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1.
Acad Pediatr ; 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32044466

RESUMO

OBJECTIVES: Our objectives were to (1) quantify the frequency of wheezing episodes and asthma diagnosis in young children in a large pediatric primary care network and (2) assess the variability in practice-level asthma diagnosis, accounting for common asthma risk factors and comorbidities. We hypothesized that significant variability in practice-level asthma diagnosis rates would remain after adjusting for associated predictors. METHODS: We generated a retrospective longitudinal birth cohort of children who visited one of 31 pediatric primary care practices within the first 6 months of life from 1/2005-12/2016. Children were observed for up to 8 years or until the end of the observation window. We used multivariable discrete time survival models to evaluate predictors of asthma diagnosis by 3-month age intervals. We compared unadjusted and adjusted proportions of children diagnosed with asthma by practice. RESULTS: Of the 161,502 children in the cohort, 34,578 children (21%) received at least one asthma diagnosis. In multivariable modeling, male gender, minority race/ethnicity, gestational age <34 weeks, allergic rhinitis, food allergy, and prior wheezing episodes were associated with asthma diagnosis. After adjusting for variation in these predictors across practices, the cumulative incidence of asthma diagnosis by practice by age 6 years ranged from 11-47% (interquartile range (IQR): 24-29%). CONCLUSIONS: Across pediatric primary care practices, adjusted incidence of asthma diagnosis by age 6 years ranged widely, though variation gauged by the IQR was more modest. Potential sources of practice-level variation, such as differing diagnosis thresholds and labeling of different wheezing phenotypes as "asthma", should be further investigated.

2.
Methods Mol Biol ; 2111: 1-20, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31933194

RESUMO

T-cell diversity is multifactorial and includes variability in antigen specificity, differentiation, function, and cell-trafficking potential. Spectral overlap limits the ability of traditional flow cytometry to fully capture the diversity of T-cell subsets and function. The development of mass cytometry permits deep immunoprofiling of T-cell subsets, activation state, and function simultaneously from even small volumes of blood. This chapter describes our methods for mass cytometry and high-throughput data analysis of T cells in patient cohorts. We provide a pipeline that includes practical considerations when customizing a panel for mass cytometry. We also provide protocols for the conjugation and titration of metal-labeled antibodies (including two T-cell panels) and a staining procedure. Finally, with the aim to support translational science, we provide R scripts that contain a detailed workflow for initial evaluation of high-dimensional data generated from cohorts of patients.

3.
Sci Immunol ; 4(40)2019 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-31586015

RESUMO

Changes in the gut microbiome caused by antibiotics can impair immune responses to influenza vaccination.

4.
J Allergy Clin Immunol ; 144(6): 1660-1673, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31445098

RESUMO

BACKGROUND: Although chiefly a B-lymphocyte disorder, several research groups have identified common variable immunodeficiency (CVID) subjects with numeric and/or functional TH cell alterations. The causes, interrelationships, and consequences of CVID-associated CD4+ T-cell derangements to hypogammaglobulinemia, autoantibody production, or both remain unclear. OBJECTIVE: We sought to determine how circulating CD4+ T cells are altered in CVID subjects with autoimmune cytopenias (AICs; CVID+AIC) and the causes of these derangements. METHODS: Using hypothesis-generating, high-dimensional single-cell analyses, we created comprehensive phenotypic maps of circulating CD4+ T cells. Differences between subject groups were confirmed in a large and genetically diverse cohort of CVID subjects (n = 69) by using flow cytometry, transcriptional profiling, multiplex cytokine/chemokine detection, and a suite of in vitro functional assays measuring naive T-cell differentiation, B-cell/T-cell cocultures, and regulatory T-cell suppression. RESULTS: Although CD4+ TH cell profiles from healthy donors and CVID subjects without AICs were virtually indistinguishable, T cells from CVID+AIC subjects exhibited follicular features as early as thymic egress. Follicular skewing correlated with IgA deficiency-associated endotoxemia and endotoxin-induced expression of activin A and inducible T-cell costimulator ligand. The resulting enlarged circulating follicular helper T-cell population from CVID+AIC subjects provided efficient help to receptive healthy donor B cells but not unresponsive CVID B cells. Despite this, circulating follicular helper T cells from CVID+AIC subjects exhibited aberrant transcriptional profiles and altered chemokine/cytokine receptor expression patterns that interfered with regulatory T-cell suppression assays and were associated with autoantibody production. CONCLUSIONS: Endotoxemia is associated with early commitment to the follicular T-cell lineage in IgA-deficient CVID subjects, particularly those with AICs.

