RESUMO
Teclistamab is a Bcell maturation antigen (BCMA)-directed bispecific antibody approved for the treatment of patients with triple-class exposed relapsed/refractory multiple myeloma. In the phase 1/2 MajesTEC-1 study, a cohort of patients who had prior BCMA-targeted therapy (antibody-drug conjugate [ADC] or CAR-T cell therapy) were enrolled to explore teclistamab in patients previously exposed to anti-BCMA treatment. At median follow-up of 28.0 months (range, 0.7-31.1), 40 patients with prior BCMA-targeted therapy had received subcutaneous 1.5 mg/kg weekly teclistamab. Median prior lines of treatment were 6 (range, 3-14). Prior anti-BCMA therapy included ADC (n = 29), CAR-T (n = 15), or both (n = 4). Overall response rate was 52.5%; 47.5% of patients achieved very good partial response or better and 30.0% achieved complete response or better. Median duration of response was 14.8 months, median progression-free survival was 4.5 months, and median overall survival was 15.5 months. The most common treatment-emergent adverse events (TEAEs) were neutropenia, infections, cytokine release syndrome, and anemia; cytopenias and infections were the most common grade ≥3 TEAEs. Infections occurred in 28 (70.0%) patients (n = 13 [32.5%] maximum grade 3/4; n = 4 [10%] grade 5). Prior to starting teclistamab, baseline BCMA expression and immune characteristics were unaffected by prior anti-BCMA treatment. The MajesTEC-1 trial cohort C results demonstrate favorable efficacy and safety of teclistamab in patients with heavily pretreated RRMM and prior anti-BCMA treatment. NCT03145181; NCT04557098.
RESUMO
ABSTRACT: Teclistamab, an off-the-shelf B-cell maturation antigen (BCMA) × CD3 bispecific antibody that mediates T-cell activation and subsequent lysis of BCMA-expressing myeloma cells, is approved for the treatment of patients with relapsed/refractory multiple myeloma (R/RMM). As a T-cell redirection therapy, clinical outcomes with teclistamab may be influenced by patient immune fitness and tumor antigen expression. We correlated tumor characteristics and baseline immune profiles with clinical response and disease burden in patients with R/RMM from the pivotal phase 1/2 MajesTEC-1 study, focusing on patients treated with 1.5 mg/kg of teclistamab (N = 165). Peripheral blood samples were collected at screening, and bone marrow samples were collected at screening and cycle 3. Better clinical outcomes to teclistamab correlated with higher baseline total T-cell counts in the periphery. In addition, responders (partial response or better) had a lower proportion of immunosuppressive regulatory T cells (Tregs), T cells expressing coinhibitory receptors (CD38, PD-1, and PD-1/TIM-3), and soluble BCMA and a T-cell profile suggestive of a more cytolytic potential, compared with nonresponders. Neither frequency of baseline bone marrow BCMA expression nor BCMA-receptor density was associated with clinical response to teclistamab. Improved progression-free survival was observed in patients with a lower frequency of T cells expressing exhaustion markers and immunosuppressive Tregs. Overall, response to teclistamab was associated with baseline immune fitness; nonresponders had immune profiles suggestive of immune suppression and T-cell dysfunction. These findings illustrate the importance of the contribution of the immune landscape to T-cell redirection therapy response. This trial was registered at www.ClinicalTrials.gov as #NCT03145181/NCT04557098.
