RESUMEN
In April 2019, the Alberta Newborn Screening Program expanded to include screening for classic galactosemia using a two-tier screening approach. This approach secondarily identifies infants with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The goals of this study were (i) to evaluate the performance of a two-tier galactosemia screening protocol, (ii) to explore the impact on and acceptability to families of reporting G6PD deficiency as a secondary finding, and (iii) assess the communication and follow-up process for positive G6PD deficiency screening results. The two-tiered galactosemia approach increased the positive predictive value (PPV) for galactosemia from 8% to 79%. An additional 119 positive newborn screen results were reported for G6PD deficiency with a PPV of 92%. The results show that there may be utility in reporting G6PD deficiency results. Most parents who participated in the study reported having some residual worry around the unexpected diagnosis; however, all thought it was helpful to know of their child's diagnosis of G6PD deficiency. Finally, the communication process for reporting G6PD deficiency newborn screen results was determined to result in appropriate follow up of infants.
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Sickle cell disease (SCD), a group of inherited red blood cell (RBC) disorders caused by pathogenic variants in the beta-globin gene (HBB), can cause lifelong disabilities and/or early mortality. If diagnosed early, preventative measures significantly reduce adverse outcomes related to SCD. In Alberta, Canada, SCD was added to the newborn screening (NBS) panel in April 2019. The primary conditions screened for are sickle cell anemia (HbS/S), HbS/C disease, and HbS/ß thalassemia. In this study, we retrospectively analyzed the first 19 months of SCD screening performance, as well as described our approach for screening of infants that have received a red blood cell transfusion prior to collection of NBS specimen. Hemoglobins eluted from dried blood spots were analyzed using the Bio-Rad™ VARIANT nbs analyzer (Bio-Rad Laboratories, Inc., Hercules, CA, USA). Targeted sequencing of HBB was performed concurrently in samples from all transfused infants. During the period of this study, 43 of 80,314 screened infants received a positive NBS result for SCD, and of these, 34 were confirmed by diagnostic testing, suggesting a local SCD incidence of 1:2400 births. There were 608 infants with sickle cell trait, resulting in a carrier frequency of 1:130. Over 98% of non-transfused infants received their NBS results within 10 days of age. Most of the 188 transfused infants and 2 infants who received intrauterine transfusions received their final SCD screen results within 21 ± 10 d of birth. Our SCD screening algorithm enables detection of affected newborns on the initial NBS specimen, independent of the reported blood transfusion status.
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The neural mechanisms contributing to flexible cognition and behavior and how they change with development and aging are incompletely understood. The current study explored intrinsic brain dynamics across the lifespan using resting-state fMRI data (n = 601, 6-85 years) and examined the interactions between age and brain dynamics among three neurocognitive networks (midcingulo-insular network, M-CIN; medial frontoparietal network, M-FPN; and lateral frontoparietal network, L-FPN) in relation to behavioral measures of cognitive flexibility. Hierarchical multiple regression analysis revealed brain dynamics among a brain state characterized by co-activation of the L-FPN and M-FPN, and brain state transitions, moderated the relationship between quadratic effects of age and cognitive flexibility as measured by scores on the Delis-Kaplan Executive Function System (D-KEFS) test. Furthermore, simple slope analyses of significant interactions revealed children and older adults were more likely to exhibit brain dynamic patterns associated with poorer cognitive flexibility compared with younger adults. Our findings link changes in cognitive flexibility observed with age with the underlying brain dynamics supporting these changes. Preventative and intervention measures should prioritize targeting these networks with cognitive flexibility training to promote optimal outcomes across the lifespan.
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Mapeo Encefálico , Longevidad , Anciano , Encéfalo/diagnóstico por imagen , Encéfalo/fisiología , Niño , Cognición/fisiología , Función Ejecutiva/fisiología , Humanos , Imagen por Resonancia Magnética , Red Nerviosa/fisiología , Vías Nerviosas/fisiologíaRESUMEN
Inherited retinal dystrophies (IRDs) affect 1 in 3000 individuals worldwide and are genetically heterogeneous, with over 270 identified genes and loci; however, there are still many identified disorders with no current genetic etiology. Whole exome sequencing (WES) provides a hypothesis-free first examination of IRD patients in either a clinical or research setting to identify the genetic cause of disease. We present a study of IRD in ten families from Alberta, Canada, through the lens of novel gene discovery. We identify the genetic etiology of IRDs in three of the families to be variants in known disease-associated genes, previously missed by clinical investigations. In addition, we identify two potentially novel associations: LRP1 in early-onset drusen formation and UBE2U in a multi-system condition presenting with retinoschisis, cataracts, learning disabilities, and developmental delay. We also describe interesting results in our unsolved cases to provide further information to other investigators of these blinding conditions.
