Translational Research Center Research Articles

Editorial introductions

Editorial introductions

Peroxidasin Is a Novel Target of Autoantibodies in Lupus Nephritis

Peroxidasin Is a Novel Target of Autoantibodies in Lupus Nephritis

CpG Methylation Inhibits Prolidase Promoter Driven Transcription

Prolidase, a cytosolic exopeptidase, and a member of the matrix metalloproteinase (MMP) family, is encoded by the PEPD gene in humans. Since Prolidase is the only enzyme which can cleave dipeptides containing C‐terminal proline, or hydroxyproline, it plays an essential role in protein metabolism, collagen turnover, and matrix remodeling. Prolidase is essential in several physiological and pathological processes such as wound healing, inflammation, angiogenesis, cell proliferation, and carcinogenesis. Surprisingly, little is known about the molecular and cellular regulation of PEPD gene expression. In initial studies, we observed a dense CG‐rich portion around the transcription start site, suggesting a possible role of promoter methylation in the transcriptional regulation of PEPD gene. To study the transcriptional regulation of PEPD gene, we cloned and characterized the human PEPD promoter. The PEPD promoter was amplified from the human genome via PCR and inserted into a luciferase reporter construct. As demonstrated in our results, increase in luciferase activity was obtained after transfection of the PEPD luciferase reporter in HEK293T, indicating the successful construction of the luciferase reporter. Next, we performed in vitro methylation of the PEPD promoter using SssI methyltransferase which methylates DNA CpG islands. Methylation was confirmed by BstUI digestion that cleaves at unmethylated CpG dinucleotides but not at methylated CpG. The CpG methylation significantly inhibited PEPD promoter activity in comparison to the unmethylated construct. Taken together, we believe, these results will generate new knowledge on the molecular regulation of prolidase and provide better insight in our understanding of regulation of prolidase expression in various physiological and pathological conditions.Support or Funding InformationSupported by National Institutes of Health (NIH) Grants DA037779 and MD007586 (to Jui Pandhare) and DA024558, DA30896, DA033892, DA021471, AI22960 and MD007586 (to Chandravanu Dash). Ireti Eni‐Aganga is supported by RISE Grant. The work is also supported by the RCMI Grant G12MD007586, the Vanderbilt CTSA Grant UL1RR024975, the Meharry Translational Research Center (MeTRC) CTSA grant (U54 RR026140 from NCRR/NIH, the U54 Grant MD007593 from NIMHD/NIH, and the Tennessee Center for AIDS Research (P30 AI110527).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

3406 Understanding the Barriers, Challenges, and Facilitators to Community-Engaged Research: A Review of a CTSA Community Engagement Pilot Program

OBJECTIVES/SPECIFIC AIMS: Engaging patients and consumers in research is a complex process where innovative strategies are needed to effectively translate scientific discoveries into improvements in the public’s health (Wilkins et. al., 2013; Terry et. al., 2013). The Clinical Translational Science Awards (CTSA)—supported by the National Institute of Health (NIH) under the auspices of the National Center for Advancing Translational Sciences (NCATS)—aim to provide resources and support needed to strengthen our nation’s clinical and translational research (CTR) enterprise. In 2008, Stanford University was awarded a CTSA from the NIH, establishing Spectrum (Stanford Center for Clinical and Translational Research and Education) and its Community Engagement (CE) Program aimed at building long-standing community-academic research partnerships for translational research in the local area surrounding Stanford University. To date, the CE Pilot Program has funded 38 pilot projects from the 2009-2017 calendar year. The purpose of this study was to understand, through a unique pilot program, the barriers, challenges, and facilitators to community-engaged research targeting health disparities as well as community-academic partnerships. METHODS/STUDY POPULATION: Investigators conducted a qualitative study of the community engagement pilot program. Previous pilot awardees were recruited via email and phone to participate in a one-hour focus group to discuss their pilot project experience—describing any barriers, challenges, and facilitators to implementing their pilot project. RESULTS/ANTICIPATED RESULTS: The focus group revealed that community engage research through the pilot program was not only appreciated by faculty, but projects were successful, and partnerships developed were sustained after funding. Specifically, the pilot program has seen success in both traditional and capacity building metrics: the initial investment of $652,250.00 to fund 38 projects has led to over $11 million dollars in additional grant funding. In addition, pilot funding has led to peer-reviewed publications, data resources for theses and dissertations, local and national presentations/news articles, programmatic innovation, and community-level impact. Challenges and barriers were mainly related to timing, grant constraints, and university administrative processes. DISCUSSION/SIGNIFICANCE OF IMPACT: The Community Engagement Pilot Program demonstrates an innovative collaborative approach to support community-academic partnerships. This assessment highlights the value and importance of pilot program to increase community engaged research targeting health disparities. Challenges are mainly administrative in nature: pilot awardees mentioned difficulties working on university quarterly timelines, challenges of subcontracting or sharing money with community partners, onerous NIH prior approval process, and limitations to carryover funding. However, pilot grants administered through the program strengthen the capacity to develop larger scale community-based research initiatives.

