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This article describes how the T1D Exchange Quality Improvement Collaborative leverages an innovative web platform, the QI Portal, to gather and store electronic medical record (EMR) data to promote benchmarking and population health improvement in a type 1 diabetes learning health system. The authors explain the value of the QI Portal, the process for mapping center-level data from EMRs using standardized data specifications, and the QI Portal’s unique features for advancing population health.

OBJECTIVES The American Diabetes Association (ADA) and the International Society for Pediatric and Adolescent Diabetes (ISPAD) have outlined standards for best practices in providing optimal diabetes care to children with type 1 diabetes (T1D). Our objectives were to design a metric that evaluated delivery of optimal diabetes care and to use this metric to drive improvement within our diabetes program. METHODS Using published guidelines, we identified 11 elements of optimal diabetes care that should be reliably delivered at our institution as standard-of-care. We utilized our electronic medical record to aid in data collection and to notify staff when to deliver specific care elements (eg, lipid collection, depression screening, etc.). We designed the T1D Care Index (T1DCI), a metric which aggregates missed opportunities to deliver elements of optimal diabetes care over a given period into a cumulative score, with a lower T1DCI reflecting better care delivery and improved program performance. RESULTS Tracking the T1DCI permitted recognition of areas to focus on quality improvement efforts, guided interventions to improve processes for care delivery, and helped determine the allocation of time and resources. Interventions resulted in improvement of care delivery across some elements of care. Overall, we observed a 26% reduction in the T1DCI after 12 months of utilization. CONCLUSIONS The T1DCI is a powerful metric to evaluate the ability of our diabetes program to standardize, quantify, and monitor delivery of optimal diabetes care to children with T1D, and to drive our program toward zero missed opportunities for quality care delivery.

Limited data are available on changes in metabolic parameters in transgender youth on testosterone therapy in comparison with cisgender females. Data from 42 transgender males on testosterone therapy were retrospectively analyzed. Body mass index (BMI) and lipid profile changes were compared with BMI-matched females. There was a significant increase in BMI over time in the transgender males as compared with the cisgender females, and a decrease in high-density lipoprotein in the transgender males after starting testosterone therapy. Longitudinal prospective studies with cisgender controls are needed to better define effects of testosterone therapy in adolescents.

Background: Insulin pump use is known to improve glycemic control in patients with type 1 diabetes (T1D), however, uptake of insulin pump varies among people in U.S. This study aims to examine the distribution of patient demographics and frequency of clinical outcomes across people using insulin pump. Methods: The analysis included 21,821 T1D patients in the T1D Exchange Quality Improvement (T1DX-QI) database for whom electronic medical record data was available in the T1DX-QI collaborative. Patients over 2 years with at least one completed clinic encounter between January 2014 - February 2020 were included for analysis. Results: In this population, 58% (N=12,729) of T1D patients were insulin pump users, whereas 42% (N=9,092) were non-users. HbA1c levels in the insulin pump group were lower compared to non- users (Mean [SD], %: 8.5 [2.6] vs. 8.9[2.1] [p Conclusions: This study highlights inequities in uptake of insulin pump therapy, while confirming previous findings demonstrating the use of insulin pump in combination with CGMs to be critical in effective management of blood glucose levels in one of the largest multi-center observational studies in the U.S. Disclosure N. Noor: Research Support; Self; Dexcom, Inc. M. A. Clements: Consultant; Self; Eli Lilly and Company, Employee; Self; Glooko, Inc., Research Support; Self; Abbott Diabetes, Dexcom, Inc. G. T. Alonso: None. S. Rompicherla: None. N. Noor: Research Support; Self; Dexcom, Inc. S. Lyons: None. J. M. Lee: Advisory Panel; Self; GoodRx. M. Gallagher: None. J. A. Indyk: None. O. Ebekozien: None. M. Greenfield: None. Funding The Leona M. and Harry B. Helmsley Charitable Trust