Assuntos
Mieloma Múltiplo , Humanos , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Mieloma Múltiplo/terapia , Masculino , Anticorpos Biespecíficos/uso terapêutico , Feminino , Antígeno de Maturação de Linfócitos B/imunologia , Pessoa de Meia-Idade , IdosoRESUMO
BACKGROUND: Racial and ethnic disparities in life expectancy in the United States have been widely documented. To date, there remains a paucity of similar data in patients with inborn errors of immunity (IEIs). OBJECTIVE: Our aim was to examine racial and ethnic differences in mortality due to an IEI in the United States. METHODS: We analyzed National Center for Health Statistics national mortality data from 2003 to 2018. We quantified age-adjusted death rate and age-specific death rate as a result of an IEI for each major racial and ethnic group in the United States and examined the association of race and ethnicity with death at a younger age. RESULTS: From 2003 to 2018, IEIs were reported as the underlying or contributing cause of death in 14,970 individuals nationwide. The age-adjusted death rate was highest among Black patients (4.25 per 1,000,000 person years), compared with 2.01, 1.71, 1.50, and 0.92 per 1,000,000 person years for White, American Indian/Alaska Native, Hispanic, and Asian/Pacific Islander patients, respectively. The odds of death before age 65 years were greatest among Black patients (odds ratio [OR] = 5.15 [95% CI = 4.61-5.76]), followed by American Indian/Alaska Native patients (OR = 3.58 [95% CI = 2.30-5.82]), compared with White patients. The odds of death before age 24 years were greater among Hispanic patients than among non-Hispanic patients (OR = 3.60 [95% CI = 3.08-4.18]). CONCLUSION: Our study highlights racial and ethnic disparities in mortality due to an IEI and the urgent need to further identify and systematically remove barriers in care for historically marginalized patients with IEIs.
Assuntos
Etnicidade , Disparidades nos Níveis de Saúde , Doenças do Sistema Imunitário , Grupos Raciais , Humanos , Estados Unidos/epidemiologia , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/mortalidadeRESUMO
BACKGROUND: Guidelines recommend shared decision-making (SDM) around mammography screening for women ≥ 75 years old. OBJECTIVE: To use microsimulation modeling to estimate the lifetime benefits and harms of screening women aged 75, 80, and 85 years based on their individual risk factors (family history, breast density, prior biopsy) and comorbidity level to support SDM in clinical practice. DESIGN, SETTING, AND PARTICIPANTS: We adapted two established Cancer Intervention and Surveillance Modeling Network (CISNET) models to evaluate the remaining lifetime benefits and harms of screening U.S. women born in 1940, at decision ages 75, 80, and 85 years considering their individual risk factors and comorbidity levels. Results were summarized for average- and higher-risk women (defined as having breast cancer family history, heterogeneously dense breasts, and no prior biopsy, 5% of the population). MAIN OUTCOMES AND MEASURES: Remaining lifetime breast cancers detected, deaths (breast cancer/other causes), false positives, and overdiagnoses for average- and higher-risk women by age and comorbidity level for screening (one or five screens) vs. no screening per 1000 women. RESULTS: Compared to stopping, one additional screen at 75 years old resulted in six and eight more breast cancers detected (10% overdiagnoses), one and two fewer breast cancer deaths, and 52 and 59 false positives per 1000 average- and higher-risk women without comorbidities, respectively. Five additional screens over 10 years led to 23 and 31 additional breast cancer cases (29-31% overdiagnoses), four and 15 breast cancer deaths avoided, and 238 and 268 false positives per 1000 average- and higher-risk screened women without comorbidities, respectively. Screening women at older ages (80 and 85 years old) and high comorbidity levels led to fewer breast cancer deaths and a higher percentage of overdiagnoses. CONCLUSIONS: Simulation models show that continuing screening in women ≥ 75 years old results in fewer breast cancer deaths but more false positive tests and overdiagnoses. Together, clinicians and 75 + women may use model output to weigh the benefits and harms of continued screening.
Assuntos
Neoplasias da Mama , Mamografia , Feminino , Humanos , Idoso de 80 Anos ou mais , Idoso , Mamografia/efeitos adversos , Mamografia/métodos , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/epidemiologia , Mama , Densidade da Mama , Simulação por Computador , Detecção Precoce de Câncer/efeitos adversos , Detecção Precoce de Câncer/métodos , Programas de Rastreamento/efeitos adversos , Programas de Rastreamento/métodosRESUMO
Malassezia are yeast species that commonly colonize healthy skin. However, they have been associated with or implicated in the pathogenesis of numerous skin disorders, particularly in the setting of pediatric populations. In this review, we will focus on several Malassezia-associated skin conditions manifesting in infants, children, and adolescents: pityriasis versicolor, Malassezia folliculitis, infantile and adolescent seborrheic dermatitis, head and neck dermatitis, and neonatal cephalic pustulosis. We examine the literature and provide an overview of these conditions, including clinical presentation in diverse skin colors, diagnosis, risk factors, and treatment and management. Additionally, we summarize and highlight some of the proposed theories on the role of Malassezia spp. in the pathogenesis of these skin conditions.
