Publications by authors named "Stephanie Wallace"

34 Publications

Genetic aortic disease epidemiology, management principles, and disparities in care.

Semin Vasc Surg 2021 Mar 6;34(1):79-88. Epub 2021 Feb 6.

Division of Vascular Surgery, Department of Surgery, University of Washington School of Medicine, 1959 NE Pacific Street, Box 356410, Seattle, WA 98195.

Patients with syndromic and nonsyndromic heritable aortopathies (also known as genetic aortic disease) are a heterogeneous group of patients who present at younger ages with more rapid growth of aortic aneurysms and/or increased frequency of dissections compared with patients with atherosclerotic aortopathies. In this review, we describe the etiology, epidemiology, and appropriate care delivery for these conditions at each stage of management. Within each section, we discuss sex, gender, and race differences and highlight disparities in care and knowledge. We then discuss the role of the vascular team throughout the cycle of care and the evolving inclusion of patient input in research. This understanding is essential to the creation of effective health care policies that support equitable, appropriate, and patient-centered clinical practices.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.semvascsurg.2021.02.012DOI Listing
March 2021

Species differences in phenobarbital-mediated UGT gene induction in rat and human liver microtissues.

Toxicol Rep 2021 29;8:155-161. Epub 2020 Dec 29.

Syngenta ltd, Bracknell, UK.

Species differences in hepatic metabolism of thyroxine (T4) by uridine diphosphate glucuronosyl transferase (UGT) and susceptibility to thyroid hormone imbalance could underlie differences in thyroid carcinogenesis caused by hepatic enzyme inducers in rats and humans. To investigate this hypothesis we examined profiles of hepatic UGT induction by the prototypical CAR activator phenobarbital (PB) in rat and human liver 3D microtissues. The rationale for this approach was that 3D microtissues would generate data more relevant to humans. Rat and human liver 3D microtissues were exposed to PB over a range of concentrations (500 u M - 2000 u M) and times (24-96 hr). Microarray and proteomics analyses were performed on parallel samples to generate integrated differentially expressed gene (DEG) datasets. Bioinformatics analysis of DEG data, including CAR response element (CRE) sequence analysis of UGT promoters, was used to assess species differences in UGT induction relative to CAR-mediated transactivation potential. A higher proportion of human UGT promoters were found to contain consensus CREs compared to the rat homologs. UGTs 1a6, 2b17 and 2b37 were upregulated by PB in rat liver 3D microtissues, but unaltered in human liver 3D microtissues. By contrast, human UGTs 1A8, 1A10 and 2B10 showed higher levels of induction (RNA and /or protein) compared to the rat homologs. There was general concordance between the presence of CREs and the induction of UGT RNA. As UGT1A and 2B isoforms metabolise T4, these results suggest that differences in UGT induction could contribute to differential susceptibility to CAR-mediated thyroid carcinogenesis in rats and humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.toxrep.2020.12.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803626PMC
December 2020

Cross-species comparison of CAR-mediated procarcinogenic key events in a 3D liver microtissue model.

Toxicol Rep 2019 24;6:998-1005. Epub 2019 Sep 24.

Syngenta ltd, Bracknell, UK.

Characterisation of the mode of action (MOA) of constitutive androstane receptor (CAR)-mediated rodent liver tumours involves measurement 5 key events including activation of the CAR receptor, altered gene expression, hepatocellular proliferation, clonal expansion and increased hepatocellular adenomas/carcinomas. To test whether or not liver 3D microtissues (LiMTs) recapitulate CAR- mediated procarcinogenic key events in response to the prototypical CAR activator phenobarbital (PB) we performed hepatocyte proliferation (LI%) analysis in rat and human LiMTs using a microTMA technology in conjunction with integrated transcriptomics (microarray) and proteomics analysis. The rationale for this approach was that LiMTs containing parenchymal and non-parenchymal cells (NPCs) are more physiologically representative of liver and thus would generate data more relevant to the in vivo situation. Rat and human LiMTs were treated with PB over a range of concentrations (500 uM - 2000 uM) and times (24 h - 96 h) in a dose-response/time-course analysis. There was a dose-dependent induction of LI% in rat LiMTs, however there was little or no effect of PB on LI% in human LiMTs. ATP levels in the rat and human LiMTs were similar to control in all of the PB treatments. There was also a dose- and time-dependent PB-mediated RNA induction of CAR regulated genes CYP2B6/Cyp2b2, CYP3A7/Cyp3a9 and UGT1A6/Ugt1a6 in human and rat LiMTs, respectively. These CAR regulated genes were also upregulated at the protein level. Ingenuity pathways analysis (IPA) indicated that there was a significant (Z score >2.0;-log p value >) activation of CAR by PB in both human and rat LiMTs. These results indicate that human and rat LiMTs showed the expected responses at the level of PB-induced hepatocyte proliferation and enzyme induction with rat LiMTs showing significant dose-dependent effects while human LiMTs showed no proliferation response but did show dose-dependent enzyme induction at the RNA and protein levels. In conclusion LiMTs serve as a model to provide mechanistic data for 3 of the 5 key events considered necessary to establish a CAR-mediated MOA for liver tumourigenesis and thus can potentially reduce the use of animals when compiling mechanistic data packages.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.toxrep.2019.09.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6816142PMC
September 2019

Clinical spectrum of individuals with pathogenic NF1 missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423: genotype-phenotype study in neurofibromatosis type 1.

Hum Mutat 2020 01 26;41(1):299-315. Epub 2019 Oct 26.

