Virginia Commonwealth University Research Articles

Formation of Al + (C 6 H 6 ) 13 : The Origin of Magic Number in Metal–Benzene Clusters Determined by the Nature of the Core

The identification of highly abundant, “magic” species in the mass spectra of clusters have proven to be valuable in nanoscience, leading to the discovery of new stable species such as fullerenes a...

Ultra-short duration direct acting antiviral prophylaxis to prevent virus transmission from hepatitis C viremic donors to hepatitis C negative kidney transplant recipients.

We conducted an adaptive design single-center pilot trial between October 2017 and November 2018 to determine the safety and efficacy of ultra-short-term perioperative pangenotypic direct acting antiviral (DAA) prophylaxis for deceased hepatitis C virus (HCV)-nucleic acid test (NAT) positive donors to HCV negative kidney recipients (D+/R-). In Group 1, 10 patients received one dose of SOF/VEL (sofusbuvir/velpatasvir) pretransplant and one dose on posttransplant Day 1. In Group 2A (N=15) and the posttrial validation (Group 2B; N=25) phase, patients received two additional SOF/VEL doses (total 4) on Days 2 and 3 posttransplant. Development of posttransplant HCV transmission triggered 12-week DAA therapy. For available donor samples (N=27), median donor viral load was 1.37E+06IU/mL (genotype [GT]1a: 70%; GT2: 7%; GT3: 23%). Overall viral transmission rate was 12% (6/50; Group 1:30% [3/10]; Group 2A:13% [2/15]; Group 2B:4% [1/25]). For the 6 viremic patients, 5 (83%) achieved sustained virologic response (3 with first-line DAA therapy; and two after retreatment with second-line DAA). At a median follow-up of 8months posttransplant, overall patient and allograft survivals were 98%, respectively. The 4-day strategy reduced viral transmission to 7.5% (3/40; 95% confidence interval [CI]: 1.8%-20.5%) and could result in avoidance of prolonged posttransplant DAA therapy for most D+/R-transplants.

PP-14, a Novel Structurally-Enhanced Antisickling Allosteric Hemoglobin Effector, Increases Oxygen Affinity and Disrupts Hemoglobin S Polymer Formation

We have previously designed and investigated novel allosteric effectors of hemoglobin (AEHs), as potential targeted treatment of sickle cell disease (SCD). In general, AEHs transiently covalently bind to hemoglobin (Hb), increase its affinity for O2, increasing the fraction of oxygenated sickle Hb (HbS), thus reducing HbS polymerization and countering red blood cell (RBC) sickling. In the current study, we designed a novel class of AEH molecules, incorporating a secondary mechanism of action (MOA), which is independent of Hb O2-affinity by interacting with the F-helix of deoxygenated HbS to directly destabilize its polymerization. Here, we report current results from our in-vitro and in-vivo studies with a representative AEH compound (PP-14). First, we assessed the anti-sickling properties in-vitro by incubating 0.5, 1, and 2 mM of PP-14 with whole blood suspensions from a subject with homozygous SCD (SS, hematocrit: 20%) under hypoxic conditions, with subsequent RBC sickling assessment by microscopy. Next, we subjected the samples to anoxia (100% N2 gas) to demonstrate the O2-affinity-independent antisickling mechanism. Subsequently, we tested residual samples for the degree of Hb modification (i.e., HbS-AEH adduct formation) and O2-affinity (p50) shifts. In a second experiment to further assess the secondary MOA, we subjected SS blood samples treated with various concentrations of PP-14 to hypoxia in the Hemox analyzer, which permitted us to obtain aliquot samples at defined pO2 values to establish pO2-dependent sickling. Additionally, we conducted in silico and in-vitro ADME studies to evaluate possible metabolic inhibition of a panel of CYP enzymes. Finally, we conducted a preliminary in-vivo PK/PD study in wild-type mice administered single doses of PP-14 via the oral (P.O.: 100-200 mg/kg) and intraperitoneal (I.P.: 75 mg/kg) routes. Serial blood samples were collected for up to 52 h after P.O., and up to 30 h after I.P. administration, and samples were assayed to quantify PP-14 concentrations. Residual blood samples were assayed for in-vivo Hb-AEH adduct formation, and the corresponding change in O2-affinity (Δp50, %). Our in-vitro studies demonstrated concentration-dependent inhibition of cell sickling of 25.5±11%, 44.4±3.8% and 90.8±1%, at 0.5, 1 and 2 mM of PP-14, respectively. HbS was modified correspondingly (38.9±9%, 55.7±4.9 %, and 92.4±9.8%), and was correlated linearly with the left-shift in OEC (Δp50 values of 11.3±5.1%, 29.0±13.2%, and 67.5±8.2%). Importantly, the antisickling effect was sustained under anoxic conditions (100% N2), strongly supporting the notion of a secondary, O2-affinity-independent MOA. Furthermore, we observed a dose-dependent delay in sickling, with initiation of sickling recorded at a pO2 level of 40 mmHg in absence of PP-14; and at 30 and 20 mmHg at 0.5, and 1 mM PP-14 concentrations, respectively. Complete inhibition of sickling was observed at 2 mM PP-14 through the lowest recorded pO2 level of 1.5 mmHg, a unique, effect not previously observed in any analogous AEH. In-vitro partitioning studies demonstrated that >90% of PP-14 partitioned into the RBC compartment when whole blood was incubated with 100-300 µM concentrations. Metabolic studies using pooled human liver microsomes (HLM) and isozyme-specific probe substrates suggested that up to 100 µM PP-14 did not inhibit CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4 or CYP2B6. Wild-type mice after I.P. administration of PP-14 (75 mg/kg, n=5) showed peak concentrations in blood at 7 hrs (416.3±81.2 µM), with corresponding PD effects (Δp50 of 41.6±13.5%; modified Hb levels of 43.6±8.0%). Orally-treated mice had peak drug concentrations after 10-24 hrs, (~150 µM at 200 mg/kg, n= 2), with corresponding PD effects (Δp50 of 36.5±7.0%; modified Hb levels of 28.8±4.9%), which declined by 52 hrs. Overall, our data confirm that PP-14 is novel antisickling AEH with a secondary, O2-independent MOA in addition to the primary O2-dependent effect, as demonstrated by the inhibition of sickling under anoxic conditions. Additionally, PP-14 showed: excellent partitioning into the RBC compartment; acceptable in-silico ADME properties and in-vivo oral bioavailability; PD effects; and low liability for metabolic drug-drug interactions. Further studies to investigate formal detailed pharmacokinetic properties, and biological activity after single- or repeat-doses in a SCD mouse model are ongoing. Disclosures Safo: Sanofi: Consultancy, Research Funding; Virginia Commonwealth University: Patents & Royalties. Pagare:Virginia Commonwealth University: Patents & Royalties. Ghatge:Virginia Commonwealth University: Patents & Royalties. Rivella:Meira GTx, Ionis Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Disc medicine, Protagonist, LIPC, Meira GTx: Consultancy. Hines:Functional Fluidics: Equity Ownership. Liu:Functional Fluidics: Employment. Zhang:Virginia Commonwealth University: Patents & Royalties. Venitz:Virginia Commonwealth University: Patents & Royalties. Abdulmalik:The Children's Hospital of Philadelphia: Patents & Royalties: Provisional Patent.

