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PURPOSE: Current and emerging treatments for Duchenne muscular dystrophy (DMD) position DMD as a candidate condition for newborn screening (NBS). In anticipation of the nomination of DMD for universal NBS, we conducted a prospective study under the Early Check voluntary NBS research program in North Carolina, United States. METHODS: We performed screening for creatine kinase-MM (CK-MM), a biomarker of muscle damage, on residual routine newborn dried blood spots (DBS) from participating newborns. Total creatine kinase testing and next generation sequencing of an 86-neuromuscular gene panel that included DMD were offered to parents of newborns who screened positive. Bivariate and multivariable analyses were performed to assess effects of biological and demographic predictors on CK-MM levels in DBS. RESULTS: We screened 13,354 newborns and identified 2 males with DMD. The provisional 1626 ng/mL cutoff was raised to 2032 ng/mL to improve specificity, and additional cutoffs (900 and 360 ng/mL) were implemented to improve sensitivity for older and low-birthweight newborns. CONCLUSION: Population-scale screening for elevated CK-MM in DBS is a feasible approach to identify newborns with DMD. Inclusion of birthweight- and age-specific cutoffs, repeat creatine kinase testing after 72 hours of age, and DMD sequencing improve sensitivity and specificity of screening.
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Distrofia Muscular de Duchenne , Masculino , Humanos , Recién Nacido , Distrofia Muscular de Duchenne/diagnóstico , Distrofia Muscular de Duchenne/epidemiología , Distrofia Muscular de Duchenne/genética , Tamizaje Neonatal , Peso al Nacer , North Carolina/epidemiología , Estudios Prospectivos , Creatina QuinasaRESUMEN
In 2022, 54% of 1.5 million children (age 0-14) living with HIV had access to anti-retroviral medication (ART). Adherence to ART for pregnant or breastfeeding HIV + women is critical for maintaining their personal health and to prevent mother-to-child-transmission (MTCT). For HIV + infants, adherence is essential to establish early viremic control and is contingent on caregiver administration. We conducted a scoping review to systematically identify and categorize the influences on ART adherence for pregnant or breastfeeding HIV + women and their HIV + infants. We searched databases in June 2023 and employed the Social-Ecological Model (SEM) to organize facilitators and barriers to adherence referenced in published articles. All articles published before 2016 were excluded due to updated guidelines from WHO on MTCT and ART. Our analysis included 52 articles. 50/52 took place in Africa and used cross-sectional and mixed-methods design. Barriers to adherence for pregnant or breastfeeding HIV + women included maternal education, self-efficacy, social support, and social/economic context. Barriers to infant adherence included development, nutrition, age of treatment initiation, disclosure, and ART side effects. Additional facilitators and barriers to adherence are presented at family, extra-familial, and socio-cultural SEM levels. Stigma was the most salient barrier referenced across the entire continuum of HIV care and all SEM levels. This review revealed a dearth of literature focusing on HIV + infants who are dependent on their caregivers for ART adherence and lack of a standard adherence measure. We identified multi-leveled influences on adherence impacting both the mother and infant and are amenable to public health intervention.
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Early Check is a voluntary, large-scale expanded newborn screening study in North Carolina that uses a self-directed web-based portal for return of normal individual research results (IRR). Little is known about participant perspectives in using web-based portals to receive IRR. This study explored user attitudes and behaviors within the Early Check portal using three methods: (1) a feedback survey available to the consenting parent of participating infants (typically mothers), (2) semi-structured interviews conducted with a subset of parents, and (3) Google Analytics. During an approximate 3-year period, 17 936 newborns received normal IRR and there were 27 812 visits to the portal. Most surveyed parents reported viewing their baby's results (86%, 1410/1639). Parents largely found the portal easy to use to get results, and helpful in understanding the results. However, 10% of parents said it was difficult to find enough information to understand their baby's results. In Early Check, providing normal IRR via the portal made a large-scale study practical, and was highly rated by most users. Return of normal IRR may be particularly amenable to web-based portals, as the consequences to participants from not viewing results are modest, and the interpretation of a normal result is relatively straightforward.
