OBJECTIVES/SPECIFIC AIMS: Discrimination within the healthcare system and physician distrust have been associated with adverse clinical outcomes for people living with HIV; however, many studies do not link these variables to biological data. We hypothesize that perceived healthcare discrimination and physician distrust associates with higher longitudinal viremia among HIV-positive women. METHODS/STUDY POPULATION: A 2006 cross-sectional survey assessed healthcare-based discrimination and physician trust in 92 HIV-positive and 46 high-risk HIV-negative women from the Washington DC Women’s Interagency HIV Study (DC-WIHS). In addition, we identified HIV viral load trajectories and demographics from the HIV-positive women who contributed≥4 semi-annual visits from 1994 to 2015. Viral suppression was defined by assay detection limits (<80 to <20 copies/mL). Group-based probability trajectory analyses grouped women based on longitudinal viral load patterns, and identified 3 groups: sustained viremia (n=32) with low-viral suppression over time, intermittent viremia (n=27) with varying suppression over time, and non-viremia (n=33) with high-longitudinal viral suppression. Ordinal logistic regression models assessed trajectory group and discrimination variables, controlling for demographics, using stepwise selection with significance level of α=0.05. RESULTS/ANTICIPATED RESULTS: Most women were African American (60%), insured at the time of visit (89%) and nonsmokers (56%). While physician trust did not differ by HIV viral trajectory group, trust was lower among HIV-negative women compared with HIV-positive women (p=0.03). Over 1 in 5 HIV-positive women reported discrimination in the healthcare system based on HIV status (21.3%). Report of discrimination based on drug/alcohol use was higher among HIV-negative participants (19.2% vs. 6.5%, p=0.01). Among women with longitudinal sustained viremia, report of discrimination based on race ethnicity (29%, p=0.004) and sexual orientation (15.6%, p=0.008) were higher than within the nonviremic and intermittent trajectory groups. DISCUSSION/SIGNIFICANCE OF IMPACT: Physician trust did not associate with increased longitudinal viral suppression among HIV-positive women in Washington, DC. Lack of physician trust among high-risk HIV-negative women could have implications for uptake of prevention methods. Reports of discrimination vary between HIV-positive and HIV-negative women in the Washington, DC area. The findings of healthcare system distrust among HIV-negative women has implications outside the realm of HIV, as this lack of trust may impact risk for other disease states among similar populations of women.

OBJECTIVES/SPECIFIC AIMS: To describe adverse behavioral symptoms attributed to droxidopa therapy for neurogenic orthostatic hypotension (nOH). METHODS/STUDY POPULATION: BACKGROUND: Droxidopa, a norepinephrine (NE) precursor, improves symptoms of nOH by replenishing NE levels. Central NE effects are poorly described but may offer potential benefits given the pathophysiologic progression of α-synuclein-related disorders. Here we report a series of cognitive and behavioral side effects linked to droxidopa therapy. METHODS: We identified 5 patients treated at Vanderbilt University who developed behavioral symptoms including mania, irritability, and disorientation shortly after the initiation of droxidopa for nOH. Comprehensive chart reviews were performed for all patients, including analysis of droxidopa titration schedule and dosing, medical comorbidities, clinical course, and outcome. All patients had symptoms of synucleinopathy, manifesting with autonomic failure, REM behavior disorder, and parkinsonism. Four met criteria for idiopathic PD, and one was diagnosed with pure autonomic failure but had concomitant symptoms of parkinsonism and REM sleep behavior disorder. RESULTS/ANTICIPATED RESULTS: Our patients had no significant cognitive or behavioral symptoms before the initiation of droxidopa. The average decrease in blood pressure upon standing was 27 mmHg systolic and 17 mmHg diastolic. Behavioral disturbances were observed early in the titration period and at relatively low doses of droxidopa (total daily doses ranging from 300 to 800 mg/day; droxidopa therapeutic dose range 900–1800 mg/d). The most common symptoms reported were mania, irritability, and confusion. Symptoms resolved with dose reduction in 4 patients, and droxidopa was discontinued in 1 patient due to persistent irritability. No other medical comorbidities or alternative etiologies were identified to explain these effects. DISCUSSION/SIGNIFICANCE OF IMPACT: Droxidopa is a prodrug designed to act peripherally, but may also have important, yet poorly described, central effects. We hypothesize that these behavioral manifestations result from an “overdose” of key NE networks linking orbitofrontal and mesolimbic regions. Further studies are warranted to better characterize central NE effects in patients treated with droxidopa.

OBJECTIVES/SPECIFIC AIMS: Background: Delirium is a well described form of acute brain organ dysfunction characterized by decreased or increased movement, changes in attention and concentration as well as perceptual disturbances (i.e., hallucinations) and delusions. Catatonia, a neuropsychiatric syndrome traditionally described in patients with severe psychiatric illness, can present as phenotypically similar to delirium and is characterized by increased, decreased and/or abnormal movements, staring, rigidity, and mutism. Delirium and catatonia can co-occur in the setting of medical illness, but no studies have explored this relationship by age. Our objective was to assess whether advancing age and the presence of catatonia are associated with delirium. METHODS/STUDY POPULATION: Methods: We prospectively enrolled critically ill patients at a single institution who were on a ventilator or in shock and evaluated them daily for delirium using the Confusion Assessment for the ICU and for catatonia using the Bush Francis Catatonia Rating Scale. Measures of association (OR) were assessed with a simple logistic regression model with catatonia as the independent variable and delirium as the dependent variable. Effect measure modification by age was assessed using a Likelihood ratio test. RESULTS/ANTICIPATED RESULTS: Results: We enrolled 136 medical and surgical critically ill patients with 452 matched (concomitant) delirium and catatonia assessments. Median age was 59 years (IQR: 52–68). In our cohort of 136 patients, 58 patients (43%) had delirium only, 4 (3%) had catatonia only, 42 (31%) had both delirium and catatonia, and 32 (24%) had neither. Age was significantly associated with prevalent delirium (i.e., increasing age associated with decreased risk for delirium) (p=0.04) after adjusting for catatonia severity. Catatonia was significantly associated with prevalent delirium (p<0.0001) after adjusting for age. Peak delirium risk was for patients aged 55 years with 3 or more catatonic signs, who had 53.4 times the odds of delirium (95% CI: 16.06, 176.75) than those with no catatonic signs. Patients 70 years and older with 3 or more catatonia features had half this risk. DISCUSSION/SIGNIFICANCE OF IMPACT: Conclusions: Catatonia is significantly associated with prevalent delirium even after controlling for age. These data support an inverted U-shape risk of delirium after adjusting for catatonia. This relationship and its clinical ramifications need to be examined in a larger sample, including patients with dementia. Additionally, we need to assess which acute brain syndrome (delirium or catatonia) develops first.

