97 results on '"Green TD"'
Search Results
2. A MARCKS-Related Peptide Inhibits Migration of Murine Macrophages.
- Author
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Green, TD, primary, Park, J, additional, Jones, SL, additional, and Adler, KB, additional
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- 2009
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3. Safe administration of the seasonal trivalent influenza vaccine to children with severe egg allergy.
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Greenhawt MJ, Spergel JM, Rank MA, Green TD, Masnoor D, Sharma H, Bird JA, Chang JE, Sinh D, Teich E, Kelso JM, and Sanders GM
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- 2012
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4. Community opinions regarding oral immunotherapy for food allergies.
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Traister RS, Green TD, Mitchell L, Greenhawt M, Traister, Russell S, Green, Todd D, Mitchell, Lynda, and Greenhawt, Matthew
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- 2012
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5. Physiologic demands of prolonged cardiopulmonary resuscitation performance by physically conditioned patients with cardiac disease.
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Smith DL, Misner JE, Dunn DS, and Green TD
- Published
- 1992
6. Empathy, understanding, and objectivity need to prevail for students with food allergies.
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Greenhawt MJ, Green TD, Pistiner M, and Mitchell L
- Published
- 2011
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7. Statistical methods for discrimination of STR genotypes using high resolution melt curve data.
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Cloudy DC, Boone EL, Kuehnert K, Smith C, Cox JO, Seashols-Williams SJ, and Green TD
- Abstract
Despite the improvements in forensic DNA quantification methods that allow for the early detection of low template/challenged DNA samples, complicating stochastic effects are not revealed until the final stage of the DNA analysis workflow. An assay that would provide genotyping information at the earlier stage of quantification would allow examiners to make critical adjustments prior to STR amplification allowing for potentially exclusionary information to be immediately reported. Specifically, qPCR instruments often have dissociation curve and/or high-resolution melt curve (HRM) capabilities; this, coupled with statistical prediction analysis, could provide additional information regarding STR genotypes present. Thus, this study aimed to evaluate Qiagen's principal component analysis (PCA)-based ScreenClust
® HRM® software and a linear discriminant analysis (LDA)-based technique for their abilities to accurately predict genotypes and similar groups of genotypes from HRM data. Melt curves from single source samples were generated from STR D5S818 and D18S51 amplicons using a Rotor-Gene® Q qPCR instrument and EvaGreen® intercalating dye. When used to predict D5S818 genotypes for unknown samples, LDA analysis outperformed the PCA-based method whether predictions were for individual genotypes (58.92% accuracy) or for geno-groups (81.00% accuracy). However, when a locus with increased heterogeneity was tested (D18S51), PCA-based prediction accuracy rates improved to rates similar to those obtained using LDA (45.10% and 63.46%, respectively). This study provides foundational data documenting the performance of prediction modeling for STR genotyping based on qPCR-HRM data. In order to expand the forensic applicability of this HRM assay, the method could be tested with a more commonly utilized qPCR platform., (© 2024. The Author(s).)- Published
- 2024
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8. Mitochondria inside acute myeloid leukemia cells hydrolyze ATP to resist chemotherapy.
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Hagen JT, Montgomery MM, Aruleba RT, Chrest BR, Green TD, Kassai M, Zeczycki TN, Schmidt CA, Bhowmick D, Tan SF, Feith DJ, Chalfant CE, Loughran TP Jr, Liles D, Minden MD, Schimmer AD, Cabot MC, Mclung JM, and Fisher-Wellman KH
- Abstract
Despite early optimism, therapeutics targeting oxidative phosphorylation (OxPhos) have faced clinical setbacks, stemming from their inability to distinguish healthy from cancerous mitochondria. Herein, we describe an actionable bioenergetic mechanism unique to cancerous mitochondria inside acute myeloid leukemia (AML) cells. Unlike healthy cells which couple respiration to the synthesis of ATP, AML mitochondria were discovered to support inner membrane polarization by consuming ATP. Because matrix ATP consumption allows cells to survive bioenergetic stress, we hypothesized that AML cells may resist cell death induced by OxPhos damaging chemotherapy by reversing the ATP synthase reaction. In support of this, targeted inhibition of BCL-2 with venetoclax abolished OxPhos flux without impacting mitochondrial membrane potential. In surviving AML cells, sustained polarization of the mitochondrial inner membrane was dependent on matrix ATP consumption. Mitochondrial ATP consumption was further enhanced in AML cells made refractory to venetoclax, consequential to downregulations in both the proton-pumping respiratory complexes, as well as the endogenous F
1 -ATPase inhibitor ATP5IF1 . In treatment-naive AML, ATP5IF1 knockdown was sufficient to drive venetoclax resistance, while ATP5IF1 overexpression impaired F1 -ATPase activity and heightened sensitivity to venetoclax. Collectively, our data identify matrix ATP consumption as a cancer-cell intrinsic bioenergetic vulnerability actionable in the context of mitochondrial damaging chemotherapy., Competing Interests: Conflicts of Interest ADS has received research funding from Takeda Pharmaceuticals and BMS, and consulting fees/honorarium from Takeda, Astra Zeneca, BMS and Novartis. ADS is named on a patent application for the use of DNT cells to treat AML. ADS is a member of the Medical and Scientific Advisory Board of the Leukemia and Lymphoma Society of Canada and the Therapy Acceleration Program for the Leukemia and Lymphoma Society. TPL has received Scientific Advisory Board membership, consultancy fees, honoraria, and/or stock options from Keystone Nano, Flagship Labs 86, Dren Bio, Recludix Pharma, Kymera Therapeutics, and Prime Genomics. DJF has received research funding, honoraria, and/or stock options from AstraZeneca, Dren Bio, Recludix Pharma, and Kymera Therapeutics.- Published
- 2024
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9. Varying Doses of Epicutaneous Immunotherapy With Viaskin Milk vs Placebo in Children With Cow's Milk Allergy: A Randomized Clinical Trial.
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Petroni D, Bégin P, Bird JA, Brown-Whitehorn T, Chong HJ, Fleischer DM, Gagnon R, Jones SM, Leonard S, Makhija MM, Oriel RC, Shreffler WG, Sindher SB, Sussman GL, Yang WH, Bee KJ, Bois T, Campbell DE, Green TD, Rutault K, Sampson HA, and Wood RA
- Subjects
- Animals, Cattle, Child, Child, Preschool, Female, Humans, Infant, Male, Allergens, Immunoglobulin E, Immunotherapy, Milk Proteins, Anaphylaxis, Milk Hypersensitivity therapy
- Abstract
Importance: No approved treatment exists for allergen-specific immunoglobulin E (IgE)-mediated cow's milk allergy (CMA), a common childhood food allergy., Objective: To assess dose, efficacy, and safety of epicutaneous immunotherapy with Viaskin milk in children with IgE-mediated CMA., Design, Setting, and Participants: A phase 1/2, 2-part, randomized, double-blind, placebo-controlled dose-ranging clinical trial in children aged 2 to 17 years with IgE-mediated CMA was conducted between November 2014 through December 2017. It took place at 17 trial sites in the US and Canada. Current CMA was confirmed by double-blind, placebo-controlled food challenge at study entry. Part A assessed the short-term safety of 150 μg, 300 μg, or 500 μg of Viaskin milk; part B evaluated the efficacy and safety of the 3 doses vs placebo over 12 months of treatment. Of the 308 screened participants with physician-diagnosed CMA, 198 met eligibility criteria (including an eliciting dose 300 mg or less) and were randomized., Intervention: Safety of Viaskin milk (150-μg, 300-μg, or 500-μg doses) was evaluated over a 3-week period (part A). In part B, 180 additional participants were randomized to receive Viaskin milk at doses of 150 μg, 300 μg, or 500 μg or placebo (1:1:1:1) for 12 months., Main Outcomes and Measures: The primary outcome was the proportion of treatment responders, defined as a 10-fold or more increase in the cumulative reactive dose of cow's milk protein (reaching at least 144 mg) or a cumulative reactive dose of cow's milk protein at 1444 mg or more at the month 12 double-blind, placebo-controlled food challenge., Results: A total of 95.5% of the randomized participants (mean [SD] age, 8 [4.17] years; 124 of 198 were male [62.6%]) completed treatment. The highest response rate was observed in participants who received Viaskin milk at the 300-μg dose with 24 of 49 responders (49.0%) overall vs 16 of 53 responders (30.2%) in the placebo group (odds ratio, 2.19; 95% CI, 0.91-5.41; P = .09), highest in the 2 to 11 years age group (22 of 38 [57.9%] vs 13 of 40 [32.5%]; P = .04). Most treatment-emergent adverse events were mild or moderate application-site reactions. One participant in the 500-μg Viaskin milk dose group experienced treatment-related anaphylaxis., Conclusions and Relevance: In this randomized clinical trial, 12 months of daily epicutaneous immunotherapy with a dose of Viaskin milk at 300 μg was associated with a statistically significant treatment response in 2- to 11-year-old children with IgE-mediated CMA. Treatment-related anaphylaxis and treatment-related discontinuation rates were low. Further research is needed to explore Viaskin milk as a viable treatment option for children with IgE-mediated CMA., Trial Registration: ClinicalTrials.gov Identifier: NCT02223182.
- Published
- 2024
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10. scPerturb: harmonized single-cell perturbation data.
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Peidli S, Green TD, Shen C, Gross T, Min J, Garda S, Yuan B, Schumacher LJ, Taylor-King JP, Marks DS, Luna A, Blüthgen N, and Sander C
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- Gene Expression Profiling methods, Epigenomics, Single-Cell Analysis, Software, Proteomics
- Abstract
Analysis across a growing number of single-cell perturbation datasets is hampered by poor data interoperability. To facilitate development and benchmarking of computational methods, we collect a set of 44 publicly available single-cell perturbation-response datasets with molecular readouts, including transcriptomics, proteomics and epigenomics. We apply uniform quality control pipelines and harmonize feature annotations. The resulting information resource, scPerturb, enables development and testing of computational methods, and facilitates comparison and integration across datasets. We describe energy statistics (E-statistics) for quantification of perturbation effects and significance testing, and demonstrate E-distance as a general distance measure between sets of single-cell expression profiles. We illustrate the application of E-statistics for quantifying similarity and efficacy of perturbations. The perturbation-response datasets and E-statistics computation software are publicly available at scperturb.org. This work provides an information resource for researchers working with single-cell perturbation data and recommendations for experimental design, including optimal cell counts and read depth., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)
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- 2024
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11. Droplet-based optical trapping for cell separation in mock forensic samples.
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Valle M, O'Brien B, Green TD, Reiner JE, and Seashols-Williams S
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- Male, Female, Humans, Cell Separation methods, Spermatozoa, Epithelial Cells, Optical Tweezers, Semen
- Abstract
Optical tweezers have a wide range of uses for mechanical manipulation of objects in the microscopic range. This includes both living and static cells in a variety of biomedical and research applications. Single-focus optical tweezers, formed by focusing a laser beam through a high numerical aperture immersion objective, create a significant force, which enables controlled transport of a variety of different cell types and morphologies in three dimensions. Optical tweezers have been previously reported to capture and separate spermatozoa from a reconstituted simulated postcoital sample. We report herein the development of a simplified, more efficient cell transfer protocol that can separate and isolate both spermatozoa as well as leukocytes, with similar efficiencies as those previously reported. The new cell transfer method was used to separate sperm cells from a reconstituted mixture of spermatozoa and vaginal epithelial cells, with complete STR profiles developed from 50 cells with little evidence of contribution from the female contributor to the mixture. This modified protocol was then used to separate 21 samples of enriched leukocytes, with trapped cells ranging from 5 to 22 cells. Complete STR profiles were developed from as few as 10 leukocytes. Thus, with minimal sample preparation and a short trapping time, this method has the potential to provide an alternative to traditional differential extraction methods for separation of sperm:nonsperm mixtures while also providing versatility for separation of cells with differing morphologies., (© 2023 The Authors. Journal of Forensic Sciences published by Wiley Periodicals LLC on behalf of American Academy of Forensic Sciences.)
