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Rabbit Model of Intra-Arterial Chemotherapy Toxicity Demonstrates Retinopathy and Vasculopathy Related to Drug and Dose, Not Procedure or Approach.
Daniels AB, Froehler MT, Nunnally AH, Pierce JM, Bozic I, Stone CA, Santapuram PR, Tao YK, Boyd KL, Himmel LE, Chen SC, Du L, Friedman DL, Richmond A
(2019) Invest Ophthalmol Vis Sci 60: 954-964
MeSH Terms: Animals, Antineoplastic Agents, Antineoplastic Agents, Alkylating, Carboplatin, Dose-Response Relationship, Drug, Electroretinography, Female, Fluorescein Angiography, Humans, Infant, Infusions, Intra-Arterial, Male, Melphalan, Models, Animal, Ophthalmic Artery, Rabbits, Retina, Retinal Diseases, Retinal Neoplasms, Retinal Vessels, Retinoblastoma, Retrospective Studies, Tomography, Optical Coherence
Show Abstract · Added July 29, 2019
Purpose - To use our intra-arterial chemotherapy (IAC) rabbit model to assess the impact of IAC procedure, drug, dose, and choice of technique on ocular structure and function, to study the nature and etiology of IAC toxicity, and to compare to observations in patients.
Methods - Rabbits received IAC melphalan (0.4-0.8 mg/kg), carboplatin (25-50 mg), or saline, either by direct ophthalmic artery cannulation, or with a technique emulating nonocclusion. Ocular structure/function were assessed with examination, electroretinography (ERG), fundus photography, fluorescein angiography, optical coherence tomography (OCT), and OCT angiography, prior to and 5 to 6 weeks after IAC. Blood counts were obtained weekly. We reviewed our last 50 IAC treatments in patients for evidence of ocular or systemic complications.
Results - No toxicity was seen in the saline control group. With standard (0.4 mg/kg) melphalan, no vascular/microvascular abnormalities were seen with either technique. However, severe microvascular pruning and arteriolar occlusions were seen occasionally at 0.8 mg/kg doses. ERG reductions were dose-dependent. Histology showed melphalan dose-dependent degeneration in all retinal layers, restricted geographically to areas of greatest vascular density. Carboplatin caused massive edema of ocular/periocular structures. IAC patients experienced occasional periocular swelling/rash, and only rarely experienced retinopathy or vascular events/hemorrhage in eyes treated multiple times with triple (melphalan/carboplatin/topotecan) therapy. Transient neutropenia occurred after 46% of IAC procedures, generally after triple therapy.
Conclusions - IAC toxicity appears to be related to the specific drug being used and is dose-dependent, rather than related to the IAC procedure itself or the specific technique selected. These rabbit findings are corroborated by our clinical findings in patients.
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23 MeSH Terms
High frequency of shared clonotypes in human B cell receptor repertoires.
Soto C, Bombardi RG, Branchizio A, Kose N, Matta P, Sevy AM, Sinkovits RS, Gilchuk P, Finn JA, Crowe JE
(2019) Nature 566: 398-402
MeSH Terms: Adult, Amino Acid Sequence, Antibodies, Antigens, B-Lymphocytes, Base Sequence, Clone Cells, Female, Fetal Blood, Healthy Volunteers, Humans, Infant, Newborn, Male, Receptors, Antigen, B-Cell, Sequence Analysis, DNA
Show Abstract · Added March 31, 2019
The human genome contains approximately 20 thousand protein-coding genes, but the size of the collection of antigen receptors of the adaptive immune system that is generated by the recombination of gene segments with non-templated junctional additions (on B cells) is unknown-although it is certainly orders of magnitude larger. It has not been established whether individuals possess unique (or private) repertoires or substantial components of shared (or public) repertoires. Here we sequence recombined and expressed B cell receptor genes in several individuals to determine the size of their B cell receptor repertoires, and the extent to which these are shared between individuals. Our experiments revealed that the circulating repertoire of each individual contained between 9 and 17 million B cell clonotypes. The three individuals that we studied shared many clonotypes, including between 1 and 6% of B cell heavy-chain clonotypes shared between two subjects (0.3% of clonotypes shared by all three) and 20 to 34% of λ or κ light chains shared between two subjects (16 or 22% of λ or κ light chains, respectively, were shared by all three). Some of the B cell clonotypes had thousands of clones, or somatic variants, within the clonotype lineage. Although some of these shared lineages might be driven by exposure to common antigens, previous exposure to foreign antigens was not the only force that shaped the shared repertoires, as we also identified shared clonotypes in umbilical cord blood samples and all adult repertoires. The unexpectedly high prevalence of shared clonotypes in B cell repertoires, and identification of the sequences of these shared clonotypes, should enable better understanding of the role of B cell immune repertoires in health and disease.
