Translational Research Network Research Articles

Randomised trial of Mentored ‘Planning to be Active+Family’ [MPBA+F] for Appalachian youth at risk for diabetes: virtual delivery protocol

IntroductionObesity (OB) in children remains a national epidemic. This trial targets children suffering from overweight (OW) and OB living in rural Appalachia. Rural Appalachia is fraught with unhealthy behaviours, high rates of OB, pre-diabetes and type 2 diabetes among children. Diabetes prevalence in Appalachia is nearly double that of other regions. The prevalence of Appalachian children suffering from OB and extreme obesity (EO) increases the severity of diabetes.Methods and analysisWe will conduct a stratified randomised-controlled trial to evaluateMentored Planning to be Active+Family (MPBA+F) among seventh grade children with OW/OB/EO from rural Appalachian counties. Based on the Social Cognitive Theory,MPBA+Fcurriculum is a self-regulation approach to physical activity (PA) developed at The Ohio State University and successfully tested for feasibility in rural Appalachian middle schools.MPBA+F(a) incorporates active skill-building activities; (b) reinforces self-regulating activities; (c) engages in individual and group PA; (d) builds the link between PA, hydration and physical health and (e) actively supports weekly PA goals. Weekly skills are incorporated into reinforcement assignments verified at the beginning the following week. The primary outcome is the average daily minutes of moderate-vigorous PA. We will stratify by sex assigned at birth and conduct intent-to-treat analysis. We use descriptive statistics to summarise cohort and group (MPBA+F or comparison) baseline characteristics and examine variable distributions. Bivariate tests examine the balance of baseline characteristics by intervention groups. Mixed-effects linear modelling will be our more primary regression strategy. A potential problem is loss of curricular integrity. Our process assessment, structured mentor training and Instructor’s Guide reduce this concern. Another concern may be the lack of reliable broadband access. Participating counties exceed 75% broadband access. Those who lose internet access may have materials mailed to their home or accessed on the study website.Ethics and disseminationThis study was reviewed and approved by the American Diabetes Association Grants Review Committee (Grant number 11-22-ICTSN-30), the host institution’s Social and Behavioral Human Subjects Review Committee (Protocol 2022B0149) and is registered on ClinicalTrials.gov (ProtocolNCT05758441). All data that can be shared without compromising human subject protections will be shared to an approved open data repository within six months of publication or 18 months of the conclusion of the funding period (November 2025) if the study remains unpublished. Dissemination to families and stakeholders is by project newsletters. Public presentation of findings will be shared at the Annual Appalachian Translational Research Network and local health department meetings.Trial registration numberNCT05758441.

Charting the Ethical Frontier in Newborn Screening Research: Insights from the NBSTRN ELSI Researcher Needs Survey

From 2008 to 2024, the Newborn Screening Translational Research Network (NBSTRN), part of the National Institute of Child Health and Human Development (NICHD) Hunter Kelly Newborn Screening Program, served as a robust infrastructure to facilitate groundbreaking research in newborn screening (NBS), public health, rare disease, and genomics. Over its sixteen years, NBSTRN developed into a significant international network, supporting innovative research on novel technologies to screen, diagnose, treat, manage, and understand the natural history of more than 280 rare diseases. The NBSTRN tools and resources were used by a variety of stakeholders including researchers, clinicians, state NBS programs, parents, families, and policy makers. Resources and expertise for the newborn screening community in ethical, legal, and social issues (ELSI) has been an important area of focus for the NBSTRN and this includes efforts across the NBS system from pilot studies of candidate conditions to public health implementation of screening for new conditions, and the longitudinal follow-up of NBS-identified individuals to inform health outcomes and disease understanding. In 2023, the NBSTRN conducted a survey to explore ELSI issues in NBS research, specifically those encountered by the NBS community. Since NBS research involves collaboration among researchers, state NBS programs, clinicians, and families, the survey was broadly designed and disseminated to engage all key stakeholders. With responses from 88 members of the NBS community, including researchers and state NBS programs, the survey found that individuals rely most on institutional and collegial resources when they encounter ELSI questions. Most survey responses ranked privacy as extremely or very important in NBS research and identified the need for policies that address informed consent in NBS research. The survey results highlight the need for improved collaborative resources and educational programs focused on ELSI for the NBS community. The survey results inform future efforts in ELSI and NBS research in the United States (U.S.) and the rest of the world, including the development of policies and expanded ELSI initiatives and tools that address the needs of all NBS stakeholders.