MetAP2 Inhibition Modifies Hemoglobin S (HbS) to Delay Polymerization and Improve Blood Flow in Sickle Cell Disease

Dilution of HbS with non-sickling hemoglobin or hemoglobin with increased oxygen affinity is clinically beneficial in sickle cell disease. Aldehydes, including 5-HMF, tucaresol or GBT440, modify the N-terminus of HbS by reversible covalent imine formation generating modified forms of HbS that resist polymerization under low oxygen concentrations. In contrast to reversible imine formation by aldehydes, we hypothesize that stable modification of HbS will result from N-terminal retention of the initiator methionine (iMet) and subsequent N-terminal acetylation of the iMet (acetyl-iMet). MetAP2 is the methionine aminopeptidase able to cleave iMet from Val1 on α-globin and βS-globin as the unfolded N-terminal peptides emerge from the ribosome. Enzyme kinetic studies with pure MetAP2 and N-terminal octapeptides showed that βS-globin peptide is a 5-fold better substrate than α-globin peptide. Lentiviral shRNA knock-down of MetAP2 in differentiating erythroid HUDEP cells in vitro confirmed that α-globin is more extensively modified than βS-globin, consistent with the enzyme kinetic data. Selective MetAP2 inhibitors used to treat cultured human erythroid cells (HUDEP and PBMC derived CD34+) and Townes SCD mice in vivo confirmed that both α-globin and βS-globin domains of HbS are extensively modified by N-terminal iMet and acetyl-iMet. N-terminal retention of iMet and subsequent acetylation creates a mixture of modified HbS tetramers with combined modifications on both globins. Cation exchange chromatography separated nine different modified HbS variants from unmodified HbS as identified by LCMS. Purified samples of HbS modified by N-terminal iMet and acetyl-iMet had increased oxygen affinity as measured by decreased P50. Modified HbS containing the acetyl-iMet-βS-globin were found to have delayed polymerization under complete hypoxia (sodium metabisulfite triggered hypoxia in 1.8 M phosphate). Two modified HbS variants were further purified for X-ray crystallography studies (βS-globin / iMet-α-globin and acetyl-iMet-βS-globin / iMet-α-globin). Oxyhemoglobin structures of both modified HbS variants were in the R2-state previously described in structures of aldehyde modified HbS. This R2-state stabilizes the oxygenated R-state of HbS from conversion to the deoxygenated T-state that initiates HbS polymerization in sickle RBC. Treatment by selective irreversible covalent or reversible MetAP2 inhibitors resulted in high levels of HbS modification (>75%) in cultured erythroid cells (HUDEP and CD34+ cells). Dose dependent modification of HbS was observed in Townes sickle cell mouse blood RBC in vivo with total modification of HbS approaching 50%. In whole blood ex vivo studies, modification of HbS decreased RBC sickling under hypoxia (4% O2) and significantly increased the affinity of RBC for oxygen (decreased P50). Blood samples from MetAP2 inhibitor treated mice were analyzed for single-cell O2 saturation of the RBC and for the fractional flow velocity drop in whole blood rheology under decreasing partial oxygen pressures. In blood from vehicle treated sickle mice, a low-saturation peak of deoxy-HbS was observed in 7.8% O2, in contrast to blood from MetAP2 inhibitor-treated mice where the low-saturation peak was only observed in 6.4% O2. Similarly, in an assay of O2 dependent blood flow rheology, the half-maximum fractional velocity drop occurred at 5% O2 in control blood decreasing to 2% O2 in MetAP2 inhibitor treated blood. Our studies show that MetAP2 inhibition results in retention of iMet on βS-globin and α-globin and allows further acetylation of the retained iMet to create a mixture of N-terminal modified HbS tetramers. These modified HbS variants resist polymerization and RBC sickling under conditions of low O2 by delaying HbS polymerization and increasing O2 affinity. Our data suggests that MetAP2 may warrant further study as a potential therapeutic target for sickle cell disease. Disclosures Demers: Sanofi: Employment. Sturtevant:Sanofi: Employment. Guertin:Sanofi: Employment. Gupta:Sanofi: Employment. Desai:Sanofi: Employment. Vieira:Sanofi: Employment. Hicks:Sanofi: Employment. Ismail:Sanofi: Employment. Safo:Sanofi: Consultancy, Research Funding; Virginia Commonwealth University: Patents & Royalties. Wood:Sanofi: Consultancy, Research Funding. Higgins:Sanofi: Consultancy, Research Funding. Light:Sanofi: Employment.