3432 Stanford MedTech: An Innovative CTSA-Supported Pilot Program

OBJECTIVES/SPECIFIC AIMS: Helping researchers assess and effectively translate innovations into healthcare improvements is a complex process (Terry et. al., 2013). The Clinical Translational Science Awards (CTSA)—supported by the National Institute of Health (NIH) under the auspices of the National Center for Advancing Translational Sciences (NCATS)— provide the resources and support needed to strengthen our nation’s clinical and translational research (CTR) enterprise. In 2008, Stanford University was awarded a CTSA from the NIH, establishing Spectrum (the Stanford Center for Clinical and Translational Research and Education). Under the Spectrum umbrella, the Byers Center for Biodesign manages the MedTech Pilot Program with the goal of translating discoveries into novel health technologies that address important unmet health needs. The MedTech Pilot Program is an innovative funding mechanism that seeks to (1) stimulate clinical translational research, (2) help promising projects bridge the gap between the bench and the patients’ bedside, and (3) encourage collaborative, transdisciplinary work. Specifically, the Pilot Program offers up to $50,000 to support projects involving medical devices and mobile technologies used for (1) therapeutic applications and (2) device-based patient-specific (or POC) diagnostic applications. This analysis of the MedTech Pilot Program will: 1) describe the Program’s structure and process; 2) highlight the intensive, hands-on mentorship and practical guidance awardees receive that enables them to more efficiently and effectively advance their projects toward patient care; and 3) characterize the progress of the 36 funded projects. METHODS/STUDY POPULATION: Key elements of the Pilot Program’s infrastructure and mentoring processes as they relate to project outcomes were identified. Additionally, outcomes data were collected from two sources: (1) annual survey of Pilot Awardees and (2) publicly available information relevant to the pilot projects. RESULTS/ANTICIPATED RESULTS: The Pilot Program’s framework and infrastructure has supported a diverse group of transdisciplinary projects. These projects were evaluated using both traditional and non-traditional metrics (e.g., patents, startups, publications). The initial investment of $1.5 million to fund 36 projects has led to over $88 million dollars in additional funding. Additionally, taking full advantage of the expertise in Silicon Valley, strong mentorship has helped advance projects along the clinical and translational path. DISCUSSION/SIGNIFICANCE OF IMPACT: The Pilot Program has benefited Stanford innovators and researchers by providing seed funding to help promising projects bridge the gap between the bench and the bedside. The intensive, hands-on mentorship, early pilot funding, and practical guidance pilot awardees receive effectively help translate their technologies into patient care.

HOXD9 Promotes the Growth, Invasion and Metastasis of Gastric Cancer Cells by Transcriptional Activation of RUFY3

