Search

In our previous studies, we demonstrated the usefulness of TanDEM-X interferometric bistatic mode with single polarization to obtain forest heights for the purposes of large area mapping. A key feature of our approach has been the use of a simplified Random Volume Over Ground (RVOG) model that locally estimates forest height. The model takes TanDEM-X interferometric coherence amplitude as an input and uses an external Digital Surface Model (DSM) to account for local slope variations due to terrain topography in order to achieve accurate forest height estimation. The selection of DSM for use as a local slope reference is essential, as an inaccurate DSM will result in less accurate terrain-correction and forest height estimation. In this paper, we assessed TanDEM-X height estimates associated with scale variations in different DSMs used in the model over a remote sensing supersite in Petawawa, Canada. The DSMs used for assessments and comparisons included ASTER GDEM, ALOS GDSM, airborne DRAPE DSM, Canadian DSM and TanDEM-X DSM. Airborne Laser Scanning (ALS) data were used as reference for terrain slope and forest height comparisons. The results showed that, with the exception of the ASTER GDEM, all DSMs were sufficiently accurate for the simplified RVOG model to provide a satisfactory estimate of stand-level forest height. When compared to the ALS 95th height percentile, the modeled forest heights had R2 values greater than 80% and Root-Mean-Square Errors (RMSE) less than 2 m. For a close similarity in slope estimation with the ALS reference, coverage across Canada and open data access, the 0.75 arc-second (20 m) resolution Canadian DSM was selected as a preferred choice for the simplified RVOG model to provide TanDEM-X height estimation in Canada.

Purpose of Review: This review aims to provide an overview of the current understanding of eosinophilic gastrointestinal disorders (EGIDs) and the role of the epithelium in influencing disease pathogenesis to inform and devise future therapeutic strategies., Recent Findings: Changes in epithelial cell structure, functions, and integrity are observed in EGIDs. In eosinophilic esophagitis (EoE), the esophageal epithelium has been shown to play key roles in perpetuating the inflammatory response in EoE through the expression of pro-inflammatory cytokines and immunological cell-surface proteins. Similar mechanisms appear to exist in the other EGIDs, including eosinophilic gastritis (EoG), eosinophilic enteritis (EoN), and eosinophilic colitis (EoC). Because of the increasing rarity of each non-EoE EGID, research focusing on how the epithelium is modulating disease in each lower gastrointestinal compartment is still in its rudimentary stages., Summary: While there has been significant progress in understanding the role of the epithelium in EoE, further research is needed to obtain a better understanding of the mechanisms mediating epithelial-immune crosstalk in non-EoE EGIDs. Using EoE-epithelial cell research to inform future EGID investigations could lead to the development of new therapeutic interventions, such as targeted therapies to restore epithelial barrier function and reduce inflammation, to improve rare disease-patient quality of life., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Objectives: Children with severe persistent asthma managed by subspecialists represent a unique patient population. The factors predisposing these children to hospital admission are poorly understood. This study aimed to identify factors associated with future emergency department (ED) visits and hospitalization in this group., Methods: A chart review was conducted for children with severe persistent asthma evaluated by a pulmonologist between January 1, 2021 and June 30, 2022. Asthma-related ED visits and hospitalizations were recorded from electronic medical records. Chi-square testing, mixed effects modeling, and logistic regression were used to analyze associations between patient characteristics and hospitalization. A secondary analysis evaluated factors contributing to ED visits., Results: We identified 244 unique patients with 487 pulmonary clinic visits. Of these, 56 % were black, 58 % had public insurance, and 32 % had a history of ICU admission for asthma. In the 12 months following a clinic visit, 84 (34 %) patients had an ED visit, and 46 (19 %) had at least one hospitalization. Secondhand smoke exposure (OR 2.74, 95 % CI 1.16-6.45), public insurance (OR 3.37, 95 % CI 1.46-7.82), and prior ICU admission (OR 2.29, 95 % CI 1.09-4.79) were positively associated with hospitalization for asthma exacerbation. Among hospitalized patients, bronchopulmonary dysplasia (BPD) and gastroesophageal reflux disease (GERD) were linked to shorter time to admission., Conclusions: Despite subspecialty care, children with severe persistent asthma exposed to cigarette smoke, with prior ICU admission, or with public insurance are at higher risk of subsequent ED visits and hospitalization. These findings will inform targeted interventions to prevent hospitalization in this patient population., Competing Interests: Declaration of competing interest The authors have no relevant financial relationships or other potential conflicts of interest to disclose., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: DICER1-related tumor predisposition increases risk for a spectrum of benign and malignant tumors. In 2018, the International Pleuropulmonary Blastoma (PPB)/DICER1 Registry published guidelines for testing and imaging-based surveillance of individuals with a known or suspected germline DICER1 pathogenic or likely pathogenic (P/LP) variant. One of the Registry's goals is to continue to refine these guidelines as additional data becomes available., Experimental Design: Individuals were enrolled in the International PPB/DICER1 Registry, the International Ovarian and Testicular Stromal Tumor Registry, and/or the National Cancer Institute Natural History of DICER1 Syndrome study., Results: Review of participant records identified 713 participants with a germline DICER1 P/LP variant from 38 countries. To date, 5 cases of type I and 29 cases of type Ir PPB have been diagnosed by surveillance in enrolled individuals. One hundred and three individuals with a germline P/LP variant developed a primary ovarian Sertoli-Leydig cell tumor (SLCT) at a median age of 14 years (range: 11 months-66 years); 13% were diagnosed under age 8 years, the current age of onset of pelvic surveillance. Additionally, 4% of SLCTs were diagnosed before the age of 4 years., Conclusion: Ongoing data collection highlights the role of lung surveillance in the detection of early PPB and suggests that imaging-based detection and early resection may decrease the risk of advanced PPB. DICER1-related ovarian tumors were detected before age 8 years, prompting the Registry to recommend earlier initiation of ovarian surveillance with pelvic ultrasound beginning at the time of detection of a germline DICER1 P/LP variant.