RESUMO
Importance: The effects of breast cancer incidence changes and advances in screening and treatment on outcomes of different screening strategies are not well known. Objective: To estimate outcomes of various mammography screening strategies. Design, Setting, and Population: Comparison of outcomes using 6 Cancer Intervention and Surveillance Modeling Network (CISNET) models and national data on breast cancer incidence, mammography performance, treatment effects, and other-cause mortality in US women without previous cancer diagnoses. Exposures: Thirty-six screening strategies with varying start ages (40, 45, 50 years) and stop ages (74, 79 years) with digital mammography or digital breast tomosynthesis (DBT) annually, biennially, or a combination of intervals. Strategies were evaluated for all women and for Black women, assuming 100% screening adherence and "real-world" treatment. Main Outcomes and Measures: Estimated lifetime benefits (breast cancer deaths averted, percent reduction in breast cancer mortality, life-years gained), harms (false-positive recalls, benign biopsies, overdiagnosis), and number of mammograms per 1000 women. Results: Biennial screening with DBT starting at age 40, 45, or 50 years until age 74 years averted a median of 8.2, 7.5, or 6.7 breast cancer deaths per 1000 women screened, respectively, vs no screening. Biennial DBT screening at age 40 to 74 years (vs no screening) was associated with a 30.0% breast cancer mortality reduction, 1376 false-positive recalls, and 14 overdiagnosed cases per 1000 women screened. Digital mammography screening benefits were similar to those for DBT but had more false-positive recalls. Annual screening increased benefits but resulted in more false-positive recalls and overdiagnosed cases. Benefit-to-harm ratios of continuing screening until age 79 years were similar or superior to stopping at age 74. In all strategies, women with higher-than-average breast cancer risk, higher breast density, and lower comorbidity level experienced greater screening benefits than other groups. Annual screening of Black women from age 40 to 49 years with biennial screening thereafter reduced breast cancer mortality disparities while maintaining similar benefit-to-harm trade-offs as for all women. Conclusions: This modeling analysis suggests that biennial mammography screening starting at age 40 years reduces breast cancer mortality and increases life-years gained per mammogram. More intensive screening for women with greater risk of breast cancer diagnosis or death can maintain similar benefit-to-harm trade-offs and reduce mortality disparities.
Assuntos
Neoplasias da Mama , Detecção Precoce de Câncer , Mamografia , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Fatores Etários , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/diagnóstico por imagem , Técnicas de Apoio para a Decisão , Reações Falso-Positivas , Incidência , Programas de Rastreamento , Uso Excessivo dos Serviços de Saúde , Guias de Prática Clínica como Assunto , Estados Unidos/epidemiologia , Modelos EstatísticosRESUMO
PURPOSE: Population newborn genetic screening for hypertrophic cardiomyopathy (HCM) is feasible, however its benefits, harms, and cost-effectiveness are uncertain. METHODS: We developed a microsimulation model to simulate a US birth cohort of 3.7 million newborns. Those identified with pathogenic/likely pathogenic variants associated with increased risk of HCM underwent surveillance and recommended treatment, whereas in usual care, individuals with family histories of HCM underwent surveillance. RESULTS: In a cohort of 3.7 million newborns, newborn genetic screening would reduce HCM-related deaths through age 20 years by 44 (95% uncertainty interval [UI] = 10-103) however increase the numbers of children undergoing surveillance by 8127 (95% UI = 6308-9664). Compared with usual care, newborn genetic screening costs $267,000 per life year saved (95% UI, $106,000 to $919,000 per life year saved). CONCLUSION: Newborn genetic screening for HCM could prevent deaths but at a high cost and would require many healthy children to undergo surveillance. This study shows how modeling can provide insights into the tradeoffs between benefits and costs that will need to be considered as newborn genetic screening is more widely adopted.
