Perspectives of paediatric providers on antibiotic stewardship in a high-prescribing rural region.

PURPOSE: Understanding drivers of antibiotic use is key to limiting the development of antimicrobial resistance. Outpatient antibiotic prescribing rates vary substantially across and within states. Kentucky is one of the highest prescribing states, and the southeastern region has rates that are drastically higher than the national average and urban areas of the state. We sought to examine provider perceptions of antibiotic use in this rural area to more effectively guide future interventions and policy. METHODS: This study utilized Medicaid prescription claims to identify providers who frequently prescribe antibiotics to children in southeastern Kentucky. Semistructured qualitative interviews were conducted to elicit provider perspectives on antibiotic overuse. FINDINGS: Individual, in-person interviews were conducted with 25 providers from a variety of practices and training backgrounds (private, nonprofit, retail, physician, advanced practice registered nurses, etc.). The following themes emerged as issues that prescribers consider to contribute to antibiotic overuse: (1) caregiver pressure, especially from grandparents or families who desire a 'quick fix'; (2) business concerns and competition and (3) cultural factors related to poverty and rural locations. Interviewed providers were supportive of public education and had mixed views on the effectiveness of delayed fill or provider feedback initiatives. CONCLUSIONS: This study highlights unique challenges associated with antibiotic prescribing in rural areas. Findings will guide future interventions through adaptation of existing strategies to better serve this vulnerable population.

Measuring perceived utility of genomic sequencing: Development and validation of the GENEtic Utility (GENE-U) scale for pediatric diagnostic testing.

PURPOSE: Measuring the effects of genomic sequencing (GS) on patients and families is critical for translational research. We aimed to develop and validate an instrument to assess parents' perceived utility of pediatric diagnostic GS. METHODS: Informed by a 5-domain conceptual model, the study comprised 5 steps: (1) item writing, (2) cognitive testing, (3) pilot testing and item reduction, (4) psychometric testing, and (5) evaluation of construct validity. Parents of pediatric patients who had received results of clinically indicated GS participated in structured cognitive interviews and 2 rounds of surveys. After eliminating items based on theory and quantitative performance, we conducted an exploratory factor analysis and calculated Pearson correlations with related instruments. RESULTS: We derived the 21-item Pediatric Diagnostic version of the GENEtic Utility (GENE-U) scale, which has a 2-factor structure that includes an Informational Utility subscale (16 items, α = 0.91) and an Emotional Utility subscale (5 items, α = 0.71). Scores can be summed to calculate a Total scale score (α = 0.87). The Informational Utility subscale was strongly associated with empowerment and personal utility of GS, and the Emotional Utility subscale was moderately associated with psychosocial impact and depression and anxiety. CONCLUSION: The pediatric diagnostic GENE-U scale demonstrated good psychometric performance in this initial evaluation and could be a useful tool for translational genomics researchers, warranting additional validation.

Ethical and Legal Issues Surrounding Genetic Testing in the NICU.

Clinicians practicing in a modern NICU are noticing an increase in the proportion of patients who undergo genetic testing as well as changes in the types of genetic testing patients receive. These trends are not surprising given the increasing recognition of the genetic causes of neonatal illness and recent advances in genetic technology. Yet, the expansion of genetic testing in the NICU also raises a number of ethical questions. In this article, we will review the ethical issues raised by genetic testing, with a focus on the practical implications for neonatologists. First, we outline the complexities of measuring benefit, or utility, for neonatal genetic testing. Next, we discuss potential harms such as inequity, unexpected findings, disability biases, and legal risks. Finally, we conclude with a discussion of ethical issues related to consent for genetic testing. Throughout this article, we highlight solutions to challenges toward the ultimate goal of minimizing harms and maximizing the substantial potential benefits of genetic medicine in the NICU.

Moving to the Middle Ground: Redefining Genomic Utility to Expand Understanding of Familial Benefit.

Translational research has tended to ignore the question of whether receiving a genomic diagnosis provides utility in community care contexts outside of doctors' offices and hospitals. However, empirical research with parents has highlighted numerous ways that a genomic diagnosis might be of practical value in the care provided by teachers, physical or occupational therapists, speech-language pathologists, behavior analysts, and nonphysician mental health providers. In this essay, we propose a new conceptual model of genomic utility that offers the opportunity to better capture a broad range of potential implications of genomic technologies for families in various social and organizational systems. We explore crucial research directions to better understand how redefined utility might affect families and nonphysician professionals.