Department of Dermatology and Venereology, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy.

We report 281 individuals carrying a pathogenic recurrent NF1 missense variant at p.Met1149, p.Arg1276, or p.Lys1423, representing three nontruncating NF1 hotspots in the University of Alabama at Birmingham (UAB) cohort, together identified in 1.8% of unrelated NF1 individuals. About 25% (95% confidence interval: 20.5-31.2%) of individuals heterozygous for a pathogenic NF1 p.Met1149, p.Arg1276, or p.Lys1423 missense variant had a Noonan-like phenotype, which is significantly more compared with the "classic" NF1-affected cohorts (all p < .0001). Furthermore, p.Arg1276 and p.Lys1423 pathogenic missense variants were associated with a high prevalence of cardiovascular abnormalities, including pulmonic stenosis (all p < .0001), while p.Arg1276 variants had a high prevalence of symptomatic spinal neurofibromas (p < .0001) compared with "classic" NF1-affected cohorts. However, p.Met1149-positive individuals had a mild phenotype, characterized mainly by pigmentary manifestations without externally visible plexiform neurofibromas, symptomatic spinal neurofibromas or symptomatic optic pathway gliomas. As up to 0.4% of unrelated individuals in the UAB cohort carries a p.Met1149 missense variant, this finding will contribute to more accurate stratification of a significant number of NF1 individuals. Although clinically relevant genotype-phenotype correlations are rare in NF1, each affecting only a small percentage of individuals, together they impact counseling and management of a significant number of the NF1 population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.23929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6973139PMC
January 2020

The pleiotropy associated with de novo variants in CHD4, CNOT3, and SETD5 extends to moyamoya angiopathy.

Genet Med 2020 02 2;22(2):427-431. Epub 2019 Sep 2.

Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.

Purpose: Moyamoya angiopathy (MMA) is a cerebrovascular disease characterized by occlusion of large arteries, which leads to strokes starting in childhood. Twelve altered genes predispose to MMA but the majority of cases of European descent do not have an identified genetic trigger.

Methods: Exome sequencing from 39 trios were analyzed.

Results: We identified four de novo variants in three genes not previously associated with MMA: CHD4, CNOT3, and SETD5. Identification of additional rare variants in these genes in 158 unrelated MMA probands provided further support that rare pathogenic variants in CHD4 and CNOT3 predispose to MMA. Previous studies identified de novo variants in these genes in children with developmental disorders (DD), intellectual disability, and congenital heart disease.

Conclusion: These genes encode proteins involved in chromatin remodeling, and taken together with previously reported genes leading to MMA-like cerebrovascular occlusive disease (YY1AP1, SMARCAL1), implicate disrupted chromatin remodeling as a molecular pathway predisposing to early onset, large artery occlusive cerebrovascular disease. Furthermore, these data expand the spectrum of phenotypic pleiotropy due to alterations of CHD4, CNOT3, and SETD5 beyond DD to later onset disease in the cerebrovascular arteries and emphasize the need to assess clinical complications into adulthood for genes associated with DD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-019-0639-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673309PMC
February 2020

Assessment of the Information Sources and Interest in Research Collaboration Among Individuals with Vascular Ehlers-Danlos Syndrome.

Ann Vasc Surg 2020 Jan 23;62:326-334. Epub 2019 Aug 23.

Division of Medical Genetics, Department of Medicine and Department of Pathology, University of Washington, Seattle, WA.

Background: Patient-centered research requires active engagement of patients. The vascular Ehlers-Danlos Syndrome (vEDS) research collaborative was established to ascertain patient-centered vEDS research priorities and to engage affected individuals as research partners. Evaluation of access to information and interest in research among individuals with vEDS was the first step undertaken as part of this work.

Methods: A 28-question survey was created to evaluate 4 domains of interest: diagnostic and clinical care history, vEDS experience, information resources, and willingness to collaborate with researchers. The survey was created in REDCap™ and disseminated between January and April 2018 via the vEDS social media pages, blogs, and advocacy Web sites. Results were collated and described. A single open-ended question yielded additional narrative data, which were analyzed qualitatively.

Results: Of the 300 responses, 228 (76%) were completed on behalf of oneself. The vEDS diagnosis was confirmed by genetic testing for 85% of respondents. When asked "Did a physician explain vEDS to you and how to manage it?" 25% answered no. Most had a primary care provider (65%), cardiologist (56%), and vascular surgeon (52%). Only 32% had a local vascular surgeon. The most commonly reported frustration was no cure/treatment available and the emergency rooms do not know what VEDS is (64.5% and 61.8%, respectively). The Internet was the most useful information source (62.3%) followed by a geneticist (18.4%). Most (87.7%) are willing to share their medical records for research studies (87.7%) and wished to be contacted about future studies (83.8%); however, only 65.4% would be willing to upload medical records via a secure confidential Web application. The most common reason for interest in research partnership was to advance research for a treatment/cure (83.8%) and helping others learn from their experiences (82.9%). The qualitative analysis provided additional insights into the patient experience living with vEDS.

Conclusions: Among individuals with vEDS, there is substantial frustration with the lack of treatment, lack of knowledge among health care providers, and a high degree of interest in research involvement. The survey highlights an opportunity to discuss the optimal modality for research participation and methodologies for building trust in the research teams. The methodology lessons learned can also be applied to other rare vascular diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.avsg.2019.06.010DOI Listing
January 2020

A Human iPSC-derived 3D platform using primary brain cancer cells to study drug development and personalized medicine.