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- 2024
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12. Alternative direct-to-amplification cell lysis techniques for forensically relevant non-sperm cells.
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Arya R, Hudson BC, and Green TD
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- Female, Male, Humans, Sodium Hydroxide, Polymerase Chain Reaction, Spermatozoa, Indicators and Reagents, DNA, Microsatellite Repeats, Semen, DNA Fingerprinting methods
- Abstract
While efforts have been made to reduce the pervasive backlog of sexual assault evidence collection kits, the actual laboratory process remains very time-consuming due to the requirement of a differential lysis step before DNA purification, as well as intricate mixture analysis towards the end of the DNA workflow. Recently, an alternative, direct-to-amplification sperm lysis method (using 1 M NaOH) was identified. However, a direct cell lysis method for non-sperm cells has not been identified yet. Thus, the primary objective of this work was to find an alternative method that is quick, inexpensive, and does not require multiple purification steps for the lysis of non-sperm cells in sexual assault samples. In this study, vaginal swab samples were lysed with the control method, prepGEM™, as well as six alternative reagents: alkaline buffer with 25-200 mM NaOH, high-salt stain extraction buffer, modified radioimmunoprecipitation assay (RIPA) buffer, mammalian protein extraction reagent (M-PER™), digitonin buffer, and urea/thiourea buffer. Quantification using Quantifiler® Trio of vaginal and semen lysates revealed that the alkaline (25 mM NaOH) and M-PER™ methods were efficient for the lysis of vaginal epithelial cells without substantial sperm cell lysis. Following quantification, analysis of STR profiles from vaginal lysates revealed that the M-PER™ method showed promising results across all metrics examined, including the percentage of detected STR alleles, mean peak heights, peak height ratio, and interlocus balance. Thus, this method was recommended as an alternative to the traditional differential lysis method for non-sperm cells given its ability to produce amplification-ready lysates without any DNA purification step., (© 2023 The Authors. Journal of Forensic Sciences published by Wiley Periodicals LLC on behalf of American Academy of Forensic Sciences.)
- Published
- 2023
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13. A quantifiler™ trio-based HRM screening assay for the accurate prediction of single source versus mixed biological samples.
- Author
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Torres D, Smith C, Williams AL, Cox JO, Seashols-Williams SJ, Boone EL, and Green TD
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- Humans, DNA Fingerprinting, DNA analysis
- Abstract
At present, the forensic DNA workflow is not capable of providing information about the contributor status (single source vs. multiple contributors) of evidentiary samples prior to end-point analysis. This exacerbates the challenges inherent to mixtures and low-template DNA samples. If additional sample information could be provided earlier in the workflow, protocols could be implemented to mitigate these challenges. An integrated Quantiplex®- high resolution melt (HRM) assay was shown to be effective in distinguishing between single source and mixture DNA samples; however, integration of the HRM assay into a more commonly used chemistry would be beneficial to the practitioner community. Thus, the assay was redesigned as an integrated Quantifiler™ Trio-HRM assay, which included the identification of a new DNA-binding dye, an increased reaction volume, and the establishment of new data analysis and standard curve metrics for all targets. This redesigned assay produced quantification values and qualitative values that were comparable to those produced when the same samples were tested using the standard Quantifiler™ Trio chemistry and settings. Further, STR profiles generated with quantification values produced from the integrated Quantifiler™ Trio-HRM assay and standard Quantifiler™ Trio chemistry were complete and fully concordant. Most importantly, the integrated Quantifiler™ Trio-HRM assay was able to accurately predict whether a sample was single source or a mixture 79.2% of the time, demonstrating the potential of this approach. With the incorporation of an expanded training set for prediction modeling, and completion of critical developmental validation studies, this assay could prove useful to the forensic DNA practitioner community., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
- Published
- 2023
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14. Immune response evolution in peanut epicutaneous immunotherapy for peanut-allergic children.
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Bastin M, Carr WW, Davis CM, Fleischer DM, Lieberman JA, Mustafa SS, Helleputte T, Bois T, Campbell DE, Green TD, and Greenhawt M
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- Humans, Child, Immunoglobulin E, Desensitization, Immunologic, Allergens, Double-Blind Method, Immunity, Arachis, Peanut Hypersensitivity therapy
- Abstract
Background: Epicutaneous immunotherapy with investigational Viaskin™ Peanut 250 μg (DBV712) has demonstrated statistically superior desensitization versus placebo in peanut-allergic children in clinical trials. It is unclear whether serologic biomarkers predict response., Methods: Serum-specific IgG4 and IgE (whole peanut and components) from subjects enrolled in the phase 3 Efficacy and Safety of Viaskin Peanut in Children With IgE-Mediated Peanut Allergy study were examined by exploratory univariate and multivariate analyses to determine trajectories and predictors of treatment response, based upon peanut protein eliciting dose (ED) at Month (M) 12 double-blind placebo-controlled food challenge., Results: Among Viaskin Peanut-treated subjects, peanut sIgG4 significantly increased from baseline through M12 and peanut sIgE peaked at M3 and fell below baseline by M12, with sIgG4 and sIgE peanut components mirroring these trajectories. Placebo subjects had no significant changes. By univariate analysis, M12 peanut sIgG4/sIgE was higher in treatment responders (p < 0.001) and had highest area under the curve (AUC) for predicting ED ≥300 mg and ≥1000 mg (AUC 69.5% and 69.9%, respectively). M12 peanut sIgG4/sIgE >20.1 predicted M12 ED ≥300 mg (80% positive predictive value). The best performing component was Ara h 1 sIgE <15.7 kU
A /L (AUC 66.5%). A multivariate model combining Ara h 1 and peanut sIgG4/sIgE had an AUC of 68.2% (ED ≥300 mg) and 67.8% (ED ≥1000 mg)., Conclusions: Peanut sIgG4 rise most clearly differentiated Viaskin Peanut versus placebo subjects. sIgG4/sIgE ratios >20.1 and the combination of Ara h 1 and peanut sIgG4/sIgE had moderate ability to predict treatment response and could potentially be useful for clinical monitoring. Additional data are needed to confirm these relationships., (© 2023 DBV Technologies S.A. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)- Published
- 2023
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15. The Evolution from Superatom- to Plasmon-Mediated Magnetic Circular Dichroism in Colloidal Metal Nanoparticles Spanning the Nonmetallic to Metallic Limits.
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Foxley J, Green TD, Tofanelli MA, Ackerson CJ, and Knappenberger KL Jr
- Abstract
The magneto-optical absorption properties of colloidal metal nanoclusters spanning nonmetallic to metallic regimes were examined using variable-temperature variable-field magnetic circular dichroism (VTVH-MCD) spectroscopy. Charge neutral Au
25 (SC8 H9 )18 exhibited MCD spectra dominated by Faraday C-terms, consistent with expectations for a nonmetallic paramagnetic nanocluster. This response is reconciled by the open-shell superatom configuration of Au25 (SC8 H9 )18 . Metallic and plasmon-supporting Au459 (pMBA)170 exhibited temperature-independent VTVH-MCD spectra dominated by Faraday A-terms. Au144 (SC8 H9 )60 , which is intermediate to the metallic and nonmetallic limits, showed the most complex VTVH-MCD response of the three nanoclusters, consisting of 19 distinguishable peaks spanning the visible and near-infrared (3.0-1.4 eV). Variable-temperature analysis suggested that none of these transitions originated from plasmon excitation. However, evidence for both paramagnetic and mixed (i.e., nondiscrete) transitions of Au144 (SC8 H9 )60 was observed. These results highlight the complexity of gold nanocluster electronic transitions that emerge as sizes approach metallic length scales. Nanoclusters in this regime may provide opportunities for tailoring the magneto-optical properties of colloidal nanostructures.- Published
- 2023
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16. Phase 3 Trial of Epicutaneous Immunotherapy in Toddlers with Peanut Allergy.
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Greenhawt M, Sindher SB, Wang J, O'Sullivan M, du Toit G, Kim EH, Albright D, Anvari S, Arends N, Arkwright PD, Bégin P, Blumchen K, Bourrier T, Brown-Whitehorn T, Cassell H, Chan ES, Ciaccio CE, Deschildre A, Divaret-Chauveau A, Dorris SL, Dorsey MJ, Eiwegger T, Erlewyn-Lajeunesse M, Fleischer DM, Ford LS, Garcia-Lloret M, Giovannini-Chami L, Hourihane JO, Jay N, Jones SM, Kerns LA, Kloepfer KM, Leonard S, Lezmi G, Lieberman JA, Lomas J, Makhija M, Parrish C, Peake J, Perrett KP, Petroni D, Pfützner W, Pongracic JA, Quinn P, Robison RG, Sanders G, Schneider L, Sharma HP, Trujillo J, Turner PJ, Tuttle K, Upton JE, Varshney P, Vickery BP, Vogelberg C, Wainstein B, Wood RA, Bee KJ, Campbell DE, Green TD, Rouissi R, Peillon A, Bahnson HT, Bois T, Sampson HA, and Burks AW
- Subjects
- Child, Preschool, Humans, Infant, Allergens adverse effects, Arachis adverse effects, Administration, Cutaneous, Anaphylaxis etiology, Desensitization, Immunologic adverse effects, Desensitization, Immunologic methods, Peanut Hypersensitivity complications, Peanut Hypersensitivity therapy
- Abstract
Background: No approved treatment for peanut allergy exists for children younger than 4 years of age, and the efficacy and safety of epicutaneous immunotherapy with a peanut patch in toddlers with peanut allergy are unknown., Methods: We conducted this phase 3, multicenter, double-blind, randomized, placebo-controlled trial involving children 1 to 3 years of age with peanut allergy confirmed by a double-blind, placebo-controlled food challenge. Patients who had an eliciting dose (the dose necessary to elicit an allergic reaction) of 300 mg or less of peanut protein were assigned in a 2:1 ratio to receive epicutaneous immunotherapy delivered by means of a peanut patch (intervention group) or to receive placebo administered daily for 12 months. The primary end point was a treatment response as measured by the eliciting dose of peanut protein at 12 months. Safety was assessed according to the occurrence of adverse events during the use of the peanut patch or placebo., Results: Of the 362 patients who underwent randomization, 84.8% completed the trial. The primary efficacy end point result was observed in 67.0% of children in the intervention group as compared with 33.5% of those in the placebo group (risk difference, 33.4 percentage points; 95% confidence interval, 22.4 to 44.5; P<0.001). Adverse events that occurred during the use of the intervention or placebo, irrespective of relatedness, were observed in 100% of the patients in the intervention group and 99.2% in the placebo group. Serious adverse events occurred in 8.6% of the patients in the intervention group and 2.5% of those in the placebo group; anaphylaxis occurred in 7.8% and 3.4%, respectively. Serious treatment-related adverse events occurred in 0.4% of patients in the intervention group and none in the placebo group. Treatment-related anaphylaxis occurred in 1.6% in the intervention group and none in the placebo group., Conclusions: In this trial involving children 1 to 3 years of age with peanut allergy, epicutaneous immunotherapy for 12 months was superior to placebo in desensitizing children to peanuts and increasing the peanut dose that triggered allergic symptoms. (Funded by DBV Technologies; EPITOPE ClinicalTrials.gov number, NCT03211247.)., (Copyright © 2023 Massachusetts Medical Society.)
