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Patients with epilepsy face heightened risk of post-ictal cardiorespiratory suppression and sudden unexpected death in epilepsy (SUDEP). Studies have shown that neuroinflammation, mediated by the activation of microglia and astrocytes, may be a cause or consequence of seizure disorders. Kcnj16 (Kir5.1) knockout rats (SS kcnj16-/- ) are susceptible to repeated audiogenic seizures and recapitulate features of human SUDEP, including post-ictal ventilatory suppression, which worsens with repeated seizures and seizure-induced mortality. In this study, we tested the hypothesis that repeated seizures cause neuroinflammation within key brainstem regions that contribute to the control of breathing. Audiogenic seizures were elicited once/day for up to 10 days in groups of adult male SS kcnj16-/- rats, from which frozen brainstem biopsies of the pre-Bötzinger complex/nucleus ambiguus (preBötC/NA), Bötzinger complex (BötC), and raphe magnus (RMg) regions were subjected to a cytokine array. Several cytokines/chemokines, including IL-1α and IL-1ß, were increased selectively in preBötC/NA after 3 or 5 days of seizures with fewer changes in other regions tested. In additional groups of male SS kcnj16-/- rats that underwent repeated seizures, we quantified microglial (IBA-1+) cell counts and morphology, specifically within the preBötC/NA region, and showed increased microglial cell counts, area, and volume consistent with microglial activation. To further test the role of inflammation in physiological responses to seizures and seizure-related mortality, additional groups of SS kcnj16-/- rats were treated with anakinra (IL-1R antagonist), ketoprofen (non-selective COX inhibitor), or saline for 3 days before and up to 10 days of seizures (1/day), and breathing was measured before, during, and after each seizure. Remarkably, IL-1R antagonism mitigated changes in post-ictal ventilatory suppression on days 7-10 but failed to prevent seizure-related mortality, whereas ketoprofen treatment exacerbated post-ictal ventilatory suppression compared to other treatment groups but prevented seizure-related mortality. These data demonstrate neuroinflammation and microglial activation within the key brainstem region of respiratory control following repeated seizures, which may functionally but differentially contribute to the pathophysiological consequences of repeated seizures.

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Collaborative quantitative scientists, including biostatisticians, epidemiologists, bio-informaticists, and data-related professionals, play vital roles in research, from study design to data analysis and dissemination. It is imperative that academic health care centers (AHCs) establish an environment that provides opportunities for the quantitative scientists who are hired as staff to develop and advance their careers. With the rapid growth of clinical and translational research, AHCs are charged with establishing organizational methods, training tools, best practices, and guidelines to accelerate and support hiring, training, and retaining this staff workforce. This paper describes three essential elements for building and maintaining a successful unit of collaborative staff quantitative scientists in academic health care centers: (1) organizational infrastructure and management, (2) recruitment, and (3) career development and retention. Specific strategies are provided as examples of how AHCs can excel in these areas.

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Background: eSource software that copies patient electronic health record data into a clinical trial electronic case report form holds promise for increasing data quality while reducing data collection, monitoring and source document verification costs. Integrating eSource into multicenter clinical trial start-up procedures could facilitate the use of eSource technologies in clinical trials. Methods: We conducted a qualitative integrative analysis to identify eSource site start-up key steps, challenges that might occur in executing those steps, and potential solutions to those challenges. We then conducted a value analysis to determine the challenges and solutions with the greatest impacts for eSource implementation teams. Results: There were 16 workshop participants: 10 pharmaceutical sponsor, 3 academic site, and 1 eSource vendor representatives. Participants identified 36 Site Start-Up Key Steps, 11 Site Start-Up Challenges, and 14 Site Start-Up Solutions for eSource-enabled studies. Participants also identified 77 potential impacts of the Challenges upon the Site Start-Up Key Steps and 70 ways in which the Solutions might impact Site Start-Up Challenges. The most important Challenges were: (1) not being able to identify a site eSource champion and (2) not agreeing on an eSource approach. The most important Solutions were: (1) vendors accepting electronic data in the FHIR standard, (2) creating standard content for eSource-related legal documents, and (3) creating a common eSource site readiness checklist. Conclusions: Site start-up for eSource-enabled multi-center clinical trials is a complex socio-technical problem. This study's Start-Up Solutions provide a basic infrastructure for scalable eSource implementation.

