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1.
Hypertension ; 75(6): 1551-1556, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32362230

RESUMO

Hypertension is associated with cardiovascular events in adults. Subclinical changes to left ventricular strain and diastolic function have been found before development of decreased left ventricular ejection fraction and cardiovascular events. Our objective was to study effects of blood pressure (BP) on ventricular function in youth across the BP spectrum. Vital signs and labs were obtained in 346 participants aged 11 to 19 years who had BP categorized as low-risk (N=144; systolic BP <75th percentile), mid-risk (N=83; systolic BP ≥80th and <90th percentile), and high-risk (N=119; systolic BP ≥90th percentile). Echocardiography was performed to assess left ventricular strain and diastolic function. Differences between groups were analyzed by ANOVA. General linear models were constructed to determine independent predictors of systolic and diastolic function. Mid-risk and high-risk participants had greater adiposity and more adverse metabolic labs (lower HDL [high-density lipoprotein], higher glucose, and higher insulin) than the low-risk group. Mid-risk and high-risk participants had significantly lower left ventricular ejection fraction and peak global longitudinal strain than the low-risk group (both P≤0.05). The E/e' ratio was higher in the high-risk group versus the low-risk and mid-risk groups, and the e'/a' ratio was lower in the high-risk versus the low-risk group (both P≤0.05). BP and adiposity were statistically significant determinants of left ventricular systolic and diastolic function. Subclinical changes in left ventricular systolic and diastolic function can be detected even at BP levels below the hypertensive range as currently defined.

2.
J Pediatr ; 221: 188-195.e1, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32446479

RESUMO

OBJECTIVE: To determine whether the Ghent Criteria (2010) can be reliably used in evaluating preadolescents and adolescents for Marfan syndrome by comparing aortic growth, systemic scores, and anthropometric features in individuals with and without Marfan syndrome. STUDY DESIGN: A retrospective chart review was completed for patients less than 15 years of age referred for Marfan syndrome. Comparisons were made between the first and last visit. Paired t tests were used to compare Ghent systemic scores. Wilcoxon rank-sum test were used to compare age, aortic root z scores, height z scores, and body mass index z scores. Recursive partitioning was used to identify combinations of factors to distinguish Marfan syndrome. RESULTS: In total, 53 individuals met inclusion criteria (29 Marfan syndrome and 24 non-Marfan syndrome). Ghent systemic score increased in the Marfan syndrome group and declined in the non-Marfan syndrome. The non-Marfan syndrome group did not develop progressive aortic root dilation with age. Individuals with Marfan syndrome had higher median height z scores than non-Marfan syndrome, with no difference in median body mass index z score between groups. A combination of aortic root z score above 0.95 and Ghent systemic score above 3 was highly indicative of a Marfan syndrome diagnosis in children less than 15 years of age. CONCLUSION: The Ghent criteria (2010) can be used to reliably exclude a diagnosis of Marfan syndrome in individuals less than 15 years of age. Genetic testing should be used as an aide in confirming or excluding the diagnosis of Marfan syndrome in individuals with an aortic root z score above 0.95 in combination with a Ghent systemic score above 3 at initial visit.

