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Specific selective serotonin reuptake inhibitors (SSRIs) metabolism is strongly influenced by two pharmacogenes, CYP2D6 and CYP2C19. However, the effectiveness of prospectively using pharmacogenetic variants to select or dose SSRIs for depression is uncertain in routine clinical practice. The objective of this prospective, multicenter, pragmatic randomized controlled trial is to determine the effectiveness of genotype-guided selection and dosing of antidepressants on control of depression in participants who are 8 years or older with ≥3 months of depressive symptoms who require new or revised therapy. Those randomized to the intervention arm undergo pharmacogenetic testing at baseline and receive a pharmacy consult and/or automated clinical decision support intervention based on an actionable phenotype, while those randomized to the control arm have pharmacogenetic testing at the end of 6-months. In both groups, depression and drug tolerability outcomes are assessed at baseline, 1 month, 3 months (primary), and 6 months. The primary end point is defined by change in Patient-Reported Outcomes Measurement Information System (PROMIS) Depression score assessed at 3 months versus baseline. Secondary end points include change inpatient health questionnaire (PHQ-8) measure of depression severity, remission rates defined by PROMIS score < 16, medication adherence, and medication side effects. The primary analysis will compare the PROMIS score difference between trial arms among those with an actionable CYP2D6 or CYP2C19 genetic result or a CYP2D6 drug-drug interaction. The trial has completed accrual of 1461 participants, of which 562 were found to have an actionable phenotype to date, and follow-up will be complete in April of 2024.
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Citocromo P-450 CYP2C19 , Citocromo P-450 CYP2D6 , Depresión , Pruebas de Farmacogenómica , Inhibidores Selectivos de la Recaptación de Serotonina , Adulto , Femenino , Humanos , Masculino , Antidepresivos/uso terapéutico , Antidepresivos/administración & dosificación , Antidepresivos/efectos adversos , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2D6/genética , Depresión/tratamiento farmacológico , Depresión/genética , Depresión/diagnóstico , Variantes Farmacogenómicas , Ensayos Clínicos Pragmáticos como Asunto , Estudios Prospectivos , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéuticoRESUMEN
There is increasing evidence of the clinical utility of genetic and genomic testing (GT); however, factors influencing personal utility of GT, especially in diverse, multilingual populations, remain unclear. We explored these factors in a diverse cohort of parents/guardians (participants) whose children received clinical GT through the NYCKidSeq program. A total of 847 participants completed surveys at baseline, post-results disclosure, and 6 months (6m) post-results. The largest population groups were Hispanic/Latino(a) (48%), White/European American (24%), and Black/African American (16%). Personal utility was assessed using the Personal Utility (PrU) scale, adapted for pediatric populations and included on the surveys. Three PrU subscales were identified using factor analysis: practical, educational, and parental psychological utility. Overall personal utility summary score and the three subscales significantly decreased after receiving results and over time. Hispanic/Latino(a) participants identified greater overall personal utility than European American and African American participants at all time points (p < 0.001) as did participants whose children received positive/likely positive results compared with those with negative and uncertain results (post-results: p < 0.001 and p < 0.001; 6m post-results: p = 0.002 and p < 0.001, respectively). Post-results, higher subscale scores were associated with lower education levels (practical, parental psychological: p ≤ 0.02) and higher levels of trust in the healthcare system (practical, parental psychological: p ≤ 0.04). These findings help to understand the perspectives of diverse parents/guardians, which is critical to tailoring pre- and post-test counseling across a variety of populations and clinical settings.
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Pruebas Genéticas , Padres , Adolescente , Adulto , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Genómica , Hispánicos o Latinos/genética , Multilingüismo , Encuestas y Cuestionarios , Blanco/genética , Negro o Afroamericano/genéticaRESUMEN
Purpose: Pharmacist-led initiatives providing optimization of medications during transitions of care (TOC) have shown to have a positive impact on prescribing practices and patient outcomes. This study aims to evaluate the role and impact of TOC pharmacist review of outpatient parenteral antimicrobial therapy (OPAT) prescriptions prior to hospital discharge. Methods: In a retrospective chart review, patients with OPAT prescriptions between November 1, 2022 and January 31, 2023 were evaluated using prescription-specific and intervention-specific data points. Prescription-specific data points included intravenous antimicrobials prescribed, indication, prescribing team, and time from OPAT prescription to TOC pharmacist review. Intervention-specific data points included antimicrobial optimization (dose/frequency, duration, and other), prescription clarification, and laboratory monitoring. Results: Of the 137 OPAT prescriptions evaluated, 67 required intervention by TOC pharmacists (48.9%). The General Infectious Disease Consult team placed 71.5% of OPAT prescriptions and required interventions less frequently (42.9%) compared to the other teams. Antimicrobial optimization interventions accounted for 54.2% of interventions, which were primarily related to medication dose and frequency. Conclusion: The TOC pharmacists can play a key role in the evaluation of OPAT prescriptions at hospital discharge. This intervention demonstrated how TOC pharmacists can effectively collaborate with the OPAT team, which builds on prior evidence of the role and value of pharmacists in the transitional care setting.
