OBJECTIVES/SPECIFIC AIMS: Persons living with HIV (PLWH) are at increased risk for fragility bone disease. Current osteoporosis screening guidelines do not account for HIV status, and clinical risk assessment tools are not sensitive in PLWH. We examined the value of traditional osteoporosis risk factors, HIV-specific indices, and bone turnover biomarkers in predicting low bone mineral density (BMD) in PLWH. METHODS/STUDY POPULATION: Demographic and clinical characteristics, dual energy x-ray absorptiometry (DXA)-derived BMD, HIV indices (viral load, CD4 count, antiretroviral therapy [ART]), and biomarkers of bone turnover (C-terminal telopeptide of collagen [CTx], osteocalcin [OCN]) were evaluated in a cross-sectional analysis of PLWH (n=248) and HIV- controls (n=183). The primary outcome was low BMD, defined as osteopenia or osteoporosis by WHO criteria. Multivariable logistic and modified Poisson regression models were used to assess associations between low BMD and covariates of interest. RESULTS/ANTICIPATED RESULTS: Overall, median age was 44 years, 48% were male, 88% were black, median body mass index (BMI) was 28 kg/m2, 72% smoked cigarettes, and 53% used alcohol; characteristics did not differ by HIV status. PLWH had a mean CD4 of 408 cells/mm3, 55% were ART-naïve, and 45% had viral suppression on ART. Overall, 25% (109/431) had low BMD, including 31% of PLWH compared to 16% of HIV- controls. In multivariable models, HIV was significantly associated with low BMD (aOR 2.46, 95%CI 1.39-4.34; aRR 1.90, 95%CI 1.18-3.07). Adjusting for HIV, three traditional risks– age, race, and BMI– were independently associated with low BMD in the full cohort. However, bone turnover markers, CTx and OCN, were better able to discriminate low vs. normal BMD in PLWH compared to HIV- controls. In PLWH, mean serum CTx was 23% higher in low vs. normal BMD (mean CTx difference=0.06 ug/mL); in HIV- controls, no association with BMD was observed (mean CTx difference=0 ug/mL). In PLWH, mean serum OCN was 38% higher in those with low vs. normal BMD (mean OCN difference=2.48 ug/mL); in HIV- controls, mean serum OCN was only 16% higher in those with low vs. normal BMD (mean OCN difference=1.08 ug/mL). DISCUSSION/SIGNIFICANCE OF IMPACT: In PLWH as opposed to HIV- controls, serum biomarkers reflecting a high bone turnover state, may discriminate individuals with low versus normal BMD. Because changes in biomarkers precede changes in BMD, these markers should be explored further either alone or in combination with traditional risk assessment tools to improve early screening for osteoporosis in PLWH.

OBJECTIVES/SPECIFIC AIMS: Our study’s primary aim is to determine if there is an association between cancer-related pain among patients who underwent major elective procedures and postoperative opioid overdose. In addition, the relationship between cancer-related pain in this population and inpatient mortality, total hospital charge and length of stay was assessed. METHODS/STUDY POPULATION: Our study sample consisted of adults 18 years and older who had at least one of eight elective procedures. Data was obtained from the National Inpatient Sample (NIS). Variables were identified using ICD-9 codes. Our primary predictor was cancer-related pain while our primary outcome was opioid overdose. Secondary outcomes were inpatient mortality, length of stay and total charge. Propensity-matched regression models were employed in assessing the association between cancer-related pain and outcomes of interest. RESULTS/ANTICIPATED RESULTS: Among 4,085,355 selected patients, 0.8% (n = 2,665) had cancer-related pain while 99.92% (n = 4,082,690) had no diagnosis of cancer-related pain. All subjects with cancer-related pain (n = 2,665) were successfully matched to subjects with no diagnosis of cancer-related pain in a 1:5 ratio yielding 13,325 controls. Patients with cancer-related pain had significantly higher odds of opioid overdose (aOR 4.82 [95% CI [2.68-8.67]; p-value <0.0001) and inpatient mortality (aOR 1.39[1.11-1.74]; p-value 0.0043). Patients with cancer-related pain were also likely to stay significantly longer in the hospital (12.76 days vs. 7.88 days) with significantly higher total hospital charges ($140,220 vs. $88,316). DISCUSSION/SIGNIFICANCE OF IMPACT: Pain is a common complication of cancer pathogenesis, diagnosis or treatment. Though a rare outcome, opioid overdose could lead to undesirable outcomes. Cancer patients undergo invasive diagnostic and therapeutic procedures as part of their cancer management or for conditions not related to their primary cancer diagnosis. Safety measures including alternatives to opioids are recommended to prevent the poor clinical outcomes and higher healthcare utilization indices associated with opioid overdose in this population.

OBJECTIVES/SPECIFIC AIMS: Cannabinoids suppress gastric acid secretion, ameliorate gastric inflammation, and promote gastric ulcer healing, all of which are triggered by H pylori (Hp). Our aim was to determine the relationship between cannabis use and: 1) H pylori infection (HPI) among community residents 2) clinical peptic ulcer disease (PUD) and its complications among hospitalized patients. METHODS/STUDY POPULATION: We performed case-control studies with records from the NHANES III (n=4,556) and HCUP-NIS 2014 (n=4,555,029), and respectively identified subjects with seropositivity for H pylori and clinical PUD, and their cannabis usage status. In the NHANES III, we estimated the adjusted prevalence rate ratio (aPRR) of having HPI with cannabis use, using generalized estimating equations. In the NIS, we propensity-matched cannabis users to non-users in ratio 1:1 (68,073:68,073) and measured the aPRR of having PUD and its complications (SAS 9.4). RESULTS/ANTICIPATED RESULTS: In NHANES III, associated with decreased HPI seropositivity were cannabis ever-users (aPRR: 0.79[0.66-0.95]), greater than 10 times lifetime usage (0.65[0.5-0.84]) and recent 31-day usage (0.67[0.48-0.98]), compared to never usage. In the HCUP-NIS, cannabis users had decreased risk for total PUD (aPRR: 0.74[0.61-0.89]), duodenal PUD (0.48[0.35-0.60]) and PUD complications including hemorrhage (0.58[0.37-0.90]), perforation (0.66[0.51-0.87]), but not obstruction (1.75[0.51-5.98]). DISCUSSION/SIGNIFICANCE OF IMPACT: Cannabis usage is related to a reduced likelihood of having HPI in the community and also mitigate against having complicated presentations to the hospital. More translational studies are needed to illuminate the details of this relationship, given the high worldwide prevalence of both cannabis use and HPI.