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Madres , Padres , Lactante , Femenino , Humanos , Recién Nacido , Encuestas y Cuestionarios , Tamizaje Neonatal , InternetRESUMEN
GM1-gangliosidosis (GM1) is a rare neurodegenerative disorder leading to early mortality and causing progressive decline of physical skills and cerebral functioning. No approved treatment for GM1 exists. In this study-the first to explore priorities of parents of subjects with pediatric onset forms of GM1-we address a crucial gap by characterizing symptoms most critical to caregivers of children with GM1 to treat. Our two-part, mixed-methods approach began with focus groups, followed by interviews with a distinct set of parents. Interviews included a prioritization activity that used best-worst scaling. Quantitative data were analyzed descriptively. Qualitative data were analyzed using thematic analysis and rapid analysis process. Parents prioritized the symptoms they believed would increase their child's lifespan and improve their perceived quality of life (QoL); these symptoms focused on communicating wants/needs, preventing pain/discomfort, getting around and moving one's body, and enhancing eating/feeding. Although lifespan was highly valued, almost all parents would not desire a longer lifespan without acceptable child QoL. Parents indicated high caregiver burden and progressive reduction in QoL for children with GM1. This novel study of caregiver priorities identified important symptoms for endpoints' selection in patient-focused drug development in the context of high disease impact and unmet treatment needs.
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Cuidadores , Gangliosidosis GM1 , Niño , Humanos , Calidad de Vida , Gangliósido G(M1) , Padres , Enfermedades RarasRESUMEN
PURPOSE OF REVIEW: There are growing expectations for the return of individual-level research results (RoR), which promotes autonomy and potential clinical and personal benefits. There are ethical and practical challenges, however, that may be exacerbated in research that assesses neurocognitive and psychological outcomes, including HIV-associated neurocognitive disorder (HAND). This paper reviews central concepts for RoR and recent empirical and conceptual articles from Alzheimer's disorder (AD) as a model for HIV. RECENT FINDINGS: Data from AD studies indicate high participant interest and low risk of harm from RoR, though additional research is needed. Investigators report a range of benefits, potential risks, and feasibility concerns. Standardized, evidence-based approaches are needed for RoR. For HIV research, we recommend a default position of offering RoR for cognitive and psychological outcomes. Investigators should justify decisions not to return results after assessing the potential value and feasibility of RoR. Longitudinal research is needed for feasible and evidence-based best practices.
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Demencia , Infecciones por VIH , Humanos , Infecciones por VIH/complicaciones , Trastornos NeurocognitivosRESUMEN
Complicated genetic mechanisms and unpredictable health risks associated with the FMR1 premutation can result in challenges for patient education when the diagnosis is made in a newborn. From October 15, 2018, to December 10, 2021, North Carolina parents could obtain FMR1 premutation results about their newborns through a voluntary expanded newborn screening research study. The study provided confirmatory testing, parental testing, and genetic counseling. We developed web-based educational materials to augment information about fragile X premutation conveyed by a genetic counselor. Many genetics education materials are developed for the lay population. However, relatively little research is published on how well individuals understand these materials. We conducted three rounds of iterative user testing interviews to help refine web-based educational materials that support understanding and self-paced learning. The participants included 25 parents with a 2-year college degree or less and without a child identified with fragile X syndrome, premutation, or gray-zone allele. Content analysis of interview transcripts resulted in iterative changes and ultimately saturation of findings. Across all rounds of interviews, there were two terms that were commonly misunderstood (fragile and carrier) and two terms that elicited initial misconceptions that were overcome by participants. Many also had difficulty understanding the relationship between fragile X premutation and fragile X syndrome as well as appreciating the implications of having a "fragile X gene." Website layout, formatting, and graphics also influenced comprehension. Despite iterative changes to the content, certain issues with understandability persisted. The findings support the need for user testing to identify misconceptions that may interfere with understanding and using genetic information. Here, we describe a process used to develop and refine evidence-based, understandable parental resources on fragile X premutation. Additionally, we provide recommendations to address ongoing educational challenges and discuss the potential impact of bias on the part of expert content developers.