Venetoclax and Cytarabine in AML Transformed from Myelofibrosis

Background Acute myeloid leukemia (AML) accounts for 1% of all newly diagnosed cancers with a mean age at diagnosis of 68. Although the majority present de novo, AML can be secondary to conditions such as myelodysplastic syndrome (MDS) and myeloproliferative neoplasms (MPNs) including polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF). The subset of patients with AML transformed from MPN continues to remain a therapeutic challenge with little data to support clinical efficacy. A large retrospective review of 273 patients revealed no significant improvement in overall survival in this patient population for those diagnosed between 1989 and 2016. Prognosis remains dismal with an overall survival of 5-7 months. Treatment options are limited and often with little proven clinical utility. Even the addition of hypomethylating agents to treatment options has failed to show any improvement in survival necessitating the investigation of new treatment options (Chihara et al, ASH 2016). In this case series, we present two AML cases that have transformed from myelofibrosis and were successfully treated with the combination of cytarabine and venetoclax. Objective Our primary objective was to determine the clinical efficacy of the combination of cytarabine and venetoclax in patients with myelofibrosis with leukemic transformation. Methods This is an observational, retrospective case series of two patients that were treated with cytarabine and venetoclax at Virginia Commonwealth University from 2018 to 2019. Both patients had previously been confirmed as meeting WHO criteria for myelofibrosis on bone marrow examination. Upon transformation to acute myeloid leukemia, again confirmed on bone marrow biopsy, both patients were transitioned to the following regimen: cytarabine 20 mg/m2 on days 1-10 of 28-day cycle in combination with venetoclax with rapid dose escalation to goal of 600mg daily with dose adjustments for medication interactions. The patient's response to therapy and side effect monitoring were performed at regular intervals in the outpatient clinic. Results Our study consisted of two females, age 65 (patient 1) and 71 (patient 2) with a median age of 68 and bone marrow biopsy confirmed diagnosis of myelofibrosis. Both females had grade 3+ fibrosis on marrow examination and both harbored JAK2 mutations on initial diagnosis of myelofibrosis. Patient 2 also demonstrated a 20q deletion. Neither female was deemed a suitable candidate for transplantation due to their age and considerable comorbidities. On transformation to leukemia, blast count burden was 27% and 23%, respectively. Patient 1 had received decitabine prior to the cytarabine/venetoclax regiment while the other had no previous therapy for her myelofibrosis or leukemia. Patient 1 was maintained on the regiment with for 10 months and nearly completed 9 cycles before patient decompensated and was transitioned to comfort care and eventually died. Complications during her treatment course included an elevated uric acid requiring a dose of rasburicase, neutropenic fever and subdural hematoma that resolved without any intervention. Patient 2 has completed 6 cycles of therapy and is now 8 months post initiation of therapy. Her most recent bone marrow biopsy showed a hypocellular bone marrow (20-30% cellularity) and severe myelofibrosis (reticulin 3/3+) with less than 1% blasts. She remains independent of transfusions. Conclusions Our case series demonstrates that the combination of cytarabine and venetoclax can be effectively used in patients with AML transformed from myelofibrosis. In a disease historically with an overall survival of 6 months, one patient survived 10 months and the other is 8 months out and currently in remission from her AML on her most recent bone marrow biopsy, and independent of transfusions. Overall, therapy has been well tolerated with manageable adverse events. Although future prospective studies are needed, the combination of cytarabine and venetoclax offers a reasonable treatment option for secondary AML transformed from myelofibrosis. Disclosures Yazbeck: Gilead Sciences: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

Real-World Use of Emicizumab in Patients with Hemophilia with and without Inhibitors

Introduction Emicizumab is a recombinant humanized monoclonal antibody that bridges factor IXa and Factor Xa and is administered via subcutaneous injection. After initial FDA approval for patients with hemophilia A (HA) and inhibitors, it was approved in October 2018 for prophylaxis in patients with HA without inhibitors of all ages. In clinical trials of subjects without inhibitors, emicizumab was studied only in those >12 years of age. The primary objective of this study was to report our "real-world", post-licensure experience with emicizumab across a more heterogenous patient population, comparing annualized bleeding rates prior to and after initiating emicizumab. Secondary objectives included evaluating for serious adverse events including death, thrombosis or drug discontinuation. Methods We conducted a multi-center observational study at 3 federally funded Hemophilia Treatment Centers: Children's Hospital of Philadelphia, Virginia Commonwealth University and Children's National Health System. Inclusion criteria included patients with HA initiated on emicizumab prior to May 15th 2019. Data extraction included: demographics, diagnosis, prior HA history (inhibitor, prophylaxis treatment regimen), emicizumab dosing data, bleeding events (all bleeds, treated bleeds, joint bleeds, traumatic bleeds) and thrombotic events from the 6 months prior to emicizumab until July 15th 2019. Annualized bleeding rates (ABR) were calculated to account for variable follow up. Wilcoxon Sign-Rank Difference Test was used to test the difference in number of bleeds and McNemar's test was used to test the difference in proportions of patients with ABR=0. Results Ninety-two patients met inclusion criteria: 89 male and 89 with severe HA (3 moderate HA) (Table 1). Age at initiation of emicizumab ranged from 5 weeks to 55 years; median 8.6 yrs (IQR 4.8-13.5 yrs). Nineteen patients had an active inhibitor at the time of starting emicizumab; the remaining 73 did not have an inhibitor, and most (86%) were on prophylaxis prior to emicizumab. Sixty-two patients were < 12 years of age (13 with inhibitors). Median duration of emicizumab therapy was 48 weeks (inhibitors) and 22 weeks (non-inhibitors), with a total follow up of 53.3 patient years. In patients with inhibitors, the ABR (treated bleeds) prior to emicizumab was 6.2 events (95% CI, 0.98 to 11.4) compared to 0.3 events (95% CI, 0 to 0.73) on emicizumab, p=0.002. In subjects without inhibitors, the ABR prior to emicizumab was 1.8 events (95% CI, 0.66 to 2.96) compared to 0.22 events (95% CI, 0.05 to 0.39) on emicizumab, p<0.001. Additional data on bleeding events is provided in Table 1. The proportion of patients with ABR=0 increased in both inhibitor (from 46% to 74%, p=0.06) and non-inhibitor subjects (from 60 to 78%, p=0.015). All patients received 1.5 mg/kg weekly x 4 loading doses, followed by either weekly (27%), every other week (70%), or monthly (3%) dosing; patients with inhibitors were more likely to receive weekly dosing. No patients who initiated emicizumab discontinued the drug or developed a neutralizing antibody to FVIII or emicizumab, although patients have not been consistently screened for these antibodies. No thrombotic or thrombotic microangiopathy events or death have occurred. Conclusions Our favorable clinical experience with emicizumab post-licensure in patients with HA is similar to that reported in the clinical trials. Although excluded from the clinical trials, patients with HA without inhibitors < 12 years accounted for the majority (67%) of our cohort. As anticipated, these younger patients appear to experience the same benefit as patients > 12. No serious drug-related adverse events were reported, although the overall study period is relatively short. Ongoing follow up of these patients, and others, will be important to assess the ongoing safety and efficacy profile of this novel therapy. Updated data on this cohort will be presented at the ASH meeting Disclosures Guelcher: NovoNordisk: Other: Advisory Board; Octapharma: Other: Advisory Board; Takeda: Other: Advisory Board; Genetech: Other: Advisory Board. Butler:pfizer: Other: Advisory board; Hema-Biologics: Consultancy; genetech: Other: Advisory board. Guerrera:Genetech: Other: Advisory Board; Kendrion: Other: Advisory Board; Shire: Other: Advisory Board; Bayer: Other: Advisory Board; Bioverativ: Consultancy; Pfizer: Other: Advisory Board; Novo Nordisk: Consultancy. Raffini:Roche: Other: Advisory Board; Bayer: Other: Advisory Board; CSL Behring: Other: Advisory Board.