- Published
- 2023
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17. A Qualitative Study to Inform Development of a Behavioral Intervention to Promote Food Allergy Self-Management and Adjustment among Early Adolescents.
- Author
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Herbert LJ, Cooke F, Ramos A, Miller E, Padgett S, and Green TD
- Abstract
Objective: Adolescence is a high-risk period for patients with food allergy (FA) as management responsibilities shift to the youth. This study used qualitative methods to explore FA experiences among a diverse pediatric FA population and inform behavioral intervention development., Methods: A total of 26 adolescents ages 9-14 years with IgE-mediated FA ( M age = 11.92 years; 62% male; 42% Black, 31% White, 12% Hispanic/Latinx) and 25 primary caregivers ( M age = 42.57 years; 32% annual income > $100,000) were recruited from FA clinics to complete separate qualitative interviews about FA-related experiences. Interviews were audio-recorded, transcribed, and entered into Dedoose, a qualitative software program. A grounded theory qualitative analytic approach was used to analyze data., Results: Emergent themes include: 1) FA is a chronic burden that affects daily life, 2) Families experience anxiety about FA, 3) Families find it challenging to transition FA management from parent to child, 4) FA families feel the need to be prepared, 5) FA families frequently advocate for their needs, and 6) Social experiences affect the FA experience., Conclusions: Adolescents with FA and their caregivers experience daily stress related to their chronic illness. A behavioral intervention that provides FA education, bolsters stress/anxiety management, assists parents in transitioning FA management responsibility to the youth, teaches executive functioning and advocacy skills, and fosters peer support could help adolescents successfully cope with and manage FA in their daily lives., Competing Interests: Conflicts of interest: The authors do not have any conflicts of interest.
- Published
- 2023
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18. The Impact of Allergy Specialty Care on Health Care Utilization Among Peanut Allergy Children in the United States.
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Greenhawt M, Abrams EM, Chalil JM, Tran O, Green TD, and Shaker MS
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- Child, United States epidemiology, Humans, Retrospective Studies, Epinephrine therapeutic use, Patient Acceptance of Health Care, Peanut Hypersensitivity epidemiology, Peanut Hypersensitivity therapy, Anaphylaxis epidemiology
- Abstract
Background: The influence of allergist management on peanut allergy (PA)-related health care utilization is unknown., Objective: To determine whether allergist care lowers PA costs., Methods: IBM MarketScan Commercial Claims and Encounters Database was analyzed for PA diagnosis/reaction-related codes (January 2010-June 2019) in patients 64 years or younger, with demographically matched non-PA food allergy controls (NPAFACs). Outcomes were measured and compared 12 months before/after first claim date., Results: Among 72,854 persons with PA (39,068 with ≥1 allergist visit, 53.6%), and 166,825 NPAFACs, the number of National Drug Codes and International Classification of Diseases, 10th Revision codes was higher for persons with PA with versus without an allergist visit during both baseline and follow-up (all P < .001). Persons with PA with versus without an allergist visit were prescribed epinephrine at significantly higher rates (RR, 1.67; P < .001). Rates of epinephrine claims, mean epinephrine costs, and proportion with peanut anaphylaxis were higher among the PA group with versus without an allergist visit (69.9% vs 63.3%; $676 vs $493, 48.9% vs 20.7%; all P < .001). The proportion with anaphylaxis episodes was higher in the PA group versus the NPAFAC group (53.1% vs 31.6%; P < .001). Total health care costs were higher in the NPAFAC group versus the PA group ($7863 vs $7261; P < .001) and lower for persons with PA with versus without an allergist visit ($6347 vs $8270; P < .001), with no significant differences in PA reaction-related costs between PA groups., Conclusions: Higher rates of anaphylaxis were seen among the PA group with versus without an allergist visit during the follow-up period (53.6% of overall PA group). Allergist care was associated with a reduction in total health care costs and higher rates of epinephrine prescription., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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19. Efficacy and safety of peanut epicutaneous immunotherapy in patients with atopic comorbidities.
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Davis CM, Lange L, Beyer K, Fleischer DM, Ford L, Sussman G, Oriel RC, Pongracic JA, Shreffler W, Bee KJ, Campbell DE, Green TD, Lambert R, Peillon A, and Bégin P
- Abstract
Background: Co-occurring atopic conditions are common in children with peanut allergy. As such, it is important to examine the safety and efficacy of epicutaneous immunotherapy with Viaskin Peanut 250 μg patch (VP250) in peanut-allergic children with these conditions., Objective: We sought to compare efficacy and safety of VP250 versus placebo in peanut-allergic children with/without ongoing atopic conditions at baseline, including asthma, atopic dermatitis/eczema, or concomitant food allergy., Methods: A subgroup analysis of peanut-allergic children aged 4 to 11 years enrolled in PEPITES (12 months) and REALISE (6 months) randomized, placebo-controlled, phase 3 trials was conducted. The efficacy outcome measure was the difference in prespecified responder rate between placebo and VP250 groups at month 12 based on eliciting dose of peanut protein using double-blind, placebo-controlled food challenge in PEPITES. Safety profiles were evaluated by baseline concomitant disease subgroup in all randomized subjects who received 1 or more dose of the study drug in PEPITES and REALISE pooled data., Results: Responder rates were significantly ( P < .05, all comparisons) greater with VP250 compared with placebo treatment regardless of whether subjects had other atopic conditions. Safety and tolerability profiles were generally similar across subgroups, with no new safety concerns detected. A trend for both higher responder rates and rates of local reactions was observed in subjects with baseline atopic dermatitis versus those without. In subjects with concomitant food allergy at baseline, higher rates of treatment-emergent adverse events, but not study discontinuations or overall rates of anaphylaxis, were observed., Conclusions: The results support the safety and efficacy of VP250 for treating peanut-allergic children with or without concomitant atopic conditions., (© 2022 The Authors.)
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- 2022
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20. Psychometric parameters of food allergy quality of life during an allergen immunotherapy trial.
- Author
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Lins de Holanda Coelho G, DunnGalvin A, Greenhawt M, Hourihane JO, Fleischer DM, Chen G, Shaker M, Campbell DE, Green TD, and Bégin P
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- Child, Desensitization, Immunologic adverse effects, Humans, Psychometrics, Quality of Life, Reproducibility of Results, Surveys and Questionnaires, Food Hypersensitivity therapy, Peanut Hypersensitivity
- Abstract
Background: The Food Allergy Quality of Life Questionnaire-Parent Form (FAQLQ-PF) is a commonly used patient-reported outcome measure in food allergy (FA) research. It was developed before FA treatment clinical trials were commonplace and is used as a secondary outcome measure in pivotal FA treatment trials. We examined the psychometric properties of the FAQLQ-PF and its relevance to children with peanut allergy engaged in an epicutaneous immunotherapy (EPIT) clinical trial., Methods: Analysis was performed on 26 universally answered items of the FAQLQ-PF, from assessments undertaken during the phase 3 PEPITES study (baseline, Month 12), which examined the safety and efficacy of EPIT for children with peanut allergy aged 4-11 years. Item response theory (IRT) was used to assess psychometric parameters of the FAQLQ-PF (i.e., discrimination, difficulty, and information). Confirmatory factor analysis was also employed; reliability was assessed using McDonald's omega (ω) and Cronbach's alpha (α)., Results: A total of 23 of 26 items presented very high discrimination levels (>1.7), and all 26 fell within the recommended difficulty threshold (between -1.5 and 1.5). The items contributed a reasonable information level for their respective factors/subdomains. The measure also presented a marginally acceptable model fit for the 3-factor structure (e.g., comparative fit index = 0.88, Tucker-Lewis index = 0.87) and good reliability levels across time points (ω and α > 0.90)., Conclusions: Herein, we present a novel reanalysis of the FAQLQ-PF items using IRT. The longitudinal performance of individual items and subscales was corroborated, and items with the highest discrimination were identified, showing that the tool is suitable for longitudinal measurements in FA treatment trials., (© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)
- Published
- 2022
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21. Safety of Epicutaneous Immunotherapy in Peanut-Allergic Children: REALISE Randomized Clinical Trial Results.
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Pongracic JA, Gagnon R, Sussman G, Siri D, Oriel RC, Brown-Whitehorn TF, Green TD, Campbell DE, Anvari S, Berger WE, Bird JA, Chan ES, Cheema A, Chinthrajah RS, Chong HJ, Dowling PJ, Fineman SM, Fleischer DM, Gonzalez-Reyes E, Kim EH, Lanser BJ, MacGinnitie A, Mehta H, Petroni D, Rupp N, Schneider LC, Scurlock AM, Sher LD, Shreffler WG, Sindher SB, Stillerman A, Wood R, Yang WH, Bois T, Sampson HA, and Bégin P
- Subjects
- Administration, Oral, Allergens therapeutic use, Arachis, Child, Desensitization, Immunologic methods, Humans, Immunologic Factors therapeutic use, Anaphylaxis etiology, Peanut Hypersensitivity drug therapy
- Abstract
Background: Treatment options for peanut allergy are limited. In previous clinical trials, epicutaneous immunotherapy with a patch containing 250-μg peanut protein (Viaskin Peanut 250 μg [VP250]) was well tolerated and statistically superior to placebo in desensitizing peanut-allergic children., Objective: To examine the safety of VP250 in children, using a study design approximating potential real-world use., Methods: REAL LIfe Use and Safety of EPIT (REALISE) is a phase 3 multicenter study consisting of a 6-month, randomized, double-blind, placebo-controlled period followed by open-label active treatment. Children aged 4 to 11 years with physician diagnosis of peanut allergy received daily treatment with placebo (6 months) or VP250 (up to 36 months). Data from the 6-month, randomized, controlled phase of REALISE are reported., Results: Three hundred ninety-three children were randomized 3:1 to receive VP250 (n = 294) or placebo (n = 99) for 6 months; 284 (72.3%) children had a history of peanut anaphylaxis. According to parent diary, all participants receiving VP250 and 83.8% receiving placebo reported at least 1 episode of local skin reaction, with frequency decreasing over time. Only 4 participants (1.4%) receiving VP250 discontinued because of adverse events (AEs). Epinephrine was administered for allergic reactions attributed to VP250 in 7 children (2.4%), of whom 5 remained in the study; none involved severe anaphylaxis. Overall, AE rates were similar among participants with and without a history of peanut anaphylaxis., Conclusions: In a study designed to mirror real-world use, VP250 was observed to be well tolerated in peanut-allergic children, consistent with previous phase 2b and 3 studies., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2022
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22. Peanut cross-contamination in randomly selected baked goods.
