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Biomedical subjects

Eric Smith

Publications and source records attributed to Eric Smith.

14 recordsLinked to original sources
PubMed2026

RBM20 Truncating Variants and Human Cardiomyopathy.

IMPORTANCE: Genetic diagnosis has become increasingly important to guide clinical decision-making for patients with dilated cardiomyopathy (DCM). Pathogenic or likely pathogenic (P/LP) missense variants in the gene RBM20 cause a highly penetrant arrhythmogenic DCM, but the role of RBM20 truncating variants (RBM20tvs) is unclear. OBJECTIVE: To assess the contribution of RBM20 variants to arrhythmogenic DCM. DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, participants in the genome-first UK Biobank (UKB) and All of Us populations were evaluated to assess the etiologic fraction, natural history and penetrance of RBM20 variants. Retrospective data were collected from an international cohort of patients with DCM and RBM20 variants identified at centers of excellence for genetic heart disease and compared based on time to event. Study dates are not disclosed because the institutional review board did not authorize the sharing of this information. EXPOSURES: RBM20 variants were compared to known P/LP variants and variants of uncertain significance in RBM20 as well as titin truncating variants (TTNtvs). MAIN OUTCOMES AND MEASURES: Major ventricular arrhythmias, end-stage heart failure, and heart failure hospitalization as measured by medical record review (retrospective cohort) and diagnostic codes (UKB). RESULTS: Two main cohorts were studied for this project. In UK Biobank, a cohort of participants with RBM20tvs, RBM20 synonymous variants, and TTNtvs was studied. Of these 4249 participants, 1869 (44%) were male. The mean (SD) age at enrollment was 56 (8.2) years. In the RBM20 registry, of 179 patients, 105 (58.6%) were male, and the mean (SD) age at enrollment was 43.8 (19.1) years. A validation cohort from the All of Us biobank was also used. This consisted of 7002 participants, 4342 of whom (62.0%) were male, and the mean (SD) age was 52.7 (16.7) years. The etiologic fraction of RBM20 variants in arrhythmogenic DCM was 0.53 (95% CI, 0.32-0.67; P&#x2009;<&#x2009;.001). In genome-first biobanks, lifetime incidence of cardiomyopathy, heart failure, or major ventricular arrhythmia diagnosis was lower in participants with RBM20 variants than in those with TTNtvs (hazard ratio, 0.55; 95% CI, 0.36-0.84; P&#x2009;<&#x2009;.001). Patients with RBM20tvs and DCM presented to referral centers later in life than those with P/LP RBM20 and DCM (mean [SD], 53 [10] vs 34 [18] years; P&#x2009;<&#x2009;.001) and were less likely to have a family history of sudden cardiac arrest (2 of 10 [20%] vs 11 of 17 [65%]; P&#x2009;=&#x2009;.046) or cardiomyopathy (2 of 10 [20%] vs 14 of 18 [78%]; P&#x2009;<&#x2009;.001). There was no significant difference in age- and sex-adjusted incident major heart failure or arrhythmia events between patients with RBM20tv and DCM or those with P/LP RBM20 and DCM, though sex-adjusted lifetime hazard was reduced in those with RBM20tv and DCM (hazard ratio, 0.13; 95% CI, 0.03-0.56; P&#x2009;=&#x2009;.01). CONCLUSIONS AND RELEVANCE: This study found that RBM20 variants contributed to arrhythmogenic DCM phenotypes but conferred reduced lifetime disease penetrance compared to TTNtvs and milder disease severity alone than P/LP RBM20 variants. Their potential for additive interactions with other damaging variants should be considered in patients with DCM and their families.

Humans↗
PubMed2003

Evolving protein interaction networks through gene duplication.