OBJECTIVES/SPECIFIC AIMS: Millions of diverse, older adults live with serious and chronic illness for which they will face complex, ongoing medical decisions. Advance care planning (ACP) has been conceptualized as a health behavior that supports adults in understanding and sharing their values, goals, and preferences for future medical care. Depression and anxiety are known barriers to participation in health behaviors. It is unknown whether depression and anxiety are associated with ACP participation or with patients’ values for future medical care. Understanding whether depression and anxiety are associated with ACP would be important to tailor ACP interventions. METHODS/STUDY POPULATION: In total, 908 English-speaking and Spanish-speaking participants ≥55 years of age were recruited from a San Francisco county hospital. We measured depression (Patient Health Questionnaire 8-item scale) and anxiety (Generalized Anxiety Disorder 7-item scale), dichotomized into none-to-mild Versus moderate-to-severe. We measured ACP engagement using a validated survey of Behavior Change Processes (e.g., knowledge, self-efficacy, readiness; 5-point Likert) and Action Measures (e.g., ask, discuss, and document one’s wishes; yes/no). We elicited values concerning life extension categorized as “life is always worth living no matter the health situation” Versus “some health situations would make life not worth living.” To explore associations, we usedχ2, Mann-Whitney tests, linear and logistic regressions. RESULTS/ANTICIPATED RESULTS: Mean participant age was 64 years±6, 80% were non-White, 40% had limited literacy, 45% were Spanish-speaking, and the prevalence of depression and anxiety was 12% and 10%, respectively. Depression and anxiety were not associated with ACP Engagement, p>0.05. However, participants with depression had an increased odds of reporting “some health situations would make life not worth living” than those not depressed, p=0.02. In multivariate linear and logistic regression, controlling for age, gender, literacy, and health status, having depression increased the odds of not valuing life extension OR 2.9 (CI: 1.7–4.9). Anxiety was not associated with values concerning life extension, p>0.05. DISCUSSION/SIGNIFICANCE OF IMPACT: Depression and anxiety were not associated with prior ACP engagement suggesting engaging patients in ACP does not increase these conditions. However, depression was associated with an increased odds of not valuing life extension and, therefore, may influence treatment choices. Longitudinal randomized controlled trials of an ACP intervention are currently underway to investigate these associations further.

OBJECTIVES/SPECIFIC AIMS: There are currently over a million survivors of childhood, adolescent, and young adult cancer in the United States, many of whom were treated with radiation therapy. Chest radiation with fields including the coronary arteries is a risk factor for cardiovascular disease. Of note, survivors are often unaware of this increased cardiovascular disease risk or, if they are aware, do not know how to mitigate the risk. Visual aids and communicating risk in terms of absolute risk reductions are shown to improve patients’ understanding. The Institute of Medicine recommends use of decision aids to optimize patient discussions of benefits and harms of therapies. Our goal is to develop and pilot test a statin therapy risk communication tool for use in high-risk cancer survivors to improve shared decision making and patient knowledge of coronary artery disease risk. METHODS/STUDY POPULATION: Participants were recruited from the adult long-term follow-up clinic at Sloan Kettering Cancer Center into 2 arms, usual care Versus intervention with the statin risk communication tool. The post-visit assessment used Likert-like scales to explore patient perceptions of statin use. The study was not powered for significance as it was a feasibility study; descriptive statistics were run to compare the 2 groups. RESULTS/ANTICIPATED RESULTS: Participants (n=45) had a mean age of 45. In the intervention group, 92% felt the information given was right compared with 73% of the usual care group. In all, 63% of the intervention arm felt the information was helpful, compared with 47% of those in usual care. And 53% of usual care would recommend the method to other patients and for other treatment choices compared to 67% of those in the intervention arm. DISCUSSION/SIGNIFICANCE OF IMPACT: This risk communication tool was assessed for acceptability and found to be more acceptable compared with usual care. In addition, we will gather further information on knowledge enhancement and decisional conflict as well as qualitative data regarding the shared decision making experience. With this information, a future randomized-controlled trial across institutions could provide information on how childhood, adolescent, and young adult survivors approach shared decision making with risk communication tools.