OBJECTIVES/SPECIFIC AIMS: Our goals were to understand the pattern, location, and extent of cardiac replacement fibrosis seen as late gadolinium enhancement on cardiovascular magnetic resonance imaging in a large cohort of cancer patients treated with anthracyclines and/or trastuzumab. METHODS/STUDY POPULATION: We performed a retrospective cohort study of consecutive adult cancer patients treated with anthracyclines and/or trastuzumab from 2004 through 2017. CMRs were analyzed for the presence, location, and pattern of LGE. RESULTS/ANTICIPATED RESULTS: Of 238 patients, 220/(92.4%) had no LGE. Among the 18/(7.6%) patients with LGE, 13/(72.2%) were ischemic in pattern (myocardial infarctions); 10 of these had known coronary artery disease (CAD). Of 5/(27.8%) patients with non-ischemic LGE, the etiologies were known for 4 – myocarditis, cardiac sarcoidosis, eosinophilic myocarditis, and acute myocardial calcification. Only 4/(1.7%) patients had unexpected LGE, of which 3 were unrecognized myocardial infarctions. DISCUSSION/SIGNIFICANCE OF IMPACT: The assessment of fibrosis helps to diagnose the cause of LVSD in cancer patients treated with potentially cardiotoxic medications. This is necessary because currently, the cause of LVSD in cancer patients cannot be established conclusively even though the cause is closely linked to patient outcomes. Our results demonstrate that cancer treatment-related LVSD is not associated with fibrosis. A minority of cancer patients with LVSD have fibrosis related to other reasons, most commonly CAD. Identification of the correct cause of LVSD in cancer patients treated with cardiotoxic medications allows for appropriate treatment. This, in turn, could improve patient outcomes.

OBJECTIVES/SPECIFIC AIMS: Delirium, a form of acute brain dysfunction, characterized by changes in attention and alertness, is a known independent predictor of mortality in the Intensive Care Unit (ICU). We sought to understand whether catatonia, a more recently recognized form of acute brain dysfunction, is associated with increased 30-day mortality in critically ill older adults. METHODS/STUDY POPULATION: 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. Coma, was defined as a Richmond Agitation Scale score of −4 or −5. We used the Cox Proportional Hazards model predicting 30-day mortality after adjusting for delirium, coma and catatonia status. RESULTS/ANTICIPATED RESULTS: We enrolled 335 medical, surgical or trauma critically ill patients with 1103 matched delirium and catatonia assessments. Median age was 58 years (IQR: 48 - 67). Main indications for admission to the ICU included: airway disease or protection (32%; N=100) or sepsis and/or shock (25%; N=79. In the unadjusted analysis, regardless of the presence of catatonia, non-delirious individuals have the highest median survival times, while delirious patients have the lowest median survival time. Comparing the absence and presence of catatonia, the presence of catatonia worsens survival (Figure 1). In a time-dependent Cox model, comparing non-delirious individuals, holding catatonia status constant, delirious individuals have 1.72 times the hazards of death (IQR: 1.321, 2.231) while those with coma have 5.48 times the hazards of death (IQR: 4.298, 6.984). For DSM-5 catatonia scores, a 1-unit increase in the score is associated with 1.18 times the hazards of in-hospital mortality. Comparing two individuals with the same delirium status, an individual with a DSM-5 catatonia score of 0 (no catatonia) will have 1.178 times the hazard of death (IQR: 1.086, 1.278), while an individual with a score of 3 catatonia items (catatonia) present will have 1.63 times the hazard of death. DISCUSSION/SIGNIFICANCE OF IMPACT: Non-delirious individuals have the highest median survival times, while those who are comatose have the lowest median survival times after a critical illness, holding catatonia status constant. Comparing the absence and presence of catatonia, the presence of catatonia seems to worsen survival. Those individual who are both comatose and catatonic have the lowest median survival time.

OBJECTIVES/SPECIFIC AIMS: The primary objective of this study is to determine the prevalence of maternal GBS colonization and demographic risk factors associated with maternal GBS colonization in Latin America. Secondary objectives include: To determine if there is an association between maternal colonization with GBS and stillbirth or preterm birth in Latin America. To determine the effect of cesarean section (CS) on the incidence of neonatal sepsis with GBS in mothers colonized with GBS. METHODS/STUDY POPULATION: Study Population: Pregnant women who received prenatal care at sites that utilize the Perinatal Information System (SIP) from 1989 through 2015, and were screened for GBS between 35 and 37 weeks of gestation. Maternal exclusion criteria included spontaneous abortion, stillbirth before 35 weeks, and lack of screening for GBS. Methods: Estimated prevalence (and 95% confidence interval) of maternal GBS colonization for the entire data set, by region, and by country. The prevalence data for each country further stratified by maternal age, ethnicity, education, civil status and habitation. Descriptive statistics calculated for each clinical prenatal and clinical perinatal health indicator as well as for each clinical history variable for GBS colonized and non-GBS colonized women. Odds ratios will be calculated for each demographic and clinical risk factor. Fisher’s exact tests will be used to test hypotheses about the relationship between maternal GBS colonization and specific perinatal outcomes such as stillbirth or preterm birth. We will use multiple logistic regression models to test the hypotheses about the relationships between demographic variables, maternal GBS colonization and perinatal outcomes. RESULTS/ANTICIPATED RESULTS: Preliminary results: 712,061 records included in database. 98,852 records with data for GBS screening. o90.6% White, 7.4% Mixed, 0.6% Black, 0.3% Native Indian, 0.1% Other. GBS prevalence among screened women, 17.5% There was a significant association between maternal GBS colonization and ethnicity (X2 (4, N=97006)=569.901, p<0.01) o Prevalence rates by ethnicity: 20.5% Black, 18.4% White, 15.2% Native Indian, 8.8% Mixed, 3.3% Other. There was a significant association between maternal GBS colonization and age (X2 (4, N=98655)=119.901, p<0.01) o Prevalence rates by age group:. Age ≤ 20 - 15.2%. Age 21-34 – 17.8%. Age ≥ 35 – 19.6% Anticipated results:. GBS positive mothers will have an increased burden of stillbirth and preterm birth compared to GBS negative mothers. Neonates born to GBS colonized mothers who deliver via cesarean section will have a decreased incidence of sepsis compared to neonates born to GBS colonized mothers who deliver vaginally DISCUSSION/SIGNIFICANCE OF IMPACT: There have been no comprehensive studies to date that use the CLAP data to characterize the epidemiology of maternal GBS colonization and GBS disease and the burden of neonatal GBS disease in Latin America. Taking advantage of this unique database, this is the first region-wide study using systematically collected data. Our preliminary analysis indicates that GBS colonization status among pregnant women in Latin America is 17.5%, which is greater than previously reported. While there is evidence that maternal carriage of GBS is associated with stillbirth, this will be the first study to quantify the burden of GBS-associated stillbirth in Latin America. Additionally, previous work has been inconclusive in regards to maternal colonization with GBS and its association with preterm birth. This will be the largest study to evaluate the association of maternal GBS carriage with preterm birth. Findings from this study have the potential to inform public health policy and interventions by identifying the prevalence and risk factors.