Peri-Procedural Management and Outcomes of Patients with Hemophilia on Emicizumab Prophylaxis

Introduction Emicizumab is a recombinant humanized monoclonal antibody that bridges factor IXa and Factor X and is administered via subcutaneous injection. It provides protection against bleeding in patients with hemophilia A (HA) with and without inhibitors of all ages. Since licensure, the use of emicizumab has increased across hemophilia treatment centers (HTCs). Management of patients on this drug who require procedures has not been well established. The objective of this study was to report peri-procedural hemostasis management as well as bleeding and thrombotic outcomes in a heterogenous group of patients with HA on emicizumab requiring interventional procedures. Methods We conducted a multi-center observational study at 3 federally funded Hemophilia Treatment Centers: Children's Hospital of Philadelphia, Virginia Commonwealth University and Children's National Health System. Inclusion criteria included patients with HA initiated on emicizumab prior to May 15th 2019 that underwent a surgical, dental or interventional procedure prior to July 15, 2019. Data extraction included: demographics, diagnosis, inhibitor, emicizumab dosing data, surgery type, factor used during surgery, and bleeding or thrombotic complications during or after surgery. Results There were a total of 19 procedures in 19 subjects during the study period. 18 were male and all had severe HA. Age at initiation of emicizumab in this cohort ranged from 5 weeks to 27 years; median 5.7 (IQR) yrs. There were 6 patients with an active inhibitor at the time of emicizumab initiation. All patients received emicizumab 3.0 mg/kg weekly x 4 loading doses, followed by either weekly (8), every other week (10), or monthly (1) dosing. There were 18 minor procedures during the study period (14 port removals and one of each of the following: PE tube removal, laparoscopic inguinal hernia repair, arthroscopy, and dental extraction) and one major procedure (intracranial ventricular shunt revision )(Table 1). Of the 14 port removals, 5 patients (1 with inhibitor) did not receive pre-procedure factor replacement; the other 7 received rVIIa or factor VIII pre-procedure and 2 of these patients received a subsequent dose as part of their plan. Three of the 14 patients that underwent port removal (one with inhibitor) were noted to have swelling and hematoma at the surgical site 1-2 days post-op and received 1-2 doses of subsequent factor to treat these bleeding events; only one of these patients did not receive pre-procedure factor. The patient who underwent major surgery received multiple doses of FVIII (to keep FVIII levels >50% x 1 week) and did not have bleeding complications. There were no thrombotic complications. Conclusions In general, the 19 patients with HA who required procedures while on emicizumab did well. Port removal was the most common procedure, which was not surprising given the transition from intravenous to subcutaneous prophylaxis. There was variation in practice, particularly in regard to the need for clotting factor prior to port removal. Most patients did well with 0-1 treatments prior to minor procedures, and no additional replacement. Although 3 of the 14 patients required 1-2 unplanned infusions of clotting factor post port removal, there was no clear relationship between pre-procedure factor replacement and post-procedure port hematoma. This observational study provides useful information for providers who manage patients with HA on emicizumab, although larger studies are clearly needed to help determine best practice. Disclosures Guelcher: Takeda: Other: Advisory Board; Octapharma: Other: Advisory Board; Genetech: Other: Advisory Board; NovoNordisk: Other: Advisory Board. Butler:Hema-Biologics: Consultancy; pfizer: Other: Advisory board; genetech: Other: Advisory board. Guerrera:Bioverativ: Consultancy; Novo Nordisk: Consultancy; Pfizer: Other: Advisory Board; Bayer: Other: Advisory Board; Shire: Other: Advisory Board; Kendrion: Other: Advisory Board; Genetech: Other: Advisory Board. Raffini:Roche: Other: Advisory Board; CSL Behring: Other: Advisory Board; Bayer: Other: Advisory Board.

