RESUMO
Individuals with cystic fibrosis (CF) develop complications of the gastrointestinal tract influenced by genetic variants outside of CFTR. Cystic fibrosis-related diabetes (CFRD) is a distinct form of diabetes with a variable age of onset that occurs frequently in individuals with CF, while meconium ileus (MI) is a severe neonatal intestinal obstruction affecting â¼20% of newborns with CF. CFRD and MI are slightly correlated traits with previous evidence of overlap in their genetic architectures. To better understand the genetic commonality between CFRD and MI, we used whole-genome-sequencing data from the CF Genome Project to perform genome-wide association. These analyses revealed variants at 11 loci (6 not previously identified) that associated with MI and at 12 loci (5 not previously identified) that associated with CFRD. Of these, variants at SLC26A9, CEBPB, and PRSS1 associated with both traits; variants at SLC26A9 and CEBPB increased risk for both traits, while variants at PRSS1, the higher-risk alleles for CFRD, conferred lower risk for MI. Furthermore, common and rare variants within the SLC26A9 locus associated with MI only or CFRD only. As expected, different loci modify risk of CFRD and MI; however, a subset exhibit pleiotropic effects indicating etiologic and mechanistic overlap between these two otherwise distinct complications of CF.
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Fibrose Cística , Diabetes Mellitus , Doenças do Recém-Nascido , Obstrução Intestinal , Fibrose Cística/complicações , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Diabetes Mellitus/genética , Estudo de Associação Genômica Ampla , Humanos , Recém-Nascido , Obstrução Intestinal/complicações , Obstrução Intestinal/genéticaRESUMO
BACKGROUND AND AIMS: It is not known why severe cystic fibrosis (CF) liver disease (CFLD) with portal hypertension occurs in only ~7% of people with CF. We aimed to identify genetic modifiers for severe CFLD to improve understanding of disease mechanisms. APPROACH AND RESULTS: Whole-genome sequencing was available in 4082 people with CF with pancreatic insufficiency (n = 516 with severe CFLD; n = 3566 without CFLD). We tested ~15.9 million single nucleotide polymorphisms (SNPs) for association with severe CFLD versus no-CFLD, using pre-modulator clinical phenotypes including (1) genetic variant ( SERPINA1 ; Z allele) previously associated with severe CFLD; (2) candidate SNPs (n = 205) associated with non-CF liver diseases; (3) genome-wide association study of common/rare SNPs; (4) transcriptome-wide association; and (5) gene-level and pathway analyses. The Z allele was significantly associated with severe CFLD ( p = 1.1 × 10 -4 ). No significant candidate SNPs were identified. A genome-wide association study identified genome-wide significant SNPs in 2 loci and 2 suggestive loci. These 4 loci contained genes [significant, PKD1 ( p = 8.05 × 10 -10 ) and FNBP1 ( p = 4.74 × 10 -9 ); suggestive, DUSP6 ( p = 1.51 × 10 -7 ) and ANKUB1 ( p = 4.69 × 10 -7 )] relevant to severe CFLD pathophysiology. The transcriptome-wide association identified 3 genes [ CXCR1 ( p = 1.01 × 10 -6 ) , AAMP ( p = 1.07 × 10 -6 ), and TRBV24 ( p = 1.23 × 10 -5 )] involved in hepatic inflammation and innate immunity. Gene-ranked analyses identified pathways enriched in genes linked to multiple liver pathologies. CONCLUSION: These results identify loci/genes associated with severe CFLD that point to disease mechanisms involving hepatic fibrosis, inflammation, innate immune function, vascular pathology, intracellular signaling, actin cytoskeleton and tight junction integrity and mechanisms of hepatic steatosis and insulin resistance. These discoveries will facilitate mechanistic studies and the development of therapeutics for severe CFLD.