Objective To assess health-related quality of life (HRQoL), psychosocial adjustment, and family functioning of children with differences of sex development (DSD) or cleft lip and/or palate (CL/P). Methods In this cross-sectional study, parents of children with DSD (n = 67), CL/P (n = 121), and a comparison group of unaffected youth (n = 126) completed standardized measures assessing family functioning and their children’s HRQoL and psychosocial adjustment. Medical charts were abstracted for youth with either congenital condition. Results Children with DSD were rated as having significantly lower HRQoL and greater internalizing problems compared to youth with CL/P and unaffected youth. Children in the DSD group were also significantly more likely to fall into the clinical risk categories for total and internalizing problems relative to the CL/P and unaffected groups. Caregivers of children with DSD were significantly more likely to endorse items about child suicidality compared with caregivers in the CL/P and unaffected groups. No significant differences were found between groups for externalizing problems or the expressiveness domain of family functioning; parents of children with DSD reported significantly less family conflict relative to the other groups and greater cohesion relative to the unaffected group. Conclusions Youth with DSD appear to be at greater risk for psychosocial problems relative to children with CL/P and unaffected peers. Results underscore the need for integrated interdisciplinary care and ongoing psychosocial risk monitoring in youth with DSD.

Introduction: Patient outcomes resulting from optimal type 1 diabetes (T1D) care have historically focused on driving a single metric, hemoglobin A1c. Our objectives were to design, build, and launch an aggregate clinical indicator that comprehensively reflects patient management status beyond hemoglobin A1c alone. This project aimed to show proof of principle that an aggregate score comprised of T1D outcome metrics could be built to track quality performance. Methods: We established an electronic medical record-based diabetes registry and utilized its population health modules to design and build this diabetes care metric. Elements representing optimal diabetes management, as defined by current guidelines and expert opinion, were identified. Nine elements fall into categories of management tools, care assessments, and complications risk. The Type 1 Diabetes Composite Score (T1DCS) aggregates these outcome measures to reflect the overall diabetes care status for each patient. Higher scores suggest better management and overall improved patient health. Results: We launched this metric build in November 2018 and applied the scoring to our T1D population (≈1,900 patients). The T1DCS quickly provides a summary of current diabetes management status. T1DCS viewed over the registry cohort demonstrates a normal distribution, and scores improved from March to September 2019, reflecting better care and outcomes, and illustrating the potential to track program effectiveness. Conclusions: The T1DCS is a useful metric to evaluate the clinical status of T1D patients, assess the capability of a clinical program to achieve optimal diabetes outcomes, identify patient diversity opportunities, and document outcome improvement as a novel comprehensive quality measure.

A minority of youth with type 1 diabetes (T1D) achieve HbA1c goals recommended by the ADA. Continuous glucose monitoring (CGM) is shown to improve glycemic control and reduce complications of disease. Despite this evidence, CGM utilization is low among youth with T1D. In this quality improvement project, we aimed to increase percentage utilization of CGM amongst our pediatric T1D clinic population from a baseline mean of 9% in 2017. Targeted interventions to achieve this goal included identification and tracking of utilizers vs. non-utilizers, creation of a standardized clinic workflow to initiate a new CGM device within the EMR, and identification of barriers to insurance coverage. CGM utilization in our pediatric T1D clinic increased from a mean 9% in 2017 to 53% in 2019. Over this same period, our clinic observed a 7% increase in patients who achieved goal HbA1c. Targeted interventions to increase CGM utilization in a pediatric T1D clinic secondarily led to improved glycemic outcomes. Disclosure K. Obrynba: None. J.A. Indyk: None. K. Gandhi: None. D.A. Buckingham: None. T. Wells: None. W.N. Wayne: None. M.K. Kamboj: Research Support; Self; Type 1 Diabetes TrialNet, Unitio, Inc.

The T1DX-QI is a type 1 diabetes learning health system including over 10 diabetes centers across the U.S. The program is coordinated by the T1D Exchange in Boston, MA. Several research studies have demonstrated the impact of insulin pump use and frequent insulin bolusing on diabetes-related clinical outcomes. Five centers in the T1DX-QI used QI methodology including Plan - Do- Study - Act (PDSA) cycles to test and expand insulin pump use initiatives among patients aged 12 - 26 years at their centers. Successful interventions include developing mobile technology classes, redesigning workflow, coaching patients to bolus for meals and corrections, and removing barriers to adoption. The centers shared data monthly with the coordinating office. These data were used for ongoing QI coaching and to promote the cross-sharing of best practices. Statistical Process Control charts with the relevant rules for fundamental improvements were used to evaluate project effectiveness. Two examples appear in Figure 1. Three of five participating centers had substantial improvement in this process, ranging from 6% - 17%. There was a 10% significant change among the collaborative cohort in 20 months. Successful QI interventions improved pump use. Further expansion is needed to increase the percentages of patients meeting bolusing goals. Disclosure O. Ebekozien: None. N. Rioles: None. J.A. Indyk: None. S. Lyons: Other Relationship; Self; Springer Publishing Company. S. Majidi: Advisory Panel; Self; Companion Medical. T. Proffitt: None. J.M. Lee: Advisory Panel; Self; Goodrx. Consultant; Self; T1D Exchange. Research Support; Self; Lenovo. Funding The Leona M. and Harry B. Helmsley Charitable Trust

