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"Jobling, Curtis"
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War of the Werelords
\"While the war between the Catlords and the Wolf embroils the Seven Realms in chaos, Drew must take his final stand against the man who has become Lyssia's deadliest villain: his own best friend, the Boarlord Hector, whose powers of dark magick are raging out of control\"-- Provided by publisher.
Book
The Cardiac Genome Clinic: implementing genome sequencing in pediatric heart disease
Purpose
This study investigated the diagnostic utility of nontargeted genomic testing in patients with pediatric heart disease.
Methods
We analyzed genome sequencing data of 111 families with cardiac lesions for rare, disease-associated variation.
Results
In 14 families (12.6%), we identified causative variants: seven were de novo (
ANKRD11
,
KMT2D
,
NR2F2
,
POGZ
,
PTPN11
,
PURA
,
SALL1
) and six were inherited from parents with no or subclinical heart phenotypes (
FLT4
,
DNAH9
,
MYH11
,
NEXMIF
,
NIPBL
,
PTPN11
). Outcome of the testing was associated with the presence of extracardiac features (
p
= 0.02), but not a positive family history for cardiac lesions (
p
= 0.67). We also report novel plausible gene–disease associations for tetralogy of Fallot/pulmonary stenosis (
CDC42BPA
,
FGD5
), hypoplastic left or right heart (
SMARCC1
,
TLN2
,
TRPM4
,
VASP
), congenitally corrected transposition of the great arteries (
UBXN10
), and early-onset cardiomyopathy (
TPCN1
). The identified candidate genes have critical functions in heart development, such as angiogenesis, mechanotransduction, regulation of heart size, chromatin remodeling, or ciliogenesis.
Conclusion
This data set demonstrates the diagnostic and scientific value of genome sequencing in pediatric heart disease, anticipating its role as a first-tier diagnostic test. The genetic heterogeneity will necessitate large-scale genomic initiatives for delineating novel gene–disease associations.
Journal Article
Nest of serpents
\"The entire kingdom of Lyssia is now at war, and the battle lines have been drawn. While Drew and his ragtag army defend the throne against Ratlords and Crowlords, Gretchen and Whitley venture on a harrowing journey through the perilous Dyrewood. But none of the Werelords counted on the return of the most terrifying monster of them all--an enemy Drew thought he'd already slain\"--Page 4 of cover.
Book
SCIP: software for efficient clinical interpretation of copy number variants detected by whole-genome sequencing
Copy number variants (CNVs) represent major etiologic factors in rare genetic diseases. Current clinical CNV interpretation workflows require extensive back-and-forth with multiple tools and databases. This increases complexity and time burden, potentially resulting in missed genetic diagnoses. We present the Suite for CNV Interpretation and Prioritization (SCIP), a software package for the clinical interpretation of CNVs detected by whole-genome sequencing (WGS). The SCIP Visualization Module near-instantaneously displays all information necessary for CNV interpretation (variant quality, population frequency, inheritance pattern, and clinical relevance) on a single page—supported by modules providing variant filtration and prioritization. SCIP was comprehensively evaluated using WGS data from 1027 families with congenital cardiac disease and/or autism spectrum disorder, containing 187 pathogenic or likely pathogenic (P/LP) CNVs identified in previous curations. SCIP was efficient in filtration and prioritization: a median of just two CNVs per case were selected for review, yet it captured all P/LP findings (92.5% of which ranked 1st). SCIP was also able to identify one pathogenic CNV previously missed. SCIP was benchmarked against AnnotSV and a spreadsheet-based manual workflow and performed superiorly than both. In conclusion, SCIP is a novel software package for efficient clinical CNV interpretation, substantially faster and more accurate than previous tools (available at https://github.com/qd29/SCIP, a video tutorial series is available at https://bit.ly/SCIPVideos).