DSD-related attitudes and beliefs held by pediatric endocrinologists and urologists: Insights from the North American disorders/differences of sex development (DSD) clinician survey

Disorders/Differences of Sex Development (DSD) encompass congenital conditions with atypical development of chromosomal, gonadal, or anatomical sex. Due to the rarity and complexity of these conditions, strong evidence for clinical practices is scarce, leading to controversies in management. This study, part of a broader project, examines changes over time in the attitudes and beliefs of DSD healthcare providers, focusing on factors contributing to patients' life satisfaction and the influence of medical specialty, gender, and age. Participants included active members of the Pediatric Endocrine Society (PES) and the Societies for Pediatric Urology (SPU) at three time points: 2003-2004 (T1), 2010-2011 (T2), and 2020 (T3). A survey covering predictors of patient life satisfaction, attitudes and beliefs regarding DSD care and outcomes, and participant characteristics was administered. Data were analyzed using descriptive statistics and Generalized Estimating Equations (GEE). Demographics: Participation rates were 56% (PES) and 64.7% (SPU) at T1, 41.1% (PES) and 52.3% (SPU) at T2, and 25.6% (PES) and 51.2% (SPU) at T3. Most participants were male (T1: 70.6%, T2: 61.7%, T3: 70.6%). Factors Affecting Life Satisfaction: Both endocrinologists and urologists ranked "gender identity consistent with assigned sex" as most important. Over time, the endorsement of some factors, such as performing genital surgery at Centers of Excellence, increased, while others, like the influence of prenatal androgen exposure determining gender identity, varied by specialty and gender. Attitudes and Beliefs: Across 18 statements, responses indicated three clusters with strong agreement, moderate agreement, and strong disagreement. Statements on the importance of family background and avoiding gender discordance were consistently endorsed, while those on delaying hypospadias repair until consent were least endorsed. The study highlights variability in beliefs about DSD management over time, influenced by specialty, gender, and age. Despite consensus on some care principles, discrepancies remain, particularly regarding the impact of prenatal androgens and the timing of surgical interventions. These findings underscore the need for regular interdisciplinary communication to align clinical practices with evidence-based guidelines and address subjective beliefs. The survey illustrates evolving perspectives among DSD healthcare providers, emphasizing the need for continued dialogue and education to bridge gaps between clinical evidence and practice. Collaborative efforts, such as the international I-DSD and the U.S. DSD Translational Research Network, are crucial for advancing patient-centered care in this field.

Discordant Prenatal Cell-Free DNA Screening vs. Diagnostic Results of Sex Chromosome Aneuploidies: Implications for Newborn Screening and Genetic Counseling.

Sex chromosome aneuploidies (SCAs) collectively occur in 1 in 500 livebirths, and diagnoses in the neonatal period are increasing with advancements in prenatal and early genetic testing. Inevitably, SCA will be identified on either routine prenatal or newborn screening in the near future. Tetrasomy SCAs are rare, manifesting more significant phenotypes compared to trisomies. Prenatal cell-free DNA (cfDNA) screening has been demonstrated to have relatively poor positive predictive values (PPV) in SCAs, directing genetic counseling discussions towards false-positive likelihood rather than thoroughly addressing all possible outcomes and phenotypes, respectively. The eXtraordinarY Babies study is a natural history study of children prenatally identified with SCAs, and it developed a longitudinal data resource and common data elements with the Newborn Screening Translational Research Network (NBSTRN). A review of cfDNA and diagnostic reports from participants identified a higher than anticipated rate of discordance. The aims of this project are to (1) compare our findings to outcomes from a regional clinical cytogenetic laboratory and (2) describe discordant outcomes from both samples. Twenty-one (10%), and seven (8.3%) cases were found to be discordant between cfDNA (result or indication reported to lab) and diagnosis for the Babies Study and regional laboratory, respectively. Discordant results represented six distinct discordance categories when comparing cfDNA to diagnostic results, with the largest groups being Trisomy cfDNA vs. Tetrasomy diagnosis (66.7% of discordance in eXtraordinarY Babies study) and Mosaicism (57.1% in regional laboratory). Traditional genetic counseling for SCA-related cfDNA results is inadequate given a high degree of discordance that jeopardizes the accuracy of the information discussed and informed decision making following prenatal genetic counseling.