OBJECTIVES/SPECIFIC AIMS: 1. Determine positive predictive value, negative predictive value, sensitivity, and specificity of Neuro ICU nurse interpretation of real-time bedside qEEG. 2. Determine difference in time to detection of first seizure between Neuro ICU nurse qEEG interpretation and EEG fellow reads of cEEG. 3. Determine what qualities of seizures make detection by neuro ICU nurses more or less likely – e.g. duration of seizures, type of seizures, spatial extent of seizures. METHODS/STUDY POPULATION: Recruit neuro ICU nurses taking care of 150 patients admitted to the Neuro ICU at Duke University Hospital who are initiated on cEEG monitoring. Nurses will be consented for their participation in the study. Neuro ICU nurses will evaluate the qEE RESULTS/ANTICIPATED RESULTS: From literature estimates of a 20% seizure prevalence in critical care settings, we hope to have 30 patients with seizures and 120 without. Based on prior study in the Duke Neuro ICU, we hypothesize that Neuro ICU nurses will have sensitivity and DISCUSSION/SIGNIFICANCE OF IMPACT: This is the first prospective study of neuro ICU nurse interpretation of real-time bedside qEEG in patients with unknown NCSE/NCS presence. If nurse sensitivity, specificity, and positive predictive value are clinically useful, which we deem would be so at a sensitivity of 70% or greater, with acceptable false alarm rate, nurse readings of qEEG could significantly decrease the time to treatment of seizures in the Neuro ICU patient population, and perhaps could improve patient outcomes.

OBJECTIVES/SPECIFIC AIMS: The main aim of this study was to investigate the interaction between glomerular filtration rate (GFR) and body mass index (as well as serum leptin) as determinants of peripheral and central insulin sensitivity (IS). METHODS/STUDY POPULATION: This was a cross-sectional investigation of 140 nondiabetic participants – 56 with CKD (GFR = 15-59 ml/min/1.73m2) and 94 with normal GFR (≥ 60 ml/min/1.73m2) – recruited as part of the relationship of insulin sensitivity in kidney disease and vascular health (RISKD) study. Peripheral (skeletal muscle) and central (hepatic) IS were assessed with the hyperinsulinemic euglycemic glucose clamp (HEGC) and homeostasis assessment of insulin resistance (HOMA-IR) respectively. Creatinine-based estimated GFR (eGFR) was obtained using the CKD-EPI equation and body mass index (BMI) was computed from baseline weight and height measurements. Linear regression models with robust standard errors (to relax homoscedasticity assumptions) and interaction terms were used to investigate GFR and BMI as predictors of HEGC-derived insulin sensitivity index (ISI) and HOMA-IR. RESULTS/ANTICIPATED RESULTS: The mean (SD) age was 53.9 (14.5) years; 50.7% were female and 36.7% were African-American. Compared to controls, CKD patients had significantly lower mean (SD) ISI [5.4 (3.2) vs. 3.1 (1.6), p < 0.0001]. Log ISI was positively correlated (r = 0.39, p < 0.0001) with eGFR and inversely correlated (−0.30, p < 0.0001) with BMI and log leptin (−0.42, p < 0.0001). In multivariable models adjusted for age, sex and race, a 10 ml/min/1.73m2 lower eGFR was associated with a greater decrease in ISI among non-obese (0.48; 95% CI: −0.25, −0.70) compared to obese participants (−0.18; 95% CI: −0.02, −0.35) (p-interaction = 0.04). Patients with low eGFR (in particular, the lower margin of the CKD stage 3 range, 30ml/min) had lower ISI even with BMI within normal range (Figure 1a). At higher eGFR, BMI had a greater impact on ISI. P-interaction = 0.046, for differential BMI effects at lower vs. higher eGFR. Log HOMA-IR was inversely correlated with eGFR (r = - 0.49, p < 0.0001) and positively correlated with BMI (r = 0.52, p < 0.0001) and log leptin (0.46, p < 0.0001). HOMA-IR was lower for persons with higher GFR compared to lower GFR, at any BMI value. For example, at a BMI of 30 and a GFR of 120, HOMA-IR was 1.2 compared to 4.8 at a GFR of 30 (Figure 1b). Also, persons with high GFR had low HOMA-IR even with BMI in the obese range. BMI had a greater effect on HOMA-IR at lower eGFR. P-interaction = 0.005, for differential BMI effects at lower vs. higher eGFR. Similar findings were obtained when using log leptin in lieu of BMI in models for ISI and HOMA-IR. DISCUSSION/SIGNIFICANCE OF IMPACT: Measures of adiposity (BMI and leptin) and GFR were independently predictive of insulin sensitivity (IS) but the magnitude of the effect of BMI (or leptin) on IS varied significantly across GFR levels and type of IS (peripheral versus central). The effect of BMI on central IS (HOMA-IR) was more pronounced at lower GFR with small changes in BMI translating into greater variations in IS. Conversely, at low GFR, peripheral IS (ISI) is less affected by BMI. Persons with GFR at the lower margin of the CKD stage 3 range were significantly insulin resistant (low ISI) regardless of their BMI. More studies are required to further elucidate these interaction patterns for central and peripheral IS.

OBJECTIVES/SPECIFIC AIMS: Cancer related pain presents a significant risk for opioid abuse among cancer survivors and contributes to the current opioid crisis. Nearly 90% of breast cancer patients have been reported to have cancer-related pain requiring treatment. Opioids, in combination with NSAIDs, have been widely used for pain management in this population despite the risk of abuse. Long-term NSAID use due to their antineoplastic and neuroprotective effects may offer additional protective effects against opioid abuse. Here, we assess the relationship between NSAID use and opioid abuse among breast cancer patients. METHODS/STUDY POPULATION: Using ICD-9-CM codes, we identified and selected women aged >18 years with breast cancer from the National Inpatient Sample (NIS). Our primary predictor was a history of long-term NSAID use. Opioid abuse was the primary outcome of interest. Secondary outcomes were inpatient mortality and length of stay. Multivariable regression models were employed in assessing the association between predictors and outcomes while adjusting for relevant covariates. RESULTS/ANTICIPATED RESULTS: Among 170,644 women with breast cancer, 7,838 (4.6%) reported a history of long-term NSAID use. Patients with a history of long-term NSAID use had lower odds of opioid abuse (aOR 0.53; 95% CI [0.32-0.88]) and in-hospital mortality (aOR 0.52; 95% CI [0.45-0.60]) and were likely to have shorter hospital stay (7.12 vs. 8.11 days) compared to women with no history of long-term NSAID use. DISCUSSION/SIGNIFICANCE OF IMPACT: Long-term NSAID use may offer a protective effect against opioid abuse and improve in-hospital outcomes translating to better quality of life and healthcare utilization indices among breast cancer patients.