Sci Rep 2019 02 5;9(1):1407. Epub 2019 Feb 5.

Center for Alternatives to Animal Testing (CAAT), Johns Hopkins University, 615 North Wolfe Street, Baltimore, MD, 21205, USA.

A high throughput histology (microTMA) platform was applied for testing drugs against tumors in a novel 3D heterotypic glioblastoma brain sphere (gBS) model consisting of glioblastoma tumor cells, iPSC-derived neurons, glial cells and astrocytes grown in a spheroid. The differential responses of gBS tumors and normal neuronal cells to sustained treatments with anti-cancer drugs temozolomide (TMZ) and doxorubicin (DOX) were investigated. gBS were exposed to TMZ or DOX over a 7-day period. Untreated gBS tumors increased in size over a 4-week culture period, however, there was no increase in the number of normal neuronal cells. TMZ (100 uM) and DOX (0.3 uM) treatments caused ~30% (P~0.07) and ~80% (P < 0.001) decreases in the size of the tumors, respectively. Neither treatment altered the number of normal neuronal cells in the model. The anti-tumor effects of TMZ and DOX were mediated in part by selective induction of apoptosis. This platform provides a novel approach for screening new anti-glioblastoma agents and evaluating different treatment options for a given patient.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-018-38130-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363784PMC
February 2019

pathogenic variants: risk for thoracic aortic disease and associated complications from the Montalcino Aortic Consortium.

J Med Genet 2019 04 19;56(4):252-260. Epub 2019 Jan 19.

Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, Texas, USA.

Background: Pathogenic variants in cause thoracic aortic aneurysms and dissections, along with aneurysms and rupture of other arteries. Here, we examined differences in clinical presentation of aortic events (dissection or surgical repair of an aneurysm) with respect to age and variant type in an international cohort of individuals with variants.

Methods: Aortic status and events, vital status and clinical features were abstracted through retrospective review of medical records of 212 individuals with 51 unique variants, including haploinsufficiency (HI) and missense substitutions in the MH2 domain, as well as novel in-frame deletions and missense variants in the MH1 domain.

Results: Aortic events were documented in 37% of cases, with dissections accounting for 70% of events. The median age at first aortic event was significantly lower in individuals with MH2 missense variants than those with HI variants (42years vs 49 years; p=0.003), but there was no difference in frequency of aortic events by variant type. The cumulative risk of an aortic event was 50% at 54 years of age. No aortic events in childhood were observed.

Conclusions: pathogenic variants cause thoracic aortic aneurysms and dissections in the majority of individuals with variable age of onset and reduced penetrance. Of the covariates examined, the type of underlying variant was responsible for some of this variation. Later onset of aortic events and the absence of aortic events in children associated with variants support gene-specific management of this disorder.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jmedgenet-2018-105583DOI Listing
April 2019

MYLK pathogenic variants aortic disease presentation, pregnancy risk, and characterization of pathogenic missense variants.

Genet Med 2019 01 20;21(1):144-151. Epub 2018 Jun 20.

Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA.

Purpose: Heritable thoracic aortic disease can result from null variants in MYLK, which encodes myosin light-chain kinase (MLCK). Data on which MYLK missense variants are pathogenic and information to guide aortic disease management are limited.

Methods: Clinical data from 60 cases with MYLK pathogenic variants were analyzed (five null and two missense variants), and the effect of missense variants on kinase activity was assessed.

Results: Twenty-three individuals (39%) experienced an aortic event (defined as aneurysm repair or dissection); the majority of these events (87%) were aortic dissections. Aortic diameters were minimally enlarged at the time of dissection in many cases. Time-to-aortic-event curves showed that missense pathogenic variant (PV) carriers have earlier-onset aortic events than null PV carriers. An MYLK missense variant segregated with aortic disease over five generations but decreases MYLK kinase acitivity marginally. Functional Assays fail to identify all pathogenic variants in MYLK.

Conclusion: These data further define the aortic phenotype associated with MYLK pathogenic variants. Given minimal aortic enlargement before dissection, an alternative approach to guide the timing of aortic repair is proposed based on the probability of a dissection at a given age.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-018-0038-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400320PMC
January 2019

LTBP3 Pathogenic Variants Predispose Individuals to Thoracic Aortic Aneurysms and Dissections.

Am J Hum Genet 2018 04;102(4):706-712

Department of Internal Medicine, University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030, USA. Electronic address:

The major diseases affecting the thoracic aorta are aneurysms and acute dissections, and pathogenic variants in 11 genes are confirmed to lead to heritable thoracic aortic disease. However, many families in which multiple members have thoracic aortic disease do not have alterations in the known aortopathy genes. Genes highly expressed in the aorta were assessed for rare variants in exome sequencing data from such families, and compound rare heterozygous variants (p.Pro45Argfs25 and p.Glu750) in LTBP3 were identified in affected members of one family. A homozygous variant (p.Asn678_Gly681delinsThrCys) that introduces an additional cysteine into an epidermal growth factor (EGF)-like domain in the corresponding protein, latent TGF-β binding protein (LTBP-3), was identified in a second family. Individuals with compound heterozygous or homozygous variants in these families have aneurysms and dissections of the thoracic aorta, as well as aneurysms of the abdominal aorta and other arteries, along with dental abnormalities and short stature. Heterozygous carriers of the p.Asn678_Gly681delinsThrCys variant have later onset of thoracic aortic disease, as well as dental abnormalities. In these families, LTBP3 variants segregated with thoracic aortic disease with a combined LOD score of 3.9. Additionally, heterozygous rare LTBP3 variants were found in individuals with early onset of acute aortic dissections, and some of these variants disrupted LTBP-3 levels or EGF-like domains. When compared to wild-type mice, Ltbp3 mice have enlarged aortic roots and ascending aortas. In summary, homozygous LTBP3 pathogenic variants predispose individuals to thoracic aortic aneurysms and dissections, along with the previously described skeletal and dental abnormalities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2018.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985335PMC
April 2018

Recessive mutations in VPS13D cause childhood onset movement disorders.