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De-identification of DICOM images is an essential component of medical image research. While many established methods exist for the safe removal of protected health information (PHI) in DICOM metadata, approaches for the removal of PHI "burned-in" to image pixel data are typically manual, and automated high-throughput approaches are not well validated. Emerging optical character recognition (OCR) models can potentially detect and remove PHI-bearing text from medical images but are very time-consuming to run on the high volume of images found in typical research studies. We present a data processing method that performs metadata de-identification for all images combined with a targeted approach to only apply OCR to images with a high likelihood of burned-in text. The method was validated on a dataset of 415,182 images across ten modalities representative of the de-identification requests submitted at our institution over a 20-year span. Of the 12,578 images in this dataset with burned-in text of any kind, only 10 passed undetected with the method. OCR was only required for 6050 images (1.5% of the dataset).

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Jobs for clinical research professionals (CRPs) have grown increasingly complex over the past 20+ years. This is due largely to additional administrative burden for investigators, study teams, sponsors, Clinical Research Organizations (CROs), and sites, particularly Academic Medical Centers (AMCs). Furthermore, National Institutes of Health (NIH) has reduced capacity to effectively fund research recognizing this is dependent on the overall congressional budget, which creates greater pressure for clinician scientists to secure external support. It is widely known clinical research will continue to become increasingly more complex for clinician scientists. This manuscript explores adoption of a clinical research competency-based job classification framework from the Joint Task Force for Clinical Trial Competency (JTFCTC) across several AMCs and the role of Human Resources (HR) in facilitating this process. This collaboration focuses on fostering successful projects tied to the business case in order to address equity and improve support for the clinical research enterprise.

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In 2016, Duke reconfigured its clinical research job descriptions and workforce to be competency-based, modeled around the Joint Taskforce for Clinical Trial Competency framework. To ensure consistency in job classification amongst new hires in the clinical research workforce, Duke subsequently implemented a Title Picker tool. The tool compares the research unit's description of job responsibility needs against those standardized job descriptions used to map incumbents in 2016. Duke worked with human resources and evaluated the impact on their process as well as on the broader community of staff who hire clinical research professionals. Implementation of the tool has enabled Duke to create consistent job classifications for its workforce and better understand who composes the clinical research professional workforce. This tool has provided valuable workforce metrics, such as attrition, hiring, etc., and strengthened our collaboration with Human Resources.

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Patients with uncontrolled epilepsy experience repeated seizures putting them at increased risk for sudden unexpected death in epilepsy (SUDEP). Data from human patients have led to the hypothesis that SUDEP results from severe cardiorespiratory suppression after a seizure, which may involve pathological deficiencies in the brainstem serotonin (5-HT) system. Rats with a genomic Kcnj16 mutation (SSKcnj16-/- rats) are susceptible to sound-induced generalized tonic-clonic seizures (GTCS) which, when repeated once daily for up to 10 days (10-day seizure protocol), increased mortality, particularly in male rats. Here, we test the hypothesis that repeated seizures across the 10-day protocol will cause a progressive ventilatory dysfunction due to time-dependent 5-HT deficiency. Initial severe seizures led to ictal and postictal apneas and transient decreases in breathing frequency, ventilatory drive, breath-to-breath variability, and brief hypoventilation. These seizure-induced effects on ventilation were exacerbated with increasing seizures and ventilatory chemoreflexes became further impaired after repeated seizures. Tissue analyses of key brainstem regions controlling breathing showed time-dependent 5-HT system suppression and increased immunoreactivity for IBA-1 (microglial marker) without changes in overall cell counts at 3, 7, and 10 days of seizures. Fluoxetine treatment in SSKcnj16-/- rats prevented repeated seizure-induced progressive respiratory suppression but failed to prevent seizure-related mortality. We conclude that repeated seizures cause a progressive compromise of ventilatory control in the immediate postictal period largely mediated by serotonin system suppression in brainstem regions of respiratory control. However, other unknown factors contribute to overall survival following repeated seizures in this model.NEW & NOTEWORTHY This study demonstrated that repeated seizures in a novel rat model (SSKcnj16-/- rats) caused a progressively greater ventilatory dysfunction in the immediate postictal period associated with brainstem serotonin (5-HT) suppression. Augmenting brain 5-HT with a selective serotonin reuptake inhibitor prevented the progressive ventilatory dysfunction induced by repeated seizures but failed to prevent seizure-related mortality, suggesting that repeated seizures may lead to cardiorespiratory suppression and failure through multiple mechanisms.