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15 MeSH Terms
Molecular and mechanical factors contributing to ductus arteriosus patency and closure.
Crockett SL, Berger CD, Shelton EL, Reese J
(2019) Congenit Heart Dis 14: 15-20
MeSH Terms: Cardiac Surgical Procedures, Ductus Arteriosus, Ductus Arteriosus, Patent, Hemodynamics, Humans, Infant, Newborn, Oxidative Stress
Show Abstract · Added November 26, 2018
Regulation of the ductus arteriosus, an essential fetal vessel connecting the pulmonary artery and aorta, is complex. Failure of this vessel to close after birth may result in a persistent left-to-right shunt through the patent ductus arteriosus, a condition associated with significant morbidities. Numerous factors contribute to the shift from fetal ductus patency to postnatal closure, requiring precise coordination of molecular cues with biomechanical forces and underlying genetic influences. Despite significant advances, questions remain regarding signaling dynamics and the natural time course of ductus closure, particularly in preterm neonates. This review highlights the contributions of early investigators and more recent clinician scientists to our understanding of the molecular and mechanical factors that mediate ductus patency and closure.
© 2019 Wiley Periodicals, Inc.
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7 MeSH Terms
Distinct mucosal microbial communities in infants with surgical necrotizing enterocolitis correlate with age and antibiotic exposure.
Romano-Keeler J, Shilts MH, Tovchigrechko A, Wang C, Brucker RM, Moore DJ, Fonnesbeck C, Meng S, Correa H, Lovvorn HN, Tang YW, Hooper L, Bordenstein SR, Das SR, Weitkamp JH
(2018) PLoS One 13: e0206366
MeSH Terms: Age Factors, Anti-Bacterial Agents, Biodiversity, Enterocolitis, Necrotizing, Female, Humans, Infant, Infant, Newborn, Intestinal Mucosa, Male, Microbiota, Pregnancy
Show Abstract · Added October 27, 2018
OBJECTIVE - Necrotizing enterocolitis (NEC) is the most common surgical emergency in preterm infants, and pathogenesis associates with changes in the fecal microbiome. As fecal samples incompletely represent microbial communities in intestinal mucosa, we sought to determine the NEC tissue-specific microbiome and assess its contribution to pathogenesis.
DESIGN - We amplified and sequenced the V1-V3 hypervariable region of the bacterial 16S rRNA gene extracted from intestinal tissue and corresponding fecal samples from 12 surgical patients with NEC and 14 surgical patients without NEC. Low quality and non-bacterial sequences were removed, and taxonomic assignment was made with the Ribosomal Database Project. Operational taxonomic units were clustered at 97%. We tested for differences between NEC and non-NEC samples in microbiome alpha- and beta-diversity and differential abundance of specific taxa between NEC and non-NEC samples. Additional analyses were performed to assess the contribution of other demographic and environmental confounding factors on the infant tissue and fecal microbiome.
RESULTS - The fecal and tissue microbial communities were different. NEC was associated with a distinct microbiome, which was characterized by low diversity, higher abundances of Staphylococcus and Clostridium_sensu_stricto, and lower abundances of Actinomyces and Corynebacterium. Infant age and vancomycin exposure correlated with shifts in the tissue microbiome.
CONCLUSION - The observed low diversity in NEC tissues suggests that NEC is associated with a bacterial bloom and a distinct mucosal bacterial community. The exact bacterial species that constitute the bloom varied by infant and were strongly influenced by age and exposure to vancomycin.
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12 MeSH Terms
Cutting Edge: IL-1α and Not IL-1β Drives IL-1R1-Dependent Neonatal Murine Sepsis Lethality.
Benjamin JT, Moore DJ, Bennett C, van der Meer R, Royce A, Loveland R, Wynn JL
(2018) J Immunol 201: 2873-2878
MeSH Terms: Animals, Animals, Newborn, Female, Humans, Infant, Newborn, Inflammation, Interleukin-1alpha, Interleukin-1beta, Male, Mice, Mice, Inbred C57BL, Receptors, Interleukin-1 Type I, Sepsis, Signal Transduction
Show Abstract · Added October 12, 2018
Sepsis disproportionately affects the very old and the very young. IL-1 signaling is important in innate host defense but may also play a deleterious role in acute inflammatory conditions (including sepsis) by promulgating life-threatening inflammation. IL-1 signaling is mediated by two distinct ligands: IL-1α and IL-1β, both acting on a common receptor (IL-1R1). IL-1R1 targeting has not reduced adult human sepsis mortality despite biologic plausibility. Because the specific role of IL-1α or IL-1β in sepsis survival is unknown in any age group and the role of IL-1 signaling remains unknown in neonates, we studied the role of IL-1 signaling, including the impact of IL-1α and IL-1β, on neonatal murine sepsis survival. IL-1 signaling augments the late plasma inflammatory response to sepsis. IL-1α and not IL-1β is the critical mediator of sepsis mortality, likely because of paracrine actions within the tissue. These data do not support targeting IL-1 signaling in neonates.
