Emerging technologies and their impact on regulatory science.

There is an evolution and increasing need for the utilization of emerging cellular, molecular and in silico technologies and novel approaches for safety assessment of food, drugs, and personal care products. Convergence of these emerging technologies is also enabling rapid advances and approaches that may impact regulatory decisions and approvals. Although the development of emerging technologies may allow rapid advances in regulatory decision making, there is concern that these new technologies have not been thoroughly evaluated to determine if they are ready for regulatory application, singularly or in combinations. The magnitude of these combined technical advances may outpace the ability to assess fit for purpose and to allow routine application of these new methods for regulatory purposes. There is a need to develop strategies to evaluate the new technologies to determine which ones are ready for regulatory use. The opportunity to apply these potentially faster, more accurate, and cost-effective approaches remains an important goal to facilitate their incorporation into regulatory use. However, without a clear strategy to evaluate emerging technologies rapidly and appropriately, the value of these efforts may go unrecognized or may take longer. It is important for the regulatory science field to keep up with the research in these technically advanced areas and to understand the science behind these new approaches. The regulatory field must understand the critical quality attributes of these novel approaches and learn from each other's experience so that workforces can be trained to prepare for emerging global regulatory challenges. Moreover, it is essential that the regulatory community must work with the technology developers to harness collective capabilities towards developing a strategy for evaluation of these new and novel assessment tools.

A community effort to identify and correct mislabeled samples in proteogenomic studies.

Sample mislabeling or misannotation has been a long-standing problem in scientific research, particularly prevalent in large-scale, multi-omic studies due to the complexity of multi-omic workflows. There exists an urgent need for implementing quality controls to automatically screen for and correct sample mislabels or misannotations in multi-omic studies. Here, we describe a crowdsourced precisionFDA NCI-CPTAC Multi-omics Enabled Sample Mislabeling Correction Challenge, which provides a framework for systematic benchmarking and evaluation of mislabel identification and correction methods for integrative proteogenomic studies. The challenge received a large number of submissions from domestic and international data scientists, with highly variable performance observed across the submitted methods. Post-challenge collaboration between the top-performing teams and the challenge organizers has created an open-source software, COSMO, with demonstrated high accuracy and robustness in mislabeling identification and correction in simulated and real multi-omic datasets.

Transcriptome Network Analysis Identifies CXCL13-CXCR5 Signaling Modules in the Prostate Tumor Immune Microenvironment.

The tumor immune microenvironment (TIME) consists of multiple cell types that contribute to the heterogeneity and complexity of prostate cancer (PCa). In this study, we sought to understand the gene-expression signature of patients with primary prostate tumors by investigating the co-expression profiles of patient samples and their corresponding clinical outcomes, in particular "disease-free months" and "disease reoccurrence". We tested the hypothesis that the CXCL13-CXCR5 axis is co-expressed with factors supporting TIME and PCa progression. Gene expression counts, with clinical attributes from PCa patients, were acquired from TCGA. Profiles of PCa patients were used to identify key drivers that influence or regulate CXCL13-CXCR5 signaling. Weighted gene co-expression network analysis (WGCNA) was applied to identify co-expression patterns among CXCL13-CXCR5, associated genes, and key genetic drivers within the CXCL13-CXCR5 signaling pathway. The processing of downloaded data files began with quality checks using NOISeq, followed by WGCNA. Our results confirmed the quality of the TCGA transcriptome data, identified 12 co-expression networks, and demonstrated that CXCL13, CXCR5 and associated genes are members of signaling networks (modules) associated with G protein coupled receptor (GPCR) responsiveness, invasion/migration, immune checkpoint, and innate immunity. We also identified top canonical pathways and upstream regulators associated with CXCL13-CXCR5 expression and function.

"I'm not what I used to be": A qualitative study exploring how young people experience being diagnosed with a chronic illness.