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Miller TA, Koppelman SJ, Bird JA, Hernandez-Trujillo V, Thyagarajan A, Mack D, Chalil JM, Green TD, and Baumert JL
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- Arachis, Enzyme-Linked Immunosorbent Assay, Humans, Nutrition Surveys, Food Hypersensitivity, Peanut Hypersensitivity epidemiology
- Abstract
Background: The current standard of care for managing peanut allergy includes avoidance of peanut and use of injectable epinephrine; however, strict avoidance is difficult and accidental ingestion is common with potentially serious consequences. Despite vigilance and efforts to minimize the risk of accidental exposure, peanut protein cross-contamination continues to occur in a variety of foods, including baked goods., Objective: To assess and quantify the presence of peanut protein contamination in certain baked goods., Methods: Randomly selected baked goods were collected from bakeries in the New York and Miami metropolitan areas that sold a variety of ethnic cuisines. A second set of samples from the same bakeries was collected at least 1 week after to evaluate between-batch variability. Samples were sent to the Food Allergy Research and Resource Program to analyze peanut contamination by enzyme-linked immunosorbent assay. Consumption estimates were based on 2003 to 2010 National Health and Nutrition Examination Survey survey data., Results: Of 154 samples from 18 bakeries, 4 (2.6%) had detectable peanut contamination with peanut protein levels ranging from 0.1 mg/100 g to 650 mg/100 g. Consumption estimates for single occasion ingestion of a contaminated item ranged from 0.07 mg to 832 mg of peanut protein., Conclusion: In this study, unintended peanut protein was present in a small, but not insignificant, proportion of baked goods, with the potential to trigger a reaction in individuals with peanut allergy. Some products contained high levels of unintended peanut protein. The current data support the potential for accidental exposure to peanut protein with its associated risk., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2022
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23. Interventional- and amputation-stage muscle proteomes in the chronically threatened ischemic limb.
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Ryan TE, Kim K, Scali ST, Berceli SA, Thome T, Salyers ZR, O'Malley KA, Green TD, Karnekar R, Fisher-Wellman KH, Yamaguchi DJ, and McClung JM
- Subjects
- Aged, Aged, 80 and over, Chronic Limb-Threatening Ischemia complications, Chronic Limb-Threatening Ischemia pathology, Cross-Sectional Studies, Extremities blood supply, Extremities innervation, Extremities physiopathology, Female, Florida, Humans, Male, Muscle, Skeletal drug effects, Muscle, Skeletal physiopathology, North Carolina, Proteome metabolism, Risk Factors, Chronic Limb-Threatening Ischemia physiopathology, Proteome pharmacology
- Abstract
Background: Despite improved surgical approaches for chronic limb-threatening ischemia (CLTI), amputation rates remain high and contributing tissue-level factors remain unknown. The purpose of this study was twofold: (1) to identify differences between the healthy adult and CLTI limb muscle proteome, and (2) to identify differences in the limb muscle proteome of CLTI patients prior to surgical intervention or at the time of amputation., Methods and Results: Gastrocnemius muscle was collected from non-ischemic controls (n = 19) and either pre-interventional surgery (n = 10) or at amputation outcome (n = 29) CLTI patients. All samples were subjected to isobaric tandem-mass-tag-assisted proteomics. The mitochondrion was the primary classification of downregulated proteins (> 70%) in CLTI limb muscles and paralleled robust functional mitochondrial impairment. Upregulated proteins (> 38%) were largely from the extracellular matrix. Across the two independent sites, 39 proteins were downregulated and 12 upregulated uniformly. Pre-interventional CLTI muscles revealed a robust upregulation of mitochondrial proteins but modest functional impairments in fatty acid oxidation as compared with controls. Comparison of pre-intervention and amputation CLTI limb muscles revealed mitochondrial proteome and functional deficits similar to that between amputation and non-ischemic controls. Interestingly, these observed changes occurred despite 62% of the amputation CLTI patients having undergone a prior surgical intervention., Conclusions: The CLTI proteome supports failing mitochondria as a phenotype that is unique to amputation outcomes. The signature of pre-intervention CLTI muscle reveals stable mitochondrial protein abundance that is insufficient to uniformly prevent functional impairments. Taken together, these findings support the need for future longitudinal investigations aimed to determine whether mitochondrial failure is causally involved in amputation outcomes from CLTI., (© 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)
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- 2022
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24. Reduction in peanut reaction severity during oral challenge after 12 months of epicutaneous immunotherapy.
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Bégin P, Bird JA, Spergel JM, Campbell DE, Green TD, Bee KJ, Lambert R, Sampson HA, and Fleischer DM
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- Administration, Oral, Allergens, Desensitization, Immunologic, Humans, Immunotherapy, Arachis adverse effects, Peanut Hypersensitivity therapy
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- 2021
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25. Predicted number of peanut-allergic patients needed to treat with epicutaneous immunotherapy (EPIT) to prevent one allergic reaction: A novel approach to assessing relevance.
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Remington BC, Koppelman SJ, Green TD, Lack G, Roberts G, and Campbell DE
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- Humans, Immunotherapy, Arachis, Peanut Hypersensitivity diagnosis, Peanut Hypersensitivity therapy
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- 2021
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26. Low lysophosphatidylcholine induces skeletal muscle myopathy that is aggravated by high-fat diet feeding.
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Ferrara PJ, Verkerke ARP, Maschek JA, Shahtout JL, Siripoksup P, Eshima H, Johnson JM, Petrocelli JJ, Mahmassani ZS, Green TD, McClung JM, Cox JE, Drummond MJ, and Funai K
- Subjects
- Animals, Female, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Muscle Contraction, Muscle, Skeletal drug effects, Muscular Diseases etiology, Muscular Diseases metabolism, 1-Acylglycerophosphocholine O-Acyltransferase physiology, Diet, High-Fat adverse effects, Lipidomics methods, Lysophosphatidylcholines toxicity, Muscle, Skeletal pathology, Muscular Diseases pathology, Obesity physiopathology
- Abstract
Obesity alters skeletal muscle lipidome and promotes myopathy, but it is unknown whether aberrant muscle lipidome contributes to the reduction in skeletal muscle contractile force-generating capacity. Comprehensive lipidomic analyses of mouse skeletal muscle revealed a very strong positive correlation between the abundance of lysophosphatidylcholine (lyso-PC), a class of lipids that is known to be downregulated with obesity, with maximal tetanic force production. The level of lyso-PC is regulated primarily by lyso-PC acyltransferase 3 (LPCAT3), which acylates lyso-PC to form phosphatidylcholine. Tamoxifen-inducible skeletal muscle-specific overexpression of LPCAT3 (LPCAT3-MKI) was sufficient to reduce muscle lyso-PC content in both standard chow diet- and high-fat diet (HFD)-fed conditions. Strikingly, the assessment of skeletal muscle force-generating capacity ex vivo revealed that muscles from LPCAT3-MKI mice were weaker regardless of diet. Defects in force production were more apparent in HFD-fed condition, where tetanic force production was 40% lower in muscles from LPCAT3-MKI compared to that of control mice. These observations were partly explained by reductions in the cross-sectional area in type IIa and IIx fibers, and signs of muscle edema in the absence of fibrosis. Future studies will pursue the mechanism by which LPCAT3 may alter protein turnover to promote myopathy., (© 2021 Federation of American Societies for Experimental Biology.)
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- 2021
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27. Racial differences in the limb skeletal muscle transcriptional programs of patients with critical limb ischemia.
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Terwilliger ZS, Ryan TE, Goldberg EJ, Schmidt CA, Yamaguchi DJ, Karnekar R, Brophy P, Green TD, Zeczycki TN, Mac Gabhann F, Annex BH, and McClung JM
- Subjects
- Adult, Amputation, Surgical, Critical Illness, Humans, Ischemia diagnosis, Ischemia genetics, Ischemia surgery, Limb Salvage, Muscle, Skeletal surgery, Race Factors, Risk Factors, Treatment Outcome, Chronic Limb-Threatening Ischemia, Peripheral Arterial Disease diagnosis, Peripheral Arterial Disease genetics, Peripheral Arterial Disease surgery
- Abstract
Critical limb ischemia (CLI) is the most severe manifestation of peripheral artery disease (PAD) and is characterized by high rates of morbidity and mortality. As with most severe cardiovascular disease manifestations, Black individuals disproportionately present with CLI. Accordingly, there remains a clear need to better understand the reasons for this discrepancy and to facilitate personalized therapeutic options specific for this population. Gastrocnemius muscle was obtained from White and Black healthy adult volunteers and patients with CLI for whole transcriptome shotgun sequencing (WTSS) and enrichment analysis was performed to identify alterations in specific Reactome pathways. When compared to their race-matched healthy controls, both White and Black patients with CLI demonstrated similar reductions in nuclear and mitochondrial encoded genes and mitochondrial oxygen consumption across multiple substrates, indicating a common bioenergetic paradigm associated with amputation outcomes regardless of race. Direct comparisons between tissues of White and Black patients with CLI revealed hemostasis, extracellular matrix organization, platelet regulation, and vascular wall interactions to be uniquely altered in limb muscles of Black individuals. Among traditional vascular growth factor signaling targets, WTSS revealed only Tie1 to be significantly altered from White levels in Black limb muscle tissues. Quantitative reverse transcription polymerase chain reaction validation of select identified targets verified WTSS directional changes and supports reductions in MMP9 and increases in NUDT4P1 and GRIK2 as unique to limb muscles of Black patients with CLI. This represents a critical first step in better understanding the transcriptional program similarities and differences between Black and White patients in the setting of amputations related to CLI and provides a promising start for therapeutic development in this population.
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- 2021
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28. Lysophospholipid acylation modulates plasma membrane lipid organization and insulin sensitivity in skeletal muscle.
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Ferrara PJ, Rong X, Maschek JA, Verkerke AR, Siripoksup P, Song H, Green TD, Krishnan KC, Johnson JM, Turk J, Houmard JA, Lusis AJ, Drummond MJ, McClung JM, Cox JE, Shaikh SR, Tontonoz P, Holland WL, and Funai K
- Subjects
- 1-Acylglycerophosphocholine O-Acyltransferase genetics, 1-Acylglycerophosphocholine O-Acyltransferase metabolism, Acylation, Animals, Cell Membrane genetics, Cell Membrane pathology, Cells, Cultured, Humans, Lysophospholipids genetics, Mice, Mice, Knockout, Muscle, Skeletal pathology, Phosphorylation genetics, Receptor, Insulin genetics, Receptor, Insulin metabolism, Cell Membrane metabolism, Insulin Resistance, Lipid Metabolism, Lysophospholipids metabolism, Muscle, Skeletal metabolism
- Abstract
Aberrant lipid metabolism promotes the development of skeletal muscle insulin resistance, but the exact identity of lipid-mediated mechanisms relevant to human obesity remains unclear. A comprehensive lipidomic analysis of primary myocytes from individuals who were insulin-sensitive and lean (LN) or insulin-resistant with obesity (OB) revealed several species of lysophospholipids (lyso-PLs) that were differentially abundant. These changes coincided with greater expression of lysophosphatidylcholine acyltransferase 3 (LPCAT3), an enzyme involved in phospholipid transacylation (Lands cycle). Strikingly, mice with skeletal muscle-specific knockout of LPCAT3 (LPCAT3-MKO) exhibited greater muscle lysophosphatidylcholine/phosphatidylcholine, concomitant with improved skeletal muscle insulin sensitivity. Conversely, skeletal muscle-specific overexpression of LPCAT3 (LPCAT3-MKI) promoted glucose intolerance. The absence of LPCAT3 reduced phospholipid packing of cellular membranes and increased plasma membrane lipid clustering, suggesting that LPCAT3 affects insulin receptor phosphorylation by modulating plasma membrane lipid organization. In conclusion, obesity accelerates the skeletal muscle Lands cycle, whose consequence might induce the disruption of plasma membrane organization that suppresses muscle insulin action.