Objective: Performance in providing optimal type 1 diabetes care has historically focused on only one metric, HbA1c. Our objectives were to design and test a metric that evaluated overall quality of care and to use this metric to drive improvement within our diabetes program. Methods: The Type 1 Diabetes Care Index (T1DCI) aggregates missed opportunities for best practices into a composite score that reflects overall program performance. Elements of optimal care that should be reliably delivered were compiled into 14 domains over three areas: (1) Delivery of patient care, (2) Preventative Screening, (3) Psychosocial support. The T1DCI is the aggregate number of missed opportunities to provide quality care over a given time period. A lower T1DCI reflects better care and overall improved system performance. Results: The T1DCI was easy to calculate and implement, and was well accepted by our diabetes team. The annual T1DCI progressively decreased from 5,338 at baseline to 3,821 after 10 months of utilization, a 14% reduction. Improvements in care were realized across some index domains and areas for focusing improvement efforts were recognized in others. New initiatives to provide optimal care were created. Conclusions: The T1DCI is a useful metric to evaluate the ability of our program to deliver optimal care, and to document performance improvement across a broad range of domains. Disclosure K. Obrynba: Consultant; Self; Dexcom, Inc. J.A. Indyk: None. K. Gandhi: None. D.A. Buckingham: None. A.M. Kramer: None. K. Hong: None. B. Glick: None. T. Wells: None. T.C. Barnard-Kirk: None. M.L. Smith: None. A.M. Moffett: None. M.K. Kamboj: None.

Background: Studies show that youth with type 1 diabetes (T1D) harbor cardiovascular risk factors and exhibit clinical signs suggestive of cardiovascular disease. ADA and ISPAD guidelines promote regular blood pressure screening to reduce cardiovascular risk, and strategies should involve effective screening and management. The diabetes clinic previously had limited measures in place to manage T1D youth with elevated blood pressure. Objective: The aim of this quality improvement (QI) project was to increase provider recognition and follow-up of TID patients with elevated blood pressure readings ≥ 95%tile for age/gender/height, from 0% to 50%, by 12/31/17 and sustain through 12/31/2018. Methods: After the QI team clarified project goals, a Key Driver Diagram (KDD) and elevated blood pressure process map was established. This algorithm aided to clarify the care process to efficiently recognize and manage youth with T1D who presented with elevated blood pressure in the outpatient diabetes clinic. A “Best Practice Alert” (BPA) was created within the electronic medical record, which alerted the diabetes care team of the presence of elevated blood pressure among T1D patients in clinic. This allowed the provider to choose electronically tracked care options in the medical record to manage elevated blood pressure among T1D patients and coordinate care among subspecialties that manage elevated blood pressure. Data reports were compiled to track utilization of the blood pressure BPA from May 2017 (initiation date) to December 2017 with ongoing data collection. Results: Upon BPA creation, process mean of the utilization and management of elevated blood pressure BPA among T1D youth increased to 73% over a 7 month period. Conclusions: This project successfully improved screening and management of T1D youth with elevated blood pressure in the outpatient setting. This project builds on comprehensive diabetes care, with the hope of reducing future cardiovascular burden for youth with T1D. Disclosure K. Gandhi: None. D.A. Buckingham: None. J. Hehmeyer: None. A.M. Kramer: None. K. Obrynba: None. J.A. Indyk: None. M.K. Kamboj: None.

The initial management of the neonate with ambiguous genitalia can be a very stressful and anxious time for families, as well as for the general practitioner or neonatologist. A timely approach must be sensitive and attend to the psychosocial needs of the family. In addition, it must also effectively address the diagnostic dilemma that is frequently seen in the care of patients with disorders of sex development (DSDs). One great challenge is assigning a sex of rearing, which must take into account a variety of factors including the clinical, biochemical and radiologic clues as to the etiology of the atypical genitalia (AG). However, other important aspects cannot be overlooked, and these include parental and cultural views, as well as the future outlook in terms of surgery and fertility potential. Achieving optimal outcomes requires open and transparent dialogue with the family and caregivers, and should harness the resources of a multidisciplinary team. The multiple facets of this approach are outlined in this review.