251 The Appalachian Translational Research Network (ATRN) Newsletter: Supporting Communication and Collaboration among Academic and Community Partners to Improve Health in Appalachia

OBJECTIVES/GOALS: The Appalachian Translational Research Network (ATRN) Newsletter provides a unique platform that facilitates communication among Appalachian-serving CTSAs/CTSIs and partnering academic and community organizations that strengthens research efforts and advances translational science across the region. METHODS/STUDY POPULATION: Published biannually, each ATRN Newsletter features content submitted by ATRN member universities and organizations. Members of the Communications Committee, who represent both CTSA- or non-CTSA- affiliated ATRN member institutions, provide as well as review and edit content for the Newsletter. Regular features include researcher and community member spotlights; funding opportunity announcements; information on upcoming seminars, trainings, and special events; and opportunities for collaborations among partnering ATRN institutions. Complementing regularly scheduled Newsletters, special editions are released as warranted, such as a special COVID-19 focused edition published in 2020. RESULTS/ANTICIPATED RESULTS: First published in 2012, the ATRN Newsletter initially represented founding ATRN institutions, the University of Kentucky and the Ohio State University CTSAs, and a readership of 50. Reflecting ATRN growth that now represents 9 academic centers including NCATS- and IDeA-funded hubs, affiliated universities and partnering organizations, readership has grown to include 500 subscribers from across the U.S. and 3 other countries. With the establishment of the official ATRN website in 2019, the ATRN Newsletter became a prominent addition, providing ATRN members’ access to both new and archived editions, thereby expanding reach and further strengthening critical communication across the Network. DISCUSSION/SIGNIFICANCE: Providing a vehicle for communication that supports ATRN collaborations and networking, the Newsletter is foundational to the success of the ATRN mission to improve health outcomes across Appalachia by fostering collaborative inter-institutional and community-academic research partnerships.

Landscape Analysis of Neurodevelopmental Comorbidities in Newborn Screening Conditions: Challenges and Opportunities.

Newborn screening (NBS) is a large-scale public health program in the US that screens 3.8 million newborns for up to 81 genetic conditions each year. Many of these conditions have comorbidities, including neurodevelopmental disorders (NDDs). These comorbidities can have a significant impact on health outcomes across the lifespan. Most screened conditions are inborn errors of metabolism. PKU, the first condition identified by NBS, is an inherited metabolic disorder that can cause developmental delays and intellectual/developmental disabilities if not treated. The Newborn Screening Translational Research Network (NBSTRN) is a program that has been funded by the National Institute of Child Health and Human Development since 2008. NBSTRN is charged with developing, maintaining, and enhancing tools, resources, and expertise supporting NBS research. One of the tasks led by NBSTRN is to provide direction for developing question/answer sets used in the Longitudinal Pediatric Data Resource (LPDR) to create consensus-based and standardized common data elements (CDEs) for NBS conditions. There is growing interest in the NBS community in assessing neurodevelopmental trajectories through long-term follow-up studies. This could be streamlined by employing uniform CDEs. To address this unmet need, we conducted a landscape analysis to (1) explore the co-occurrence of NDD-related comorbidities and NBS conditions using text mining in MedGen, (2) compile a list of NDD-related CDEs from existing repositories as well as LPDR data dictionaries, and (3) identify challenges and knowledge gaps hindering the early identification of risks for NDDs in NBS conditions. Our findings can inform future efforts toward advancing the research infrastructure for this established public health program. The renewed awareness of the risk of NDDs after a positive NBS and diagnosis could lead to improved treatment guidelines for mental health conditions.

Evaluating governance in a clinical and translational research organization.