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The COVID-19 pandemic brought about unprecedented changes and uncertainty to the daily lives of youth. The range of adjustment in light of a near-universal experience of COVID restrictions highlights the importance of identifying factors that may render some individuals more susceptible to heightened levels of anxiety during stressful life events than others. Two risk factors to consider are temperamental behavioral inhibition (BI) and difficulties in emotion regulation (ER). As such, the current paper focused on BI examined prior to COVID, because of its developmental link to anxiety and ER, as difficulties may be associated with differences in anxiety. We examined a neurocognitive marker of ER processes, delta-beta coupling (DBC). The current paper had two goals: (1) to examine BI in relation to COVID-related worry and social anxiety experienced during the pandemic, and (2) to explore the role of individual differences in early DBC in the relationship between BI and anxiety outcomes 6 months apart during COVID-19 (n = 86; T1 Mage = 15.95, SD = 1.73; T6 Mage = 16.43, SD = 1.73). We found support for the moderating role of DBC in the relationship between BI levels and social anxiety disorder (SAD) symptom severity during the pandemic. Here, high BI was predictive of increased SAD symptom levels in adolescents with stronger DBC.
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COVID-19 , Pandemias , Humanos , Adolescente , Ansiedad/psicología , Trastornos de Ansiedad , MiedoRESUMEN
PURPOSE: To better understand the effects of returning diagnostic sequencing results on clinical actions and economic outcomes for pediatric patients with suspected genetic disorders. METHODS: Longitudinal physician claims data after diagnostic sequencing were obtained for patients aged 0 to 21 years with neurologic, cardiac, and immunologic disorders with suspected genetic etiology. We assessed specialist consultation rates prompted by primary diagnostic results, as well as marginal effects on overall 18-month physician services and costs. RESULTS: We included data on 857 patients (median age: 9.6 years) with a median follow-up of 17.3 months after disclosure of diagnostic sequencing results. The likelihood of having ≥1 recommendation for specialist consultation in 155 patients with positive findings was high (72%) vs 23% in 443 patients with uncertain findings and 21% in 259 patients with negative findings (P < .001). Follow-through consultation occurred in 30%. Increases in 18-month physician services and costs following a positive finding diminished after multivariable adjustment. Also, no significant differences between those with uncertain and negative findings were demonstrated. CONCLUSION: Our study did not provide evidence for significant increases in downstream physician services and costs after returning positive or uncertain diagnostic sequencing findings. More large-scale longitudinal studies are needed to confirm these findings.
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Revelación , Médicos , Humanos , Niño , Costos y Análisis de CostoRESUMEN
OBJECTIVE: To evaluate the effect of oropharyngeal colostrum immunotherapy (OCI) on the mortality of preterm newborns (PTNB) with very low birth weight (VLBW). METHOD: Non-randomized clinical trial, carried out with 138 mother-child pairs attended at a public maternity hospital. The treatment group used raw colostrum, dripping 4 drops (0.2 ml) into the oropharyngeal mucosa, totaling 8 administrations in 24 h, up to the 7th complete day of life (OCI). The control group was composed of newborns admitted to the same maternity hospital before the implementation of the OCI. Analyzes were performed: descriptive, bivariate, multiple logistic regression, and survival analysis, with a significance level of 5% and 95% CI. RESULTS: The treatment group had an RR of death of 0.26 (95% CI = 0.07-0.67; p = 0.00), adjusted for maternal age, marital status, gestational hypertension, type of delivery, number of prenatal visits, and birth weight. Number Needed to Treat (NNT) demonstrated that for every 5 individuals treated with OCI, one death was prevented NNT = 4.9 (95% CI = 1.84-5.20); however, for PTNB with VLBW who remained hospitalized for 50, 100 and 150 days, the NNT reduces to 4, 4 and 3, respectively. CONCLUSION: The OCI proved to be a beneficial intervention, since it reduced the risk of mortality in PTNB with VLBW when compared to the control group.