Regular physical activity is an important component in the management of both type 1 and type 2 diabetes mellitus (T1DM and T2DM), as it has the potential to improve glycemic control, delay cardiovascular complications, and increase overall well-being. Unfortunately, many children and adolescents with diabetes do not partake in regular exercise and physical activity for multiple reasons. This review identifies the barriers to participation from the aspect of the patient, caregiver, and the healthcare provider. The management of physical activity of children and adolescents with diabetes mellitus is unique and requires an understanding of exercise physiology and how it differs in these children and adolescents from those without the condition. These individuals are at risk for important and potentially life threatening complications including, but not limited to, severe or delayed nocturnal hypoglycemia. It is essential to identify these risks as well as, monitor and manage adjustments to carbohydrate intake and insulin dosing through basal-bolus regimen or insulin pump adjustments appropriately before, during, and after the exercise activity. This review discusses these issues and also outlines differences in management between patients with T1DM and T2DM.

Summary Short introduction/Background Children affected by differences/disorders of sex development (DSDs) and their families are vulnerable to significant risks across developmental stages that threaten quality of life and psychosocial functioning. Accordingly, both experts in DSD treatment and patient advocacy groups have endorsed the incorporation of psychosocial care into interdisciplinary management of DSD conditions. Objective This study assessed psychosocial needs and received services reported by parents of children with DSD treated at two large US academic medical centers. Specifically, differences in parents' perceptions of psychosocial service needs were compared between those who received or did not receive interdisciplinary care that included psychology/social work professionals. Study design In a cross-sectional study, sixty-four parents of children with DSD aged 0–19 years attending two major academic centers with interdisciplinary teams completed a questionnaire about their receipt and perception of 12 individual psychosocial services throughout their child's DSD treatment. Results Receipt of individual psychosocial services ranged from 27 to 81%. Most commonly, parents reported having a psychosocial provider explain medical terms and answer questions after talking with a doctor (81%), assist with words and terms to describe the condition and treatment (69%), and help navigate the hospital system (63%). Families positively endorsed psychosocial services, with 91–100% of services received rated as helpful. Parents of children who received care as part of an interdisciplinary team were significantly more likely to receive psychosocial services than those treated by single providers (e.g., urologists). Specific gaps in psychosocial care were noted in regard to access to mental health providers familiar with DSD, fertility counseling, and support with community advocacy (e.g., arranging for accommodations at the school or advocating on patient's behalf with the insurance company). Among families who had not received them, services most desired were assistance with words and terms to describe condition or treatment; explanation of medical terms and answering questions after meeting with a doctor; connection to resources such as books, pamphlets, websites, and support groups; and a central care coordinator for the medical team. Discussion and Conclusion Families value psychosocial services but are far less likely to receive services if they are not seen in an interdisciplinary clinic visit that includes a psychosocial provider. Families desire but often lack mental health, advocacy, and fertility-related support. This study highlights the need for sustained psychosocial follow-up across development, even in the absence of pressing medical concerns, to provide support and anticipatory guidance as needs and issues evolve. Extended Summary Table . Psychosocial services received by DSD interdisciplinary clinic visit (yes/no). Psychosocial service received Interdisciplinary DSD clinic visit p-value Yes No n % n % Emotional support for the family at diagnosis 24 63.2 4 15.4 0.0002 Strategies for talking with others about diagnosis 22 57.9 6 23.1 0.006 Ways to help the family talk with the child about diagnosis 26 68.4 6 23.1 0.0004 Central contact person or care coordinator 21 55.3 7 26.9 0.03 Emotional support as the child aged 26 68.4 4 16.0 Patient and family advocacy to the community (e.g., school, insurance company) 15 39.5 2 7.7 0.005 Connection to resources (e.g., books, support groups) 26 68.4 7 26.9 0.001 Mental health services with a provider who is knowledgeable about the condition 22 57.9 2 7.7 Individual to talk with the child about fertility 15 39.5 2 7.7 0.005 DSD, difference or disorder of sex development.

