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Hepatitis C virus (HCV) uniquely requires the liver-specific microRNA-122 for replication, yet global effects on endogenous miRNA targets during infection are unexplored. Here, high-throughput sequencing and crosslinking immunoprecipitation (HITS-CLIP) experiments of human Argonaute (AGO) during HCV infection showed robust AGO binding on the HCV 5'UTR at known and predicted miR-122 sites. On the human transcriptome, we observed reduced AGO binding and functional mRNA de-repression of miR-122 targets during virus infection. This miR-122 "sponge" effect was relieved and redirected to miR-15 targets by swapping the miRNA tropism of the virus. Single-cell expression data from reporters containing miR-122 sites showed significant de-repression during HCV infection depending on expression level and site number. We describe a quantitative mathematical model of HCV-induced miR-122 sequestration and propose that such miR-122 inhibition by HCV RNA may result in global de-repression of host miR-122 targets, providing an environment fertile for the long-term oncogenic potential of HCV.
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Hepacivirus/metabolismo , Hepatite C/metabolismo , Hepatite C/virologia , MicroRNAs/metabolismo , RNA Viral/metabolismo , Proteínas Argonautas/metabolismo , Sequência de Bases , Linhagem Celular Tumoral , Fatores de Iniciação em Eucariotos/metabolismo , Hepacivirus/genética , Humanos , Fígado/metabolismo , Fígado/virologia , Dados de Sequência Molecular , RNA Viral/química , Replicação ViralRESUMO
Systemic lupus erythematosus (SLE) is prototypical autoimmune disease driven by pathological T cell-B cell interactions1,2. Expansion of T follicular helper (TFH) and T peripheral helper (TPH) cells, two T cell populations that provide help to B cells, is a prominent feature of SLE3,4. Human TFH and TPH cells characteristically produce high levels of the B cell chemoattractant CXCL13 (refs. 5,6), yet regulation of T cell CXCL13 production and the relationship between CXCL13+ T cells and other T cell states remains unclear. Here, we identify an imbalance in CD4+ T cell phenotypes in patients with SLE, with expansion of PD-1+/ICOS+ CXCL13+ T cells and reduction of CD96hi IL-22+ T cells. Using CRISPR screens, we identify the aryl hydrocarbon receptor (AHR) as a potent negative regulator of CXCL13 production by human CD4+ T cells. Transcriptomic, epigenetic and functional studies demonstrate that AHR coordinates with AP-1 family member JUN to prevent CXCL13+ TPH/TFH cell differentiation and promote an IL-22+ phenotype. Type I interferon, a pathogenic driver of SLE7, opposes AHR and JUN to promote T cell production of CXCL13. These results place CXCL13+ TPH/TFH cells on a polarization axis opposite from T helper 22 (TH22) cells and reveal AHR, JUN and interferon as key regulators of these divergent T cell states.
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The rate of pediatric hospitalization for cutaneous pathology has been increasing in recent years, often requiring the expertise of consulting pediatric dermatologists; however, the infrastructure of inpatient pediatric dermatology consultative services remains poorly characterized. We sought to assess the structure, consult volume, physician compensation, and utilization of teledermatology in pediatric dermatology inpatient services to better understand the current care model. Our survey of 118 pediatric dermatologists revealed that 89% of respondents see between 1 and 10 new consults per week, 39% perform all inpatient consults including evening and weekends without assistance from other providers, 71% do not have protected time during the week to provide inpatient consultations, and only 10% receive financial compensation via stipend. By highlighting both the high demand for pediatric consultative dermatology as well as the significant burden placed on these providers by existing practice models, we hope to encourage a reappraisal of the current infrastructure of pediatric inpatient dermatology to increase structural and financial support for this vital service.