Background: The transcription factor HOXD9 is one of the members of the HOX family, which plays an important role in neoplastic processes. However, the role of HOXD9 in the growth and metastasis of gastric cancer (GC) remains to be elucidated. Methods: In vitro functional role of HOXD9 and RURY3 in GC cells was determined using the TMA-based immunohistochemistry, western blot, EdU incorporation, gelatin zymography, luciferase, chromatin Immunoprecipitation (ChIP) and cell invasion assays. In vivo tumour growth and metastasis were conducted in nude mice. Findings: HOXD9 is overexpressed in GC cells and tissues. The high expression of HOXD9 was correlated with poor survival in GC patients. Functionally, HOXD9 expression significantly promoted the proliferation, invasion and migration of GC cells. Mechanically, HOXD9 directly associated with the RUFY3 promoter to increase the transcriptional activity of RUFY3. Inhibition of RUFY3 attenuated the proliferation, migration and invasiveness of HOXD9-overexpressing GC cells in vitro and in vivo. Moreover, both HOXD9 and RUFY3 were highly expressed in cancer cells but not in normal gastric tissues, with their expressions being positively correlated. Interpretation: The evidence presented here suggests that the HOXD9-RUFY3 axis promotes the development and progression of human GC. Funding Statement: This study was supported by grants from the National Natural Science Funds of China (Nos.81672875 and 81772964). The funding organization: the Guangzhou Pilot Project of the Clinical and Translational Research Center (early gastrointestinal cancer, No.7415696196402). Declaration of Interests: The authors declare that they have no conflict of interest. Ethics Approval Statement: This study was reviewed and approved by the Medical Ethics Committee of Nanfang Hospital (NFEC-2017-062), Southern Medical University, Guangzhou, China. All animal studies were approved by the Institutional Animal Care and Use Committee of Committee of Nanfang Hospital.

Abstract OT1-13-02: Molecular testing for minority patients with or at high risk for cancer

Abstract PURPOSE: Meharry Medical College is a participant in eMERGE (Electronic Medical Records and Genomics); a multicenter network sponsored by NHGRI/NIMHD with the primary goal to develop, disseminate, and apply approaches to research that combine biorepositories with electronic medical records (EMR) for genomic discovery and medicine implementation research. The consortium also focuses on ethical issues involving privacy, confidentiality, and interaction with the broader community. Individual institutions created protocols around research questions individualized to their populations. METHODS: We enrolled 500 African Americans with or at high-risk for the four most common cancers (prostate, colorectal, breast, lung) to examine possible genetic and proteomic differences to account for health disparities in this population. We will perform DNA, RNA, and proteomics analyses pertinent to these cancers and obtain corresponding clinical history from the EMR with planned long-term follow up. RESULTS: 500 subjects (211 female) were enrolled over 11 months from Nashville General Hospital including the following cancer/at-risk participants (Breast 59/37; Colorectal 17/128; prostate 31/136; lung 16/76). Most individuals stated that they participated for potential benefit to themselves, family members, or humankind and only 11 percent of potential participants declined. Little concern has been voiced for providing samples for genetic analysis. A genetic counselor will meet with the participants that are found to have pathogenic or likely pathogenic mutations while study investigators will share results with those that are not found to have mutations. Participants will be queried regarding understanding of the genetic testing results and followed for one year to evaluate if they underwent recommended testing and to follow for cancer outcomes. CONCLUSION: The inclusion of diverse groups in genomic research is critical to identify possible reasons for health disparities and to study the understanding of genetic testing and ethical issues surrounding this topic. In this study, African-Americans are participating willingly in clinical research to examine possible genetic and/or social bases for cancer disparities. ACKNOWLEDGEMENT: NIMHD (U54MD007593) to the Meharry Translational Research Center (MeTRC); National Human Genome Research Institute (NHGRI); National Institute of Allergy and Infectious Disease (NIAID). Citation Format: Singh R, Bayan MA, Kadari S, Nganteh MN, Jacksonm M, Woodson LM, Shamsuddin AS, Lemus BY, Pratap S, Murray JJ, Adunyah SE, Lammers PE. Molecular testing for minority patients with or at high risk for cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT1-13-02.

The impact of interpersonal early life trauma on cardio-metabolic health in post-9/11 veterans.