Tiered Oral Therapy Protocol for Sickle Cell Vaso-Occlusive Crisis

Background: Adults with sickle cell disease (SCD) often present with extremely painful acute vaso-occlusive crises (VOC). VOC guidelines quote studies supporting early initiation of opioids, but are lacking in a standardized approach to achieve adequate analgesia and subsequent de-escalation. Various SCD studies comparing continuous basal versus demand bolus patient-controlled analgesia (PCA) show conflicting outcomes. Thus the objective of our pilot was to develop a standardized approach to pain management utilizing PCA and a Tiered Oral Therapy Protocol (TOTP) in an effort to affect healthcare utilization by decreasing length of stay without increasing readmission rates. Methods: We studied admissions of 31 SCD (any genotype) patients (8 males, 23 females) ≥ 18 years old, all African-American, admitted for VOC, and treated by hospitalist providers using TOTP on one medical unit at Virginia Commonwealth University Health System from July 2018 to June 2019. Inpatient admissions for one calendar year prior to the initial TOTP admission served as the patient's historical control. TOTP is guided by the patient's individualized treatment plan and starts with continuation of their home basal dosing, demand dose only PCA, and immediate-release oral opioids for additional breakthrough pain. TOTP goals are aggressive up-titration of opioids until adequate analgesia. After a period of stability the next phase encourages timely, aggressive down-titration of opioids to speed discharge. We primarily compared length of stay (LOS), hospital charges, and 30-day readmission rates for TOTP vs historical controls. Secondarily, we compared adverse safety events: opioid-related rapid responses, naloxone administration, or falls. Results: Utilization of TOTP resulted in reductions in LOS (21%, 4.7 days controls vs. 3.7 days TOTP, p<0.014), and hospital charges ($1,627,497.73 controls vs. $944,528.96 TOTP, p=0.1403), and an insignificant increase in the 30-day readmission rate (35.6% controls vs. 42.7% TOTP, p=0.5027). Hospital charge data is difficult to interpret as a full year of post TOTP encounters are not available for all patients. There were no TOTP vs. historical control differences in opioid-related safety events. Conclusion: Standardization of therapy using the TOTP improved length of stay and reduced charges for patients with sickle cell disease admitted for acute VOC without increasing adverse safety events or significantly impacting the 30 day readmission rate. We have enlarged this pilot to include other VCU medical units, to test whether we can reproduce our initial one-unit success. Further, we recommend TOTP implementation and testing in other hospitals to exclude secondary trends, since TOTP was but one among several interventions in a VCU Adult SCD Medical Home. Figure Disclosures Smith: Novartis: Consultancy, Honoraria.

Case Management Featuring Community Health Workers Reduces Inpatient Health Care Utilization in Adults with Sickle Cell Disease

Background: Hospital readmission rates and acute care utilization among adults with sickle cell disease (SCD) are almost twice the rates of children. Adult patients may have complex medical and psychosocial needs that are not adequately addressed in fragmented healthcare systems. Few systems have implemented evidence-based, comprehensive care for SCD adults, shown to improve both medical and psychosocial outcomes in chronic diseases. Case management (CM) and community health workers (CHWs) are two evidence-based health management strategies that can help reduce health risks, reduce readmission rates, and improve patient-provider relationships. Methods: After years of attempting adult SCD CM with two MDs and one advanced practice provider (APP), Virginia Commonwealth University Medical Center (VCU) built upon a pilot study of CM and CHWs and implemented a multi-disciplinary Adult Sickle Cell Medical Home that assigned one of two CHWs for CM of the 50 highest SCD adult utilizers ranked by calendar year (CY) 2017 VCU charges, then by CY 2017 inpatient days. CHWs followed patients in and out of the hospital, and met with them at home. They were joined by a social worker who provided CM and behavioral therapy, an additional APP, and a project manager. This team met weekly. Medical Home leaders and quality improvement (QI) specialists enlisted other periodic caregivers to form QI teams with Medical Home workers focusing on behavioral health, ambulatory management, inpatient management, and emergency department (ED) management. A prior authorization specialist handled administrative access to opioids. Evaluation compared utilization during CY 2017 (pre-intervention) versus CY 2018 (intervention). For all patients we compared the average 30-day readmission rate, the average length of stay (ALOS), the average 3-Day ED return rate, the number of ED discharges, the numbers of inpatient days, inpatient discharges, and outpatient visits, the number of patients who used the ED, and total VCU charges. For the 50 highest utilizers, we compared the 30-day readmission rate, ALOS, total inpatient days and total VCU charges. VCU had no ambulatory SCD infusion unit, and the VCU ED did not have a special SCD rapid triage protocol. There was no control group. Analysis consisted of chi square and paired and unpaired t-tests. Results: Among 567 SCD adults (Table), including 231 males and 336 females, ages 18 - 80, comparing pre-intervention to intervention, average utilization and VCU charges were either numerically or statistically significantly reduced, with the exception of outpatient visits, which remained flat. For the 50 highest utilizers, mean 30-day readmission rates were flat (45.98% vs 44.35%, p=0.7257), ALOS was significantly reduced (6.1 days vs 4.8 days, p<0.0001), inpatient days were reduced (206 days vs 106 days), and total charges were significantly reduced (25.43%, $5,297,323.73 vs $3,950,267.26, p=0.0037). Conclusions: At VCU, a multi-disciplinary Adult Sickle Cell Medical Home that featured intensive CM and CHWs, but no infusion center or rapid ED triage, reduced annual utilization for adult SCD patients. CM program elements that were most effective should be studied in the future. A randomized controlled trial of CM and CHWs would strengthen evidence of their efficacy in improving utilization. Table. Disclosures Smith: Novartis: Consultancy, Honoraria. Lipato:Novartis: Honoraria. Roberts:Truven Health Analytics: Consultancy; Community Health Network of Connecticut: Consultancy.

Responsivity of Utilization Rates to the Intensity of Case Management over Time Among High-Utilizing Adults with Sickle Cell Disease

Background: Case management (CM) and community health workers (CHWs) are two evidence-based health management strategies that can help reduce health risks, reduce readmission rates, and improve patient-provider relationships, all of which may be suboptimal in adults with sickle cell disease (SCD). In Fiscal Year (FY) 2016, the actual average vs. expected average length of stay (ALOS) among SCD adults at Virginia Commonwealth University Medical Center (VCU), an urban academic medical center, was 6.7 days vs 4.2 days. The 30-day readmission rate was 33.7%. We have previously presented results of a year-long pilot CM and CHW intervention for five of VCU's highest adult SCD utilizers, measured by calendar year (CY) 2015 VCU charges (Sop, et al., Blood 2017). Comparing CYs 2015 and 2016, there were numeric improvements in inpatient discharges, 30-day readmissions, 3-Day Emergency Department (ED) returns, ED discharges, outpatient visits, inpatient days, and total VCU charges. Herein, we show results of an extension of the pilot to evaluate responsivity to change over time: whether these improvements were lost among these same patients in the subsequent year (CY 2017) with diminished CM due to loss of funding, and whether they recurred in CY 2018, when CM was more robust as a result of new, more stable funding. Methods: Using the VCU charge and utilization database, we compared the above utilization variables for the five highest CY 2015 utilizers in CYs 2018, 2017, 2016 and 2015. The five original patients included 2 males and 3 females aged between 25-31 years old. One of the females passed away in 2016. Results: There was a trend toward numerically lower utilization during the two CM and CHW years (2016 and 2018), compared to the two diminished CM years (2015 and 2017). Inpatient discharges, inpatient days, and total charges see-sawed according to the intensity of intervention, going down during the year of the initial intervention, rising during the year after intervention, and going down again with resumption of intervention. However, there were notable exceptions: 30-day re-admissions were the lowest in 2017 a diminished intervention year; 3-day ED returns were flat throughout; ED discharges declined throughout, and; outpatient visits rose throughout. Conclusions: These pilot results must be interpreted with caution, since the sample was very small, and interventions were not standardized or randomized, so that secondary trends could be excluded. We found that, after diminution in 2017 of an initial CM and CHW intervention in 2016, several of the initial 2015-to-2016 improvements in academic medical center utilization for five high-utilizing adult SCD patients deteriorated. Subsequently, these improvements recurred when CM and CHWs were reapplied in 2018. We also found that other utilization improvements were sustained despite diminution or resumption of the intervention. This pilot result lays the groundwork for larger, more rigorous CM and CHW Table Disclosures Smith: Novartis: Consultancy, Honoraria. Lipato:Novartis: Honoraria.