BACKGROUND: Childhood long-term conditions are usually diagnosed in infancy or early childhood. Little is known about the particular experiences and needs of young people who receive a chronic illness diagnosis during adolescence or late childhood. This paper will examine this experience in relation to multiple sclerosis (MS), which is increasingly being diagnosed before adulthood. AIMS: To explore how young people experience an MS diagnosis. METHODS: Qualitative study using a grounded theory approach. In-depth interviews were conducted with 21 young people diagnosed with MS. Participants were recruited through health service and voluntary sector organizations in the United Kingdom. RESULTS: Young people's pre-illness normality was disrupted by the diagnosis of a chronic illness (MS). Participants experienced their body as changed physically, cognitively, and emotionally and as changeable due to symptom unpredictability. This influenced how participants perceived and presented their identity, disrupted their relationships, and altered their future biography. Young people developed strategies to manage their condition and identities in order to incorporate MS into their current and future lives, which required continual illness and identity work in response to changing symptoms, social contexts, and relationships. CONCLUSIONS: Although young peoples' experience of living with chronic illness has been widely explored, the aftermath of diagnosis has been underresearched from their perspective. This study contributes to this knowledge gap by illuminating how young people experience a chronic illness diagnosis and negotiate the resulting changes to their identity, relationships, and future. The findings suggest that young people need preparation and support in disclosing their diagnosis to others. Professionals supporting young people with long-term conditions need to work closely with specialist mental health services to ensure that they receive appropriate emotional support. Schools have an important role in ensuring young people with long-term conditions achieve their academic potential and receive appropriate careers advice.

Parents' perceived obstacles to pediatric clinical trial participation: Findings from the clinical trials transformation initiative.

Enrollment of children into pediatric clinical trials remains challenging. More effective strategies to improve recruitment of children into trials are needed. This study used in-depth qualitative interviews with parents who were approached to enroll their children in a clinical trial in order to gain an understanding of the barriers to pediatric clinical trial participation. Twenty-four parents whose children had been offered the opportunity to participate in a clinical trial were interviewed: 19 whose children had participated in at least 1 clinical trial and 5 who had declined participation in any trial. Each study aspect, from the initial explanation of the study to the end of the study, can affect the willingness of parents to consent to the proposed study and future studies. Establishing trust, appropriate timing, a transparent discussion of risks and benefits oriented to the layperson, and providing motivation for children to participate were key factors that impacted parents' decisions. In order for clinical trial accrual to be successful, parents' priorities and considerations must be a central focus, beginning with initial trial design. The recommendations from the parents who participated in this study can be used to support budget allocations that ensure adequate training of study staff and improved staffing on nights and weekends. Studies of parent responses in outpatient settings and additional inpatient settings will provide valuable information on the consent process from the child's and parent's perspectives. Further studies are needed to explore whether implementation of such strategies will result in improved recruitment for pediatric clinical trials.

Living with uncertainty and hope: A qualitative study exploring parents' experiences of living with childhood multiple sclerosis.

Background There is growing recognition that multiple sclerosis is a possible, albeit uncommon, diagnosis in childhood. However, very little is known about the experiences of families living with childhood multiple sclerosis and this is the first study to explore this in depth. Objective Our objective was to explore the experiences of parents of children with multiple sclerosis. Methods Qualitative in-depth interviews with 31 parents using a grounded theory approach were conducted. Parents were sampled and recruited via health service and voluntary sector organisations in the United Kingdom. Results Parents' accounts of life with childhood multiple sclerosis were dominated by feelings of uncertainty associated with four sources; diagnostic uncertainty, daily uncertainty, interaction uncertainty and future uncertainty. Parents attempted to manage these uncertainties using specific strategies, which could in turn create further uncertainties about their child's illness. However, over time, ongoing uncertainty appeared to give parents hope for their child's future with multiple sclerosis. Conclusion Illness-related uncertainties appear to play a role in generating hope among parents of a child with multiple sclerosis. However, this may lead parents to avoid sources of information and support that threatens their fragile optimism. Professionals need to be sensitive to the role hope plays in supporting parental coping with childhood multiple sclerosis.