The Consortium of Eosinophilic Gastrointestinal disease Researchers (CEGIR) and The International Gastrointestinal Eosinophil Researchers (TIGERs) organized a daylong symposium at the 2024 annual meeting of the American Academy of Allergy, Asthma & Immunology. The symposium featured new discoveries in basic and translational research as well as debates on the mechanisms and management of eosinophilic gastrointestinal diseases. Updates on recent clinical trials and consensus guidelines were also presented. We summarize the updates on eosinophilic gastrointestinal diseases presented at the symposium., Competing Interests: Disclosure statement Supported by U54AI117804 (Consortium of Eosinophilic Gastrointestinal Disease Researchers), which is part of the Rare Disease Clinical Research Network (RDCRN), an initiative of the Office of Rare Disease Research (ORDR), National Center for Advancing Translational Sciences (NCATS), and is funded through collaboration between National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NCATS, and in part by the Division of Intramural Research, NIAID/NIH. CEGIR is also supported by patient advocacy groups including American Partnership for Eosinophilic Disorders (APFED), Campaign Urging Research for Eosinophilic Diseases (CURED), and Eosinophilic Family Coalition (EFC). As a member of the RDCRN, CEGIR is also supported by its Data Management and Coordinating Center (DMCC) (U2CTR002818). Funding support for the DMCC is provided by the NCATS and the National Institute of Neurological Disorders and Stroke (NINDS). B.L.W. was funded by NIH/NIAID (K23AI158813). E.M.A. was funded by the NIH (KL2TR002552, K12TR004410). S.S.A. was funded by NIH/NIDDK (R56AI092135). S.J.A. was funded by NIH/National Heart, Lung, and Blood Institute (NHLBI) (R01HL153170). D.A.H. was directly supported by the Hartwell Foundation, the Food Allergy Fund, and a faculty development award from the American Academy of Allergy, Asthma & Immunology. Allergy research in the Hill laboratory was supported by NIH/NHLBI (R01HL162715) and the Children’s Hospital of Philadelphia Research Institute. J.W.C. was supported by the NIH (K23DK129784). F.L.K. was funded by APFED HOPE Pilot Grant 2023 and NIH/NIAID K23AI171085. M.A.R. was funded by the NIH (K08AI148456). L.A.S. was supported by NIH/NIAID (R01AI168134). The contents are those of the authors and do not necessarily represent the official views or an endorsement by the NIH or other funders. None of the funding sources had a role in the design or conduct of the study. Disclosure of potential conflict of interest: B. L. Wright reports in-kind support from Regeneron in the form of study drug (dupilumab and placebo) for a clinical trial of milk oral immunotherapy. J. P. Abonia reports receipt of payment or honoraria for lectures from Takeda Global Research and Development; participation on a data safety monitoring board for OctaPharma USA; and receipt of grants or contracts from Cures Within Reach and Celgene. E. M. Abud is coinventor of patent WO/2018/160496 (microglia differentiation and use); serves as advisory board member and consulting agreements with StemPharm and Neucyte; and reports advisory board participation for Amgen and AstraZeneca. S. S. Aceves is coinventor of oral viscous budesonide, patented by the University of California, San Diego, and licensed by Takeda (oral budesonide suspension); has acted as speaker for Regeneron/Sanofi; and has received research funding from Bristol Myers Squibb. S. J. Ackerman is chief science officer and executive board member of EnteroTrack; has received patents on the Esophageal String Test (EST); has consulted for Areteia Pharmaceuticals; and has participated on the medical advisory panel of the American Partnership for Eosinophilic Disorders (APFED). M. Braskett reports acting as scientific advisor to Bryn Pharma; and receipt of royalties from UpToDate. J. W. Chang reports consulting for Regeneron/Sanofi, Takeda, and Bristol Myers Squibb. M. Chehade reports consulting for Regeneron/Sanofi, Adare/Ellodi, AstraZeneca, Bristol Myers Squibb, Allakos, Shire/Takeda, Phathom, and Recludix Pharma; and receipt of research funding from Regeneron, Allakos, AstraZeneca, Adare/Ellodi, Bristol Myers Squibb, Danone, and Shire/Takeda. G. M. Constantine reports speaker honoraria from PeerView CME. C. M. Davis reports research funding from NIH/NIAID, DBV, Regeneron, AstraZeneca, Takeda, and Allergenis; and educational funding from Genentech. E. S. Dellon reports research funding from Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, Eupraxia, Ferring, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/BMS, Regeneron, Revolo, and Shire/Takeda; consulting for Abbott, AbbVie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Apollo, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Bryn, Calypso, Celgene/Receptos/BMS, Celldex, Eli Lilly, EsoCap, Eupraxia, Dr Falk Pharma, Ferring, GSK, Gossamer Bio, Holoclara, Invea, Knightpoint, Landos, LucidDx, Morphic, Nexstone Immunology/Uniquity, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE, and Upstream Bio; and receipt of educational grants from Allakos, Aqilion, Holoclara, and Invea. R. Durban reports consulting for Sanofi, AstraZeneca, Reckitt/Mead Johnson Nutrition, Abbott Nutrition, and Nutricia North America. D. A. Hill has received a patent related to the utilization of food-specific T-cell responses for the diagnosis and management of EoE. E. T. Jensen reports consulting fees from Regeneron, Jazz Pharmaceuticals, and TARGET-RWE. A. Kewalramani reports sitting on the Sanofi Mid-Atlantic Regional Respiratory Field medical advisory board. P. Khoury and A. D. Klion report royalties from UpToDate. F. L. Kuang reports research funding from AstraZeneca. E. C. McGowan reports funding from NIH/NIAID and American College of Gastroenterology; and consulting for Regeneron/Sanofi and Takeda. J. M. Spergel reports grant support from the NIH, Regeneron/Sanofi, and Novartis; and has consulted for Regeneron/Sanofi, Allakos, Readysetfood, Novartis, and Bristol Myers Squibb. A. M. Uchida reports consulting for Regeneron/Sanofi, Takeda, and AstraZeneca. J. B. Wechslerc reports consulting for Allakos, Ellodi, Regeneron/Sanofi/Genzyme, Bristol Myers Squibb, Invea Therapeutics, CellDex, and AstraZeneca; and clinical trial/research funding from Allakos and Regeneron/Sanofi. R. D. Pesek reports consulting for Regeneron. The rest of the authors declare that they have no relevant conflicts of interest., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Social media is increasingly used by patients for the management of skin conditions like acne, despite the potential risk for low-quality information. This study surveyed 45 participants between the ages of 12 and 17 years to investigate factors that could be associated with social media use among adolescents with acne. The likelihood of social media use was not significantly increased by clinical severity of acne, more severe physical barriers (greater than or equal to 20 miles to the dermatology clinic), more severe temporal barriers (waiting 12 or more weeks for a first dermatology appointment), or worsened quality of life (assessed via the Skindex-Teen score). This study increases understanding of adolescents' social media behaviors, particularly as a way to seek information for skin conditions like acne., (© 2024 Wiley Periodicals LLC.)

Background: Anaplastic sarcoma of the kidney (ASK) is a DICER1-related neoplasm first identified as a distinctive tumor type through the evaluation of unusual cases of putative anaplastic Wilms tumors. Subsequent case reports identified the presence of biallelic DICER1 variants as well as progression from cystic nephroma, a benign DICER1-related neoplasm. Despite increasing recognition of ASK as a distinct entity, the optimal treatment remains unclear., Methods: Individuals with known or suspected DICER1-related tumors including ASK were enrolled in the International Pleuropulmonary Blastoma/DICER1 Registry. Additionally, a comprehensive review of reported cases of ASK was undertaken, and data were aggregated for analysis with the aim to identify prognostic factors and clinical characteristics to guide decisions regarding genetic testing, treatment, and surveillance., Results: Ten cases of ASK were identified in the Registry along with 37 previously published cases. Staging data, per Children's Oncology Group guidelines, was available for 40 patients: 13 were stage I, 12 were stage II, 10 were stage III, and five were stage IV. Outcome data were available for 37 patients. Most (38 of 46) patients received upfront chemotherapy and 14 patients received upfront radiation. Two-year event-free survival (EFS) for stage I-II ASK was 81.8% (95% confidence interval [CI]: 67.2%-99.6%), compared with 46.6% EFS (95% CI: 24.7%-87.8%) for stage III-IV (p = .07). Two-year overall survival (OS) for stage I-II ASK was 88.9% (95% CI: 75.5%-100.0%), compared with 70.0% (95% CI: 46.7%-100.0%) for stage III-IV (p = .20). Chemotherapy was associated with improved EFS and OS with hazard ratios of 0.09 (95% CI: 0.02-0.31) and 0.08 (95% CI: 0.02-0.42), respectively., Conclusion: ASK is a rare DICER1-related renal neoplasm. In the current report, we identify clinical and treatment-related factors associated with outcome including the importance of chemotherapy in treating ASK. Ongoing data collection and genomic analysis are indicated to optimize outcomes for children and adults with these rare tumors., (© 2024 Wiley Periodicals LLC.)

Introduction: Although Hispanic White (HW) females have a lower incidence of breast cancer than non-Hispanic White (NHW) females, breast cancer risk is unclear for HW females after benign breast disease (BBD)., Methods: We compared BBD characteristics and subsequent breast cancer risk among HW and NHW females in New Mexico using a population-based collection of benign breast biopsies (1996-2007). BBD was categorized as nonproliferative disease (NPD), proliferative disease without atypia (PDWA), or atypical hyperplasia (AH). Breast cancer risk was assessed as absolute risk (AR) using cumulative incidence and RR by comparing the number of breast cancer events in BBDs to non-BBD., Results: This study included 3,684 HW and 6,587 NHW females with BBD. HW females had similar proportions of NPD (58.6% vs. 54.3%), PDWA (21.4% vs. 23.5%), and AH (3.6% vs. 3.3%) as NHW females. Breast cancer risk among all females with BBD was higher than population-based expected rates (RR, 1.87) and was similar for HW and NHW subgroups (RR = 1.99 vs. 1.84). As expected, breast cancer risk increased with increasing BBD severity, both overall [RR, 1.81 (NPD), 1.85 (PDWA), and 3.10 (AH)] and in the HW and NHW subgroups. Adjusted AR of breast cancer at 5 years also increased with the severity of BBD (HW vs. NHW; NPD: 1.4% vs. 2.1%; PDWA: 1.5% vs. 2.7%; AH: 6% vs. 4.8%)., Conclusions: We found similar breast cancer RRs and ARs in HW and NHW. Risk counseling should ensure that HW females receive breast cancer clinical management warranted by their similar absolute risks., Impact: The present population-based provides evidence for the clinical management of HW females with BBD for the prevention of breast cancer., (©2024 American Association for Cancer Research.)