The topology of the proteome map revealed by recent large-scale hybridization methods has shown that the distribution of protein-protein interactions is highly heterogeneous, with many proteins having few edges while a few of them are heavily connected. This particular topology is shared by other cellular networks, such as metabolic pathways, and it has been suggested to be responsible for the high mutational homeostasis displayed by the genome of some organisms. In this paper we explore a recent model of proteome evolution that has been shown to reproduce many of the features displayed by its real counterparts. The model is based on gene duplication plus re-wiring of the newly created genes. The statistical features displayed by the proteome of well-known organisms are reproduced and suggest that the overall topology of the protein maps naturally emerges from the two leading mechanisms considered by the model.

Animals↗
PubMed2003

Quantitative model of price diffusion and market friction based on trading as a mechanistic random process.

We model trading and price formation in a market under the assumption that order arrival and cancellations are Poisson random processes. This model makes testable predictions for the most basic properties of markets, such as the diffusion rate of prices (which is the standard measure of financial risk) and the spread and price impact functions (which are the main determinants of transaction cost). Guided by dimensional analysis, simulation, and mean-field theory, we find scaling relations in terms of order flow rates. We show that even under completely random order flow the need to store supply and demand to facilitate trading induces anomalous diffusion and temporal structure in prices.

Journal Article↗
PubMed2003

Use of a caudal auricular axial pattern flap in three cats and one dog following orbital exenteration.

Orbital exenteration accompanied by wide eyelid excision in the cat and dog may leave a defect that cannot be closed in a primary fashion. This report describes the use of a caudal auricular axial pattern flap to effect closure following orbital exenteration in three cats and one dog. The most common complication was distal flap necrosis, which necessitated a second surgery in two patients.

Animals↗
PubMed2003

Mortality in Emergency Department Sepsis (MEDS) score: a prospectively derived and validated clinical prediction rule.

OBJECTIVES: Our objectives were a) to identify univariate correlates of death in emergency department patients at risk for infection; b) to perform multivariate analyses and identify independent predictors of death; and c) to develop and internally validate a prediction rule that may be used in the emergency department to risk stratify patients into different risk groups to predict their mortality rate. DESIGN: Prospective cohort study. SETTING: Emergency department of an urban university referral center. PATIENTS: Consecutive emergency department patients, aged 18 or older, who were at risk for infection, as indicated by the emergency department physician ordering a blood culture between February 1, 2000, and February 1, 2001. Of 3,301 eligible patient visits, 3,179 (96%) were enrolled. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was 28-day in-hospital mortality rate. There were 2,070 visits in the derivation set, with 110 deaths (5.3%), and 1,109 visits in the validation set, with 63 deaths (5.7%). Independent multivariate predictors of death were terminal illness (odds ratio, 6.1; 95% confidence interval, 3.6-10.2), tachypnea or hypoxia (2.7, 1.6-4.3), septic shock (2.7, 1.2-5.7), platelet count <150,000 (2.5, 1.5-4.3), band proportion >5% (2.3, 1.5-3.5), age >65 (2.2, 1.3-3.6), lower respiratory infection (1.9, 1.2-3.0), nursing home residence (1.9, 1.2-3.0), and altered mental status (1.6, 1.0-2.6). The clinical prediction rule stratified patients into mortality risk groups of very low, 0.9% (95% confidence interval, 0.2-1.5%); low, 2.0% (0.8-3.2%); moderate, 7.8% (5.6-10%); high, 20% (13-27%); and very high, 50% (36.1-64%) in the derivation set. Mortality rates for the corresponding risk groups in the validation set were 1.1%, 4.4%, 9.3%, 16%, and 39%, respectively. The receiver operating characteristic area for the rule was 0.82 in the derivation set and 0.78 in the validation set. CONCLUSIONS: In patients with suspected infection, this model identifies significant correlates of death and allows stratification of patients according to mortality risk. As new therapies become available for patients with sepsis syndromes, the ability to predict mortality risk may be helpful in triage and treatment decisions.

Age Distribution↗
PubMed2002

Acetylation of interferon regulatory factor-7 by p300/CREB-binding protein (CBP)-associated factor (PCAF) impairs its DNA binding.