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Calostro , Nacimiento Prematuro , Recién Nacido , Humanos , Femenino , Embarazo , Recién Nacido de muy Bajo Peso , Peso al Nacer , Inmunoterapia , Conducta de Reducción del RiesgoRESUMEN
Abstract Objective To evaluate the effect of oropharyngeal colostrum immunotherapy (OCI) on the mortality of preterm newborns (PTNB) with very low birth weight (VLBW). Method Non-randomized clinical trial, carried out with 138 mother-child pairs attended at a public maternity hospital. The treatment group used raw colostrum, dripping 4 drops (0.2 ml) into the oropharyngeal mucosa, totaling 8 administrations in 24 h, up to the 7th complete day of life (OCI). The control group was composed of newborns admitted to the same maternity hospital before the implementation of the OCI. Analyzes were performed: descriptive, bivariate, multiple logistic regression, and survival analysis, with a significance level of 5% and 95% CI. Results The treatment group had an RR of death of 0.26 (95% CI = 0.07-0.67; p= 0.00), adjusted for maternal age, marital status, gestational hypertension, type of delivery, number of prenatal visits, and birth weight. Number Needed to Treat (NNT) demonstrated that for every 5 individuals treated with OCI, one death was prevented NNT = 4.9 (95% CI = 1.84-5.20); however, for PTNB with VLBW who remained hospitalized for 50, 100 and 150 days, the NNT reduces to 4, 4 and 3, respectively. Conclusion The OCI proved to be a beneficial intervention, since it reduced the risk of mortality in PTNB with VLBW when compared to the control group.
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Abstract Objectives: to evaluate the effect of oropharyngeal colostrum immunotherapy on the length of hospital stay in preterm newborns with very low birth weight. Methods: interventional ambispective study, which consisted of eight daily administrations of 0.2 ml (four drops) of colostrum, totaling up to 56 syringes (for up to seven days). The control was historic. The main independent variable: length of hospital stay (days). Survival analysis was performed using the Kaplan-Meier Method and the survival effect was estimated - Log Rank Test (Mantel-Cox) and Breslow Test (Generalized Wilcoxon). A significance level of 5% was adopted. Results: of the 109 mother/child pairs, 56 were part of the treatment and 53 were part of the control group. There was no association between oropharyngeal colostrum immunotherapy and length of stay for preterm newborns with very low birth weight in the general sample. However, after stratification, a shorter hospital stay (42 versus 51 days, HR= 1.78, CI95%=1.02-3.09, p=0.04) was demonstrated among premature infants with ≥28 gestational weeks undergoing oropharyngeal colostrum immunotherapy. Conclusions: we found an association between oropharyngeal colostrum immunotherapy and shorter median length of hospital stay in the subgroup of premature infants ≥ 28 weeks of gestational age, but we did not find significant differences in those <28 weeks.
Resumo Objetivos: avaliar o efeito da imunoterapia orofaríngea de colostro no tempo de internamento hospitalar de recém-nascidos pré-termos de muito baixo peso. Métodos: estudo de intervenção, ambispectivo, que consistiu em oito administrações diárias de 0,2 ml (quatro gotas) de colostro, totalizando até 56 seringas (por até sete dias). O controle foi histórico. A variável independente principal: tempo de permanência hospitalar (dias). Realizada análise de sobrevivência pelo Método de Kaplan-Meier e estimado o efeito da sobrevida - Teste de Log Rank (Mantel-Cox) e Teste de Breslow (Wilcoxon Generalizado). Adotou-se o nível de significância de 5%. Resultados: das 109 duplas mães/filho, 56 fizeram parte da análise do grupo tratamento e 53 do controle. Não houve associação entre imunoterapia orofaríngea de colostro e tempo de internamento de recém-nascidos pré-termos de muito baixo peso na amostra geral. Após estratificação demonstrou-se menor tempo de permanência hospitalar (43 versus 51 dias, HR=1,78, IC95%= 1,02-3,09, p=0,04) entre os prematuros com ≥28 semanas gestacionais submetidos a imunoterapia orofaríngea de colostro. Conclusões: encontrou-se associação entre imunoterapia orofaríngea de colostro e menor mediana de tempo de internamento hospitalar no subgrupo de prematuros ≥ 28 semanas de idade gestacional, porém não foram encontradas diferenças significativas naqueles < 28 semanas.