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BACKGROUND: Prior studies of early antibiotic use and growth have shown mixed results, primarily on cross-sectional outcomes. This study examined the effect of oral antibiotics before age 24 months on growth trajectory at age 2-5 years. METHODS: We captured oral antibiotic prescriptions and anthropometrics from electronic health records through PCORnet, for children with ≥1 height and weight at 0-12 months of age, ≥1 at 12-30 months, and ≥2 between 25 and 72 months. Prescriptions were grouped into episodes by time and by antimicrobial spectrum. Longitudinal rate regression was used to assess differences in growth rate from 25 to 72 months of age. Models were adjusted for sex, race/ethnicity, steroid use, diagnosed asthma, complex chronic conditions, and infections. RESULTS: 430,376 children from 29 health U.S. systems were included, with 58% receiving antibiotics before 24 months. Exposure to any antibiotic was associated with an average 0.7% (95% CI 0.5, 0.9, p < 0.0001) greater rate of weight gain, corresponding to 0.05 kg additional weight. The estimated effect was slightly greater for narrow-spectrum (0.8% [0.6, 1.1]) than broad-spectrum (0.6% [0.3, 0.8], p < 0.0001) drugs. There was a small dose response relationship between the number of antibiotic episodes and weight gain. CONCLUSION: Oral antibiotic use prior to 24 months of age was associated with very small changes in average growth rate at ages 2-5 years. The small effect size is unlikely to affect individual prescribing decisions, though it may reflect a biologic effect that can combine with others.
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Antibacterianos , Estatura , Antibacterianos/uso terapéutico , Niño , Preescolar , Estudios Transversales , Humanos , Lactante , Prescripciones , Aumento de PesoRESUMEN
OBJECTIVES: The coronavirus disease (COVID-19) pandemic is an unprecedented event with massive global health and socio-economic impacts on vulnerable populations, especially people living with HIV. The epidemic has severely affected Thailand's economy and potentially impacted the financial and psychological wellbeing of Thai HIV-positive men who have sex with men (MSM). METHODS: Between 15 June and 10 December 2020, we conducted qualitative interviews with 26 MSM living with HIV in Thailand who participate in an Adam's Love We Care Study. We intentionally recruited individuals who may have experienced a greater impact of COVID-19. Interviews explored worry, stigma and stress surrounding COVID-19, and multiple domains of potential COVID-19 impact: financial/employment, HIV service delivery and antiretroviral (ART) adherence during the first 10 months of the COVID-19 pandemic. RESULTS: Participants perceived themselves as immunocompromised and susceptible, and feared contracting COVID-19. Participants worried that contracting COVID-19 would lead to HIV status disclosure and stigmatization. Participants had considerable worry about job loss as a result of the economic downturn, and some shared challenges associated with relocation and re-engaging with HIV care. Financial stress and lack of basic necessities caused by job losses were commonly reported. Participants reported optimal ART adherence as a consequence of local HIV service delivery responses, convenient ART refills and Adam's Love online support interventions. CONCLUSIONS: Our study highlights that the COVID-19 pandemic produced high levels of anxiety and concerns about additional stigma among MSM living with HIV. It had a significant negative effect on the daily lives of our participants. These findings indicate a need for the provision of confidential COVID-19 diagnosis and care, relief programmes, vaccination roll-out equity, and addressing employment needs of vulnerable populations.
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COVID-19 , Infecciones por VIH , Minorías Sexuales y de Género , Prueba de COVID-19 , Infecciones por VIH/epidemiología , Homosexualidad Masculina , Humanos , Masculino , Pandemias , SARS-CoV-2 , TailandiaRESUMEN
HIV remission trials often require temporary stopping of antiretroviral therapy (ART)-an approach called analytic treatment interruption (ATI). Trial designs resulting in viremia raise risks for participants and sexual partners. We conducted a survey on attitudes about remission trials, comparing ART resumption criteria (lower-risk "time to rebound" and higher-risk "sustained viremia") among participants from an acute HIV cohort in Thailand. Analyses included Wilcoxon-Ranks and multivariate logistic analysis. Most of 408 respondents supported ATI trials, with slightly higher approval of, and willingness to participate in, trials using time to rebound versus sustained viremia criteria. Less than half of respondents anticipated disclosing trial participation to partners and over half indicated uncertainty or unwillingness about whether partners would be willing to use PrEP. Willingness to participate was higher among those who rated higher trial approval, lower anticipated burden, and those expecting to make the decision independently. Our findings support acceptability of ATI trials among most respondents. Participant attitudes and anticipated behaviors, especially related to transmission risk, have implications for future trial design and informed consent.