This study examined the impact of early life trauma (ELT) on cardio-metabolic health in veterans from post-9/11 conflicts who experience significant stress from deployment and reintegration. Three hundred thirty-seven veterans from the Translational Research Center for Traumatic Brain Injury and Stress Disorders study underwent physiological assessments, including blood pressure and waist circumference. Fasting blood samples were collected to measure metabolic syndrome (MetS; cholesterol/triglycerides/glucose). ELT history was determined using the Traumatic Life Events Questionnaire. Posttraumatic stress disorder (PTSD) symptoms were assessed using the Clinician-Administered PTSD Scale. Logistic regression models examined the association of ELT and MetS diagnostic criteria while controlling for confounders. The adjusted logistic regression showed a significant relationship between interpersonal ELT (IP ELT) and risk of MetS, with IP ELT having an approximately 3-fold increase in the risk of cardio- metabolic syndrome compared with those with no trauma (odds ratio [OR] = 3.06, p < .05). IP ELT was associated with over a 2-fold increased risk of elevated triglycerides compared with those with no trauma (OR = 2.06, p < .05). PTSD symptoms also explained in part the IP-ELT/MetS relationship. Veterans with any ELT were significantly more likely to meet for a current diagnosis of PTSD. Our findings suggest that veterans with IP ELT are more likely to meet MetS and PTSD diagnostic criteria than veterans without IP ELT. This is concerning considering the young age of the sample and stresses the importance of an integrated and holistic approach in the assessment of physical and mental health in returning veterans. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Tobacco dependence is associated with increased risk for multi-morbid clustering of posttraumatic stress disorder, depressive disorder, and pain among post-9/11 deployed veterans.

Tobacco use is highly prevalent among individuals with posttraumatic stress disorder (PTSD), depressive disorders, and pain. Research has revealed pairwise relationships among these conditions but has not examined more complex relationships that may influence symptom severity, chronicity, and treatment outcome. To examine the clustering of current PTSD, depressive disorders, and clinically significant pain according to current tobacco use and dependence among post-9/11 deployed veterans. Logistic regression was used to examine the clustering of these conditions in relationship to current tobacco use/dependence, while adjusting for age and total combat exposure, in 343 post-9/11 deployed veterans enrolled in the Translational Research Center for TBI and Stress Disorders (TRACTS) cohort (Mage = 32.1+8.3years; 38% current tobacco use; 25% low and 12% moderate/high tobacco dependence). A three-way clustering of PTSD, depressive disorder, and pain was more likely than any single or pairwise combination of these conditions in moderate/high tobacco-dependent veterans compared to tobacco non-users (adjusted ORs = 3.50 to 4.18). This multi-morbidity cluster also was associated with increased PTSD severity. Moderate to high dependence on tobacco is associated with substantially increased clustering of PTSD, depression, and clinically significant pain in veterans. Research examining synergistic interactions among these conditions, biological vulnerabilities shared among them, and the direct impact of tobacco use on the pathophysiology of PTSD, depression, and pain is needed. The results of such work may spur development of more effective integrated treatments to reduce the negative impact of these multi-morbid conditions on veterans' wellbeing and long-term health.

Tolerance Induction Program Effect Explains Variation in Wheal Size, sIgE, and IgG4 in Peanut Allergic Children

Background: Tolerance induction oral immunotherapy, unique to our centre and termed the Tolerance Induction Program (TIP), has shown promise as a safe form of treatment in peanut allergic children. Evaluations of emerging treatments for peanut allergy typically report from a population average perspective. Our study sought to compare rate of decline in peanut-skin prick testing wheal size and sIgE following one year of high dose, weekly peanut immunotherapy using the standard population average approach to findings that account for subject variation in intercepts and slopes. Methods: This is a descriptive study in 51 peanut allergic children who underwent TIP at the Translational Pulmonary and Immunology Research Centre in Long Beach, California. Post intervention reductions in peanutwheal size and sIgE were assessed using Wilcoxen signed rank test and mixed effects modelling procedures. Results: The population average approach estimated reduction in wheal size to 29% of baseline value (p<0.001), compared to 41% after adjustment for random intercepts and slopes, p<0.001. Reduction in sIgE to 30% of baseline value using the population average approach (p<0.001), compared to 46% in the random intercepts model (p<0.001), and 44% in the random intercepts and slopes model (p=0.064). Conclusions: Tolerance induction oral immunotherapy significantly reduced peanut-SPT wheal size and sIgE in peanut allergic children. The subject specific approach produced more conservative effect estimates than observed using the standard population average approach.

Positron emission tomography of tau in Iraq and Afghanistan Veterans with blast neurotrauma.