Interferon regulatory factor 7 (IRF7) is an interferon-inducible transcription factor required for induction of delayed early interferon alpha genes and the onset of a potent antiviral state. After induction of IRF7 by autocrine interferon, latent IRF7 is activated by virus-induced phosphorylation on serine residues within the C-terminal regulatory domain. Although it is likely that IRF7 is subjected to a cascade of events responsible for regulating its biological activity, to date no mechanism other than phosphorylation has been reported to modulate IRF7 activity. Here, we report that IRF7 is acetylated in vivo by the histone acetyltransferases p300/CBP-associated factor (PCAF) and GCN5. The single lysine residue target for acetylation, lysine 92, is located in the DNA-binding domain and is conserved throughout the entire IRF family. Mutation of lysine 92 resulted in complete abolition of DNA binding ability. However, a mutant that cannot be acetylated by PCAF due to a change in the surrounding amino acid context of lysine 92 showed increased DNA binding and activity compared with wild type IRF7. Conversely, we showed that acetylated IRF7 displayed impaired DNA binding capability and that over-expression of PCAF led to decreased IRF7 activity. Together, our results strongly suggest that acetylation of lysine 92 negatively modulates IRF7 DNA binding.

Acetylation↗
PubMed2002

IFN-Stimulated transcription through a TBP-free acetyltransferase complex escapes viral shutoff.

Type I interferon (IFN) stimulates transcription through a heteromeric transcription factor that contains tyrosine-phosphorylated STAT2. We show that STAT2 recruits histone acetyltransferases (HAT) through its transactivation domain, resulting in localized transient acetylation of histones. GCN5, but not p300/CBP or PCAF, is required for STAT2 function. However, GCN5 function is impaired by the transcriptional antagonist, adenovirus E1A oncoprotein. The TFIID component TAF(II)130 potentiates STAT2 function, but TAF(II)28 or the HAT activity of TAF(II)250 do not, and transcriptional induction can proceed independently of the TATA-binding protein, TBP. Moreover, IFN-stimulated transcription was resistant to poliovirus-targeted degradation by TBP, and continued despite host-cell transcriptional shutoff during poliovirus infection. We conclude that a non-classical transcriptional mechanism combats an anticellular action of poliovirus, through a TBP-free TAF-containing complex and GCN5.

3C Viral Proteases↗
PubMed2002

Enhancement and diversification of IFN induction by IRF-7-mediated positive feedback.

Interferons (IFN) are potent components of the innate immune response to microbial infection. The genes for type I IFN (IFN-alpha and IFN-beta) are rapidly induced in response to viral infection through a mechanism that involves latent cellular transcription factors that are activated in response to innate recognition of viral components. IFN regulatory factor (IRF) proteins are key to this regulation, and their conversion from latent to active involves virus-induced serine phosphorylation. Differential utilization of distinct IRF proteins by different members of the type I IFN gene family produces a graded induction of gene expression, resulting in tight control of these cytokines through a positive feedback mechanism. Early response to virus causes secretion of a subset of IFN genes through the action of IRF-3 in conjunction with additional transcription factors, such as NF-kappaB and activator protein-1 (AP-1) (c-jun/ATF). This early IFN acts in an autocrine manner to stimulate production of IRF-7, a transcription factor capable of activating the many additional members of the IFN-alpha gene family. The dependence of IRF-7 on virus-induced phosphorylation for its activity insures that IFN production is limited to virus-infected cells. Characterization of the cellular components involved in viral detection and IRF activation will further delineate this vital mechanism of innate immune response.

Amino Acid Sequence↗
PubMed2002

The role of fetal nuchal translucency in prenatal screening.