The Parent PrU: A measure to assess personal utility of pediatric genomic results.

PURPOSE: We aimed to adapt and validate an existing patient-reported outcome measure, the personal-utility (PrU) scale, for use in the pediatric genomic context. METHODS: We adapted the adult version of the PrU and obtained feedback from 6 parents whose child had undergone sequencing. The resulting measure, the Parent PrU, was administered to parents of children in 4 pediatric cohorts of the Clinical Sequencing Evidence-Generating Research consortium after they received their children's genomic results. We investigated the measure's structural validity and internal consistency. RESULTS: We conducted a principal-axis factor analysis with oblimin rotation on data from 755 participants to determine structural validity. These analyses yielded a 3-factor solution, accounting for 76% of the variance in the 16 items. We used Cronbach's α to assess the internal consistency of each factor: (1) child benefits (α = .95), (2) affective parent benefits (α = .90), and (3) parent control (α = .94). CONCLUSION: Our evidence suggests that the Parent PrU scale has potential as a measure for assessing parent-reported personal utility of their children's genomic results. Additional research is needed to further validate the Parent PrU scale, including by comparing its findings with utility assessments reported by clinicians and children themselves.

Parents' Perspectives on the Utility of Genomic Sequencing in the Neonatal Intensive Care Unit.

BACKGROUND: It is critical to understand the wide-ranging clinical and non-clinical effects of genome sequencing (GS) for parents in the NICU context. We assessed parents' experiences with GS as a first-line diagnostic tool for infants with suspected genetic conditions in the NICU. METHODS: Parents of newborns (N = 62) suspected of having a genetic condition were recruited across five hospitals in the southeast United States as part of the SouthSeq study. Semi-structured interviews (N = 78) were conducted after parents received their child's sequencing result (positive, negative, or variants of unknown significance). Thematic analysis was performed on all interviews. RESULTS: Key themes included that (1) GS in infancy is important for reproductive decision making, preparing for the child's future care, ending the diagnostic odyssey, and sharing results with care providers; (2) the timing of disclosure was acceptable for most parents, although many reported the NICU environment was overwhelming; and (3) parents deny that receiving GS results during infancy exacerbated parent-infant bonding, and reported variable impact on their feelings of guilt. CONCLUSION: Parents reported that GS during the neonatal period was useful because it provided a "backbone" for their child's care. Parents did not consistently endorse negative impacts like interference with parent-infant bonding.

Concordance of International Regulation of Pediatric Health Research.

OBJECTIVE: To assess the comparability of international ethics principles and practices used in regulating pediatric research as a first step in determining whether reciprocal deference for international ethics review is feasible. Prior studies by the authors focused on other aspects of international health research, such as biobanks and direct-to-participant genomic research. The unique nature of pediatric research and its distinctive regulation by many countries warranted a separate study. STUDY DESIGN: A representative sample of 21 countries was selected, with geographical, ethnic, cultural, political, and economic diversity. A leading expert on pediatric research ethics and law was selected to summarize the ethics review of pediatric research in each country. To ensure the comparability of the responses, a 5-part summary of pediatric research ethics principles in the US was developed by the investigators and distributed to all country representatives. The international experts were asked to assess and describe whether principles in their country and the US were congruent. Results were obtained and compiled in the spring and summer of 2022. RESULTS: Some of the countries varied in their conceptualization or description of one or more ethical principles for pediatric research, but overall, the countries in the study demonstrated a fundamental concordance. CONCLUSIONS: Similar regulation of pediatric research in 21 countries suggests that international reciprocity is a viable strategy.

Words matter: The language of difference in human genetics.

Diversity, equity, and inclusion efforts in academia are leading publishers and journals to re-examine their use of terminology for commonly used scientific variables. This reassessment of language is particularly important for human genetics, which is focused on identifying and explaining differences between individuals and populations. Recent guidance on the use of terms and symbols in clinical practice, research, and publications is beginning to acknowledge the ways that language and concepts of difference can be not only inaccurate but also harmful. To stop perpetuating historical wrongs, those of us who conduct and publish genetic research and provide genetic health care must understand the context of the terms we use and why some usages should be discontinued. In this article, we summarize critiques of terminology describing disability, sex, gender, race, ethnicity, and ancestry in research publications, laboratory reports, diagnostic codes, and pedigrees. We also highlight recommendations for alternative language that aims to make genetics more inclusive, rigorous, and ethically sound. Even though norms of acceptable language use are ever changing, it is the responsibility of genetics professionals to uncover biases ingrained in professional practice and training and to continually reassess the words we use to describe human difference because they cause harm to patients.

