimaging
Show Abstract · Added March 3, 2020
PURPOSE - Cerebral amyloid angiopathy is a vasculopathy caused by β-amyloid deposition in cerebral arterioles and capillaries. It is closely linked to Alzheimer's disease and predisposes elderly patients to intracerebral hemorrhage, transient focal neurological episodes, and cognitive impairment. Because of a predilection for symptomatic hemorrhage, particularly in the frontal lobes, cerebral amyloid angiopathy may also cause a dysexecutive syndrome.
RECENT FINDINGS - In this case series, we describe presentations of classic clinical dementia syndromes which are not are widely thought to be associated with cerebral amyloid angiopathy, namely logopenic variant primary progressive aphasia (n = 3), normal pressure hydrocephalus (n = 3), and Lewy body dementia (n = 2). In every case, after a clinical diagnosis was established, neuroimaging, brain biopsy, and/or autopsy confirmed the presence of cerebral amyloid angiopathy. Cerebral amyloid angiopathy has significant clinical implications, and its ability to mimic and/or contribute to other clinical dementia syndromes can complicate its diagnosis. This series of cases broadens the range of clinical scenarios associated with cerebral amyloid angiopathy.
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12 MeSH Terms
Critical role of bacterial dissemination in an infant rabbit model of bacillary dysentery.
Yum LK, Byndloss MX, Feldman SH, Agaisse H
(2019) Nat Commun 10: 1826
MeSH Terms: Animals, Animals, Newborn, Colon, Diarrhea, Disease Models, Animal, Dysentery, Bacillary, Epithelial Cells, Female, Gastrointestinal Hemorrhage, HT29 Cells, Humans, Intestinal Mucosa, Pregnancy, Rabbits, Shigella flexneri, Type III Secretion Systems
Show Abstract · Added March 30, 2020
The bacterial pathogen Shigella flexneri causes 270 million cases of bacillary dysentery (blood in stool) worldwide every year, resulting in more than 200,000 deaths. A major challenge in combating bacillary dysentery is the lack of a small-animal model that recapitulates the symptoms observed in infected individuals, including bloody diarrhea. Here, we show that similar to humans, infant rabbits infected with S. flexneri experience severe inflammation, massive ulceration of the colonic mucosa, and bloody diarrhea. T3SS-dependent invasion of epithelial cells is necessary and sufficient for mediating immune cell infiltration and vascular lesions. However, massive ulceration of the colonic mucosa, bloody diarrhea, and dramatic weight loss are strictly contingent on the ability of the bacteria to spread from cell to cell. The infant rabbit model features bacterial dissemination as a critical determinant of S. flexneri pathogenesis and provides a unique small-animal model for research and development of therapeutic interventions.
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Incidence of and risk factors for major haemorrhage in patients treated with ibrutinib: An integrated analysis.
Brown JR, Moslehi J, Ewer MS, O'Brien SM, Ghia P, Cymbalista F, Shanafelt TD, Fraser G, Rule S, Coutre SE, Dilhuydy MS, Cramer P, Jaeger U, Dreyling M, Byrd JC, Treon S, Liu EY, Chang S, Bista A, Vempati R, Boornazian L, Valentino R, Reddy V, Mahler M, Yang H, Graef T, Burger JA
(2019) Br J Haematol 184: 558-569
MeSH Terms: Aged, Female, Hematologic Neoplasms, Hemorrhage, Humans, Incidence, Male, Middle Aged, Pyrazoles, Pyrimidines, Randomized Controlled Trials as Topic, Risk Factors, Time Factors
Show Abstract · Added December 13, 2018
Ibrutinib, a Bruton tyrosine kinase inhibitor, is approved for treatment of various B-cell malignancies. In ibrutinib clinical studies, low-grade haemorrhage was common, whereas major haemorrhage (MH) was infrequent. We analysed the incidence of and risk factors for MH from 15 ibrutinib clinical studies (N = 1768), including 4 randomised controlled trials (RCTs). Rates of any-grade bleeding were similar for single-agent ibrutinib and ibrutinib combinations (39% and 40%). Low-grade bleeding was more common in ibrutinib-treated than comparator-treated patients (35% and 15%), and early low-grade bleeding was not associated with MH. The proportion of MH in RCTs was higher with ibrutinib than comparators (4.4% vs. 2.8%), but after adjusting for longer exposure with ibrutinib (median 13 months vs. 6 months), the incidence of MH was similar (3.2 vs. 3.1 per 1000 person-months). MH led to treatment discontinuation in 1% of all ibrutinib-treated patients. Use of anticoagulants and/or antiplatelets (AC/AP) during the study was common (~50% of patients) and had an increased exposure-adjusted relative risk for MH in both the total ibrutinib-treated population (1.9; 95% confidence interval, 1.2-3.0) and RCT comparator-treated patients (2.4; 95% confidence interval, 1.0-5.6), indicating that ibrutinib may not alter the effect of AC/AP on the risk of MH in B-cell malignancies.