Military personnel are often exposed to multiple instances of various types of head trauma. As a result, there has been increasing concern recently over identifying when head trauma has resulted in a brain injury and what, if any, long-term consequences those brain injuries may have. Efforts to develop equipment to protect soldiers from these long-term consequences will first require understanding the types of head trauma that are likely responsible. In this study, we sought to identify the types of head trauma most likely to lead to the deposition of tau, a protein identified as a likely indicator of long-term negative consequences of brain injury. To define the types of head trauma in a military population, we applied a factor analysis to interviews from a larger cohort of 428 Veterans enrolled in the Translational Research Center for Traumatic Brain Injury and Stress Disorders. Three factors were identified: Blast Exposure, Symptom Duration, and Blunt Concussion. Sixteen male Veterans from this study and one additional male civilian (aged 25–69, mean 35.2 years) underwent simultaneous positron emission tomography/magnetic resonance imaging using a tracer that binds to tau protein, the ligand T807/AV-1451 (Flortaucipir). Standard uptake value ratios to the isthmus of the cingulate were calculated from a 20-minute time frame 70 min post-injection. We found that tracer uptake throughout the brain was associated with Blast Exposure factor beta weights, but not with either Symptom Duration or Blunt Concussion. Associations with uptake were located primarily in the cerebellar, occipital, inferior temporal and frontal regions. The data suggest that in this small, relatively young cohort of Veterans, elevated T807/AV-1451 uptake is associated with exposure to blast neurotrauma. These findings are unanticipated, as they do not match histopathological descriptions of tau pathology associated with head trauma. Continued work will be necessary to understand the nature of the regional T807/AV-1451 uptake and any associations with clinical symptoms.

Prevalence of metabolic syndrome in Gwalior region of Central India: A comparative study using NCEP ATP III, IDF and Harmonized criteria

BackgroundThe aim of this study is to determine the prevalence of Metabolic syndrome (MetS) in the people of Gwalior. Three criteria viz., National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria, International Diabetes Federation (IDF) criteria and Harmonized criteria for MetS were employed to assess the prevalence of metabolic syndrome in this region, their concordance with respect to this population was recorded. MethodsThe cross-sectional study involved the people, who had attended the Diabetes clinic at the Centre for Translational Research, Jiwaji University during 2015-2017. A total of 1190 participants within the age group of 20–79 years of either gender were included in the study. Anthropometric parameters, blood pressure, blood glucose and lipid profile of all subjects were assessed. Student's ‘t’ test, Kappa statistics and Binary logistic regression model were used to analyze the data. ResultsThe percentage of prevalent MetS was found to be 72.7, 50.2 and 53.9 following Harmonized criteria, NCEP ATPIII and IDF criteria respectively. The prevalence was found to be maximum in centrally obese female population, aged between 51 and 60 years with the presence of hyperglycemia and reduced HDL– C. Harmonized and IDF criteria showed good agreement (κ 0.85). Regression analysis showed that, high body mass index, hypertension and dyslipedimia were the most critical predictive risk factors of MetS. ConclusionsMaximum prevalence of MetS was recorded when the Harmonized criteria was followed. A good agreement was observed between Harmonized vs. IDF criteria. MetS if detected early especially in apparently healthy subjects; paves way for preventive measures to be designed in order to avert the incidence of diabetes and other risks related to cardio vascular disease.

Analysis and management of the national natural science foundation of china in a special hospital

Objective To explore the management model of scientific research projects based on the application of the National Natural Science Foundation of China (NSFC). Methods We retrospectively analyzed the NSFC funding of our hospital during 2009-2017. Results Our hospital sets up the pre-experiment special project of NSFC and full-time policy, development translational medicine research center platform, introduce and train scientific talents, strength the delicacy management of scientific research and so on. Through the above measurements, NSFC funding in our hospital was significantly improved. The number of projects approved increased from 1 to 23, and the amount approved increased from 300 thousand to 21 million 350 thousand yuan during the eight yesrs. Conclusions The policy, platform, personnel and delicacy management have effectively improved the quality and quantity of NSFC, and promote the sustainable development of the hospital science and technology. Key words: National Natural Science Foundation of China; Project application; Project management; Hospital; Scientific research

Self-harm in a primary care cohort of older people: incidence, clinical management, and risk of suicide and other causes of death