Objective: Sertoli-Leydig cell tumors (SLCTs) are rare sex cord-stromal tumors, representing <0.5% of all ovarian tumors. We sought to describe prognostic factors, treatment and outcomes for individuals with ovarian SLCT., Methods: Individuals with SLCT were enrolled in the International Pleuropulmonary Blastoma/DICER1 Registry and/or the International Ovarian and Testicular Stromal Tumor Registry. Medical records were systematically abstracted, and pathology was centrally reviewed when available., Results: In total, 191 participants with ovarian SLCT enrolled, with most (92%, 175/191) presenting with FIGO stage I disease. Germline DICER1 results were available for 156 patients; of these 58% had a pathogenic or likely pathogenic germline variant. Somatic (tumor) DICER1 testing showed RNase IIIb hotspot variants in 97% (88/91) of intermediately and poorly differentiated tumors. Adjuvant chemotherapy was administered in 40% (77/191) of cases, and among these, nearly all patients received platinum-based regimens (95%, 73/77), and 30% (23/77) received regimens that included an alkylating agent. Three-year recurrence-free survival for patients with stage IA tumors was 93.6% (95% CI: 88.2-99.3%) compared to 67.1% (95% CI: 55.2-81.6%) for all stage IC and 60.6% (95% CI: 40.3-91.0%) for stage II-IV (p < .001) tumors. Among patients with FIGO stage I tumors, those with mesenchymal heterologous elements treated with surgery alone were at higher risk for recurrence (HR: 74.18, 95% CI: 17.99-305.85)., Conclusion: Most individuals with SLCT fare well, though specific risk factors such as mesenchymal heterologous elements are associated with poor prognosis. We also highlight the role of DICER1 surveillance in early detection of SLCT, facilitating stage IA resection., Competing Interests: Declaration of competing interest Dr. Hill is owner of ResourcePath LLC, a company which does research and development of laboratory tests including for DICER1 cancers. That work is unrelated to the information presented in this article. Dr. Stewart provides telegenetics services for Genome Medical, Inc., in accordance with relevant National Cancer Institute policies. The remaining authors have no conflicts to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Adipose tissue macrophages (ATMs) influence obesity-associated metabolic dysfunction, but the mechanisms by which they do so are not well understood. We show that miR-6236 is a bona fide miRNA that is secreted by ATMs during obesity. Global or myeloid cell-specific deletion of miR-6236 aggravates obesity-associated adipose tissue insulin resistance, hyperglycemia, hyperinsulinemia, and hyperlipidemia. miR-6236 augments adipocyte insulin sensitivity by inhibiting translation of negative regulators of insulin signaling, including PTEN. The human genome harbors a miR-6236 homolog that is highly expressed in the serum and adipose tissue of obese people. hsa-MIR-6236 expression negatively correlates with hyperglycemia and glucose intolerance, and positively correlates with insulin sensitivity. Together, our findings establish miR-6236 as an ATM-secreted miRNA that potentiates adipocyte insulin signaling and protects against metabolic dysfunction during obesity., (© 2024. The Author(s).)

Background: Pleuropulmonary blastoma (PPB), the hallmark tumour associated with DICER1 -related tumour predisposition, is characterised by an age-related progression from a cystic lesion (type I) to a high-grade sarcoma with mixed cystic and solid features (type II) or purely solid lesion (type III). Not all cystic PPBs progress; type Ir (regressed), hypothesised to represent regressed or non-progressed type I PPB, is an air-filled, cystic lesion lacking a primitive sarcomatous component. This study aims to evaluate the prevalence of non-progressed lung cysts detected by CT scan in adolescents and adults with germline DICER1 pathogenic/likely pathogenic (P/LP) variants., Methods: Individuals were enrolled in the National Cancer Institute Natural History of DICER1 Syndrome study, the International PPB/ DICER1 Registry and/or the International Ovarian and Testicular Stromal Tumor Registry. Individuals with a germline DICER1 P/LP variant with first chest CT at 12 years of age or older were selected for this analysis., Results: In the combined databases, 110 individuals with a germline DICER1 P/LP variant who underwent first chest CT at or after the age of 12 were identified. Cystic lung lesions were identified in 38% (42/110) with a total of 72 cystic lesions detected. No demographic differences were noted between those with lung cysts and those without lung cysts. Five cysts were resected with four centrally reviewed as type Ir PPB., Conclusion: Lung cysts are common in adolescents and adults with germline DICER1 variation. Further study is needed to understand the mechanism of non-progression or regression of lung cysts in childhood to guide judicious intervention., Competing Interests: Competing interests: Dr Hill is the owner of ResourcePath LLC, a company which does research and development of laboratory tests including for DICER1-related cancers. The work is unrelated to the information presented in this article. Dr Stewart provides telegenetics services for Genome Medical, Inc, in accordance with relevant National Cancer Institute policies. The remaining authors have no conflicts to disclose., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Objectives: Respiratory viral infections increase risk of asthma in infants and children. Infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus can cause severe lung inflammation and prolonged respiratory symptoms. We sought to determine whether SARS-CoV-2 infection modified pediatric incident asthma risk., Methods: This retrospective cohort study examined children ages 1 to 16 within the Children's Hospital of Philadelphia Care Network who received polymerase chain reaction (PCR) testing for SARS-CoV-2 between March 1, 2020 and February 28, 2021. Multivariable Cox regression models assessed the hazard ratio of new asthma diagnosis between SARS-CoV-2 PCR positive and SARS-CoV-2 PCR negative groups within an 18-month observation window. Models were adjusted for demographic characteristics, socioeconomic variables, and atopic comorbidities., Results: There were 27 423 subjects included in the study. In adjusted analyses, SARS-CoV-2 PCR positivity had no significant effect on the hazard of new asthma diagnosis (hazard ratio [HR]: 0.96; P = .79). Black race (HR: 1.49; P = .004), food allergies (HR: 1.26; P = .025), and allergic rhinitis (HR: 2.30; P < .001) significantly increased the hazard of new asthma diagnosis. Preterm birth (HR: 1.48; P = .005) and BMI (HR: 1.13; P < .001) significantly increased the hazard of new asthma diagnosis for children <5 years old., Conclusions: SARS-CoV-2 PCR positivity was not associated with new asthma diagnosis in children within the observation period, although known risk factors for pediatric asthma were confirmed. This study informs the prognosis and care of children with a history of SARS-CoV-2 infection., (Copyright © 2024 by the American Academy of Pediatrics.)

Objectives: There is little data evaluating procedural skills in current rural pediatric practices. In order to prepare a cadre of pediatricians to work in rural settings, we require an understanding of the unique procedural skills needed by rural pediatric providers. Our objective was to determine how often pediatricians performed various procedural skills, determine the importance of these skills to current practice, and how they differ between rural and urban pediatric providers., Methods: A survey evaluating pediatrician utilization of the 13 required Accreditation Council Graduate Medical Education procedural skills in current practice was developed and distributed to pediatric providers in New Mexico. Descriptive statistics were used to profile participants and describe survey responses. Chi-square tests were used to evaluate differences by urban setting or IHS. Fisher's exact test was employed to assess differences if cell sizes were less than five. All p-values were two sided with alpha=.05. Benjamini-Hochberg method was used to control for type 1 errors., Results: Fifty-two of 216 pediatric providers responded. The majority surveyed performed each of the 13 procedures less than monthly but competency in many of these procedures is important. Thirty-two respondents submitted free-text responses recommending competence with tracheostomy changes, gastrostomy-tube changes/cares, and circumcision., Conclusion: Majority of surveyed pediatricians performed the required procedures less than monthly but deemed several procedures to be important. Rural pediatricians recommended specific procedural skills needed in rural practice. All trainees receive procedural skills training. However, trainees interested in rural practice may need additional training in specific skills different than their non-rural counterparts., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

