Publications by authors named "Jeffery A Goldstein"

30 Publications

  • Page 1 of 1

Maternal vs Fetal Origin of Placental Intervillous Thrombi.

Am J Clin Pathol 2021 Sep 21. Epub 2021 Sep 21.

Departments of Pathology, Chicago, IL, USA.

Objectives: To determine maternal vs fetal origin for blood in placental intervillous thrombi (IVTs).

Methods: We used comparative analysis of microsatellites (short tandem repeats [STRs]), sex chromosome fluorescence in situ hybridization (FISH), and immunohistochemistry (IHC) for fetal (ɑ-fetoprotein [AFP]) and maternal (immunoglobulin M [IgM]) serum proteins to distinguish the origin of IVTs. Using an informatics approach, we tested the association between IVTs and fetomaternal hemorrhage (FMH).

Results: In 9 of 10 cases, the preponderance of evidence showed that the thrombus was mostly or entirely maternal in origin. In 1 case, the thrombus was of mixed origins. STR testing was prone to contamination by entrapped fetal villi. FISH was useful but limited only to cases with male fetuses. IgM showed stronger staining than AFP in 9 cases, supporting maternal origin. By informatics, we found no association between IVTs and FMH.

Conclusions: Evidence supports a maternal origin for blood in IVTs. IHC for IgM and AFP may be clinically useful in determining maternal vs fetal contribution to IVTs.
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http://dx.doi.org/10.1093/ajcp/aqab139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8500002PMC
September 2021

Laboratory analysis of symptomatic and asymptomatic pregnant patients with SARS-CoV-2 infection.

Am J Obstet Gynecol MFM 2021 Aug 14;3(6):100458. Epub 2021 Aug 14.

Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL (Drs Fisher and Miller).

Background: Inflammatory biomarkers have been used to portend disease severity in nonpregnant individuals with SARS-CoV-2 infection. However, currently, limited data are available, and with mixed results, to elucidate which inflammatory biomarkers may be most associated with clinical phenotype in pregnant patients.

Objective: We aimed to compare laboratory findings among pregnant patients with SARS-CoV-2 infection by symptom status and disease severity.

Study Design: We retrospectively evaluated pregnant patients with positive SARS-CoV-2 infection, confirmed through polymerase chain reaction testing, at an urban academic US hospital between March 2020 and October 2020, performed for reported symptoms or universal screening on admission. In our hospital, all patients with SARS-CoV-2 infection were recommended to have baseline laboratory testing, including leukocyte, neutrophil, and lymphocyte counts; aspartate aminotransferase and alanine aminotransferase; high-sensitivity C-reactive protein; procalcitonin; lactate dehydrogenase; D-dimer; and ferritin. We performed multivariable logistic regression to evaluate peak laboratory abnormalities significantly associated with symptomatic SARS-CoV-2 infection and disease severity with gestational age at diagnosis, maternal age, and obesity as covariates. The sensitivity and specificity of laboratory abnormalities were calculated to identify symptomatic vs asymptomatic infection and severe to critical disease vs mild to moderate disease.

Results: We identified 175 pregnant patients with SARS-CoV-2 infection, of whom 100 (57%) were symptomatic; 17 (17%) of those who were symptomatic had a severe to critical disease. Laboratory data were available for 128 patients, of whom 67 (52%) were symptomatic. Compared with asymptomatic individuals, symptomatic individuals were more likely to exhibit elevated high-sensitivity C-reactive protein levels after adjusting for gestational age (adjusted odds ratio, 5.67; 95% confidence interval, 1.42-22.52; sensitivity, 81%; specificity, 43%). In symptomatic individuals, transaminitis (adjusted odds ratio, 5.67; 95% confidence interval, 1.27-25.43), elevated procalcitonin levels (adjusted odds ratio, 16.60; 95% confidence interval, 2.61-105.46), and elevated lactate dehydrogenase levels (adjusted odds ratio, 17.55; 95% confidence interval, 2.51-122.78) were independently associated with severe to critical disease rather than mild to moderate disease after adjusting for maternal age and obesity. For differentiating disease severity, sensitivity rates for transaminitis, procalcitonin elevation, and lactate dehydrogenase elevation were 47%, 87%, and 53%, respectively, whereas the specificity rates were 89%, 63%, and 90%, respectively.

Conclusion: Inflammatory biomarkers in pregnant patients with SARS-CoV-2 infection exhibited vast heterogeneity, poor discriminative ability, and thereby limited clinical utility. Larger registry studies should evaluate which inflammatory biomarkers may be most useful for risk stratification and prognostication of pregnant patients with SARS-CoV-2 infection, taking into account the physiology of pregnancy.
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http://dx.doi.org/10.1016/j.ajogmf.2021.100458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8364143PMC
August 2021

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Vaccination in Pregnancy: Measures of Immunity and Placental Histopathology.