Copyright © 2018 by The American Association of Immunologists, Inc.
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14 MeSH Terms
Molecular and epidemiologic characterization of Wilms tumor from Baghdad, Iraq.
Phelps HM, Al-Jadiry MF, Corbitt NM, Pierce JM, Li B, Wei Q, Flores RR, Correa H, Uccini S, Frangoul H, Alsaadawi AR, Al-Badri SAF, Al-Darraji AF, Al-Saeed RM, Al-Hadad SA, Lovvorn Iii HN
(2018) World J Pediatr 14: 585-593
MeSH Terms: Adaptor Proteins, Signal Transducing, Child, Preschool, DNA Topoisomerases, Type II, Female, Homeodomain Proteins, Humans, Immunohistochemistry, Infant, Insulin-Like Growth Factor II, Iraq, Kidney Neoplasms, Male, Multiplex Polymerase Chain Reaction, Mutation, N-Myc Proto-Oncogene Protein, Nerve Tissue Proteins, Neural Cell Adhesion Molecules, Nuclear Proteins, Poly-ADP-Ribose Binding Proteins, Receptors, Retinoic Acid, Sequence Analysis, DNA, Transcription Factors, Tumor Suppressor Protein p53, Tumor Suppressor Proteins, WT1 Proteins, Wilms Tumor, beta Catenin
Show Abstract · Added January 28, 2019
BACKGROUND - Wilms tumor (WT) is the most common childhood kidney cancer worldwide, yet its incidence and clinical behavior vary according to race and access to adequate healthcare resources. To guide and streamline therapy in the war-torn and resource-constrained city of Baghdad, Iraq, we conducted a first-ever molecular analysis of 20 WT specimens to characterize the biological features of this lethal disease within this challenged population.
METHODS - Next-generation sequencing of ten target genes associated with WT development and treatment resistance (WT1, CTNNB1, WTX, IGF2, CITED1, SIX2, p53, N-MYC, CRABP2, and TOP2A) was completed. Immunohistochemistry was performed for 6 marker proteins of WT (WT1, CTNNB1, NCAM, CITED1, SIX2, and p53). Patient outcomes were compiled.
RESULTS - Mutations were detected in previously described WT "hot spots" (e.g., WT1 and CTNNB1) as well as novel loci that may be unique to the Iraqi population. Immunohistochemistry showed expression domains most typical of blastemal-predominant WT. Remarkably, despite the challenges facing families and care providers, only one child, with combined WT1 and CTNNB1 mutations, was confirmed dead from disease. Median clinical follow-up was 40.5 months (range 6-78 months).
CONCLUSIONS - These data suggest that WT biology within a population of Iraqi children manifests features both similar to and unique from disease variants in other regions of the world. These observations will help to risk stratify WT patients living in this difficult environment to more or less intensive therapies and to focus treatment on cell-specific targets.
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27 MeSH Terms
A Type 1 Diabetes Genetic Risk Score Predicts Progression of Islet Autoimmunity and Development of Type 1 Diabetes in Individuals at Risk.
Redondo MJ, Geyer S, Steck AK, Sharp S, Wentworth JM, Weedon MN, Antinozzi P, Sosenko J, Atkinson M, Pugliese A, Oram RA, Type 1 Diabetes TrialNet Study Group
(2018) Diabetes Care 41: 1887-1894
MeSH Terms: Adolescent, Adult, Autoantibodies, Autoimmunity, Child, Child, Preschool, Diabetes Complications, Diabetes Mellitus, Type 1, Disease Progression, Female, Genetic Predisposition to Disease, Genotype, HLA-DQ Antigens, Humans, Infant, Islets of Langerhans, Male, Middle Aged, Polymorphism, Single Nucleotide, Prognosis, Risk Factors, Young Adult
Show Abstract · Added July 23, 2018
OBJECTIVE - We tested the ability of a type 1 diabetes (T1D) genetic risk score (GRS) to predict progression of islet autoimmunity and T1D in at-risk individuals.