4.
Artigo em Inglês | MEDLINE | ID: mdl-32302785

RESUMO

BACKGROUND: Nonlesional skin in atopic dermatitis (AD) is abnormal, but the pathobiology of lesional and nonlesional skin and the definition of endotypes are poorly understood. OBJECTIVE: To define lesional and nonlesional endotypes of AD by building the first US-based early-life prospective cohort of children with AD, the Mechanisms of Progression from AD to Asthma in Children cohort. METHODS: We assessed lesional and nonlesional skin transepidermal water loss, filaggrin (FLG) and alarmin (S100A8, S100A9) expression, staphylococcal colonization, and patterns of aeroallergen and food sensitization to define nonlesional and lesional phenotypes and endotypes. RESULTS: Pathophysiologic changes were present in lesional and nonlesional skin and were associated with SCORing for Atopic Dermatitis. Nonlesional skin had features characteristic of diseased skin including low FLG and high alarmin expression, and increased colonization with Staphylococcus aureus. In a multivariate model, nonlesional, but not lesional, FLG expression was associated with the development of cosensitization and moderate to severe AD. Lesional skin was characterized by further deficits in FLG expression (P < .001), but alarmin expression was the same as observed in nonlesional skin. CONCLUSIONS: This study reveals that events in the nonlesional, not the lesional, skin promote the subsequent development of AD severity and cosensitization, which is a key risk factor for allergic comorbidities. Collectively, these data suggest the presence of a subclinical eczema endotype that may predispose to the development of allergic disease in the absence of overt eczema. This may represent a new definition of the atopic march that starts with skin barrier dysfunction rather than eczema.

5.
J Urol ; : 101097JU0000000000001070, 2020 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-32259466

RESUMO

PURPOSE: Pathologic and oncologic outcomes of delayed radical prostatectomy (RP) following prostate cancer active surveillance (AS) are not well established. To determine the pathologic and oncologic outcomes of favorable risk, Grade Group (GG) =1, prostate cancer (PCa) managed with AS and progressing to RP for clinically significant (CS) PCa (GG ≥ 2). MATERIALS AND METHODS: Between 1992-2015, 170 men with favorable-risk PCa underwent delayed RP for CSPCa (ASRP) at the Princess Margaret Cancer Centre. Pathologic and oncologic outcomes of the ASRP cohort were compared with a matched cohort treated with upfront RP (n=405) immediately before surgery. Biochemical recurrence (BCR) free survival, overall survival (OS), and cancer-specific survival (CSS) were compared. We examined the association between delayed RP and adverse pathology at RP and BCR using Logistic and Cox regression analyses, respectively. RESULTS: The median time spent on AS before RP was 31.0 months. At RP, pT3 (extraprostatic extension, seminal vesicle invasion), positive surgical margin, and pN1rates were comparable between the two cohorts. Median follow-up after RP was 5.6 years. The five-year BCR-free survival rate in the ASRP cohort and upfront RP cohort were 85.8% and 82.4%, respectively (p=0.38). OS, CSS were comparable between the two groups. Delayed RP was not associated with adverse pathologic outcomes and BCR on regression analyses. CONCLUSIONS: Curative-intent RP after a period of AS results in excellent pathologic and oncologic outcomes at five years. A period of AS does not result in inferior outcomes compared to patients with similar risk characteristics undergoing upfront RP.

7.
Artigo em Inglês | MEDLINE | ID: mdl-32197970

RESUMO

BACKGROUND: There is strong evidence for a role of type 2 cytokines in the pathogenesis of eosinophilic esophagitis (EoE); however, heterogeneity in type 2 gene expression has not been examined. OBJECTIVE: We examined type 2 immunity-associated gene expression in esophageal biopsies aiming to determine the degree of cytokine heterogeneity and its potential clinical significance. METHODS: Patients (n=312) were recruited from 10 sites associated with the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR). In addition to histologic and endoscopic assessment, esophageal biopsies were examined for expression of 96 genes within the EoE Diagnostic Panel (EDP). RESULTS: Five subgroups of patients with active EoE were identified by unsupervised clustering based on expression of IL4, IL5, IL13, CCL26, TSLP, CLC, CCR3, and CPA3. These groups differed in age (P < 0.02) and EDP score (P <1.08E-30) but not eosinophil levels. Group V patients had the highest expression of IL5, TSLP, CCL26, and genes associated with tissue remodeling such as COL8A1, ACTG2 and TSPAN12. IL5 and IL13 were highly expressed in group IV; however, groups IV and V differed in age (34 vs. 14 years, P < 0.001). Groups II and III, which exhibited intermediate expression of IL5 and CPA3, were differentiated by high TSLP and IL13 in group III. CONCLUSION: We observed heterogeneous type 2 gene expression among patients with active EoE. Type 2 gene overexpression was not directly proportional to disease features; this was especially true for tissue remodeling events. These findings highlight a clinical opportunity for leveraging molecular endotypes to implement personalized medicine in EoE.