Obstet Gynecol 2021 08;138(2):281-283

Feinberg School of Medicine, Northwestern University, and the Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.

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http://dx.doi.org/10.1097/AOG.0000000000004457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288194PMC
August 2021

Chorioamnionitis and Risk for Maternal and Neonatal Sepsis: A Systematic Review and Meta-analysis.

Obstet Gynecol 2021 06;137(6):1007-1022

Pennsylvania State University, University Park, Pennsylvania; and Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Objective: To estimate the risk of maternal and neonatal sepsis associated with chorioamnionitis.

Data Sources: PubMed, BIOSIS, and ClinicalTrials.gov databases were systematically searched for full-text articles in English from inception until May 11, 2020.

Methods Of Study Selection: We screened 1,251 studies. Randomized controlled trials, case-control, or cohort studies quantifying a relationship between chorioamnionitis and sepsis in mothers (postpartum) or neonates born at greater than 22 weeks of gestation were eligible. Studies were grouped for meta-analyses according to exposures of histologic or clinical chorioamnionitis and outcomes of maternal or neonatal sepsis.

Tabulation, Integration, And Results: One hundred three studies were included, and 55 met criteria for meta-analysis (39 studies of preterm neonates, 10 studies of general populations of preterm and term neonates, and six studies of late preterm and term neonates). Study details and quantitative data were abstracted. Random-effects models were used to generate pooled odds ratios (ORs); most studies only reported unadjusted results. Histologic chorioamnionitis was associated with confirmed and any early-onset neonatal sepsis (unadjusted pooled ORs 4.42 [95% CI 2.68-7.29] and 5.88 [95% CI 3.68-9.41], respectively). Clinical chorioamnionitis was also associated with confirmed and any early-onset neonatal sepsis (unadjusted pooled ORs 6.82 [95% CI 4.93-9.45] and 3.90 [95% CI 2.74-5.55], respectively). Additionally, histologic and clinical chorioamnionitis were each associated with higher odds of late-onset sepsis in preterm neonates. Confirmed sepsis incidence was 7% (early-onset) and 22% (late-onset) for histologic and 6% (early-onset) and 26% (late-onset) for clinical chorioamnionitis-exposed neonates. Three studies evaluated chorioamnionitis and maternal sepsis and were inconclusive.

Conclusion: Both histologic and clinical chorioamnionitis were associated with early- and late-onset sepsis in neonates. Overall, our findings support current guidelines for preventative neonatal care. There was insufficient evidence to determine the association between chorioamnionitis and maternal sepsis.

Systematic Review Registration: PROSPERO, CRD42020156812.
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http://dx.doi.org/10.1097/AOG.0000000000004377DOI Listing
June 2021

Cord blood antibodies following maternal coronavirus disease 2019 vaccination during pregnancy.

Am J Obstet Gynecol 2021 08 1;225(2):192-194. Epub 2021 Apr 1.

Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL.

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http://dx.doi.org/10.1016/j.ajog.2021.03.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012273PMC
August 2021

GestAltNet: aggregation and attention to improve deep learning of gestational age from placental whole-slide images.

Lab Invest 2021 07 5;101(7):942-951. Epub 2021 Mar 5.

Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

The placenta is the first organ to form and performs the functions of the lung, gut, kidney, and endocrine systems. Abnormalities in the placenta cause or reflect most abnormalities in gestation and can have life-long consequences for the mother and infant. Placental villi undergo a complex but reproducible sequence of maturation across the third-trimester. Abnormalities of villous maturation are a feature of gestational diabetes and preeclampsia, among others, but there is significant interobserver variability in their diagnosis. Machine learning has emerged as a powerful tool for research in pathology. To capture the volume of data and manage heterogeneity within the placenta, we developed GestaltNet, which emulates human attention to high-yield areas and aggregation across regions. We used this network to estimate the gestational age (GA) of scanned placental slides and compared it to a baseline model lacking the attention and aggregation functions. In the test set, GestaltNet showed a higher r (0.9444 vs. 0.9220) than the baseline model. The mean absolute error (MAE) between the estimated and actual GA was also better in the GestaltNet (1.0847 weeks vs. 1.4505 weeks). On whole-slide images, we found the attention sub-network discriminates areas of terminal villi from other placental structures. Using this behavior, we estimated GA for 36 whole slides not previously seen by the model. In this task, similar to that faced by human pathologists, the model showed an r of 0.8859 with an MAE of 1.3671 weeks. We show that villous maturation is machine-recognizable. Machine-estimated GA could be useful when GA is unknown or to study abnormalities of villous maturation, including those in gestational diabetes or preeclampsia. GestaltNet points toward a future of genuinely whole-slide digital pathology by incorporating human-like behaviors of attention and aggregation.
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http://dx.doi.org/10.1038/s41374-021-00579-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933605PMC
July 2021

Multi-region saliency-aware learning for cross-domain placenta image segmentation.