RESEARCH DESIGN AND METHODS - We studied the 1,244 TrialNet Pathway to Prevention study participants (T1D patients' relatives without diabetes and with one or more positive autoantibodies) who were genotyped with Illumina ImmunoChip (median [range] age at initial autoantibody determination 11.1 years [1.2-51.8], 48% male, 80.5% non-Hispanic white, median follow-up 5.4 years). Of 291 participants with a single positive autoantibody at screening, 157 converted to multiple autoantibody positivity and 55 developed diabetes. Of 953 participants with multiple positive autoantibodies at screening, 419 developed diabetes. We calculated the T1D GRS from 30 T1D-associated single nucleotide polymorphisms. We used multivariable Cox regression models, time-dependent receiver operating characteristic curves, and area under the curve (AUC) measures to evaluate prognostic utility of T1D GRS, age, sex, Diabetes Prevention Trial-Type 1 (DPT-1) Risk Score, positive autoantibody number or type, HLA DR3/DR4-DQ8 status, and race/ethnicity. We used recursive partitioning analyses to identify cut points in continuous variables.
RESULTS - Higher T1D GRS significantly increased the rate of progression to T1D adjusting for DPT-1 Risk Score, age, number of positive autoantibodies, sex, and ethnicity (hazard ratio [HR] 1.29 for a 0.05 increase, 95% CI 1.06-1.6; = 0.011). Progression to T1D was best predicted by a combined model with GRS, number of positive autoantibodies, DPT-1 Risk Score, and age (7-year time-integrated AUC = 0.79, 5-year AUC = 0.73). Higher GRS was significantly associated with increased progression rate from single to multiple positive autoantibodies after adjusting for age, autoantibody type, ethnicity, and sex (HR 2.27 for GRS >0.295, 95% CI 1.47-3.51; = 0.0002).
CONCLUSIONS - The T1D GRS independently predicts progression to T1D and improves prediction along T1D stages in autoantibody-positive relatives.
© 2018 by the American Diabetes Association.
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22 MeSH Terms
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
Towards a greater understanding of the ductus arteriosus.
Reese J
(2018) Semin Perinatol 42: 199-202
MeSH Terms: Cardiovascular Surgical Procedures, Ductus Arteriosus, Ductus Arteriosus, Patent, History, 15th Century, History, 20th Century, History, Ancient, Humans, Infant, Newborn, Infant, Premature, Perinatology
Added November 26, 2018
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10 MeSH Terms
Improving the value of care for appendectomy through an individual surgeon-specific approach.
Robinson JR, Carter NH, Gibson C, Brinkman AS, Van Arendonk K, Speck KE, Danko ME, Jackson GP, Lovvorn HN, Blakely ML
(2018) J Pediatr Surg 53: 1181-1186
MeSH Terms: Adolescent, Appendectomy, Appendicitis, Child, Child, Preschool, Cost-Benefit Analysis, Female, Hospital Costs, Humans, Infant, Infant, Newborn, Laparoscopy, Male, Operating Rooms, Prospective Studies, Quality of Health Care, Surgeons, Tennessee, Treatment Outcome
Show Abstract · Added June 27, 2018
PURPOSE - Standardized care via a unified surgeon preference card for pediatric appendectomy can result in significant cost reduction. The purpose of this study was to evaluate the impact of cost and outcome feedback to surgeons on value of care in an environment reluctant to adopt a standardized surgeon preference card.
METHODS - Prospective observational study comparing operating room (OR) supply costs and patient outcomes for appendectomy in children with 6-month observation periods both before and after intervention. The intervention was real-time feedback of OR supply cost data to individual surgeons via automated dashboards and monthly reports.
RESULTS - Two hundred sixteen children underwent laparoscopic appendectomy for non-perforated appendicitis (110 pre-intervention and 106 post-intervention). Median supply cost significantly decreased after intervention: $884 (IQR $705-$1025) to $388 (IQR $182-$776), p<0.001. No significant change was detected in median OR duration (47min [IQR 36-63] to 50min [IQR 38-64], p=0.520) or adverse events (1 [0.9%] to 6 [4.7%], p=0.062). OR supply costs for individual surgeons significantly decreased during the intervention period for 6 of 8 surgeons (87.5%).
CONCLUSION - Approaching value measurement with a surgeon-specific (rather than group-wide) approach can reduce OR supply costs while maintaining excellent clinical outcomes.
LEVEL OF EVIDENCE - Level II.
Copyright © 2018 Elsevier Inc. All rights reserved.
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19 MeSH Terms