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Infecciones por VIH , Viremia , Antirretrovirales/uso terapéutico , Actitud , Causalidad , Infecciones por VIH/tratamiento farmacológico , Humanos , Encuestas y Cuestionarios , Carga Viral , Viremia/tratamiento farmacológicoRESUMEN
BACKGROUND AND OBJECTIVES: Projections that 60 transformative cell and gene therapies could be approved by the U.S. Food and Drug Administration (FDA) within 10 years underscore an urgent need to modernize the newborn screening (NBS) system. This study convened expert stakeholders to assess challenges to the NBS system and propose solutions for its modernization. METHODS: NBS stakeholders (researchers, clinicians, state NBS leaders, advocates, industry professionals, and current/former advisory committee members) participated in one of five mixed-stakeholder panel discussions. Prior to panels, participants completed a survey in which they reviewed and ranked NBS challenges generated from relevant literature. During panels, participants deliberated on challenges and explored potential solutions. Pre-panel survey data were analyzed descriptively. Data from panel discussions were analyzed using a rapid qualitative analysis. RESULTS: Median scores of the ranked challenges (1 = most important) reveal the top three most important barriers to address: critical missing data for NBS decision-making (Median = 2), burden on state NBS laboratories (Median = 3), and the amount of time required for state-level implementation of screening for new conditions (Median = 4). Panel discussions were rooted in recurring themes: the infant's well-being should be the focal point; the transformative therapy pipeline, although undeniably positive for individuals with rare diseases, is a threat to NBS capacity; decisions about modernizing NBS should be evidence-based; additional financial support is required but not sufficient for modernization; and modernization will require participation of multiple NBS stakeholders. This final overarching theme is reported in depth, including expertise, coordination, and collaboration challenges facing NBS and novel approaches to oversight, partnership, and coordination that were suggested by participants. CONCLUSIONS: This study engaged representatives from multiple stakeholder groups to generate potential solutions to challenges facing NBS in the United States. These solutions provide a rich starting point for policy makers and other stakeholders who desire to maximize the impact of new transformative therapies for babies, families, and society.
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Tamizaje Neonatal , Participación de los Interesados , Humanos , Recién Nacido , Encuestas y Cuestionarios , Estados UnidosRESUMEN
Since nearly one-fifth of US adults have a psychiatric disorder, genetic counselors (GCs) will see many patients with these indications. However, GCs' reports of inadequate preparation and low confidence in providing care for patients with psychiatric disorders can limit their ability to meet patient's needs. How frequently psychiatric disorders present in GC sessions is currently unclear. Here, we used deidentified electronic health records (EHR) to estimate the prevalence of 16 psychiatric disorders. In 7,155 GC patients, 34% had a diagnostic code associated with a psychiatric disorder; 23% with anxiety/phobic disorders; 21% with mood disorder/depression; 5% with attention deficit hyperactivity disorder (ADHD); and 1% with psychotic disorders. Compared to 415,709 demographically matched controls, GC patients showed a significantly higher prevalence of psychiatric disorders (GC prevalence: 34%, matched prevalence: 30%, p-value < 0.0001) driven predominantly by anxiety disorder, major depressive disorder, generalized anxiety disorder, and ADHD. Within GC specialties (prenatal: n = 2,674, cancer: n = 1,474, pediatric: n = 465), only pediatric GC patients showed a significant increase in psychiatric disorder prevalence overall (pediatric GC prevalence: 28%, matched prevalence: 13%, p-value < 0.0001). However, significant evidence of increased prevalence existed for generalized anxiety disorder (prenatal GC prevalence 6.4%, matched prevalence: 4.9%, p-value < 0.0001), anxiety disorders (cancer GC prevalence: 26%, matched prevalence: 21%, p-value < 0.0001 and pediatric GC prevalence: 12%, matched prevalence: 5.5%), and ADHD (pediatric GC prevalence: 18%, matched prevalence: 7.9%, p-value < 0.0001). These results highlight the need for additional guidance around care for patients with psychiatric disorders and the value of EHR-based research in genetic counseling.