Assuntos
Cardiomiopatia Hipertrófica , Testes Genéticos , Criança , Humanos , Recém-Nascido , Adulto Jovem , Adulto , Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/genética , Triagem Neonatal , Análise de Custo-EfetividadeRESUMO
Cooperative DNA binding is a key feature of transcriptional regulation. Here we examined the role of cooperativity in Notch signaling by CRISPR-mediated engineering of mice in which neither Notch1 nor Notch2 can homo- or heterodimerize, essential for cooperative binding to sequence-paired sites (SPS) located near many Notch-regulated genes. Although most known Notch-dependent phenotypes were unaffected in Notch1/2 dimer-deficient mice, a subset of tissues proved highly sensitive to loss of cooperativity. These phenotypes include heart development, compromised viability in combination with low gene dose, and the gut, developing ulcerative colitis in response to 1% dextran sulfate sodium (DSS). The most striking phenotypes-gender imbalance and splenic marginal zone B-cell lymphoma-emerged in combination with gene dose reduction or when challenged by chronic fur mite infestation. This study highlights the role of the environment in malignancy and colitis and is consistent with Notch-dependent anti-parasite immune responses being compromised in Notch dimer-deficient animals.
Assuntos
Linfócitos B/imunologia , Dosagem de Genes , Coração/embriologia , Homeostase , Intestinos/patologia , Infestações por Ácaros/imunologia , Receptores Notch/genética , Células-Tronco/patologia , Alelos , Animais , Sequência de Bases , Proliferação de Células , Cromatina/metabolismo , Sulfato de Dextrana , Ventrículos do Coração/embriologia , Ventrículos do Coração/patologia , Camundongos , Ácaros/fisiologia , Modelos Biológicos , Multimerização Proteica , Receptores Notch/metabolismo , Baço/imunologia , Esplenomegalia/imunologia , Esplenomegalia/parasitologia , Células-Tronco/metabolismoRESUMO
Neonatal lupus erythematosus (NLE) is an uncommon disorder affecting approximately one out of 20 000 live births in the United States. Common manifestations of NLE include cutaneous eruptions and cardiac involvement. The typical rash of NLE most closely resembles the rash of subacute cutaneous lupus erythematosus both clinically and histopathologically. We present a case of reactive granulomatous dermatitis (RGD) associated with NLE in a 3-month-old male in whom the initial histopathology and immunohistochemistry were concerning for hematologic malignancy. RGD is a unifying term used to describe cutaneous granulomatous eruptions that occur in response to a variety of stimuli, including autoimmune connective tissue diseases. Our case demonstrates the range of histopathological findings that may be present in the setting of NLE.
Assuntos
Doenças Autoimunes , Dermatite , Exantema , Lúpus Eritematoso Cutâneo , Lúpus Eritematoso Sistêmico , Recém-Nascido , Humanos , Masculino , Lactente , Lúpus Eritematoso Sistêmico/complicações , Doenças Autoimunes/complicações , Lúpus Eritematoso Cutâneo/patologia , Dermatite/etiologia , OligopeptídeosRESUMO
BACKGROUND/OBJECTIVES: The emergency department (ED) is a common point of care for many pediatric hidradenitis suppurativa (HS) patients; however, ED care may not align with recommended treatment standards. The objective of this study is to describe the care pediatric HS patients receive in the ED compared to both HS management guidelines and the management of pediatric skin and soft tissue abscess (SSTA) patients. METHODS: We performed a retrospective chart review of pediatric HS and SSTA patients who presented to a single pediatric ED. Demographic and ED encounter data including medications, procedures, recommendations, consults, and referrals were collected. RESULTS: 58 HS and 175 SSTA charts were reviewed. 69.5% of patients were female and 93.6% were African American/Black. 29.3% of HS and 61.7% of SSTA encounters involved incision and drainage (I&D); 62.1% of HS and 70.1% of SSTA encounters involved the prescription or administration of oral clindamycin; 3.4% of HS and 0.6% of SSTA encounters involved dermatology consultation in the ED; and 22.4% of HS and 5.1% of SSTA encounters involved outpatient referrals to dermatology. CONCLUSIONS: Our data reveal a pediatric HS and SSTA population that is predominantly female and African American/Black. Significant differences were found in the average ages and number of lesions between HS and SSTA patients. I&D and oral clindamycin were the most common treatments across groups; however, I&D was performed significantly more frequently among SSTA encounters than HS encounters. Our results suggest that subtle knowledge gaps may exist in ED provider management of pediatric HS.