Ann Neurol 2018 06 10;83(6):1089-1095. Epub 2018 Apr 10.

Department of Pediatrics, Saint Justine University Hospital Center and University of Montreal, Montreal, Canada.

VPS13 protein family members VPS13A through VPS13C have been associated with various recessive movement disorders. We describe the first disease association of rare recessive VPS13D variants including frameshift, missense, and partial duplication mutations with a novel complex, hyperkinetic neurological disorder. The clinical features include developmental delay, a childhood onset movement disorder (chorea, dystonia, or tremor), and progressive spastic ataxia or paraparesis. Characteristic brain magnetic resonance imaging shows basal ganglia or diffuse white matter T2 hyperintensities as seen in Leigh syndrome and choreoacanthocytosis. Muscle biopsy in 1 case showed mitochondrial aggregates and lipidosis, suggesting mitochondrial dysfunction. These findings underline the importance of the VPS13 complex in neurological diseases and a possible role in mitochondrial function. Ann Neurol 2018;83:1089-1095.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.25204DOI Listing
June 2018

Molecular genetic testing for hereditary ataxia: What every neurologist should know.

Neurol Clin Pract 2018 Feb;8(1):27-32

Division of Genetic Medicine, Department of Pediatrics (SEW), and Departments of Neurology and Medicine (TDB), University of Washington, Seattle.

Purpose Of Review: Because of extensive clinical overlap among many forms of hereditary ataxia, molecular genetic testing is often required to establish a diagnosis. Interrogation of multiple genes has become a popular diagnostic approach as the cost of sequence analysis has decreased and the number of genes associated with overlapping phenotypes has increased. We describe the benefits and limitations of molecular genetic tests commonly used to determine the etiology of hereditary ataxia.

Recent Findings: There are more than 300 hereditary disorders associated with ataxia. The most common causes of hereditary ataxia are expansion of nucleotide repeats within 7 genes: , , , , , (spinocerebellar ataxia type 6), and (Friedreich ataxia). Recent reports describing the use of clinical exome sequencing to identify causes of hereditary ataxia may lead neurologists to start their clinical investigation with a less sensitive molecular test providing a misleading "negative" result.

Summary: The majority of individuals with hereditary ataxias have nucleotide repeat expansions, pathogenic variants that are not detectable with clinical exome sequencing. Multigene panels that include specific assays to determine nucleotide repeat lengths should be considered first in individuals with hereditary ataxia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/CPJ.0000000000000421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839675PMC
February 2018

Parent Perspectives of Support Received from Physicians and/or Genetic Counselors Following a Decision to Continue a Pregnancy with a Prenatal Diagnosis of Trisomy 13/18.

J Genet Couns 2018 06 27;27(3):656-664. Epub 2017 Oct 27.

Sarah Lawrence College, Bronxville, NY, USA.

Families that choose to continue a pregnancy with a prenatal diagnosis of Trisomy 13/18 are a minority that present unique challenges for those in charge of their care. This study investigated the extent to which these patients felt supported by their healthcare providers, and any differences in the perceived level of support experienced by those working with a physician versus those working with a genetic counselor. Two online support groups, SOFT and Hope for Trisomy, distributed an online survey to their members. Means, standard deviations and chi-square analysis were calculated to describe their responses. One-hundred fourteen surveys were included in the final analysis. Respondents were more likely to agree that genetic counselors provided unbiased information in a way that they understood, compared to physicians. Review of qualitative responses found that portrayal of Trisomy 13/18 by healthcare providers used directive language when describing the lethality, morbidity and burden of the condition. Language included terms such as "incompatible with life" and comments on burden to other family members. Healthcare providers can assist families that receive a prenatal diagnosis of Trisomy 13 or 18 by providing up-to-date written resources and connecting them with support groups for parents who have received a similar diagnosis. Our study found that involving genetic counselors in the prenatal care of these patients is likely beneficial.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10897-017-0168-6DOI Listing
June 2018

Strengthening STEM Education through Community Partnerships.

Sci Educ Civ Engagem 2016 ;8(2):20-33

California State University.

California State University San Marcos (CSUSM) and San Marcos Elementary Schools have established a partnership to offer a large-scale community service learning opportunity to enrich science curriculum for K-5 students. It provides an opportunity for science, technology, engineering, and math (STEM) majors to give back to the community, allowing them to experience teaching in an elementary classroom setting, in schools that lack the resources and science instructor specialization needed to instill consistent science curricula. CSUSM responded to this need for more STEM education by mobilizing its large STEM student body to design hands-on, interactive science lessons based on Next Generation Science Standards (NGSS). Since 2012, the program has reached out to over four thousand K-5 students, and assessment data have indicated an increase in STEM academic performance and interest.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5512595PMC
January 2016

Impact of preoperative screening for rectal colonization with fluoroquinolone-resistant enteric bacteria on the incidence of sepsis following transrectal ultrasound guided prostate biopsy.