OBJECTIVES/SPECIFIC AIMS: Electronic health records have become the fulcrum for efforts by institutions to reduce errors, improve safety, reduce cost, and improve compliance with recommended guidelines. In recent times they are also being considered as a potential game changer for improving patient recruitment for clinical trials (CT). Although the use of CDS for clinical care is partially understood, its use for CT patient identification and recruitment is young and a great deal of experimental and theoretical research is needed in this area to optimize the use of CDS tools that personalize patient care by identifying relevant clinical trials and other research interventions. The use of CDS tools for CT recruitment offers a great deal of possibilities, but some initial usage has been disappointing. This may not be surprising because, while the implementation of these interventions is somewhat simple, ensuring that they are embedded into the right point of the care providers workflow is highly complex and may affect many actors in a clinical care setting, including patients, nurses, physicians, clinical coordinators, and investigators. Overcoming the challenges of alerting providers regarding their patient’s eligibility for clinical trials is an important and difficult challenge. Translating that effort into effective recruitment will require understanding of the psychological and workflow barriers and facilitators for how providers respond to automated alerts requesting patient referrals. Evidence from using CDS for clinical care that shows alerts become increasingly ignored over time or with more exposure (1, 2). The features, timing, and method of these alerts are important usability factors that may influence effectiveness of the referral process. Focus group methods capture the shared perspectives of a phenomenon and have been shown to be an effective method for identifying perceptions, attitudes, information needs, and other human factors effecting workflow (3, 4). Our objective was to develop a generalizable method for measuring physician and clinic level factors defining a successful point of care recruitment program in an outpatient care setting. To achieve this we attempted to (a) Characterize provider’s attitudes regarding CTs referrals and research. (b) Identify perceived workflow strategies and facilitators relevant to CT recruitment in primary care. (c) Develop and test a pilot instrument. METHODS/STUDY POPULATION: The methods had 3 phases: focus groups, development of item pool, and tool development. Focus group topics were developed by 4 experienced investigators, with training in biomedical informatics, cognitive psychology, human factors, and workflow analysis, based upon a knowledge of the literature. A script was developed and the methods were piloted with a group of 4 clinicians. In all, 16 primary care providers, 5 clinic directors, and 6 staff supervisors participated in 6 focus groups, with an average of 5 participants each, to discuss clinical trial recruitment at the point of care. Focus groups were conducted by the development team. Audio recording were content coded and analyzed to identify themes by consensus of 3 authors. Item Pool generation involved extracting items identified in the focus group analysis, selecting a subset deemed most interesting based on knowledge of the recruitment literature and iteratively writing and refining questions. Instrument development consisted of piloting an initial 7-item questionnaire with a local primary provider sample. Questions were correlated with the item pool and limited to reduce provider burden, based on those that the study team deemed most applicable to information technology supported recruitment. Descriptive statistical analysis was performed on the pilot survey results. An online survey was developed based on the findings of the focus groups and emailed to 127 primary care providers who were invited to participate. In total, 36 questionnaires were completed. This study was approved by the University of Utah Institutional Review Board. RESULTS/ANTICIPATED RESULTS: The results section is organized into 3 sections: (a) Focus groups, (b) Item generation; and (c) Questionnaire pilot. (I) (1) Focus Groups. Themes identified through a qualitative review are presented below with illustrative comments of participants. The diversity of attitudes and willingness to support clinical trial recruitment varied so substantially that no single pattern emerged. Attitudes ranged from enthusiastic support, to interest in some trials to disinterest or distrust in trials in general. Compensation for time spent, which could be monetary, informational, or through professional recognition; and provider relationship with the study team or pre-selection of specific trials by a clinic oversight committee, and importance to providers practice positively affected willingness to help recruit. “I would love to get people into clinical trials as much as possible... If it works for them you are going to help a whole lot of other people.” If we felt like we have done every possible thing that was already established as evidence-based and it didn’t work out, then we would consider the trials. I think that studies are more beneficial for specific specialists... There might be a whole slew of things that I never deal with or don’t care about because it’s not prevalent for my patient population. Local and reputable... A long distance someone asking to do something is just not the same as someone in the trenches with you. The bottom line is how much work is involved at our end and if there is going to be any compensation for that. I think also the providers would like have feedback on what they referred them to. And how did it go? So did we pick the right patient? ... It helps us to know, did they even sign up for the study? Getting your name on a research paper would be nice too. Lack of information regarding trials reduced support for recruitment of patients. Providers stated that they do not know how to quickly find information about studies, nor do they have time to find the information, and therefore cannot efficiently council patients regarding trial participation. Notifications regarding clinical trials that were deemed to be important included: Trial coordinator intention to recruit patients, enrollment of a patient in a clinical drug trial, trial progress and result updates, and reports of effectiveness of provider recruitment efforts. Perceived information needs regarding trials that providers are referring patients to included: trial purpose, design, benefits and risks, potential side effects, intervention details, medication class (mechanism of action), drug interactions with study drug, study timeline, coordinator contact information, link to print off patient handouts, enrollment instructions, and a link to study website. (2) It’s just we don’t know any of the information ... and it can’t take any of our time. ... I don’t have time to research it. Sometimes the patients ask me questions about it and I would like to be in a position where I have some information about it before I am asked. It would be nice to be notified if they [my patients] are enrolled in the trial, when it turns into actual recruitment. I do like to know if they’re in [a trial] so that when they come in for problems, I at least know that they might be on a study medication so I can be safe. I’ll get an ER message, “The patient got admitted. There blood pressure’s, you know, tanked, because they’re on a study drug I didn’t know anything about.” if there’s certain side effects that I need to be watching out for. It would also be good to have a contact person from the study in case we need to notify them of. “this person’s possible having an adverse event. Look into it more.” (3) Provider burden associated with patient recruitment appeared to be a deterrent. These burdens included adding to the providers task list, increasing the time required to complete a visit, and usurpation of control over the patients care plan with the associated effect on provider quality scores. We don’t have time. I mean, we don’t even take a lunch break. I have 15 minutes and now this is taking this many minutes away from my 15 minutes. I am just sick of extra work. We already have so much extra work. It’s just more stuff to do. We are maxed out on stuff to do. Right now, part of our compensation depends on having our patients A1Cs controlled. And so if we’re taking a chance that maybe they’re getting a medicine, maybe they’re not, maybe it’ll help, maybe it won’t, its gonna further delay our ability to get paid. Cause they’re like “I’m not going to let you go mess up my patient and I’m going to have to deal with the consequences is kind of the way they think. If you’re going to put the patient in a study, being able drop them from our registry so we don’t get penalized for a negative outcome [is important]. (4) Patient’s needs were a priority among factors influencing likelihood to help recruitment patients. Providers considered perceived benefit or risk to the patient, such as additional healthcare services, increased monitoring, financial assistance, or access to new treatments when other options have been ineffective, important; as well as continuance of established care that has proven effective, and ethical recruitment that addresses language and mental health to ensure that patients can make decisions regarding study participation. If there’s something great that’s gonna benefit a patient, I would definitely wanna know about it to give them that option. You know that’s what we wanna try to do is make our patients better. Someone who is really well controlled and doing well, I would not tend to put them toward the study. Just keep going with what’s working right now. Sometimes there’s financial incentives for them to participate, so you know, if its a good fit its easy to at least offer that to the patient. They get treatment maybe that they can’t afford. You don’t want to be seen as somebody who's forcing a patient... if their provider is telling them this is a good idea you are more likely to get your patient to do it. I think they have to understand what a clinical trial is, first of all, in that it’s a trial. Right? We’re trying to figure out if a certain treatment is good or not. It may not work. It may work. With many patients, they don’t only have medical problems, but significant mental illness that sometimes interferes a lot with just our treatment of them here for their clinical problems. And so, that probably would interfere with someone’s ability to understand and consent to a trial. And the patients have the right to make that choice. I don’t need to be—I don’t mind influencing them on things I know about, I think are invaluable, but I don’t need to be a barrier to them. (5) Perceived responsibility in trial recruitment varied substantially, from no involvement at all, to prescreening, counseling, or recruiting patients. Some providers felt that they should have the right to say “no” to recruitment of their patients while others believed prescreening was an unnecessary burden, outside of their role as a primary care provider. if someone prescreens and thinks its appropriate and gives me that judgment call to say, do you think it would be a good fit? I think one of them, they sent, and I said, Oh, I don’t think it would be a good fit because of this...So that would be fine. I don’t think I need to be a gatekeeper for studies. I mean, if there’s people that qualify for a study, and there’s a great study that’s been approved, and they can recruit them without me knowing, that doesn’t bother me in the slightest. I liked how it was—I could do a simple referral ... someone else figured out the qualifications. if we knew of ongoing studies and if we thought a certain patient may qualify for a certain study, we just contact the coordinator, and then they just take care of the rest. I think that appropriate ... from our perspective, would be, “Are you interested?” “This is the number for a person who can sit with you, talk with you about a trial, tell you everything about it, answer your questions, and then you can make a decision.” I’m not going to let you go mess up my patient and I’m going to have to deal with the consequences. (6) A clinic-implementation approach that systemizes workflow, limits the number of trials providers are asked to recruit for, and minimizes provider time burden is needed. Suggested methods for informing providers of patient clinical trial eligibility included: email, alerts, in-basket messages, texts, phone-calls, and in-person contact. People are so sick of change, change, change, change ... if there’s no stability whatsoever, then people get frustrated and start to burn out. Having my staff remember how to do it correctly and I remember what studies we have going ... it becomes somewhat of a burden... it’s hard for us to remember as we are flying through our day. There just needs to be a clear understanding with those roles... Who does the patient call? We don’t want to look like we don’t know what we are doing. There probably should be a selection committee put together from various people who have stakes in the community, at least who can say, “This would be applicable for xx clinic.” (7) Provider Suggestions Providers had multiple suggestions regarding notification methods. (II) Development of item pool and construction of questionnaire The specific items were constructed from literature review on physician’s attitudes and results from the focus group. The overarching concern was on readability, brief questionnaire size, and relevance. A large item were constructed and then reduced through piloting. (III) Questionnaire Pilot Results: The 7-item pilot questionnaire was completed by 36 physicians (28% response rate). In this section, we report the empirical results. DISCUSSION/SIGNIFICANCE OF IMPACT: Discussion Relevance of Methods. Overall, the described methods for determining components for a recruitment program in primary care shows early promise. The focus groups that consisted of providers, staff and administrators resulted in insights as to workflows, attitudes, and clinical processes. These insights significantly varied across clinics. This variation supported the need for an individualized clinic-based approach that will meet local needs. During the course of the study, participants were willing to participate in all activities (although some requested payment). We were able to conduct the focus groups as scheduled and obtained the desired input. The analysis of the focus group transcripts was performed using iterative discussions and did not needed any special adaptation for this area of study. The pilot survey response rate was within the expected for this type of study. Focus groups can rapidly provide rich information regarding attitudes and other factors affecting provider participation at the point of care. However, findings from focus groups must always be confirmed through larger studies. It is important to keep the focus groups small and to hold multiple focus groups to offset the more vocal participants that may influence comments of others. This study shows that using our 3-step approach it is possible to gather important information on clinician’s and staff perceptions and needs to participate in point of care patient recruitment for CT. The focus groups also provide an important step for survey construction. Designing surveys empirically requires multiple validation efforts, which will be conducted in the future. However, we can draw preliminary conclusions from the results of the pilot study which are quite informative and they are discussed below. Near future work will be to expand the response rate through additional local survey and conduct formal psychometric testing and validation both locally and nationally. A final validation will be proposed through the CTSA consortiums. Variation in responses. There was a lack of normal curves in our survey results. This points to the need to target education and recruitment efforts by provider type (with similar perspectives). Identification of these types would be useful. Some specific points regarding variability that should be considered in program design. Preferences for trail recruitment methods. Many trial recruitment notification methods have the potential to be successful when used judiciously and done well, particularly if the trial coordinator/provider relationship is supported by reciprocal benefits to the provider. Consistency in workflow within seems paramount to success. Providers can pull some notifications at a time they choose, while other notifications interrupt and must be used sparingly. Some allow review of multiple patients at the same time, and some foster easy access to the patient’s medical record. Conclusions. The authors recommend that recruitment HIT be customizable at the clinic and provider level by responsibility and interest to allow selection of level of information, delivery method, that is, email, text, in-basket, alert, dashboard, mail; frequency of notification, and an opt out feature. These customizable options will allow for better support of clinic workflow or goals. There is the potential with machine learning technology to monitor provider interactions with trial notifications and for the system to automatically make adjustments to the method and level that best supports each physician. Limitations: The major limitation is the focus on one site only and one delivery system (university based). The low response makes generalization difficult. Efforts to improve the rate are underway. Many populations are under-represented in Utah. Full psychometric analysis was not conducted but will part of the final project.