Pattern Recognit Lett 2020 Dec;140:165-171

The Pennsylvania State University, University Park, PA, USA.

We propose a multi-region saliency-aware learning (MSL) method for cross-domain placenta image segmentation. Unlike most existing image-level transfer learning methods that fail to preserve the semantics of paired regions, our MSL incorporates the attention mechanism and a saliency constraint into the adversarial translation process, which can realize multi-region mappings in the semantic level. Specifically, the built-in attention module serves to detect the most discriminative semantic regions that the generator should focus on. Then we use the attention consistency as another guidance for retaining semantics after translation. Furthermore, we exploit the specially designed saliency-consistent constraint to enforce the semantic consistency by requiring the saliency regions unchanged. We conduct experiments using two real-world placenta datasets we have collected. We examine the efficacy of this approach in (1) segmentation and (2) prediction of the placental diagnoses of fetal and maternal inflammatory response (FIR, MIR). Experimental results show the superiority of the proposed approach over the state of the art.
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http://dx.doi.org/10.1016/j.patrec.2020.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727399PMC
December 2020

Maternal-Fetal Inflammation in the Placenta and the Developmental Origins of Health and Disease.

Front Immunol 2020 13;11:531543. Epub 2020 Nov 13.

Department of Nutritional Sciences, College of Health and Human Development, Penn State University, University Park, PA, United States.

Events in fetal life impact long-term health outcomes. The placenta is the first organ to form and is the site of juxtaposition between the maternal and fetal circulations. Most diseases of pregnancy are caused by, impact, or are reflected in the placenta. The purpose of this review is to describe the main inflammatory processes in the placenta, discuss their immunology, and relate their short- and long-term disease associations. Acute placental inflammation (API), including maternal and fetal inflammatory responses corresponds to the clinical diagnosis of chorioamnionitis and is associated with respiratory and neurodevelopmental diseases. The chronic placental inflammatory pathologies (CPI), include chronic villitis of unknown etiology, chronic deciduitis, chronic chorionitis, eosinophilic T-cell vasculitis, and chronic histiocytic intervillositis. These diseases are less-well studied, but have complex immunology and show mechanistic impacts on the fetal immune system. Overall, much work remains to be done in describing the long-term impacts of placental inflammation on offspring health.
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http://dx.doi.org/10.3389/fimmu.2020.531543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691234PMC
April 2021

LabWAS: Novel findings and study design recommendations from a meta-analysis of clinical labs in two independent biobanks.

PLoS Genet 2020 11 11;16(11):e1009077. Epub 2020 Nov 11.

Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, United States of America.

Phenotypes extracted from Electronic Health Records (EHRs) are increasingly prevalent in genetic studies. EHRs contain hundreds of distinct clinical laboratory test results, providing a trove of health data beyond diagnoses. Such lab data is complex and lacks a ubiquitous coding scheme, making it more challenging than diagnosis data. Here we describe the first large-scale cross-health system genome-wide association study (GWAS) of EHR-based quantitative laboratory-derived phenotypes. We meta-analyzed 70 lab traits matched between the BioVU cohort from the Vanderbilt University Health System and the Michigan Genomics Initiative (MGI) cohort from Michigan Medicine. We show high replication of known association for these traits, validating EHR-based measurements as high-quality phenotypes for genetic analysis. Notably, our analysis provides the first replication for 699 previous GWAS associations across 46 different traits. We discovered 31 novel associations at genome-wide significance for 22 distinct traits, including the first reported associations for two lab-based traits. We replicated 22 of these novel associations in an independent tranche of BioVU samples. The summary statistics for all association tests are freely available to benefit other researchers. Finally, we performed mirrored analyses in BioVU and MGI to assess competing analytic practices for EHR lab traits. We find that using the mean of all available lab measurements provides a robust summary value, but alternate summarizations can improve power in certain circumstances. This study provides a proof-of-principle for cross health system GWAS and is a framework for future studies of quantitative EHR lab traits.
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http://dx.doi.org/10.1371/journal.pgen.1009077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682892PMC
November 2020

AI-PLAX: AI-based placental assessment and examination using photos.

Comput Med Imaging Graph 2020 09 1;84:101744. Epub 2020 Jun 1.