Assuntos
Hidradenite Supurativa , Humanos , Feminino , Criança , Masculino , Hidradenite Supurativa/terapia , Hidradenite Supurativa/tratamento farmacológico , Estudos Retrospectivos , Clindamicina/uso terapêutico , Serviço Hospitalar de EmergênciaRESUMO
Vitiligo-like changes are an uncommon cutaneous manifestation of graft-versus-host disease (GVHD). We report three cases and review the literature of pediatric patients with vitiligo-like changes associated with GVHD. Improved characterization of this phenomenon may lend insight into the biologic pathways that underlie both vitiligo and GVHD.
Assuntos
Doença Enxerto-Hospedeiro , Hipopigmentação , Vitiligo , Humanos , Criança , Vitiligo/etiologia , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/complicaçõesRESUMO
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is transmitted human-to-human via aerosols and air-borne droplets. Therefore, capturing and destroying viruses from indoor premises are essential to reduce the probability of human exposure and virus transmission. While the heating, ventilation, and air conditioning (HVAC) systems help in reducing the indoor viral load, a targeted approach is required to effectively remove SARS-CoV-2 from indoor air to address human exposure concerns. The present study demonstrates efficient trapping and destruction of SARS-CoV-2 via nano-enabled filter technology using the UV-A-stimulated photoelectrochemical oxidation (PECO) process. Aerosols containing SARS-CoV-2 were generated by nebulization inside an air-controlled test chamber where an air purifier (Air Mini+) was placed. The study demonstrated the efficient removal of SARS-CoV-2 (99.98 %) from the test chamber in less than two minutes and PECO-assisted destruction (over 99%) on the filtration media in 1 h. Furthermore, in a real-world scenario, the Molekule Air-Pro air purifier removed SARS-CoV-2 (a negative RT-qPCR result post-running the filter device) from the circulating air in a COVID-19 testing facility. Overall, the ability of two FDA-approved class II medical devices, Molekule Air-Mini+ and Air-Pro air purifiers, to remove and destroy SARS-CoV-2 in indoor settings was successfully demonstrated. The study indicates that as the "tripledemic" of COVID-19, influenza, and respiratory syncytial virus (RSV) overwhelm the healthcare facilities in the USA, the use of a portable air filtration device will help contain the spread of the viruses in close door facilities, such as in schools and daycare facilities.
Assuntos
Filtros de Ar , Poluição do Ar em Ambientes Fechados , COVID-19 , Humanos , SARS-CoV-2 , Teste para COVID-19 , Aerossóis e Gotículas Respiratórios , Poluição do Ar em Ambientes Fechados/prevenção & controleRESUMO
Herpes zoster is rare in healthy and immunocompetent children. While disseminated presentations of zoster are often concerning for underlying immunodeficiency, non-disseminated zoster can also be a presenting illness in such patients. Here, we report a case of non-disseminated herpes zoster in a presumably healthy immunized child that led to a diagnosis of human immunodeficiency virus infection.