OBJECTIVES/SPECIFIC AIMS: Chronic obstructive pulmonary disease (COPD) is a leading cause of both hospitalizations and readmissions in the United States, and about 1 in 5 hospitalized patients with COPD will be readmitted within 30 days. COPD-focused self-management programs are frequently used to help patients better manage their symptoms and prevent hospitalization. However, while the majority of patients with COPD have at least one comorbidity, most trials of COPD self-management programs either excluded patients with significant comorbidities or did not analyze the impact of comorbidities on patient outcomes. Using data from the BREATHE trial of a COPD self-management program, this study aims to determine if patient post-intervention outcomes differ based on the intensity and type of patient comorbidities. METHODS/STUDY POPULATION: In total, 240 patients hospitalized for COPD were randomly assigned to either a comprehensive self-management intervention or usual transitional care. Primary outcomes for this trial were the number of COPD-related hospitalizations and emergency department visits at 6 months and changes in COPD-specific quality of life. To determine whether patient comorbidities modify the effect of the self-management intervention on readmission and quality of life outcomes, we will compare patient outcomes across groups stratified by comorbidity burden (Charlson Comorbidity Index) and type (baseline diagnosis of congestive heart failure, diabetes, and depression). In addition, we will use regression analysis with interaction terms to test for interaction between comorbidity burden/type and intervention assignment. RESULTS/ANTICIPATED RESULTS: We hypothesize that the effect of the self-management intervention will differ in patients with greater comorbidity burden due to competing medical demands for patients with multimorbidity. DISCUSSION/SIGNIFICANCE OF IMPACT: The results of this study will help clinicians better target disease-specific self-management programs to the groups of patients with COPD who are likely to receive the greatest benefit from this type of intervention.

OBJECTIVES/SPECIFIC AIMS: Familial partial lipodystrophy (FPLD) is an inherited, rare syndrome characterized by selective absence of adipose tissue from extremities which is associated with severe insulin resistance, and metabolic dyslipidemia (with hypertriglyceridemia, and low HDL) Typically, 30%–50% of patients with FPLD demonstrate a pathogenic variant in Lamin A (LMNA) gene that is associated with inherited cardiomyopathy and arrhythmia syndromes. We inquired the prevalence of having abnormal ECGs and echocardiograms in FPLD and whether there is a difference in evaluated parameters with respect to genotype. METHODS/STUDY POPULATION: We conducted a retrospective review of an established a cohort of 58 patients (age range: 12–71, M/F 8/50) with FPLD. Demographic characteristics, genotype, fasting triglyceride, hemoglobin A1c, LDL, and HDL levels were collected; ECGs and echocardiograms were also interrogated. RESULTS/ANTICIPATED RESULTS: Out of 58 patients, 22 (38 %) displayed a pathogenic variant in the LMNA gene. In total, 71% of patients (41/58) had an abnormal ECG and echocardiogram; 40% (23/58) of the patients displayed an arrhythmia on the ECGs (13 in the patients with LMNA variants and 10 in the non-LMNA group). The likelihood of having an arrhythmia was significantly higher in the patients with LMNA variants versus those without (odds ratio of 3.4, CI: 1.1–10.6). DISCUSSION/SIGNIFICANCE OF IMPACT: The overall prevalence of abnormal ECHO and/or ECG is high at 45/58 (78 %) in FPLD. Patients with LMNA variants have a 3.4 times increased risk of developing cardiac arrhythmias compared to those without. We recommend vigilant, monitoring for cardiac disease in FPLD and for arrhythmias in patients with FPLD and LMNA variants.