Res Rep Urol 2017 24;9:37-41. Epub 2017 Feb 24.

Department of Urology, Cooper University Hospital; Department of Surgery, Cooper University School of Medicine, Camden, NJ, USA.

With the universal adoption of antibiotic prophylaxis prior to prostate biopsy, the current risk of post-biopsy infection (including sepsis) is <2%. Preoperative prophylactic antibiotic regimens can vary, and although fluoroquinolones have emerged as the standard of care, there is no universally agreed upon preoperative antibiotic regimen. Recently, an increase in the proportion of postoperative infections caused by fluoroquinolone-resistant (as well as other ) has led to the exploration of simple, practical, and cost-effective methods to minimize this postoperative infection risk. We performed a prospective, nonrandomized, controlled study of preoperative rectal cultures to screen for rectal colonization with fluoroquinolone-resistant bacteria using ciprofloxacin-supplemented MacConkey agar culture media. To evaluate the feasibility and practicality of this test, one provider used the results of rectal swab cultures collected during the preoperative outpatient evaluation to adjust each patient's preoperative antibiotic prophylaxis when fluoroquinolone-resistant enteric bacteria were detected, whereas two other providers continued usual preoperative care and empiric antimicrobial prophylaxis. Rectal colonization with fluoroquinolone-resistant bacteria was detected in 19/152 (12.5%) of patients. In our intention-to-treat analysis (N=268), the rate of post-biopsy sepsis was 3.6% lower in the group that was screened for rectal colonization with fluoroquinolone-resistant bacteria prior to transrectal prostate biopsy. The observed risk reduction in the rectal screening group trended toward, but did not achieve, statistical significance. We suggest that preoperative screening for rectal colonization with fluoroquinolone-resistant enteric bacteria may be a useful step toward mitigating post-prostate biopsy sepsis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/RRU.S117206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5338954PMC
February 2017

Whole-exome sequencing reveals an inherited R566X mutation of the epithelial sodium channel β-subunit in a case of early-onset phenotype of Liddle syndrome.

Cold Spring Harb Mol Case Stud 2016 11;2(6):a001255

Department of Pediatric Cardiology, Johns Hopkins All Children's Hospital, St. Petersburg, Florida 33701, USA.

To comprehensively evaluate a European-American child with severe hypertension, whole-exome sequencing (WES) was performed on the child and parents, which identified causal variation of the proband's early-onset disease. The proband's hypertension was resistant to treatment, requiring a multiple drug regimen including amiloride, spironolactone, and hydrochlorothiazide. We suspected a monogenic form of hypertension because of the persistent hypokalemia with low plasma levels of renin and aldosterone. To address this, we focused on rare functional variants and indels, and performed gene-based tests incorporating linkage scores and allele frequency and filtered on deleterious functional mutations. Drawing upon clinical presentation, 27 genes were selected evidenced to cause monogenic hypertension and matched to the gene-based results. This resulted in the identification of a stop-gain mutation in an epithelial sodium channel (ENaC), , an established Liddle syndrome gene, shared by the child and her father. Interestingly, the father also harbored a missense mutation (p.Trp552Arg) in the α-subunit of the ENaC trimer, , possibly pointing to pseudohypoaldosteronism type I. This case is unique in that we present the early-onset disease and treatment response caused by a canonical stop-gain mutation (p.Arg566*) as well as ENaC digenic hits in the father, emphasizing the utility of WES informing precision medicine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/mcs.a001255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5111009PMC
November 2016

Cumulative Effect of Racial Discrimination on the Mental Health of Ethnic Minorities in the United Kingdom.

Am J Public Health 2016 07 14;106(7):1294-300. Epub 2016 Apr 14.

All of the authors are with Centre on Dynamics of Ethnicity, University of Manchester, Manchester, Lancashire, UK.

Objectives: To examine the longitudinal association between cumulative exposure to racial discrimination and changes in the mental health of ethnic minority people.

Methods: We used data from 4 waves (2009-2013) of the UK Household Longitudinal Study, a longitudinal household panel survey of approximately 40 000 households, including an ethnic minority boost sample of approximately 4000 households.

Results: Ethnic minority people who reported exposure to racial discrimination at 1 time point had 12-Item Short Form Health Survey (SF-12) mental component scores 1.93 (95% confidence interval [CI] = -3.31, -0.56) points lower than did those who reported no exposure to racial discrimination, whereas those who had been exposed to 2 or more domains of racial discrimination, at 2 different time points, had SF-12 mental component scores 8.26 (95% CI = -13.33, -3.18) points lower than did those who reported no experiences of racial discrimination. Controlling for racial discrimination and other socioeconomic factors reduced ethnic inequalities in mental health.

Conclusions: Cumulative exposure to racial discrimination has incremental negative long-term effects on the mental health of ethnic minority people in the United Kingdom. Studies that examine exposure to racial discrimination at 1 point in time may underestimate the contribution of racism to poor health.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2105/AJPH.2016.303121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4984732PMC
July 2016

Precision medical and surgical management for thoracic aortic aneurysms and acute aortic dissections based on the causative mutant gene.

J Cardiovasc Surg (Torino) 2016 Apr 2;57(2):172-7. Epub 2016 Feb 2.