© 2018 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.
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13 MeSH Terms
In-Hospital Pediatric Stroke Alert Activation.
Barry M, Le TM, Gindville MC, Jordan LC
(2018) Pediatr Neurol 88: 31-35
MeSH Terms: Adolescent, Child, Child, Preschool, Emergency Service, Hospital, Female, Hemorrhage, Humans, Infant, Magnetic Resonance Imaging, Male, Neurologic Examination, Stroke, Time Factors, Tomography Scanners, X-Ray Computed, Young Adult
Show Abstract · Added March 24, 2020
BACKGROUND - Pediatric stroke alerts or "code strokes" allow for rapid evaluation, imaging, and treatment of children presenting with stroke-like symptoms. In a previous study of emergency department-initiated pediatric stroke alerts, 24% of children had confirmed strokes. The purpose of this study was to characterize in-hospital pediatric stroke alerts.
METHODS - Demographic and clinical information was obtained from a quality improvement database and medical records for children (zero to 20 years) at a single institution for whom a stroke alert was activated after hospital admission between April 2011 and December 2016. Stroke alert activation criteria included a new focal neurological defect occurring within 48 hours. A neurologist evaluated the patient within 15 minutes and rapid magnetic resonance imaging was available.
RESULTS - Medical personnel activated in-hospital stroke alerts for 56 children (median age 6.5 years, interquartile range 1 to 13, 52% male). Stroke was the final diagnosis of 25 (45%), 72% ischemic, and 28% hemorrhagic strokes. Other diagnoses included neurological urgencies: seizure (21%), posterior reversible encephalopathy syndrome (7%), transient ischemic attack (5%), and acute disseminated encephalomyelitis (4%). Of the stroke diagnoses, 68% were stroke alerts called in the pediatric intensive care unit or pediatric cardiac intensive care unit. Rapid neuroimaging was completed in 91%; magnetic resonance imaging brain was the first image in 55%.
CONCLUSIONS - Of in-hospital pediatric stroke alerts, 45% were stroke while 38% were other neurological conditions requiring urgent evaluation. In-hospital stroke alerts were commonly activated for children with complicated medical histories. Rapid neurological evaluation facilitated care. No child underwent thrombolysis or thrombectomy.
Copyright © 2018. Published by Elsevier Inc.
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Inhibitory Anti-Peroxidasin Antibodies in Pulmonary-Renal Syndromes.
McCall AS, Bhave G, Pedchenko V, Hess J, Free M, Little DJ, Baker TP, Pendergraft WF, Falk RJ, Olson SW, Hudson BG
(2018) J Am Soc Nephrol 29: 2619-2625
MeSH Terms: Adolescent, Adult, Aged, Aged, 80 and over, Anti-Glomerular Basement Membrane Disease, Antibodies, Antineutrophil Cytoplasmic, Antibody Specificity, Autoantibodies, Autoantigens, Child, Cohort Studies, Collagen Type IV, Extracellular Matrix Proteins, Female, Glomerulonephritis, Hemorrhage, Humans, Lung Diseases, Male, Middle Aged, Models, Immunological, Peroxidase, Peroxidases, Young Adult
Show Abstract · Added March 3, 2020
BACKGROUND - Goodpasture syndrome (GP) is a pulmonary-renal syndrome characterized by autoantibodies directed against the NC1 domains of collagen IV in the glomerular and alveolar basement membranes. Exposure of the cryptic epitope is thought to occur disruption of sulfilimine crosslinks in the NC1 domain that are formed by peroxidasin-dependent production of hypobromous acid. Peroxidasin, a heme peroxidase, has significant structural overlap with myeloperoxidase (MPO), and MPO-ANCA is present both before and at GP diagnosis in some patients. We determined whether autoantibodies directed against peroxidasin are also detected in GP.