The Pennsylvania State University, University Park, PN, USA. Electronic address:

Post-delivery analysis of the placenta is useful for evaluating health risks of both the mother and baby. In the U.S., however, only about 20% of placentas are assessed by pathology exams, and placental data is often missed in pregnancy research because of the additional time, cost, and expertise needed. A computer-based tool that can be used in any delivery setting at the time of birth to provide an immediate and comprehensive placental assessment would have the potential to not only to improve health care, but also to radically improve medical knowledge. In this paper, we tackle the problem of automatic placental assessment and examination using photos. More concretely, we first address morphological characterization, which includes the tasks of placental image segmentation, umbilical cord insertion point localization, and maternal/fetal side classification. We also tackle clinically meaningful feature analysis of placentas, which comprises detection of retained placenta (i.e., incomplete placenta), umbilical cord knot, meconium, abruption, chorioamnionitis, and hypercoiled cord, and categorization of umbilical cord insertion type. We curated a dataset consisting of approximately 1300 placenta images taken at Northwestern Memorial Hospital, with hand-labeled pixel-level segmentation map, cord insertion point and other information extracted from the associated pathology reports. We developed the AI-based Placental Assessment and Examination system (AI-PLAX), which is a novel two-stage photograph-based pipeline for fully automated analysis. In the first stage, we use three encoder-decoder convolutional neural networks with a shared encoder to address morphological characterization tasks by employing a transfer-learning training strategy. In the second stage, we employ distinct sub-models to solve different feature analysis tasks by using both the photograph and the output of the first stage. We evaluated the effectiveness of our pipeline by using the curated dataset as well as the pathology reports in the medical record. Through extensive experiments, we demonstrate our system is able to produce accurate morphological characterization and very promising performance on aforementioned feature analysis tasks, all of which may possess clinical impact and contribute to future pregnancy research. This work is the first for comprehensive, automated, computer-based placental analysis and will serve as a launchpad for potentially multiple future innovations.
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http://dx.doi.org/10.1016/j.compmedimag.2020.101744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533514PMC
September 2020

Placental Pathology in COVID-19.

Am J Clin Pathol 2020 07;154(2):279

Northwestern University Chicago, IL.

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http://dx.doi.org/10.1093/ajcp/aqaa101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314265PMC
July 2020

Placental pathology in COVID-19.

medRxiv 2020 May 12. Epub 2020 May 12.

Objectives: To describe histopathologic findings in the placentas of women with COVID-19 during pregnancy.

Methods: Pregnant women with COVID-19 delivering between March 18, 2020 and May 5, 2020 were identified. Placentas were examined and compared to historical controls and women with placental evaluation for a history of melanoma.

Results: 16 placentas from patients with SARS-CoV-2 were examined (15 with live birth in the 3rd trimester 1 delivered in the 2nd trimester after intrauterine fetal demise). Compared to controls, third trimester placentas were significantly more likely to show at least one feature of maternal vascular malperfusion (MVM), including abnormal or injured maternal vessels, as well as delayed villous maturation, chorangiosis, and intervillous thrombi. Rates of acute and chronic inflammation were not increased. The placenta from the patient with intrauterine fetal demise showed villous edema and a retroplacental hematoma.

Conclusions: Relative to controls, COVID-19 placentas show increased prevalence of features of maternal vascular malperfusion (MVM), a pattern of placental injury reflecting abnormalities in oxygenation within the intervillous space associated with adverse perinatal outcomes. Only 1 COVID-19 patient was hypertensive despite the association of MVM with hypertensive disorders and preeclampsia. These changes may reflect a systemic inflammatory or hypercoagulable state influencing placental physiology.
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http://dx.doi.org/10.1101/2020.05.08.20093229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274231PMC
May 2020

EHRs could clarify drug safety in pregnant people.

Nat Med 2020 06;26(6):820-821

Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

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http://dx.doi.org/10.1038/s41591-020-0925-1DOI Listing
June 2020

Placental Pathology in COVID-19.

Am J Clin Pathol 2020 06;154(1):23-32

Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL.

Objectives: To describe histopathologic findings in the placentas of women with coronavirus disease 2019 (COVID-19) during pregnancy.

Methods: Pregnant women with COVID-19 delivering between March 18, 2020, and May 5, 2020, were identified. Placentas were examined and compared to historical controls and women with placental evaluation for a history of melanoma.

Results: Sixteen placentas from patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were examined (15 with live birth in the third trimester, 1 delivered in the second trimester after intrauterine fetal demise). Compared to controls, third trimester placentas were significantly more likely to show at least one feature of maternal vascular malperfusion (MVM), particularly abnormal or injured maternal vessels, and intervillous thrombi. Rates of acute and chronic inflammation were not increased.The placenta from the patient with intrauterine fetal demise showed villous edema and a retroplacental hematoma.

Conclusions: Relative to controls, COVID-19 placentas show increased prevalence of decidual arteriopathy and other features of MVM, a pattern of placental injury reflecting abnormalities in oxygenation within the intervillous space associated with adverse perinatal outcomes. Only 1 COVID-19 patient was hypertensive despite the association of MVM with hypertensive disorders and preeclampsia. These changes may reflect a systemic inflammatory or hypercoagulable state influencing placental physiology.
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http://dx.doi.org/10.1093/ajcp/aqaa089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279066PMC
June 2020

Perivascular epithelioid cell tumors (PEComa) in pregnancy with uterine rupture and ongoing abdominal gestation: A case report.