Summary Introduction Patients with gonadal dysgenesis (GD) with a Y chromosome have an increased risk of gonadal neoplasm. Few data exist on the ability of imaging to detect malignancy in intra-abdominal gonads in these patients. Objective We aimed to determine the correlation between preoperative imaging findings and gonadal pathology in GD patients with Y chromosome material. Methods A retrospective review was performed of patients with XY or XO/XY GD who underwent gonadectomy at our institution from 2003 to 2017. Patients were assessed preoperatively with ultrasonography; some additionally underwent MRI. Results The series consisted of 10 patients, all with female gender and non-palpable gonads. Median age was 13.1 years (range 2.4–18.3 years). Overall, four of the ten patients (40%) had a tumor (gonadoblastoma or dysgerminoma) on final pathology. Four patients had a gonad or gonads that were definitively seen on ultrasonography. All visualized gonads were described as “normal” or “small” with the exception of one patient, who had a normal MRI. Three of the four patients in this group had a tumor on final pathology. The remaining six patients had a gonad or gonads that were not definitively visualized on ultrasound; one patient in this group had a tumor on final pathology. Overall, five of seven gonads (71%) definitively visualized on ultrasound had tumor on final pathology, and two of thirteen gonads (15%) not visualized on ultrasound had tumor on final pathology; this difference was statistically significant (p = 0.012). Three patients were imaged with MRI. Of the gonads that could be visualized on MRI, no definitive abnormalities were seen. All patients imaged with MRI had tumors on final pathology. Discussion Both ultrasound and MRI are relatively poor at identifying and characterizing intra-abdominal gonads in GD patients. The majority of patients who had a neoplasm had normal imaging findings. Gonads that were definitively visualized on ultrasound were more likely to contain neoplasms that could not be visualized, which perhaps because of tumor growth. No other consistent imaging findings of malignancy were found. Our study included ultrasound evaluations that were completed over 10 years ago and not performed by pediatric ultrasonographers, which may have biased the results. However, results suggest that when discussing gonadectomy with GD patients, one should not be reassured by “normal” imaging findings. Neither ultrasound nor MRI should be relied on for surveillance in GD patients who decide against gonadectomy. Conclusion A normal ultrasound or MRI does not rule out neoplasm in GD patients with intra-abdominal gonads.

Laminins are extracellular matrix proteins that participate in neuronal development, survival, and regeneration. During excitotoxin challenge in the mouse hippocampus, neuron interaction with laminin-10 (α5,β1,γ1) protects against neuronal death. To investigate how laminin is involved in neuronal viability, we infused laminin-1 (α1,β1,γ1) into the mouse hippocampus. This infusion specifically disrupted the endogenous laminin layer. This disruption was at least partially due to the interaction of the laminin-1 γ1 chain with endogenous laminin-10, because infusion of anti-laminin γ1 antibody had the same effect. The disruption of the laminin layer by laminin-1 1) did not require the intact protein because infusion of plasmin-digested laminin-1 gave similar results; 2) was posttranscriptional, because there was no effect on laminin mRNA expression; and 3) occurred in both tPA–/–and plasminogen–/–mice, indicating that increased plasmin activity was not responsible. Finally, although tPA–/–mice are normally resistant to excitotoxin-induced neurodegeneration, disruption of the endogenous laminin layer by laminin-1 or anti-laminin γ1 antibody renders the tPA–/–hippocampal neurons sensitive to kainate. These results demonstrate that neuron interactions with the deposited matrix are not necessarily recapitulated by interactions with soluble components and that the laminin matrix is a dynamic structure amenable to modification by exogenous molecules.

Laminins are important components of the extracellular matrix, and participate in neuronal development, survival and regeneration. The tissue plasminogen activator/plasmin extracellular protease cascade and downstream laminin degradation are implicated in excitotoxin-induced neuronal degeneration. To determine which specific laminin chains are involved, we investigated the expression of laminins in the hippocampus, and the cell types expressing them. Reverse transcription-PCR demonstrated that the messenger RNAs for all laminin chains could be detected in the hippocampus. To determine the localization of laminin chain expression, immunostaining was used. This method showed that alpha5, beta1 and gamma1 are most highly expressed in the neuronal cell layers. Immunoblotting confirmed the hippocampal expression of the chains alpha5, beta1 and gamma1, and RNA in situ hybridization showed a neuronal expression pattern of alpha5, beta1 and gamma1. At early time points following intrahippocampal injection of kainate, alpha5, beta1 and gamma1 chain immunoreactivities were lost. In addition, tissue plasminogen activator-deficient mice, which are resistant to kainate-induced neuronal death, show no significant change in laminins alpha5, beta1 and gamma1 after intrahippocampal kainate injection. Taken together, these results suggest that laminin-10 (alpha5-beta1-gamma1) comprises a major neuronal laminin in the mouse hippocampus, and is degraded before neuronal death during excitotoxic injury by the tissue plasminogen activator/plasmin protease cascade. By identifying a neuronal laminin (laminin-10) that participates in neuronal degeneration after excitotoxic injury, this study clarifies the molecular definition of the extracellular matrix in the hippocampus and further defines a pathway for mechanisms of neuronal death.