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Trastorno por Déficit de Atención con Hiperactividad , Trastorno Depresivo Mayor , Trastornos Mentales , Adulto , Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Trastorno por Déficit de Atención con Hiperactividad/epidemiología , Trastorno por Déficit de Atención con Hiperactividad/genética , Niño , Comorbilidad , Trastorno Depresivo Mayor/diagnóstico , Trastorno Depresivo Mayor/epidemiología , Trastorno Depresivo Mayor/genética , Registros Electrónicos de Salud , Asesoramiento Genético , Humanos , Trastornos Mentales/diagnóstico , Trastornos Mentales/epidemiología , Trastornos Mentales/genéticaRESUMEN
OBJECTIVE: Predictive testing for familial disorders can guide healthcare and reproductive decisions. Familial disorders with onset in childhood (e.g., autism spectrum disorder [ASD]) are promising targets for presymptomatic prediction; however, little is known about parent perceptions of risk to their children in the presymptomatic period. The current study examined risk perceptions in parents of infants at high familial risk for ASD enrolled in a longitudinal study of brain and behavior development. METHODS: Semistructured interviews were conducted with 37 parents of high-risk infants during the presymptomatic window (3-15 months) that precedes an ASD diagnosis. Infants were identified as high familial risk due to having an older sibling with ASD. Parent interview responses were coded and interpreted to distill emerging themes. RESULTS: The majority of parents were aware of the increased risk of ASD for their infants, and risk perceptions were influenced by comparisons to their older child with ASD. Parents reported a variety of negative emotions in response to perceived risk, including worry, fear, and sadness, and described impacts of perceived risk on their behavior: increased vigilance to emerging symptoms, altered reproductive and healthcare decisions, and seeking ongoing assessment through research. CONCLUSIONS: Parents of children at high familial risk for childhood-onset disorders like ASD face a period of challenging uncertainty during early development. In anticipation of a future in which presymptomatic testing for ASD is made available, it is important to understand how parents react to and cope with the elevated-but still highly uncertain-risk conveyed by family history.
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Trastorno del Espectro Autista/genética , Predisposición Genética a la Enfermedad , Conocimientos, Actitudes y Práctica en Salud , Padres/psicología , Trastorno del Espectro Autista/psicología , Emociones/fisiología , Femenino , Humanos , Lactante , Entrevistas como Asunto , Estudios Longitudinales , Masculino , Factores de RiesgoRESUMEN
Uncertainty is a challenging aspect of caring for children with Duchenne/Becker muscular dystrophies (DBMD). Although uncertainty is often perceived as a state to be avoided, hope may influence caregivers' perceptions of uncertainty as opportunity. The goal of this cross-sectional quantitative study was to pilot a novel measure of state-based hope, and test relationships among uncertainty, hope, spirituality, and coping efficacy in mothers of children with DBMD. Mothers (n = 202) were recruited through DuchenneConnect, Parent Project Muscular Dystrophy, and Cincinnati's Children Hospital. A one-component solution for the novel Parent Hope Scale explained 44.3% of the variance, and the measure showed high internal consistency. Higher hope (P < 0.001), further disease progression (P = 0.042), and older mother's age (P = 0.001) were significantly associated with lower perceptions of uncertainty. Mothers reporting less hope (P < 0.001), higher perceptions of uncertainty (P < 0.001), and less spirituality (P = 0.001) reported lower coping efficacy. As such, hope appears to be a key variable in shaping uncertainty appraisals and facilitating coping efficacy. While further research is needed, counseling aimed at bolstering hope, particularly among less-hopeful mothers, and interventions to reappraise uncertainty, may be helpful in promoting coping efficacy.