Case Rep Womens Health 2020 Jan 11;25:e00172. Epub 2020 Jan 11.

Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, United States of America.

Perivascular epithelioid cell tumors (PEComa) represent a rare family of tumors characterized by distinct histology and immunohistochemistry characteristics. Approximately one-quarter of reported cases are gynecologic in origin and associated pregnancies are rare. We report a case of PEComa in pregnancy with initial undiagnosed presentation at 18 weeks of gestation and subsequent presentation and diagnosis at 30 weeks of gestation. Abdominal pain led to the use of magnetic resonance imaging, which raised concerns about placentation abnormality and abdominal pregnancy. Exploratory laparotomy was notable for a 10 cm by 15 cm posterior uterine defect through which the placenta and amniotic sac containing the fetus were extruded. Placenta-like tissue was noted to be invading through the anterior wall of the uterus, which led to concern regarding placenta percreta. A total abdominal hysterectomy and bilateral salpingectomy were then performed, given the complete loss of normal uterine architecture. Pathology returned with findings of placenta accreta and PEComa. Indolent uterine rupture in the setting of PEComa led to an ongoing viable abdominal pregnancy. Uterine PEComa can masquerade as a placenta and lead to obstetrical complications.
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http://dx.doi.org/10.1016/j.crwh.2020.e00172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962696PMC
January 2020

Seasonal Variation of Chronic Villitis of Unknown Etiology.

Pediatr Dev Pathol 2020 Aug 10;23(4):253-259. Epub 2019 Dec 10.

Department of Pathology and Laboratory Medicine, NorthShore University HealthSystem, University of Chicago Pritzker School of Medicine, Evanston, Illinois.

Introduction: Chronic villitis of unknown etiology (VUE) is a chronic inflammatory lesion of the placenta. VUE is hypothesized to result from an alloimmune response or as response to an unidentified infection. Lack of a seasonal trend is thought to support VUE as an alloimmune response, though data on seasonal VUE trends are limited.

Methods: Data were obtained from a hospital in Chicago, Illinois, from 2011-2016. Placentas sent to pathology were reviewed using a standardized protocol, and VUE cases were identified based on an automated text search of pathology records. We used monthly VUE prevalence estimates to investigate the annual trend, and we used Poisson regression to evaluate seasonal variation in the number of VUE cases.

Results: There were 79 825 deliveries within the study period. Pathologists evaluated 12 074 placentas and identified 2873 cases of VUE. Regression results indicate that the risk of VUE is 16% to 17% higher in the fall and winter as compared to the summer (fall relative risk [RR]: 1.17, 95% confidence interval [CI]: 1.06-1.29; winter RR: 1.16, 95% CI: 1.05-1.29).

Discussion: Our results suggest that there may be seasonal variation in VUE prevalence, particularly for low-grade VUE. Future studies should evaluate seasonal variation in a representative sample rather than relying on pathology reports to estimate prevalence.
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http://dx.doi.org/10.1177/1093526619892353DOI Listing
August 2020

Timing of Placenta Examination Orders: How Long Should Placentas Be Stored Before Discarding?

Pediatr Dev Pathol 2019 Nov-Dec;22(6):601-602. Epub 2019 May 30.

Department of Pathology, Northwestern University, Chicago, Illinois.

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http://dx.doi.org/10.1177/1093526619853101DOI Listing
May 2020

Refractory hypoglycemia in a pediatric patient with desmoplastic small round cell tumor.

J Pediatr Endocrinol Metab 2018 Aug;31(8):947-950

Division of Endocrinology, Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, 225 E Chicago Avenue, Box 54, Chicago, IL, USA.

Background Tumor-induced hypoglycemia is a rare and serious complication that is usually a consequence of either excessive insulin secretion (insulinoma) or because of non-islet cell tumor hypoglycemia (NICTH). NICTH is a rare phenomenon seen most often in adult patients. It is associated with different tumor types. Here, we report the first case to the best of our knowledge in the literature of a pediatric patient with NICTH associated with desmoplastic small round cell tumor (DSRT). Case presentation This is a 15-year-old girl who presented with symptomatic hypoglycemia and abdominal mass. She required an intravenous glucose infusion rate as high as 9 mg/kg/min in addition to glucose containing oral supplements in order to maintain her blood glucose above 60 mg/dL. Computed tomography (CT) scan of the chest, abdomen and pelvis showed multiple hepatic lesions with an intraperitoneal soft tissue mass which subsequently was diagnosed as DSRT. When the blood glucose was 45 mg/dL, the insulin, growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels were suppressed with an appropriate elevation of cortisol. Subsequently, an insulin-like growth factor-2 (IGF-2) level was sent and the IGF-2:IGF-1 ratio was found to be elevated >10 consistent with NICTH. After the first dose of chemotherapy, hypoglycemia improved, and she was weaned off glucose containing fluids. Conclusions NICTH should be considered in all cancer patients regardless of their age with refractory hypoglycemia.
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http://dx.doi.org/10.1515/jpem-2018-0107DOI Listing
August 2018

Gestational diabetes mellitus is associated with increased CD163 expression and iron storage in the placenta.