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Quality clinical research is essential for health care progress and is the mission of academic health centers. Yet ensuring quality depends on an institution's ability to measure, control, and respond to metrics of trial performance. Uninformed clinical research provides little benefit to health care, drains institutional resources, and may waste participants' time and commitment. Opportunities for ensuring high-quality research are multifactorial, including training, evaluation, and retention of research workforces; operational efficiencies; and standardizing policies and procedures. Duke University School of Medicine has committed to improving the quality and informativeness of our clinical research enterprise through investments in infrastructure with significant focus on optimizing research management system integration as a foundational element for quality management. To address prior technology limitations, Duke has optimized Advarra's OnCore for this purpose by seamlessly integrating with the IRB system, electronic health record, and general ledger. Our goal was to create a standardized clinical research experience to manage research from inception to closeout. Key drivers of implementation include transparency of research process data and generating metrics aligned with institutional goals. Since implementation, Duke has leveraged OnCore data to measure, track, and report metrics resulting in improvements in clinical research conduct and quality.

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The clinical and translational research enterprise is recognized by many as the "evidence generation system." While there have been several calls to revolutionize this enterprise to more effectively deliver the fruits of biomedical science to patients and society, significant issues across the clinical research workforce are pervasive. Perhaps the most visible sign is the widening gap between supply and demand for competent staff. Underpinning this, is a perfect storm of complex issues. Now reaching crisis point, this problem is far bigger than a staffing issue and ultimately jeopardizes the "engine" of drug and device development. With the current perilous state of the workforce, proposed enterprise fixes are likely to languish far out of reach, given that even "business as usual" is under threat. In fact, a glaring disconnect is evident between the visionary discourse on how to revolutionize the clinical research enterprise and the sober recognition that operationalization of any such vision rests on the shoulders of a workforce that's in dire straits. In this article, we provide a brief forensic analysis of the workforce problem and an initial indication of where solutions may lie.

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Over the past 7 years, Duke has implemented competency-based job classifications for clinical research professionals (CRPs) with a defined pathway for career advancement. The workforce is defined specifically as the collection of staff employed across the clinical research enterprise to operationalize clinical research and human participatory protocols through the hands-on conduct of protocol activities including participant enrollment, regulatory coordination, study documentation, data collection and management, and sponsor engagement. The competency framework for this critical workforce laid the foundation for a centrally developed on-demand onboarding program at Duke. The self-paced program is designed to engage learners through competency-based learning modules, guided mentor/manager discussions, and applied learning activities. Consisting of an initial E-Learning orientation to clinical research at Duke, called Express Start, followed by a 90-day role-based Onboarding Learning Plan, our onboarding program includes training in foundational pre-defined core competency areas and customizable learning paths. Associated Engagement Activity Packets for many clinical research competencies encourage mentor and/or manager involvement and hands-on learning for the employee through suggested enrichment activities. The program has been widely adopted for CRPs within the Duke University Schools of Medicine and Nursing, and newly hired CRPs and their managers have expressed satisfaction with these centrally offered tools. In this paper, we describe the methods used to develop and implement our competency-based onboarding program. We will share an evaluation of the program and planned next steps for expanding the suite of onboarding resources.

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Background: Adequate equitable recruitment of underrepresented groups in clinical research and trials is a national problem and remains a daunting challenge to translating research discoveries into effective healthcare practices. Engagement, recruitment, and retention (ER&R) training programs for Clinical Research Professionals (CRPs) often focus on policies and regulations. Although some training on the importance of diversity and inclusion in clinical research participation has recently been developed, there remains a need for training that couples critical equity, diversity, and inclusion (EDI) concepts with skill development in effective recruitment and retention strategies, regulations, and best practices. Approach and methods: We developed the ER&R Certificate program as a holistic approach to provide Duke University CRPs the opportunity to build competency in gap areas and to increase comfort in championing equitable partnerships with clinical research participants. The thirteen core and elective courses include blended learning elements, such as e-learning and wiki journaling prompts, to facilitate meaningful discussions. Pre- and post-assessments administered to CRP program participants and their managers assessed program impact on CRP skills in ER&R tasks and comfort in equitable, diverse, and inclusive engagement of clinical research participants. Results and discussion: Results from the first two cohorts indicate that CRPs perceived growth in their own comfort with program learning objectives, especially those centered on participant partnership and EDI principles, and most managers witnessed growth in competence and responsibility for ER&R-related tasks. Results suggest value in offering CRPs robust training programs that integrate EDI and ER&R training.