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OBJECTIVE: We aimed to determine the frequency and types of infections in hospitalized children with childhood-onset systemic lupus erythematosus (cSLE), and to identify risk factors for intensive care unit (ICU) admission and mortality. METHODS: We conducted a retrospective study of youth aged 2 to 21 years using International Classification of Diseases (ICD) codes for SLE assigned during admission to a hospital participating in the Pediatric Health Information System, a database of United States children's hospitals, from 2009 to 2021. Generalized linear mixed effects models were used to identify risk factors for ICU admission and mortality among children hospitalized with infection. RESULTS: We identified 8588 children with cSLE and ≥ 1 hospitalization. Among this cohort, there were 26,269 hospitalizations, of which 13% had codes for infections, a proportion that increased over time (P = 0.04). Bacterial pneumonia was the most common hospitalized infection. In-hospital mortality occurred in 0.4% (n = 103) of cSLE hospitalizations for any indication and 2% of hospitalizations for infection (n = 60). The highest mortality rates occurred with Pneumocystis jirovecii pneumonia (21%) and other fungal infections (21%). Lupus nephritis (LN) and endstage renal disease (ESRD) were associated with increased odds of ICU admission (odds ratio [OR] 1.47 [95% CI 1.2-1.8] and OR 2.40 [95% CI 1.7-3.4]) among children admitted for serious infection. ESRD was associated with higher mortality (OR 2.34 [95% CI 1.1-4.9]). CONCLUSION: Hospitalizations with ICD codes for infection comprised a small proportion of cSLE admissions but accounted for the majority of mortality. The proportion of hospitalizations for infection increased over time. LN and ESRD were risk factors for poor outcomes.
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Rationale: Lung disease is the major cause of morbidity and mortality in persons with cystic fibrosis (pwCF). Variability in CF lung disease has substantial non-CFTR (CF transmembrane conductance regulator) genetic influence. Identification of genetic modifiers has prognostic and therapeutic importance. Objectives: Identify genetic modifier loci and genes/pathways associated with pulmonary disease severity. Methods: Whole-genome sequencing data on 4,248 unique pwCF with pancreatic insufficiency and lung function measures were combined with imputed genotypes from an additional 3,592 patients with pancreatic insufficiency from the United States, Canada, and France. This report describes association of approximately 15.9 million SNPs using the quantitative Kulich normal residual mortality-adjusted (KNoRMA) lung disease phenotype in 7,840 pwCF using premodulator lung function data. Measurements and Main Results: Testing included common and rare SNPs, transcriptome-wide association, gene-level, and pathway analyses. Pathway analyses identified novel associations with genes that have key roles in organ development, and we hypothesize that these genes may relate to dysanapsis and/or variability in lung repair. Results confirmed and extended previous genome-wide association study findings. These whole-genome sequencing data provide finely mapped genetic information to support mechanistic studies. No novel primary associations with common single variants or rare variants were found. Multilocus effects at chr5p13 (SLC9A3/CEP72) and chr11p13 (EHF/APIP) were identified. Variant effect size estimates at associated loci were consistently ordered across the cohorts, indicating possible age or birth cohort effects. Conclusions: This premodulator genomic, transcriptomic, and pathway association study of 7,840 pwCF will facilitate mechanistic and postmodulator genetic studies and the development of novel therapeutics for CF lung disease.
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Fibrose Cística , Humanos , Fibrose Cística/genética , Estudo de Associação Genômica Ampla/métodos , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Gravidade do Paciente , Pulmão , Proteínas Associadas aos Microtúbulos/genéticaRESUMO
OBJECTIVE(S): To estimate nutritional status in a large cohort of infants with orofacial clefts in the US, overall and by cleft type from birth to 6 months of age. STUDY DESIGN: We conducted a cross-sectional study in infants with orofacial clefts by examining growth by month between birth and 6 months of age. Infants with at least one weight measurement at a single US regional tertiary care pediatric hospital with an interdisciplinary cleft team between 2010 and 2020 were included. We calculated the average weight-for-age z scores and weight-for-length z scores. We calculated the proportion of infants underweight and wasting with z scores below -2 SDs monthly from birth to 6 months of age. We used t tests to compare the distribution of weight for age z-score and weight for length z-score among children with orofacial clefts to a normal distribution. RESULTS: We included 883 infants with orofacial clefts. Compared with expected proportion of underweight infants (2.3%), a larger proportion of infants with orofacial clefts were underweight between birth and 1 month (10.6%), peaking between 2 and 3 months (27.1%), and remaining high between 5 and 6 months (16.3%). Compared with the expected proportion of infants with wasting (2.3%), a higher proportion of infants with orofacial clefts experienced wasting between birth and 1 month (7.3%), peaking between 2 and 3 months (12.8%), and remaining high between 5 and 6 months (5.3%). Similar findings were observed for all cleft types and regardless of comorbidities. CONCLUSION(S): A substantial proportion of infants with orofacial clefts compared with normative peers have malnutrition in the first 6 months of life in the US.