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Humanos , Recién Nacido , Orofaringe , Recien Nacido Prematuro , Calostro , Recién Nacido de muy Bajo Peso , Inmunoterapia , Tiempo de InternaciónRESUMEN
OBJECTIVE: Hearing loss has been pointed out as a potential predictor for cognitive decline. This study conducted a systematic review to evaluate the scientific evidence on the association between hearing loss in the elderly and cognitive decline, as well as whether race/color influences this relationship. METHOD: The search for studies was performed in the following electronic databases: MedLine/PubMed Web of Science, Scopus and Virtual Health Library, and MedRkiv up to August 2022. Studies with epidemiological designs that assess the association between hearing loss and cognitive decline in the elderly were eligible for inclusion. Three independent reviewers performed the selection, data extraction and evaluation of the quality of the studies using the Newcastle-Ottawa Scale. A meta-analysis using a random effects model estimated the global association measurements (Beta coefficient: ß) and their 95% confidence intervals (95%CI), and the Higgins and Thompson indicator (I2) was also estimated to assess statistical heterogeneity among the studies. RESULTS: 5,207 records were identified in the database surveys, of which only 18 were eligible studies, totaling 19,551 individuals. Hearing loss was associated with cognitive decline in the elderly, with statistical significance: ß = -0.13; 95%CI = -0.23 to -0.04; I2 = 98.70%). For black individuals, the magnitude of the association increased: ß = -0.64; 95%CI = -3.36 to 2.07; I2 = 95.65%, but it was not statistically significant. CONCLUSION: The findings of this systematic review showed the existence of a significant relationship between hearing loss and cognitive decline in the elderly, as well as signaling that among black individuals the magnitude of the association can be increased.
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Disfunción Cognitiva , Sordera , Pérdida Auditiva , Humanos , Anciano , Disfunción Cognitiva/epidemiología , Pérdida Auditiva/complicaciones , Pérdida Auditiva/epidemiología , Encuestas y Cuestionarios , Bases de Datos FactualesRESUMEN
Digital solutions are needed to support rapid increases in the application of genetic/genomic tests (GTs) in diverse clinical settings and patient populations. We developed GUÍA, a bilingual digital application that facilitates disclosure of GT results. The NYCKidSeq randomized controlled trial enrolled diverse children with neurologic, cardiac, and immunologic conditions who underwent GTs. The trial evaluated GUÍA's impact on understanding the GT results by randomizing families to results disclosure genetic counseling with GUÍA (intervention) or standard of care (SOC). Parents/legal guardians (participants) completed surveys at baseline, post-results disclosure, and 6 months later. Survey measures assessed the primary study outcomes of participants' perceived understanding of and confidence in explaining their child's GT results and the secondary outcome of objective understanding. The analysis included 551 diverse participants, 270 in the GUÍA arm and 281 in SOC. Participants in the GUÍA arm had significantly higher perceived understanding post-results (OR = 2.8, CI[1.004, 7.617], p = 0.049) and maintained higher objective understanding over time (OR = 1.1, CI[1.004, 1.127], p = 0.038) compared to SOC. There was no impact on perceived confidence. Hispanic/Latino(a) individuals in the GUÍA arm maintained higher perceived understanding (OR = 3.9, CI[1.603, 9.254], p = 0.003), confidence (OR = 2.7, CI[1.021, 7.277], p = 0.046), and objective understanding (OR = 1.1, CI[1.009, 1.212], p = 0.032) compared to SOC. This trial demonstrates that GUÍA positively impacts understanding of GT results in diverse parents of children with suspected genetic conditions and builds a case for utilizing GUÍA to deliver complex results. Continued development and evaluation of digital applications in diverse populations are critical for equitably scaling GT offerings in specialty clinics.