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Dermatologia , Humanos , Criança , Estados Unidos , Pele , Inquéritos e Questionários , Recursos Humanos , Encaminhamento e ConsultaRESUMO
BACKGROUND: Cutaneous (or "Metastatic") Crohn disease (CCD) is a rare and underrecognized disease characterized by cutaneous granulomatous inflammation. We describe patient demographics, clinical characteristics, histology, and treatment of 89 pediatric cases of CCD, including 78 previously reported and 11 new cases seen at four academic institutions. We emphasize the efficacy of biologic mono- and dual therapy. METHODS: PubMed identified cases using keywords including "metastatic Crohn disease" and "cutaneous Crohn disease". Patients were identified by retrospective review of the electronic health record including histopathologic diagnosis consistent with CCD. Chart review collected demographic, clinical, and histologic data. RESULTS: Most pediatric patients with CCD are male 55% (49/89), present with edema (73/89, 82%) and erythema (47/89, 53%) of the genitals (33/49, 67%), and have intestinal Crohn disease (69/89, 78%). Oral corticosteroids (53/75, 71%) and metronidazole (29/75, 39%) are the most frequently prescribed medications. Of the 17 patients treated with tumor necrosis factor (TNF)-blockade, 94% (16/17) had partial or total clearance. Ustekinumab resulted in clearance of cutaneous disease in two patients (2/3, 67%) and partial clearance in one patient (1/3, 33%). Two cases achieved total clearance with the use of dual biologic therapy defined as the use of two biologic therapies with differing mechanisms of action or the use of a biologic therapy and small molecule inhibitor. CONCLUSIONS: TNF blockade is an effective treatment for pediatric CCD, and interleukin-12/23 inhibitors may be similarly effective. Consideration of dual biologic therapy may be useful in pediatric patients requiring discordant therapies for their intestinal and cutaneous CD.
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Early in the COVID-19 pandemic, anti-malarial agent hydroxychloroquine (HCQ) was touted as a potentially effective COVID-19 treatment due to its purported antiinflammatory and antiviral effects.
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Alopecia , Tratamento Farmacológico da COVID-19 , Cicatriz , Hidroxicloroquina , Alopecia/diagnóstico , Alopecia/tratamento farmacológico , Antivirais/uso terapêutico , Humanos , Hidroxicloroquina/uso terapêutico , Pandemias , Pontuação de Propensão , Resultado do TratamentoRESUMO
A 54-year-old woman presented with erythematous annular and indurated plaques on her face, trunk, and extremities and had false-positive syphilis test results during 2 pregnancies 25 and 22 years prior. What would you do next?
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A man presented with a pruritic cutaneous eruption that began on his scalp and face and over 2 months spread across most of his body. Physical examination revealed confluent salmon-colored plaques with areas of unaffected skin; waxy, exfoliative scale on the volar aspect of the hands and feet; and ectropion. He had no history of psoriasis, atopic dermatitis, or other skin disorder, and no recent viral or bacterial infection. What is the diagnosis and what would you do next?
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Exantema , Humanos , Exantema/etiologiaAssuntos
Infecções por Coronavirus/prevenção & controle , Dermatologia/educação , Educação de Pós-Graduação em Medicina/organização & administração , Corpo Clínico Hospitalar/organização & administração , Avaliação de Resultados em Cuidados de Saúde , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Recursos Humanos/organização & administração , Atitude do Pessoal de Saúde , COVID-19 , Infecções por Coronavirus/epidemiologia , Feminino , Humanos , Unidades de Terapia Intensiva/organização & administração , Masculino , Inovação Organizacional , Pandemias/estatística & dados numéricos , Pneumonia Viral/epidemiologia , Estados UnidosRESUMO
Importance: Objectively determining disease progression in craniofacial morphea (CM) is challenging, as clinical findings of disease activity are often lacking. Objective: To evaluate the utility of 3-dimensional (3D) stereophotogrammetry in detecting disease progression in CM over time. Design, Setting, and Participants: This prospective cohort study included 27 pediatric and adult patients with CM from 2 hospitals in Boston (Boston Children's Hospital and Brigham & Women's Hospital) consecutively enrolled from April 1, 2019, to March 1, 2023. Review of 3D stereophotogrammetry images and data analysis occurred from March 1 to April 1, 2023. Main Outcomes and Measures: Clinical and 3D stereophotogrammetry assessments were performed at 2- to 12-month intervals, depending on the clinical context. The 3D stereophotogrammetry images were then qualitatively rated as demonstrating no progression or definitive progression by an expert (board-certified plastic craniofacial surgeon) and nonexpert (board-certified dermatologist) in 3D stereophotogrammetry. In addition, κ coefficients were calculated for interrater reliability. Results: Of 27 patients with CM (19 female; median age, 14 [range, 5-40] years) and 3D stereophotogrammetry images obtained from a minimum of 2 time points (median, 4 [range, 2-10] images) spaced a median of 3 (range, 2-12) months apart, 10 experienced progression of their disease based on clinical assessments performed during the study period. In all cases in which clinical progression was favored, blinded qualitative assessment of 3D stereophotogrammetry images also favored progression with substantial interrater reliability (κ = 0.80 [95% CI, 0.61-0.99]). Furthermore, review of 3D stereophotogrammetry detected occult progression of asymmetry not noted on clinical examination in 3 additional patients. Conclusions and Relevance: In this prospective cohort study, blinded assessment of sequential 3D stereophotogrammetry images in patients with CM not only corroborated clinical assessment of disease progression but also detected occult progression of facial asymmetry not appreciable on clinical examination alone. Therefore, 3D stereophotogrammetry may serve as a useful adjunct to clinical examination of patients with CM over time. Future investigations are warranted to validate 3D stereophotogrammetry as an outcome measure in CM.