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Cuidadores/psicología , Esperanza , Distrofia Muscular de Duchenne/psicología , Incertidumbre , Adaptación Psicológica , Adolescente , Adulto , Niño , Preescolar , Estudios Transversales , Demografía , Femenino , Humanos , Lactante , Recién Nacido , Estudios Longitudinales , Madres , Motivación , Análisis de Regresión , Espiritualidad , Encuestas y Cuestionarios , Adulto JovenRESUMEN
In the field of biomedical HIV prevention, researchers have meaningfully incorporated behavioral and social sciences research (BSSR) into numerous clinical trials, though the timing and degree of integration have been highly variable. The literature offers few frameworks that systematically characterize these collaborations. To fill this gap, we developed a typology of BSSR approaches within biomedical HIV prevention research. Focusing on trials that had safety and/or efficacy endpoints, we identified five approaches for combining BSSR and clinical research: formative, embedded, parallel, explanatory, and implications. We describe each approach and provide illustrative examples. By offering a shared vocabulary for distinguishing the timing and design of collaborative BSSR and clinical research, this typology can facilitate greater transparency in collaborators' expectations and responsibilities, and help collaborators address challenges likely to be associated with such interdisciplinary research.
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Infecciones por VIH/prevención & control , Investigación Interdisciplinaria , Conducta Social , Investigación Biomédica , Ensayos Clínicos como Asunto , VIH , Humanos , Ciencias SocialesRESUMEN
BACKGROUND: Newborn screening (NBS) occupies a unique space at the intersection of translational science and public health. As the only truly population-based public health program in the United States, NBS offers the promise of making the successes of translational medicine available to every infant with a rare disorder that is difficult to diagnose clinically, but for which strong evidence indicates that presymptomatic treatment will substantially improve outcomes. Realistic NBS policy requires data, but rare disorders face a special challenge: Screening cannot be done without supportive data, but adequate data cannot be collected in the absence of large-scale screening. The magnitude and scale of research to provide this expanse of data require working with public health programs, but most do not have the resources or mandate to conduct research. METHODS: To address this gap, we have established Early Check, a research program in partnership with a state NBS program. Early Check provides the infrastructure needed to identify conditions for which there have been significant advances in treatment potential, but require a large-scale, population-based study to test benefits and risks, demonstrate feasibility, and inform NBS policy. DISCUSSION: Our goal is to prove the benefits of a program that can, when compared with current models, accelerate understanding of diseases and treatments, reduce the time needed to consider inclusion of appropriate conditions in the standard NBS panel, and accelerate future research on new NBS conditions, including clinical trials for investigational interventions. TRIAL REGISTRATION: Clinicaltrials.gov registration # NCT03655223 . Registered on August 31, 2018.
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Síndrome del Cromosoma X Frágil/diagnóstico , Atrofia Muscular Espinal/diagnóstico , Tamizaje Neonatal , Salud Pública , Investigación Biomédica Traslacional , Diagnóstico Precoz , Femenino , Estudios de Seguimiento , Síndrome del Cromosoma X Frágil/epidemiología , Política de Salud , Humanos , Recién Nacido , Consentimiento Informado , Internet , Colaboración Intersectorial , Masculino , Atrofia Muscular Espinal/epidemiología , North Carolina/epidemiología , Evaluación de Resultado en la Atención de Salud/métodos , Selección de Paciente , Evaluación de Programas y Proyectos de Salud , Estudios Prospectivos , Grupos de AutoayudaRESUMEN
Psychiatric genetics research is improving our understanding of the biological underpinnings of neurodiversity and mental illness. Using psychiatric genetics in ways that maximize benefits and minimize harms to individuals and society depends largely on how the ethical, legal, and social implications (ELSI) of psychiatric genetics are managed. The International Society of Psychiatric Genetics (ISPG) is the largest international organization dedicated to psychiatric genetics. Given its history, membership, and international reach, we believe the ISPG is well-equipped to contribute to the resolution of these ELSI challenges. As such, we recently created the ISPG Ethics Committee, an interdisciplinary group comprised of psychiatric genetics researchers, clinical geneticists, genetic counselors, mental health professionals, patients, patient advocates, bioethicists, and lawyers. This article highlights key ELSI challenges identified by the ISPG Ethics Committee to be of paramount importance for the ethical translation of psychiatric research into society in three contexts: research settings, clinical settings, and legal proceedings. For each of these arenas, we identify and discuss pressing psychiatric genetics ELSI dilemmas that merit attention and require action. The goal is to increase awareness about psychiatric genetics ELSI issues and encourage dialogue and action among stakeholders.