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Revelación , Asesoramiento Genético , Niño , Humanos , Pruebas Genéticas , Padres , GenómicaRESUMEN
Background: Digital solutions are needed to support rapid increases in the application of genetic and genomic tests (GT) in diverse clinical settings and patient populations. We developed GUÍA, a bi-lingual web-based platform that facilitates disclosure of GT results. The NYCKidSeq randomized controlled trial evaluated GUÍA's impact on understanding of GT results. Methods: NYCKidSeq enrolled diverse children with neurologic, cardiac, and immunologic conditions who underwent GT. Families were randomized to genetic counseling with GUÍA (intervention) or standard of care (SOC) genetic counseling for results disclosure. Parents/legal guardians (participants) completed surveys at baseline, post-results disclosure, and 6-months later. Survey measures assessed the primary study outcomes of perceived understanding of and confidence in explaining their child's GT results and the secondary outcome of objective understanding. We used regression models to evaluate the association between the intervention and the study outcomes. Results: The analysis included 551 participants, 270 in the GUÍA arm and 281 in SOC. Participants' mean age was 41.1 years and 88.6% were mothers. Most participants were Hispanic/Latino(a) (46.3%), White/European American (24.5%), or Black/African American (15.8%). Participants in the GUÍA arm had significantly higher perceived understanding post-results (OR=2.8, CI[1.004,7.617], P=0.049) and maintained higher objective understanding over time (OR=1.1, CI[1.004, 1.127], P=0.038) compared to those in the SOC arm. There was no impact on perceived confidence. Hispanic/Latino(a) individuals in the GUÍA arm maintained higher perceived understanding (OR=3.9, CI[1.6, 9.3], P=0.003), confidence (OR=2.7, CI[1.021, 7.277], P=0.046), and objective understanding (OR=1.1, CI[1.009, 1.212], P=0.032) compared to SOC . Conclusions: This trial demonstrates that GUÍA positively impacts understanding of GT results in diverse parents of children with suspected genetic conditions. These findings build a case for utilizing GUÍA to deliver complex and often ambiguous genetic results. Continued development and evaluation of digital applications in diverse populations are critical for equitably scaling GT offerings in specialty clinics. Trial Registration: Clinicaltrials.gov identifier NCT03738098.
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Copy number variations (CNVs) play a significant role in human disease. While chromosomal microarray has traditionally been the first-tier test for CNV detection, use of genome sequencing (GS) is increasing. We report the frequency of CNVs detected with GS in a diverse pediatric cohort from the NYCKidSeq program and highlight specific examples of its clinical impact. A total of 1052 children (0-21 years) with neurodevelopmental, cardiac, and/or immunodeficiency phenotypes received GS. Phenotype-driven analysis was used, resulting in 183 (17.4%) participants with a diagnostic result. CNVs accounted for 20.2% of participants with a diagnostic result (37/183) and ranged from 0.5 kb to 16 Mb. Of participants with a diagnostic result (n = 183) and phenotypes in more than one category, 5/17 (29.4%) were solved by a CNV finding, suggesting a high prevalence of diagnostic CNVs in participants with complex phenotypes. Thirteen participants with a diagnostic CNV (35.1%) had previously uninformative genetic testing, of which nine included a chromosomal microarray. This study demonstrates the benefits of GS for reliable detection of CNVs in a pediatric cohort with variable phenotypes.
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Variaciones en el Número de Copia de ADN , Pruebas Genéticas , Humanos , Niño , Variaciones en el Número de Copia de ADN/genética , Mapeo Cromosómico/métodos , Pruebas Genéticas/métodos , Fenotipo , Análisis por MicromatricesRESUMEN
PURPOSE: Adoption of genome sequencing (GS) as a first-line test requires evaluation of its diagnostic yield. We evaluated the GS and targeted gene panel (TGP) testing in diverse pediatric patients (probands) with suspected genetic conditions. METHODS: Probands with neurologic, cardiac, or immunologic conditions were offered GS and TGP testing. Diagnostic yield was compared using a fully paired study design. RESULTS: A total of 645 probands (median age 9 years) underwent genetic testing, and 113 (17.5%) received a molecular diagnosis. Among 642 probands with both GS and TGP testing, GS yielded 106 (16.5%) and TGPs yielded 52 (8.1%) diagnoses (P < .001). Yield was greater for GS vs TGPs in Hispanic/Latino(a) (17.2% vs 9.5%, P < .001) and White/European American (19.8% vs 7.9%, P < .001) but not in Black/African American (11.5% vs 7.7%, P = .22) population groups by self-report. A higher rate of inconclusive results was seen in the Black/African American (63.8%) vs White/European American (47.6%; P = .01) population group. Most causal copy number variants (17 of 19) and mosaic variants (6 of 8) were detected only by GS. CONCLUSION: GS may yield up to twice as many diagnoses in pediatric patients compared with TGP testing but not yet across all population groups.