The Consortium of Eosinophilic Gastrointestinal Diseases and The International Gastrointestinal Eosinophil Researchers organized a day-long symposium at the 2022 Annual Meeting of the American Academy of Allergy, Asthma & Immunology. The symposium featured a review of recent discoveries in the basic biology and pathogenesis of eosinophilic gastrointestinal diseases (EGIDs) in addition to advances in our understanding of the clinical features of EGIDs. Diagnostic and management approaches were reviewed and debated, and clinical trials of emerging therapies were highlighted. Herein, we briefly summarize the breakthrough discoveries in EGIDs., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Competing Interests: AM is on the medical advisory board for Regeneron, Bristol Meyers Squib, and Nexstone Immunology and her lab receives research funding from Allakos and Morphic. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Germline pathogenic loss-of-function (pLOF) variants in DICER1 are associated with a predisposition for a variety of solid neoplasms, including pleuropulmonary blastoma and Sertoli-Leydig cell tumor (SLCT). The most common DICER1 pLOF variants include small insertions or deletions leading to frameshifts, and base substitutions leading to nonsense codons or altered splice sites. Larger deletions and pathogenic missense variants occur less frequently. Identifying these variants can trigger surveillance algorithms with potential for early detection of DICER1 -related cancers and cascade testing of family members. However, some patients with DICER1 -associated tumors have no pLOF variants detected by germline or tumor testing. Here, we present two patients with SLCT whose tumor sequencing showed only a somatic missense DICER1 RNase IIIb variant. Conventional exon-directed germline sequencing revealed no pLOF variants. Using a custom capture panel, we discovered novel intronic variants, ENST00000343455.7: c.1752+213A>G and c.1509+16A>G, that appear to interfere with normal splicing. We suggest that when no DICER1 pLOF variants or large deletions are discovered in exonic regions despite strong clinical suspicion, intron sequencing and splicing analysis should be performed.

Objectives: Describe clinical and epidemiologic patterns of pediatric allergy using longitudinal electronic health records (EHRs) from a multistate consortium of US practices., Methods: Using the multistate Comparative Effectiveness Research through Collaborative Electronic Reporting EHR database, we defined a cohort of 218 485 children (0-18 years) who were observed for ≥5 years between 1999 and 2020. Children with atopic dermatitis (AD), immunoglobulin E-mediated food allergy (IgE-FA), asthma, allergic rhinitis (AR), and eosinophilic esophagitis (EoE) were identified using a combination of diagnosis codes and medication prescriptions. We determined age at diagnosis, cumulative incidence, and allergic comorbidity., Results: Allergic disease cumulative (and peak age of) incidence was 10.3% (4 months) for AD, 4.0% (13 months) for IgE-FA, 20.1% (13 months) for asthma, 19.7% (26 months) for AR, and 0.11% (35 months) for EoE. The most diagnosed IgE-FAs were peanut (1.9%), egg (0.8%), and shellfish (0.6%). A total of 13.4% of children had ≥2 allergic conditions, and respiratory allergies (ie, asthma, AR) were commonly comorbid with each other, and with other allergic conditions., Conclusions: We detail pediatric allergy patterns using longitudinal, health care provider-based data from EHR systems across multiple US states and varied pediatric practice types. Our results support the population-level allergic march progression and indicate high rates of comorbidity among children with food and respiratory allergies., (Copyright © 2023 by the American Academy of Pediatrics.)

Extracellular vesicles (EVs) are nanometer size lipid particles that are released from virtually every cell type. Recent studies have shown that miRNAs carried by EVs play important roles in intercellular and interorgan communication. In the context of obesity and insulin resistance, EV-derived miRNAs functionally bridge major metabolic organs, including the adipose tissue, skeletal muscle, liver, and pancreas, to regulate insulin secretion and signaling. As a result, many of these EV-derived miRNAs have been proposed as potential disease biomarkers and/or therapeutic agents. However, the field's knowledge of EV miRNA-mediated regulation of mammalian metabolism is still in its infancy. Here, we review the evidence indicating that EV-derived miRNAs provide cell-to-cell and organ-to-organ communication to support metabolic health, highlight the potential medical relevance of these discoveries, and discuss the most important knowledge gaps and future directions for this field., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 The Author(s), Published by Wolters Kluwer Health, Inc.)

Congenital cystic pulmonary lesions (CCPLs) are represented by the following entities: congenital pulmonary airway malformation (CPAM), formerly congenital cystic adenomatoid malformation, extra- and intralobar sequestration (EIS), congenital lobar emphysema (overexpansion), and bronchogenic cyst. The developmental model of CPAM histogenesis by Stocker proposed perturbations designated as CPAM type 0 to type 4 without known or specific pathogenetic mechanisms along the airway from the bronchus to the alveolus. This review highlights mutational events either at the somatic level in KRAS (CPAM types 1 and possibly 3) or germline variants in congenital acinar dysplasia, formerly CPAM type 0, and pleuropulmonary blastoma (PPB), type I, formerly CPAM type 4. The potential for overt malignant progression exists in the case of PPB type I and CPAM type 1 in some cases to well-differentiated mucinous adenocarcinoma. On the other hand, CPAM type 2 is an acquired lesion resulting from interruption in lung development secondary to bronchial atresia. The latter is also regarded as the etiology of EIS whose pathologic features are similar, if not identical, to CPAM type 2. These observations have provided important insights into the pathogenetic mechanisms in the development of the CPAMs since the Stocker classification.

Background: Pleuropulmonary blastoma (PPB) is the most common lung cancer of infancy and early childhood. Type I PPB is a purely cystic lesion that has a microscopic population of primitive small cells with or without rhabdomyoblastic features and may progress to type II or III PPB, whereas type Ir lacks primitive small cells., Methods: Children with suspected PPB were enrolled in the International PPB/DICER1 Registry. Pathology was centrally reviewed, and follow-up was ascertained annually., Results: Between 2006 and 2022, 205 children had centrally reviewed type I or Ir PPB; 39% of children with type I and 5% of children with type Ir PPB received chemotherapy. Outcomes were favorable, although 11 children (nine with type I and two with type Ir PPB) experienced progression to type II/III (n = 8) or regrowth of type I PPB at the surgical site (n = 3), none of whom received chemotherapy before progression. Age and cyst size in combination were more suitable than either factor alone in predicting whether a particular lesion was type I or Ir PPB., Conclusions: For young children with type I PPB, outcomes are favorable, but complete resection is indicated because of the risk for progression. Chemotherapy may be useful in a subset of children at increased risk for recurrence/progression. Efforts to risk stratify children with type I PPB to optimize outcomes while reducing treatment-related side effects are underway., (© 2022 American Cancer Society.)

Current therapeutic strategies for treating nonalcoholic steatohepatitis (NASH) have failed to alleviate liver fibrosis, which is a devastating feature leading to hepatic dysfunction. Here, we integrated single-nucleus transcriptomics and epigenomics to characterize all major liver cell types during NASH development in mice and humans. The bifurcation of hepatocyte trajectory with NASH progression was conserved between mice and humans. At the nonalcoholic fatty liver (NAFL) stage, hepatocytes exhibited metabolic adaptation, whereas at the NASH stage, a subset of hepatocytes was enriched for the signatures of cell adhesion and migration, which were mainly demarcated by receptor tyrosine kinase ephrin type B receptor 2 (EphB2). EphB2, acting as a downstream effector of Notch signaling in hepatocytes, was sufficient to induce cell-autonomous inflammation. Knockdown of Ephb2 in hepatocytes ameliorated inflammation and fibrosis in a mouse model of NASH. Thus, EphB2-expressing hepatocytes contribute to NASH progression and may serve as a potential therapeutic target.