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Fenda Labial , Fissura Palatina , Humanos , Lactente , Criança , Fenda Labial/complicações , Fenda Labial/epidemiologia , Fissura Palatina/complicações , Fissura Palatina/epidemiologia , Estudos Transversais , Estado Nutricional , MagrezaRESUMO
BACKGROUND: The prevalence of atopic diseases has increased with atopic dermatitis (AD) as the earliest manifestation. We assessed if molecular risk factors in atopic mothers influence their infants' susceptibility to an atopic disease. METHODS: Pregnant women and their infants with (n = 174, high-risk) or without (n = 126, low-risk) parental atopy were enrolled in a prospective birth cohort. Global differentially methylated regions (DMRs) were determined in atopic (n = 92) and non-atopic (n = 82) mothers. Principal component analysis was used to predict atopy risk in children dependent on maternal atopy. Genome-wide transcriptomic analyses were performed in paired atopic (n = 20) and non-atopic (n = 15) mothers and cord blood. Integrative genomic analyses were conducted to define methylation-gene expression relationships. RESULTS: Atopic dermatitis was more prevalent in high-risk compared to low-risk children by age 2. Differential methylation analyses identified 165 DMRs distinguishing atopic from non-atopic mothers. Inclusion of DMRs in addition to maternal atopy significantly increased the odds ratio to develop AD in children from 2.56 to 4.26. In atopic compared to non-atopic mothers, 139 differentially expressed genes (DEGs) were identified significantly enriched of genes within the interferon signaling pathway. Expression quantitative trait methylation analyses dependent on maternal atopy identified 29 DEGs controlled by 136 trans-acting methylation marks, some located near transcription factors. Differential expression for the same nine genes, including MX1 and IFI6 within the interferon pathway, was identified in atopic and non-atopic mothers and high-risk and low-risk children. CONCLUSION: These data suggest that in utero epigenetic and transcriptomic mechanisms predominantly involving the interferon pathway may impact and predict the development of infant atopy.
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Dermatite Atópica , Criança , Lactente , Humanos , Feminino , Gravidez , Pré-Escolar , Dermatite Atópica/epidemiologia , Dermatite Atópica/genética , Estudos Prospectivos , Fatores de Risco , Família , TranscriptomaRESUMO
BACKGROUND: The schoolyard environment provides key opportunities to promote physical activity and socioemotional development for children. Schoolyards can also serve as a community park resource outside of school hours. We aimed to: (i) implement and evaluate reliability of the System for Observing Outdoor Play Environments in Neighborhood Schools (SOOPEN), (ii) assess schoolyard use by children during recess and community members of all ages outside of school hours, and (iii) investigate relationships of schoolyard and children´s group characteristics with physical activity levels and prosocial interactions. METHODS: In this cross-sectional study, we observed student and community visitor behavior using SOOPEN at three urban elementary schoolyards in Tacoma, Washington, USA, prior to renovations intended to expand each facility's use as a community park in neighborhoods with poor park access. We assessed interrater reliability using intraclass correlation coefficients and described current levels of schoolyard use (at the group level), physical activity, and prosocial behavior. Physical activity was assessed on a five-point scale and dichotomized to indicate moderate-to-vigorous physical activity (MVPA). Social interactions were coded as prosocial, antisocial, or neutral. We examined associations of selected schoolyard features and group characteristics with group MVPA and prosocial behavior during recess using modified Poisson regression to estimate prevalence ratios (PR) and 95% confidence intervals (CI). RESULTS: We observed a total of 981 activity-defined, informal groups in the schoolyards, and achieved good to excellent interrater reliability using SOOPEN. Community use of the schoolyards during evenings and weekends was limited (n = 56 groups). During 26, 25-50 min recess periods (n = 833 groups), 19% of groups were engaged in MVPA. Schoolyard areas with paved surfaces were associated with more MVPA (PR = 1.52, 95% CI: 1.04, 2.23) compared to field/grass areas; supervised groups were associated with less MVPA than groups not directly supervised by an adult (PR = 0.59, 95% CI: 0.36, 0.96). Schoolyard characteristics were not associated with prosocial behavior. Mixed-gender groups were associated with more MVPA and more prosocial behavior. CONCLUSIONS: Our study using SOOPEN, a reliable new activity observation tool, highlights the multi-dimensional dynamics of physical activity and social interactions in schoolyards, which could be leveraged to promote healthy behaviors during and outside of school hours.