Institutional Development Awards for Clinical and Translational Research (IDeA-CTR) networks, funded by NIH/NIGMS, aim to advance CTR infrastructure to address historically unmet state and regional health needs. Success depends on the response to actionable feedback to IDeA-CTR leadership from network partners and governance groups through annual surveys, interviews, and governance body recommendations. The Great Plains IDeA-CTR applied internal formative meta-evaluation to evaluate dispositions of 172 governance recommendations from 2017 to 2021. Results provided insights to improve the classification and quality of recommendations, credibility of evaluation processes, responsiveness to recommendations, and communications and governance in a complex CTR network comprising multiple coalitions.

NBSTRN Tools to Advance Newborn Screening Research and Support Newborn Screening Stakeholders.

Rapid advances in the screening, diagnosis, and treatment of genetic disorders have increased the number of conditions that can be detected through universal newborn screening (NBS). However, the addition of conditions to the Recommended Uniform Screening Panel (RUSP) and the implementation of nationwide screening has been a slow process taking several years to accomplish for individual conditions. Here, we describe web-based tools and resources developed and implemented by the newborn screening translational research network (NBSTRN) to advance newborn screening research and support NBS stakeholders worldwide. The NBSTRN's tools include the Longitudinal Pediatric Data Resource (LPDR), the NBS Condition Resource (NBS-CR), the NBS Virtual Repository (NBS-VR), and the Ethical, Legal, and Social Issues (ELSI) Advantage. Research programs, including the Inborn Errors of Metabolism Information System (IBEM-IS), BabySeq, EarlyCheck, and Family Narratives Use Cases, have utilized NBSTRN's tools and, in turn, contributed research data to further expand and refine these resources. Additionally, we discuss ongoing tool development to facilitate the expansion of genetic disease screening in increasingly diverse populations. In conclusion, NBSTRN's tools and resources provide a trusted platform to enable NBS stakeholders to advance NBS research and improve clinical care for patients and their families.

RadioTransNet, Radiotherapy Translational and Preclinical Research Network: Results from the dedicated French cancer institute (INCa) call for projects

PurposeThe RadioTransNet project is a French initiative structuring preclinical and translational research in radiation therapy for cancer at national level. The network's activities are organized around four chosen priorities, which are: target definition, normal tissue, combined treatments and dose modelling. The subtargets linked to these four major priorities are unlimited. They include all aspects associated with fundamental radiobiology, preclinical studies, imaging, medical physics research and transversal components clearly related to these scientific areas, such as medical oncology, radio-diagnostics, nuclear medicine and cost-effectiveness considerations. MethodDuring its first phase of activity, four workshops following the consensus conference model and based on scientific and medical state of the art in radiotherapy and radiobiology were organized on the four above-mentioned objectives to identify key points. Then a road map has been defined and served as the basis for the opening in 2022 of a dedicated call, SEQ-RTH22, proposed by the French cancer national institute (INCa). ResultsFour research projects submitted by RadioTransNet partners have been selected to be supported by INCa: the first by Professor Anne Laprie from Oncopole Claudius-Regaud and Inserm ToNic in Toulouse on neurocognition and health after pediatric irradiation, the second submitted by Fabien Milliat from IRSN aims to study decryption and targeting of endothelial cell–immune cells interactions to limit radiation-induced intestinal toxicity, the third project, submitted by Yolanda Prezado from institut Curie–CNRS on proton minibeam radiotherapy as a new approach to reduce toxicity, and the latest project proposed by R. de Crevoisier from centre Eugène-Marquis in Rennes on predictive multiscale models of head and neck radiotoxicity induced for optimized personalized radiation therapy. Topics of each of these projects are presented here. ConclusionRadioTransNet project has been launched in 2018, supported by INCa, in order to structure and promote preclinical research in oncology radiotherapy and to favor collaboration between the actors of this research. INCa relied on RadioTransNet initiatives and activities, resulting in the opening of dedicated call for projects. Beyond its first main goals, RadioTransNet network is able to help to fund the human and technical resources necessary to conduct optimal translational and preclinical research in radiation oncology.

Information sharing in differences of sex development: The creation of a caregiver-support tool.