OBJECTIVES/SPECIFIC AIMS: Traditional clinical trials typically enroll a homogenous population to test the efficacy of an intervention. Pragmatic trials deliberately enroll a more diverse population to enhance generalizability, but doing so may increase heterogeneity of treatment effect among subpopulations. For example, the effect of a treatment on an outcome may vary based on patients’ sex, comorbidities, or baseline risk of experiencing the outcome. We hypothesized that heterogeneity of treatment effect by baseline risk for the outcome could be demonstrated in a large pragmatic clinical trial. METHODS/STUDY POPULATION: We performed a prespecified secondary analysis of a recent pragmatic trial comparing balanced crystalloids Versus 0.9% saline among critically ill adults. The primary endpoint of the trial was major adverse kidney events within 30 days of ICU admission, censored at hospital discharge (MAKE30). MAKE30 is a composite outcome of all-cause mortality, new renal replacement therapy, or persistent renal dysfunction. Using a previously published model with high predictive accuracy for MAKE30 (area under the curve=0.903), we calculated the baseline risk of MAKE30 for all trial participants. We then developed a logistic regression model for MAKE30 with independent covariates of fluid group assignment, baseline risk of MAKE30 as a nonlinear continuous variable, and the interaction between group assignment and MAKE30 baseline risk. RESULTS/ANTICIPATED RESULTS: Among 15,802 patients from 5 intensive care units enrolled in the original trial, 126 had missing variables for predicted risk of MAKE30. Mean predicted risk of MAKE30 among all patients was 15.4%; median was 4.4% (interquartile range 2.2%–17.1%). Predicted risk of MAKE30 did not significantly differ between groups (p=0.61 by Mann-Whitney U-test). The incidence of MAKE30 in the trial was 14.9%, and the prediction model was well-calibrated overall (AUC=0.891). In a logistic regression model examining the interaction between group assignment and predicted risk of MAKE30, group assignment significantly affected MAKE30 (odds ratio saline:balanced 1.13, 95% CI: 1.02–1.27, p=0.02), but we observed no interaction between the effect of group assignment on MAKE30 and patients’ predicted risk of MAKE30 at baseline (p=0.66 for interaction term). DISCUSSION/SIGNIFICANCE OF IMPACT: In a large pragmatic trial demonstrating a significant difference in the primary outcome of MAKE30 between balanced crystalloids and saline, a previously published model accurately predicted MAKE30 using baseline factors. However, contrary to our hypothesis, the baseline risk of MAKE30 did not modify the effect of fluid group on the observed incidence of MAKE30. Our analysis could not account for unmeasured confounders and may be underpowered to detect a significant interaction. Our findings suggest that the impact of balanced crystalloids versus normal saline on renal outcomes in critically patients is consistent across all levels of risk.

OBJECTIVES/SPECIFIC AIMS: The central aim of the study is to examine the effect of a Dietary Approaches to Stop Hypertension (DASH) diet on hemodynamic, cardiometabolic, and inflammatory markers in advanced heart failure patients with implanted hemodynamic monitoring devices. METHODS/STUDY POPULATION: This pilot study will employ a clinical feeding trial using a 1-group pre-post test design with an anticipated sample size of n=36 (n=20 plus 44% expected attrition). Heart failure patients 18+ years of age with English language literacy, classified as NYHA functional stage III, regardless of ventricular ejection fraction, who have undergone CardioMEMS™ hemodynamic monitoring device (St. Jude Medical, Atlanta, GA, USA) implantation and have received optimized heart failure therapy for 3+ months will be recruited at Piedmont Athens Regional Hospital in Athens, GA. The study is divided in (a) a calibration (self-selected diet) and (b) a DASH feeding intervention phase (each 21 days in length). The DASH meals will strictly follow meal planning guidelines published by the National Heart, Lung, and Blood Institute of the National Institutes of Health, and be prepared under the supervision of a registered dietitian at the University Health Center in Athens, GA. The DASH diet is a heart-healthy eating pattern that is focused on adequate consumption of fruits, vegetables, whole grains, low-fat dairy, fish, poultry, beans, nuts, and vegetables oils while emphasizing limited intake of foods containing saturated fat, such as fatty red meats, full-fat dairy products, and tropical oils, such as coconut, palm kernel, and palm oils, as well as sugar-sweetened beverages and sweets. Participants will visit the University of Georgia Clinical and Translational Research Unit on 3 occasions at baseline, upon completion of the calibration phase, and following completion of the intervention phase for repeated collection of anthropometric (height, weight, waist and hip circumference, percent body fatness), cardiometabolic (blood pressure, blood glucose, HbA1C, lipid panel, basic metabolic panel, BNP, NT-proBNP, troponin 1, MR-proADM, sST2), functional status (6-min walk test), inflammatory (IL-1a, IL-1b, IL-6, TNF-a), and self-reported measures (demographic and economic characteristics, health, chronic diseases, perceived stress, heart failure-related quality of life, social support, sleep quality, food insecurity, tobacco smoking status, healthcare utilization, medication adherence). Hemodynamic marker (pulmonary artery pressure, heart rate) and pharmacotherapy information (medication count, type, strength, and dosing) will be obtained from through retrospective assessment of EHR data. Descriptive statistics [percentage, mean (SD), median (IQR), mode, range] will be used to describe sample characteristics at each of the study visits, as well as characteristics of participants’ self-selected diets during the calibration phase. To measure changes in hemodynamic, cardiometabolic, and inflammatory markers pre-post DASH diet intervention, we will use paired Student t-tests (normal distribution) or Wilcoxon rank-sum tests (non-normal distribution), as appropriate. Data collection will be carried out between February and November 2018. RESULTS/ANTICIPATED RESULTS: The study builds upon previous studies showing improvement of ventricular function, arterial stiffness, oxidative stress, and blood pressure after short-term consumption of a sodium-restricted DASH diet in heart failure patients with preserved ejection fraction, and will provide new information on the cumulative effect of short-term adherence with a DASH diet on indicators of heart failure complications, including hemodynamic, cardiometabolic, and inflammatory markers. In addition, it will give better insight on heart failure patients’ habitual dietary intake in the context of other sociodemographic, economic, health, and social factors. DISCUSSION/SIGNIFICANCE OF IMPACT: Findings from the proposed study will provide key knowledge of dietary influences on ventricular function in order to define evidence-based diet therapy needed for the early prevention of HF complications in advanced heart failure patients.