Division of Medical Genetics, Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA -

Almost one-quarter of patients presenting with thoracic aortic aneurysms (TAAs) or acute aortic dissections (TAADs) have an underlying mutation in a specific gene. A subset of these patients will have systemic syndromic features, for example, skeletal features in patients with Marfan Syndrome. It is important to note that the majority of patients with thoracic aortic disease will not have these syndromic features but many will have a family history of the disease. The genes predisposing to these thoracic aortic diseases are inherited in an autosomal dominant manner, and thirteen genes have been identified to date. As the clinical phenotype associated with each specific gene is defined, the data indicate that the underlying gene dictates associated syndromic features. More importantly, the underlying gene also dictates the aortic disease presentation, the risk for dissection at a given range of aortic diameters, the risk for additional vascular diseases and what specific vascular diseases occur associated with the gene. These results lead to the recommendation that the medical and surgical management of these patients be dictated by the underlying gene, and for patients with mutations in ACTA2, the specific mutation in the gene.
View Article and Find Full Text PDF

Download full-text PDF

Source
April 2016

High Incidence of Noonan Syndrome Features Including Short Stature and Pulmonic Stenosis in Patients carrying NF1 Missense Mutations Affecting p.Arg1809: Genotype-Phenotype Correlation.

Hum Mutat 2015 Nov 21;36(11):1052-63. Epub 2015 Aug 21.

Chaim Sheba Medical Center, Tel Hashomer, Israel.

Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders, affecting 1:3,000 worldwide. Identification of genotype-phenotype correlations is challenging because of the wide range clinical variability, the progressive nature of the disorder, and extreme diversity of the mutational spectrum. We report 136 individuals with a distinct phenotype carrying one of five different NF1 missense mutations affecting p.Arg1809. Patients presented with multiple café-au-lait macules (CALM) with or without freckling and Lisch nodules, but no externally visible plexiform neurofibromas or clear cutaneous neurofibromas were found. About 25% of the individuals had Noonan-like features. Pulmonic stenosis and short stature were significantly more prevalent compared with classic cohorts (P < 0.0001). Developmental delays and/or learning disabilities were reported in over 50% of patients. Melanocytes cultured from a CALM in a segmental NF1-patient showed two different somatic NF1 mutations, p.Arg1809Cys and a multi-exon deletion, providing genetic evidence that p.Arg1809Cys is a loss-of-function mutation in the melanocytes and causes a pigmentary phenotype. Constitutional missense mutations at p.Arg1809 affect 1.23% of unrelated NF1 probands in the UAB cohort, therefore this specific NF1 genotype-phenotype correlation will affect counseling and management of a significant number of patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5049609PMC
http://dx.doi.org/10.1002/humu.22832DOI Listing
November 2015

Impact of an integrated transition management program in primary care on hospital readmissions.

J Healthc Qual 2015 Jan-Feb;37(1):81-92

Poorly executed transitions in care from hospital to home are associated with increased vulnerability to adverse medication events and hospital readmissions, and also excess healthcare costs. Efforts to improve care coordination on hospital discharge have been shown to reduce hospital readmission rates but often rely on interventions that are not fully integrated within the primary care setting. The Patient Centered Medical Home (PCMH) model, whose core principles include care coordination in the posthospital setting, is an approach that addresses transitions in care in a more integrated fashion. We examined the impact of multicomponent transition management (TM) services on hospital readmission rates and time to hospital readmission among 118 patients enrolled in a TM program that is part of Care By Design, the University of Utah Community Clinics' version of the PCMH. We conducted a retrospective analysis comparing outcomes for patients before receiving TM services with outcomes for the same patients after receiving TM services. The all-cause 30-day hospital readmission rate decreased from 17.9% to 8.0%, and the mean time to hospital readmission within 180 days was delayed from 95 to 115 days. These findings support the effectiveness of TM activities integrated within the primary care setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/01.JHQ.0000460119.68190.98DOI Listing
November 2016

A novel missense mutation in POMT1 modulates the severe congenital muscular dystrophy phenotype associated with POMT1 nonsense mutations.

Neuromuscul Disord 2014 Apr 11;24(4):312-20. Epub 2014 Jan 11.

Department of Neurology, University of Washington, Seattle, WA, United States; Department of Pediatrics, University of Washington, Seattle, WA, United States; Seattle Children's Hospital, Seattle, WA, United States. Electronic address:

Mutations in POMT1 lead to a group of neuromuscular conditions ranging in severity from Walker-Warburg syndrome to limb girdle muscular dystrophy. We report two male siblings, ages 19 and 14, and an unrelated 6-year old female with early onset muscular dystrophy and intellectual disability with minimal structural brain anomalies and no ocular abnormalities. Compound heterozygous mutations in POMT1 were identified including a previously reported nonsense mutation (c.2167dupG; p.Asp723Glyfs*8) associated with Walker-Warburg syndrome and a novel missense mutation in a highly conserved region of the protein O-mannosyltransferase 1 protein (c.1958C>T; p.Pro653Leu). This novel variant reduces the phenotypic severity compared to patients with homozygous c.2167dupG mutations or compound heterozygous patients with a c.2167dupG mutation and a wide range of other mutant POMT1 alleles.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nmd.2014.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3959257PMC
April 2014

Improving the value of costly genetic reference laboratory testing with active utilization management.

Arch Pathol Lab Med 2014 Jan;138(1):110-3

From the Department of Laboratories (Drs Dickerson, Cole, Jack, Rutledge, and Astion and Mss Conta and Wellner) and the Division of Genetic Medicine (Dr Wallace), Seattle Children's Hospital, Seattle, Washington; the Departments of Laboratory Medicine (Drs Dickerson, Jack, Rutledge, and Astion) and Pathology (Dr Cole), University of Washington, Seattle; and the Department of Pediatrics, University of Washington School of Medicine, Seattle (Dr Wallace).