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Background: Identification of evidence-based factors related to status of the clinical research professional (CRP) workforce at academic medical centers (AMCs) will provide context for National Center for Advancing Translational Science (NCATS) policy considerations and guidance. The objective of this study is to explore barriers and opportunities related to the recruitment and retention of the CRP workforce. Materials and Methods: Qualitative data from a series of Un-Meeting breakout sessions and open-text survey questions were analyzed to explore barriers and recommendations for improving AMC CRP recruitment, retention and diversity. Results: While certain institutions have established competency-based frameworks for job descriptions, standardization remains generally lacking across CTSAs. AMCs report substantial increases in unfilled CRP positions leading to operational instability. Data confirmed an urgent need for closing gaps in CRP workforce at AMCs, especially for attracting, training, retaining, and diversifying qualified personnel. Improved collaboration with human resource departments, engagement with principal investigators, and overcoming both organizational and resource challenges were suggested strategies, as well as development of outreach to universities, community colleges, and high schools raising awareness of CRP career pathways. Discussion: Based on input from 130 CRP leaders at 35 CTSAs, four National Institute of General Medical Sciences' Institutional Development Award (IDeA) program sites, along with industry and government representatives, we identified several barriers to successful recruitment and retention of a highly trained and diverse CRP workforce. Results, including securing institutional support, champions, standardizing and adopting proven national models, improving local institutional policies to facilitate CRP hiring and job progression point to potential solutions.

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BACKGROUND: Opioid-induced respiratory depression can be partially antagonized in the preBötzinger Complex and Parabrachial Nucleus/Kölliker-Fuse Complex. We hypothesized that additional opioid antagonism in the caudal medullary raphe completely reverses the opioid effect. METHODS: In adult ventilated, vagotomized, decerebrate rabbits, we administrated remifentanil intravenously at "analgesic", "apneic", and "very high" doses and determined the reversal with sequential naloxone microinjections into the bilateral Parabrachial Nucleus/Kölliker-Fuse Complex, preBötzinger Complex, and caudal medullary raphe. In separate animals, we injected opioid antagonists into the raphe without intravenous remifentanil. RESULTS: Sequential naloxone microinjections completely reversed respiratory rate depression from "analgesic" and "apneic" remifentanil, but not "very high" remifentanil concentrations. Antagonist injection into the caudal medullary raphe without remifentanil independently increased respiratory rate. CONCLUSIONS: Opioid-induced respiratory depression results from a combined effect on the respiratory rhythm generator and respiratory drive. The effect in the caudal medullary raphe is complex as we also observed local antagonism of endogenous opioid receptor activation, which has not been described before.

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Case studies are an effective active learning method that increases student engagement and are readily adaptable from in-person to online learning environments. In this perspective, Neuroscience Case Network fellows (NeuroCaseNet; NSF-RCN-UBE Grant #1624104) provide specific examples of how case studies were successfully adapted for synchronous and asynchronous online learning, including general strategies and best practices for adapting case studies into both online learning environments.

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Case studies and student-led learning activities are both effective active learning methods for increasing student engagement, promoting student learning, and improving student performance. Here, we describe combining these instructional methods to use student-created case studies as assessment for an online neurovirology module in a neuroanatomy and physiology course. First, students learned about neurovirology in a flipped classroom format using free, open-access virology resources. Then, students used iterative writing practices to write an interrupted case study incorporating a patient narrative and primary literature data on the neurovirulent virus of their choice, which was graded as a writing assessment. Finally, students exchanged case studies with their peers, and both taught and completed the case studies as low-stakes assessment. Student performance and evaluations support the efficacy of case studies as assessment, where iterative writing improved student performance, and students reported increased knowledge and confidence in the corresponding learning objectives. Overall, we believe that using student-created case studies as assessment is a valuable, student-led extension of effective case study pedagogy, and has wide applicability to a variety of undergraduate courses.

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A fictitious patient, Miguel, has been diagnosed with drug-resistant epilepsy and is awaiting neurosurgery. While in the hospital, Miguel agrees to participate in a research study in which depth electrodes are used to record neuronal activity in response to a range of stimuli. Interestingly, a neuron is identified that seems to respond selectively to video clips of the animated satirical TV show The Simpsons. Students are challenged to make observations, formulate and revise hypotheses, and interpret data, excerpted from an authentic dataset derived from actual patients in a 2008 Science paper. Students then consider implications for these data, evaluate their ability to generalize to non-human (rodent) models, and speculate about future directions for this research. Adaptations of this case have been implemented in introductory and advanced neuroscience courses. Students responded positively to the case, and reported gains in science competence and identity, particularly in the introductory courses. Suggestions for implementation and adaptation of this experience are offered. While this case has been implemented in undergraduate neuroscience courses, it might also be used in physiology, psychology, biology, research methods, or clinical courses.