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Investigación Genética/ética , Genómica/ética , Trastornos Mentales/genética , Comités de Ética/tendencias , HumanosRESUMEN
Antisense oligonucleotide (AON)-mediated exon skipping is an emerging therapeutic for individuals with Duchenne muscular dystrophy (DMD). Skipping of exons adjacent to common exon deletions in DMD using AONs can produce in-frame transcripts and functional protein. Targeted skipping of DMD exons 8, 44, 45, 50, 51, 52, 53, and 55 is predicted to benefit 47% of affected individuals. We observed a correlation between mutation subgroups and age at loss of ambulation in the Duchenne Registry, a large database of phenotypic and genetic data for DMD (N = 765). Males amenable to exon 44 (N = 74) and exon 8 skipping (N = 18) showed prolonged ambulation compared to other exon skip groups and nonsense mutations (P = 0.035 and P < 0.01, respectively). In particular, exon 45 deletions were associated with prolonged age at loss of ambulation relative to the rest of the exon 44 skip amenable cohort and other DMD mutations. Exon 3-7 deletions also showed prolonged ambulation relative to all other exon 8 skippable mutations. Cultured myotubes from DMD patients with deletions of exons 3-7 or exon 45 showed higher endogenous skipping than other mutations, providing a potential biological rationale for our observations. These results highlight the utility of aggregating phenotypic and genotypic data for rare pediatric diseases to reveal progression differences, identify potentially confounding factors, and probe molecular mechanisms that may affect disease severity.
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Distrofina/genética , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/genética , Oligodesoxirribonucleótidos Antisentido/genética , Adolescente , Adulto , Factores de Edad , Biopsia , Codón sin Sentido/genética , Distrofina/antagonistas & inhibidores , Exones/genética , Femenino , Fibroblastos/patología , Genotipo , Humanos , Estimación de Kaplan-Meier , Tiempo de Internación , Masculino , Músculo Esquelético/patología , Distrofia Muscular de Duchenne/patología , Distrofia Muscular de Duchenne/terapia , Mioblastos/patología , Oligodesoxirribonucleótidos Antisentido/uso terapéutico , Cultivo Primario de Células , Sistema de Registros , Eliminación de Secuencia/genética , Caracteres Sexuales , Adulto JovenRESUMEN
To describe the long-term effect of steroid treatment on weight in nonambulatory males with Duchenne Muscular Dystrophy (DMD), we identified 392 males age 7-29 years with 4,512 weights collected after ambulation loss (176 steroid-naïve and 216 treated with steroids ≥6 months) from the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet). Comparisons were made between the weight growth curves for steroid-naïve males with DMD, steroid-treated males with DMD, and the US pediatric male population. Using linear mixed-effects models adjusted for race/ethnicity and birth year, we evaluated the association between weight-for-age and steroid treatment characteristics (age at initiation, dosing interval, cumulative duration, cumulative dose, type). The weight growth curves for steroid-naïve and steroid-treated nonambulatory males with DMD were wider than the US pediatric male growth curves. Mean weight-for-age z scores were lower in both steroid-naïve (mean = -1.3) and steroid-treated (mean = -0.02) nonambulatory males with DMD, compared to the US pediatric male population. Longer treatment duration and greater cumulative dose were significantly associated with lower mean weight-for-age z scores. Providers should consider the effect of steroid treatment on weight when making postambulation treatment decisions for males with DMD.