Context: Tests that are performed outside of the ordering institution, send-out tests, represent an area of risk to patients because of complexity associated with sending tests out. Risks related to send-out tests include increased number of handoffs, ordering the wrong or unnecessary test, specimen delays, data entry errors, preventable delays in reporting and acknowledging results, and excess financial liability. Many of the most expensive and most misunderstood tests are send-out genetic tests.

Objective: To design and develop an active utilization management program to reduce the risk to patients and improve value of genetic send-out tests.

Design: Send-out test requests that met defined criteria were reviewed by a rotating team of doctoral-level consultants and a genetic counselor in a pediatric tertiary care center.

Results: Two hundred fifty-one cases were reviewed during an 8-month period. After review, nearly one-quarter of genetic test requests were modified in the downward direction, saving a total of 2% of the entire send-out bill and 19% of the test requests under management. Ultimately, these savings were passed on to patients.

Conclusions: Implementing an active utilization strategy for expensive send-out tests can be achieved with minimal technical resources and results in improved value of testing to patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5858/arpa.2012-0726-OADOI Listing
January 2014

Recurrent HERV-H-mediated 3q13.2-q13.31 deletions cause a syndrome of hypotonia and motor, language, and cognitive delays.

Hum Mutat 2013 Oct 13;34(10):1415-23. Epub 2013 Aug 13.

Signature Genomic Laboratories, PerkinElmer, Inc, Spokane, Washington.

We describe the molecular and clinical characterization of nine individuals with recurrent, 3.4-Mb, de novo deletions of 3q13.2-q13.31 detected by chromosomal microarray analysis. All individuals have hypotonia and language and motor delays; they variably express mild to moderate cognitive delays (8/9), abnormal behavior (7/9), and autism spectrum disorders (3/9). Common facial features include downslanting palpebral fissures with epicanthal folds, a slightly bulbous nose, and relative macrocephaly. Twenty-eight genes map to the deleted region, including four strong candidate genes, DRD3, ZBTB20, GAP43, and BOC, with important roles in neural and/or muscular development. Analysis of the breakpoint regions based on array data revealed directly oriented human endogenous retrovirus (HERV-H) elements of ~5 kb in size and of >95% DNA sequence identity flanking the deletion. Subsequent DNA sequencing revealed different deletion breakpoints and suggested nonallelic homologous recombination (NAHR) between HERV-H elements as a mechanism of deletion formation, analogous to HERV-I-flanked and NAHR-mediated AZFa deletions. We propose that similar HERV elements may also mediate other recurrent deletion and duplication events on a genome-wide scale. Observation of rare recurrent chromosomal events such as these deletions helps to further the understanding of mechanisms behind naturally occurring variation in the human genome and its contribution to genetic disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.22384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4599348PMC
October 2013

Sexual and general offending trajectories of men referred for civil commitment.

Sex Abuse 2014 Aug 8;26(4):311-29. Epub 2013 Jul 8.

Department of Mathematics and Statistics, Lancaster University, UK.

Policies aimed at managing high-risk offenders, which include sex offenders, often assume they are a homogeneous population. These policies also tend to assume the pattern of offending is the same for all sex offenders, and is stable. This study challenges these assumptions by examining the life course offending trajectories of 780 convicted adult male sexual offenders. The men were referred to the Massachusetts Treatment Center for civil commitment between 1959 and 1984. The changing number of both sexual and any offenses were examined by age using Group-Based Trajectory Modeling. We identified a four-trajectory model for all offending and a four-trajectory model for sexual offending. The identified groups varied in several offending patterns including criminal onset, length of criminal careers, age of peak offending, and time of entry into the treatment center. Late adult onset of sex offending was found to be associated with child molestation, whereas early-onset trajectories were associated with rape. Implications for future research and policy are discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1079063213492341DOI Listing
August 2014

Physicochemical aspects of the coformulation of colistin and azithromycin using liposomes for combination antibiotic therapies.

J Pharm Sci 2013 May 21;102(5):1578-87. Epub 2013 Mar 21.

Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), Parkville Victoria 3052, Australia.

Remote loading of azithromycin into liposomes, and subsequent release behavior in the presence of colistin, has been investigated with a view to understand the potential of liposomes to enable the coformulation of these two antibiotics for application in inhalation therapy. Azithromycin was successfully encapsulated into liposomes by remote loading (encapsulation efficiency > 98%). Slow release of azithromycin was achieved in the presence of cholesterol in a concentration-dependent manner, with a 4:1 mol ratio of phospholipid-cholesterol releasing 22% azithromycin in 24 h, whereas a 2:1 mol ratio released only 4.9% of azithromycin in 24 h. Addition of colistin to the formulation with increasing concentration did not change the loading behavior, but accelerated drug release, increasing the percentage of released azithromycin from 4.9% to 30% over 24 h. The permeabilizing ability of colistin on liposomes is consistent with its permeabilizing effect on bacterial cells. This behavior opens opportunities to tailor the release rate of drugs coformulated with colistin using liposomes as the carrier.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jps.23508DOI Listing
May 2013

Drug release from nanomedicines: Selection of appropriate encapsulation and release methodology.

Drug Deliv Transl Res 2012 Aug 3;2(4):284-92. Epub 2012 Mar 3.

Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Melbourne, Victoria 3052, Australia.