Social support can be a protective factor against the negative mental health outcomes experienced by some parents and caregivers of children with differences of sex development (DSD). However, established social support networks can be difficult to access due to caregiver hesitancy to share information with others about their child's diagnosis. Health care providers in the field of DSD, and particularly behavioral health providers, are well positioned to help caregivers share information with the important people in their lives in order to access needed social support. This article summarizes the development of a clinical tool to help clinicians facilitate discussions regarding information sharing with caregivers of children with DSD. Members of the psychosocial workgroup for the DSD -Translational Research Network completed a survey about their experiences facilitating information sharing discussions with caregivers of children with DSD and other health populations. The results of this survey were used to develop a clinical tool using ongoing iterative feedback from workgroup members, based on principles of user-centered design and quality improvement. Workgroup members consider information sharing an important aspect of working with caregivers of children with DSD. Additional resources and tools were identified as potentially helpful to these discussions. The DSD Sharing Health Information Powerfully-Team Version (SHIP-T) is a resource tool for DSD health care team members to utilize in hospital and ambulatory settings to help caregivers of children with DSD share information with their social support networks. The final SHIP-T is included in this article. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Design and implementation of the participatory German network for translational dementia care research (TaNDem) - A Qualitative Study on the Perspectives of Stakeholders and Healthcare Providers in Dementia Care Research.

Currently, there is a lack of sustainable, translational structures in dementia care research that enable a nationally guided participatory interaction between research, care practice, and those affected by dementia. A close cooperation between research and care practice with a simultaneous inclusion of those affected by dementia is essential to translate scientific evidence into practice and address routine care needs in healthcare research. Within the project TaNDem we aim to close the gap between research and practice by establishing a translational dementia care research network with participatory elements. We interviewed healthcare providers to identify their expectations for the design and implementation of this network. We interviewed n = 87 stakeholders in healthcare practice and healthcare research within focus group interviews. We followed a structured interview guide including, questions about (i) the main objectives and areas of such network, (ii) the preferred way of coordination, collaboration, and interaction, (iii) and barriers and facilitators of implementation. The recorded interviews were transcribed and analyzed using qualitative content analysis according to Mayring. Interviewees expressed the desire for an understandable translation of research results for practitioners, for a strengthening of networking, and for interaction between research and practice. Stakeholders would like to see evaluations of healthcare situations in specific geographic regions and the involvement of people affected by dementia in research. Furthermore, they preferred better communication between researchers and practitioners, support in identifying suitable cooperation partners, and a unified approach towards health policy. According to collaboration, regional and national meetings as well as communication channels could be implemented via online platforms, databases, or local advisory hubs. Obstacles mentioned include limitations in terms of staff, budget and time of stakeholders, as well as regional differences and duplicate structures. To successfully implement the TaNDem network, there should be local contact persons. Furthermore, the cooperation should be based on trust and jointly defined objectives that add value to the individual's work of each member of the research network. The results show that stakeholders in healthcare practice and healthcare research have similar expectations related to a participatory collaboration that provides an added value to all participants.

Circulating cell-free endometrial DNA level is unaltered during menstruation and in endometriosis.