Am J Reprod Immunol 2018 10 9;80(4):e13020. Epub 2018 Jul 9.

Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.

Problem: GDM has been associated with disturbances in iron homeostasis and exaggerated immune activation. We sought to investigate the extent to which placental iron storage and macrophage accumulations were altered in GDM.

Method Of Study: We conducted a retrospective, case-control study of archived placental tissues obtained from 22 pregnancies complicated by GDM and 22 unaffected controls. Controls were matched to cases based on maternal age, gestational age at birth, and method of delivery. Placental tissues were assessed for altered histology and CD68 and CD163 staining. Tissue iron was assessed using Prussian blue staining.

Results: Maternal hematocrit levels were higher in GDM participants compared to controls (P = 0.02). The presence of meconium-laden macrophages was significantly greater within the amnion of GDM cases (adjusted odds ratio (OR) 12.51). Although the total abundance of CD68-expressing macrophages was not significantly different between groups, we detected a significantly greater abundance of CD163 expression within the chorion and decidua of cases. The total area staining positive for iron was 24% (95% confidence intervals of 2%-46%) greater in GDM placentae versus controls.

Conclusion: GDM is associated with altered placental histology and increases in meconium-laden macrophages. Greater iron stores within the placentae of women with GDM is consistent with reports that iron excess is associated with an increased risk for GDM. The higher level of expression of CD163 on macrophage-like cells of the chorion and decidua in GDM suggests an increase in M2-like macrophages. Overall, our results add to growing evidence that GDM has direct effects on placental structure.
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http://dx.doi.org/10.1111/aji.13020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6193471PMC
October 2018

PregOMICS-Leveraging systems biology and bioinformatics for drug repurposing in maternal-child health.

Am J Reprod Immunol 2018 08 4;80(2):e12971. Epub 2018 May 4.

Section of Infectious Disease, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

Obstetric diseases remain underserved and understudied. Drug repurposing-utilization of a drug whose use is accepted in one condition for a different condition-could represent a rapid and low-cost way to identify new therapies that are known to be safe. In diseases of pregnancy, the known safety profile is a strong additional incentive. We describe the techniques and steps used in the use of 'omics data for drug repurposing. We illustrate these techniques using case studies of published drug repurposing projects. We provide a set of available databases with low barriers to entry which investigators can use to perform their own projects. The promise of 'omics techniques is unbiased screening, either of all drug targets or of all patients using particular drugs to find which are likely to alter disease risk or progression. However, we caution that reproducibility across the underlying studies, and thus the drugs suggested for repurposing, can be poor. We suggest that improved nosology, for example correlating patient clinical conditions with placental pathology, could yield more robust associations. We conclude that 'omics-driven drug repurposing represents a potential fruitful path to discover new, safe treatments of obstetric diseases.
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http://dx.doi.org/10.1111/aji.12971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105384PMC
August 2018

Calcium channel blockers as drug repurposing candidates for gestational diabetes: Mining large scale genomic and electronic health records data to repurpose medications.

Pharmacol Res 2018 04 12;130:44-51. Epub 2018 Feb 12.

Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, United States; Department of Medicine, Vanderbilt University Medical Center, United States. Electronic address:

New therapeutic approaches are needed for gestational diabetes mellitus (GDM), but must show safety and efficacy in a historically understudied population. We studied associations between electronic medical record (EMR) phenotypes and genetic variants to uncover drugs currently considered safe in pregnancy that could treat or prevent GDM. We identified 129 systemically active drugs considered safe in pregnancy targeting the proteins produced from 196 genes. We tested for associations between GDM and/or type 2 diabetes (DM2) and 306 SNPs in 130 genes represented on the Illumina Infinium Human Exome Bead Chip (DM2 was included due to shared pathophysiological features with GDM). In parallel, we tested the association between drugs and glucose tolerance during pregnancy as measured by the glucose recorded during a routine 50-g glucose tolerance test (GTT). We found an association between GDM/DM2 and the genes targeted by 11 drug classes. In the EMR analysis, 6 drug classes were associated with changes in GTT. Two classes were identified in both analyses. L-type calcium channel blocking antihypertensives (CCBs), were associated with a 3.18 mg/dL (95% CI -6.18 to -0.18) decrease in glucose during GTT, and serotonin receptor type 3 (5HT-3) antagonist antinausea medications were associated with a 3.54 mg/dL (95% CI 1.86-5.23) increase in glucose during GTT. CCBs were identified as a class of drugs considered safe in pregnancy could have efficacy in treating or preventing GDM. 5HT-3 antagonists may be associated with worse glucose tolerance.
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http://dx.doi.org/10.1016/j.phrs.2018.02.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5965292PMC
April 2018

Clinical trial spots for cancer patients by tumour type: The cancer trials portfolio at clinicaltrials.gov.

