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"Prince, Andrea"
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Family Based Whole Exome Sequencing Reveals the Multifaceted Role of Notch Signaling in Congenital Heart Disease
Left-ventricular outflow tract obstructions (LVOTO) encompass a wide spectrum of phenotypically heterogeneous heart malformations which frequently cluster in families. We performed family based whole-exome and targeted re-sequencing on 182 individuals from 51 families with multiple affected members. Central to our approach is the family unit which serves as a reference to identify causal genotype-phenotype correlations. Screening a multitude of 10 overlapping phenotypes revealed disease associated and co-segregating variants in 12 families. These rare or novel protein altering mutations cluster predominantly in genes (NOTCH1, ARHGAP31, MAML1, SMARCA4, JARID2, JAG1) along the Notch signaling cascade. This is in line with a significant enrichment (Wilcoxon, p< 0.05) of variants with a higher pathogenicity in the Notch signaling pathway in patients compared to controls. The significant enrichment of novel protein truncating and missense mutations in NOTCH1 highlights the allelic and phenotypic heterogeneity in our pediatric cohort. We identified novel co-segregating pathogenic mutations in NOTCH1 associated with left and right-sided cardiac malformations in three independent families with a total of 15 affected individuals. In summary, our results suggest that a small but highly pathogenic fraction of family specific mutations along the Notch cascade are a common cause of LVOTO.
Journal Article
Eshkol-Wachman Movement Notation in Diagnosis: The Early Detection of Asperger's Syndrome
The diagnostic criteria of Asperger's syndrome (AS), considered a part of the autistic spectrum disorder, are still unclear. A critical marker, which distinguishes AS from autism, is the presence of language. The ability of a child with AS to acquire and use language early results in the fact that AS usually is diagnosed much later than autism. Autism is not usually diagnosed until around the age of 3, whereas AS usually is not diagnosed until the child is 6 or 7 years of age. In the present article, using Eshkol-Wachman movement notation, we present evidence that abnormal movement patterns can be detected in AS in infancy. This finding suggests that AS can be diagnosed very early, independent of the presence of language. As shown earlier by us, almost all of the movement disturbances in autism can be interpreted as infantile reflexes \"gone astray\"; i.e., some reflexes are not inhibited at the appropriate age in development, whereas others fail to appear when they should. This phenomenon appears to apply to AS as well. Based on preliminary results, a simple test using one such reflex is proposed for the early detection of a subgroup of children with AS or autism.
Journal Article
Improving Recruitment for a Newborn Screening Pilot Study with Adaptations in Response to the COVID-19 Pandemic
Seven months after the launch of a pilot study to screen newborns for Duchenne Muscular Dystrophy (DMD) in New York State, New York City became an epicenter of the coronavirus disease 2019 (COVID-19) pandemic. All in-person research activities were suspended at the study enrollment institutions of Northwell Health and NewYork-Presbyterian Hospitals, and study recruitment was transitioned to 100% remote. Pre-pandemic, all recruitment was in-person with research staff visiting the postpartum patients 1–2 days after delivery to obtain consent. With the onset of pandemic, the multilingual research staff shifted to calling new mothers while they were in the hospital or shortly after discharge, and consent was collected via emailed e-consent links. With return of study staff to the hospitals, a hybrid approach was implemented with in-person recruitment for babies delivered during the weekdays and remote recruitment for babies delivered on weekends and holidays, a cohort not recruited pre-pandemic. There was a drop in the proportion of eligible babies enrolled with the transition to fully remote recruitment from 64% to 38%. In addition, the proportion of babies enrolled after being approached dropped from 91% to 55%. With hybrid recruitment, the proportion of eligible babies enrolled (70%) and approached babies enrolled (84%) returned to pre-pandemic levels. Our experience adapting our study during the COVID-19 pandemic led us to develop new recruitment strategies that we continue to utilize. The lessons learned from this pilot study can serve to help other research studies adapt novel and effective recruitment methods.
Journal Article
Inmate died from asphyxiation, inquest rules
[Darwin Frerichs] said he noticed a blanket covering [Clifford Morgan Rosiak]'s cell door when he was conducting his routine prisoner count just after 10 p.m. Frerichs took the blanket down and looked into the darkened cell. Rosiak had a coaxial cable around his neck, tied to a shelf about five feet (1.5 metres) off the ground, said Frerichs, who immediately called for help. [Bruce Vogel] said samples of Rosiak's handwriting seemed to match the writing on the note. The note referred to past events Rosiak had participated in and felt guilty about.
Newspaper Article
Elranatamab in relapsed or refractory multiple myeloma: phase 2 MagnetisMM-3 trial results
Elranatamab is a humanized B-cell maturation antigen (BCMA)-CD3 bispecific antibody. In the ongoing phase 2 MagnetisMM-3 trial, patients with relapsed or refractory multiple myeloma received subcutaneous elranatamab once weekly after two step-up priming doses. After six cycles, persistent responders switched to biweekly dosing. Results from cohort A, which enrolled patients without prior BCMA-directed therapy (
n
= 123) are reported. The primary endpoint of confirmed objective response rate (ORR) by blinded independent central review was met with an ORR of 61.0% (75/123); 35.0% ≥complete response. Fifty responders switched to biweekly dosing, and 40 (80.0%) improved or maintained their response for ≥6 months. With a median follow-up of 14.7 months, median duration of response, progression-free survival and overall survival (secondary endpoints) have not been reached. Fifteen-month rates were 71.5%, 50.9% and 56.7%, respectively. Common adverse events (any grade; grade 3–4) included infections (69.9%, 39.8%), cytokine release syndrome (57.7%, 0%), anemia (48.8%, 37.4%), and neutropenia (48.8%, 48.8%). With biweekly dosing, grade 3–4 adverse events decreased from 58.6% to 46.6%. Elranatamab induced deep and durable responses with a manageable safety profile. Switching to biweekly dosing may improve long-term safety without compromising efficacy. ClinicalTrials.gov identifier:
NCT04649359
.