METHODS - We used ELISA and competitive binding assays to assess the presence and specificity of autoantibodies in serum from patients with GP and healthy controls. Peroxidasin activity was fluorometrically measured in the presence of partially purified IgG from patients or controls. Clinical disease severity was gauged by Birmingham Vasculitis Activity Score.
RESULTS - We detected anti-peroxidasin autoantibodies in the serum of patients with GP before and at clinical presentation. Enriched anti-peroxidasin antibodies inhibited peroxidasin-mediated hypobromous acid production . The anti-peroxidasin antibodies recognized peroxidasin but not soluble MPO. However, these antibodies did crossreact with MPO coated on the polystyrene plates used for ELISAs. Finally, peroxidasin-specific antibodies were also found in serum from patients with anti-MPO vasculitis and were associated with significantly more active clinical disease.
CONCLUSIONS - Anti-peroxidasin antibodies, which would previously have been mischaracterized, are associated with pulmonary-renal syndromes, both before and during active disease, and may be involved in disease activity and pathogenesis in some patients.
Copyright © 2018 by the American Society of Nephrology.
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Changing patterns of patent ductus arteriosus surgical ligation in the United States.
Reese J, Scott TA, Patrick SW
(2018) Semin Perinatol 42: 253-261
MeSH Terms: Cerebral Intraventricular Hemorrhage, Cross-Sectional Studies, Ductus Arteriosus, Patent, Enterocolitis, Necrotizing, Female, Humans, Infant, Extremely Low Birth Weight, Infant, Newborn, Infant, Very Low Birth Weight, Ligation, Male, Practice Patterns, Physicians', Retrospective Studies, Treatment Outcome, United States, Vocal Cord Paralysis
Show Abstract · Added November 26, 2018
Optimal management of patent ductus arteriosus (PDA) is unclear. One treatment, surgical ligation, is associated with adverse outcomes. We reviewed data from the Kids' Inpatient Database (2000-2012) to determine if PDA ligation rates: (1) changed over time, (2) varied geographically, or (3) influenced surgical complication rates. In 2012, 47,900 infants <1500g birth weight were born in the United States, including 2,800 undergoing PDA ligation (5.9%). Ligation was more likely in infants <1000g (85.9% vs. 46.2%), and associated with necrotizing enterocolitis (59.2% vs. 37.5%), BPD (54.6% vs. 15.2%), severe intraventricular hemorrhage (16.4% vs. 5.3%), and hospital transfer (37.6% vs. 16.4%). Ligation rates peaked in 2006 at 87.4 per 1000 hospital births, dropping to 58.8 in 2012, and were consistently higher in Western states. Infants undergoing ligation were more likely to experience comorbidities. Rates of ligation-associated vocal cord paralysis increased over time (1.2-3.9%); however, mortality decreased (12.4-6.5%). Thus, PDA ligation has become less frequent, although infants being ligated are smaller and more medically complex. Despite increase in some complications, mortality rates improved perhaps reflecting advances in care.
Copyright © 2018 Elsevier Inc. All rights reserved.
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16 MeSH Terms
Neurologic Outcome Predictors in Pediatric Intracerebral Hemorrhage: A Prospective Study.