OBJECTIVES/SPECIFIC AIMS: The aims of this project are to: (1) examine placebo effects on subjective and objective outcome measures, (2) determine if an increase in the placebo is associated with changes in benefit, (3) evaluate if the trauma related insomnia placebo group in our study has different side effect reports compared with insomnia placebo participants in previous suvorexant trials, and (4) (Exploratory) examine associations between the placebo group’s characteristics (e.g., trauma/PTSD severity, demographics) and placebo effects. METHODS/STUDY POPULATION: The parent study is a randomized double-blind placebo-controlled clinical trial (clinicaltrials.gov ID: NCT02704754) of suvorexant for treatment of adults (age 18–55) with insomnia that started or worsened after trauma exposure. Suvorexant is a first in class orexin antagonist and is approved by the FDA for the indication of insomnia. In this 6-week trial, all participants initially take 10 mg of suvorexant/placebo, and the dose will be increased to 20 mg if participants continue to experience clinically significant insomnia symptoms 1 week after starting the medication. Sleep outcomes will be measured by polysomnography, daily sleep diary, and the Insomnia Severity Index. RESULTS/ANTICIPATED RESULTS: We hypothesize that (1) within the placebo group data both subjectively and objectively measured outcomes will similarly show improvement in insomnia symptoms, (2) the increase of the placebo medication dose will result in an increased benefit, (3) the trauma-related insomnia placebo group will have the same type and similar rate of side effects reported in previous suvorexant trials. DISCUSSION/SIGNIFICANCE OF IMPACT: Most previous studies examining placebo effects focused on pain and depression. Information obtained from this project will complement our current understanding of placebo effects by characterizing placebo effects on trauma-related insomnia. This study will inform the development of novel strategies to maximize utility of placebos in future clinical trials.

OBJECTIVES/SPECIFIC AIMS: Therapeutic hypothermia (TH) is a neuroprotective therapy regularly used in newborn infants following traumatic births. The infant’s temperature is maintained at 33.5°C for 72 hours by a cooling blanket upon which the infant is placed. Parents are not permitted to hold their infant while TH is ongoing due to concerns for unintentional rewarming or accidental dislodging of catheters or other monitoring equipment. Our prior qualitative research with nurse and parent interviews described the inability to hold an infant during TH as a significant source of stress. We assessed the feasibility of a 30-minute period of maternal holding for infants being actively treated with TH and assessed both the maternal experience of holding and the nurse experience of supporting holding. METHODS/STUDY POPULATION: This was a feasibility study employing a mixed-methods approach. Inclusion criteria were gestational age at birth of 35 weeks or greater, absence of clinical or electrographic seizures during the first 24 hours of TH, and designation as “clinically stable” by the attending neonatologist with the infant on room air, nasal cannula, or continuous positive airway pressure. Quantitative data were obtained from vital sign monitoring every 2 minutes before, during and after holding and from maternal and nurse research surveys. Qualitative data were obtained from nurse surveys. Infant rewarming was prevented through use of a thin foam insulating barrier placed between mother and infant during holding. Adverse events were defined as a change in infant temperature greater than 0.5°C above or below 33.5°C, accidental dislodging of central lines/disruption of EEG leads or early termination of holding due vital sign instability present for greater than 2 recorded measurements including infant bradycardia defined as heart rate less than 80 beats per minute, hypotension defined as mean arterial pressure less than 40 mmHg or oxygen saturation of less than 93%. RESULTS/ANTICIPATED RESULTS: There were 10 newborn infants undergoing TH for neonatal encephalopathy (median gestational age 39.4 weeks) and their mothers (median age=31 years) were recruited. Infants remained on the hypothermia blanket during holding and were transferred safely to their mother’s arms without medical equipment malfunction/dislodgement. Holding occurred at a median of 47 hours of life. The mean temperature prior to holding was 33.4°C and at completion of holding the mean temperature was 33.5°C (p=0.18). There were no significant bradycardia, hypotension or oxygen desaturation events. In total, 80% of mothers reported difficulty bonding with their baby prior to holding and 90% reported a high level of stress before holding. After holding, all mothers felt their bond was “stronger” or “much stronger” and all felt “less stressed” or “much less stressed.” After holding, 75% of nurses reported that they felt a more positive emotional response to the infant. One nurse stated, “being a part of this emotional experience made me feel closer and more connected to this family and gave me a different perspective on just what they had been dealing with and feeling since giving birth to their child.” In free text responses, on 5 separate occasions, nurses commented on the relaxed, calmed or less irritable appearance of the infant while being held during TH. DISCUSSION/SIGNIFICANCE OF IMPACT: In this sample of term infants treated with TH, a 30-minute period of maternal holding was not associated with increased temperature or other adverse events. Holding during TH was associated with extremely positive feedback from mothers and nurses. Future larger studies could consider assessing the impact of holding on endocrinological markers of stress and bonding, on infant glycemic control, on breastfeeding success rates, and the impact of earlier and improved bonding on the developmental outcomes of children held during their treatment with TH. Increasing the duration of holding and allowing both parents to hold on more than one occasion during the 72 hours of TH may increase the proposed benefits of this intervention.

OBJECTIVES/SPECIFIC AIMS: Alcohol use disorder (AUD) has been associated with greater discounting of delayed rewards relative to healthy controls. The relationship, however, has been inconsistent, likely because previous studies had relatively small sample sizes and inadequately controlled for comorbid psychopathology and substance use. In the present study, we analyzed one of the largest clinical research samples to date to assess the influence of alcohol use on delay discounting, and examine the influence of confounding variables including substance use disorder. METHODS/STUDY POPULATION: In total, 801 participants completed a delay discounting task where they chose between smaller, immediately available monetary amounts ($0–$90) and $100 available after a delay of 7–30 days. Delay discounting behavior was summarized as the natural log of k, a constant derived from a hyperbolic discounting equation. Participants also completed Structured Clinical Interviews for DSM-IV disorders, 90-day Timeline Followback interviews, and the Fagerström Test for Nicotine Dependence. Participants were divided into 4 groups: healthy controls (n=298), past AUD (n=69), and current AUD with (n=224) and without (n=210) comorbid psychopathology or substance use disorder. Kruskal-Wallis test was used to examine the effect of group on delay discounting. RESULTS/ANTICIPATED RESULTS: There were significant differences in the distribution of delay discounting scores by group (H=80.195, p<0.001). Healthy controls and past AUD showed lower levels of delay discounting than current AUD and current AUD+comorbidity groups with medium effect sizes (Cohen’s d=−0.635 and Cohen’s d=−0.614, respectively). There were nearly no differences between current AUD with and without comorbid psychopathology groups (Cohen’s d=−0.024). The past AUD group showed almost no difference relative to the healthy control group (Cohen’s d=0.007). DISCUSSION/SIGNIFICANCE OF IMPACT: Individuals with current AUD were shown to discount rewards greater than those without current AUD, although comorbid psychopathology did not significantly affect discounting. Surprisingly, individuals with past AUD were more similar to controls than to those with current AUD. Our findings suggest that current problematic alcohol use is related to greater discounting of delayed rewards, but comorbid diagnoses do not significantly impact this relationship. However, once problematic patterns of alcohol use cease, delay discounting appears to return to levels comparable to healthy controls.