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Exercício Físico , Interação Social , Criança , Adulto , Humanos , Estudos Transversais , Reprodutibilidade dos Testes , Exercício Físico/psicologia , Instituições AcadêmicasRESUMO
OBJECTIVES: To determine whether youth with white coat hypertension on initial ambulatory blood pressure monitoring (ABPM) continue to demonstrate the same pattern on repeat ABPM. STUDY DESIGN: Retrospective longitudinal cohort study of patients referred for high blood pressure (BP) and diagnosed with white coat hypertension by ABPM who had follow-up ABPM 0.5-4.6 years later at 11 centers in the Pediatric Nephrology Research Consortium. We classified ABPM phenotype using the American Heart Association guidelines. At baseline, we classified those with hypertensive BP in the clinic as "stable white coat hypertension," and those with normal BP as "intermittent white coat hypertension." We used multivariable generalized linear mixed effect models to estimate the association of baseline characteristics with abnormal ABPM phenotype progression. RESULTS: Eighty-nine patients met the inclusion criteria (median age, 13.9 years; 78% male). Median interval time between ABPM measurements was 14 months. On follow-up ABPM, 61% progressed to an abnormal ABPM phenotype (23% ambulatory hypertension, 38% ambulatory prehypertension). Individuals age 12-17 years and those with stable white coat hypertension had greater proportions progressing to either prehypertension or ambulatory hypertension. In the multivariable models, baseline wake systolic BP index ≥0.9 was significantly associated with higher odds of progressing to ambulatory hypertension (OR 3.07, 95% CI 1.02-9.23). CONCLUSIONS: The majority of the patients with white coat hypertension progressed to an abnormal ABPM phenotype. This study supports the 2017 American Academy of Pediatrics Clinical Practice Guideline's recommendation for follow-up of ABPM in patients with white coat hypertension.
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Hipertensão , Nefrologia , Pediatria , Pré-Hipertensão , Hipertensão do Jaleco Branco , Adolescente , Pressão Sanguínea/fisiologia , Monitorização Ambulatorial da Pressão Arterial , Criança , Feminino , Humanos , Hipertensão/complicações , Estudos Longitudinais , Masculino , Estudos Retrospectivos , Hipertensão do Jaleco Branco/diagnósticoRESUMO
OBJECTIVES: Acute osteomyelitis is a challenging diagnosis to make in the pediatric emergency department (ED), in part because of variability in its presentation. There are limited data detailing the presenting features of pediatric osteomyelitis, factors that are essential to understand to inform diagnostic decision making. We sought to describe relevant clinical data that contributed to the diagnosis of acute osteomyelitis in children presenting to a pediatric ED. METHODS: This was a 10-year retrospective cohort study of patients 18 years or younger diagnosed with acute osteomyelitis in the ED of a large tertiary care children's hospital. Collected data included demographics, clinical history, patient-reported symptoms, vital signs, physical examination findings, and results of basic laboratory, microbiologic, and imaging studies. Descriptive statistics were used to summarize key findings. RESULTS: Two hundred eleven cases of acute osteomyelitis were identified during the study period. The median age was 8.4 years, with 61.1% male. One hundred twenty-seven patients (60.2%) presented to care more than once before being diagnosed. Common symptoms included pain (94.3%), functional limitation (83.9%), and fever (76.3%). Common examination findings included functional limitation (78.2%), focal tenderness (73.5%), and swelling (52.1%). One hundred seventeen patients (55.5%) were febrile during their ED evaluation. Elevated C-reactive protein (>0.8 mg/dL, 92.9%) and erythrocyte sedimentation rate (>10 mm/h, 94.3%) were the most sensitive laboratory markers. CONCLUSIONS: Fever may be absent in up to a quarter of pediatric patients with acute osteomyelitis. Although highly sensitive, inflammatory marker elevations were more modest than those reported previously in cases of pediatric septic arthritis.