Background: Osteomyelitis in children may produce severe sequelae. However, the frequency and distribution of such complications by type of osteomyelitis (chronic or acute) is not well described., Methods: We searched the HealthFacts® database (containing medical information on 68 million individual patients in the United States) with 238 International Classification of Diseases (ICD) version 10 codes for acute osteomyelitis and chronic osteomyelitis appearing in 2015. Outcomes were recorded for each subject, including development of limb length discrepancies, pathologic fractures, mortality, and need for multiple surgeries or prolonged orthopedic care (one to two years following diagnosis). Gender, age and season of diagnosis were also assessed. Chi-square tests were used to compare differences between categorical variables, and t-tests between continuous variables., Results: Eight hundred sixty-nine subjects were included (57.4% male). Children with chronic osteomyelitis were older than those with acute osteomyelitis (median 9.5 years vs 12.0, respectively, p = .0004). Diagnoses were more common in winter (p = .0003). Four subjects died while hospitalized during the study period (two with acute osteomyelitis, two with chronic osteomyelitis). Limb length discrepancies were rare and similarly distributed between infection types (≤ 1.3% of subjects, p = .83). Subjects with chronic osteomyeltis were more likely to require long-term orthopedic follow-up (14.0% vs. 4.8% for acute osteomyelitis, p < .0001), suffer from pathologic fractures (1.5% vs < 1.0%, p = .003) and to require multiple surgeries (46.0% vs. 29.3%, p = .04)., Conclusions: Though infrequent, serious outcomes from osteomyelitis are more common with chronic osteomyelitis than acute osteomyelitis., (© 2023. The Author(s).)

Purpose: Pleuropulmonary blastoma (PPB) is the most common primary lung neoplasm of infancy and early childhood. Type II and type III PPB have historically been associated with a poor prognosis., Methods: Patients with known or suspected PPB were enrolled in the International PPB/ DICER1 Registry. Medical records were abstracted with follow-up ascertained annually. All PPB diagnoses were confirmed by central pathology review. Beginning in 2007, the IVADo regimen (ifosfamide, vincristine, actinomycin-D, and doxorubicin) was recommended as a potential treatment regimen for children with type II and type III PPB. This regimen was compared with a historical control cohort., Results: From 1987 to 2021, 314 children with centrally confirmed type II and type III PPB who received upfront chemotherapy were enrolled; 132 children (75 with type II and 57 with type III) received IVADo chemotherapy. Adjusted analyses suggest improved overall survival for children treated with IVADo in comparison with historical controls with an estimated hazard ratio of 0.65 (95% CI, 0.39 to 1.08). Compared with localized disease, distant metastasis at diagnosis was associated with worse PPB event-free survival and overall survival with hazard ratio of 4.23 (95% CI, 2.42 to 7.38) and 4.69 (95% CI, 2.50 to 8.80), respectively., Conclusion: The use of IVADo in children with type II and type III PPB resulted in similar-to-improved outcomes compared with historical controls. Inferior outcomes with metastatic disease suggest the need for novel therapies. This large cohort of uniformly treated children with advanced PPB serves as a benchmark for future multicenter therapeutic studies for this rare pediatric tumor.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with increased levels of autoantibodies targeting immunological proteins such as cytokines and chemokines. Reports further indicate that COVID-19 patients may develop a broad spectrum of autoimmune diseases due to reasons not fully understood. Even so, the landscape of autoantibodies induced by SARS-CoV-2 infection remains uncharted territory. To gain more insight, we carried out a comprehensive assessment of autoantibodies known to be linked to diverse autoimmune diseases observed in COVID-19 patients in a cohort of 231 individuals, of which 161 were COVID-19 patients (72 with mild, 61 moderate, and 28 with severe disease) and 70 were healthy controls. Dysregulated IgG and IgA autoantibody signatures, characterized mainly by elevated concentrations, occurred predominantly in patients with moderate or severe COVID-19 infection. Autoantibody levels often accompanied anti-SARS-CoV-2 antibody concentrations while stratifying COVID-19 severity as indicated by random forest and principal component analyses. Furthermore, while young versus elderly COVID-19 patients showed only slight differences in autoantibody levels, elderly patients with severe disease presented higher IgG autoantibody concentrations than young individuals with severe COVID-19. This work maps the intersection of COVID-19 and autoimmunity by demonstrating the dysregulation of multiple autoantibodies triggered during SARS-CoV-2 infection. Thus, this cross-sectional study suggests that SARS-CoV-2 infection induces autoantibody signatures associated with COVID-19 severity and several autoantibodies that can be used as biomarkers of COVID-19 severity, indicating autoantibodies as potential therapeutical targets for these patients., (© 2023 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

Objectives: Dog bites occur frequently in the United States, yet there are no clear guidelines for prescribing antibiotic prophylaxis in healthy children after a dog bite. The aim of our study was to assess antibiotic prophylaxis and subsequent rates of infection after dog bites in children. We hypothesized a negative association between prophylactic prescription of any antimicrobial and return visit within 14 days for infection., Methods: In this retrospective cohort study, we assessed the frequency of antibiotic prophylaxis prescribed after dog bite injuries in patients 0 to 18 years old and subsequent return visits for infection using 2016 to 2017 medical and pharmacy claims derived from the IBM MarketScan Research Databases. We used the International Classification of Diseases-10 code W54 for dog bites then used keyword searches to find diagnoses (including infection), wound descriptions, and medications., Results: Over the 2-year period, 22,911 patients were seen for dog bites that were not coded as infected. The majority, 13,043 (56.9%), were prescribed an antibiotic at the initial visit and 9868 (43.1%) were not. Of those prescribed antibiotics, 98 (0.75%; 95% confidence interval [CI], 0.60-0.90) returned with an infection, compared with 59 (0.60%; 95% CI, 0.44-0.75) of those not prescribed antibiotics. Receiving an antibiotic prescription at the initial visit was associated with a reduced rate of return for wound infection only among children whose wounds were repaired or closed. Children not receiving a prescription whose wounds were repaired were more than twice as likely to return with an infection in the subsequent 14 days as children whose wounds were not repaired (odds ratio, 2.2; 95% CI, 1.2-4.0)., Conclusions: Most children are prescribed antibiotics at an initial emergency department visit after a dog bite. However, very few return for infection independent of antimicrobial prophylaxis, which suggests antibiotics are overprescribed in this setting., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Thyroblastoma, a primary thyroid neoplasm with histological features of primitive thyroid tissue has recently been described and is included as a distinct entity in the most recent edition of the World Health Organization (WHO) Classification of Tumors (5th edition). In this study, we expand the clinical, morphological, and molecular profile of this aggressive neoplasm. Patient Findings: The patients are females, 19 and 45 years of age, referred for large thyroid nodules. Tumor morphology is biphasic, composed of nests and follicles of epithelial cells, some with colloid-like secretions reminiscent of fetal thyroid follicles intertwined with a primitive stromal spindle cell component. By immunohistochemistry, the epithelial component is diffusely positive for PAX8 and TTF1 markers. Molecular studies showed DICER1 aberrations. Conclusion: A primary primitive thyroid malignancy reminiscent of early fetal embryology with no teratoid element, recently reported as thyroblastoma represents a unique entity, novel in its description, and is likely underdiagnosed.