9.
Artigo em Inglês | MEDLINE | ID: mdl-32108714

RESUMO

OBJECTIVE: This study examined whether carrying dopamine-related "risk" genes-either the dopamine transporter (DAT1) 10-repeat allele or dopamine receptor-4 (DRD4) 7-repeat allele-moderated the association of family environment and executive function (EF) following traumatic brain injury (TBI) in early childhood. METHODS: Caregivers of children with TBI or orthopedic injury (OI) completed the Behavior Rating Inventory of Executive Function (BRIEF) at postinjury visits. General linear models examined gene by environment interactions as moderators of the effects of TBI on EF at 12 months and 7 years postinjury. RESULTS: At 12 months, we did not find any significant gene by environment interactions. At 7 years, we found a significant 3-way interaction among combined carrier status, level of permissive parenting, and injury type. For children exposed to more optimal parenting, carriers of DAT1 and/or DRD4 risk alleles with TBI showed significantly worse parent-reported EF than carriers with OI. In those with less optimal parenting, carriers and noncarriers with TBI, as well as carriers with OI, showed significantly worse parent-reported EF than noncarriers with OI, with medium to large effect sizes. CONCLUSIONS: The findings highlight the importance of considering polygenetic and environmental factors in future studies of recovery following TBI and other injuries in childhood.

10.
J Neurotrauma ; 2020 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-32024452

RESUMO

The addition of genetic factors to prognostic models of neurobehavioral recovery following pediatric traumatic brain injury (TBI) may account for unexplained heterogeneity in outcomes. The present study examined the cumulative influence of candidate genes involved in the inflammatory response on long-term neurobehavioral recovery in children with early childhood TBI relative to children with orthopedic injuries (OI). Participants were drawn from a prospective, longitudinal study evaluating outcomes of children who sustained TBI (n = 67) or OI (n = 68) between the ages of 3 and 7 years. Parents completed ratings of child executive function and behavior at an average of 6.8 years after injury. Exploratory unweighted and weighted polygenic risk scores (PRS) were constructed from single nucleotide polymorphisms (SNPs) across candidate inflammatory response genes (i.e., angiotensin converting enzyme [ACE], brain-derived neurotrophic factor [BDNF], interleukin-1 receptor antagonist [IL1RN], and 5'-ectonucleotidase [NT5E]) that showed nominal (p ≤ 0.20) associations with outcomes in the TBI group. Linear regression models tested the PRS × injury group (TBI vs. OI) interaction term and post-hoc analyses examined the effect of PRS within each injury group. Higher inflammatory response PRS were associated with more executive dysfunction and behavior problems in children with TBI but not in children with OI. The cumulative influence of inflammatory response genes as measured by PRS explained additional variance in long-term neurobehavioral outcomes, over and above well-established predictors and single candidate SNPs tested individually. The results suggest that some of the unexplained heterogeneity in long-term neurobehavioral outcomes following pediatric TBI may be attributable to a child's genetic predisposition to a greater or lesser inflammatory response to TBI.