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Artrite Infecciosa , Osteomielite , Sedimentação Sanguínea , Criança , Serviço Hospitalar de Emergência , Feminino , Humanos , Lactente , Masculino , Osteomielite/diagnóstico , Osteomielite/epidemiologia , Estudos RetrospectivosRESUMO
OBJECTIVES: Leftover opioids can contribute to misuse and abuse. Recommended dosing quantities in the electronic medical record can guide prescribing patterns. We hypothesized that decreasing the default from 30 doses to 12 doses would decrease the overall number of opioids prescribed without increasing second opioid prescriptions or additional health utilization. METHODS: We performed a single-center retrospective study of children with forearm and elbow fractures who presented to the emergency department for evaluation and subsequent orthopedic follow-up between January 15, and September 19, 2017. The default dispensing quantity was decreased on June 1, 2016 from 30 doses to 12 doses. Patients were categorized to preintervention and postintervention groups. We compared the number of opioids prescribed, second opioid prescriptions, emergency department visits, and pain-related telephone calls and orthopedic visits with χ2 and logistic regression analyses. RESULTS: There were 1107 patients included. Rates of opioid prescribing were similar preintervention and postintervention (61% vs 56%, P = 0.13). After the change to the default quantity, the median number of doses decreased from 18 to 12 doses, with opioid prescriptions of 30 or more doses dropping from 35% to 11%. No significant association was found between preintervention versus postintervention, opioid prescription at discharge, and having 1 or more pain-related or unexpected follow-up visits. CONCLUSIONS: Lowering the default dispensing quantity of opioids in the electronic medical record decreases the number of opioids prescribed without increasing second prescriptions or additional health care utilization. These findings suggest that a further reduction in the number of opioids prescribed for upper-extremity fractures may be possible.
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Analgésicos Opioides , Registros Eletrônicos de Saúde , Analgésicos Opioides/uso terapêutico , Criança , Prescrições de Medicamentos , Humanos , Padrões de Prática Médica , Estudos RetrospectivosRESUMO
BACKGROUND: Pulmonary exacerbations (PEx) in people with cystic fibrosis (PwCF) are associated with significant morbidity. While standard PEx treatment for PwCF with Pseudomonas aeruginosa infection includes two IV antipseudomonal antibiotics, little evidence exists to recommend this approach. This study aimed to compare clinical outcomes of single versus double antipseudomonal antibiotic use for PEx treatment. METHODS: Retrospective cohort study using the linked CF Foundation Patient Registry-Pediatric Health Information System dataset. PwCF were included if hospitalized between 2007 and 2018 and 6-21 years of age. Regression modeling accounting for repeated measures was used to compare lung function outcomes between single versus double IV antipseudomonal antibiotic regimens using propensity-score weighting to adjust for relevant confounding factors. RESULTS: Among 10,660 PwCF in the dataset, we analyzed 2,578 PEx from 1,080 PwCF, of which 455 and 2,123 PEx were treated with 1 versus 2 IV antipseudomonal antibiotics, respectively. We identified no significant differences between PEx treated with 1 versus 2 IV antipseudomonal antibiotics either in change between pre- and post-PEx percent predicted forced expiratory volume in one second (ppFEV1) (-0.84%, [95% CI -2.25, 0.56]; P = 0.24), odds of returning to ≥90% of baseline ppFEV1 within 3 months following PEx (Odds Ratio 0.83, [95% CI 0.61, 1.13]; P = 0.24) or time to next PEx requiring IV antibiotics (Hazard Ratio 1.04, [95% CI 0.87, 1.24]; P = 0.69). CONCLUSIONS: Use of 2 IV antipseudomonal antibiotics for PEx treatment in young PwCF was not associated with greater improvements in measured respiratory and clinical outcomes compared to treatment with 1 IV antipseudomonal antibiotic.
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Fibrose Cística , Infecções por Pseudomonas , Antibacterianos/uso terapêutico , Criança , Fibrose Cística/complicações , Fibrose Cística/tratamento farmacológico , Volume Expiratório Forçado , Humanos , Infecções por Pseudomonas/tratamento farmacológico , Estudos RetrospectivosRESUMO
BACKGROUND: Facioscapulohumeral muscular dystrophy (FSHD) is a patchy and slowly progressive disease of skeletal muscle. For MRI to be a useful biomarker in an FSHD clinical trial, it should reliably detect changes over relatively short time-intervals (~ 1 year). We hypothesized that fatty change over the study course would be most likely in muscles already demonstrating disease progression, and that the degree of MRI burden would be correlated with function. METHODS: We studied 36 patients with FSHD and lower-extremity weakness at baseline. Thirty-two patients returned in our 12-month longitudinal observational study. We analyzed DIXON MRI images of 16 lower-extremity muscles in each patient and compared them to quantitative strength measurement and ambulatory functional outcome measures. RESULTS: There was a small shift to higher fat fractions in the summed muscle data for each patient, however individual muscles demonstrated much larger magnitudes of change. The greatest increase in fat fraction was observed in muscles having an intermediate fat replacement at baseline, with minimally (baseline fat fraction < 0.10) or severely (> 0.70) affected muscles less likely to progress. Functional outcome measures did not demonstrate marked change over the interval; however, overall MRI disease burden was correlated with functional outcome measures. Direct comparison of the tibialis anterior (TA) fat fraction and quantitative strength measurement showed a sigmoidal relationship, with steepest drop being when the muscle gets more than ~ 20% fatty replaced. CONCLUSIONS: Assessing MRI changes in 16 lower-extremity muscles across 1 year demonstrated that those muscles having an intermediate baseline fat fraction were more likely to progress. Ambulatory functional outcome measures are generally related to overall muscle MRI burden but remain unchanged in the short term. Quantitative strength measurement of the TA showed a steep loss of strength when more fatty infiltration is present suggesting that MRI may be preferable for following incremental change or modulation with drug therapy.