The characterization of encapsulation efficiency and in vitro drug release from nanoparticle-based formulations often requires the separation of nanoparticles from unencapsulated drug. Inefficient separation of nanoparticles from the medium in which they are dispersed can lead to inaccurate estimates of encapsulation efficiency and drug release. This study establishes dynamic light scattering as a simple method for substantiation of the effectiveness of the separation process. Colistin-loaded liposomes, as an exemplar nano-sized delivery particle, were diluted to construct a calibration curve relating the amount of light scattering to liposome concentration. Dynamic light scattering revealed that, in the case of ultracentrifugation and centrifugal ultrafiltration, approximately 2.9% of the total liposomes remained in supernatants or filtrates, respectively. In comparison, filtrates obtained using pressure ultrafiltration contained less than 0.002% of the total liposomes from the formulation. Subsequent release studies using dialysis misleadingly implied a slow release of colistin over >48 h. In contrast, pressure ultrafiltration revealed immediate equilibration to the equilibrium distribution of colistin between the liposome and aqueous phases upon dilution. Pressure ultrafiltration is therefore recommended as the optimal method of choice for studying release kinetics of drug from nanomedicine carriers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13346-012-0064-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3482165PMC
August 2012

Interaction of colistin and colistin methanesulfonate with liposomes: colloidal aspects and implications for formulation.

J Pharm Sci 2012 Sep 23;101(9):3347-59. Epub 2012 May 23.

Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.

Interaction of colistin and colistin methanesulfonate (CMS) with liposomes has been studied with the view to understanding the limitations to the use of liposomes as a more effective delivery system for pulmonary inhalation of this important class of antibiotic. Thus, in this study, liposomes containing colistin or CMS were prepared and characterized with respect to colloidal behavior and drug encapsulation and release. Association of anionic CMS with liposomes induced negative charge on the particles. However, degradation of the CMS to form cationic colistin over time was directly correlated with charge reversal and particle aggregation. The rate of degradation of CMS was significantly more rapid when associated with the liposome bilayer than when compared with the same concentration in aqueous solution. Colistin liposomes carried positive charge and were stable. Encapsulation efficiency for colistin was approximately 50%, decreasing with increasing concentration of colistin. Colistin was rapidly released from liposomes on dilution. Although the studies indicate limited utility of colistin or CMS liposomes for long duration controlled-release applications, colistin liposomes were highly stable and may present a potential opportunity for coformulation of colistin with a second antibiotic to colocalize the two drugs after pulmonary delivery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jps.23203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3437939PMC
September 2012

Recurrent 200-kb deletions of 16p11.2 that include the SH2B1 gene are associated with developmental delay and obesity.

Genet Med 2010 Oct;12(10):641-7

Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, USA.

Purpose: The short arm of chromosome 16 is rich in segmental duplications, predisposing this region of the genome to a number of recurrent rearrangements. Genomic imbalances of an approximately 600-kb region in 16p11.2 (29.5-30.1 Mb) have been associated with autism, intellectual disability, congenital anomalies, and schizophrenia. However, a separate, distal 200-kb region in 16p11.2 (28.7-28.9 Mb) that includes the SH2B1 gene has been recently associated with isolated obesity. The purpose of this study was to better define the phenotype of this recurrent SH2B1-containing microdeletion in a cohort of phenotypically abnormal patients not selected for obesity.

Methods: Array comparative hybridization was performed on a total of 23,084 patients in a clinical setting for a variety of indications, most commonly developmental delay.

Results: Deletions of the SH2B1-containing region were identified in 31 patients. The deletion is enriched in the patient population when compared with controls (P = 0.003), with both inherited and de novo events. Detailed clinical information was available for six patients, who all had developmental delays of varying severity. Body mass index was ≥95th percentile in four of six patients, supporting the previously described association with obesity. The reciprocal duplication, found in 17 patients, does not seem to be significantly enriched in our patient population compared with controls.

Conclusions: Deletions of the 16p11.2 SH2B1-containing region are pathogenic and are associated with developmental delay in addition to obesity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/GIM.0b013e3181ef4286DOI Listing
October 2010

Self-assembly behavior of colistin and its prodrug colistin methanesulfonate: implications for solution stability and solubilization.

J Phys Chem B 2010 Apr;114(14):4836-40

Facility for Anti-Infective Drug Development and Innovation, Monash Institute of Pharmaceutical Sciences, Parkville, Melbourne, Victoria 3052, Australia.

Colistin is an amphiphilic antibiotic that has re-emerged into clinical use due to the increasing prevalence of difficult-to-treat Gram-negative infections. The existence of self-assembling colloids in solutions of colistin and its derivative prodrug, colistin methanesulfonate (CMS), was investigated. Colistin and CMS reduced the air-water interfacial tension, and dynamic light scattering (DLS) studies showed the existence of 2.07 +/- 0.3 nm aggregates above 1.5 mM for colistin and of 1.98 +/- 0.36 nm aggregates for CMS above 3.5 mM (mean +/- SD). Above the respective critical micelle concentrations (CMC) the solubility of azithromycin, a hydrophobic antibiotic, increased approximately linearly with increasing surfactant concentration (5:1 mol ratio colistin:azithromycin), suggestive of hydrophobic domains within the micellar cores. Rapid conversion of CMS to colistin occurred below the CMC (60% over 48 h), while conversion above the CMC was less than 1%. The formation of colistin and CMS micelles demonstrated in this study is the proposed mechanism for solubilization of azithromycin and the concentration-dependent stability of CMS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jp100458xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2881163PMC
April 2010
-->