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Predisposición Genética a la Enfermedad , Patología Molecular , Humanos , Niño , Pruebas Genéticas/métodos , Secuencia de Bases , Mapeo CromosómicoRESUMEN
An acidic extracellular pH value (pHe) is characteristic of many cancers, in contrast to the physiologic pHe found in most benign cells. This difference in pH offers a unique opportunity to design and engineer chemicals that can be employed for pH-selective reactions in the extracellular fluid of cancer cells. The viability of human skin melanoma and corresponding fibroblasts exposed to CaS dispersions is reported. The viability of melanoma cells decreases with CaS dispersion concentration and reaches 57% at 3%, a value easily distinguishable from melanoma control experiments. In contrast, the viability of benign fibroblasts remains nearly constant within experimental error over the range of dispersion concentrations studied. The CaS dispersions facilitate vinculin delocalization in the cytoplasmic fluid, a result consistent with improved focal adhesion kinase (FAK) regulation in melanoma cells. Thermodynamic considerations are consistent with the formation of H 2 S from CaS in the presence of protons. The thermodynamic prediction is verified in independent experiments with solid CaS and acidic aqueous solutions. The amount of H 2 S formed decreases with pH. An activation energy for the process of (30 ± 10) kJ/mol in the temperature range of 280 to 330 K is estimated from initial rate measurements as a function of temperature. The total Gibbs energy minimization approach was employed to establish the distribution of sulfides-including H 2 S in the gas and aqueous phases-from the dissociation of CaS as a function of pH to mimic physiologically relevant pH values. Theoretical calculations suggest that partially protonated CaS in solution can be stable until the sulfur atom bonds to two hydrogen atoms, resulting in the formation of Ca2+ and H 2 S , which can be solvated and/or released to the gas phase. Our results are consistent with a model in which CaS is dissociated in the extracellular fluid of melanoma cells selectively. The results are discussed in the context of the potential biomedical applications of CaS dispersions in cancer therapies.
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INTRODUCTION: This study provides long-term evidence that profiles of temperament during adolescence are associated with happiness and health over two decades later. METHODS: Data are based on the ongoing Fullerton Longitudinal Study, a community-based sample in the United States. At 14 and 16 years, adolescents (N = 111; 52% male, 90% Euro-American) and their mothers (N = 105) completed the Dimensions of Temperament Survey-Revised, a scale designed specifically to assess adolescents' temperament across a set of attributes. When adolescents reached age 38 years in 2017, they completed scales measuring comprehensive happiness and global health. RESULTS: Latent profile analysis (LPA), a person-centered approach, was conducted for adolescents' and for mothers' temperament ratings separately. Distinct two-profile solutions, labeled more regulated and less regulated, emerged for each informant. These were comparable in features across informants. Only the adolescents' self-rated profiles, controlling for sex and family SES, revealed a conceptually meaningful and statistically significant relation to the distal outcomes of health and happiness two decades later. CONCLUSIONS: Adolescents with temperament profiles characterized as more regulated, in contrast to less regulated, reported being happier and healthier upon entering middle adulthood. Implications for intervention are presented.
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Felicidad , Temperamento , Femenino , Humanos , Masculino , Adolescente , Adulto , Estudios Longitudinales , Madres , Encuestas y CuestionariosRESUMEN
BACKGROUND: The COVID-19 pandemic forced healthcare institutions and many clinical research programs to adopt telehealth modalities in order to mitigate viral spread. With the expanded use of telehealth, there is the potential to increase access to genomic medicine to medically underserved populations, yet little is known about how best to communicate genomic results via telehealth while also ensuring equitable access. NYCKidSeq, a multi-institutional clinical genomics research program in New York City, launched the TeleKidSeq pilot study to assess alternative forms of genomic communication and telehealth service delivery models with families from medically underserved populations. METHODS: We aim to enroll 496 participants between 0 and 21 years old to receive clinical genome sequencing. These individuals have a neurologic, cardiovascular, and/or immunologic disease. Participants will be English- or Spanish-speaking and predominantly from underrepresented groups who receive care in the New York metropolitan area. Prior to enrollment, participants will be randomized to either genetic counseling via videoconferencing with screen-sharing or genetic counseling via videoconferencing without screen-sharing. Using surveys administered at baseline, results disclosure, and 6-months post-results disclosure, we will evaluate the impact of the use of screen-sharing on participant understanding, satisfaction, and uptake of medical recommendations, as well as the psychological and socioeconomic implications of obtaining genome sequencing. Clinical utility, cost, and diagnostic yield of genome sequencing will also be assessed. DISCUSSION: The TeleKidSeq pilot study will contribute to innovations in communicating genomic test results to diverse populations through telehealth technology. In conjunction with NYCKidSeq, this work will inform best practices for the implementation of genomic medicine in diverse, English- and Spanish-speaking populations.