OBJECTIVES/SPECIFIC AIMS: Morphea (localized scleroderma) is an autoimmune disease characterized that is widely thought to have a monophasic course, in which an initial period of inflammation (activity) ultimately results in scarring, atrophy, and functional impairment (damage). Understanding the long-term clinical course of morphea is important for the planning of future interventional studies, and as a tool for clinicians in determining risk for poor disease outcomes. METHODS/STUDY POPULATION: We conducted a prospective cohort study of 130 participants enrolled in the Morphea in Children and Adults Cohort over a median follow-up time of 4.3 years, to determine the rates of response to treatment and disease recurrence as measured by the Localized Scleroderma Cutaneous Assessment Tool (LoSCAT). To determine risk factors for recurrence of disease activity, survival analysis using the log-rank test was used to compare subgroups by morphea type, therapy, and age at disease onset. RESULTS/ANTICIPATED RESULTS: Within a 1-year follow-up period, 66% of patients treated with methotrexate and 46% of patients with UVA1 phototherapy had achieved complete response to treatment. In patients who had achieved response to treatment, 29% experienced disease recurrence at an average of 1.7 years after documented disease inactivity. Patients with generalized morphea experienced higher recurrence rates than those with linear morphea (HR: 3.03, 95% CI: 1.48–6.22), and those treated with UVA1 phototherapy had higher recurrence over those treated with methotrexate (HR: 2.33, 95% CI: 1.03–5.31). In patients with follow-up periods longer than 5 years (n=50), disease recurrence was observed in 44% of patients and the majority of recurrence represented new activity in an area of pre-existing morphea (82%). DISCUSSION/SIGNIFICANCE OF IMPACT: This study highlights the previously under-studied dynamic long-term course of morphea, and identifies the clinical characteristics that predispose patients to having a relapsing-remitting course. We conclude that patients with morphea should be followed closely over time even in the absence of disease activity due to the potential for disease recurrence.

OBJECTIVES/SPECIFIC AIMS: Test the hypothesis that neprilysin inhibition with sacubitril/valsartan will increase endogenous intact GLP-1 after a mixed meal compared with valsartan. METHODS/STUDY POPULATION: Adults 18–80 years with pre-diabetes or type 2 diabetes and elevated blood pressure. RESULTS/ANTICIPATED RESULTS: We anticipate higher intact GLP-1 area under the cure after the meal when subjects receive sacubitril/valsartan compared with valsartan. DISCUSSION/SIGNIFICANCE OF IMPACT: Neprilysin inhibition may be a target for anti-diabetes therapy by decreasing degradation of GLP-1.

OBJECTIVES/SPECIFIC AIMS: The ACT Network was developed by 46 members of the CTSA Program hubs in collaboration with NCATS to help investigators explore and validate feasibility of clinical studies in real-time using linked electronic health record data for cohort discovery. ACT is being disseminated nationally across the CTSA consortium. METHODS/STUDY POPULATION: Diffusion of Innovation Theory and Lean Start-Up principles inform dissemination strategies. Core materials were developed nationally and are being tailored to meet local CTSA dissemination norms. An advisory board, with expertise in communications, journalism, customer channel management, pharmaceutical commercialization and health IT entrepreneurship, is providing strategic advice to develop and refine dissemination strategies. Evaluation of dissemination methods will include network usage and web analytics for the ACT Network’s interactive digital content and log-in portal, and surveys-interviews of ACT users using the RE-AIM implementation framework. RESULTS/ANTICIPATED RESULTS: Formative research identified ACT’s primary value proposition for clinical researchers: “Explore patient populations in depth, in real time, from your desktop;” “Confirm study feasibility by iteratively testing and refining inclusion and exclusion criteria;” “Demonstrate feasibility in funding proposals and IRB submissions;” and “Identify collaborating sites for multi-site studies by searching for patients across the CTSA network.” Early dissemination metrics, including number-type of registered users, queries performed, and web analytics, will be presented. DISCUSSION/SIGNIFICANCE OF IMPACT: Researchers nationwide face common barriers in accruing enough participants for clinical trials. The inability to identify the right number and type of people to participate often makes clinical trials slow and costly. Better cohort discovery at the protocol development phase is a necessary requirement. By end of 2018, the ACT Network will reach 60% of the CTSA consortium providing a new tool for investigators to improve the design and execution of clinical trials.

OBJECTIVES/SPECIFIC AIMS: To study the role of OSA as an independent predictor of perioperative outcomes. METHODS/STUDY POPULATION: For this single-institution cohort study, we included data from patients who were enrolled into 1 of 3 prospective parent studies. All participants underwent in-patient surgeries, excluding neurosurgeries, which required general anesthesia and a postoperative stay of at least 1 day. Patients included in this study were assessed daily for postoperative delirium and pain severity as part of the parent studies. In the current study, determination of delirium diagnosis was based on the 3-minute Diagnostic Confusion Assessment Method (3D-CAM), and the Visual Analogue Pain Scale (VAS) was used for pain severity. Data on OSA diagnosis (determined by sleep study); OSA risk (determined by the STOP-Bang tool; snoring, tiredness, observed apnea, high blood pressure, body mass index>35 kg/m2, age>50, neck circumference, male gender); and compliance with treatment were obtained from the preoperative assessment record. Participants were grouped into 1 of 3 categories: high risk of OSA (HR-OSA; including patients with a previous positive sleep study or STOP-Bang score ≥5); intermediate risk of OSA (IR-OSA; including patients with a STOP-Bang score of 3 or 4); and low risk of OSA (LR-OSA; including patients with a previous negative sleep study or STOP-Bang score <3). Candidate risk factors for delirium and pain were also extracted from this record. RESULTS/ANTICIPATED RESULTS: Logistic regression will be used to test whether OSA independently predicts postoperative delirium and linear regression to assess OSAs relationship to acute pain severity. We hypothesize that patients in the HR-OSA category will experience a higher incidence of postoperative delirium and greater postoperative pain severity. We also predict a step-wise increase in risk of these adverse outcomes when analyzing patients stratified by OSA risk (HR-OSA vs. IR-OSA vs. LR-OSA). For our secondary analyses, we anticipate these outcomes are modified by compliance with CPAP treatment. We believe patients with OSA who do not use prescribed CPAP will experience a higher incidence of postoperative delirium as well as increased pain severity. DISCUSSION/SIGNIFICANCE OF IMPACT: OSA is a common and frequently undiagnosed perioperative problem associated with altered pain processing and a high incidence of postoperative delirium. While likely providing stronger evidence of OSA’s reported impact on postoperative delirium and pain, our findings might also help discern points of intervention for treatment and prevention. Since OSA’s presumed impact poses challenges to clinicians and patients, prospective, randomized trials testing preventative or mitigating interventions are necessary. We hope to use these results to design such trials and clinical plans, with the goal of reducing postoperative delirium and acute postsurgical pain severity for the large number of patients at risk due to OSA.