Assuntos
Infecções por HIV , Herpes Zoster , Criança , Pré-Escolar , Infecções por HIV/complicações , Infecções por HIV/diagnóstico , Herpes Zoster/complicações , Herpes Zoster/diagnóstico , Herpesvirus Humano 3 , HumanosRESUMO
BACKGROUND/OBJECTIVES: Follicular keratosis (FK) is a poorly understood disorder presenting with multiple, grouped hyperkeratotic follicular papules typically affecting the chin or jawline. This study describes the clinical presentation, histopathology, management, and outcomes of a series of pediatric patients of color with FK of the face, thought to be related to rubbing or friction on the skin. METHODS: Retrospective review of 20 pediatric patients with FK of the face who presented to our pediatric dermatology practice between April 2019 and October 2021. RESULTS: Twenty patients (mean age 12.1 years, 13 females), all self-identified as Black/African American, were included. All presented with an initially asymptomatic, hyperpigmented patch containing multiple hyperkeratotic follicular papules, located on the cheek, chin, upper lip, and/or jawline. Five patients endorsed a history of rubbing the site. Nine patients had onset of the lesions during the COVID-19 pandemic. Treatments included topical vitamin D analogs, corticosteroids, and/or retinoids. Topical vitamin D analogs and retinoids improved the texture and hyperpigmentation of the follicular lesions in only four patients, while topical corticosteroids had no effect. Histopathological examination of two patients revealed multiple dilated follicles containing keratinized material and associated with a sparse dermal inflammatory infiltrate in one patient and granulomatous inflammation within the dermis in the other. CONCLUSIONS: In our cohort of pediatric patients with FK, patients of color were preferentially affected, and all cases were associated with hyperpigmentation. Some patients presented during the COVID-19 pandemic suggesting that friction from facial mask wearing may have induced or exacerbated this uncommon condition.
Assuntos
COVID-19 , Doença de Darier , Doenças do Cabelo , Hiperpigmentação , Anormalidades Múltiplas , Criança , Sobrancelhas/anormalidades , Feminino , Humanos , Hiperpigmentação/etiologia , Masculino , Pandemias , Retinoides , Vitamina DRESUMO
BACKGROUND: Radiation Therapists (RTs) are a key professional grouping in the delivery of health services for cancer patients. The education of RTs in New Zealand has evolved in response to regulatory and clinical workforce requirements. To date, it has lacked a fundamental underpinning of educational theory. Stakeholders, including students, were canvassed for their perspectives on the drivers behind the current curriculum with a view to developing theory which could shape future curricular development. METHODS: A focus group was conducted with eight student RTs enrolled at the time of the study. A process driven by Constructivist Grounded Theory principles was adopted for the analysis of the resulting data. RESULTS: Four themes were established to represent the data: "Being" is prized over "doing", Change is inevitable, A framework for Professional Identity formation and Modelling is key to learning. CONCLUSIONS: There is utility in exploring the student perspective around curriculum. The data suggest that students on this programme are engaged with the process of preparing for practice and the connected learning experiences. There is a focus on the patient and the personal values and qualities which result from that focus. While specialist knowledge and technical skills are required for delivering patient care, it is fully expected those aspects of the clinical role will significantly change over time. Even at this early stage in their careers, students recognise the development and need for professional identity formation. Role models are perceived to be a vital part of student learning, be they positive or negative. Scrutiny of the study findings provides reason to question some assumptions which are sometimes made about student practitioners based on factors such as age and gender and the assumed universal ability of practitioners to teach the next generation. The perspectives gained inform the next stage of data collection from this group and theory building that will be reported outside the confines of this article.