Objective: Antiretroviral therapy (ART) extends the life of people with HIV (PWH), but these individuals are at increased risk for obesity, dyslipidemia, diabetes, and cardiovascular disease. These comorbidities may be a consequence of HIV-related chronic inflammation and/or adverse effects of ART on tissue regulatory adipose tissue macrophages (ATMs). We sought to determine the effects of HIV/ART on metabolically beneficial ATM populations and functions., Design: We examined subcutaneous ATMs from PWH on integrase inhibitor-containing ART ( n  = 5) and uninfected persons ( n  = 9). We complemented these studies with ex vivo and in vitro analyses of peripheral blood mononuclear cell (PBMC) and murine macrophage lipid metabolism and fatty acid oxidation gene expression., Methods: ATM populations were examined by flow cytometry. Macrophage lipid metabolism and fatty acid oxidation gene expression were examined by Seahorse assay and quantitative PCR., Results: Adipose tissue from PWH had reduced populations of metabolically activated CD9 + ATMs compared to that of uninfected controls ( P  < 0.001). PBMCs of PWH had lower fatty acid metabolism compared to those of uninfected controls ( P  < 0.01). Analysis of murine macrophages revealed that dolutegravir reduced lipid metabolism ( P  < 0.001) and increased expression of the fatty acid beta-oxidation enzyme enoyl-CoA hydratase, short chain 1 ( P  < 0.05)., Conclusions: We report the loss of metabolically beneficial ATM populations in PWH on ART, altered fatty acid metabolism of blood immune cells, and evidence that dolutegravir alters macrophage fatty acid metabolism. Future studies should examine direct or indirect effects and mechanisms of dolutegravir, and other integrase inhibitors and ART classes, on fatty acid beta-oxidation., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Topical povidone-iodine, chlorhexidine, bacitracin, and vancomycin are commonly used antiseptic and antimicrobial agents to reduce risk and treat surgical site infections in numerous orthopedic procedures. Chondrocytes potentially may be exposed to these agents during operative procedures. The impact of these topical agents on chondrocyte viability is unclear. The goal of this study is to determine human chondrocyte viability ex vivo after exposure to commonly used concentrations of these topical antiseptic and antimicrobial agents. Human osteochondral plugs were harvested from the knee joint of a human decedent within 36 hours of death. Individual human osteochondral plugs were exposed to normal saline as a control; a range of concentrations of povidone-iodine (0.25%, 0.5%, and 1%), chlorhexidine (0.01% and 0.5%), and bacitracin (10,000 units/L, 50,000 units/L, and 100,000 units/L) for 1-minute lavage; or a 48-hour soak in vancomycin (0.16 mg/mL, 0.4 mg/mL, and 1.0 mg/mL) with nutrient media. Chondrocyte viability was evaluated with a live/dead viability assay at 0, 2, 4, and 6 days after exposure to bacitracin at 0, 3, and 6 days). Control subjects showed greater than 70% viability at all time points. Povidone-iodine, 0.5% chlorhexidine, and vancomycin showed significant cytotoxicity, with viability dropping to less than 40% by day 6. Chondrocytes exposed to 0.01% chlorhexidine maintained viability. Chondrocytes exposed to bacitracin showed viability until day 3, when there was a large drop in viability. Commonly used topical concentrations of povidone-iodine, vancomycin, and bacitracin are toxic to human chondrocytes ex vivo. A low concentration of chlorhexidine appears safe. Caution should be used when articular cartilage may be exposed to these agents during surgery. [ Orthopedics . 2022;45(5):e263-e268.].

Background: COVID-19 can cause some individuals to experience chronic symptoms. Rates and predictors of chronic COVID-19 symptoms are not fully elucidated., Objective: To examine occurrence and patterns of post-acute sequelae of SARS-CoV2 infection (PASC) symptomatology and their relationship with demographics, acute COVID-19 symptoms and anti-SARS-CoV-2 IgG antibody responses., Methods: A multi-stage observational study was performed of adults (≥18 years) from 5 US states. Participants completed two rounds of electronic surveys (May-July 2020; April-May 2021) and underwent testing to anti-SARS-CoV-2 nucleocapsid protein IgG antibody testing. Latent Class Analysis was used to identify clusters of chronic COVID-19 symptoms., Results: Overall, 390 adults (median [25%ile, 75%ile] age: 42 [31, 54] years) with positive SARS-CoV-2 antibodies completed the follow-up survey; 92 (24.7%) had ≥1 chronic COVID-19 symptom, with 11-month median duration of persistent symptoms (range: 1-12 months). The most common chronic COVID-19 symptoms were fatigue (11.3%), change in smell (9.5%) or taste (5.6%), muscle or joint aches (5.4%) and weakness (4.6%). There were significantly higher proportions of ≥1 persistent COVID-19 symptom (31.5% vs. 18.6%; Chi-square, P = 0.004), and particularly fatigue (15.8% vs. 7.3%, P = 0.008) and headaches (5.4% vs. 1.0%, P = 0.011) in females compared to males. Chronic COVID-19 symptoms were also increased in individuals with ≥6 acute COVID-19 symptoms, Latent class analysis revealed 4 classes of symptoms. Latent class-1 (change of smell and taste) was associated with lower anti-SARS-CoV-2 antibody levels; class-2 and 3 (multiple chronic symptoms) were associated with higher anti-SARS-CoV-2 antibody levels and more severe acute COVID-19 infection., Limitations: Ambulatory cohort with less severe acute disease., Conclusion: Individuals with SARS-CoV-2 infection commonly experience chronic symptoms, most commonly fatigue, changes in smell or taste and muscle/joint aches. Female sex, severity of acute COVID-19 infection, and higher anti-SARS-CoV-2 IgG levels were associated with the highest risk of having chronic COVID-19 symptoms., Competing Interests: The authors have declared that no competing interests exist.

Age-related macular degeneration (AMD), the leading cause of irreversible blindness among Americans over 50, is characterized by dysfunction and death of retinal pigment epithelial (RPE) cells. The RPE accumulates iron in AMD, and iron overload triggers RPE cell death in vitro and in vivo. However, the mechanism of RPE iron accumulation in AMD is unknown. We show that high-fat-diet-induced obesity, a risk factor for AMD, drives systemic and local inflammatory circuits upregulating interleukin-1β (IL-1β). IL-1β upregulates RPE iron importers and downregulates iron exporters, causing iron accumulation, oxidative stress, and dysfunction. We term this maladaptive, chronic activation of a nutritional immunity pathway the cellular iron sequestration response (CISR). RNA sequencing (RNA-seq) analysis of choroid and retina from human donors revealed that hallmarks of this pathway are present in AMD microglia and macrophages. Together, these data suggest that inflamed adipose tissue, through the CISR, can lead to RPE pathology in AMD., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in the Journal of Clinical Oncology , to patients seen in their own clinical practice ., Competing Interests: Joyce T. TurnerOther Relationship: Kognito D. Ashley HillEmployment: ResourcePathLeadership: ResourcePathStock and Other Ownership Interests: ResourcePath Jeffrey S. DomePatents, Royalties, Other Intellectual Property: Rockland ImmunochemicalsNo other potential conflicts of interest were reported.

This report documents a unique multicystic neoplasm of the liver in an 8-month-old boy with a heterozygous germline pathogenic DICER1 variant. This neoplasm, initially considered most likely a mesenchymal hamartoma based on imaging, demonstrated the characteristic histologic pattern of embryonal rhabdomyosarcoma residing in the subepithelial or cambium layer-like zone of the epithelial-lined cysts. Thus, although the differential diagnosis includes mesenchymal hamartoma, a young child with a multicystic mass lesion in the liver, lung, or kidney should both raise the possibility of a germline pathogenic DICER1 variant and also not be mistaken for one of the other hepatic neoplasms of childhood., (© 2021. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)

Background: Dupilumab has been approved to treat atopic dermatitis, asthma, and nasal polyps and is in active clinical trials for the treatment of eosinophilic esophagitis (EoE). Given its shared immunopathology, we hypothesized that EoE symptoms and inflammation would improve when dupilumab therapy was used for other allergic indications., Objective: To measure the clinical and histologic response in EoE to dupilumab when treating other atopic diseases., Methods: We completed a retrospective chart review of all patients at Children's Hospital of Philadelphia and Rady Children Hospital who were prescribed dupilumab for atopic dermatitis, asthma, or nasal polyps and had a concomitant clinical diagnosis of EoE. Demographic information along with histology, symptom scores, medications, and diet information were collected. Response to dupilumab was evaluated., Results: A total of 45 patients were identified. Of which, 11 patients were prescribed dupilumab for asthma, 27 for atopic dermatitis, 3 for nasal polyps, and 4 for compassionate use for EoE. There was no follow-up data for 8 patients. Follow-up histology was available for 26 patients: 22 of 26 had less than 6 eosinophils per high power field after the initiation of dupilumab with significant improvement (pre: 52.9 + 35.1 to post: 4.5 + 10.9 eosinophils/high power field, P < .005). A total of 28 patients had improvement of symptoms, with 24 patients reporting complete resolution of symptoms after dupilumab initiation. Reductions in EoE treatment medications (swallowed steroids, proton pump inhibitors) or expansion of diet occurred in 29 patients treated with dupilumab., Conclusion: Dupilumab therapy initiated for atopic disease effectively induces symptomatic and histologic remission of esophageal disease and reduces the need for EoE-directed therapy in patients with concomitant EoE., (Copyright © 2022 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Variants of concern (VOC) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including alpha, beta, gamma, delta, and omicron, threaten to prolong the pandemic, leading to more global morbidity and mortality. Genome sequencing is the mainstay of tracking the evolution of the virus, but is costly, slow, and not easily accessible. Multiplex quantitative RT-PCR assays for SARS-CoV-2 have been developed that identify all VOCs as well as other mutations of interest in the viral genome, nine mutations in total, using single-nucleotide discriminating molecular beacons. The presented variant molecular beacon assays showed a limit of detection of 50 copies of viral RNA, with 100% specificity. Twenty-six SARS-CoV-2-positive patient samples were blinded and tested using a two-tube assay. When testing patient samples, the assay was in full agreement with results from deep sequencing with a sensitivity and specificity of 100% (26 of 26). We have used our design methodology to rapidly design an assay that detects the new omicron variant. This omicron assay was used to accurately identify this variant in 17 of 33 additional patient samples. These quantitative RT-PCR assays identify all currently circulating VOCs of SARS-CoV-2, as well as other important mutations in the spike protein coding sequence. These assays can be easily implemented on broadly available five-color thermal cyclers and will help track the spread of these variants., (Copyright © 2022 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Extrapulmonary DICER1-associated sarcomas (DS) can harbor morphological features overlapping with pleuropulmonary blastoma. We report three children with intracranial and genital tract sarcomas, suspected to have DS based on a heterogeneous yet defining combination of spindle-cell sarcomatous and blastemal morphology, with rhabdomyomatous differentiation. Foci of immature cartilage at diagnosis (n = 2/3) and increased neuroepithelial differentiation at recurrence (n = 1) were noted. Morphological suspicion prompted somatic testing at reference centers, confirming likely biallelic, loss-of-function, and "hotspot" missense DICER1 variants in all three tumors. This can serve as a model for this diagnosis in resource-limited settings and has implications for germline testing, surveillance, and tumor management., (© 2021 Wiley Periodicals LLC.)