OBJECTIVES/SPECIFIC AIMS: This study seeks to evaluate the role of PCOS in insulin resistance and sleep apnea in adolescents. METHODS/STUDY POPULATION: 37 adolescent patients 13-21 with PCOS (27 obese, 11 lean), along with 8 controls ages 18-21 were recruited. Subjects underwent a hyperinsulinemic euglycemic clamp study and a proportion of the PCOS subjects also underwent polysomnography. Baseline parameters were compared and M/I (index of insulin sensitivity), and GIR were compared. RESULTS/ANTICIPATED RESULTS: M/I was only statistically significantly different between obese PCOS subjects vs control (0.056 vs 0.17, p=0.0061). GIR was higher in the obese PCOS group compared to the lean PCOS group (2.48 vs 6.79, p=0.0001). There were no differences in GIR between the lean PCOS subjects and control (6.79 vs 9.08, p=0.30). 21 obese PCOS subjects and 10 lean PCOS underwent polysomnography. None of the lean PCOS subjects had obstructive sleep apnea (OSA). 8 of the obese subjects had OSA. DISCUSSION/SIGNIFICANCE OF IMPACT: More studies are needed to assess insulin sensitivity and sleep apnea in adolescents with lean PCOS. Our study did not find more insulin resistance in adolescents with PCOS compared to lean controls apart from what would be expected from obesity. Of adolescent obese subjects with PCOS, OSA seems quite prevalent and providers should consider screening and referral for these patients.

OBJECTIVES/SPECIFIC AIMS: Intensive lifestyle change (e.g., the Diabetes Prevention Program) and metformin reduce type 2 diabetes risk among patients with prediabetes. However, real-world uptake remains low. Shared decision-making (SDM) may increase awareness and help patients select and follow through with informed options for diabetes prevention that are aligned with their preferences.The objective was to test the effectiveness of a prediabetes SDM intervention. METHODS/STUDY POPULATION: This was a cluster-randomized controlled trial in 20 primary care clinics within a large regional health system. Participants were overweight/obese adults with prediabetes (BMI>24 kg/m2 and HbA1c 5.7-6.4%) were enrolled from 10 SDM intervention clinics. Propensity score matching was used to identify control patients from 10 usual care clinics.Intervention clinic patients were invited to participate in a face-to-face SDM visit with a pharmacist who used a decision aid (DA) to describe prediabetes and four possible options for diabetes prevention; DPP, DPP +/− metformin, metformin only, or usual care. RESULTS/ANTICIPATED RESULTS: Uptake of DPP and/or metformin was higher among SDM participants (n=351) than controls receiving usual care (n = 1,028; 38% vs. 2%, p<.001). At 12-months follow-up, adjusted weight loss (lbs.) was greater among SDM participants than controls (−5.3 vs. −0.2, p < .001). DISCUSSION/SIGNIFICANCE OF IMPACT: A prediabetes SDM intervention led by pharmacists increased patient engagement in evidence-based options for diabetes prevention and was associated with significantly greater uptake of DPP and/or metformin at 4-months and weight loss at 12-months. Prediabetes SDM may be a promising approach to enhance prevention efforts among patients at increased risk.

OBJECTIVES/SPECIFIC AIMS: People with metabolically abnormal obesity (MAO), defined as those with insulin resistance and high intrahepatic triglyceride, are at high risk for developing type 2 diabetes and cardiovascular disease. Weight loss through reduced energy intake and increased physical activity has profound impacts on improving cardiometabolic function. However, the specific additional effects of exercise training with diet-induced weight loss on metabolic function are equivocal. METHODS/STUDY POPULATION: A comparative trial is ongoing in MAO adults undergoing 8-10% weight loss induced by a very-low fat plant-based (PB) diet with structured exercise training (n=8) compared to the same weight loss induced by the PB diet alone (n=3). RESULTS/ANTICIPATED RESULTS: Preliminary results indicate that, PB diet with or without exercise training results in significant weight loss concomitant with enhanced insulin sensitivity, reduced intrahepatic triglyceride, reduced 24-hour postprandial glucose response, reduced fat mass, and reduced diastolic blood pressure. Those undergoing PB diet with exercise training had greater improvements in muscular strength and cardiorespiratory fitness than those undergoing PB diet alone. Differences between intervention groups for other cardiometabolic measures are not yet known. DISCUSSION/SIGNIFICANCE OF IMPACT: Each of the interventions resulted in improved cardiometabolic measures; however the extent of the differences between the interventions is not yet clear. It is hypothesized that compared with weight loss induced by a PB diet, the same weight loss induced by a PB diet and structured exercise training will i) cause greater improvement in skeletal muscle insulin sensitivity, ii) will attenuate the usual decline in muscle mass while increasing strength, and iii) result in greater increases in left ventricular diastolic function. The long-term objective of this proposal is to provide a foundation for future studies evaluating mechanisms for the effects of exercise in cardiometabolic disease prevention and therapy.