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- 2021
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29. Post hoc analysis of epicutaneous immunotherapy for peanut allergy phase 3 results: Relevance for exposure through restaurant meals.
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Remington BC, Campbell DE, Green TD, Fleischer DM, and Koppelman SJ
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- Allergens, Arachis, Child, Child, Preschool, Double-Blind Method, Humans, Desensitization, Immunologic methods, Dietary Exposure, Peanut Hypersensitivity therapy, Restaurants
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- 2021
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30. Values of College Students in Iran and the United States Who Admire Celebrities.
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McCutcheon LE, Green TD, Besharat MA, Edman JL, Wenger JL, and Shabahang R
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- Female, Humans, Iran, Male, Psychometrics, United States, Universities, Young Adult, Attitude, Famous Persons, Students psychology
- Abstract
This study had two goals. The first goal was to compare scores on the Celebrity Attitude Scale (CAS) and values of college students in Iran and the United States on how they differ in their admiration for their favorite celebrities. The second goal was to examine additional psychometric data on the Twenty Item Values Inventory (TWIVI). We administered the TWIVI, the CAS, and demographic items to 200 students at a university in Iran, and 199 students at one university and two colleges in the United States. The results revealed that Iranian students scored about the same as American students on the CAS, and both samples scored higher per item on Celebrity Attitude Scale Entertainment-Social, the entertainment or social subscale as compared with the two more problematic subscales of the CAS. Stepwise multiple regressions showed that Hedonism and Power predicted total CAS scores for Americans and Tradition and Stimulation predicted total CAS scores for Iranians. We found that the TWIVI performed reasonably well given its brevity. That is, predictions stemming from Schwartz's values theory were generally confirmed in both samples by data obtained from the TWIVI.
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- 2021
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31. Improvements in Quality of Life in Children Following Epicutaneous Immunotherapy (EPIT) for Peanut Allergy in the PEPITES and PEOPLE Studies.
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DunnGalvin A, Fleischer DM, Campbell DE, O'B Hourihane J, Green TD, Sampson HA, and Greenhawt M
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- Allergens, Child, Desensitization, Immunologic, Follow-Up Studies, Humans, Immunotherapy, Quality of Life, Food Hypersensitivity, Peanut Hypersensitivity therapy
- Abstract
Background: Food allergy quality of life (FAQL) is impaired in children with peanut allergy. Food Allergy Quality of Life Questionnaires (FAQLQs) provide disease-specific insight into the burden of peanut allergy and potential FAQL changes after peanut immunotherapy., Objective: To examine FAQL changes in children after treatment with epicutaneous immunotherapy for peanut allergy (250 μg, daily epicutaneous peanut protein; DBV712 250 μg)., Methods: FAQL was prospectively measured using the FAQLQ parent proxy form (Food Allergy Quality of Life Questionnaire-Parent Proxy Form [FAQLQ-PF], for children aged ≤12 years) and child form (Food Allergy Quality of Life Questionnaire-Child Form [FAQLQ-CF], child rated if aged ≥8 years) during the 12-month double-blind, randomized, controlled Peanut EPIT Efficacy and Safety Study (PEPITES) trial and the initial 12 months of the open-label PEPITES Open Label Extension Study (PEOPLE) follow-up study. Data were analyzed for between-group differences after treatment unblinding., Results: FAQLQs from placebo participants (FAQLQ-PF: 96; FAQLQ-CF: 47) and treatment group participants (FAQLQ-PF: 209; FAQLQ-CF: 105) were analyzed. Twenty-four-month global FAQL scores (FAQLQ-PF/FAQLQ-CF) were significantly improved in the treatment group versus the placebo group (least squares mean, 0.34, P = .008, and 0.46, P = .023, respectively). At 24 months, there was significant FAQLQ-PF score improvement in participants initially randomized to treatment who met the efficacy primary end point (n = 74; least squares mean, 0.55; P < .001) and in participants with any eliciting dose increase (n = 127; least squares mean, 0.66; P < .001). FAQLQ-PF improvements were observed in social dietary limitations (P = .002), food-related anxiety (P = .029), and emotional impact (P = .048) domains. FAQLQ-CF improvements were observed in risk of accidental exposure (P = .002) and allergen avoidance (P = .04) domains. Nearly all outcomes met a nontreatment context minimal clinically important difference previously cited for FAQLQ., Conclusions: Epicutaneous immunotherapy treatment was observed to be associated with significant global and domain-specific FAQL improvement (FAQLQ-PF/FAQLQ-CF), largely driven by increases in eliciting dose, in children with peanut allergy., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2021
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32. Sustained unresponsiveness to peanut after long-term peanut epicutaneous immunotherapy.
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Brown-Whitehorn TF, de Blay F, Spergel JM, Green TD, Peillon A, Sampson HA, and Campbell DE
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- Administration, Oral, Allergens therapeutic use, Desensitization, Immunologic, Humans, Immunotherapy, Arachis, Peanut Hypersensitivity drug therapy
- Published
- 2021
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33. Transformative instruction or old wine in new skins? Exploring how and why educators use HyperDocs.
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Carpenter JP, Trust T, and Green TD
- Abstract
HyperDocs are interactive, digital teaching and learning materials created, disseminated, and remixed by educators. To date, HyperDocs have not been the subject of published, peer-reviewed research. To address this research gap, we engaged in exploratory, primarily qualitative research to systematically examine how and why teachers use HyperDocs. We used an online survey to gather data on educators' ( N = 261) uses of and perceptions regarding HyperDocs. Analysis suggested a wide range of definitions of, purposes for, and approaches to HyperDoc use, indicating that educators are adapting HyperDocs to their practice in myriad ways. Consistent with the openness and flexibility in finding, remixing, and using HyperDocs, educators identified a number of benefits of using these tools in their practice, including changes in student engagement and learning, shifts in instructional design and delivery, and changes in their own support and dispositions. Analysis of examples of HyperDocs shared by a subset of participants suggested some mismatch between rhetoric about HyperDocs and what was actually incorporated into them. We discuss these findings in relation to the work of educators and the future of research on HyperDocs and other crowdsourced teaching and learning initiatives., (© 2020 Elsevier Ltd. All rights reserved.)
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- 2020
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34. Long-term, open-label extension study of the efficacy and safety of epicutaneous immunotherapy for peanut allergy in children: PEOPLE 3-year results.
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Fleischer DM, Shreffler WG, Campbell DE, Green TD, Anvari S, Assa'ad A, Bégin P, Beyer K, Bird JA, Brown-Whitehorn T, Byrne A, Chan ES, Cheema A, Chinthrajah S, Chong HJ, Davis CM, Ford LS, Gagnon R, Greenhawt M, Hourihane JO, Jones SM, Kim EH, Lange L, Lanser BJ, Leonard S, Mahler V, Maronna A, Nowak-Wegrzyn A, Oriel RC, O'Sullivan M, Petroni D, Pongracic JA, Prescott SL, Schneider LC, Smith P, Staab D, Sussman G, Wood R, Yang WH, Lambert R, Peillon A, Bois T, and Sampson HA
- Subjects
- Administration, Cutaneous, Adolescent, Allergens administration & dosage, Biomarkers, Child, Child, Preschool, Female, Follow-Up Studies, Humans, Immunoglobulin E immunology, Male, Treatment Outcome, Allergens immunology, Desensitization, Immunologic adverse effects, Desensitization, Immunologic methods, Peanut Hypersensitivity immunology, Peanut Hypersensitivity therapy
- Abstract
Background: The PEPITES (Peanut EPIT Efficacy and Safety) trial, a 12-month randomized controlled study of children with peanut allergy and 4 to 11 years old, previously reported the safety and efficacy of epicutaneous immunotherapy (EPIT) for peanut allergy (250 μg, daily epicutaneous peanut protein; DBV712 250 μg)., Objective: We sought to assess interim safety and efficacy of an additional 2 years of EPIT from the ongoing (5-year treatment) PEOPLE (PEPITES Open-Label Extension) study., Methods: Subjects who completed PEPITES were offered enrollment in PEOPLE. Following an additional 2 years of daily DBV712 250 μg, subjects who had received DBV712 250 μg in PEPITES underwent month-36 double-blind, placebo-controlled food challenge with an optional month-38 sustained unresponsiveness assessment., Results: Of 213 eligible subjects who had received DBV712 250 μg in PEPITES, 198 (93%) entered PEOPLE, of whom 141 (71%) had assessable double-blind, placebo-controlled food challenge at month 36. At month 36, 51.8% of subjects (73 of 141) reached an eliciting dose of ≥1000 mg, compared with 40.4% (57 of 141) at month 12; 75.9% (107 of 141) demonstrated increased eliciting dose compared with baseline; and 13.5% (19 of 141) tolerated the full double-blind, placebo-controlled food challenge of 5444 mg. Median cumulative reactive dose increased from 144 to 944 mg. Eighteen subjects underwent an optional sustained unresponsiveness assessment; 14 of those (77.8%) maintained an eliciting dose of ≥1000 mg at month 38. Local patch-site skin reactions were common but decreased over time. There was no treatment-related epinephrine use in years 2 or 3. Compliance was high (96.9%), and withdrawals due to treatment-related adverse events were low (1%)., Conclusions: These results demonstrate that daily EPIT treatment for peanut allergy beyond 1 year leads to continued response from a well-tolerated, simple-to-use regimen., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2020
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35. Improvements in eliciting dose across baseline sensitivities following 12 months of epicutaneous immunotherapy (EPIT) in peanut-allergic children aged 4 to 11 years.
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Greenhawt M, Kim EH, Campbell DE, Green TD, Lambert R, and Fleischer DM
- Subjects
- Allergens, Child, Child, Preschool, Desensitization, Immunologic, Humans, Immunotherapy, Arachis, Peanut Hypersensitivity therapy
- Published
- 2020
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36. PFKFB3-mediated glycolysis rescues myopathic outcomes in the ischemic limb.
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Ryan TE, Schmidt CA, Tarpey MD, Amorese AJ, Yamaguchi DJ, Goldberg EJ, Iñigo MM, Karnekar R, O'Rourke A, Ervasti JM, Brophy P, Green TD, Neufer PD, Fisher-Wellman K, Spangenburg EE, and McClung JM
- Subjects
- Animals, Genetic Therapy, Hindlimb blood supply, Humans, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mitochondria, Muscle metabolism, Muscle, Skeletal metabolism, Muscular Diseases etiology, Muscular Diseases metabolism, Muscular Diseases pathology, Phosphofructokinase-2 genetics, Transcriptome, Glycolysis, Hindlimb pathology, Ischemia complications, Mitochondria, Muscle pathology, Muscle, Skeletal pathology, Muscular Diseases prevention & control, Phosphofructokinase-2 administration & dosage
- Abstract
Compromised muscle mitochondrial metabolism is a hallmark of peripheral arterial disease, especially in patients with the most severe clinical manifestation - critical limb ischemia (CLI). We asked whether inflexibility in metabolism is critical for the development of myopathy in ischemic limb muscles. Using Polg mtDNA mutator (D257A) mice, we reveal remarkable protection from hind limb ischemia (HLI) due to a unique and beneficial adaptive enhancement of glycolytic metabolism and elevated ischemic muscle PFKFB3. Similar to the relationship between mitochondria from CLI and claudicating patient muscles, BALB/c muscle mitochondria are uniquely dysfunctional after HLI onset as compared with the C57BL/6 (BL6) parental strain. AAV-mediated overexpression of PFKFB3 in BALB/c limb muscles improved muscle contractile function and limb blood flow following HLI. Enrichment analysis of RNA sequencing data on muscle from CLI patients revealed a unique deficit in the glucose metabolism Reactome. Muscles from these patients express lower PFKFB3 protein, and their muscle progenitor cells possess decreased glycolytic flux capacity in vitro. Here, we show supplementary glycolytic flux as sufficient to protect against ischemic myopathy in instances where reduced blood flow-related mitochondrial function is compromised preclinically. Additionally, our data reveal reduced glycolytic flux as a common characteristic of the failing CLI patient limb skeletal muscle.