Neurodegenerative diseases cause considerable morbidity and mortality throughout the world. Using an excitotoxin-induced model for neurodegeneration, the extracellular serine proteases tissue plasminogen activator (tPA) and plasmin(ogen) have recently been implicated in neuronal death in the mouse hippocampus. The search for plasmin substrates in the brain has revealed that the extracellular matrix (ECM) is an important factor influencing neuronal viability. The study of neuronal ECM proteins and the extracellular proteases that act upon them could have important therapeutic implications for the use of thrombolytics in stroke, and for the development of new treatments for neurodegenerative disease. This review summarizes recent research efforts that characterize the extracellular proteases and ECM proteins involved in neuronal death, and relates the potential clinical significance.

Background/Aims: The diagnostic criteria for critical illness-related corticoid insufficiency (CIRCI) are not well established, particularly for children. In addition to alterations in adrenal function, cellular resistance to glucocorticoid action could contribute to CIRCI due to alterations in the functioning of the intracellular receptor protein for corticosteroids, the glucocorticoid receptor (GR). Methods: We have therefore undertaken a pilot, prospective study to assess whether cellular GR activity can be measured in peripheral blood mononuclear cells (PBMCs) from critically ill children. Results: Total and cytoplasmic, but not nuclear GR levels were significantly lower in PBMCs from critically ill children (i.e. sepsis/septic shock and traumatic brain injury) compared to healthy controls. While total cortisol concentrations did not differ between test groups, salivary and serum-free cortisol concentrations were significantly greater in both groups of children with critical illness. Cortisol-binding globulin levels were significantly lower in patients with sepsis/septic shock. Conclusions: The lower total and cytoplasmic receptor levels in critically ill children suggest that the GR-mediated response to exogenous glucocorticoid therapy may be limited. However, the nuclear transport of GR in critically ill patients suggests that residual receptors in these patients retain functionality and may be accessible to therapeutic treatments that maximize their activity.

Whereas thyroid nodules are less common among children than among adults, the anxiety generated by the finding of a thyroid nodule is high because 20% of nodules found in children contain thyroid cancer. Discovery of a nodule in the context of hyperthyroidism is usually comforting due to the presumption that the nodule represents a benign toxic adenoma.An 11-year-old girl presented with heavy menses, fatigue, and a right thyroid mass. Laboratory evaluation revealed elevated triiodothyronine and undetectable thyroid-stimulating hormone. Thyroid ultrasonography revealed a 3.5 cm nonhomogenous nodule, and scintigraphy was consistent with an autonomous hyper-functioning nodule. Fine-needle aspiration biopsy could not rule out malignancy, and patient underwent right hemithyroidectomy and isthmusectomy. Pathology was consistent with papillary thyroid carcinoma.We report the discovery of papillary thyroid carcinoma in an autonomously hyperfunctioning nodule in an 11-year-old girl. Detection of an autonomously functioning thyroid nodule in children and adolescents does not exclude the possibility of thyroid carcinoma and warrants careful evaluation and appropriate therapy.

Neuronal damage in the CNS after excitotoxic injury is correlated with blood-brain barrier (BBB) breakdown. We have used a glutamate analog injection model and genetically altered mice to investigate the relationship between these two processes in the hippocampus. Our results show that BBB dysfunction occurs too late to initiate neurodegeneration. In addition, plasma infused directly into the hippocampus is not toxic and does not affect excitotoxin-induced neuronal death. To test plasma protein recruitment in neuronal degeneration, we used plasminogen-deficient (plg−/−) mice, which are resistant to excitotoxin-induced degeneration. Plasminogen is produced in the hippocampus and is also present at high levels in plasma, allowing us to determine the contribution of each source to cell death. Intrahippocampal delivery of plasminogen to plg−/−mice restored degeneration to wild-type levels, but intravenous delivery of plasminogen did not. Finally, although the neurons in plg−/−mice do not die after excitotoxin injection, BBB breakdown occurs to a similar extent as in wild-type mice, indicating that neuronal death is not necessary for BBB breakdown. These results indicate that excitotoxin-induced neuronal death and BBB breakdown are separable events in the hippocampus.