Families' and healthcare professionals' perceptions of healthcare services for children and young people with medically unexplained symptoms: a narrative review of the literature.

Children and young people frequently report physical complaints that have no observable physical pathology known as medically unexplained symptoms (MUS). Research suggests that MUS are associated with substantial physical and psychological impairments and may have a negative impact on children's and young people's functional status and well-being in the long term. Due to the potentially complex needs of this group, children and young people with MUS may require timely access to suitable health and social care services to effectively manage symptoms and achieve their academic, social and personal potential. Families and professionals can offer important insights into the availability and appropriateness of current community and specialist health and social care services. This review is the first critical evaluation and synthesis of research that has examined families' and healthcare professionals' (HCP) perceptions of healthcare services for children and young people with MUS. A systematic search of electronic databases and manual searches of key journals and reference lists identified 17 papers from 15 studies for inclusion in the review. The review highlights the paucity of rigorously conducted research on this topic. Studies have been narrowly focused on the views of a homogeneous group of mothers and young people attending single centres. There has been some attempt to examine doctors' views, but the perceptions of children, fathers and health and social care professionals are absent or under-represented, and multi-site and longitudinal studies are lacking. Thematic analysis of the results from the included studies suggests that knowledge, communication, health beliefs and healthcare settings are factors that influence families' and HCPs' perceptions of services. Families report dissatisfaction with some HCPs' approach to managing MUS. The findings suggest that children and young people with MUS are at risk of receiving suboptimal care and support because there is insufficient research to inform high-quality, evidence-based practice.

Paediatric multiple sclerosis: a qualitative study of families' diagnosis experiences.

OBJECTIVE: To examine children's and parents' experiences of obtaining a diagnosis of paediatric multiple sclerosis (MS) and identify potential facilitators and barriers to early diagnosis. DESIGN: Qualitative, semi-structured interviews conducted face-to-face in home settings with 31 parents and 21 children and adolescents (8-17 years old) with a clinical diagnosis of MS. Participants were recruited from 16 NHS Trusts and four MS voluntary organisations in the UK. Interviews were recorded and transcribed verbatim and analysed using the constant comparative method. RESULTS: Time to diagnosis ranged from 1 to 96 months (median 11.5, mean 23.3, SD 27.3). The findings suggest that delayed presentation to healthcare services, generalists' assumptions about the nature of reported symptoms, lack of awareness of paediatric MS and delayed referral to specialists in paediatric MS were barriers to early investigation and accurate diagnosis. Children, adolescents and parents felt that their concerns about the child's health were not always taken seriously during medical consultations and that clinicians could be reluctant to diagnose MS in childhood. This created additional uncertainty about the child's condition and long-term prognosis. CONCLUSIONS: Obtaining a diagnosis of paediatric MS can be a challenging and lengthy process with potentially adverse implications for the health of children/adolescents. Valuing families' knowledge and experience of their child's health, performing a thorough medical examination early in the disease course and organising prompt referrals may aid the early investigation and diagnosis of this disease. In view of the diagnostic challenges, children/adolescents with suspected MS would benefit from early referrals to specialists in paediatric MS.

Teachers' perspectives of supporting pupils with long-term health conditions in mainstream schools: a narrative review of the literature.

Teachers are supporting an increasing number of pupils with long-term health conditions in mainstream schools. The aim of this literature review was to critically appraise and synthesise research that has examined teachers' perceptions of the key barriers and facilitators to supporting pupils with long-term conditions, teachers' training needs and interventions that aim to improve teachers' knowledge of long-term conditions, and teachers' confidence in supporting children and young people. A narrative literature review was conducted using a systematic search of computerised databases and manual searches of key journals and reference lists to retrieve studies published between 2003 and 2013. Studies were critically appraised and key themes across studies identified. In total, 61 papers from 58 studies were included in the review. The findings suggest that teachers receive little formal training relevant to long-term condition management and are fearful of the risks involved in teaching children and young people with long-term conditions. Communication between families, school and health and social care services appears to be poor. Educational programmes developed in conjunction with and/or delivered by healthcare professionals seem to have the potential to increase teachers' knowledge and confidence. This review suggests that healthcare professionals have an important role to play in supporting teachers in identifying and meeting the needs of pupils with long-term conditions. It is vital that pupils with long-term conditions receive appropriate care and support in schools to ensure their safety and help them to integrate with their peers and achieve their academic potential. Limitations in the current evidence are highlighted and implications for future research are identified.