Journal Article
Max Helsing and the thirteenth curse
Max is just your average kid growing up in Gallows Hill, a small town outside of Boston--well, except that he lives in a gothic mansion with an old former prizefighter, and his after-school job is carrying on the monster-hunting tradition of his family, the van Helsings. Max always tries to be kind and fair to the ghouls, demons, and other creatures he encounters, so he's confused when monsters start attacking him, even those he thought of as friends. Max discovers he's been cursed by an evil Warlock who intends to reclaim the earth for the monsters.
Book
Assessment of the Implementation of Pharmacogenomic Testing in a Pediatric Tertiary Care Setting
Pharmacogenomic (PGx) testing provides preemptive pharmacotherapeutic guidance regarding the lack of therapeutic benefit or adverse drug reactions of PGx targeted drugs. Pharmacogenomic information is of particular value among children with complex medical conditions who receive multiple medications and are at higher risk of developing adverse drug reactions.
To assess the implementation outcomes of a PGx testing program comprising both a point-of-care model that examined targeted drugs and a preemptive model informed by whole-genome sequencing that evaluated a broad range of drugs for potential therapy among children in a pediatric tertiary care setting.
This cohort study was conducted at The Hospital for Sick Children in Toronto, Ontario, from January 2017 to September 2020. Pharmacogenomic analyses were performed among 172 children who were categorized into 2 groups: a point-of-care cohort and a preemptive cohort. The point-of-care cohort comprised 57 patients referred to the consultation clinic for planned therapy with PGx targeted drugs and/or for adverse drug reactions, including lack of therapeutic benefit, after the receipt of current or past medications. The preemptive cohort comprised 115 patients who received exploratory whole-genome sequencing-guided PGx testing for their heart conditions from the cardiac genome clinic at the Ted Rogers Centre for Heart Research.
Patients received PGx analysis of whole-genome sequencing data and/or multiplex genotyping of 6 pharmacogenes (CYP2C19, CYP2C9, CYP2D6, CYP3A5, VKORC1, and TPMT) that have established PGx clinical guidelines.
The number of patients for whom PGx test results warranted deviation from standard dosing regimens.
A total of 172 children (mean [SD] age, 8.5 [5.6] years; 108 boys [62.8%]) were enrolled in the study. In the point-of-care cohort, a median of 2 target genes (range, 1-5 genes) were investigated per individual, with CYP2C19 being the most frequently examined; genotypes in 21 of 57 children (36.8%) were incompatible with standard treatment regimens. As expected from population allelic frequencies, among the 115 children in the whole-genome sequencing-guided preemptive cohort, 92 children (80.0%) were recommended to receive nonstandard treatment regimens for potential drug therapies based on their 6-gene pharmacogenetic profile.
In this cohort study, among both the point-of-care and preemptive cohorts, the multiplex PGx testing program provided dosing recommendations that deviated from standard regimens at an overall rate that was similar to the population frequencies of relevant variants.
Journal Article
غضب الأسود
تحكي قصة (غضب الأسود) الصادرة عن دار الساقي بلبنان، والتي قام بتأليفها (كورتيس جوبلينغ) في حوالي (383) صفحة من القطع المتوسط، عن شاب مستذئب، وعندما يختطف المستأسد، الأمير لوكاس، الليدي غريتشن، ينطلق درو وأصدقاؤه في مطاردة محفوفة بالمخاطر لمنع الأمير من الهرب إلى موطنه باست، وبينما يواجه درو أسيادا متحولين جددا مروعين خلال مغامرته، يقاد إلى مدينة خليج غالا الغريبة، حيث قوى أونيكس ووحش باست في انتظاره.
BOOK
Haploinsufficiency of vascular endothelial growth factor related signaling genes is associated with tetralogy of Fallot
Purpose
To determine disease-associated single-gene variants in conotruncal defects, particularly tetralogy of Fallot (TOF).
Methods
We analyzed for rare loss-of-function and deleterious variants in
FLT4
(VEGFR3) and other genes in the vascular endothelial growth factor (VEGF) pathway, as part of a genome sequencing study involving 175 adults with TOF from a single site.