Using Lean Six Sigma to Develop a Patient Centered Medical Home for Adults with Sickle Cell Disease

Background: Adults with sickle cell disease (SCD) suffer poor quality, disparities, higher utilization and mortality, and unmet medical need. Thus, in 2017 Virginia Commonwealth University Health (VCU) used pilot results and axioms of the Patient-Centered Medical Home (PCMH) and Lean Six Sigma quality improvement to build an Adult SCD Medical Home. Methods and Results: VCU funded the program in October 2017. We implemented it over the next fifteen months. We first used a Six Sigma QI cycle called DMAIC (Define, Measure, Analyze, Improve and Control). Define: we defined three improvement targets in year one: inpatient, emergency department (ED), and ambulatory care. Behavioral health, program evaluation, ambulatory clinical policies, and pediatric to adult transition were added in year two. We identified ourselves or recruited hospital partners as champions/leaders for each care target area. Each formed a multidisciplinary implementation team. The inpatient care team actually preceded Medical Home funding. Where feasible, each team conducted PDSA cycles to test and improve best practices or metrics. Measure: we ranked 567 adult SCD patients based on their CY 2017 30-day readmissions, length of stay, 3-day ED returns, ED discharges, inpatient days and discharges, outpatient visits, ED use, and charges. Each team also developed metrics. Analyze: The top 50 highest utilizers by charges were targeted for intervention. Improve: We aimed for six 12-month intervention patient results: 1) reduce readmissions by 15%; 2) reduce average length of stay by 1.5 days; 3) reduce charges by 15%; 4) improve compliance with SCD inpatient guidelines; 5) improve quality, safety, and financial reporting; 6) improve patient experience. Leaders also used Six Sigma tools weekly to oversee teams, identify resources, plan, and hire staff: for example, we ranked the urgency of steps using "Now, Later, Latest" process charts, and documented progress using "Quick Wins" communication logs. Control: Processes were continuously amended. Stakeholders met and supported us monthly to quarterly. We distributed an annual report. Metric results are presented in a separate abstract. Conclusion: Lean Six Sigma QI principles were effective for developing and implementing an adult SCD medical home. We believe the above processes could be replicated elsewhere. Figure Disclosures Lipato: Novartis: Honoraria. Smith:Novartis: Consultancy, Honoraria.

Creating a learner performance dashboard for programmatic assessment.

The Clinical TeacherVolume 17, Issue 3 p. 261-266 Clinical Teacher's Toolbox Creating a learner performance dashboard for programmatic assessment Sally A Santen, Corresponding Author Sally A Santen Sally.santen@vcuhealth.org orcid.org/0000-0002-8327-8002 Department of Emergency Medicine, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, USACorresponding author's contact details: Sally A Santen, Department of Emergency Medicine, VCU School of Medicine, Virginia Commonwealth University, Richmond, Virginia 23284-2512, USA. E-mail: Sally.santen@vcuhealth.orgSearch for more papers by this authorLeif Myklebust, Leif Myklebust University of Michigan Medical School, Ann Arbor, Michigan, USASearch for more papers by this authorClare Cabrera, Clare Cabrera University of Michigan Medical School, Ann Arbor, Michigan, USASearch for more papers by this authorJohmarx Patton, Johmarx Patton University of Michigan Medical School, Ann Arbor, Michigan, USASearch for more papers by this authorMark Grichanik, Mark Grichanik Rush Medical College of Rush University, Chicago, Illinois, USASearch for more papers by this authorNikki L Bibler Zaidi, Nikki L Bibler Zaidi University of Michigan Medical School, Ann Arbor, Michigan, USASearch for more papers by this author Sally A Santen, Corresponding Author Sally A Santen Sally.santen@vcuhealth.org orcid.org/0000-0002-8327-8002 Department of Emergency Medicine, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, USACorresponding author's contact details: Sally A Santen, Department of Emergency Medicine, VCU School of Medicine, Virginia Commonwealth University, Richmond, Virginia 23284-2512, USA. E-mail: Sally.santen@vcuhealth.orgSearch for more papers by this authorLeif Myklebust, Leif Myklebust University of Michigan Medical School, Ann Arbor, Michigan, USASearch for more papers by this authorClare Cabrera, Clare Cabrera University of Michigan Medical School, Ann Arbor, Michigan, USASearch for more papers by this authorJohmarx Patton, Johmarx Patton University of Michigan Medical School, Ann Arbor, Michigan, USASearch for more papers by this authorMark Grichanik, Mark Grichanik Rush Medical College of Rush University, Chicago, Illinois, USASearch for more papers by this authorNikki L Bibler Zaidi, Nikki L Bibler Zaidi University of Michigan Medical School, Ann Arbor, Michigan, USASearch for more papers by this author First published: 12 November 2019 https://doi.org/10.1111/tct.13106Citations: 2 Editor's note: Programmatic assessment is a process that is gaining traction in medical and health professional education. It is an approach that aligns with competency-based education. Routine and longitudinal data are collected about learners’ competence, and their progress is regularly reviewed and analysed. Typically, a variety of assessment methods are used with the overall aim of allowing both learners and educators to gain an understanding of the extent of learning and to maximise feedback for optimal educational impact (assessment for learning). Eventually the process may be used for high-stakes decisions at the end of a programme or phase of study (assessment of learning). In this toolbox article the authors describe how they have developed a method of visually representing medical student attainment during programmatic assessment on a dashboard. This development required input from educators, faculty members and information technology staff. The graphs obtained can help students and staff to see how a student is performing over time. The authors share feedback on the approach from learners and faculty members and provide recommendations for readers who may wish to develop something similar. Funding: None. Conflict of interest: The University of Michigan Medical School and Virginia Commonwealth University obtain funding for the Accelerating Change in Medical Education Grant from the American Medical Association. Acknowledgements: None. Ethical approval: This was not a research study; therefore, ethical approval was not obtained. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume17, Issue3June 2020Pages 261-266 RelatedInformation

Nurturing the Student, Sustaining the Mission: 20 Years of the International/Inner-City/Rural Preceptorship Program.