5.
Sci Transl Med ; 11(496)2019 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-31189717

RESUMO

The gut microbiota is a key environmental determinant of mammalian metabolism. Regulation of white adipose tissue (WAT) by the gut microbiota is a process critical to maintaining metabolic fitness, and gut dysbiosis can contribute to the development of obesity and insulin resistance (IR). However, how the gut microbiota regulates WAT function remains largely unknown. Here, we show that tryptophan-derived metabolites produced by the gut microbiota controlled the expression of the miR-181 family in white adipocytes in mice to regulate energy expenditure and insulin sensitivity. Moreover, dysregulation of the gut microbiota-miR-181 axis was required for the development of obesity, IR, and WAT inflammation in mice. Our results indicate that regulation of miR-181 in WAT by gut microbiota-derived metabolites is a central mechanism by which host metabolism is tuned in response to dietary and environmental changes. As we also found that MIR-181 expression in WAT and the plasma abundance of tryptophan-derived metabolites were dysregulated in a cohort of obese human children, the MIR-181 family may represent a potential therapeutic target to modulate WAT function in the context of obesity.

6.
Vaccine ; 37(30): 4172-4176, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31186192

RESUMO

BACKGROUND: The Sentinel Initiative was established in 2008 to monitor the safety of FDA-regulated medical products. We evaluated the positive predictive value (PPV) of ICD-9 codes for post-vaccination febrile seizures to identify optimal algorithms for use in post-market safety surveillance. METHODS: We identified ICD-9 diagnosis codes for fever and seizures in the emergency department or inpatient setting after vaccinations of interest from July 1, 2010 to June 30, 2011. Medical record review was conducted to verify febrile seizure events. RESULTS: Of 216 potential febrile seizures identified with one or more seizure codes (the broadest algorithm), 152 were chart-confirmed (i.e., documentation of fever within 24 h of seizure or clinician diagnosis of febrile seizure; PPV 70%, 95% CI 64, 76%). Two codes specific for febrile seizures produced the highest PPV (PPV 91%, 95% CI 85, 95%) and accounted for 140 confirmed febrile seizures. In the absence of febrile seizure codes, other seizure codes yielded much lower PPVs, regardless of the presence of fever codes. CONCLUSIONS: Our results indicate that ICD-9 diagnosis codes in the inpatient and emergency department settings have high predictive value for identifying febrile seizures within the Sentinel Distributed Database. While the PPV of the algorithm based on any diagnosis code for seizure is moderate, the algorithm limited to febrile seizure codes has a high PPV (>90%) and captures the vast majority of confirmed cases identified by the broadest algorithm, suggesting that the narrower algorithm limited to febrile seizure codes may be preferred.

7.
Sci Immunol ; 4(35)2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053657

RESUMO

Longitudinal study of immune function yields cytometric and transcriptomic measures of immune age.

8.
Front Pediatr ; 7: 170, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31139601

RESUMO

We report outcomes after hematopoietic stem cell transplant for three patients with X-MAID, including 1 patient from the originally described cohort and two brothers with positive TREC newborn screening for SCID who were found to have a T-B-NK+ SCID phenotype attributable to X-linked moesin associated immunodeficiency (X-MAID). A c.511C>T variant in moesin was identified via exome sequencing in the older of these siblings in the setting of low lymphocyte counts and poor proliferative responses consistent with SCID. He received reduced intensity conditioning due to CMV, and was transplanted with a T-depleted haploidentical (maternal) donor. His post-transplant course was complicated by hemolytic anemia, neutropenia, and sepsis. He had poor engraftment, requiring a 2nd transplant. His younger brother presented with the same clinical phenotype and was treated with umbilical cord blood transplant following myeloablative conditioning, has engrafted and is doing well. The third case also presented with severe lymphopenia in infancy, received a matched related bone marrow transplant following myeloablative conditioning, has engrafted and is doing well. These cases represent a novel manifestation of non-radiosensitive X-linked form of T-B-NK+ SCID that is able to be detected by TREC based newborn screening and effectively treated with HCT.