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Purpose: Adoption of genome sequencing (GS) as a first-line test requires evaluation of its diagnostic yield. We evaluated the GS and targeted gene panel (TGP) testing in diverse pediatric patients (probands) with suspected genetic conditions. Methods: Probands with neurologic, cardiac, or immunologic conditions were offered GS and TGP testing. Diagnostic yield was compared using a fully paired study design. Results: 645 probands (median age 9 years) underwent genetic testing, and 113 (17.5%) received a molecular diagnosis. Among 642 probands with both GS and TGP testing, GS yielded 106 (16.5%) and TGPs yielded 52 (8.1%) diagnoses ( P < .001). Yield was greater for GS vs . TGPs in Hispanic/Latino(a) (17.2% vs . 9.5%, P < .001) and White/European American (19.8% vs . 7.9%, P < .001), but not in Black/African American (11.5% vs . 7.7%, P = .22) population groups by self-report. A higher rate of inconclusive results was seen in the Black/African American (63.8%) vs . White/European American (47.6%; P = .01) population group. Most causal copy number variants (17 of 19) and mosaic variants (6 of 8) were detected only by GS. Conclusion: GS may yield up to twice as many diagnoses in pediatric patients compared to TGP testing, but not yet across all population groups.
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Ordered cell cycle progression is coordinated by cyclin dependent kinases (CDKs). CDKs often phosphorylate substrates at multiple sites clustered within disordered regions. However, for most substrates, it is not known which phosphosites are functionally important. We developed a high-throughput approach, Phosphosite Scanning, that tests the importance of each phosphosite within a multisite phosphorylated domain. We show that Phosphosite Scanning identifies multiple combinations of phosphosites that can regulate protein function and reveals specific phosphorylations that are required for phosphorylation at additional sites within a domain. We applied this approach to the yeast transcription factor Hcm1, a conserved regulator of mitotic genes that is critical for accurate chromosome segregation. Phosphosite Scanning revealed a complex CDK-regulatory circuit that mediates Cks1-dependent phosphorylation of key activating sites in vivo. These results illuminate the mechanism of Hcm1 activation by CDK and establish Phosphosite Scanning as a powerful tool for decoding multisite phosphorylated domains.
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Quinasas Ciclina-Dependientes , Proteínas de Saccharomyces cerevisiae , Fosforilación , Quinasas Ciclina-Dependientes/genética , Quinasas Ciclina-Dependientes/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Factores de Transcripción/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Factores de Transcripción Forkhead/metabolismoRESUMEN
The increased use of next-generation sequencing has expanded our understanding of the involvement and prevalence of mosaicism in genetic disorders. We describe a total of eleven cases: nine in which mosaic variants detected by genome sequencing (GS) and/or targeted gene panels (TGPs) were considered to be causative for the proband's phenotype, and two of apparent parental mosaicism. Variants were identified in the following genes: PHACTR1, SCN8A, KCNT1, CDKL5, NEXMIF, CUX1, TSC2, GABRB2, and SMARCB1. In addition, we identified one large duplication including three genes, UBE3A, GABRB3, and MAGEL2, and one large deletion including deletion of ARFGAP1, EEF1A2, CHRNA4, and KCNQ2. All patients were enrolled in the NYCKidSeq study, a research program studying the communication of genomic information in clinical care, as well as the clinical utility and diagnostic yield of GS for children with suspected genetic disorders in diverse populations in New York City. We observed variability in the correlation between reported variant allele fraction and the severity of the patient's phenotype, although we were not able to determine the mosaicism percentage in clinically relevant tissue(s). Although our study was not sufficiently powered to assess differences in mosaicism detection between the two testing modalities, we saw a trend toward better detection by GS as compared with TGP testing. This case series supports the importance of mosaicism in childhood-onset genetic conditions and informs guidelines for laboratory and clinical interpretation of mosaic variants detected by GS.