Results
We identified nine (5.1%) probands with novel
FLT4
variants: seven loss-of-function, including an 8-kb deletion, and two predicted damaging. In ten other probands we found likely disruptive variants in VEGF-related genes:
KDR
(VEGFR2; two stopgain and two nonsynonymous variants),
VEGFA
,
FGD5
,
BCAR1
,
IQGAP1
,
FOXO1
, and
PRDM1
. Detection of VEGF-related variants (19/175, 10.9%) was associated with an increased prevalence of absent pulmonary valve (26.3% vs. 3.4%,
p
< 0.0001) and right aortic arch (52.6% vs. 29.1%,
p
= 0.029). Extracardiac anomalies were rare. In an attempt to replicate findings, we identified three loss-of-function or damaging variants in
FLT4
,
KDR
, and
IQGAP1
in ten independent families with TOF.
Conclusion
Loss-of-function variants in
FLT4
and
KDR
contribute substantially to the genetic basis of TOF. The findings support dysregulated VEGF signaling as a novel mechanism contributing to the pathogenesis of TOF.
Journal Article
صحوة الذئب
يتناول الكتاب قصة المستذئبين وتدور الأحداث عندما تكون الأجواء صافية، يستطيع درو فيران، ابن السادسة عشرة، أن يشتم رائحة مخلوق مفترس. عندما يبزغ القمر من بين الغيوم، تجتاحه حمى مرعبة. وعندما يهاجم وحش ضار منزله يتمزق لحمه، وتصبح أصابعه مخالب، ويضطر درو إلى الهروب من العائلة، ساعيا لإيجاد ملجأ في أكثر الأماكن سرية في ليسيا. كيف يمكن درو أن يثبت أنه ليس العدو لرجال الدوق بيرغان الذين ألقوا القبض عليه ؟ وهل يمكنه مقاتلة المخلوقات المتحولة العازمة على سحقه، والسيطرة على الحيوان الذي يسكنه ؟.
BOOK
Genes and pathways implicated in tetralogy of Fallot revealed by ultra-rare variant burden analysis in 231 genome sequences
Recent genome-wide studies of rare genetic variants have begun to implicate novel mechanisms for tetralogy of Fallot (TOF), a severe congenital heart defect (CHD). To provide statistical support for case-only data without parental genomes, we re-analyzed genome sequences of 231 individuals with TOF or related CHD. We adapted a burden test originally developed for de novo variants to assess singleton variant burden in individual genes, and in gene-sets corresponding to functional pathways and mouse phenotypes, accounting for highly correlated gene-sets, and for multiple testing. The gene burden test identified a significant burden of deleterious missense variants in NOTCH1 (Bonferroni-corrected p-value <0.01). These NOTCH1 variants showed significant enrichment for those affecting the extracellular domain, and especially for disruption of cysteine residues forming disulfide bonds (OR 39.8 vs gnomAD). Individuals with NOTCH1 variants, all with TOF, were enriched for positive family history of CHD. Other genes not previously implicated in TOF had more modest statistical support and singleton missense variant results were non-significant for gene-set burden. For singleton truncating variants, the gene burden test confirmed significant burden in FLT4. Gene-set burden tests identified a cluster of pathways corresponding to VEGF signaling (FDR=0%), and of mouse phenotypes corresponding to abnormal vasculature (FDR=0.8%), that suggested additional candidate genes not previously identified (e.g., WNT5A and ZFAND5). Analyses using unrelated sequencing datasets supported specificity of the findings for CHD. The findings support the importance of ultra-rare variants disrupting genes involved in VEGF and NOTCH signaling in the genetic architecture of TOF. These proof-of-principle data indicate that this statistical methodology could assist in analyzing case-only sequencing data in which ultra-rare variants, whether de novo or inherited, contribute to the genetic etiopathogenesis of a complex disorder.
Paper