Is circulating cell-free DNA (cirDNA) from the endometrium elevated during menstruation and in endometriosis? Endometrial cirDNA does not increase during menstruation and is not elevated in endometriosis. Changes in cirDNA associated with common benign conditions are a potential source of false positives in cancer diagnostic applications, but also present an opportunity for biomarker development for diseases such as endometriosis. Elevated cirDNA has been reported in endometriosis patients compared to healthy community controls, but no difference in total or endometrial cirDNA has been found between patients with endometriosis and patients with other gynaecological conditions. Likewise, menstruation is a potential driver of changes in cirDNA levels and tissue profile, but total and endothelial cirDNA do not increase during menstruation. For endometriosis comparisons, 59 participants with surgically confirmed endometriosis and 27 laparoscopic patients without endometriosis (hospital controls) were prospectively recruited, while 25 healthy community participants (healthy controls) were recruited in a university setting. Total and endometrial cirDNA and cirDNA fragmentation were measured across the three groups. For menstrual comparisons, 36 matched non-menstruating and menstruating samples were collected from healthy women recruited within a university setting, and the endometrial cirDNA was compared between the two groups. cirDNA was extracted from venous blood plasma then quantitated by quantitative PCR of ALU repetitive element (115 bp) and TP53 gene sequence (105 bp) for total concentration. cirDNA derived from the endometrium was quantitated by methylation-specific droplet digital PCR of a FAM101A region (69 bp) after bisulfite conversion of the DNA. A cirDNA size fragmentation ratio was obtained by quantifying a long segment of ALU repetitive element (247 bp) and expressing the amount relative to the 115 bp ALU target. No differences in cirDNA level were found in any comparison populations in this study. Mean total cirDNA was unchanged between healthy controls (ALU-115-3.31 ng/ml; TP53-2.73 ng/ml), hospital controls (ALU-115-3.47 ng/ml; TP53-2.83 ng/ml) and endometriosis patients (ALU-115-3.35 ng/ml; TP53-2.66 ng/ml). Likewise, endometrial cirDNA was unchanged between healthy controls (18.3 copies/ml), hospital controls (20.6 copies/ml) and endometriosis patients (22 copies/ml). Endometrial cirDNA did not change during menstruation (non-menstruating: 38 copies/ml; menstruating: 33 copies/ml). Irrespective of endometriosis diagnosis, blood from patients undergoing laparoscopy (hospital controls: 0.77; endometriosis patients: 0.79), had a significantly higher cirDNA size ratio than community-recruited healthy controls (0.64), indicating increased abundance of long cirDNA fragments. It was not possible to completely match the age, BMI and parity between the three cohorts investigated, however of these, only age has been shown to influence circulating DNA levels and not within the age range of our cohort. Blood from community-recruited healthy women and women undergoing laparoscopy was collected via antecubital vein venepuncture (processed within 3 h) and with either peripheral cannula or venepuncture (processed within 6 h), respectively, which could potentially impact the size distribution of circulating DNA fragments. For the collection of non-menstruating phase blood samples, we did not differentiate between follicular phase, ovulation and luteal phase. Thus, only the mensturating samples were collected at a consistent phase, and any fluctuations in cirDNA that occur at the other phases may have obscured small changes during menstruation. There is no evidence that cirDNA has potential as a diagnostic biomarker for endometriosis. Endometriosis, representing a common benign gynaecological condition, and menstruation, representing a normal physiological occurrence in women, should not affect methylation-based diagnostics in other disease areas, including oncology. N.L.Y.: Australian Government Research Training Program (RTP) Stipend through The University of New South Wales, Translational Cancer Research Network PhD Scholarship Top-Up Award via the Cancer Institute NSW, Beth Yarrow Memorial Award in Medical Science, UNSW Completion Scholarship; C.E.H.: Gynaecological Oncology Fund of the Royal Hospital for Women; K.W.: Ovarian Cancer Research Foundation and CAMILLA AND MARC. C.E.F.: UNSW Women's Wellbeing Academy and the Australian Human Rights Institute. We declare the following competing interest: K.W. holds stock in Guardant Health, Exact Sciences and Epigenomics AG. No other authors have competing interests. N/A.

Newborn Screening for Duchenne Muscular Dystrophy: First Year Results of a Population-Based Pilot.

Advancements in therapies for Duchenne muscular dystrophy (DMD) have made diagnosis within the newborn period a high priority. We undertook a consortia approach to advance DMD newborn screening in the United States. This manuscript describes the formation of the Duchenne Newborn Screening Consortium, the development of the pilot protocols, data collection tools including parent surveys, and findings from the first year of a two-year pilot. The DMD pilot design is population-based recruitment of infants born in New York State. Data tools were developed to document the analytical and clinical validity of DMD NBS, capture parental attitudes, and collect longitudinal health information for diagnosed newborns. Data visualizations were updated monthly to inform the consortium on enrollment. After 12 months, 15,754 newborns were screened for DMD by the New York State Newborn Screening (NYS NBS) Program. One hundred and forty screened infants had borderline screening results, and sixteen infants were referred for molecular testing. Three male infants were diagnosed with dystrophinopathy. Data from the first year of a two-year NBS pilot for DMD demonstrate the feasibility of NBS for DMD. The consortia approach was found to be a useful model, and the Newborn Screening Translational Research Network’s data tools played a key role in describing the NBS pilot findings and engaging stakeholders.