Specialized medical school educational tracks aim to increase the primary care workforce. The International/Inner-City/Rural Preceptorship (I2CRP) Program is unique in addressing multiple communities, a large cohort and applying the Self Determination Theory framework. This study examined program impact by analyzing the numbers of graduates matched into primary care and practicing in medically underserved communities. We compared the match list of I2CRP graduates between 2000 and 2017 (n=204) to non-I2CRP Virginia Commonwealth University School of Medicine (VCU SOM) graduates (n=3,037). We analyzed the matches into primary care, National Health Service Corps (NHSC) priority specialties, and NHSC priority plus general surgery. We searched a federal database to determine which graduates are practicing in workforce shortage areas. Many more I2CRP graduates matched to primary care (71.1%), compared to non-I2CRP graduates (38.2%; P<.001). Within primary care, I2CRP graduates matched to family medicine more frequently than non-I2CRP graduates (36.3% vs 8.4%). Eighteen percent of posttraining I2CRP graduates work in rural areas and 41% work in medically underserved areas. I2CRP graduates are more likely to match to family medicine and primary care. I2CRP curriculum nurtures new medical students' interest in primary care, and self-determination theory provides a framework to organize the program curriculum. The program's impact endures as evidenced by participants' continued work in underserved areas after residency. Increasing support for such programs may help address the primary care physician shortage in medically underserved areas.

Genotype imputation and reference panel: a systematic evaluation on haplotype size and diversity.

Here, 622 imputations were conducted with 394 customized reference panels for Han Chinese and European populations. Besides validating the fact that imputation accuracy could always benefit from the increased panel size when the reference panel was population specific, the results brought two new thoughts. First, when the haplotype size of the reference panel was fixed, the imputation accuracy of common and low-frequency variants (Minor Allele Frequency (MAF) > 0.5%) decreased while the population diversity of the reference panel increased, but for rare variants (MAF < 0.5%), a small fraction of diversity in panel could improve imputation accuracy. Second, when the haplotype size of the reference panel was increased with extra population-diverse samples, the imputation accuracy of common variants (MAF > 5%) for the European population could always benefit from the expanding sample size. However, for the Han Chinese population, the accuracy of all imputed variants reached the highest when reference panel contained a fraction of an extra diverse sample (8-21%). In addition, we evaluated the imputation performances in the existing reference panels, such as the Haplotype Reference Consortium (HRC), 1000 Genomes Project Phase 3 and the China, Oxford and Virginia Commonwealth University Experimental Research on Genetic Epidemiology (CONVERGE). For the European population, the HRC panel showed the best performance in our analysis. For the Han Chinese population, we proposed an optimum imputation reference panel constituent ratio if researchers would like to customize their own sequenced reference panel, but a high-quality and large-scale Chinese reference panel was still needed. Our findings could be generalized to the other populations with conservative genome; a tool was provided to investigate other populations of interest (https://github.com/Abyss-bai/reference-panel-reconstruction).

The Mid-Atlantic Twin Registry of Virginia Commonwealth University.

The Mid-Atlantic Twin Registry (MATR) is a population-based registry of more than 60,000 twins primarily born or living in Virginia, North Carolina and South Carolina. Researchers may utilize the MATR for administration of research services, including study recruitment, data or sample (e.g., DNA) collection, archival dataset creation, as well as data collection through mailed, phone or online surveys. In addition, the MATR houses the MATR Repository, with over 1700 DNA samples primarily from whole blood available for researchers interested in DNA genotyping. For over 40 years MATR twins have participated in research studies with investigators from a range of scientific disciplines and institutions. These studies, which have resulted in numerous publications, explored diverse topics, including substance use, smoking behaviors, developmental psychopathology, bullying, children's health, cardiovascular disease, cancer, the human microbiome, epigenetics of aging, children of twins and sleep homeostasis. Researchers interested in utilizing twins are encouraged to contact the MATR to discuss potential research opportunities.

Using a Game-Based Learning Platform to Increase Student Engagement in the Classroom

The Department of Clinical Laboratory Sciences at Virginia Commonwealth University incorporated the use of a game-based learning platform into a junior level Immunology course. The primary goal of this addition was to increase student engagement during review sessions. In previous years, each Immunology class was started with a review of material from an earlier lecture. The review consisted of short answer and multiple choice questions as a means to highlight important concepts and allow additional opportunities for students to ask questions. During these review periods it was observed that class participation ranged from 3-20%. Additionally, those who did participated were the same students in each class period. The incorporation of the game-based learning pAlatform into review sessions involved asking review questions in multiple choice format with 30 seconds of time for students to answer after each question was asked. This new format resulted in class participation increasing to 95-100%. Review of student answers also allowed the instructor to determine which areas the students needed additional assistance with before exams. Student feedback indicated that they enjoyed the ability to be anonymous when answering questions while still getting immediate feedback. This new review format will be utilized in additional courses, specifically Immunohematology. Furthermore, this game-based platform will be used to review material with senior students in their advanced senior level courses.