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Distrofia Muscular Facioescapuloumeral , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Músculo Esquelético/diagnóstico por imagem , Distrofia Muscular Facioescapuloumeral/diagnóstico por imagem , Avaliação de Resultados em Cuidados de SaúdeRESUMO
BACKGROUND: Children with asthma, even those with severe persistent disease, can have forced expiratory volume in 1 second (FEV1 ) values ≥100% of predicted, while others have diminished FEV1 . OBJECTIVE: We sought to characterize the lung mechanical properties underlying these two asthma phenotypes and the mechanisms explaining the paradox of severe asthmatic children, whom when clinically stable can have an FEV1 >100% of predicted, but during an acute bronchospastic episode can experience a life-threatening asthma event. METHODS: Lung mechanics were evaluated in three groups of children: asthmatics with FEV1 ≥100% (HFEV1 ; n = 13), asthmatics with FEV1 ≤80% (LFEV1 ; n = 14) and non-asthmatic controls (n = 10). A linear mixed model was used to examine the relationship between volume and static transpulmonary pressures obtained at total lung capacity (TLC); actual TLC %of predicted and flow; and static transpulmonary pressure and flow. RESULTS: HFEV1 asthmatics had larger airways (FEV1 z-scores 1.12 vs -2.37; P < .05), greater lung volumes (mean % of predicted TLC 134.8% vs 109.6%; P < .05) and lower airway resistance (mean %of predicted Raw 101.9% vs 199.9%; P < .05) compared to the LFEV1 group. Moreover, HFEV1 asthmatics had significantly reduced elastic recoil pressure (pressure-volume curve shifted upward and to the left) and higher lung compliance (0.21 vs 00.9 L/cm H2 O; P < .05) compared to the LFEV1 group. The pressure-flow curves revealed the LFEV1 group to have significantly increased resistance to flow in the upstream segment of the airways at all lung volumes studied compared to HFEV1 . CONCLUSION AND CLINICAL RELEVANCE: HFEV1 asthmatic children display distinct lung mechanical proprieties compared to their LFEV1 asthmatic peers. With loss of elastic recoil pressure, the HFEV1 group could generate normal FEV1 due to proportionally enlarged airways and reduced airway resistance, while airflow limitation in the LFEV1 is due to increased airway resistance. Loss of elastic recoil and interdependence during acute bronchoconstriction episodes may predispose the HFEV1 group to catastrophic reductions in airflow.
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Asma/fisiopatologia , Pulmão/fisiopatologia , Mecânica Respiratória , Adolescente , Criança , Feminino , Volume Expiratório Forçado , Humanos , MasculinoRESUMO
PURPOSE: In a large, prospective, multi-institutional active surveillance cohort we evaluated whether African American men are at higher risk for reclassification. MATERIALS AND METHODS: The Canary PASS (Prostate Active Surveillance Study) is a protocol driven, active surveillance cohort with a prespecified prostate specific antigen and surveillance biopsy regimen. Men included in this study had Gleason Grade Group 1 or 2 disease at diagnosis and fewer than 5 years between diagnosis and enrollment, and had undergone 1 or more surveillance biopsies. The reclassification risk, defined as an increase in the Gleason score on subsequent biopsy, was compared between African American and Caucasian American men using Cox proportional hazards models. In the subset of men who underwent delayed prostatectomy the rate of adverse pathology findings, defined as pT3a or greater disease, or Gleason Grade Group 3 or greater, was compared in African American and Caucasian American men. RESULTS: Of the 1,315 men 89 (7%) were African American and 1,226 (93%) were Caucasian American. There was no difference in the treatment rate in African American and Caucasian American men. In multivariate models African American race was not associated with the risk of reclassification (HR 1.16, 95% CI 0.78-1.72). Of the 441 men who underwent prostatectomy after a period of active surveillance the rate of adverse pathology was similar in those who were African American and Caucasian American (46% vs 47%, p=0.99). CONCLUSIONS: Of men on active surveillance who followed a standardized protocol of regular prostate specific antigen testing and biopsy those who were African American were not at increased risk for pathological reclassification while on active surveillance, or for adverse pathology findings at prostatectomy. Active surveillance appears to be an appropriate management strategy for African American men with favorable risk prostate cancer.