OBJECTIVES/SPECIFIC AIMS: If intranasal ketamine can be utilized for pain control in cancer patients, this could provide them with superior analgesia and better quality of life, without the risk of significant respiratory depression associated with opioid medications. We seek to obtain preliminary data via a clinical trial addressing safety, feasibility, and utility of this novel technique for the treatment of persistent uncontrolled cancer pain. These findings would be an important initial step towards testing the effectiveness of intranasal ketamine as a non-opioid medication for cancer pain used as potential maintenance outpatient therapy. These initial findings would be applied to a subsequent trial to determine the effectiveness and associated toxicities of ketamine in a larger sample of cancer patients, and address the compelling need to identify new, successful management therapies for cancer pain. Specific Aims: 1. To evaluate (pharmacodynamic) effects of NAS ketamine on Patient Reported Outcomes (PROs), such as pain scores, side effects, depression, quality of life, and functional status. A clinical trial will be conducted where NAS ketamine will be given to a sample of patients with cancer related pain. Patient Reported Outcomes (PROs), such as pain scores, depression, quality of life, and functional status will be noted on Numerical Pain Rating Scale (NPRS), Montgomery Asberg Depression Rating Scale (MADRS), and Edmonton Symptom Assessment (ESAS), Eastern Cooperative Oncology Group (ECOG) and Patient Reported Outcome Measurement Information System (PROMIS) scales respectively. 1. To measure pharmacokinetics of NAS ketamine through analysis of ketamine and its metabolite norketamine to determine pharmacokinetic properties. During this clinical trial blood samples will be drawn at specified intervals and sent for analysis. 3. To determine opioid sparing effect of NAS ketamine. Opioid use will be measured by documenting use of rescue medications prior to and during the study and by evaluating total opioid consumption prior to and during the study. METHODS/STUDY POPULATION: Study sample: In the search for improved therapies for chronic cancer pain, medications with novel mechanisms of action have been sought. One such promising pharmacologic approach is ketamine. We specifically intend to measure utility of ketamine in patients with pain related to cancer or cancer treatment. Ketamine has shown to reverse central sensitization and opioid tolerance in rat models. Since ketamine is Scheduled III in United States and has abuse potential, we do not intend for ketamine to replace opioids, but use in patients who have failed opioid therapy. Since the investigators of the study practice at Emory, subjects will be from oncology and pain clinics (the supportive oncology clinic, oncology clinics, the pain clinic and Acute Pain Service) at Emory. The trial will be conducted at the Phase 1 Unit of the Winship Cancer Institute (WCI) at Emory. Subjects may be identified and contacted via telephone with information about the study prior to their next clinic appointment in order to allow time for them to consider the study. Eligibility criteria: Patients will be eligible to participate if they are: 1. Adults with uncontrolled cancer related pain a. Male and female subjects at least 18 years of age. b. Patients with uncontrolled pain related to cancer or cancer treatment. c. Uncontrolled pain will be defined as i. pain which persists for more than 7 days and is rated >/=4 on NPRS, and/or ii. use of breakthrough medication more than 4 times in 24 hours d. Failed other pain medications such non-steroidal anti-inflammatories such as ibuprofen, acetaminophen, opioids such as tramadol, hydrocodone, oxycodone etc. and antineuropathics such as gabapentin. 2. Able to provide informed consent a. Patients who are able to understand written and verbal English. Patients will be excluded from the study if they have any of the following: 1. Conditions increasing the risk of side effects from ketamine a. Conditions not safe due to cardiovascular effects of ketamine i. Presence of severe cardiac disease-EF <15% in patients with known history of cardiac disease ii. Uncontrolled Stage 2 hypertension or greater (systolic blood pressure > 160 and/or diastolic blood pressure >100) iii. Baseline tachycardia, HR >100 b. Conditions not safe due to potential effect of ketamine on intracranial and intraocular pressure i. Presence of elevated ICP ii. Uncontrolled glaucoma c. Presence of uncontrolled depression or other psychiatric comorbidity with psychosis 2. Conditions not safe due to potential side effects reported in ketamine abusers a. History of liver disease b. History of interstitial cystitis 3. Conditions where delivery of intranasal medications may be unreliable a. Active allergic or infectious rhinitis b. Patients with lesions of nasal mucosa 4. Conditions where fetus may be exposed to ketamine in utero (ketamine is category C medication) a. Pregnant women, nursing mothers and women of childbearing potential not using contraception known to be highly effective. b. Highly effective contraception methods include combination of any two of the following: Use of oral, injected or implanted hormonal methods of contraception or; Placement of an intrauterine device (IUD) or intrauterine system (IUS); Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository; Total abstinence; Male/female sterilization. 5. Conditions with medication abuse potential a. Illicit substance abuse within the past 6 months b. Documented history of medication abuse/misuse (e.g. Unsanctioned dose escalation, broken opioid agreement etc.) 6. Conditions where ketamine metabolism may be altered, resulting in erroneous dose response relationship a. Clinical requirement for medications that are concurrent inducers or strong inhibitors of CYP3A4. CYP3A4 substrates are allowed. (Ketamine is metabolized by CYP3A4) Study sample limitations: Subject factors that may affect the final resultant study sample of subjects with full data for analysis. 1. Subjects who may not get pain relief with ketamine may not follow up and resulting incomplete data not eligible for analysis that may erroneously enhance positive effect of ketamine on pain relief. To account for this effort will be made to document the reason for lack of follow-up by contacting patient via telephone or at next scheduled clinic visit within Emory Healthcare. 2. Since patients coming to Emory are typically insured, the study will not adequately capture indigent population. It is not the intention of the current study to investigate differences in pain characteristics or responses of patients with insurance vs indigent population and will need to be addressed via future trials. Since this is a single center trial, the results of this trial might lack external validity required to support widespread changes in practice. This will be a pilot trial to figure out likely most efficacious dose. If this trial is successful, a multi-site randomized clinical trial will be conducted next. Primary Study Measures Primary exposure Intranasal Ketamine for cancer related pain Ketamine is an FDA approved anesthetic with amnesic, analgesic, dissociative, and sedative properties. It is unique among anesthetic agents in that it does not depress cardiovascular and respiratory systems. Ketamine is a noncompetitive, antagonist of N-methyl-D-aspartate (NMDA) receptors that blocks the NMDA channel in the open state by binding to the phencyclidine (PCP) site located within the lumen of the channel. Antagonism of NMDA receptors produces antinociception of persistent or neuropathic pain in animal models and analgesia in pain states in humans. The NMDA receptor is believed to play a role in the development of opioid tolerance and ketamine has been shown in a rat model to prevent fentanyl-induced hyperalgesia and subsequent acute morphine tolerance 5. Ketamine also interacts at a number of other receptor sites to block pain. Some of these sites include voltage-sensitive calcium channels, depression of sodium channels, modulation of cholinergic neurotransmission, and inhibition of uptake of serotonin and norepinephrine. Ketamine also interacts with kappa and mu opioid receptors; however, in humans, naloxone, an opioid antagonist, does not antagonize the analgesic effects of ketamine. Safety and efficacy of ketamine as an anesthetic and analgesic agent is well-documented 2-4. Ketamine is not labeled by the FDA as an analgesic agent. Low (subanesthestic) doses of ketamine have minimal adverse impact upon cardiovascular or respiratory function but produce analgesia and modulate central sensitization, hyperalgesia, and opioid tolerance. Cancer pain, especially in end stages, can be very complicated and is mediated by a variety of pathways: visceral, nociceptive, neuropathic and central. If ketamine can be utilized for pain in end stage cancer patients, this could provide them with superior analgesia and better quality of life, without the risk of significant respiratory depression associated with opioid medications. One of the challenges that we face with ketamine is the route of administration. The most common route is intravascular or intramuscular. Although it has been given orally and rectally, the bioavailability of ketamine when given via these routes is limited to 20-30%. Intranasal (NAS) administration has advantages of being needle free method of administration with potential for outpatient therapy. It lacks hepatic first pass effect resulting in higher bioavailability compared to oral route. Large surface area, uniform temperature, high permeability and extensive vascularity of the nasal mucosa facilitate rapid systemic absorption of intranasal administered drugs 6. In the pilot trial conducted by the study investigators, single dosage of intranasal ketamine has been shown to be feasibility and effective option for temporary pain reduction in patients with cancer related pain. The investigators now seek to obtain feasibility and efficacy data on long-term use of intranasal ketamine for cancer related pain. Ketamine is a scheduled III medication. A physician with a DEA license can order intranasal ketamine from a compounding pharmacy. Primary outcome of interest: Pain scores will be recorded on Numerical Pain Rating Scale (NPRS) at regular intervals throughout the study. NPRS is the most responsive tool to document pain intensity when compared to Visual Analogue Scale (VAS) and Visual Rating Scale (VRS) for measuring pain, 7 showing higher compliance rates, better responsiveness, ease of use, and good applicability relative to VAS/VRS8. Minimal clinically important differences (MCIDs) for pain ratings varies substantially based on patient population and statistical technique used, range of 0.4 to 3.7 points has been reported as a MCID. In general, improvements of pain severity</=1.5 points on NPRS could be seen as clinically irrelevant 9-13. Above that value, the cutoff point for “clinical relevance” depends on patients’ baseline pain severity, and ranges from 2.4 to 5.3 11-13. Higher baseline scores require larger raw changes to represent clinically important differences 14. Primary aim: To determine efficacy of intranasal ketamine in reducing cancer related pain. A clinical trial will be conducted to determine effect of intranasal ketamine on cancer related pain. Pain scores will be recorded on Numerical Pain Rating Scale (NPRS) at regular intervals throughout the study. Minimal clinically important differences (MCIDs) for pain ratings varies substantially based on patient population and statistical technique used, range of 0.4 to 3.7 points has been reported as a MCID. In general, improvements of pain severity</=1.5 points on NPRS could be seen as clinically irrelevant 9-13. Above that value, the cutoff point for “clinical relevance” depends on patients’ baseline pain severity, and ranges from 2.4 to 5.3 11-13. Higher baseline scores require larger raw changes to represent clinically important differences 14. Several clinical trials for pain have reported a reduction of 2 points on NPRS to be clinically important.15-17 Therefore for the purposes of this study, MCID of 2 was used for sample size calculations. A prior research study done by Carr et al. studied effects of intranasal ketamine for breakthrough pain in patients with chronic pain of various etiologies. 18 Total number of subjects in this study was 20 (4 of these had cancer related pain).This study demonstrated a mean reduction of 2.7 units on NPRS (P<0.0001), with standard deviation of 1.87. Since MCID is 2, effect size using this (MCID/SD) = 1.05. Power and sample size table: Assumptions: 1. T-test is the appropriate test (may not be the appropriate test since we have a small sample size and may not be able to assume normality of means based on the central limit theorem) 2. Distribution of reductions in pain score is normal 3. Effect size of 1.05 is clinically meaningful; Sample Size: A sample size of 7 from a population of 20 (in the study done by Carr etal.) achieves 80% power to detect a NPRS difference of −2 between the null hypothesis mean of 0.0 and the alternative hypothesis mean of 2 with an estimated standard deviation (SD) of 1.87 and with a significance level (alpha) of 0.05 using paired t-test assuming that the actual distribution is normal. We will include 10 patients to account for the possibility that the observed pain reduction in the current study may be different than the study done by Carr, as in this study patients were given ketamine for breakthrough pain, as opposed to for baseline pain. We will enroll 25 patients in the study to account for potential dropouts. RESULTS/ANTICIPATED RESULTS: Majority of subjects experienced the largest decrease in their pain with the 10mg IV dose. Side effects included nausea/vomiting and a feeling of unreality. All side effects resolved by the end of each study visit. No severe adverse events occurred. DISCUSSION/SIGNIFICANCE OF IMPACT: Further study is required to elucidate safety of NAS ketamine with long term use for cancer related pain.