SummaryBackgroundSelf-harm is a major risk factor for suicide, with older adults (older than 65 years) having reportedly greater suicidal intent than any other age group. With the aging population rising and paucity of research focus in this age group, the extent of the problem of self-harm needs to be established. In a primary care cohort of older adults we aimed to investigate the incidence of self-harm, subsequent clinical management, prevalence of mental and physical diagnoses, and unnatural-cause mortality risk, including suicide.MethodsThe UK Clinical Practice Research Datalink contains anonymised patient records from general practice that routinely capture clinical information pertaining to both primary and secondary care services. We identified 4124 adults aged 65 years and older with a self-harm episode ascertained from Read codes recorded during 2001–14. We calculated standardised incidence and in 2854 adults with at least 12 months follow-up examined the frequency of psychiatric referrals and prescription of psychotropic medication after self-harm. We estimated prevalence of mental and physical illness diagnoses before and after self-harm and, using Cox regression in a matched cohort, we examined cause-specific mortality risks.FindingsOverall incidence of self-harm in older adults aged 65 years and older was 4·1 per 10 000 person-years with stable gender-specific rates observed over the 13-year period. After self-harm, 335 (11·7%) of 2854 adults were referred to mental health services, 1692 (59·3%) were prescribed an antidepressant, and 336 (11·8%) were prescribed a tricyclic antidepressant (TCA). Having a diagnosed previous mental illness was twice as prevalent in the self-harm cohort as in the comparison cohort (prevalence ratio 2·10 [95% CI 2·03–2·17]) and with a previous physical health condition prevalence was 20% higher in the self-harm cohort compared to the comparison cohort (1·20 [1·17–1·23]). Adults from the self-harm cohort (n=2454) died from unnatural causes an estimated 20 times more frequently than the comparison cohort (n=48 921) during the first year. A markedly elevated risk of suicide (hazard ratio 145·4 [95% CI 53·9–392·3]) was observed in the self-harm cohort.InterpretationWithin primary care, we have identified a group of older adults at high risk from unnatural death, particularly within the first year of self-harm. We have highlighted a high frequency of prescription of TCAs, known to be potentially fatally toxic in overdose. We emphasise the need for early intervention, careful alternative prescribing, and increased support when older adults consult after an episode of self-harm and with other health conditions.FundingNational Institute for Health Research Greater Manchester Patient Safety Translational Research Centre.

Prevalence of Comorbid Mental and Physical Illnesses and Risks for Self-Harm and Premature Death Among Primary Care Patients Diagnosed with Fatigue Syndromes

Background: Fatigue syndromes affect large numbers of individuals, yet evidence from epidemiological studies on adverse outcomes, such as premature death, is limited. Methods: Cohort study involving 385 general practices in England that contributed to the Clinical Practice Research Datalink (CPRD) with linked inpatient Hospital Episode Statistics (HES) and Office for National Statistics (ONS) cause of death information. A total of 10,477 patients aged 15 years and above, diagnosed with a fatigue syndrome during 2000-2014, were individually matched with up to 20 comparator patients without history of having a fatigue syndrome. Prevalence ratios (PRs) were estimated to compare the fatigue syndrome and comparison cohorts on clinical characteristics. Adjusted hazard ratios (HRs) for subsequent adverse outcomes were estimated from stratified Cox regression models. Outcomes: Among patients diagnosed with fatigue syndromes, we found elevated baseline prevalence of: any psychiatric illness (PR 1.77; 95% CI 1.72-1.82), anxiety disorders (PR 1.92; 1.85-1.99), depression (PR 1.89; 1.83-1.96), psychotropic prescriptions (PR 1.68; 1.64-1.72), and comorbid physical illness (PR 1.28; 1.23-1.32). We found no significant differences in risks for: all-cause mortality (HR 0.99; 0.91-1.09), natural death (HR 0.99; 0.90-1.09), unnatural death (HR 1.00; 0.59-1.72), or suicide (HR 1.68; 0.78-3.63). We did, however, observe a significantly elevated non-fatal self-harm risk: HR 1.83; 1.56-2.15. Interpretation: The absence of elevated premature mortality risk is reassuring. The raised prevalence of mental illness and increased non-fatal self-harm risk indicate a need for enhanced assessment and management of psychopathology associated with fatigue syndromes. Funding: NIHR Greater Manchester Patient Safety Translational Research Centre. Conflict of interest statement: PDW is a member of the Independent Medical Experts Group; an advisory non-departmental public body, which advises the UK Ministry of Defence regarding the Armed Forces Compensation Scheme. In the past, PDW has provided unpaid advice to the UK Department for Work and Pensions regarding mental health issues. PDW does paid consultancy work for a re-insurance company. NK is supported by Greater Manchester Mental Health and Social Care Trust. NK chaired the guideline development group for the 2012 NICE guidelines on the longer term management of self-harm and currently chairs the guideline development group for the NICE depression in adults guideline. NK is also a member of the Suicide Prevention Advisory Group at the Department of Health. Ethical Approval Statement: The study was approved by the independent scientific advisory committee (ISAC) for Clinical Practice Research Datalink research (protocol number: 16_050R).