Pediatric tumors are uncommon, yet are the leading cause of cancer-related death in childhood. Tumor types, molecular characteristics, and pathogenesis are unique, often originating from a single genetic driver event. The specific diagnostic challenges of childhood tumors led to the development of the first World Health Organization (WHO) Classification of Pediatric Tumors. The classification is rooted in a multilayered approach, incorporating morphology, IHC, and molecular characteristics. The volume is organized according to organ sites and provides a single, state-of-the-art compendium of pediatric tumor types. A special emphasis was placed on "blastomas," which variably recapitulate the morphologic maturation of organs from which they originate. SIGNIFICANCE: In this review, we briefly summarize the main features and updates of each chapter of the inaugural WHO Classification of Pediatric Tumors, including its rapid transition from a mostly microscopic into a molecularly driven classification systematically taking recent discoveries in pediatric tumor genomics into account., (©2021 The Authors; Published by the American Association for Cancer Research.)

DICER1 syndrome (OMIM 606241, 601200) is a rare autosomal dominant familial tumor predisposition disorder with a heterozygous DICER1 germline mutation. The most common tumor seen clinically is the pleuropulmonary blastoma (PPB), a lung neoplasm of early childhood which is classified on its morphologic features into four types (IR, I, II and III) with tumor progression over time within the first 4-5 years of life from the prognostically favorable cystic type I to the unfavorable solid type III. Following the initial report of PPB, its association with other cystic neoplasms was demonstrated in family studies. The detection of the germline mutation in DICER1 provided the opportunity to identify and continue to recognize a number seemingly unrelated extrapulmonary neoplasms: Sertoli-Leydig cell tumor, gynandroblastoma, embryonal rhabdomyosarcomas of the cervix and other sites, multinodular goiter, differentiated and poorly differentiated thyroid carcinoma, cervical-thyroid teratoma, cystic nephroma-anaplastic sarcoma of kidney, nasal chondromesenchymal hamartoma, intestinal juvenile-like hamartomatous polyp, ciliary body medulloepithelioma, pituitary blastoma, pineoblastoma, primary central nervous system sarcoma, embryonal tumor with multilayered rosettes-like cerebellar tumor, PPB-like peritoneal sarcoma, DICER1-associated presacral malignant teratoid neoplasm and other non-neoplastic associations. Each of these neoplasms is characterized by a second somatic mutation in DICER1. In this review, we have summarized the salient clinicopathologic aspects of these tumors whose histopathologic features have several overlapping morphologic attributes particularly the primitive mesenchyme often with rhabdomyoblastic and chondroid differentiation and an uncommitted spindle cell pattern. Several of these tumors have an initial cystic stage from which there is progression to a high grade, complex patterned neoplasm. These pathologic findings in the appropriate clinical setting should serve to alert the pathologist to the possibility of a DICER1-associated neoplasm and initiate appropriate testing on the neoplasm and to alert the clinician about the concern for a DICER1 mutation., (© 2021. The Author(s).)

Background: Respiratory viruses, air pollutants, and aeroallergens are all implicated in worsening pediatric asthma symptoms, but their relative contributions to asthma exacerbations are poorly understood. A significant decrease in asthma exacerbations has been observed during the coronavirus disease 2019 pandemic, providing a unique opportunity to study how major asthma triggers correlate with asthma activity., Objective: To determine whether changes in respiratory viruses, air pollutants, and/or aeroallergens during the coronavirus disease 2019 pandemic were concomitant with decreased asthma exacerbations., Methods: Health care utilization and respiratory viral testing data between January 1, 2015, and December 31, 2020, were extracted from the Children's Hospital of Philadelphia Care Network's electronic health record. Air pollution and allergen data were extracted from US Environmental Protection Agency public databases and a National Allergy Bureau-certified station, respectively. Pandemic data (2020) were compared with historical data., Results: Recovery of in-person asthma encounters during phased reopening (June 6 to November 15, 2020) was uneven: primary care well and specialty encounters reached 94% and 74% of prepandemic levels, respectively, whereas primary care sick and hospital encounters reached 21% and 40% of prepandemic levels, respectively. During the pandemic, influenza A and influenza B decreased to negligible frequency when compared with prepandemic cases, whereas respiratory syncytial virus and rhinovirus infections decreased to low (though nonnegligible) prepandemic levels, as well. No changes in air pollution or aeroallergen levels relative to historical observations were noted., Conclusions: Our results suggest that viral respiratory infections are a primary driver of pediatric asthma exacerbations. These findings have broad relevance to both clinical practice and the development of health policies aimed at reducing asthma morbidity., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Purpose: Antihypertensives are commonly prescribed medications and their effect on breast cancer recurrence and mortality is not clear, particularly among specific molecular subtypes of breast cancer: luminal, triple-negative (TN), and HER2-overexpressing (H2E)., Methods: A population-based prospective cohort study of women aged 20-69 diagnosed with a first primary invasive breast cancer between 2004 and 2015 was conducted in the Seattle, Washington and Albuquerque, New Mexico greater metropolitan areas. Multivariable-adjusted Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for risks of breast cancer recurrence, breast cancer-specific mortality, and all-cause mortality associated with hypertension and antihypertensives., Results: In this sample of 2,383 luminal, 1,559 TN, and 615 H2E breast cancer patients, overall median age was 52 (interquartile range, 44-60). Hypertension and current use of antihypertensives were associated with increased risks of all-cause mortality in each subtype. Current use of angiotensin-converting enzyme inhibitors was associated with increased risks of both recurrence and breast cancer-specific mortality among luminal patients (HR: 2.5; 95% CI: 1.5, 4.3 and HR: 1.9; 95% CI: 1.2, 3.0, respectively). Among H2E patients, current use of calcium channel blockers was associated with an increased risk of breast cancer-specific mortality (HR: 1.8; 95% CI: 0.6, 5.4)., Conclusion: Our findings suggest that some antihypertensive medications may be associated with adverse breast cancer outcomes among women with certain molecular subtypes. Additional studies are needed to confirm these findings., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Eosinophilic esophagitis (EoE) is a T-cell-mediated disease that is caused by specific foods and results in esophageal dysfunction. Existing allergy testing modalities are not helpful when attempting to identify EoE-causal foods necessitating empiric food elimination and recurrent endoscopy. The goal of this study was to identify and compare allergen-specific immune features that can be assayed in a minimally invasive manner to predict clinical food allergy in EoE., Methods: We obtained blood samples from control subjects (n = 17), subjects with clinical EoE milk allergy (n = 17), and subjects with immunoglobulin E-mediated milk allergy (n = 9). We measured total and milk-specific plasma immunoglobulin G (IgG)4 levels and peripheral memory CD4 + T helper (T H ) cell proliferation and cytokine production after stimulation with endotoxin-depleted milk proteins. Sensitivity and specificity for predicting clinical EoE milk allergy were calculated and compared between approaches., Results: Total and milk-specific IgG4 levels were not significantly different between control subjects and subjects with clinical EoE milk allergy. Stimulation with milk proteins caused T H lymphocytes from subjects with clinical EoE milk allergy to proliferate more (%P1 of 38.3 ± 4.6 vs. 12.7 ± 2.8, p < 0.0001), and produce more type 2 cytokines (%IL-4 + of 33.7 ± 2.8 vs. 6.9 ± 1.6, p < 0.0001) than cells from control subjects. Milk-dependent memory T H -cell proliferation (sensitivity and specificity of 88% and 82%, respectively) and interleukin 4 (IL-4) production (sensitivity and specificity of 100%) most strongly predicted clinical EoE milk allergy., Conclusions: Peripheral markers of allergen-specific immune activation may be useful in identifying EoE-causal foods. Assaying milk-dependent IL-4 production by circulating memory T H lymphocytes most accurately predicts clinical EoE milk allergy., (© 2021 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Introduction: Pleuropulmonary blastoma (PPB), a rare childhood neoplasm of the lung, is linked to pathogenic DICER1 variants. We investigated checkpoint inhibitor markers including Programmed Death Ligand 1 (PD-L1), PD1, CD8 and tumor mutational burden (TMB) in PPB., Material and Methods: Cases were collected from departmental archives and the International PPB/ DICER1 Registry. Immunohistochemistry (IHC) for PD-L1, PD-1, CD8 and DNA mismatch repair (MMR) genes were performed. In addition, normal-tumor paired whole exome sequencing (WES) was performed in two cases., Results: Twenty-five PPB cases were studied, consisting of Type I (n = 8, including 2 Ir), Type II (n = 8) and Type III (n = 9). PD-L1 combined positive score (CPS) of 1, 4 and 80 was seen in three (3/25, 12.0%) cases of Type II PPB with negative staining in the remaining cases. PD-1 and CD8 stains demonstrated positive correlation ( P  < .05). The density of PD1 and CD8 in the interface area was higher than within tumor ( P  < .05). The MMR proteins were retained. TMB was 0.65 mutations/Mb in type II PPB with high expression of PD-L1, and 0.94 mutations/Mb in one negative PD-L1 case with metastatic tumor., Conclusion: A small subpopulation of PPB patient might benefit from checkpoint immunotherapy due to positive PD-L1 staining.