Essential Medication Information for Patients: Ensuring Access.

The US Food and Drug Administration (FDA) is developing a new framework to provide patients with quality, up-to-date prescription product information that will promote the safe use of prescribed medication. The goal of this new Patient Medication Information is to provide patient-oriented information for each prescription product. Described in this article are the efforts of the FDA to help ensure that patients receive essential prescription medication information.

Intra- and interreader reproducibility of magnetic resonance imaging for quantifying the lipid-rich necrotic core is improved with gadolinium contrast enhancement.

PURPOSE: To test the hypothesis that intra- and interreader reproducibility for measuring the lipid-rich necrotic core (LR-NC) size is significantly improved with gadolinium (Gd) contrast-enhanced magnetic resonance imaging (CEMRI) compared to non-CEMRI. MATERIALS AND METHODS: Thirty-seven individuals with >50% carotid artery stenosis underwent carotid MRI at 1.5T (pre- and postcontrast T1-weighted (T1W), T2-weighted (T2W), proton density-weighted (PDW), and three-dimensional time-of-flight (TOF) sequences). Two independent readers measured the mean area of the LR-NC from the precontrast images only, followed by a second measurement using the additional postcontrast images. One reader repeated the measurements after an interval of five months. Intra- and interreader reproducibility was analyzed by means of the intraclass correlation coefficient (ICC), coefficient of variation (CV), and standard deviation (SD). RESULTS: The CV decreased from 33.7% to 8.8% for intrareader measurements of the LR-NC, and from 33.5% to 17.6% for interreader measurements. The SD was significantly smaller with CEMRI than with non-CEMRI (P = 0.003 and P = 0.006, respectively). The ICC increased from 0.94 to 0.99 and from 0.85 to 0.93 for the intra- and interreader measurements, respectively. CONCLUSION: Reader reproducibility for in vivo MRI quantification of LR-NC size is significantly improved by the addition of Gd contrast in individuals with >50% carotid stenosis.

Vulnerable plaque detection by 3.0 tesla magnetic resonance imaging.

RATIONALE AND OBJECTIVES: A clinical case report is presented on a 76-year-old man who volunteered for a 3.0 T magnetic resonance (MR) carotid protocol. The subject was referred for carotid endarterectomy and histology was performed on the ex vivo specimen and compared with the in vivo images. METHODS: The 3.0 and 1.5 T (obtained for comparison) MR protocol consisted of 2-dimensional (2D) and 3-dimensional (3D) multicontrast bright and black blood imaging for detecting the lumen and vessel wall. RESULTS: The combination of multicontrast black blood transverse images and the 3D time of flight transverse images provided visualization of a narrowed internal carotid artery lumen 4 mm above of the bifurcation and the presence of a complex atherosclerotic plaque containing a large lipid pool, calcification, and intact fibrous cap. Quantitative comparisons including vessel lumen and plaque area, signal-to-noise (SNR) and contrast-to-noise (CNR) ratios were obtained for 1.5 and 3.0 T image data. Plaque composition was verified with histology. Macrophages were also detected in the shoulders of the plaque as demonstrated by CD68 staining and corresponded with a small hyperintense area in the T2W images at 3.0 T, but not observed in comparable 1.5 T images. CONCLUSIONS: High field 3.0 T multicontrast MRI of atherosclerotic plaque has been validated with histology comparison and provides improved detection of complex atherosclerotic plaque with increased SNR and CNR compared with 1.5 T. Further studies validating contrast mechanisms of plaque at 3.0 T are required, but atherosclerotic plaque imaging has clear benefit from application at the higher magnetic field strength.