11.
J Clin Anesth ; 62: 109738, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32058259

RESUMO

STUDY OBJECTIVE: To employ systems biology-based machine learning to identify biologic processes over-represented with genetic variants (gene enrichment) implicated in post-surgical pain. DESIGN: Informed systems biology based integrative computational analyses. SETTING: Pediatric research and teaching institution. INTERVENTIONS: Pubmed search (01/01/2001-10/31/2017) was performed to identify "training" genes associated with postoperative pain in humans. Candidate genes were identified and prioritized using Toppgene suite, based on functional enrichment using several gene ontology annotations, and curated gene sets associated with mouse phenotype-knockout studies. MEASUREMENTS: Computationally top-ranked candidate genes and literature-curated genes were included in pathway enrichment analyses. Hierarchical clustering was used to visualize select functional enrichment results between the two phenotypes. MAIN RESULTS: Literature review identified 38 training genes associated with postoperative pain and 31 with CPSP. We identified 2610 prioritized novel candidate genes likely associated with acute and chronic postsurgical pain, the top 10th percentile jointly enriched (p 0.05; Benjamini-Hochberg correction) several pathways, topmost being cAMP response element-binding protein and ion channel pathways. Heat maps demonstrated enrichment of inflammatory/drug metabolism processes in acute postoperative pain and immune mechanisms in CPSP. CONCLUSION: High interindividual variability in pain responses immediately after surgery and risk for CPSP suggests genetic susceptibility. Lack of large homogenous sample sizes have led to underpowered genetic association studies. Systems biology can be leveraged to integrate genetic-level data with biologic processes to generate prioritized candidate gene lists and understand novel biological pathways involved in acute postoperative pain and CPSP. Such data would be key to informing future polygenic studies with targeted genome wide profiling. This study demonstrates the utility of functional annotation - based prioritization and enrichment approaches and identifies novel genes and unique/shared biological processes involved in acute and chronic postoperative pain. Results provide framework for future targeted genetic profiling of CPSP risk, to enable preventive and therapeutic approaches.

13.
Eur Respir J ; 55(4)2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32029443

RESUMO

The pro-inflammatory cytokine interleukin (IL)-6 has been associated with outcomes in small pulmonary arterial hypertension (PAH) cohorts composed largely of patients with severe idiopathic PAH (IPAH). It is unclear whether IL-6 is a marker of critical illness or a mechanistic biomarker of pulmonary vascular remodelling. We hypothesised that IL-6 is produced by pulmonary vascular cells and sought to explore IL-6 associations with phenotypes and outcomes across diverse subtypes in a large PAH cohort.IL-6 protein and gene expression levels were measured in cultured pulmonary artery smooth muscle cells (PASMCs) and endothelial cells (PAECs) from PAH patients and healthy controls. Serum IL-6 was measured in 2017 well-characterised PAH subjects representing each PAH subgroup. Relationships between IL-6 levels, clinical variables, and mortality were analysed using regression models.Significantly higher IL-6 protein and gene expression levels were produced by PASMCs than by PAECs in PAH (p<0.001), while there was no difference in IL-6 between cell types in controls. Serum IL-6 was highest in PAH related to portal hypertension and connective tissue diseases (CTD-PAH). In multivariable modelling, serum IL-6 was associated with survival in the overall cohort (hazard ratio 1.22, 95% CI 1.08-1.38; p<0.01) and in IPAH, but not in CTD-PAH. IL-6 remained associated with survival in low-risk subgroups of subjects with mild disease.IL-6 is released from PASMCs, and circulating IL-6 is associated with specific clinical phenotypes and outcomes in various PAH subgroups, including subjects with less severe disease. IL-6 is a mechanistic biomarker, and thus a potential therapeutic target, in certain PAH subgroups.

14.
J Allergy Clin Immunol ; 145(1): 9-15, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31910986

RESUMO

Eosinophilic esophagitis (EoE) is a chronic allergic disease associated with marked mucosal eosinophil accumulation. Multiple studies have reported a strong familial component to EoE, with the presence of EoE increasing the risk for other family members with EoE. Epidemiologic studies support an important role for environmental risk factors as modulators of genetic risk. In a small percentage of cases, including patients who have Mendelian diseases with co-occurrent EoE, rare genetic variation with large effect sizes could mediate EoE and explain multigenerational incidence in families. Common genetic risk variants mediate genetic risk for the majority of patients with EoE. Across the 31 reported independent EoE risk loci (P < 10-5), most of the EoE risk variants are located in between genes (36.7%) or within the introns of genes (42.4%). Although some variants do change the amino acid sequence of genes (2.2%), only 3 of the 31 EoE risk loci harbor an amino acid-changing variant. Thus most EoE risk loci are outside of the coding regions of genes, suggesting a key role for gene regulation in patients with EoE, which is consistent with most other complex diseases.