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Discapacidades del Desarrollo/genética , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad/genética , Drusas Retinianas/genética , Retinosquisis/genética , Adolescente , Adulto , Anciano , Niño , Discapacidades del Desarrollo/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Linaje , Drusas Retinianas/patología , Retinosquisis/patología , Síndrome , Secuenciación del ExomaRESUMEN
This study aims to evaluate the notification process of sickle cell trait (SCT) identified by newborn screening in Alberta. On April 1, 2019, Alberta began newborn screening for sickle cell disease (SCD) and elected to report sickle cell trait (SCT). For 1 year, healthcare providers (HCPs) were sent a questionnaire which addressed the perceived importance of disclosing the SCT results, whether HCPs felt competent in disclosing the result, knowledge of available resources, and comfort with coordinating and interpreting testing for the newborn's parents. As a control, we collected data from HCPs receiving positive cystic fibrosis (CF) newborn screen results. A total of 107 out of 203 SCT questionnaires were returned and 41 of 66 CF questionnaires were returned. Respondents felt it was important that the results be shared with families (98% and 100%, respectively). Most respondents felt competent (SCT: 95%; CF: 85%), and willing to disclose the result to the family (SCT: 92%; CF: 88%). Fewer respondents were comfortable interpreting the results (SCT: 70%; CF: 51%)), and willing to arrange parental testing (SCT: 61%; CF: 59%). Family practitioners were significantly more willing to arrange SCT parental testing (88%) compared to pediatricians (40%) (OR = 5.3; CI 1.9, 15.4; p < 0.001). HCP comments revealed two themes: referral to another HCP for follow-up and identification of the primary HCP. Results support this disclosure process, and HCPs felt comfortable following up with SCT newborn screen results. The study identified challenges such as pediatricians being less comfortable ordering parental testing and the ordering HCP not always being the primary care provider.
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Busulfan is an alkylating agent used in chemotherapy conditioning regimens prior to hematopoietic stem cell transplantation (HSCT). However, its administration is associated with a great risk of adverse toxicities, which have been historically attributed to busulfan's mechanism of non-specific DNA alkylation. A phase II generated metabolite of busulfan, EdAG (γ-glutamyldehydroalanylglycine), is a dehydroalanine analog of glutathione (GSH) with an electrophilic moiety, suggesting it may bind to proteins and disrupt biological function. However, EdAG's reactions with common cellular thiols such as glutathione (GSH) and l-cysteine are understudied, along with possible inhibition of glutathionylation-dependent enzymes (with active site cysteine residues). We established a physiologically-relevant in vitro model to readily measure thiol loss over time. Using this model, we compared the apparent rates of thiol depletion in the presence of EdAG or arecoline, a toxic constituent of the areca (betel) nut and known GSH depletor. Simulated kinetic modeling revealed that the mean (±SE) alpha (α) second order rate constants describing GSH and l-cysteine depletion in the presence of EdAG were 0.00522 (0.00845) µM-1âmin-1 and 0.0207 (0.00721) µM-1âmin-1, respectively; in the presence of arecoline, the apparent rates of depletion were 0.0619 (0.009) µM-1âmin-1 and 0.2834 (0.0637) µM-1âmin-1 for GSH and l-cysteine, respectively. Under these experimental conditions, we conclude that EdAG was a weaker electrophile than arecoline. Arecoline and EdAG both depleted apparent l-cysteine concentrations to a much greater extent than GSH, approximately 4.58-fold and 3.97-fold change greater, respectively. EdAG modestly inhibited (â¼20%) the human thioredoxin-1 (hTrx-1) catalyzed reduction of insulin with a mean IC50 of 93 µM [95% CI: 78.6-110 µM). In summary, EdAG's ability to spontaneously react with endogenous thiols and inhibit hTrx-1 are potentially biochemically relevant in humans. These findings continue to support the growing concept that EdAG, an underrecognized phase II metabolite of busulfan, plays a role in untoward cellular toxicities during busulfan pharmacotherapy.