Assuntos
Currículo , Estudantes , Humanos , Nova Zelândia , Aprendizagem , Grupos FocaisRESUMO
PURPOSE: Prolidase deficiency is a rare inborn error of metabolism causing ulcers and other skin disorders, splenomegaly, developmental delay, and recurrent infections. Most of the literature is constituted of isolated case reports. We aim to provide a quantitative description of the natural history of the condition by describing 19 affected individuals and reviewing the literature. METHODS: Nineteen patients were phenotyped per local institutional procedures. A systematic review following PRISMA criteria identified 132 articles describing 161 patients. Main outcome analyses were performed for manifestation frequency, diagnostic delay, overall survival, symptom-free survival, and ulcer-free survival. RESULTS: Our cohort presented a wide variability of severity. Autoimmune disorders were found in 6/19, including Crohn disease, systemic lupus erythematosus, and arthritis. Another immune finding was hemophagocytic lymphohistiocytosis (HLH). Half of published patients were symptomatic by age 4 and had a delayed diagnosis (mean delay 11.6 years). Ulcers were present initially in only 30% of cases, with a median age of onset at 12 years old. CONCLUSION: Prolidase deficiency has a broad range of manifestations. Symptoms at onset may be nonspecific, likely contributing to the diagnostic delay. Testing for this disorder should be considered in any child with unexplained autoimmunity, lower extremity ulcers, splenomegaly, or HLH.
Assuntos
Doença de Crohn , Úlcera da Perna , Deficiência de Prolidase , Criança , Pré-Escolar , Diagnóstico Tardio , Humanos , Fenótipo , Deficiência de Prolidase/diagnóstico , Deficiência de Prolidase/genéticaRESUMO
Eosinophils and neutrophils are critical for host defense, yet gaps in understanding how granulocytes differentiate from hematopoietic stem cells (HSCs) into mature effectors remain. The pseudokinase tribbles homolog 1 (Trib1) is an important regulator of granulocytes; knockout mice lack eosinophils and have increased neutrophils. However, how Trib1 regulates cellular identity and function during eosinophilopoiesis is not understood. Trib1 expression markedly increases with eosinophil-lineage commitment in eosinophil progenitors (EoPs), downstream of the granulocyte/macrophage progenitor (GMP). Using hematopoietic- and eosinophil-lineage-specific Trib1 deletion, we found that Trib1 regulates both granulocyte precursor lineage commitment and mature eosinophil identity. Conditional Trib1 deletion in HSCs reduced the size of the EoP pool and increased neutrophils, whereas deletion following eosinophil lineage commitment blunted the decrease in EoPs without increasing neutrophils. In both modes of deletion, Trib1-deficient mice expanded a stable population of Ly6G+ eosinophils with neutrophilic characteristics and functions, and had increased CCAAT/enhancer binding protein α (C/EBPα) p42. Using an ex vivo differentiation assay, we found that interleukin 5 (IL-5) supports the generation of Ly6G+ eosinophils from Trib1-deficient cells, but is not sufficient to restore normal eosinophil differentiation and development. Furthermore, we demonstrated that Trib1 loss blunted eosinophil migration and altered chemokine receptor expression, both in vivo and ex vivo. Finally, we showed that Trib1 controls eosinophil identity by modulating C/EBPα. Together, our findings provide new insights into early events in myelopoiesis, whereby Trib1 functions at 2 distinct stages to guide eosinophil lineage commitment from the GMP and suppress the neutrophil program, promoting eosinophil terminal identity and maintaining lineage fidelity.
Assuntos
Eosinófilos/metabolismo , Regulação da Expressão Gênica , Células Progenitoras de Granulócitos e Macrófagos/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Mielopoese , Neutrófilos/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Animais , Eosinófilos/citologia , Células Progenitoras de Granulócitos e Macrófagos/citologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos , Camundongos Transgênicos , Neutrófilos/citologia , Proteínas Serina-Treonina Quinases/biossíntese , Proteínas Serina-Treonina Quinases/genéticaRESUMO
BACKGROUND: The distribution of pediatric-onset morphea and site-based likelihood for extracutaneous complications has not been well characterized. OBJECTIVE: To characterize the lesional distribution of pediatric-onset morphea and to determine the sites with the highest association of extracutaneous manifestations. METHODS: A retrospective cross-sectional study was performed. Using clinical photographs, morphea lesions were mapped onto body diagrams using customized software. RESULTS: A total of 823 patients with 2522 lesions were included. Lesions were more frequent on the superior (vs inferior) anterior aspect of the head and extensor (vs flexor) extremities. Linear morphea lesions were more likely on the head and neck, whereas plaque and generalized morphea lesions were more likely on the trunk. Musculoskeletal complications were more likely with lesions on the extensor (vs flexor) extremity (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.2-3.4), whereas neurologic manifestations were more likely with lesions on the anterior (vs posterior) (OR, 2.8; 95% CI, 1.7-4.6) and superior (vs inferior) aspect of the head (OR, 2.3; 95% CI, 1.6-3.4). LIMITATIONS: Retrospective nature and the inclusion of only patients with clinical photographs. CONCLUSION: The distribution of pediatric-onset morphea is not random and varies with body site and within individual body sites. The risk stratification of extracutaneous manifestations by body site may inform decisions about screening for extracutaneous manifestations, although prospective studies are needed.