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Negro ou Afro-Americano/estatística & dados numéricos , Próstata/patologia , Neoplasias da Próstata/diagnóstico , Conduta Expectante/estatística & dados numéricos , Idoso , Biópsia com Agulha de Grande Calibre/normas , Biópsia com Agulha de Grande Calibre/estatística & dados numéricos , Humanos , Calicreínas/sangue , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Guias de Prática Clínica como Assunto , Estudos Prospectivos , Antígeno Prostático Específico/sangue , Prostatectomia/estatística & dados numéricos , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Estados Unidos , Conduta Expectante/normas , População Branca/estatística & dados numéricosRESUMO
OBJECTIVE: To determine the stability of ambulatory blood pressure monitoring (ABPM) over time in children referred for evaluation of elevated BPs and assess for factors predicting change. STUDY DESIGN: This retrospective chart review conducted at Seattle Children's Hospital and University of Pittsburgh Medical Center Children's Hospital of Pittsburgh identified 124 children referred for elevated BPs with 2 ABPM studies at least 6 months apart. All subjects received lifestyle counseling. Subjects with secondary hypertension (HTN) or on antihypertensive medication were excluded. ABPM phenotype was classified using American Heart Association guidelines as showing normal BP, prehypertension, and HTN. Generalized linear mixed effect regression models were used to regress stable, improving, or worsening HTN outcomes at study follow-up on baseline BP index and load variables. RESULTS: The median age of patients was 14.1 years (73% males) and the median interval between studies was 18 months. ABPM phenotype changed in 58 of 124 children, with 16% worsening and 31% improving. Older age was associated with persistence of HTN. Although not significant, decrease in body mass index z-score tracked with sustained normal ambulatory BPs. CONCLUSIONS: Although the sample size is small, our study suggests ABPM phenotype shows variability over time. Further study is required to identify factors supporting risk for progression of ABPM phenotype over time.
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Monitorização Ambulatorial da Pressão Arterial/métodos , Pressão Sanguínea , Hipertensão/diagnóstico , Pré-Hipertensão/diagnóstico , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Progressão da Doença , Feminino , Humanos , Masculino , Fenótipo , Estudos RetrospectivosRESUMO
OBJECTIVES: To determine the level of agreement between automated office blood pressures (AOBP), auscultated or manual office BP (manual office blood pressure), and 24-hour ABPM, and to explore the ability of AOBP and manual office blood pressure to correctly identify daytime ambulatory hypertension in children. STUDY DESIGN: We retrospectively compared BPs obtained by AOBP and manual office blood pressure to predict daytime hypertension on ABPM. Six BPs were taken by AOBP followed by manual office blood pressure. Office hypertension was defined by BPs ≥95th percentile for sex and height percentiles for those <13 years of age and a BP of ≥130/80 mm Hg for ages ≥13 years. Daytime ambulatory hypertension was diagnosed if mean wake BPs were ≥95th percentile and BP loads were ≥25%. Application of adult ABPM thresholds for daytime hypertension (130/80 mm Hg) was assessed in ages ≥13 years. Sensitivity and specificity were calculated considering ABPM as the reference. RESULTS: Complete data were available for 187 patient encounters. Overall, the best agreement was found if both AOBP and manual office blood pressure showed hypertension, but owing to low sensitivity up to 49% of children with hypertension would be misclassified. The use of adult thresholds for ABPM did not improve agreement. CONCLUSIONS: Neither AOBP nor manual office blood pressure confirm or exclude daytime ambulatory hypertension with confidence. These results suggest an ongoing role for ABPM in evaluation of hypertension in children.