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- 2020
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37. An evaluation of factors influencing response to epicutaneous immunotherapy for peanut allergy in the PEPITES trial.
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Fleischer DM, Chinthrajah S, Scurlock AM, Campbell DE, Green TD, Bee KJ, Peillon A, Ocheltree T, and Sampson HA
- Subjects
- Allergens immunology, Arachis immunology, Child, Child, Preschool, Double-Blind Method, Female, Humans, Immunoglobulin E blood, Infusions, Subcutaneous, Male, Predictive Value of Tests, Prognosis, Transdermal Patch, Treatment Outcome, Desensitization, Immunologic methods, Peanut Hypersensitivity therapy
- Abstract
Background: Epicutaneous immunotherapy (EPIT) for peanut allergy is a potential novel immunotherapy that utilizes the unique cutaneous immunologic properties to induce desensitization. A randomized, double-blind, placebo-controlled Phase 3 trial (PEPITES) in peanut-allergic children 4-11 years demonstrated an epicutaneous patch (DBV712) with 250 µg peanut protein was statistically superior to placebo in inducing desensitization following 12 months of daily treatment. Objective: To investigate what baseline and in-study factors influenced response to DBV712 250 µg, with a focus on patch adhesion, by posthoc analysis of PEPITES data. Methods: A posthoc multivariate model built with log-transformed Month 12 eliciting dose (ED) as the dependent variable was used to assess the influence of baseline characteristics and patch adhesion. Baseline characteristics and treatment response were also evaluated by stratifying subjects into decile subgroups by patch detachment rates over the 12-month study. Results: Multivariate analysis identified higher baseline ED and lower baseline peanut-specific IgE as the variables most predictive of higher Month 12 ED, followed by mean daily patch application duration, baseline SCORing Atopic Dermatitis (SCORAD) score, and age. By decile stratification, no association between patch detachment and treatment response was identified for 80% of DBV712-treated subjects. All DBV712-treated subjects, including those with the highest patch detachment rates, demonstrated treatment benefit measured by fold-changes in geometric mean ED. Conclusion: We identified subject baseline characteristics of higher baseline ED and lower baseline peanut-specific IgE as most predictive of higher Month 12 ED. For the majority of treated subjects, patch detachment did not impact treatment response. A minority of subjects, highly sensitive to peanut at baseline, had lower prespecified responder rates and higher patch detachment rates, yet still benefited from treatment based upon fold-changes in ED.
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- 2020
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38. Evaluation of daily patch application duration for epicutaneous immunotherapy for peanut allergy.
- Author
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Fleischer DM, Spergel JM, Kim EH, Campbell DE, Green TD, Bee KJ, Lambert R, Ocheltree T, and Sampson HA
- Subjects
- Administration, Cutaneous, Adolescent, Adult, Allergens therapeutic use, Child, Child, Preschool, Clinical Trials, Phase III as Topic, Female, Healthy Volunteers, Humans, Male, Plant Proteins therapeutic use, Randomized Controlled Trials as Topic, Time Factors, Young Adult, Allergens administration & dosage, Desensitization, Immunologic methods, Peanut Hypersensitivity drug therapy, Plant Proteins administration & dosage, Transdermal Patch
- Abstract
Background: Epicutaneous immunotherapy is a potential novel immunotherapy that utilizes unique cutaneous immunologic properties. In a phase III, randomized, double-blind, placebo controlled clinical trial, an epicutaneous patch (DBV712) with 250 µg of peanut protein applied once daily for 12-months was statistically superior to placebo in desensitizing children with peanut allergy (ages 4-11 years) (N = 356). Objective: To assess the relationship between the hours of daily application time and the efficacy of DBV712 250 µg. Methods: DBV712 250 µg was applied to 30 nonallergic volunteers for various durations from 2 to 24 hours and then assayed for residual peanut protein. Patch application data from the phase III clinical trial were analyzed post hoc according to prespecified responder rates and changes in the eliciting dose (ED), as measured by the geometric mean (GM) ED ratio (12 months/baseline). Results: Following application, there was a marked decrease in peanut protein on the patches from 2 to 12 hours. After 12 hours, the median peanut protein recovered was below quantification limits. The median daily patch application duration in subjects from the phase III clinical trial was 21.1 hours (DBV712 250 µg) and 22.4 hours (placebo). Ninety-five percent of the treated population achieved >10 hours per day mean application. Response rates and GM ED ratios were similar among subjects across a range of application durations; e.g. , in those with a mean duration of >10 hours, the response rate was 36.6% and the GM ED ratio was 3.8, comparable with 42.6% and 4.0, respectively, in those with a mean duration of >20 hours. In DBV712 250 µg subjects with >16 hours mean application duration (84.5% of the treated population), the response rate was 38.8% versus 13.4% for placebo (difference, 24.4% [95% confidence interval, 15.5-34.0%]; p < 0.001). Conclusion: An evaluation of residual peanut protein on patches following application and post hoc analysis of phase III data strongly suggest that allergen delivery is attained with 12-16 hours of daily patch application time, sufficient to drive clinically meaningful desensitization to peanut after 12 months.
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- 2020
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39. Unmet needs of children with peanut allergy: Aligning the risks and the evidence.
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Chan ES, Dinakar C, Gonzales-Reyes E, Green TD, Gupta R, Jones D, Wang J, Winders T, and Greenhawt M
- Subjects
- Age Factors, Caregivers, Child, Consensus Development Conferences as Topic, Desensitization, Immunologic, Expert Testimony, Humans, Information Dissemination, Patient Education as Topic, Risk, United States epidemiology, Anaphylaxis epidemiology, Anaphylaxis prevention & control, Evidence-Based Practice, Health Services Accessibility statistics & numerical data, Peanut Hypersensitivity epidemiology
- Abstract
Background: Peanut allergy is a potentially severe and lifelong allergy, with few effective treatments or preventive measures., Objective: To convene an expert panel of allergists, pediatricians, and advocates to discuss and highlight unmet needs in the prevention and management of peanut allergies., Methods: Literature searches of PubMed were performed. The panel evaluated published data on the prevention of peanut allergy, treatment of existing peanut allergy, and management of reactions after unintentional peanut exposures., Results: The following key unmet needs in the prevention and management of peanut allergy were identified: (1) enhancing and optimizing implementation of early peanut introduction as a means of preventing the development of peanut allergy, (2) developing knowledge translation strategies regarding the safety and efficacy data for current and emerging immunotherapies for peanut-allergic children to support their use in clinical practice, and (3) promoting understanding of true exposure risk in allergic individuals and ensuring access to epinephrine for unintentional exposures that provoke severe reactions. Practitioners should help educate caregivers about the actual risks associated with peanut allergy and its prevention and management so that treatment decisions can be evidence based rather than fear based. Support tools are needed to help address caregiver goals, expectations, and psychological barriers, as well as identify facilitators for prevention and treatment strategies., Conclusion: There are significant unmet needs in our understanding of peanut allergy; addressing these needs will help to enhance understanding of how to most effectively prevent and treat peanut allergy, as well as educate the food-allergic and nonallergic community regarding current evidence-based practices., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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40. Effects of fasting on isolated murine skeletal muscle contractile function during acute hypoxia.
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Schmidt CA, Goldberg EJ, Green TD, Karnekar RR, Brault JJ, Miller SG, Amorese AJ, Yamaguchi DJ, Spangenburg EE, and McClung JM
- Subjects
- Adenine Nucleotides analysis, Adenine Nucleotides metabolism, Animals, Energy Metabolism, Glycogen analysis, Glycogen metabolism, Hypoxia physiopathology, Male, Mice, Mice, Inbred BALB C, Muscle, Skeletal physiopathology, Physical Conditioning, Animal, Fasting adverse effects, Hypoxia metabolism, Muscle Contraction, Muscle, Skeletal metabolism
- Abstract
Stored muscle carbohydrate supply and energetic efficiency constrain muscle functional capacity during exercise and are influenced by common physiological variables (e.g. age, diet, and physical activity level). Whether these constraints affect overall functional capacity or the timing of muscle energetic failure during acute hypoxia is not known. We interrogated skeletal muscle contractile properties in two anatomically distinct rodent hindlimb muscles that have well characterized differences in energetic efficiency (locomotory- extensor digitorum longus (EDL) and postural- soleus muscles) following a 24 hour fasting period that resulted in substantially reduced muscle carbohydrate supply. 180 mins of acute hypoxia resulted in complete energetic failure in all muscles tested, indicated by: loss of force production, substantial reductions in total adenosine nucleotide pool intermediates, and increased adenosine nucleotide degradation product-inosine monophosphate (IMP). These changes occurred in the absence of apparent myofiber structural damage assessed histologically by both transverse section and whole mount. Fasting and the associated reduction of the available intracellular carbohydrate pool (~50% decrease in skeletal muscle) did not significantly alter the timing to muscle functional impairment or affect the overall force/work capacities of either muscle type. Fasting resulted in greater passive tension development in both muscle types, which may have implications for the design of pre-clinical studies involving optimal timing of reperfusion or administration of precision therapeutics., Competing Interests: The authors have declared that no competing interests exist.
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- 2020
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41. Commercial claims costs related to health care resource use associated with a diagnosis of peanut allergy.
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Shaker M, Chalil JM, Tran O, Vlahiotis A, Shah H, King T, Green TD, and Greenhawt M
- Subjects
- Adolescent, Adult, Child, Child, Preschool, Cohort Studies, Female, Humans, Infant, Infant, Newborn, Insurance Claim Review, Male, Middle Aged, Retrospective Studies, United States, Young Adult, Cost of Illness, Health Care Costs, Peanut Hypersensitivity economics
- Abstract
Background: Peanut allergy (PA) affects approximately 1.6 million US children. The current standard of care is strict avoidance and prompt reaction treatment. Peanut allergy health care costs and health care resource utilization (HCRU) are poorly understood., Objective: To estimate PA health care costs and HCRU using a nationally representative commercial payer database., Methods: The IBM MarketScan Commercial Claims and Encounters Database was examined for PA diagnosis/reaction codes between January 2010 and October 2016 in patients 64 years of age or younger, with age cohort-matched controls. Outcomes were measured 12 months before and after the first claim date. Health care costs and HCRU were compared using Student's t tests and χ
2 tests., Results: Patients with a PA-related diagnostic code (n = 41,675) incurred almost double all-cause health care costs vs controls ($6436 vs $3493, P < .001), mainly from inpatient and outpatient medical costs ($5002 vs $2832, P < .001). More than one third of the PA group patients (36%) had a code indicative of an anaphylactic reaction during follow-up. Mean PA or reaction-related code costs per visit totaled $7921 for hospitalizations and $1115 for emergency department (ED) visits. Costs were 30% lower in patients with asthma codes without PA codes vs those with both codes ($5678 vs $8112, P < .001); all-cause ED costs were more than double in patients with atopic dermatitis codes with PA codes vs those without PA codes ($654 vs $308, P < .001)., Conclusion: National commercial payer claims data indicate a significant health care burden associated with a PA-related code, including over $6400/patient in annual all-cause costs and increased health care utilization., (Copyright © 2020. Published by Elsevier Inc.)- Published
- 2020
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42. Estimated risk reduction to packaged food reactions by epicutaneous immunotherapy (EPIT) for peanut allergy.