OBJECTIVES/SPECIFIC AIMS: Compare the short- and long-term effects of 2 treatments, MST and SF, on limitations in function, pain, and movement characteristics. The movement characteristics included the amount of early excursion (1st half of decent) of the knee, hip, and lumbar spine during a functional activity test of picking up an object. METHODS/STUDY POPULATION: 154 participants were randomized to 6, 1-hour treatment sessions (once/week for 6 weeks) of MST or SF. The MST group received individualized training to modify pain-provoking altered movement patterns during functional activities. The SF group received exercises for trunk strength and trunk and limb flexibility. At baseline, post-treatment and 6-month follow-up participants completed the modified Oswestry Disability Questionnaire (MODQ, a functional limitation measure; 0-100%), the Numeric Pain Rating Scale (NRS, average pain prior 7 days; 0-10) and a standardized pick up an object test, where sagittal plane knee, hip and lumbar spine excursion were calculated using 3D motion capture. A mixed model repeated measures ANOVA was used to examine the following effects: Treatment group (Tx), Time and Tx X Time for each self-report and movement variable. When the ANOVA was significant (p < 0.05), a priori planned contrasts were examined. RESULTS/ANTICIPATED RESULTS: There was a significant Tx X Time interaction (p < 0.01) for each outcome. Baseline: MST and SF were similar in MODQ scores [Δ 0.4% (−3.4 − 2.9)], NRS [Δ 0.0 (−0.6 − 0.6)], knee [Δ 2.2° (−6.7 − 2.5)], hip [Δ 0.4° (−2.9 − 2.5)], and lumbar spine [Δ 0.1° (−1.4 − 1.2)] early excursion. Post-Treatment: Both group’s MODQ and NRS scores decreased (p < 0.01), but MST had a greater reduction in MODQ scores [Δ −7.6% (−3.9 − −11.0)] and lower average NRS scores [Δ −0.8 (−0.1 − −1.4)] compared to SF. MST changed knee [Δ +18.6° (14.6 − 22.1)], hip [Δ +10.8° (8.5 − 13.1)], and lumbar spine [Δ −2.0° (−3.0 − −1.0)] early excursion, while SF did not change early joint excursion (all p > 0.72). 6-Month Follow-up: The differences between MST and SF were maintained for all outcomes (p > 0.26). DISCUSSION/SIGNIFICANCE OF IMPACT: MST was more effective at reducing functional limitations and pain and improving movement patterns during a functional activity compared to SF. For all variables, the differences identified during treatment between MST and SF were maintained at 6-month follow-up. Therefore compared to SF, MST that targets performance of altered movement patterns during functional activities appears to be superior for attaining and maintaining changes in functional limitations, pain, and movement characteristics in people with CLBP.