Eur J Cancer 2015 Nov 25;51(17):2718-23. Epub 2015 Aug 25.

Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, United States. Electronic address:

Background: Although participation in cancer clinical trials is low, little is known about the number of available clinical trials, and open spots for patients. Moreover, it is unclear what the relationship is between clinical trial openings and the incidence and mortality of cancer subtypes.

Methodology: We identified the number of phase I, phase II and phase III registered at clinicaltrials.gov by cancer (tumour) type. All counts were over the preceding 5 years (2008-2013). We compared these counts against the incidence and prevalence of disease reported by Surveillance, Epidemiology and End Results (SEER) database for 32 common cancers.

Results: From 2008 to 2013, 3879 phase I trials, 4982 phase II trials and 1379 phase III trials concerning a cancer subtype were registered in clinicaltrials.gov. These trials had a cumulative proposed recruitment of 203,396, 421,502 and 697,787 patients, respectively. Trial enrollment varied by tumour type, with both over and under-representation occurring.

Conclusion: Opportunities to enroll in clinical trials vary by phase and tumour type. Oncologists must remain committed to clinical trials.
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http://dx.doi.org/10.1016/j.ejca.2015.07.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4663106PMC
November 2015

Differential diagnostic considerations of desmoid-type fibromatosis.

Adv Anat Pathol 2015 Jul;22(4):260-6

Department of Pathology, Vanderbilt University Medical Center, Nashville, TN.

Fibrous and myofibroblastic tumors of soft tissue often present the surgical pathologist with a difficult differential diagnosis because of the number of diagnostic possibilities and morphologic similarities among cytologically bland spindle-cell tumors. Prototypical in this regard is desmoid-type fibromatosis. In a review of 320 surgical specimens diagnosed as desmoid tumor, 94 (29%) were discovered to be misclassified as such. The most common lesions in this series were Gardner fibroma, scar tissue, superficial fibromatosis, nodular fasciitis, myofibroma, and collagenous fibroma. Four sarcomas were also misinterpreted as desmoid-type fibromatosis (3 low-grade fibromyxoid sarcomas and 1 unclassified spindle-cell sarcoma). We take this opportunity to compare and contrast desmoid tumor and several of the soft tissue tumors that should be considered in the differential diagnosis thereof.
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http://dx.doi.org/10.1097/PAP.0000000000000077DOI Listing
July 2015

Disease specific productivity of american cancer hospitals.

PLoS One 2015 17;10(3):e0121233. Epub 2015 Mar 17.

Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America.

Context: Research-oriented cancer hospitals in the United States treat and study patients with a range of diseases. Measures of disease specific research productivity, and comparison to overall productivity, are currently lacking.

Hypothesis: Different institutions are specialized in research of particular diseases.

Objective: To report disease specific productivity of American cancer hospitals, and propose a summary measure.

Method: We conducted a retrospective observational survey of the 50 highest ranked cancer hospitals in the 2013 US News and World Report rankings. We performed an automated search of PubMed and Clinicaltrials.gov for published reports and registrations of clinical trials (respectively) addressing specific cancers between 2008 and 2013. We calculated the summed impact factor for the publications. We generated a summary measure of productivity based on the number of Phase II clinical trials registered and the impact factor of Phase II clinical trials published for each institution and disease pair. We generated rankings based on this summary measure.

Results: We identified 6076 registered trials and 6516 published trials with a combined impact factor of 44280.4, involving 32 different diseases over the 50 institutions. Using a summary measure based on registered and published clinical trails, we ranked institutions in specific diseases. As expected, different institutions were highly ranked in disease-specific productivity for different diseases. 43 institutions appeared in the top 10 ranks for at least 1 disease (vs 10 in the overall list), while 6 different institutions were ranked number 1 in at least 1 disease (vs 1 in the overall list).

Conclusion: Research productivity varies considerably among the sample. Overall cancer productivity conceals great variation between diseases. Disease specific rankings identify sites of high academic productivity, which may be of interest to physicians, patients and researchers.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0121233PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4364111PMC
February 2016

Excess SMAD signaling contributes to heart and muscle dysfunction in muscular dystrophy.

Hum Mol Genet 2014 Dec 28;23(25):6722-31. Epub 2014 Jul 28.