β-Cell secretory defects are present in pancreatic insufficient cystic fibrosis with 1-hour oral glucose tolerance test glucose ≥155 mg/dL.

Patients with pancreatic insufficient cystic fibrosis (PI-CF) meeting standard criteria for normal glucose tolerance display impaired β-cell secretory capacity and early-phase insulin secretion defects. We sought evidence of impaired β-cell secretory capacity, a measure of functional β-cell mass, among those with early glucose intolerance (EGI), defined as 1-hour oral glucose tolerance test (OGTT) glucose ≥155 mg/dL (8.6 mmol/L). A cross-sectional study was conducted in the Penn and CHOP Clinical & Translational Research Centers. PI-CF categorized by OGTT as normal (PI-NGT: 1-hour glucose <155 mg/dL and 2-hour <140 mg/dL [7.8 mmol/L]; n = 13), PI-EGI (1-hour ≥155 mg/dL and 2-hour <140 mg/dL; n = 13), impaired (PI-IGT: 2-hour ≥140 and <200 mg/dL [11.1 mmol/L]; n = 8), and diabetic (cystic fibrosis-related diabetes, CFRD: 2-hour ≥200 mg/dL; n = 8) participated. Post-prandial glucose tolerance and insulin secretion, and β-cell secretory capacity and demand were derived from mixed-meal tolerance tests (MMTTs), and glucose-potentiated arginine (GPA) tests, respectively. PI-EGI had elevated post-prandial glucose with reduced early-phase insulin secretion during MMTT compared to PI-NGT (P < .05). PI-EGI also exhibited impaired acute insulin and C-peptide responses to GPA (P < .01 vs PI-NGT), measures of β-cell secretory capacity. Proinsulin secretory ratios were higher under hyperglycemic clamp conditions in PI-IGT and CFRD (P < .05 vs PI-NGT), and correlated with 1-hour glucose in PI-CF (P < .01). PI-CF patients with 1-hour OGTT glucose ≥155 mg/dL already manifest impaired β-cell secretory capacity with associated early-phase insulin secretion defects. Avoiding hyperglycemia in patients with EGI may be important for preventing excessive insulin demand indicated by disproportionately increased proinsulin secretion.

Building a Hybrid Gross Anatomy Curriculum: Integration of Virtual &amp; Cadaveric Models