OBJECTIVES/SPECIFIC AIMS: The goal of this study is to measure speech fluency and brain activity before and after 5 days of behavioral speech fluency training alone (sham group) or speech training plus stimulation (active group). A 1-month follow up will also be completed. The first primary outcome measure is changes in brain activation in speech motor control/timing network. The second primary outcome measure is changes in percentage of stuttered syllables during speech sample (speech fluency). The secondary outcome measure is changes from baseline on the Overall Assessment of Speakers Experience of Stuttering (OASES), a detailed subject rating of how stuttering affects their lives. METHODS/STUDY POPULATION: This study is a between subjects, counterbalanced, sham-controlled, double-blind design. Participants will be 40 adults who stutter who will be randomized (using minimization) into either the active or sham stimulation group, with all other study procedures being the same in both groups. Participants will completed 2 days of baseline testing, 5 consecutive days of brain stimulation during speech training, 2 days of post-testing, and a 1-month follow up. All outcome measures will be completed immediately before and after the 5 days of brain stimulation, as well as at follow-up. as of submission, 10 subjects have completed the study. Data collection is ongoing. RESULTS/ANTICIPATED RESULTS: Expected results. Questions this study aims to answer: 1) Does a more intensive training period lead to decreased stuttering? We expect that both groups will show improvements in speech fluency immediately after training. We expect that those in the active group will continue to exhibit improved speech fluency at 1 month follow up. 2) Does a more intensive training period lead to changes in brain activity? We expect that both groups will exhibit increased activity in auditory/motor regions immediately after training. We expect that the active group will continue to exhibit an increase in activity in these regions at 1 month follow up. DISCUSSION/SIGNIFICANCE OF IMPACT: This is the first RCT study involving brain stimulation in adults who stutter. We expect to provide preliminary evidence for the effectiveness of tDCS as an augmentative agent for increased speech fluency in adults who stutter during a brief, intensive training paradigm. We also expect to be able to provide information on the effects of tDCS on brain activity in speech and auditory-motor regions of the brain. The findings will add to the growing body of literature suggesting that developmental stuttering is a neurodevelopmental disorder with roots in timing and rhythmic aspects of speech motor control and auditory-motor integration.

OBJECTIVES/SPECIFIC AIMS: Cesarean delivery is typically performed in the extremely preterm period (23 to 28 weeks) when the fetus is in breech presentation to avoid the potential risk of head entrapment by an insufficiently dilated cervix during a vaginal delivery. Assessment of the prevalence of extremely preterm breech cesarean delivery would help to appropriately guide future clinical interventions designed to increase the feasibility of vaginal delivery for this sub-group of patients. METHODS/STUDY POPULATION: We performed a cross-sectional study of the 2106 U.S. National Vital Statistics birth certificate database to estimate the prevalence of cesarean deliveries performed during the period of gestation from 23 to 28 weeks with a fetus in breech presentation. RESULTS/ANTICIPATED RESULTS: An analysis of the total births in the 2016 registry (3,945,875) was performed. The gestational age was limited to the target range of 23 0/7 to 27 6/7 weeks. Multiple gestation deliveries were excluded. This yielded 16,092 births of which 4,849 were noted to have breech presentation. The proportion of cesarean deliveries performed for singleton breech fetuses at this gestational range was 87% (4,203/4,849). DISCUSSION/SIGNIFICANCE OF IMPACT: The probability of undergoing a cesarean delivery for an extremely preterm fetus in breech presentation is notably higher (87%) when compared to an overall cesarean delivery rate of 31.9%. Specific interventions to allow for vaginal delivery in this particular sub-group of the obstetric population would be useful to reduce maternal morbidity by increasing vaginal deliveries. Future work will attempt to address innovative solutions to prevent head entrapment by the cervix in this particular population and ultimately avoid cesarean delivery.

OBJECTIVES/SPECIFIC AIMS: To describe the epidemiology of patients with carbapenem-resistant Enterobacteriaceae (CRE) bacteriuria in metropolitan Atlanta, GA and to identify risk factors associated with progression to an invasive CRE infection. We hypothesize that having an indwelling urinary catheter increases the risk of progression. METHODS/STUDY POPULATION: The Georgia Emerging Infections Program (EIP) performs active population- and laboratory-based surveillance to identify CRE isolated from a sterile site (e.g. blood) or urine among patients who reside in the 8-county metropolitan Atlanta area (population ~4 million). The Georgia EIP performs a chart review of each case to extract data on demographics, culture location, resistance patterns, healthcare exposures, and other underlying risk factors. We used a retrospective cohort study design to include all Georgia EIP cases with Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Enterobacter cloacae, or Klebsiella (formerly Enterobacter) aerogenes, adapting the current EIP definition of resistance to only include isolates resistant to meropenem, imipenem or doripenem (minimum inhibitory concentration ≥ 4) first identified in a urine culture from 8/1/2011 to 7/31/2017. Patients with CRE identified in a sterile site culture prior to a urine culture will be excluded. Within this cohort, we will identify which patients had a subsequent similar CRE isolate identified from a sterile site between one day and one year after the original urine culture was identified (termed “progression”). CRE isolates will be defined as similar if they are the same species and have the same carbapenem susceptibility pattern. Univariable analyses using T-tests or other nonparametric tests for continuous variables, and Chi-square tests (or Fisher’s exact tests as appropriate) for categorical variables will compare patient demographics, comorbidities and presence of invasive devices including urinary catheters between patients who had progression to an invasive infection and those who did not have progression. Covariates with a p-value of < 0.2 will be eligible for inclusion in the multivariable logistic regression model with progression to invasive infection as the primary outcome. All statistical analyses will be done in SAS 9.4. RESULTS/ANTICIPATED RESULTS: From 8/1/2011 to 7/31/2017 we have preliminarily identified 546 patients with CRE first identified in urine, representing an annual incidence rate of 1.1 cases per 100,000 population. Most cases were K. pneumoniae (352, 64%), followed by E. coli (117, 21%), E. cloacae (48, 9%), K. aerogenes (18, 3%), and K. oxytoca (11, 2%). The mean patient age was 64 +/− 18 years and the majority (308, 56%) were female. Clinical characterization through chart review was available for 507 patients. The majority of the patients were black (301, 59%), followed by white (166, 33%), Asian (12, 2%), and other or unknown race (28, 6%). 466 (92%) patients had at least one underlying comorbid condition with a median Charlson Comorbidity Index of 3 (IQR 1-5). 460 (91%) infections were considered healthcare-associated (366 community-onset and 94 hospital-onset), while 44 (9%) were community-associated. 279 (55%) patients had a urinary catheter within the two days prior to the CRE culture. The analysis of patients who progress to an invasive CRE infection, including the results of the univariable and multivariable analyses assessing risk factors for progression is in progress and will be reported in the future. DISCUSSION/SIGNIFICANCE OF IMPACT: In metropolitan Atlanta, the annual incidence of CRE first isolated in urine was estimated to be 1.1 cases per 100,000 population between 2011 and 2017, with the majority of the cases being K. pneumoniae. Most patients had prior healthcare exposure and more than 50% of the patients had a urinary catheter. Our anticipated results will identify risk factors associated with progression from CRE bacteriuria to an invasive infection with a specific focus on having a urinary catheter, as this is a potentially modifiable characteristic that could be a target of future interventions.