15.
Chest ; 2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31987881

RESUMO

BACKGROUND: Three biomarkers, soluble suppression of tumorigenicity 2 (ST2), galectin 3 (Gal3), and N-terminal brain natriuretic peptide prohormone (NT-proBNP), are approved for noninvasive risk assessment in left-sided heart failure, and small observational studies have shown their prognostic usefulness in heterogeneous pulmonary hypertension cohorts. We examined associations between these biomarkers and disease severity and survival in a large cohort of patients with pulmonary arterial hypertension (PAH) (ie, group 1 pulmonary hypertension). We hypothesized that additive use of biomarkers in combination would improve the prognostic value of survival models. METHODS: Biomarker measurements and clinical data were obtained from 2,017 adults with group 1 PAH. Associations among biomarker levels and clinical variables, including survival times, were examined with multivariable regression models. Likelihood ratio tests and the Akaike information criterion were used to compare survival models. RESULTS: Higher ST2 and NT-proBNP were associated with higher pulmonary pressures and vascular resistance and lower 6-min walk distance. Higher ST2 and NT-proBNP levels were associated with increased risk of death (hazard ratios: 2.79; 95% CI, 2.21-3.53; P < .001 and 1.84; 95% CI, 1.62-2.10; P < .001, respectively). The addition of ST2 to survival models composed of other predictors of survival, including NT-proBNP, significantly improved model fit and predictive capacity. CONCLUSIONS: ST2 and NT-proBNP are strong, noninvasive prognostic biomarkers in PAH. Despite its prognostic value in left-sided heart failure, Gal3 was not predictive in PAH. Adding ST2 to survival models significantly improves model predictive capacity. Future studies are needed to develop multimarker assays that improve noninvasive risk stratification in PAH.

16.
J Pediatr Gastroenterol Nutr ; 70(5): 598-603, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31977951

RESUMO

OBJECTIVES: Eosinophilic esophagitis (EoE) is characterized by remissions and relapses. Guidelines defining remission do not exist and therefore remission is inconsistently identified. We sought to define histology remission in EoE. METHODS: Esophageal biopsies, obtained at the time the validated pediatric EoE symptoms scores v2.0 (PEESS v2.0) questionnaire was completed (N = 42), were scored using the validated EoE Histology Scoring System. An EoE Histology Remission Score (EoEHRS) was constructed and specified that in all esophageal sites sampled the peak eosinophil count was <15 per high power field (HPF); in addition, neither the total grade (severity of pathology) nor stage (extent of pathology) scores could exceed 3 (possible total maximum score for each was 24). Spearman correlation coefficients were generated for histology/symptom correlations; coefficient range 0.31 to 0.50 was considered moderate. RESULTS: EoE Histology Scoring System composite and individual feature scores from proximal and distal esophageal biopsies correlated moderately with PEESS v2.0 mean scores (0.48-0.36, P < 0.01), and with scores in the dysphagia (0.39-0.30, P ≤ 0.01), pain (0.48-0.34, P ≤ 0.01), and gastroesophageal reflux disease (0.51-0.32, P ≤ 0.01) domains. Biopsies that met full EoEHRS criteria had reduced biomarkers, specifically expression of the mast cell markers CPA3 and tryptase mRNA, and reduced eosinophil peroxidase deposition (P < 0.03), compared to those with nonremission scores. Subjects whose biopsies met EoEHRS remission criteria reported reduced symptoms for all domains except nausea and vomiting (P ≤ 0.01). CONCLUSIONS: The EoEHRS correlated with reduced biomarkers of disease activity and reduced symptoms, and therefore may be useful to inform clinical care and interstudy comparisons.