Cadaveric dissection is an important feature in a gross anatomy curriculum for medical practitioners. Currently, no other experience imparts a realistic, tactile understanding of tissues and organs necessary for actual surgical experience. Many students find cadaver dissection to be a beneficial experience. However, cadaveric dissection programs have three major drawbacks: (1) they require expensive logistical infrastructures to obtain, process, &amp; utilize human gifts, (2) they provide limited exposure to the range of anatomical variation, and (3) they require students to study from textbook atlases as well as the physical dissection. This is a valuable experience, but can lead to confusion and loss of information when the cadaver does not match textbook anatomy or when structure is destroyed in the dissection process.To address these issues, many schools have looked at replacing physical cadavers with virtual models. Such “virtual cadavers” are relatively inexpensive and easier to work with. The best‐known example is the Visible Human Project[i], a publicly available dataset of a male and female cadaver in both annotated, Hi‐Res, cross‐sectional images &amp; CT scans. Unfortunately, this is a limited dataset, which is not representative of the variation in population. Further, students lose the tactile experience of dissection, which is unique and has long‐lasting impacts throughout their medical education.To bridge this gap, the University at Buffalo (UB) is developing a hybrid gross anatomy program which integrates both formats. The program will leverage the Anatomical Gift program at UB, which provides 600–700 cadavers per year to schools across NY state, as well as state‐of‐the‐art imaging facilities at our Clinical and Translational Research Center, where cadavers are CT‐imaged at Hi‐Res. These scans are currently provided to students for dissection prep and review.To develop this program, several challenges must be addressed. Non‐contrast (NC) CT images must be processed to generate usable information for gross anatomy students. Registration must be performed to align samples for analysis (F1). Segmentation of structures to obtain virtual models is performed (F2). Finally, analytics must be performed to obtain anatomically relevant, quantitative information pertaining to structures such as probabilistic atlas creation (F3). These sample datasets will require novel automated deep learning methods to generate adequate models &amp; analytics.In terms of education, the hybrid program must develop strategies to marry virtual models and dissection in a way that enhances learning without burdening students. Metrics must be implemented to define criteria for course improvement, success, &amp; attrition. Students with special needs will need to be considered. The distribution format and access of the medical data will need to be assessed.The hybrid gross anatomy program will provide students with the benefits of dissection exposure, medical image utilization and a better understanding of human variation. The program offers exciting opportunities for technological and educational innovation.Support or Funding InformationIMSD R25 GM095459: Enabling Access to Cutting‐Edge Biomedical and Behavioral Science, Integration of Physical and Virtual Cadavers in a Hybrid Gross Anatomy Curriculum Center for Educational Innovation Grant.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Embedded research: a promising way to create evidence-informed impact in public health?

Embedded research (ER) is recognized as one way to strengthen the integration of evidence into public health (PH) practice. In this paper, we outline a promising example of the co-production of research evidence between Fuse, the UKCRC Centre for Translational Research in Public Health and a local authority (LA) in north east England. We critically examine attempts to share and use research findings to influence decision-making in a LA setting, drawing on insights from PH practitioners, managers, commissioners and academic partners involved in this organizational case study. We highlight what can be achieved as a co-located embedded researcher. The benefits and risks of ER are explored, alongside our reflections on the added value of this approach and the institutional prerequisites necessary for it to work. We argue that while this is not a new methodological approach, its application in PH as a way to facilitate evidence use is novel, and raises pragmatic and theoretical questions about the nature of impact and the extent to which it can be engineered. With increased situated understanding of organizational culture and norms and greater awareness of the socio-political realities of PH, ER enables new co-produced solutions to become possible.

Highlights From the Circulation Family of Journals.

Highlights From the Circulation Family of Journals.

Continuous Glucose Monitoring for Hypoglycemia Avoidance and Glucose Counterregulation in Long-Standing Type 1 Diabetes.

Patients with long-standing type 1 diabetes (T1D) are at increased risk for severe hypoglycemia because of defects in glucose counterregulation and recognition of hypoglycemia symptoms, in part mediated through exposure to hypoglycemia. To determine whether implementation of real-time continuous glucose monitoring (CGM) as a strategy for hypoglycemia avoidance could improve glucose counterregulation in patients with long-standing T1D and hypoglycemia unawareness. Eleven patients with T1D disease duration of ∼31 years were studied longitudinally in the Clinical & Translational Research Center of the University of Pennsylvania before and 6 and 18 months after initiation of CGM and were compared with 12 nondiabetic control participants. Endogenous glucose production response derived from paired hyperinsulinemic stepped-hypoglycemic and euglycemic clamps with infusion of 6,6-2H2-glucose. In patients with T1D, hypoglycemia awareness (Clarke score) and severity (HYPO score and severe events) improved (P < 0.01 for all) without change in hemoglobin A1c (baseline, 7.2% ± 0.2%). In response to insulin-induced hypoglycemia, endogenous glucose production did not change from before to 6 months (0.42 ± 0.08 vs 0.54 ± 0.07 mg·kg-1·min-1) but improved after 18 months (0.84 ± 0.15 mg·kg-1·min-1; P < 0.05 vs before CGM), albeit remaining less than in controls (1.39 ± 0.11 mg·kg-1·min-1; P ≤ 0.01 vs all). Real-time CGM can improve awareness and reduce the burden of problematic hypoglycemia in patients with long-standing T1D, but with only modest improvement in the endogenous glucose production response that is required to prevent or correct low blood glucose.