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Remington BC, Krone T, Kim EH, Bird JA, Green TD, Lack G, Fleischer DM, and Koppelman SJ
- Subjects
- Administration, Cutaneous, Allergens adverse effects, Antigens, Plant adverse effects, Child, Child, Preschool, Double-Blind Method, Food Contamination, Humans, Plant Proteins, Dietary adverse effects, Risk Reduction Behavior, Allergens administration & dosage, Antigens, Plant administration & dosage, Arachis adverse effects, Desensitization, Immunologic, Peanut Hypersensitivity therapy, Plant Proteins, Dietary administration & dosage
- Abstract
Background: Peanut allergy is a generally persistent, sometimes life-threatening food allergy. With no treatments demonstrating the ability to cure a food allergy, the focus of drugs in development has been on providing a level of protection against accidental exposure reactions. However, no study has estimated the relative risk reduction of a food-allergic population receiving a specific immunotherapeutic treatment for their allergies., Objective: To estimate the relative risk reduction when consuming peanut-contaminated packaged food products in a double-blind, placebo-controlled Phase 3 study population of children treated with epicutaneous immunotherapy (EPIT) for 12 months with either a patch containing 250 μg peanut protein (250-μg patch) or a placebo patch., Methods: The probability of an allergic reaction due to the unintended presence of peanut protein in packaged food products was modeled per study group and food category combination using Monte Carlo simulations. Risks per eating occasion of a contaminated packaged food product and the number of individuals per study population predicted to react on a yearly basis were investigated., Results: The population treated with the 250-μg patch demonstrated a significantly increased dose-response distribution after 12 months of treatment, which resulted in a relative risk reduction of 73.2% to 78.4% when consuming peanut-contaminated packaged food products. In contrast, no statistically significant change was observed for the placebo group at the 12-month point., Conclusion: Our study estimates a substantial relative risk reduction for allergic reactions among peanut-allergic children after 12 months of EPIT with the 250-μg patch, supporting the potential real-world clinical relevance of this investigational immunotherapy and its possible role as a future therapy for peanut-allergic children. ClinicalTrials.gov Identifier: NCT02636699., (Copyright © 2019 The Netherlands Organisation for Applied Scientific Research TNO. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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43. Temporal Association Between Ischemic Muscle Perfusion Recovery and the Restoration of Muscle Contractile Function After Hindlimb Ischemia.
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Goldberg EJ, Schmidt CA, Green TD, Karnekar R, Yamaguchi DJ, Spangenberg EE, and McClung JM
- Abstract
During incomplete skeletal muscle recovery from ischemia, such as that occurs with critical limb ischemia, the temporal relationship between recovery of muscle capillary perfusion and contractile function is poorly defined. We examined this relationship in BALB/cJ mice ( N = 24) following unilateral hindlimb ischemia (HLI), which pre-clinically mimics the myopathy observed in critical limb ischemia patients. Specifically, we examined this relationship in two phenotypically distinct muscles (i.e., "oxidative" soleus - Sol and "glycolytic" extensor digitorum longus - EDL) 14- or 56-days after HLI. Although overall limb blood flow (LDPI) reached its' recovery peak (48% of control) by HLI d14, the capillary networks in both the Sol and EDL (whole mount confocal imaging) were disrupted and competent muscle capillary perfusion (perfused lectin
+ μm2 /muscle μm2 ) remained reduced. Interestingly, both Sol and EDL muscles recovered their distinct capillary structures and perfusion (Con Sol; 0.056 ± 0.02 lectin+ μm2 /muscle μm2 , and Con EDL; 0.039 ± 0.005 lectin+ μm2 /muscle μm2 ) by HLI d56 (Sol; 0.062 ± 0.011 lectin+ μm2 /muscle μm2 and EDL; 0.0035 ± 0.005 lectin+ μm2 /muscle μm2 ), despite no further improvement in limb blood flow (LDPI). Both muscles suffered severe myopathy, indicated by loss of dystrophin positive immunostaining and the absence of stimulation induced isometric force production at HLI d14. Dystrophin immunofluorescence returned at HLI d56, although neither myofiber CSA (μm2 ) nor isometric force production (58 and 28% sustained deficits, Sol and EDL, respectively) recovered completely in either muscle. In summary, we reveal that the temporal relationship between the restoration of muscle capillary perfusion and functional ischemic skeletal muscle regeneration favors competent muscle capillary perfusion recovery in BALB/c mice in a phenotypically non-distinct manner.- Published
- 2019
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44. Overexpression of Long-Chain Acyl-CoA Synthetase 5 Increases Fatty Acid Oxidation and Free Radical Formation While Attenuating Insulin Signaling in Primary Human Skeletal Myotubes.
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Kwak HB, Woodlief TL, Green TD, Cox JH, Hickner RC, Neufer PD, and Cortright RN
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- Cells, Cultured, Female, Free Radicals metabolism, Humans, Lipid Metabolism, Mitochondria, Muscle metabolism, Obesity metabolism, Oxidation-Reduction, Coenzyme A Ligases metabolism, Fatty Acids metabolism, Insulin metabolism, Muscle Fibers, Skeletal metabolism, Muscle, Skeletal metabolism, Signal Transduction
- Abstract
In rodent skeletal muscle, acyl-coenzyme A (CoA) synthetase 5 (ACSL-5) is suggested to localize to the mitochondria but its precise function in human skeletal muscle is unknown. The purpose of these studies was to define the role of ACSL-5 in mitochondrial fatty acid metabolism and the potential effects on insulin action in human skeletal muscle cells (HSKMC). Primary myoblasts isolated from vastus lateralis (obese women (body mass index (BMI) = 34.7 ± 3.1 kg/m²)) were transfected with ACSL-5 plasmid DNA or green fluorescent protein (GFP) vector (control), differentiated into myotubes, and harvested (7 days). HSKMC were assayed for complete and incomplete fatty acid oxidation ([1-
14 C] palmitate) or permeabilized to determine mitochondrial respiratory capacity (basal (non-ADP stimulated state 4), maximal uncoupled (carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone (FCCP)-linked) respiration, and free radical (superoxide) emitting potential). Protein levels of ACSL-5 were 2-fold higher in ACSL-5 overexpressed HSKMC. Both complete and incomplete fatty acid oxidation increased by 2-fold ( p < 0.05). In permeabilized HSKMC, ACSL-5 overexpression significantly increased basal and maximal uncoupled respiration ( p < 0.05). Unexpectedly, however, elevated ACSL-5 expression increased mitochondrial superoxide production (+30%), which was associated with a significant reduction ( p < 0.05) in insulin-stimulated p-Akt and p-AS160 protein levels. We concluded that ACSL-5 in human skeletal muscle functions to increase mitochondrial fatty acid oxidation, but contrary to conventional wisdom, is associated with increased free radical production and reduced insulin signaling.- Published
- 2019
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45. Effect of Epicutaneous Immunotherapy vs Placebo on Reaction to Peanut Protein Ingestion Among Children With Peanut Allergy: The PEPITES Randomized Clinical Trial.
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Fleischer DM, Greenhawt M, Sussman G, Bégin P, Nowak-Wegrzyn A, Petroni D, Beyer K, Brown-Whitehorn T, Hebert J, Hourihane JO, Campbell DE, Leonard S, Chinthrajah RS, Pongracic JA, Jones SM, Lange L, Chong H, Green TD, Wood R, Cheema A, Prescott SL, Smith P, Yang W, Chan ES, Byrne A, Assa'ad A, Bird JA, Kim EH, Schneider L, Davis CM, Lanser BJ, Lambert R, and Shreffler W
- Subjects
- Administration, Cutaneous, Child, Child, Preschool, Confidence Intervals, Double-Blind Method, Eating immunology, Female, Humans, Male, Peanut Hypersensitivity immunology, Treatment Outcome, Allergens administration & dosage, Arachis immunology, Desensitization, Immunologic methods, Peanut Hypersensitivity therapy, Transdermal Patch adverse effects
- Abstract
Importance: There are currently no approved treatments for peanut allergy., Objective: To assess the efficacy and adverse events of epicutaneous immunotherapy with a peanut patch among peanut-allergic children., Design, Setting, and Participants: Phase 3, randomized, double-blind, placebo-controlled trial conducted at 31 sites in 5 countries between January 8, 2016, and August 18, 2017. Participants included peanut-allergic children (aged 4-11 years [n = 356] without a history of a severe anaphylactic reaction) developing objective symptoms during a double-blind, placebo-controlled food challenge at an eliciting dose of 300 mg or less of peanut protein., Interventions: Daily treatment with peanut patch containing either 250 μg of peanut protein (n = 238) or placebo (n = 118) for 12 months., Main Outcomes and Measures: The primary outcome was the percentage difference in responders between the peanut patch and placebo patch based on eliciting dose (highest dose at which objective signs/symptoms of an immediate hypersensitivity reaction developed) determined by food challenges at baseline and month 12. Participants with baseline eliciting dose of 10 mg or less were responders if the posttreatment eliciting dose was 300 mg or more; participants with baseline eliciting dose greater than 10 to 300 mg were responders if the posttreatment eliciting dose was 1000 mg or more. A threshold of 15% or more on the lower bound of a 95% CI around responder rate difference was prespecified to determine a positive trial result. Adverse event evaluation included collection of treatment-emergent adverse events (TEAEs)., Results: Among 356 participants randomized (median age, 7 years; 61.2% male), 89.9% completed the trial; the mean treatment adherence was 98.5%. The responder rate was 35.3% with peanut-patch treatment vs 13.6% with placebo (difference, 21.7% [95% CI, 12.4%-29.8%; P < .001]). The prespecified lower bound of the CI threshold was not met. TEAEs, primarily patch application site reactions, occurred in 95.4% and 89% of active and placebo groups, respectively. The all-causes rate of discontinuation was 10.5% in the peanut-patch group vs 9.3% in the placebo group., Conclusions and Relevance: Among peanut-allergic children aged 4 to 11 years, the percentage difference in responders at 12 months with the 250-μg peanut-patch therapy vs placebo was 21.7% and was statistically significant, but did not meet the prespecified lower bound of the confidence interval criterion for a positive trial result. The clinical relevance of not meeting this lower bound of the confidence interval with respect to the treatment of peanut-allergic children with epicutaneous immunotherapy remains to be determined., Trial Registration: ClinicalTrials.gov Identifier: NCT02636699.
- Published
- 2019
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46. Extensive skeletal muscle cell mitochondriopathy distinguishes critical limb ischemia patients from claudicants.