A 2-year-old boy presented with a large cystic and solid chest mass arising from the lung, radiographically consistent with pleuropulmonary blastoma (PPB). He underwent right lower lobectomy with resection of a well-circumscribed, mixed solid and cystic mass. The solid areas were composed of cords and nests of tumor cells in the myxoid stroma and retiform foci whose pathologic and immunophenotypic findings were consistent with a sex cord-stromal tumor with features of a Sertoli-Leydig cell tumor. Tumor testing showed a pathogenic variant in the DICER1 RNase IIIb hotspot domain. Family history was suggestive of DICER1 germline pathogenic DICER1 variation in absence of a detectable germline variant. He received 12 cycles of chemotherapy with ifosfamide, vincristine, dactinomycin and doxorubicin (IVADo) and surgery with complete response. One year after completion of chemotherapy, imaging studies showed concern for recurrence confirmed by thorascopic biopsy of a pleural-based mass. He is currently receiving cisplatin-based chemotherapy with reduction in tumor size. Review of the literature showed no similar cases; however, review of our pathology files revealed a single similar case of anterior mediastinal Sertoli cell tumor in a 3-year-old girl., (© 2021 Wiley Periodicals LLC.)

Objective: The classical allergic march model posits that atopy begins in infancy with atopic dermatitis and progresses to asthma and allergic rhinitis in a subset of individuals. The growing prevalence and severity of allergic diseases have prompted renewed interest in refining this model. This review outlines epidemiologic evidence for the existence of allergic march trajectories (distinct paths of atopy development in individuals); reviews the roles that genetics, environment, and disease endotypes play in determining trajectory outcomes; and discusses the clinical utility of the trajectory model., Data Sources: PubMed search of English-language articles and reviews without date limits pertaining to the epidemiology, genetics, and immunologic mechanisms of allergic march trajectories and disease endotypes., Study Selections: Studies and reviews were selected based on their high quality and direct relevance to the review topic., Results: Recent work in the field has revealed that immunoglobulin E-mediated food allergy and eosinophilic esophagitis are components of the allergic march. Furthermore, the field is acknowledging that variability exists in the number and sequence of allergic manifestations that individuals develop. These allergic march pathways, or trajectories, are influenced by genetic, environmental, and psychosocial factors that are incompletely understood., Conclusion: Continued elucidation of the landscape and origins of allergic march trajectories will inform efforts to personalize allergic disease prevention, diagnosis, and treatment., (Copyright © 2021 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: The complex relationship between clinical manifestations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and individual immune responses is not fully elucidated., Objective: To examine phenotypes of symptomatology and their relationship with positive anti-SARS-CoV-2 IgG antibody responses., Methods: An observational study was performed of adults (≥18 years) from 5 US states. Participants completed an electronic survey and underwent testing to anti-SARS-CoV-2 nucleocapsid protein IgG antibody between May and July 2020. Latent class analysis was used to identify characteristic symptom clusters., Results: Overall, 9507 adults (mean age, 39.6 ± 15.0 years) completed the survey; 6665 (70.1%) underwent antibody testing for anti-SARS-CoV-2 IgG. Positive SARS-CoV-2 antibodies were associated with self-reported positive SARS-CoV-2 nasal swab result (bivariable logistic regression; odds ratio [95% CI], 5.98 [4.83-7.41]), household with 6 or more members (1.27 [1.14-1.41]) and sick contact (3.65 [3.19-4.17]), and older age (50-69 years: 1.55 [1.37-1.76]; ≥70 years: 1.52 [1.16-1.99]), but inversely associated with female sex (0.61 [0.55-0.68]). Latent class analysis revealed 8 latent classes of symptoms. Latent classes 1 (all symptoms) and 4 (fever, cough, muscle ache, anosmia, dysgeusia, and headache) were associated with the highest proportion (62.0% and 57.4%) of positive antibodies, whereas classes 6 (fever, cough, muscle ache, headache) and 8 (anosmia, dysgeusia) had intermediate proportions (48.2% and 40.5%), and classes 3 (headache, diarrhea, stomach pain) and 7 (no symptoms) had the lowest proportion (7.8% and 8.5%) of positive antibodies., Conclusions: SARS-CoV-2 infections manifest with substantial diversity of symptoms, which are associated with variable anti-SARS-CoV-2 IgG antibody responses. Prolonged fever, anosmia, and receiving supplemental oxygen therapy had strongest associations with positive SARS-CoV-2 IgG., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Study Objective: Rhabdomyosarcomas (RMSs) of the female genital tract (FGT) have been recently shown to be associated with germline pathogenic variation in DICER1, which can underlie a tumor predisposition disorder. We sought to determine the incidence of a pathogenic variation in DICER1 in a cohort of RMSs of the FGT, as well as to evaluate the clinicopathological features and outcomes of the patients. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: We retrospectively reviewed medical records of the patients diagnosed with RMS of the FGT between 1990 and 2019. Molecular genetic sequencing of the tumor to detect an RNase IIIb domain hot spot mutation in DICER1 samples was performed in 7 patients. Individuals with a missense mutation in the tumor were also screened for a loss of function germline mutation in DICER1., Results: Of 210 cases of pediatric RMS, 11 arose from the FGT. Molecular genetic sequencing of the tumor samples revealed a somatic missense mutation in the RNase IIIb domain of DICER1 in a total of 3 patients, 2 patients with embryonal RMS of the cervix/uterus, and 1 patient with ovarian embryonal RMS. As a result of genetic testing for the loss of function germline mutation in DICER1, a heterozygous pathogenic variant was also found in 2 of these patients., Conclusion: Despite the limited number of patients, our findings suggest that it is important to be aware of the possible association between RMS of FGT and pathogenic germline DICER1 variants because the detection of this mutation in a patient or relatives can provide the opportunity for surveillance of related conditions that might improve long-term outcomes and survival., (Copyright © 2021 Elsevier Ltd. All rights reserved.)