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Determinação da Pressão Arterial/métodos , Hipertensão/diagnóstico , Adolescente , Criança , Feminino , Humanos , Masculino , Visita a Consultório Médico , Estudos RetrospectivosRESUMO
Treatment with mechanical ventilation is associated with chronic lung disease and poor neurologic outcomes in very premature neonates. Surfactant replacement in patients with respiratory distress syndrome reduces need for mechanical ventilation and may be most beneficial when performed early.
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PURPOSE: Outcomes in patients who enroll in active surveillance programs for prostate cancer while receiving 5α-reductase inhibitors have not been well defined. We sought to determine the association of 5α-reductase inhibitor use with the risk of reclassification in the PASS (Canary Prostate Active Surveillance Study). MATERIALS AND METHODS: Participants in the multicenter PASS were enrolled between 2008 and 2016. Study inclusion criteria were current or never 5α-reductase inhibitors use, Gleason score 3 + 4 or less prostate cancer at diagnosis, less than a 34% core involvement ratio at diagnosis and 1 or more surveillance biopsies. Included in study were 1,009 men, including 107 on 5α-reductase inhibitors and 902 who had never received 5α-reductase inhibitors. Reclassification was defined as increase in the Gleason score and/or an increase to 34% or greater in the ratio of biopsy cores positive for cancer. Adverse pathology at prostatectomy was defined as Gleason 4 + 3 or greater and/or nonorgan confined disease (pT3 or N1). RESULTS: On multivariable analysis there was no difference in reclassification between men who had received and those who had never received 5α-reductase inhibitors (HR 0.81, p = 0.31). Patients who had received 5α-reductase inhibitors were less likely to undergo radical prostatectomy (8% vs 18%, p = 0.01) or any definitive treatment (19% vs 24%, p = 0.04). In the 167 participants who underwent radical prostatectomy there was no suggestion of a difference in the rate of adverse pathology findings at prostatectomy between 5α-reductase inhibitor users and nonusers. CONCLUSIONS: Continued 5α-reductase inhibitor use after an initial diagnosis of prostate cancer was not associated with the risk of reclassification on active surveillance in men in the PASS cohort.
Assuntos
Inibidores de 5-alfa Redutase/uso terapêutico , Vigilância da População , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Idoso , Estudos de Coortes , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Antígeno Prostático Específico/sangue , Prostatectomia , Neoplasias da Próstata/mortalidade , Conduta ExpectanteRESUMO
BACKGROUND: Aspirin desensitization provides long-term clinical benefits. The exact mechanisms of aspirin desensitization are not clearly understood. OBJECTIVE: We sought to evaluate the effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on T-cell activation of the IL-4 pathway in aspirin-sensitive patients with asthma and control subjects. METHODS: A total of 11 aspirin-sensitive patients with asthma, 10 aspirin-tolerant patients with asthma, and 10 controls without asthma were studied. PBMCs were stimulated with an anti-CD3 antibody and IL-4 or IL-12, with and without the presence of NSAIDs. The expression of phosphorylated signal transducers and activators of transcription 6 (pSTAT6), phosphorylated signal transducers and activators of transcription 4, and IL-4 was detected in CD4 T cells by flow cytometry. RESULTS: Stimulation with a combination of anti-CD3 and IL-4 induced pSTAT6 in CD4 T cells from all subjects. The induction of pSTAT6 was significantly higher in aspirin-sensitive patients with asthma than in controls subjects. The increase in pSTAT6 was inhibited in a dose-dependent manner by aspirin and indomethacin and minimally by sodium salicylate. This inhibition was strongest in aspirin-sensitive patients. Two-group comparisons showed significant differences in pSTAT6 inhibition by all concentrations of indomethacin and aspirin: between aspirin-sensitive and aspirin-tolerant groups and between aspirin-sensitive and control groups. No differences were found between aspirin-tolerant and control groups at all 3 concentrations. The inhibition of pSTAT6 was associated with reduced IL-4 expression. CONCLUSIONS: NSAIDs inhibited signal transducers and activators of transcription 6 signaling in CD4 T cells. This inhibition was significantly higher in aspirin-sensitive patients than in aspirin-tolerant subjects and was associated with reduced expression of IL-4. These findings have implications for clinical benefits of aspirin desensitization in aspirin-sensitive patients with asthma.