Population-Based Screening of Newborns: Findings From the NBS Expansion Study (Part One).

Each year, through population-based newborn screening (NBS), 1 in 294 newborns is identified with a condition leading to early treatment and, in some cases, life-saving interventions. Rapid advancements in genomic technologies to screen, diagnose, and treat newborns promise to significantly expand the number of diseases and individuals impacted by NBS. However, expansion of NBS occurs slowly in the United States (US) and almost always occurs condition by condition and state by state with the goal of screening for all conditions on a federally recommended uniform panel. The Newborn Screening Translational Research Network (NBSTRN) conducted the NBS Expansion Study to describe current practices, identify expansion challenges, outline areas for improvement in NBS, and suggest how models could be used to evaluate changes and improvements. The NBS Expansion Study included a workshop of experts, a survey of clinicians, an analysis of data from online repositories of state NBS programs, reports and publications of completed pilots, federal committee reports, and proceedings, and the development of models to address the study findings. This manuscript (Part One) reports on the design, execution, and results of the NBS Expansion Study. The Study found that the capacity to expand NBS is variable across the US and that nationwide adoption of a new condition averages 9.5 years. Four factors that delay and/or complicate NBS expansion were identified. A companion paper (Part Two) presents a use case for each of the four factors and highlights how modeling could address these challenges to NBS expansion.

Special issue: Newborn screening research.

This Special Issue provides a wide-ranging update from the front lines of newborn screening (NBS) research and is the result of conversations and collaborations facilitated by the Newborn Screening Translational Research Network (NBSTRN) across the NBS community and their extended networks. For 14 years NBSTRN has accelerated research efforts to advance NBS by creating a research infrastructure available to the NBS community to discover novel technologies to screen, diagnose, and treat newborns.Authors in this Special issues share their innovative and impactful efforts to advance NBS to include additional conditions, populations, genomics, and information sharing.

Multi-modal immune profiling of mucinous ovarian carcinoma: analysis from the Ovarian Tumor Tissue Analysis/Multidisciplinary Ovarian Cancer Outcomes Group consortia

Abstract Mucinous ovarian carcinoma (MOC) is a rare histotype of ovarian cancer. Women with advanced disease (FIGO stage III/IV) have very poor outcomes, with 5-year survival of <20%. Little is known about the anti-tumor immune response in MOC, limiting potential immunotherapeutic options for patients. Immune data from 3 platforms were analysed. A NanoString mRNA expression panel with 39 immune-related genes (n=60 MOC, n=4198 other ovarian histotypes), a NanoString mRNA plexset with PD-1, PD-L1 (n=241 MOC, n=115 upper and lower gastrointestinal (GI) cancers), and 2 multicolor immunofluorescence (mcIF) panels (n=121 MOC) for CD68, PD-L1, PD-1, CD8 and FOXP3. Data overlapped all platforms for 22 MOC. Immune marker expression by ovarian cancer histotype was measured. Uni- and multivariable Cox Proportional Hazards assessed overall survival (OS) within MOC. Hierarchical clustering looked for subgroups of patients based on co-expression of immune genes. Compared to more common high-grade serous ovarian cancer (HGSC) and GI cancers, MOC were less immunologically active. High IGHM expression was associated with poorer OS (HR 1.31 (95% CI 1.02–1.69), p=0.033). High tumor densities of FOXP3 and PD-1 positive cells conferred poorer OS in a model with age, stage and site; however, these and PD-L1 and CD68 were associated with grade. The 39 gene NanoString and mcIF datasets revealed 4 clusters, roughly translating to immune cold, moderate and hot (groups 3,4). mcIF analysis revealed a subset with PD-L1 expression in the absence of T-regulatory cell infiltrates. This study provides novel insights into the MOC immune landscape. Despite relatively low immune activity overall, immunotherapy could be explored for a subset of patients with MOC. Supported by NSW Ministry of Health and UNSW Sydney, through the NSW Health PhD Scholarship Program 2017-2022; Translational Cancer Research Network top-up scholarship 2021

Towards Equal Footing: Building community with rurality in mind

🎧 A conversation about communicating amongst scientists, clinicians, policy makers, and rural communities with the communications specialist of the Northern New England Clinical & Translational Research Network (1h 15m with transcript).