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Antineoplásicos Alquilantes/química , Arecolina/química , Busulfano/química , Glutatión/análogos & derivados , Glutatión/química , Tiorredoxinas/química , Arecolina/antagonistas & inhibidores , Biotransformación , Cisteína/antagonistas & inhibidores , Cisteína/química , Glutatión/antagonistas & inhibidores , Humanos , Cinética , Soluciones , Tiorredoxinas/antagonistas & inhibidores , Agua/químicaRESUMEN
OBJECTIVE: Brain dynamics underlie flexible cognition and behavior, yet little is known regarding this relationship in autism spectrum disorder (ASD). We examined time-varying changes in functional co-activation patterns (CAPs) across rest and task-evoked brain states to characterize differences between children with ASD and typically developing (TD) children and identify relationships with severity of social behaviors and restricted and repetitive behaviors. METHOD: 17 children with ASD and 27 TD children ages 7-12 completed a resting-state fMRI scan and four runs of a non-cued attention switching task. Metrics indexing brain dynamics were generated from dynamic CAPs computed across three major large-scale brain networks: midcingulo-insular (M-CIN), medial frontoparietal (M-FPN), and lateral frontoparietal (L-FPN). RESULTS: Five time-varying CAPs representing dynamic co-activations among network nodes were identified across rest and task fMRI datasets. Significant Diagnosis × Condition interactions were observed for the dwell time of CAP 3, representing co-activation between nodes of the M-CIN and L-FPN, and the frequency of CAP 1, representing co-activation between nodes of the L-FPN. A significant brain-behavior association between dwell time of CAP 5, representing co-activation between nodes of the M-FPN, and social abilities was also observed across both groups of children. CONCLUSION: Analysis of brain co-activation patterns reveals altered dynamics among three core networks in children with ASD, particularly evident during later stages of an attention task. Dimensional analyses demonstrating relationships between M-FPN dwell time and social abilities suggest that metrics of brain dynamics may index individual differences in social cognition and behavior.
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Trastorno del Espectro Autista , Trastorno del Espectro Autista/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Mapeo Encefálico , Niño , Cognición , Humanos , Imagen por Resonancia Magnética , Vías Nerviosas/diagnóstico por imagenRESUMEN
PURPOSE: To assess the safety of a recombinant adeno-associated viral vector expressing REP1 (rAAV2.REP1) in choroideremia subjects. METHODS: Design: Phase I clinical trial. PARTICIPANTS: Six adult male subjects, 30-42 years of age, with genetically confirmed choroideremia (CHM) were enrolled. The eye with the worse vision, for all subjects, received a single subfoveal injection of 0.1 mL rAAV2.REP1 containing 1011 genome particles. Subjects were followed up for 2 years thereafter. OUTCOME MEASURES: The primary outcome measure was safety, determined by the number of ocular and systemic adverse events assessed by ophthalmic examination, spectral-domain optical coherence tomography (SD-OCT), and short-wavelength autofluorescence (FAF). Secondary outcome measures were the change from baseline in best-corrected visual acuity (BCVA) in the treated eye compared to the untreated eye, changes in visual function using microperimetry, and the area of retinal pigment epithelium (RPE) preservation by FAF. RESULTS: One subject had an 8-ETDRS-letter BCVA loss from baseline measured at 24 months, while 1 subject had a ≥15-letter BCVA gain. A similar improvement was noted in the untreated eye of another subject throughout the follow-up period. Microperimetry sensitivity showed no improvement or significant change up to 2 years after vector administration. The area of preserved RPE as measured by FAF was noted to decline at a similar rate between the treated and untreated eyes. One subject experienced a serious adverse event: a localized intraretinal immune response, resulting in marked decline in visual function and loss of SD-OCT outer retinal structures. CONCLUSIONS: One serious adverse event was experienced in 6 subjects treated with a subfoveal injection of AAV2.REP1. The area of remaining functional RPE in the treated eye and untreated eye declined at the same rate over a 2-year period. Fundus autofluorescence area is a remarkably predictive biomarker and objective outcome measure for future studies of ocular gene therapy in CHM subjects.