Department of Medicine Department of Human Genetics, The University of Chicago, Chicago, IL, USA and

Disruption of the dystrophin complex causes muscle injury, dysfunction, cell death and fibrosis. Excess transforming growth factor (TGF) β signaling has been described in human muscular dystrophy and animal models, where it is thought to relate to the progressive fibrosis that characterizes dystrophic muscle. We now found that canonical TGFβ signaling acutely increases when dystrophic muscle is stimulated to contract. Muscle lacking the dystrophin-associated protein γ-sarcoglycan (Sgcg null) was subjected to a lengthening protocol to produce maximal muscle injury, which produced rapid accumulation of nuclear phosphorylated SMAD2/3. To test whether reducing SMAD signaling improves muscular dystrophy in mice, we introduced a heterozygous mutation of SMAD4 (S4) into Sgcg mice to reduce but not ablate SMAD4. Sgcg/S4 mice had improved body mass compared with Sgcg mice, which normally show a wasting phenotype similar to human muscular dystrophy patients. Sgcg/S4 mice had improved cardiac function as well as improved twitch and tetanic force in skeletal muscle. Functional enhancement in Sgcg/S4 muscle occurred without a reduction in fibrosis, suggesting that intracellular SMAD4 targets may be important. An assessment of genes differentially expressed in Sgcg muscle focused on those encoding calcium-handling proteins and responsive to TGFβ since this pathway is a target for mediating improvement in muscular dystrophy. These data demonstrate that excessive TGFβ signaling alters cardiac and muscle performance through the intracellular SMAD pathway.
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http://dx.doi.org/10.1093/hmg/ddu390DOI Listing
December 2014

Interplay between heart and skeletal muscle disease in heart failure: the 2011 George E. Brown Memorial Lecture.

Circ Res 2012 Mar;110(5):749-54

Department of Medicine, University of Chicago, Chicago, IL 60637, USA.

The study of single gene disorders often provides insight for more complex human disease. Mutations in the genes encoding the dystrophin protein complex cause muscular dystrophy and cardiomyopathy by destabilizing the plasma membrane of skeletal myofibers and cardiomyocytes. In these diseases, progressive skeletal muscle degeneration and weakness contribute to cardiac dysfunction. Moreover, the pace and pattern of muscle weakness, along with onset of cardiomyopathy, is highly variable even when associated with the same identical mutation. Using a mouse model of muscular dystrophy and cardiomyopathy, we identified genetic loci that modify muscle pathology and cardiac fibrosis. Distinct genetic modifiers were identified for diaphragm and abdominal musculature, and these genetic intervals differ from those that regulate pathology in the skeletal muscle of the limbs and the heart. One modifier gene was identified and highlights the importance of the transforming growth factor-β pathway in the pathogenesis of muscular dystrophy and cardiomyopathy. We determined that canonical transforming growth factor-β signaling contributes to heart and muscle dysfunction using a Drosophila model. Together, these studies demonstrate the value of using a genetically sensitized model to uncover pathways that regulate heart failure and muscle weakness.
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http://dx.doi.org/10.1161/CIRCRESAHA.111.256776DOI Listing
March 2012

SMAD signaling drives heart and muscle dysfunction in a Drosophila model of muscular dystrophy.

Hum Mol Genet 2011 Mar 6;20(5):894-904. Epub 2010 Dec 6.

Department of Pathology, The University of Chicago, Chicago, IL, USA.

Loss-of-function mutations in the genes encoding dystrophin and the associated membrane proteins, the sarcoglycans, produce muscular dystrophy and cardiomyopathy. The dystrophin complex provides stability to the plasma membrane of striated muscle during muscle contraction. Increased SMAD signaling due to activation of the transforming growth factor-β (TGFβ) pathway has been described in muscular dystrophy; however, it is not known whether this canonical TGFβ signaling is pathogenic in the muscle itself. Drosophila deleted for the γ/δ-sarcoglycan gene (Sgcd) develop progressive muscle and heart dysfunction and serve as a model for the human disorder. We used dad-lacZ flies to demonstrate the signature of TGFβ activation in response to exercise-induced injury in Sgcd null flies, finding that those muscle nuclei immediately adjacent to muscle injury demonstrate high-level TGFβ signaling. To determine the pathogenic nature of this signaling, we found that partial reduction of the co-SMAD Medea, homologous to SMAD4, or the r-SMAD, Smox, corrected both heart and muscle dysfunction in Sgcd mutants. Reduction in the r-SMAD, MAD, restored muscle function but interestingly not heart function in Sgcd mutants, consistent with a role for activin but not bone morphogenic protein signaling in cardiac dysfunction. Mammalian sarcoglycan null muscle was also found to exhibit exercise-induced SMAD signaling. These data demonstrate that hyperactivation of SMAD signaling occurs in response to repetitive injury in muscle and heart. Reduction of this pathway is sufficient to restore cardiac and muscle function and is therefore a target for therapeutic reduction.
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http://dx.doi.org/10.1093/hmg/ddq528DOI Listing
March 2011

Mechanisms of muscle weakness in muscular dystrophy.

J Gen Physiol 2010 Jul;136(1):29-34

Department of Pathology and 2 Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.

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http://dx.doi.org/10.1085/jgp.201010436DOI Listing
July 2010
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