Return of non-ACMG recommended incidental genetic findings to pediatric patients: considerations and opportunities from experiences in genomic sequencing.

BACKGROUND: The uptake of exome/genome sequencing has introduced unexpected testing results (incidental findings) that have become a major challenge for both testing laboratories and providers. While the American College of Medical Genetics and Genomics has outlined guidelines for laboratory management of clinically actionable secondary findings, debate remains as to whether incidental findings should be returned to patients, especially those representing pediatric populations. METHODS: The Sequencing Analysis and Diagnostic Yield working group in the Clinical Sequencing Evidence-Generating Research Consortium has collected a cohort of pediatric patients found to harbor a genomic sequencing-identified non-ACMG-recommended incidental finding. The incidental variants were not thought to be associated with the indication for testing and were disclosed to patients and families. RESULTS: In total, 23 "non-ACMG-recommended incidental findings were identified in 21 pediatric patients included in the study. These findings span four different research studies/laboratories and demonstrate differences in incidental finding return rate across study sites. We summarize specific cases to highlight core considerations that surround identification and return of incidental findings (uncertainty of disease onset, disease severity, age of onset, clinical actionability, and personal utility), and suggest that interpretation of incidental findings in pediatric patients can be difficult given evolving phenotypes. Furthermore, return of incidental findings can benefit patients and providers, but do present challenges. CONCLUSIONS: While there may be considerable benefit to return of incidental genetic findings, these findings can be burdensome to providers and present risk to patients. It is important that laboratories conducting genomic testing establish internal guidelines in anticipation of detection. Moreover, cross-laboratory guidelines may aid in reducing the potential for policy heterogeneity across laboratories as it relates to incidental finding detection and return. However, future discussion is required to determine whether cohesive guidelines or policy statements are warranted.

Data sharing and community-engaged research.

Data sharing must be accompanied by responsibility sharing.

Addressing underrepresentation in genomics research through community engagement.

The vision of the American Society of Human Genetics (ASHG) is that people everywhere will realize the benefits of human genetics and genomics. Implicit in that vision is the importance of ensuring that the benefits of human genetics and genomics research are realized in ways that minimize harms and maximize benefits, a goal that can only be achieved through focused efforts to address health inequities and increase the representation of underrepresented communities in genetics and genomics research. This guidance is intended to advance community engagement as an approach that can be used across the research lifecycle. Community engagement uniquely offers researchers in human genetics and genomics an opportunity to pursue that vision successfully, including by addressing underrepresentation in genomics research.

Newborn screening for neurodevelopmental diseases: Are we there yet?

In the US, newborn screening (NBS) is a unique health program that supports health equity and screens virtually every baby after birth, and has brought timely treatments to babies since the 1960's. With the decreasing cost of sequencing and the improving methods to interpret genetic data, there is an opportunity to add DNA sequencing as a screening method to facilitate the identification of babies with treatable conditions that cannot be identified in any other scalable way, including highly penetrant genetic neurodevelopmental disorders (NDD). However, the lack of effective dietary or drug-based treatments has made it nearly impossible to consider NDDs in the current NBS framework, yet it is anticipated that any treatment will be maximally effective if started early. Hence there is a critical need for large scale pilot studies to assess if and how NDDs can be effectively screened at birth, if parents desire that information, and what impact early diagnosis may have. Here we attempt to provide an overview of the recent advances in NDD treatments, explore the possible framework of setting up a pilot study to genetically screen for NDDs, highlight key technical, practical, and ethical considerations and challenges, and examine the policy and health system implications.

Challenges for precision public health communication in the era of genomic medicine.

Although still in the early stages of development, the advent of fast, high-output, and cost-effective next-generation DNA sequencing technology is moving precision medicine into public health. Before this shift toward next-generation sequencing in public health settings, individual patients met geneticists after showing symptoms and through limited family screening. In the new era of precision public health, everyone is a possible participant in genetic sequencing, simply by being born (newborn screening), by donating blood (biobanking), or through population screening. These initiatives are increasingly offered to individuals throughout their life and more individuals are encountering opportunities to use DNA sequencing. This article raises awareness of these growing areas and calls for different models of public engagement and communication about genomics, including screening asymptomatic populations, obtaining consent for unspecified and unforeseen future uses of genomic data, and managing variants of uncertain significance. Given that such communication challenges loom large, established norms of practice in genomic medicine and research should be reconsidered.