Bright and black blood imaging of the carotid bifurcation at 3.0T.

PURPOSE: The aim of this study was to evaluate our preliminary experience at 3.0 T with imaging of the carotid bifurcation in healthy and atherosclerotic subjects. Application at 3.0 T is motivated by the signal-to-noise gain for improving spatial resolution and reducing signal averaging requirements. MATERIALS AND METHODS: We utilized a dual phased array coil and applied 2D, 3D time of flight (TOF) and turbo spin echo (TSE) sequences with comparison of two lumen signal suppression methods for black blood (BB) TSE imaging including double inversion preparation (DIR) and spatial presaturation pulses. The signal-to-noise ratios (SNR) of healthy carotid vessel walls were compared in 2D and 3D BB TSE acquisitions. The bright and black blood multi-contrast exam was demonstrated for a complex carotid plaque. RESULTS: Contrast-to-noise (CNR) greater than 150 was achieved between the lumen and suppressed background for 3D TOF. For BB, both methods provided sufficient lumen signal suppression but slight residual flow artifacts remained at the bifurcation level. As expected 3D TSE images had higher SNR compared to 2D, but increased motion sensitivity is a significant issue for 3D at high field. For multi-contrast imaging of atherosclerotic plaque, fibrous, calcified and lipid components were resolved. The CNR ratio of fibrous (bright on PDW, T2W) and calcified (dark in T1W, T2W, PDW) plaque components was maximal in the T2W images. The 3D TOF angiogram indicating a 40% stenosis was complemented by 3D multi-planar reformat of BB images that displayed plaque extent. Detection of intimal thickening, the earliest change associated with atherosclerotic progression was observed in BB PDW images at 3.0 T. CONCLUSIONS: High SNR and CNR images have been demonstrated for the healthy and diseased carotid. Improvements in RF coils along with pulse sequence optimization, and evaluation of endogenous and exogenous contrast mechanisms will further enhance carotid imaging at 3.0T.

Comparison of cardiac MRI on 1.5 and 3.0 Tesla clinical whole body systems.

RATIONALE AND OBJECTIVES: A cardiac imaging pilot study was performed on 1.5 and 3.0 Tesla (T) whole body magnetic resonance units equipped with identical gradient sets and geometrically equivalent body coils. The goals were to compare the signal-to-noise (SNR) and contrast-to-noise (CNR) ratios on matched studies conducted at both field strengths and demonstrate the potential for functional and morphologic cardiac evaluation at 3.0 T. METHODS: Short axis cine true fast imaging with steady precession (True FISP) was compared at 1.5 and 3.0 T using the body coil in transmit-receive mode and transmit-only with single loop and phased array receiver coils. SNR of the myocardium and CNR of the ventricular blood and myocardium were calculated from a quantitative region of interest analysis of these data. Additionally at 3.0 T, long axis and 4-chamber cine as well as "dark blood" imaging are demonstrated with sequence and parameter settings comparable to current state of the art for cardiac evaluation at 1.5 T. RESULTS: The 3.0 T data consistently demonstrates increases in SNR when all imaging conditions are closely matched but the increase has a large variability ranging from 20 to 85% depending on the radiofrequency coil configuration. Ventricular blood-myocardium CNR greater than 30 is obtained at 3.0 T, which is comparable to an optimized 1.5 T acquisition despite the specific absorption rate limitation of flip angle to nearly one half the value. The increased SNR at 3.0 T improves detection of fine anatomic detail, such as the chordae tendineae and mitral valve structure. CONCLUSIONS: Increased specific absorption rate can be a limiting fact; however, we have demonstrated that 3.0 T cardiac imaging shows gains in SNR while maintaining the CNR. The SNR gain is advantageous, and phased array coil technology is key for improving cardiac magnetic resonance imaging at 3.0 T.