In a pivotal phase 2 trial, elranatamab, a bispecific antibody targeting B-cell maturation antigen (BCMA) and CD3, had a confirmed objective response rate of 61% in patients with relapsed or refractory multiple myeloma who had not previously received BCMA-directed therapy.
Journal Article
Woman avoids jail for leaving teen to freeze
[Teresa McLeod] was driving a medical van Nov. 29, 1995 when she picked up [Becky Charles] and four other passengers in Saskatoon for a four-hour drive back to La Ronge. McLeod finally told Charles to get out of the cab about 30 kilometres outside La Ronge. When McLeod arrived in La Ronge, she phoned the cab company owner again. He contacted the RCMP, who sent a car to the junction where Charles had been dropped off. Police could not find her.
Newspaper Article
On the estimation of inverse-probability-of-censoring weights for the evaluation of survival prediction error
Inverse probability weighting (IPW) is a popular method for making inferences regarding unobserved or unobservable data of a target population based on observed data. This paper considers IPW applied to right-censored time-to-event data. We investigate the behavior of the inverse-probability-of-censoring weighted (IPCW) Brier score, which is frequently used to assess the predictive performance of time-to-event models. A key requirement of the IPCW Brier score is the estimation of the censoring distribution, which is needed to compute the weights. The established paradigm of splitting a dataset into a training and a test set for model fitting and evaluation raises the question which of these datasets to use in order to fit the censoring model. There seems to be considerable disagreement between authors with regards to this issue, and no standard has been established so far. To shed light on this important question, we conducted a comprehensive experimental study exploring various data scenarios and estimation schemes. We found that it is generally of little importance which dataset is used to model the censoring distribution. However, in some circumstances, such as in the case of a covariate-dependent censoring process, a small sample size, or when dealing with noisy data, it may be advisable to use the test set instead of the training set to model the censoring distribution. A detailed set of practical recommendations concludes our paper.
Journal Article
Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder
Stephan Zuchner, Taosheng Huang and colleagues show that recessive mutations in
SLC25A46
cause optic atrophy with additional neurological symptoms. They further show that
SLC25A46
encodes a modified mitochondrial solute transporter linked to mitochondrial dynamics.
Dominant optic atrophy (DOA)
1
,
2
and axonal peripheral neuropathy (Charcot-Marie-Tooth type 2, or CMT2)
3
are hereditary neurodegenerative disorders most commonly caused by mutations in the canonical mitochondrial fusion genes
OPA1
and
MFN2
, respectively
4
. In yeast, homologs of OPA1 (Mgm1) and MFN2 (Fzo1)
5
,
6
work in concert with Ugo1, for which no human equivalent has been identified thus far
7
. By whole-exome sequencing of patients with optic atrophy and CMT2, we identified four families with recessive mutations in
SLC25A46
. We demonstrate that SLC25A46, like Ugo1, is a modified carrier protein that has been recruited to the outer mitochondrial membrane and interacts with the inner membrane remodeling protein mitofilin (Fcj1). Loss of function in cultured cells and in zebrafish unexpectedly leads to increased mitochondrial connectivity, while severely affecting the development and maintenance of neurons in the fish. The discovery of
SLC25A46
strengthens the genetic overlap between optic atrophy and CMT2 while exemplifying a new class of modified solute transporters linked to mitochondrial dynamics.
Journal Article
The persistent lack of knowledge and misunderstanding of the Genetic Information Nondiscrimination Act (GINA) more than a decade after passage
Purpose
More than a decade after the Genetic Information Nondiscrimination Act (GINA) was passed, there is a paucity of research on the general public’s awareness of GINA. This study’s objective was to assess knowledge of GINA and concerns of genetic discrimination.
Methods
A quota-based sample of US adults (
N
= 421) was recruited via Qualtrics Research Services to complete an online survey.
Results
Overall, participants had a mean age of 43.1 (SD = 13.9), 51.8% identified as female, 63.1% identified as non-Hispanic White, and 38.4% had ≥4-year college degree. Respondents reported relatively low subjective knowledge of GINA (M = 3.10, SD = 1.98; 7-point Likert scale). Among respondents reporting high subjective knowledge of GINA (16.2%), 92.6% incorrectly reported or did not know that GINA does not covers life, long-term care, and disability insurance, and this number was 82.4% for auto or property insurance. Respondents were relatively likely to decline genetic testing due to concerns about results being used to determine eligibility for employment (M = 4.68, SD = 1.89) or health insurance (M = 4.94, SD = 1.73). There were few consistent demographic associations with either subjective or objective knowledge of GINA.
Conclusion
This study highlights continued public concern about genetic discrimination and a lack of awareness and understanding of GINA and its scope of protections.
Journal Article