Case Report: Capitalizing on Development and Activity-Dependent Plasticity, an Interaction With Pediatric-Onset Spinal Cord Injury.

Background: Spinal cord injury (SCI) in infancy halts typical development secondary to paralysis/paresis and the limited ability to engage with the environment. Traditional therapies further restrict a child via bracing, equipment, and medications. In contrast, activity-based restorative therapies (ABRT) promote activation of the neuromuscular system below the level of injury and affords a more typical sensorimotor experience. Case Description: A premature male infant exhibiting hypotonia, poor head control, and extremity weakness was diagnosed at age 5 months with a remote incomplete upper cervical SCI based on magnetic resonance imaging (MRI), presumed to have occurred perinatally. From 4 to 15 months of age, he received physical, occupational and speech therapies. Enrolled in an ABRT program at 15 months, he was unable to sit, pull-to-stand, stand, or walk and had upper extremity impairments. Results of the Bayley-III Scales of Infant and Toddler Development revealed gross and fine motor scores consistent with a 4-month-old. Methods: Activity-based restorative therapies was provided 5 day/week: 1.5 h of activity-based locomotor training and 1 h of activity-based occupational therapy. Results: Activity-based restorative therapies are reported for 177 sessions and are on-going. Improvements are noted in trunk control, standing, walking, grasp, in-hand manipulation, and associated kinematics. Bayley-III fine motor score improved to that of a 16-month-old and gross motor score to that of a 7-month-old. Discussion: While the two treatment periods (i.e., 4-15 months old and 15-24 months) were each ∼9 months, the child's accelerated progress toward typical development during the latter, ABRT period is noteworthy. In comparison to the period of traditional therapies in which paralysis was compounded by a restrictive environment and compensation, ABRT provided a potentially rich sensorimotor experience with an emphasis on active weight-bearing and proper kinematics to activate the neuromuscular system below the lesion in an age-appropriate, task-specific context of activities. Improved physical capacity enabled exploration more typically associated with development at this age expanding the positive impact to other developmental domains.

Spinal Cord Injury at Birth, Expected Medical and Health Complexity in Chronic Injury Guided Anew by Activity-Based Restorative Therapy: Case Report.

As infancy is characterized by rapid physical growth and critical periods of development, disruptions due to illness or disease reveal vulnerability associated with this period. Spinal cord injury (SCI) has devastating consequences at any age, but its onset neonatally, at birth, or within the first year of life multiplies its impact. The immediate physical and physiological consequences are obvious and immense, but the effects on the typical trajectory of development are profound. Activity-based restorative therapies (ABRT) capitalize on activity-dependent plasticity of the neuromuscular system below the lesion and when provided to children with SCI aim to improve the child's neuromuscular capacity, health and quality of life. This is a report of an infant with a cervical SCI at birth resulting in paralysis of leg and trunk muscles and paresis of arm and hands who was enrolled in an ABRT program at 3 years of age. After 59 sessions of ABRT, the child demonstrated significant improvements in trunk control and arm function, as well as social and emotional development. Despite the chronicity of injury and low expectations for improvement with therapeutic interventions, ABRT had a positive impact on the child's physical capacity and provided benefits across multiple developmental domains.

Impact of returning unsolicited genomic results to nongenetic health care providers in the eMERGE III Network.

PURPOSE: As genomic sequencing becomes more common, medically actionable secondary findings will increasingly be returned to health care providers (HCPs), who will be faced with managing the resulting patient care. These findings are generally unsolicited, ie, unrelated to the sequencing indication and/or ordered by another clinician. METHODS: To understand the impact of receiving unsolicited results, we interviewed HCPs who received genomic results for patients enrolled in the Electronic Medical Records and Genomics (eMERGE) Phase III Network, which returned results on >100 actionable genes to eMERGE participants and HCPs. RESULTS: In total, 16 HCPs across 3 eMERGE sites were interviewed about their experience of receiving a positive (likely pathogenic or pathogenic), negative, or variant of uncertain significance result for a patient enrolled in eMERGE Phase III and about managing their patient on the basis of the result. Although unsolicited, HCPs felt responsible for managing the patient's resulting medical care. HCPs indicated that clinical utility depended on the actionability of results, and whereas comfort levels varied, confidence was improved by the availability of subspecialist consults. HCPs were concerned about patient anxiety, insurability, and missing an actionable result in the electronic health record. CONCLUSION: Our findings help inform best practices for return of unsolicited genomic screening findings in the future.