9.
Front Pediatr ; 7: 160, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31114772

RESUMO

In this report, we describe a novel T437N STAT1 mutation found in a mother and 3 of her 4 children which we demonstrate yields gain-of-function. All of the four patients with the T437N STAT1 mutation experienced lymphadenopathy. However, two of the children developed Nodular Lymphocyte Predominant Hodgkin Lymphoma (NHLPL) and have responded to chemotherapeutic regimens. The fourth sibling had neither the STAT1 variant nor lymphadenopathy or malignancy. To our knowledge this is the first description of a potential association between STAT1 GOF mutations and lymphoma development.

10.
Dev Cell ; 49(1): 10-29, 2019 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-30930166

RESUMO

Single-cell gene expression analyses of mammalian tissues have uncovered profound stage-specific molecular regulatory phenomena that have changed the understanding of unique cell types and signaling pathways critical for lineage determination, morphogenesis, and growth. We discuss here the case for a Pediatric Cell Atlas as part of the Human Cell Atlas consortium to provide single-cell profiles and spatial characterization of gene expression across human tissues and organs. Such data will complement adult and developmentally focused HCA projects to provide a rich cytogenomic framework for understanding not only pediatric health and disease but also environmental and genetic impacts across the human lifespan.


Assuntos
Desenvolvimento Embrionário/genética , Redes Reguladoras de Genes/genética , Pediatria/tendências , Análise de Célula Única/métodos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento/genética , Humanos , Distribuição Tecidual/genética
11.
Sci Immunol ; 4(31)2019 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-30610015

RESUMO

The immunometabolic pivot from reliance on fatty acid oxidation to glycolysis during T cell activation is, in part, reliant on the regulation of translation of key metabolic enzymes.

12.
Asthma Res Pract ; 5: 1, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30680222

RESUMO

Background: Asthma is a chronic inflammatory lung disease that affects 18.7 million U.S. adults. Electronic health records (EHRs) are a unique source of information that can be leveraged to understand factors associated with asthma in real-life populations. In this study, we identify demographic factors and comorbidities associated with asthma exacerbations among adults according to EHR-derived data and compare these findings to those of epidemiological studies. Methods: We obtained University of Pennsylvania Hospital System EHR-derived data for asthma encounters occurring between 2011 and 2014. Regression analyses were performed to model asthma exacerbation frequency as explained by age, sex, race/ethnicity, health insurance type, smoking status, body mass index (BMI) and various comorbidities. We analyzed data from the National Health and Nutrition Examination Survey (NHANES) from 2001 to 2012 to compare findings with those from the EHR-derived data. Results: Based on data from 9068 adult patients with asthma, 33.37% had at least one exacerbation over the four-year study period. In a proportional odds logistic regression predicting number of exacerbations during the study period (levels: 0, 1-2, 3-4, 5+ exacerbations), after controlling for age, race/ethnicity, sex, health insurance type, and smoking status, the highest odds ratios (ORs) of significantly associated factors were: chronic bronchitis (2.70), sinusitis (1.50), emphysema (1.39), fluid and electrolyte disorders (1.35), class 3 obesity (1.32), and diabetes (1.28). An analysis of NHANES data showed associations for class 3 obesity, anemia and chronic bronchitis with exacerbation frequency in an adjusted model controlling for age, race/ethnicity, sex, financial class and smoking status. Conclusions: EHR-derived data is helpful to understand exacerbations in real-life asthma patients, facilitating design of detailed studies and interventions tailored for specific populations.

13.
Sci Immunol ; 3(27)2018 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-30194242

RESUMO

An alternate strategy is described for enumerating peripheral immune cells in health and disease by epigenetic quantitative PCR.