PURPOSE OF REVIEW: An update of findings from studies on first trimester nuchal translucency screening. RECENT FINDINGS: New first trimester markers can substantially improve efficacy of screening. When fully informed, preliminary data indicate that women prefer first trimester above second trimester testing. SUMMARY: Recent reports on nuchal translucency screening reiterate the importance of standardization of technique and quality control as proposed by the Fetal Medicine Foundation in London. Effective quality control can be achieved through quantitative analysis of operator specific data. Three-dimensional ultrasound does not provide substantially higher success rates in obtaining reliable nuchal translucency measurements than two-dimensional ultrasound. New data confirm the previously reported association between increased nuchal translucency and increased rate of spontaneous fetal loss, genetic syndromes and a high prevalence (15%) of anomalies, among which cardiac defects are the commonest. Researchers agree that increased nuchal translucency ought to be an indication for specialized echocardiography. Promising data have become available on new markers that can enhance first trimester screening. It is estimated that when assessment of nasal bone and maternal serum analytes are taken into account, first trimester screening can identify 97.5% of trisomy 21 pregnancies for a 5% false-positive rate. It is stressed that parents need to be informed about the possible implications of screening before testing. Preliminary data indicate that when appropriately informed, women prefer first trimester above second trimester testing. Furthermore, the uptake of screening is likely to be relatively low among younger women.

Biomarkers↗
PubMed2002

Arthrographic findings in Legg-Calvé-Perthes disease.

Plain radiographs and arthrograms on 46 patients with Legg-Calvé-Perthes were evaluated. Measurements of containment including epiphyseal extrusion, caput index, femoral subluxation, percentage acetabular coverage, were determined. Only with arthrography are measurements of acetabular coverage, subluxation and epiphyseal extrusion consistent and reliable. The concept of eccentricity was developed to assist in the understanding of femoral containment.

Arthrography↗
PubMed2002

Prenatal diagnosis of sex differentiation disorders: the role of fetal ultrasound.

We describe our experience with prenatal diagnosis of sex differentiation disorders, with focus on the role of ultrasound scans for coherent assessment of prenatal diagnosis. Over a 5-yr period all cases suspected of sexual ambiguity based on abnormal ultrasonographic scans (US) or US/genotype US discrepancy were evaluated prenatally by three modalities: 1) repeated fetal US; 2) genetic studies, primarily karyotype and fluorescence in situ hybridization analysis of sex-determining region on the Y gene (SRY); and 3) hormonal assays of amniotic fluid. Of approximately 10,000 gestations, 16 fetuses underwent prenatal evaluation. Twelve were referred because of an abnormal US and 4 because of genotype-phenotype discrepancy. Five fetuses were diagnosed with female pseudohermaphroditism (21-hydroxylase deficiency in 3 and urorectal septum malformation sequence in 2). Four fetuses were diagnosed with male pseudohermaphroditism (1 with steroid sulfatase deficiency, 1 with presumed camptomelic dysplasia, and 2 undetermined). Five cases had chromosomal abnormalities, and 2 had 46,XX+SRY sex reversal. In all genetic females the uterus was observed on US. In 11 cases initial US scan was performed at 13-15 wk; in 7 of 11, although the initial scan was normal, a repeated scan later in gestation revealed an abnormality. Repeated US scans performed at 13-15 and 22-24 wk gestation are a helpful tool in prenatal diagnosis of sex differentiation disorders. Our data suggest that both size and structure anomalies of the reproductive structures may evolve throughout pregnancy, and that they represent a developmental biological process rather than a single nonprogressive pathological event. US scan after approximately 19 wk enables detection of the uterus and provides pivotal information in cases of ambiguity. If the uterus appears normal, the most likely diagnosis is a virilized karyotypic female. Prenatal diagnosis allows for early parental counseling and anticipation of medical management postnatally.

Amniotic Fluid↗
PubMed2000

Goal negotiation with older people in three day care settings.

Drawing on a wider study of effectiveness in three models of day care, this paper explores the process and outcome of goal negotiation with older people in a day hospital, an outreach service and a day centre. Using qualitative data from interviews with day care attenders and focus groups with service providers, differing perspectives on goal setting and achievement are presented. It concludes with a brief discussion of this approach in the wider context of promoting older people's participation in decision-making in day care settings, where the espoused emphasis is on maintaining and maximising personal autonomy and independent living.

Journal Article↗