17.
Genet Med ; 22(2): 371-380, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31481752

RESUMO

PURPOSE: Clinicians and researchers must contextualize a patient's genetic variants against population-based references with detailed phenotyping. We sought to establish globally scalable technology, policy, and procedures for sharing biosamples and associated genomic and phenotypic data on broadly consented cohorts, across sites of care. METHODS: Three of the nation's leading children's hospitals launched the Genomic Research and Innovation Network (GRIN), with federated information technology infrastructure, harmonized biobanking protocols, and material transfer agreements. Pilot studies in epilepsy and short stature were completed to design and test the collaboration model. RESULTS: Harmonized, broadly consented institutional review board (IRB) protocols were approved and used for biobank enrollment, creating ever-expanding, compatible biobanks. An open source federated query infrastructure was established over genotype-phenotype databases at the three hospitals. Investigators securely access the GRIN platform for prep to research queries, receiving aggregate counts of patients with particular phenotypes or genotypes in each biobank. With proper approvals, de-identified data is exported to a shared analytic workspace. Investigators at all sites enthusiastically collaborated on the pilot studies, resulting in multiple publications. Investigators have also begun to successfully utilize the infrastructure for grant applications. CONCLUSIONS: The GRIN collaboration establishes the technology, policy, and procedures for a scalable genomic research network.

19.
Clin Genet ; 97(2): 312-320, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31654527

RESUMO

Genomic testing of adolescents is increasing yet engaging them in decision-making is not routine. We assessed decisional conflict in adolescents and a parent making independent decisions about actual genomic testing results and factors that influenced their choices. We enrolled 163 dyads consisting of an adolescent (13-17 years) not selected based on a specific clinical indication and one parent. After independently choosing categories of conditions to learn for the adolescent, participants completed the validated Decisional Conflict Scale and a survey assessing factors influencing their respective choices. Adolescents had higher decisional conflict scores than parents (15.6 [IQR:4.7-25.6] vs 9.4 [IQR:1.6-21.9]; P = .0007). Adolescents with clinically significant decisional conflict were less likely to choose to learn all results than adolescents with lower decisional conflict (19.6% vs 80.4%; P < .0001) and less likely to report their choices were influenced by actionability of results (33.3% vs 18.9%; P = .044) and feeling confident they can deal with the results (71.2% vs 91.9%; P = .0005). Our findings suggest higher decisional conflict in adolescents may influence the type and amount of genomic results they wish to learn. Additional research assessing decisional conflict and factors influencing testing choices among adolescents in clinical settings are required.

20.
J Adolesc Health ; 66(3): 288-295, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31685375

RESUMO

PURPOSE: Adolescents will increasingly be involved in decisions about the return of genomic results. We examined adolescents' and parents' decisions about learning actual genomic research results for the adolescent and whether choices were associated with participants' demographic factors. METHODS: Adolescents aged between 13 and 17 years and a parent (dyads) were recruited through flyers, social media, employee emails, and clinic visits at a pediatric hospital. Dyads used a decision tool to independently choose the categories of conditions they wanted to learn about the adolescent. They then came together to discuss their independent decisions and make final joint decisions. Conditions were categorized by preventability, treatability, adult-onset conditions, and carrier status. Participants could make granular choices by including or excluding conditions in each category. Categorical choices were collapsed into the "aggregate choice" to learn all or not all results. RESULTS: Study visits were completed by 163 dyads. Adolescents were less likely than their parents to independently choose to learn all results (64.4% vs. 76.1%; p = .0056). Parents were less likely to independently choose to learn all results for their daughters than their sons (odds ratio = .41, 95% confidence interval .18-.96; p = .032). Black adolescents were less likely to independently choose to learn all results than white adolescents (odds ratio = .22; 95% confidence interval .08-.55; p = .0015). After making joint decisions, 70.6% of dyads chose to learn all results. CONCLUSIONS: Adolescents independently wanted to learn less genomic information than their parents. Although adolescents cannot legally make genomic testing decisions without parental permission, adolescents' should be engaged in decisions about the return of genomic results.

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