A Breakthrough in Understanding the Pathogenesis of Molar Hypomineralisation: The Mineralisation-Poisoning Model.

Popularly known as “chalky teeth”, molar hypomineralisation (MH) affects over 1-in-5 children worldwide, triggering massive amounts of suffering from toothache and rapid decay. MH stems from childhood illness and so offers a medical-prevention avenue for improving oral and paediatric health. With a cross-sector translational research and education network (The D3 Group; thed3group.org) now highlighting this global health opportunity, aetiological understanding is urgently needed to enable better awareness, management and eventual prevention of MH. Causation and pathogenesis of “chalky enamel spots” (i.e., demarcated opacities, the defining pathology of MH) remain unclear despite 100 years of investigation. However, recent biochemical studies provided a pathomechanistic breakthrough by explaining several hallmarks of chalky opacities for the first time. This article outlines these findings in context of previous understanding and provides a working model for future investigations. The proposed pathomechanism, termed “mineralisation poisoning”, involves localised exposure of immature enamel to serum albumin. Albumin binds to enamel-mineral crystals and blocks their growth, leading to chalky opacities with distinct borders. Being centred on extracellular fluid rather than enamel-forming cells as held by dogma, this localising pathomechanism invokes a new type of connection with childhood illness. These advances open a novel direction for research into pathogenesis and causation of MH, and offer prospects for better clinical management. Future research will require wide-ranging inputs that ideally should be coordinated through a worldwide translational network. We hope this breakthrough will ultimately lead to medical prevention of MH, prompting global health benefits including major reductions in childhood tooth decay.

Accelerating the Pace of Newborn Screening Research to Advance Disease Understanding and Improve Health Outcomes:: Key Efforts of the Newborn Screening Translational Research Network (NBSTRN).

Each year in the United States, neonatal screening leads to approximately 1 in 220 newborns being identified with a condition that requires treatment, and in some cases, life-saving interventions. Research that discovers new technologies to screen, diagnose, and treat diseases helps to expand the number of conditions that are candidates for nationwide screening. The National Institute of Child Health and Human Development (NICHD) Hunter Kelly Newborn Screening Research Program funds research to advance newborn screening (NBS). A key effort is the Newborn Screening Translational Research Network (NBSTRN). For fourteen years, the American College of Medical Genetics and Genomics (ACMG) has developed and coordinated the activities of the NBSTRN. This article provides an overview of the NBSTRN.

Genetic counselor roles in the undiagnosed diseases network research study: Clinical care, collaboration, and curation.

Genetic counselors (GCs) are increasingly filling important positions on research study teams, but there is limited literature describing the roles of GCs in these settings. GCs on the Undiagnosed Diseases Network (UDN) study team serve in a variety of roles across the research network and provide an opportunity to better understand genetic counselor roles in research. To quantitatively characterize the tasks regularly performed and professional fulfillment derived from these tasks, two surveys were administered to UDN GCs in a stepwise fashion. Responses from the first, free-response survey elicited the scope of tasks which informed development of a second structured, multiple-select survey. In survey 2, respondents were asked to select which roles they performed. Across 19 respondents, roles in survey 2 received a total of 947 selections averaging approximately 10 selections per role. When asked to indicate what roles they performed, respondent selected a mean of 50 roles (range 22-70). Survey 2 data were analyzed via thematic coding of responses and hierarchical cluster analysis to identify patterns in responses. From the thematic analysis, 20 non-overlapping codes emerged in seven categories: clinical interaction and care, communication, curation, leadership, participant management, research, and team management. Three themes emerged from the categories that represented the roles of GCs in the UDN: clinical care, collaboration, and curation. Cluster analyses showed that responses were more similar among individuals at the same institution than between institutions. This study highlights the ways GCs apply their unique skill set in the context of a clinical translational research network. Additionally, findings from this study reinforce the wide applicability of core skills that are part of genetic counseling training. Clinical literacy, genomics expertise and analysis, interpersonal, psychosocial and counseling skills, education, professional practice skills, and an understanding of research processes make genetic counselors well suited for such roles and poised to positively impact research experiences and outcomes for participants.