14.
Ann Allergy Asthma Immunol ; 121(5): 561-567, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30170026

RESUMO

BACKGROUND: Pediatric asthma is a major contributor to emergency room utilization and hospital readmission rates. OBJECTIVE: To develop an allergy department‒based intervention to improve follow-up appointment scheduling processes for pediatric asthma patients after discharge for asthma exacerbation. METHODS: This quality improvement study was conducted in the allergy clinic of an urban, tertiary children's hospital. Children receiving subspecialty allergy care for asthma were included into the intervention group during the intervention period. The quality improvement intervention consisted of 3 attempts by telephone to reach the family to schedule the follow-up appointment. If this was unsuccessful or if the appointment was not kept, then a reminder letter was sent to the family. The primary outcome of interest in this study was the percent of postdischarge follow-up appointments scheduled within 30 days of discharge. Secondary outcomes measured were the percent of allergy appointments attended within 30 days of discharge and the 30-day hospital readmission rate. RESULTS: Demographics did not differ significantly between the intervention and baseline preintervention year. The initial baseline scheduled allergy follow-up visit rate was 48.8 ± 13.3% of patients discharged per month. This increased to an overall rate of 75.7 ± 20.1% patients scheduling allergy follow-up within 30 days of discharge during the intervention year. We also observed a significant increase in attended allergy visits 30 days postdischarge from 35.5 ± 15.6% in year 1 to 53.9 ± 25.5% during the intervention year and a significant decrease in the 30-day readmission rate on the allergy service. CONCLUSION: These data suggests that minor changes in allergy practice organization can significantly affect posthospitalization follow-up rates and decrease asthma readmission rates.


Assuntos
Agendamento de Consultas , Asma/terapia , Serviço Hospitalar de Emergência , Hospitais Pediátricos , Readmissão do Paciente/estatística & dados numéricos , Adolescente , Criança , Pré-Escolar , Continuidade da Assistência ao Paciente/normas , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Alta do Paciente , Atenção Primária à Saúde , Modelos de Riscos Proporcionais , Melhoria de Qualidade/organização & administração
16.
Sci Immunol ; 3(23)2018 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-29728427

RESUMO

A human antibody that prevents EBV infection is identified by studying memory B cells that recognize core EBV fusion proteins.


Assuntos
Pesquisa Biomédica , Herpesvirus Humano 4 , Vacinas
17.
J Pediatric Infect Dis Soc ; 7(suppl_1): S18-S24, 2018 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-29746679

RESUMO

Chronic granulomatous disease (CGD), a primary immunodeficiency characterized by a deficient neutrophil oxidative burst and the inadequate killing of microbes, is well known to cause a significantly increased risk of invasive infection. However, infectious complications are not the sole manifestations of CGD; substantial additional morbidity is driven by noninfectious complications also. These complications can include, for example, a wide range of inflammatory diseases that affect the gastrointestinal tract, lung, skin, and genitourinary tract and overt autoimmune disease. These diseases can occur at any age and are especially problematic in adolescents and adults with CGD. Many of these noninfectious complications present a highly challenging therapeutic conundrum, wherein immunosuppression must be balanced against an already markedly increased risk of invasive fungal and bacterial infections. In this review, the myriad noninfectious complications of CGD are discussed, as are important gaps in our understanding of these processes, which warrant further investigation.


Assuntos
Granuloma/etiologia , Doença Granulomatosa Crônica/complicações , Doenças Inflamatórias Intestinais/etiologia , Pneumopatias/etiologia , Doenças Autoimunes/complicações , Diagnóstico Diferencial , Humanos , Doenças Inflamatórias Intestinais/diagnóstico , Pneumopatias/diagnóstico
18.
J Clin Immunol ; 38(4): 540-541, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29781065

RESUMO

The original version of this article unfortunately contained mistakes in some of the author names and affiliations. The correct list of author names and affiliations is below, with the corrections in bold.

19.
J Clin Immunol ; 38(3): 320-329, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29675737

RESUMO

Genetic testing plays a critical role in diagnosis for many primary immunodeficiency diseases. The goals of this report are to outline some of the challenges that clinical immunologists face routinely in the use of genetic testing for patient care. In addition, we provide a review of the types of genetic testing used in the diagnosis of PID, including their strengths and limitations. We describe the strengths and limitations of different genetic testing approaches for specific clinical contexts that raise concern for specific PID disorders in light of the challenges reported by the clinical immunologist members of the CIS in a recent membership survey. Finally, we delineate the CIS's recommendations for the use of genetic testing in light of these issues.


Assuntos
Testes Genéticos , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/genética , Biomarcadores , Estudos de Associação Genética , Predisposição Genética para Doença , Testes Genéticos/métodos , Testes Genéticos/normas , Estudo de Associação Genômica Ampla , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Síndromes de Imunodeficiência/terapia , Diagnóstico Pré-Natal , Análise de Sequência de DNA
20.
Sci Immunol ; 3(20)2018 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-29429980

RESUMO

Novel unbiased strategy for identification of peptide antigens bound by tumor-infiltrating lymphocyte T cell receptors.


Assuntos
Linfócitos do Interstício Tumoral/imunologia , Receptores de Antígenos de Linfócitos T
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