Educational Outcomes Resulting From Restructuring a Scholarship Course for Doctor of Pharmacy Students

Objective. To compare educational outcomes between two iterations of a scholarship and research course for Doctor of Pharmacy (PharmD) students at Virginia Commonwealth University's School of Pharmacy. Methods. The first iteration of a course intended to teach pharmacy students the knowledge and skills necessary to design and conduct research involved lectures and application exercises, including limited guided questions about different aspects of the research process. In the fall of 2015, multiple structured activities and accompanying grading rubrics, each designed around the structure and content of a section of a research proposal, were introduced to the course to supplement lectures. Both iterations of the course culminated with students submitting a research proposal. After establishing interrater reliability, faculty members graded a random sample of 20 research proposals, 10 from each version of the course, and section-specific and overall proposal scores were compared. Results. In the proposals submitted after the course revisions, significant improvements in three areas were identified: the overall score, the section-specific scores for research hypothesis/specific aims, and institutional review board (IRB) discussion/informed consent. Nominal, though not statistically significant, improvements were observed in other sections. Conclusion. Additional research is needed regarding the best instructional strategies to reinforce data analysis and statistical testing knowledge and skills in PharmD students. Overall, our findings support the hypothesis that a more formalized, guided approach for teaching research methods improves learning outcomes for PharmD students.

The electronic exhibition space as a catalyst for engagement and inquiry

The Cabell Screen, a 400 square foot media display installed on the façade of James Branch Cabell Library is a recent venue for artistic and scholarly expression at Virginia Commonwealth University Libraries. Spanning two floors of the main academic library building, the Cabell Screen displays curated electronic exhibitions of still and moving images to thousands of people who walk by the building each day. With no additional budget or staffing, a committee of librarians developed a mission statement, content strategy, and workflows to program and promote content. While the Cabell Screen uses a specific type of technology, the practices established at VCU Libraries can be applied to a range of budgets and media, including projections and monitors, to create a dedicated electronic exhibition space.

Lyme disease vaccines face familiar challenges, both societal and scientific

Just over 20 years ago, a Lyme disease vaccine called LYMErix was approved for sale in the United States. Researchers designed the vaccine to prevent the transmission of the tick-borne pathogen Borellia burgdorferi , which spurs a bacterial infection that can cause fever, headaches, and joint pain if left untreated. The black-legged or deer tick ( Ixodes scapularis ) is responsible for transmitting Lyme disease in the northeast, mid-Atlantic, and north-central United States. Image credit: Shutterstock/Steven Ellingson. LYMErix was on the market for just four years. Concerns over adverse reactions and a lukewarm reception from public health agencies led the vaccine’s manufacturer, SmithKline Beecham, to shelve the product in 2002. Since then, the need for a vaccine has grown. An estimated 300,000 people are diagnosed with Lyme disease in the United States annually, and reported cases of the disease have tripled since the 1990s. In some counties in the northeast United States, disease incidence has increased more than 300% over a 20-year period. “The people who live along the northeast corridor among the Mississippi River valley have suffered greatly because there is no Lyme vaccine,” says Gregory Poland, a vaccine researcher at the Mayo Clinic in Rochester, MN. Now, a new round of Lyme disease vaccines is in development. European biotech company Valneva is in phase 2 clinical trials for a vaccine against six strains of Borrelia , which causes the disease in Europe and the United States. And researchers are working to develop a vaccine against Lyme disease based on a vaccine for dogs that was released in 2016. The pressure is on this time around to make the “perfect vaccine,” says immunologist Richard Marconi at the Virginia Commonwealth University in Richmond, one of the researchers working on the dog vaccine–inspired approach. No doubt, concerns about the original vaccine are something …

PREDOCTORAL EDUCATION IN CONE BEAM COMPUTED TOMOGRAPHY

Background The introduction of cone beam computed tomography (CBCT) into the dental field in 1998 has become increasingly essential to dental diagnosis and treatment. CBCT can be used for implant placement, orthodontics, endodontics, and pathology detection. Although it is a very useful imaging technology, the teaching and training of CBCT in most dental school curricula are still limited. It would be a tremendous benefit for dental students to graduate with the knowledge on how to utilize CBCT properly and understand the value of CBCT in dental practice. Objective(s) The purpose of this study was to assess the knowledge of predoctoral dental students through didactic and clinical courses pertaining to CBCT education and provide an accurate indication of the necessity of CBCT training in the future. Study Design A literature review was conducted using electronic databases from the year of 2007 to 2017 to fabricate the survey questions. The survey was given to the predoctoral dental students from the LECOM School of Dental Medicine and the Virginia Commonwealth University School of Dental Medicine via email through SurveyMonkey (n = 103). The preliminary data were collected and analyzed accordingly. Results One hundred and three survey responses were collected and analyzed. Even though 28.16% of the predoctoral dental students planned on specializing after dental school, almost half of the predoctoral students (50.49%) had not received CBCT training in dental school. 59.34% of predoctoral dental students strongly agreed that the utilization of CBCT can be essential in practicing dentistry; implant placement (93.10%) was the number one procedure that would need CBCT. Most predoctoral dental students (70.89%) strongly agreed that education about CBCT should be part of the dental school curriculum. The introduction of cone beam computed tomography (CBCT) into the dental field in 1998 has become increasingly essential to dental diagnosis and treatment. CBCT can be used for implant placement, orthodontics, endodontics, and pathology detection. Although it is a very useful imaging technology, the teaching and training of CBCT in most dental school curricula are still limited. It would be a tremendous benefit for dental students to graduate with the knowledge on how to utilize CBCT properly and understand the value of CBCT in dental practice. The purpose of this study was to assess the knowledge of predoctoral dental students through didactic and clinical courses pertaining to CBCT education and provide an accurate indication of the necessity of CBCT training in the future. A literature review was conducted using electronic databases from the year of 2007 to 2017 to fabricate the survey questions. The survey was given to the predoctoral dental students from the LECOM School of Dental Medicine and the Virginia Commonwealth University School of Dental Medicine via email through SurveyMonkey (n = 103). The preliminary data were collected and analyzed accordingly. One hundred and three survey responses were collected and analyzed. Even though 28.16% of the predoctoral dental students planned on specializing after dental school, almost half of the predoctoral students (50.49%) had not received CBCT training in dental school. 59.34% of predoctoral dental students strongly agreed that the utilization of CBCT can be essential in practicing dentistry; implant placement (93.10%) was the number one procedure that would need CBCT. Most predoctoral dental students (70.89%) strongly agreed that education about CBCT should be part of the dental school curriculum.