Porcari GS, Beslow LA, Ichord RN, Licht DJ, Kleinman JT, Jordan LC
(2018) Stroke 49: 1755-1758
MeSH Terms: Adolescent, Brain, Cerebral Hemorrhage, Child, Child, Preschool, Female, Humans, Infant, Infant, Newborn, Male, Neuroimaging, Organ Size, Predictive Value of Tests, Prognosis, Recovery of Function
Show Abstract · Added March 24, 2020
BACKGROUND AND PURPOSE - Intracerebral hemorrhage is a considerable source of morbidity and mortality. This 3-center study describes outcomes of pediatric intracerebral hemorrhage and identifies 2-year neurological outcome predictors.
METHODS - Children 29 days to 18 years of age presenting with intracerebral hemorrhage from March 2007 to May 2015 were enrolled prospectively. Exclusion criteria included trauma; intracranial tumor; hemorrhagic transformation of arterial ischemic stroke or cerebral sinovenous thrombosis; isolated subdural, epidural, or subarachnoid hemorrhage; and abnormal baseline neurological function. Intracerebral hemorrhage and total brain volumes were measured on neuroimaging. The Pediatric Stroke Outcome Measure assessed outcomes.
RESULTS - Sixty-nine children were included (median age: 9.7 years; interquartile range: 2.2-14). Six children (9%) died during hospitalization. Outcomes in survivors were assessed at early follow-up in 98% (median 3.1 months; interquartile range: 3.1-3.8) and at later follow-up in 94% (median: 2.1 years; interquartile range: 1.3-2.8). Over a third had a significant disability at 2 years (Pediatric Stroke Outcome Measure >2). Total Pediatric Stroke Outcome Measure score improved over time (=0.0003), paralleling improvements in the sensorimotor subscore (=0.0004). Altered mental status (odds ratio, 13; 95% confidence interval, 3.9-46; <0.001), hemorrhage volume ≥4% of total brain volume (odds ratio, 17; 95% confidence interval, 1.9-156; =0.01), and intensive care unit length of stay (odds ratio, 1.1; 95% confidence interval, 1.0-1.2; =0.002) were significantly associated with poor 2-year outcome.
CONCLUSIONS - Over one third of children experienced significant disability at 2 years. Improvements in outcomes were driven by recovery of sensorimotor function. Altered mental status, hemorrhage volume ≥4% of total brain volume, and intensive care unit length of stay were independent predictors of significant disability at 2 years.
© 2018 American Heart Association, Inc.
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High Frequency of Ovarian Cyst Development in Vhl;Snf5 Mice.
Kuwahara Y, Kennedy LM, Karnezis AN, Mora-Blanco EL, Rogers AB, Fletcher CD, Huntsman DG, Roberts CWM, Rathmell WK, Weissman BE
(2018) Am J Pathol 188: 1510-1516
MeSH Terms: Animals, Female, Hemorrhage, Mice, Mice, Knockout, Mutation, Ovarian Cysts, Phenotype, SMARCB1 Protein, Von Hippel-Lindau Tumor Suppressor Protein
Show Abstract · Added October 30, 2019
The new paradigm of mutations in chromatin-modifying genes as driver events in the development of cancers has proved challenging to resolve the complex influences over disease phenotypes. In particular, impaired activities of members of the SWI/SNF chromatin remodeling complex have appeared in an increasing variety of tumors. Mutations in SNF5, a member of this ubiquitously expressed complex, arise in almost all cases of malignant rhabdoid tumor in the absence of additional genetic alterations. Therefore, we studied how activation of additional oncogenic pathways might shift the phenotype of disease driven by SNF5 loss. With the use of a genetically engineered mouse model, we examined the effects of a hypomorphic Vhl allele on disease phenotype, with a modest up-regulation of the hypoxia response pathway. Snf5;Vhl mice did not demonstrate a substantial difference in overall survival or a change in malignant rhabdoid tumor development. However, a high percentage of female mice showed complex hemorrhagic ovarian cysts, a phenotype rarely found in either parental mouse strain. These lesions also showed mosaic expression of SNF5 by immunohistochemistry. Therefore, our studies implicate that modest changes in angiogenic regulation interact with perturbations of SWI/SNF complex activity to modulate disease phenotypes.
Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
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