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Corticoesteroides/farmacología , Corticoesteroides/uso terapéutico , Peso Corporal/efectos de los fármacos , Distrofia Muscular de Duchenne/tratamiento farmacológico , Adolescente , Adulto , Niño , Humanos , Masculino , Distrofia Muscular de Duchenne/fisiopatología , Caminata , Adulto JovenRESUMEN
PURPOSE: Patient preference information (PPI) have an increasing role in regulatory decision-making, especially in benefit-risk assessment. PPI can also facilitate prioritization of symptoms to treat and inform meaningful selection of clinical trial endpoints. We engaged patients and caregivers to prioritize symptoms of Duchenne and Becker muscular dystrophy (DBMD) and explored preference heterogeneity. METHODS: Best-worst scaling (object case) was used to assess priorities across 11 symptoms of DBMD that impact quality of life and for which there is unmet need. Respondents selected the most and least important symptoms to treat among a subset of five. Relative importance scores were estimated for each symptom, and preference heterogeneity was identified using mixed logit and latent class analysis. RESULTS: Respondents included patients (n = 59) and caregivers (n = 96) affected by DBMD. Results indicated that respondents prioritized "weaker heart pumping" [score = 5.13; 95% CI (4.67, 5.59)] and pulmonary symptoms: "lung infections" [3.15; (2.80, 3.50)] and "weaker ability to cough" [2.65; (2.33, 2.97)] as the most important symptoms to treat and "poor attention span" as the least important symptom to treat [- 5.23; (- 5.93, - 4.54)]. Statistically significant preference heterogeneity existed (p value < 0.001). At least two classes existed with different priorities. Priorities of the majority latent class (80%) reflected the aggregate results, whereas the minority latent class (20%) did not distinguish among pulmonary and other symptoms. CONCLUSIONS: Estimates of the relative importance for symptoms of Duchenne muscular dystrophy indicated that symptoms with direct links to morbidity and mortality were prioritized above other non-skeletal muscle symptoms. Findings suggested the existence of preference heterogeneity for symptoms, which may be related to symptom experience.
Asunto(s)
Cuidadores/psicología , Distrofia Muscular de Duchenne/psicología , Participación del Paciente/psicología , Calidad de Vida/psicología , Adolescente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Distrofia Muscular de Duchenne/patología , Adulto JovenRESUMEN
BACKGROUND/AIMS: Pediatric rare disease presents a challenging situation of high unmet need and a limited pool of potential clinical trial participants. Understanding perspectives of parents of children who have not participated in trials may facilitate approaches to optimize participation rates. The objective of this study was to explore factors associated with parental interest in enrolling children with pediatric neuromuscular disorders in clinical trials. METHODS: Parents of individuals with Duchenne or Becker muscular dystrophy and spinal muscular atrophy were recruited through advocacy organizations, a registry, and clinics. These parents ( N = 203) completed a questionnaire including assessments of barriers and facilitators to clinical trial participation, parents' interest in trial participation, and their perceptions of others' views about participation in a clinical trial. RESULTS: Trial interest in participating parents was high (64% combined group). The most highly endorsed barrier to participation was the possibility of receiving placebo, followed by not having enough information on risks and trial procedures. Compared to parents of children with Duchenne or Becker muscular dystrophy, parents of children with spinal muscular atrophy endorsed significantly more information and knowledge barriers. The greatest facilitators of participation were (1) confidence in improving disease understanding and (2) guarantee to receive the treatment after a successful trial. A logistic regression model, χ2 (4, n = 188) = 80.64, p < .001, indicated that higher perceived barriers and more frequent trial communication by the provider were associated with lower interest, while positive trial perceptions by the child's providers and concordance in trial perceptions among those close to the decision-maker were associated with higher interest. CONCLUSION: We found high parental interest in pediatric neuromuscular trials that was tempered by concerns about the potential for randomization to a placebo arm. Participants perceived that their trial participation would be facilitated by additional education and guidance from their clinicians. Yet, intentions were negatively associated with frequency of provider communication, perhaps reflecting waning parental interest with a greater understanding of limitations in trial access, increased sophistication in their understanding of trial design, and appreciation of potential burden. To support parents' informed decisions, it is important to educate them to evaluate the quality of research, as well as providing lay information explaining the use of placebo, trial processes, and potential barriers to long-term drug access. Our findings should inform the development of targeted educational content, clinician training, and decision support tools.