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Ryan TE, Yamaguchi DJ, Schmidt CA, Zeczycki TN, Shaikh SR, Brophy P, Green TD, Tarpey MD, Karnekar R, Goldberg EJ, Sparagna GC, Torres MJ, Annex BH, Neufer PD, Spangenburg EE, and McClung JM
- Subjects
- Aged, Aged, 80 and over, Ankle Brachial Index methods, Atherosclerosis, Cellular Microenvironment physiology, Cross-Sectional Studies, Female, Humans, Intermittent Claudication diagnosis, Intermittent Claudication physiopathology, Male, Middle Aged, Mitochondria, Muscle genetics, Muscle, Skeletal cytology, Muscle, Skeletal metabolism, Muscle, Skeletal pathology, Peripheral Arterial Disease complications, Phenotype, RNA, Messenger genetics, Exome Sequencing methods, Intermittent Claudication genetics, Ischemia pathology, Mitochondria, Muscle pathology, Peripheral Arterial Disease genetics
- Abstract
The most severe manifestation of peripheral arterial disease (PAD) is critical limb ischemia (CLI). CLI patients suffer high rates of amputation and mortality; accordingly, there remains a clear need both to better understand CLI and to develop more effective treatments. Gastrocnemius muscle was obtained from 32 older (51-84 years) non-PAD controls, 27 claudicating PAD patients (ankle-brachial index [ABI] 0.65 ± 0.21 SD), and 19 CLI patients (ABI 0.35 ± 0.30 SD) for whole transcriptome sequencing and comprehensive mitochondrial phenotyping. Comparable permeabilized myofiber mitochondrial function was paralleled by both similar mitochondrial content and related mRNA expression profiles in non-PAD control and claudicating patient tissues. Tissues from CLI patients, despite being histologically intact and harboring equivalent mitochondrial content, presented a unique bioenergetic signature. This signature was defined by deficits in permeabilized myofiber mitochondrial function and a unique pattern of both nuclear and mitochondrial encoded gene suppression. Moreover, isolated muscle progenitor cells retained both mitochondrial functional deficits and gene suppression observed in the tissue. These findings indicate that muscle tissues from claudicating patients and non-PAD controls were similar in both their bioenergetics profile and mitochondrial phenotypes. In contrast, CLI patient limb skeletal muscles harbor a unique skeletal muscle mitochondriopathy that represents a potentially novel therapeutic site for intervention.
- Published
- 2018
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47. Elucidating Structural Evolution of Perylene Diimide Aggregates Using Vibrational Spectroscopy and Molecular Dynamics Simulations.
- Author
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Mattson MA, Green TD, Lake PT, McCullagh M, and Krummel AT
- Abstract
Perylene diimides (PDIs) are a family of molecules that have potential applications to organic photovoltaics. These systems typically aggregate cofacially due to π-stacking interactions between the aromatic perylene cores. In this study, the structure and characteristics of aggregated N, N'-bis(2,6-diisopropylphenyl)-3,4,9,10-perylenetetracarboxylic diimide (common name lumogen orange), a perylene diimide (PDI) with sterically bulky imide functional groups, were investigated using both experimental vibrational spectroscopy and molecular dynamics (MD) simulations. Samples of lumogen orange dispersed in chloroform exhibited complex aggregation behavior, as evidenced by the evolution of the FTIR spectrum over a period of several hours. While for many PDI systems with less bulky imide functional groups aggregation is dominated by π-stacking interactions between perylene cores, MD simulations of lumogen orange dimers indicated a second, more energetically favorable aggregate structure mediated by "edge-to-edge" interactions between PDI units. Two-dimensional infrared spectroscopy together with orientational statistics obtained from MD simulations were employed to identify and rationalize aggregation-induced coupling between vibrational modes.
- Published
- 2018
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48. Strain-Dependent Variation in Acute Ischemic Muscle Injury.
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Schmidt CA, Amorese AJ, Ryan TE, Goldberg EJ, Tarpey MD, Green TD, Karnekar RR, Yamaguchi DJ, Spangenburg EE, and McClung JM
- Subjects
- Animals, Cell Survival physiology, Dystrophin metabolism, Hindlimb blood supply, Hindlimb physiopathology, Ischemia metabolism, Ischemia physiopathology, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Muscle Contraction physiology, Muscle, Skeletal blood supply, Muscle, Skeletal physiopathology, Species Specificity, Hindlimb pathology, Ischemia pathology, Muscle, Skeletal pathology
- Abstract
Limited efficacy of clinical interventions for peripheral arterial disease necessitates a better understanding of the environmental and genetic determinants of tissue pathology. Existing research has largely ignored the early skeletal muscle injury response during hind limb ischemia (HLI). We compared the hind limb muscle response, after 6 hours of ischemia, in two mouse strains that differ dramatically in their postischemic extended recovery: C57BL/6J and BALB/cJ. Perfusion, measured by laser Doppler and normalized to the control limb, differed only slightly between strains after HLI (<12% across all measures). Similar (<10%) effect sizes in lectin-perfused vessel area and no differences in tissue oxygen saturation measured by reflectance spectroscopy were also found. Muscles from both strains were functionally impaired after HLI, but greater muscle necrosis and loss of dystrophin-positive immunostaining were observed in BALB/cJ muscle compared with C57BL/6J. Muscle cell-specific dystrophin loss and reduced viability were also detected in additional models of ischemia that were independent of residual perfusion differences. Our results indicate that factors other than the completeness of ischemia alone (ie, background genetics) influence the magnitude of acute ischemic muscle injury. These findings may have implications for future development of therapeutic interventions for limb ischemia and for understanding the phasic etiology of chronic and acute ischemic muscle pathophysiology., (Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
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49. Effect of Varying Doses of Epicutaneous Immunotherapy vs Placebo on Reaction to Peanut Protein Exposure Among Patients With Peanut Sensitivity: A Randomized Clinical Trial.
- Author
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Sampson HA, Shreffler WG, Yang WH, Sussman GL, Brown-Whitehorn TF, Nadeau KC, Cheema AS, Leonard SA, Pongracic JA, Sauvage-Delebarre C, Assa'ad AH, de Blay F, Bird JA, Tilles SA, Boralevi F, Bourrier T, Hébert J, Green TD, Gerth van Wijk R, Knulst AC, Kanny G, Schneider LC, Kowalski ML, and Dupont C
- Subjects
- Administration, Cutaneous, Adolescent, Adult, Child, Dose-Response Relationship, Immunologic, Double-Blind Method, Female, Humans, Male, Middle Aged, Allergens administration & dosage, Arachis immunology, Desensitization, Immunologic methods, Peanut Hypersensitivity therapy
- Abstract
Importance: Epicutaneous immunotherapy may have potential for treating peanut allergy but has been assessed only in preclinical and early human trials., Objective: To determine the optimal dose, adverse events (AEs), and efficacy of a peanut patch for peanut allergy treatment., Design, Setting, and Participants: Phase 2b double-blind, placebo-controlled, dose-ranging trial of a peanut patch in peanut-allergic patients (6-55 years) from 22 centers, with a 2-year, open-label extension (July 31, 2012-July 31, 2014; extension completed September 29, 2016). Patients (n = 221) had peanut sensitivity and positive double-blind, placebo-controlled food challenges to an eliciting dose of 300 mg or less of peanut protein., Interventions: Randomly assigned patients (1:1:1:1) received an epicutaneous peanut patch containing 50 μg (n = 53), 100 μg (n = 56), or 250 μg (n = 56) of peanut protein or a placebo patch (n = 56). Following daily patch application for 12 months, patients underwent a double-blind, placebo-controlled food challenge to establish changes in eliciting dose., Main Outcomes and Measures: The primary efficacy end point was percentage of treatment responders (eliciting dose: ≥10-times increase and/or reaching ≥1000 mg of peanut protein) in each group vs placebo patch after 12 months. Secondary end points included percentage of responders by age strata and treatment-emergent adverse events (TEAEs)., Results: Of 221 patients randomized (median age, 11 years [quartile 1, quartile 3: 8, 16]; 37.6% female), 93.7% completed the trial. A significant absolute difference in response rates was observed at month 12 between the 250-μg (n = 28; 50.0%) and placebo (n = 14; 25.0%) patches (difference, 25.0%; 95% CI, 7.7%-42.3%; P = .01). No significant difference was seen between the placebo patch vs the 100-μg patch. Because of statistical testing hierarchical rules, the 50-μg patch was not compared with placebo. Interaction by age group was only significant for the 250-μg patch (P = .04). In the 6- to 11-year stratum, the response rate difference between the 250-μg (n = 15; 53.6%) and placebo (n = 6; 19.4%) patches was 34.2% (95% CI, 11.1%-57.3%; P = .008); adolescents/adults showed no difference between the 250-μg (n = 13; 46.4%) and placebo (n = 8; 32.0%) patches: 14.4% (95% CI, -11.6% to 40.4%; P = .40). No dose-related serious AEs were observed. The percentage of patients with 1 or more TEAEs (largely local skin reactions) was similar across all groups in year 1: 50-μg patch = 100%, 100-μg patch = 98.2%, 250-μg patch = 100%, and placebo patch = 92.9%. The overall median adherence was 97.6% after 1 year; the dropout rate for treatment-related AEs was 0.9%., Conclusions and Relevance: In this dose-ranging trial of peanut-allergic patients, the 250-μg peanut patch resulted in significant treatment response vs placebo patch following 12 months of therapy. These findings warrant a phase 3 trial., Trial Registration: clinicaltrials.gov Identifier: NCT01675882.
- Published
- 2017
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50. Multicenter prevalence of anaphylaxis in clinic-based oral food challenges.
- Author
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Akuete K, Guffey D, Israelsen RB, Broyles JM, Higgins LJ, Green TD, Naimi DR, MacGinnitie AJ, Vitalpur G, Minard CG, and Davis CM
- Subjects
- Adolescent, Anaphylaxis diagnosis, Anaphylaxis physiopathology, Arachis chemistry, Arachis immunology, Child, Child, Preschool, Food Hypersensitivity diagnosis, Food Hypersensitivity physiopathology, Humans, Incidence, Infant, Linear Models, Prevalence, Risk, Sex Factors, Skin Tests, United States epidemiology, Allergens immunology, Anaphylaxis epidemiology, Food Hypersensitivity epidemiology
- Abstract
Background: Although previous single-center studies report the rate of anaphylaxis for oral food challenges (OFCs) as 9% to 11%, little is known regarding the epidemiology of clinical OFCs across multiple centers in the United States., Objective: To examine the epidemiology, symptoms, and treatment of clinical low-risk OFCs in the nonresearch setting., Methods: Data were obtained from 2008 to 2013 through a physician survey in 5 food allergy centers geographically distributed across the United States. Allergic reaction rates and the association of reaction rates with year, hospital, and demographics were determined using a linear mixed model. Meta-analysis was used to pool the proportion of reactions and anaphylaxis with inverse-variance weights using a random-effects model with exact confidence intervals (CIs)., Results: A total of 6,377 OFCs were performed, and the pooled estimate of anaphylaxis was 2% (95% CI, 1%-3%). The rate of allergic reactions was 14% (95% CI, 13%-16%) and was consistent during the study period (P = .40). Reaction rates ranged from 13% to 33%. Males reacted 16% more frequently than females (95% CI, 4%-37.5%; P = .04). Foods challenged in 2013 varied geographically, with peanut as the most challenged food in the Northeast, Midwest, and West and egg as the most challenged in the South., Conclusion: As the largest national survey of allergic reactions of clinical open OFCs in a nonresearch setting in the United States, this study found that performing clinical nonresearch open low-risk OFCs results in few allergic reactions, with 86% of challenges resulting in no reactions and 98% without anaphylaxis., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
- Full Text
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