Assuntos
Transtornos da Cefaleia/epidemiologia , Doenças Musculoesqueléticas/epidemiologia , Esclerodermia Localizada/epidemiologia , Convulsões/epidemiologia , Idade de Início , Criança , Pré-Escolar , Estudos Transversais , Eletroencefalografia/estatística & dados numéricos , Feminino , Transtornos da Cefaleia/diagnóstico , Transtornos da Cefaleia/etiologia , Humanos , Imageamento por Ressonância Magnética/estatística & dados numéricos , Masculino , Doenças Musculoesqueléticas/diagnóstico , Doenças Musculoesqueléticas/etiologia , Fotografação , Estudos Retrospectivos , Medição de Risco/estatística & dados numéricos , Esclerodermia Localizada/complicações , Esclerodermia Localizada/diagnóstico , Convulsões/diagnóstico , Convulsões/etiologia , Pele/diagnóstico por imagemRESUMO
Erythema ab igne is an uncommon dermatosis characterized by erythematous or hyperpigmented reticular patches that appear after prolonged localized heat exposure. We present three cases of erythema ab igne in pediatric patients who presented in March and April of 2021 and share a history of space heater usage while engaging in remote schooling during the COVID-19 pandemic.
Assuntos
COVID-19 , Pandemias , Criança , Eritema/epidemiologia , Eritema/etiologia , Temperatura Alta , Humanos , SARS-CoV-2RESUMO
BACKGROUND/OBJECTIVES: Confluent and reticulated papillomatosis is a skin condition with unclear etiology and limited understanding of risk factors, comorbidities, and treatment strategies in the pediatric population. This study aims to describe the varied presentations and outcomes of confluent and reticulated papillomatosis and report associated comorbidities in pediatric patients. METHODS: In this retrospective single-institution case-control study, pediatric patients with a diagnosis of confluent and reticulated papillomatosis seen between 2012 and 2020 were matched approximately 1:5 with an acne vulgaris cohort based on diagnosis, setting, and time period when seen. The primary measures were the clinical features, demographics, comorbidities, treatment, and outcomes of patients with confluent and reticulated papillomatosis. Univariate and multivariable analyses were conducted to describe the association of confluent and reticulated papillomatosis with several potential risk factors and comorbidities. RESULTS: Patients with confluent and reticulated papillomatosis typically presented in adolescence with a median age of 14 years and female predominance. In a multivariable analysis, patients with confluent and reticulated papillomatosis were significantly more likely to identify as Black, be overweight or obese, and have concurrent acanthosis nigricans compared to control patients. Most of the confluent and reticulated papillomatosis patients were treated with oral minocycline or doxycycline. Although all patients who received antibiotics responded to treatment, approximately half presented with recurrence, typically within 1-2 years of first treatment. CONCLUSIONS: Confluent and reticulated papillomatosis is a disorder that presents in adolescence and appears to be more frequent in patients who are Black, obese, or overweight, and also have acanthosis nigricans. Clinicians should assess patients with confluent and reticulated papillomatosis for comorbidities, particularly those associated with insulin resistance, which may help reduce long-term disease burden.