OBJECTIVES/SPECIFIC AIMS: Pembrolizumab is an anti-PD-1 immune checkpoint antibody that has demonstrated promising anti-tumor activity in patients with solid tumor malignancies, including patients with brain metastases from malignant melanoma and non-small cell lung cancer. Leptomeningeal disease (LMD) is a rare form of malignant spread to the central nervous system (CNS), that occurs in 2%–10% of patients with solid tumors, most commonly in breast cancer and non-small cell lung cancer. We propose an open-label phase II study of pembrolizumab in patients with LMD from advanced solid tumors (NCT03091478). This study aims to determine if pembrolizumab therapy can lead to a radiologic, cytologic or clinical response in the CNS, in patients with LMD. METHODS/STUDY POPULATION: Patients with pathologically confirmed advanced solid tumors, and either radiologic or cytologic evidence of LMD, will be identified at a single institution. Radiologic LMD will be defined as a >4 mm area of measurable LMD on gadolinium-enhanced MRI brain/total-spine; and cytologic LMD will be defined as the presence of malignant cells on CSF cytology. Patients will be excluded if they have: active autoimmune conditions that require immunosuppression, received radiation therapy to the only area of measurable LMD within 3 months of study enrollment, have an ECOG performance status <1. Once enrolled, patients will receive pembrolizumab 200 mg intravenously every 3-weeks, until disease progression or unacceptable toxicity. Patients will have CSF sample sampling, blood draws, radiologic imaging of the body (CT), brain/total-spine (gadolinium-enhanced MRI) pre-treatment, after 2 and after 4 cycles of therapy, for response assessment and correlative studies. The primary endpoint of the study is CNS response assessed at 12 weeks/after 4 cycles of pembrolizumab, defined either as radiologic response (reduction in size of LMD on gadolinium-enhanced MRI) and/or cytologic response (conversion of positive to negative CSF cytology on 2 consecutive samples) and/or clinical response. Secondary endpoints will include progression-free survival, overall survival, and safety. To explore the mechanisms by which pembrolizumab may affect LMD, we will assess dynamic changes in genomic and immunologic markers in the CSF and serum pre and post pembrolizumab using next-generation sequencing and multi-color flow cytometry, respectively. RESULTS/ANTICIPATED RESULTS: We will aim to accrue a total of 20 patients, allowing for a 10% drop-out rate, the final sample size will include 18 patients who have received at least 1 dose of pembrolizumab. CNS-response at 12 weeks will be assessed radiologically +/− cytologically, and the proportion of patients with CNS response and associated 95% confidence interval with be reported. CNS-progression-free survival and overall survival will be assessed using the Kaplan-Meier method. Cause of death will be recorded. Safety will be assessed as detailed above, and monitored as per an institutional Data Safety and Monitoring Plan. Exploratory endpoints will include genomic testing of tumor cells and cell-free DNA in CSF and serum, and immunologic studies of immune cells in CSF and serum at pre-defined timepoints. These data will be presented descriptively. We conservatively estimate that we will accrue 1 patient per month at our institution. Study duration will be approximately 24 months, allowing 18 months for accrual and 6 months for follow-up and data analysis. DISCUSSION/SIGNIFICANCE OF IMPACT: There are no currently FDA-approved therapies for patients with LMD from solid tumors. Anti-PD-1 immunotherapy is a promising class of agents, with known efficacy in patients with CNS metastatic disease, across tumor types. This study seeks to identify whether pembrolizumab may lead to CNS responses in patients with LMD. Additionally, genomic and immunologic analyses in CSF and blood pre and post-pembrolizumab may identify mechanisms by which immunotherapy affects the CNS in patients with LMD.

OBJECTIVES/SPECIFIC AIMS: In patients with recurrent glioblastoma (GBM) who undergo a second surgery following standard chemoradiotherapy, histopathologic examination of the resected tissue often reveals a combination of viable tumor and treatment-related inflammatory changes. However, it remains unclear whether the degree of viable tumor Versus “treatment effect” in these specimens impacts prognosis. We sought to determine whether the percentage of viable tumor Versus “treatment effect” in recurrent GBM surgical samples, as assessed by a trained neuropathologist and quantified on a continuous scale, is associated with overall survival. METHODS/STUDY POPULATION: We reviewed the records of 47 patients with histopathologically confirmed GBM who underwent surgical resection as the first therapeutic modality for suspected radiographic progression following standard radiation therapy and temozolomide. The percentage of viable tumor Versus “treatment effect” in each specimen was estimated by one neuropathologist who was blinded to patient outcomes. RESULTS/ANTICIPATED RESULTS: After adjusting for other known prognostic factors in a multivariate Cox proportional hazards model, there was no association between the degree of viable tumor and overall survival (HR 0.83; 95% CI, 0.20–3.4; p=0.20). DISCUSSION/SIGNIFICANCE OF IMPACT: These results suggest that, in patients who undergo resection for recurrent GBM following standard first-line chemoradiotherapy, histopathologic quantification of the degree of viable tumor Versus “treatment effect” present in the surgical specimen has limited prognostic influence and clinical utility.

OBJECTIVES/SPECIFIC AIMS: MicroRNAs are small, non-coding RNAs that control gene expression by inhibiting protein translation. Preclinical studies in rodent stroke models suggest that changes in microRNA expression contribute to neural repair mechanisms. To our knowledge, no one has previously assessed microRNA changes during the recovery phase of human stroke. Our goal was to determine whether patients with significant upper limb recovery following stroke have alteration of neural repair-related microRNA expression when compared to those with poor recovery. METHODS/STUDY POPULATION: Plasma was collected at 19 days post-stroke from 27 participants with mild-moderate upper extremity impairment enrolled in the Critical Periods After Stroke Study. MicroRNA expression was assessed using TaqMan microRNA assays (Thermo Fisher Scientific). Good recovery was defined as ≥6 point change in the Action Research Arm Test (ARAT) score from baseline to 6 months. Bioinformatics analysis compared the plasma microRNA expression profiles of participants with good Versus poor recovery. Candidate biomarkers were identified after correcting for multiple comparisons using a false discovery rate <0.05. RESULTS/ANTICIPATED RESULTS: Eleven microRNAs had significantly altered expression in the good (n=22) Versus poor (n=5) recovery groups, with 2 showing increased expression—miR-371-3p and miR-520g, and 9 showing decreased expression—miR-449b, miR-519b, miR-581, miR-616, miR-892b, miR-941, miR-1179, miR-1292, and miR1296. Three of these could be implicated in neural repair mechanisms. Elevated miR-371-3p levels increase the likelihood that pluripotent stem cells will differentiate into neural progenitors. MiR-892b decreases levels of amyloid precursor protein, which has been implicated as a regulator of synapse formation. Finally miR-941, the only known human-specific microRNA, downregulates the CSPα protein which is involved in neurotransmitter release. DISCUSSION/SIGNIFICANCE OF IMPACT: This preliminary study suggests that circulating microRNAs in the plasma may help serve as biomarkers of neural repair and aid in understanding human neural repair mechanisms. If validated in larger studies with appropriate controls, these markers could aid in timing rehabilitation therapy or designing recovery-based therapeutics.