OBJECTIVES/SPECIFIC AIMS: There has been substantial research showing that there are race and sex differences on alcohol use. Similarly, race and sex disparities are also seen in a variety of different factors that impact drinking behaviors and other health outcomes. One of these factors of interest is Adverse Childhood Experiences (ACEs) which is associated with an increased risk for excessive alcohol use and the harmful effects of drinking. Several studies have shown that racial minorities and females have a greater risk of ACEs, which may be partly related to various structural factors (i.e. poverty) and social norms. Although there has been a substantial amount of research done on ACEs, very few studies have looked at how their interaction with race and sex can influence alcohol-related behaviors. METHODS/STUDY POPULATION: 1,509 participants who self-identified as either Black or White were recruited through a screening protocol at the NIAAA where they completed a series of questionnaires. We categorized the participants into two groups based on the Structured Clinical Interview for DSM-IV disorders: Alcohol Dependent individuals (N=921) with either a past and/or current diagnosis and Non-dependent individuals (N=588). ACEs exposure was assessed using the Childhood Trauma Questionnaire (CTQ). We looked at both total score and the 5 subscales: emotional abuse, physical abuse, sexual abuse, physical neglect, and emotional neglect. Drinking behaviors were assessed using a 90-day Timeline Followback interview and the Alcohol Use Disorder Identification Test (AUDIT). The non-dependent sample was 63% White and 55% male while the alcohol dependent sample was 47% White and 70% male. We tested the interaction effects using ANOVA. RESULTS/ANTICIPATED RESULTS: In the ND sample, there were significant race*sex*ACEs effects for average drinks per day with CTQ total score (P = 0.007), physical abuse (P = 0.005), and physical neglect (P = 0.003). There was also a 3-way interaction with physical neglect on heavy drinking days (P = 0.039) and a 2-way race*ACEs interaction on AUDIT total with physical abuse (P = 0.048). In the AD sample, there were significant 2-way race*ACEs interactions for three drinking outcomes: heavy drinking days with physical neglect (P = 0.009), AUDIT-Harmful Use subscore with CTQ total score (P = 0.028) and physical neglect (P = 0.001), AUDIT-Total score with CTQ total score (P = 0.007), physical abuse (P = 0.042), sexual abuse (P = 0.024), and physical neglect (P = 0.003). There were also 3-way interactions for AUDIT-Harmful use (P = 0.013) and AUDIT-Total scores (P = 0.011) with emotional abuse. DISCUSSION/SIGNIFICANCE OF IMPACT: Our results indicate that there are both 2-way (race*ACEs) and 3-way (race*sex*ACEs) interaction effects on alcohol consumption and the related negative effects for both non-dependent and dependent samples. There were no sex*ACEs interaction effects in either sample implying that race may play a bigger role in differentiating drinking outcomes by ACEs across males and females. However, contrary to our expectations, race seemed to be protective factor for Black participants against both alcohol consumption and the negative effects despite having higher rates of ACEs exposure. Future analyses will explore personality measures as potential mediators of the relationship between ACEs and alcohol use. Also, analyses will look to see if there are any behavioral factors that may contribute to resiliency among minority populations.

OBJECTIVES/SPECIFIC AIMS: 1. To assess feasibility (efficacy, safety, acceptability) of the menstrual cup for managing urinary incontinence among women with obstetric fistula 2. To examine pre-implementation facilitators and barriers (including appropriateness) among additional stakeholders METHODS/STUDY POPULATION: Sequential explanatory mixed methods study whereby repeated measures clinical trial results are explained by subsequent interviews with additional women with OF on coping and stigma and other stakeholders on perceptions of fistula self-management. RESULTS/ANTICIPATED RESULTS: Of the 32 patients screened, 11 were eligible (100% consent rate). At baseline, mean (±SD) leakage in ml was 63.2 (±49.2) (95% CI: 30.2-96.3) over two hours, while the mean leakage over two hours of use of the cup was 16.8 (±16.5) (95% CI: 5.7-27.9). The mean difference of 46.4 (±52.1) ml with use of the cup (95% CI: 11.4-81.4) was statistically significant (p = 0.02). With the cup, women experienced an average 61.0% (±37.4) (95% CI: 35.9-86.2) leakage reduction, a difference 10/11 users (91.0%) perceived in reduced leakage. One participant, reporting four previous surgical attempts, experienced a 78.7% leakage reduction. Acceptability was high–women could easily insert (8/11), remove (8/11), and comfortably wear (11/11) the cup and most (10/11) would recommend it. No adverse effects attributable to the intervention were observed on exam, although some women perceived difficulties with insertion and removal. Data collection tools were appropriate with slight modification advised. Interviews highlighted that women were already using various active coping and resistance strategies but lacked access to tools to support coping. Additional stakeholders reported the innovation was a simple, low-cost device that is an appropriate fit with ongoing fistula programming. Pre-implementation facilitators include the clear relative advantage to existing self-management strategies, the potential to build upon existing partnerships to implement, and a tension for change to address surgical gaps. Barriers included additional stakeholder’s perceptions of low user acceptability and appropriateness in some cases and the need for additional study data to inform decision making for practice and policy. DISCUSSION/SIGNIFICANCE OF IMPACT: The innovation is efficacious, acceptable, adds to current coping strategies, and fits within existing fistula programs. Stakeholders’ pre-implementation perceptions highlight the importance of partnerships and the need for an evidence base related to effectiveness, acceptability, and cost. Challenges to address include access to resources within these contexts (water, soap, and safe space to empty cup) and development of a culturally appropriate counseling message. Future research warranted.

OBJECTIVES/SPECIFIC AIMS: Metachromatic leukodystrophy (MLD) is a rare, lysosomal storage disorder caused by decreased enzymatic activity of arylsulfatase A. This can be the result of mutations in the ASA gene, or in rare cases PSAP. Historically, MLD has been subdivided into 3 forms based on age of onset: late infantile, juvenile, and adult. These subtypes were defined decades ago, prior to the appreciation of the full clinical spectrum of this lysosomal storage disorder and the advent of genetic testing. As a consequence, these empiric age-based historical definitions do not fully account for the spectrum of disease and are not founded in evidence-based analysis of phenotypic cohorts. Additionally, the antiquated definitions do not fully predict presenting features or disease course, and they fail to stratify outcomes in the few therapies currently available to treat this disease. As novel targeted therapeutics are developed, it is essential to have a clear understanding of the clinical presentation and natural history of MLD. Without properly defined sub-populations, it is difficult to design a therapeutic clinical trial that can demonstrate efficacy in a heterogeneous group. METHODS/STUDY POPULATION: In this project, we collected the retrospective natural history of over 50 individuals from around the world. We created an electronic database in REDCap to able to longitudinally collect clinical information. Using this retrospective natural history approach to understanding the disease course of individuals affected by MLD, we were able to characterize age of onset, delay to diagnosis, and common presenting features. RESULTS/ANTICIPATED RESULTS: Our results suggest distinct clinical phenotypic subgroups, with distinct presentations. DISCUSSION/SIGNIFICANCE OF IMPACT: With a better understanding of the natural history of MLD, we will be able to better counsel families and to design clinical trials with more coherent cohorts and more appropriate clinical endpoints.