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Behaviorally inhibited (BI) temperament is marked by heightened behavioral sensitivity to environmental threats. The degree to which threat sensitivity is reflected in cardiorespiratory responses has been relatively unexplored. Female college students were exposed to modest hypercapnia (7.0% CO2) or ambient air (AA) while engaging in a computerized task with cued reinforcement features. All physiological variables except for blood pressure were processed in 4 min epochs corresponding to pre-exposure, exposure, and post-exposure. Primary respiratory measures were respiratory frequency (fb), tidal volume (VT), and minute ventilation (VE). Electrocardiograms (ECGs) were processed using ARTiiFACT software with resultant heart rate variability (HRV) measures in the frequency domain and time domain. Consistent with the literature, modest hypercapnia increased VT, Fb, and VE. No differences in respiratory parameters were detected between BI and non-behaviorally inhibited individuals (NI). For HRV in the time domain, RMSSD and NN50 values increased during CO2 inhalation which then returned to pre-exposure levels after CO2 cessation. Hypercapnia increased high frequency (HF) power which then recovered. BI exhibited reduced low frequency (LF) power during the pre-exposure period. For NI, LF power reduced over the subsequent phases ameliorating differences between BI and NI. Hypercapnia improved the task performance of BI. This is the largest study of female reactivity to hypercapnia and associated HRV to date. In general, hypercapnia increased time domain HRV and HF power, suggesting a strong vagal influence. Those expressing BI exhibited similar respiratory and HRV reactivity to NI despite inherently reduced LF power. Although 7% CO2 represents a mild challenge to the respiratory and cardiovascular systems, it is nonetheless sufficient to explore inherent difference in stress reactivity in those vulnerable to develop anxiety disorders.

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INTRODUCTION: A new competency-based job framework was implemented for clinical research professionals at a large, clinical research-intensive academic medical center. This study evaluates the rates of turnover before and after implementation of the new framework. Turnover in this workforce (as with most) is costly; it contributes to wasted dollars and lost productivity since these are highly specialized positions requiring extensive training, regardless of experience in the field. METHODS: Trends in employee turnover for 3 years prior to and after the implementation of competency-based job framework for clinical research positions were studied using human resources data. Employee demographics, turnover rates, and comparisons to national statistics are summarized. RESULTS: Employee turnover within the clinical research professional jobs has decreased from 23% to 16%, a 45% reduction, since the implementation of competency-based job framework. CONCLUSION: The new jobs and career ladders, both of which are centered on a competency-based framework, have decreased the overall turnover rate in this employee population. Since little is known about the rates of turnover in clinical research, especially in the academic medical setting, the results of this analysis can provide important insights to other academic medical centers on both employee turnover rate in general and the potential impact of implementing large-scale competency-based job changes.

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INTRODUCTION: Scientific quality and feasibility are part of ethics review by Institutional Review Boards (IRBs). Scientific Review Committees (SRCs) were proposed to facilitate this assessment by the Clinical and Translational Science Award (CTSA) SRC Consensus Group. This study assessed SRC feasibility and impact at CTSA-affiliated academic health centers (AHCs). METHODS: SRC implementation at 10 AHCs was assessed pre/post-intervention using quantitative and qualitative methods. Pre-intervention, four AHCs had no SRC, and six had at least one SRC needing modifications to better align with Consensus Group recommendations. RESULTS: Facilitators of successful SRC implementation included broad-based communication, an external motivator, senior-level support, and committed SRC reviewers. Barriers included limited resources and staffing, variable local mandates, limited SRC authority, lack of anticipated benefit, and operational challenges. Research protocol quality did not differ significantly between study periods, but respondents suggested positive effects. During intervention, median total review duration did not lengthen for the 40% of protocols approved within 3 weeks. For the 60% under review after 3 weeks, review was lengthened primarily due to longer IRB review for SRC-reviewed protocols. Site interviews recommended designing locally effective SRC processes, building buy-in by communication or by mandate, allowing time for planning and sharing best practices, and connecting SRC and IRB procedures. CONCLUSIONS: The CTSA SRC Consensus Group recommendations appear feasible. Although not conclusive in this relatively short initial implementation, sites perceived positive impact by SRCs on study quality. Optimal benefit will require local or federal mandate for implementation, adapting processes to local contexts, and employing SRC stipulations.