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Esclerodermia Localizada , Adulto , Humanos , Feminino , Criança , Adolescente , Reprodutibilidade dos Testes , Estudos Prospectivos , Esclerodermia Localizada/diagnóstico por imagem , Imageamento Tridimensional/métodos , Fotogrametria/métodos , Progressão da DoençaRESUMO
Vulvar dermatology represents a challenge for many providers. Given that the vulva is both a gynecologic and dermatologic organ, patients with cutaneous lesions involving the vulva may present to primary care, gynecology, or dermatology. Particularly within dermatology, the vulva remains understudied, which can lead to anxiety among providers regarding appropriate next steps in the diagnosis and management of vulvar lesions. Thus, the purpose of this review is to highlight commonly encountered anatomic variants and benign neoplasms of the vulva, distinguish them from key pathologic mimickers, and provide guidance to practicing dermatologists on what may constitute normal vulvar variations.
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Importance: To date, no study has characterized the mucocutaneous features seen in hospitalized children with multisystem inflammatory syndrome in children (MIS-C) or the temporal association of these findings with the onset of systemic symptoms. Objective: To describe the mucocutaneous findings seen in children with MIS-C during the height of the coronavirus disease 2019 (COVID-19) pandemic in New York City in 2020. Design, Setting, and Participants: A retrospective case series was conducted of 35 children admitted to 2 hospitals in New York City between April 1 and July 14, 2020, who met Centers for Disease Control and Prevention and/or epidemiologic criteria for MIS-C. Main Outcomes and Measures: Laboratory and clinical characteristics, with emphasis on mucocutaneous findings, of children who met criteria for MIS-C. The characterization of mucocutaneous features was verified by 2 board-certified pediatric dermatologists. Results: Twenty-five children (11 girls [44%]; median age, 3 years [range, 0.7-17 years]) were identified who met definitional criteria for MIS-C; an additional 10 children (5 girls [50%]; median age, 1.7 years [range, 0.2-15 years]) were included as probable MIS-C cases (patients met all criteria with the exception of laboratory test evidence of severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] infection or known exposure). The results of polymerase chain reaction tests for SARS-CoV-2 were positive for 10 patients (29%), and the results of SARS-CoV-2 immunoglobulin G tests were positive for 19 patients (54%). Of the 35 patients, 29 (83%) exhibited mucocutaneous changes, with conjunctival injection (n = 21), palmoplantar erythema (n = 18), lip hyperemia (n = 17), periorbital erythema and edema (n = 7), strawberry tongue (n = 8), and malar erythema (n = 6) being the most common findings. Recognition of mucocutaneous findings occurred a mean of 2.7 days (range, 1-7 days) after the onset of fever. The duration of mucocutaneous findings varied from hours to days (median duration, 5 days [range, 0-11 days]). Neither the presence nor absence of mucocutaneous findings was significantly associated with overall disease severity. Conclusions and Relevance: In this case series of hospitalized children with suspected MIS-C during the COVID-19 pandemic, a wide spectrum of mucocutaneous findings was identified. Despite their protean and transient nature, these mucocutaneous features serve as important clues in the recognition of MIS-C.
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COVID-19/complicações , Dermatopatias/etiologia , Síndrome de Resposta Inflamatória Sistêmica/complicações , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Mucosa , Cidade de Nova Iorque , Estudos RetrospectivosRESUMO
This case report describes a 14-year-old girl with juvenile dermatomyositis who presented with a 6-year history of a pruritic, photosensitive eruption involving her face, neck, trunk, and extremities and was successfully treated with anifrolumab.
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Dermatomiosite , Humanos , Dermatomiosite/tratamento farmacológico , Pele , Anticorpos Monoclonais Humanizados/uso terapêutico , Administração CutâneaRESUMO
This case series describes the outcomes among adolescent patients with systemic lupus erythematosus and refractory discoid lupus erythematosus treated with anifrolumab.