Citations

Abstract Electronic medical records (EMRs) have gained widespread use in clinical practice and by default serve as a large patient database with potential for use in clinical research. Although there remains significant interest in leveraging EMRs for research purposes, extraction of data has proven to be complex and with insufficient accuracy. We describe the limitations of an EMR in our attempt to conduct a seemingly simple study aimed at validating variables identified in the PRECiSE 3, a 7-year open label safety and efficacy study of certolizumab pegol in Crohn’s disease that identified clinical factors that predicted both short- and long-term efficacy. A multicenter, retrospective cohort study from 8 academic and large community practices was performed, and data were collected from each respective EMR. Significant challenges with reliable capture of key data elements were encountered, and overall a screen fail rate of 91.8% across all sites was seen. We describe these challenges and potential future directions to work together to advance accuracy and implementation of the use of EMRs in inflammatory bowel disease.

This discussion panel will focus on solutions for mitigating the negative impact of interruptions in healthcare. Five human factors practitioners who work within healthcare systems will present solutions of mitigating the negative impact of interruptions on safety and quality with the acknowledgement that interruptions in and of themselves should not be viewed as purely negative (i.e. some interruptions are not only necessary but beneficial to patient care). Additionally, one panelist will focus on the difficulties in bridging the gap between research and practice in this arena. The session will lead to an interactive discussion about how human factors methods can be adapted and applied to identify and develop realistic, impactful solutions that improve safety by eliminating the negative impact of interruptions in applied healthcare settings.

Abstract Inhibition of the AAA ATPase, p97, was recently shown to be a novel method for targeting the ubiquitin proteasome system, and CB-5083, a first-in-class inhibitor of p97, has demonstrated broad antitumor activity in a range of both hematologic and solid tumor models. Here, we show that CB-5083 has robust activity against multiple myeloma cell lines and a number of in vivo multiple myeloma models. Treatment with CB-5083 is associated with accumulation of ubiquitinated proteins, induction of the unfolded protein response, and apoptosis. CB-5083 decreases viability in multiple myeloma cell lines and patient-derived multiple myeloma cells, including those with background proteasome inhibitor (PI) resistance. CB-5083 has a unique mechanism of action that combines well with PIs, which is likely owing to the p97-dependent retro-translocation of the transcription factor, Nrf1, which transcribes proteasome subunit genes following exposure to a PI. In vivo studies using clinically relevant multiple myeloma models demonstrate that single-agent CB-5083 inhibits tumor growth and combines well with multiple myeloma standard-of-care agents. Our preclinical data demonstrate the efficacy of CB-5083 in several multiple myeloma disease models and provide the rationale for clinical evaluation as monotherapy and in combination in multiple myeloma. Mol Cancer Ther; 16(11); 2375–86. ©2017 AACR.

Purpose To analyze failure rate in 2‐year increments to determine if graft choice changed over time and graft failure rate. Methods A prospective 2002‐2008 database was used to identify risk factors for anterior cruciate ligament (ACL) retear. Subjects who had primary ACL retear with no history of contralateral surgery and 2‐year follow‐up were included. Subjects who underwent a multiligament reconstruction were excluded. Graft type, age, sex, smoking status, body mass index, Marx activity level at index surgery, medial and lateral meniscus status at time of ACL retear, sport played after ACL reconstruction, and clinical site were evaluated. Analysis was repeated using 2002‐2003 (early) and 2007‐2008 (late) 2‐year databases. Analysis of variance with post hoc analysis was performed to detect significant differences in age and Marx score by graft type over time. Results Two‐year follow‐up for graft failure was obtained on 2,497 of 2,692 (93%) subjects. There were 112 of 2,497 (4.5%) ACL retears identified at 2‐year follow‐up. The only predictor that changed between early/late periods was allograft use. Allograft odds ratio decreased from 13.1 to 9.5 ( P < .01). Allografts were used in older patients (31‐40 years) and with lower Marx scores (10‐8) from early to late periods. The mean age of subjects who received bone–patellar tendon–bone autografts did not significantly change over time (22.8‐23.5). The mean age of subjects who received hamstring autografts fell (27.9‐25.5). The mean age of subjects who received allografts rose significantly (31.3‐39.8, P < .01). The mean Marx score of subjects who received bone–patellar tendon–bone and hamstring autografts did not significantly change over time. The mean Marx score of subjects who received allografts decreased significantly ( P < .01). Conclusions After early recognition, allograft use in young active patients was a risk factor for retear; graft choice by surgeons changed in the late period to use of allografts in older and less‐active patients, which correlated with a significant decrease in retear risk. Level of Evidence Level III, case control study.

Mycobacterium abscessus was isolated from the lungs of an owl monkey which died 27 days after intraperitoneal injection of herpes virus-infected Vero cells. The lungs and liver had multiple microscopic granulomas with acid-fast microorganisms. The mycobacteria also were isolated from a Vero-cell culture inoculated with a suspension of lung and liver. The same microorganism was eventually isolated from Vero cells of the same source as that used to propagate the herpes virus for the original attempt to infect the monkey.

AbstractBackgroundWe report the accumulated experience with ventral intermediate nucleus deep brain stimulation for medically refractory orthostatic tremor.MethodsData from 17 patients were reviewed, comparing presurgical, short‐term (0‐48 months), and long‐term (≥48 months) follow‐up. The primary end point was the composite activities of daily living/instrumental activities of daily living score. Secondary end points included latency of symptoms on standing and treatment‐related complications.ResultsThere was a 21.6% improvement (P = 0.004) in the composite activities of daily living/instrumental activities of daily living score, which gradually attenuated (12.5%) in the subgroup of patients with an additional long‐term follow‐up (8 of 17). The latency of symptoms on standing significantly improved, both in the short‐term (P = 0.001) and in the long‐term (P = 0.018). Three patients obtained no/minimal benefit from the procedure.ConclusionsDeep brain stimulation of the ventral intermediate nucleus was, in general, safe and well tolerated, yielding sustained benefit in selected patients with medically refractory orthostatic tremor. © 2017 International Parkinson and Movement Disorder Society

370 Background: The Phase 1 portion of a Phase 1/2 trial of Necuparanib (“Necu”) combined with nab-paclitaxel (nabP) + gemcitabine (gem) in patients with metastatic pancreatic cancer (ClinicalTrials.gov Identifier NCT01621243) showed acceptable safety and tolerability and encouraging signals of activity and established a dose for the randomized, placebo (PBO)-controlled Phase 2 portion. Methods: In Phase 2, patients received daily s.c. injections of either 5 mg/kg Necu daily or PBO, combined with i.v. 125 mg/m2 nabP and 1000 mg/m2 gem (Days 1, 8, 15 of each 28-day cycle). The primary endpoint was overall survival (OS); other endpoints included progression-free survival (PFS), response rates, safety, and CA19.9 levels. An interim futility analysis was conducted in July 2016 once 57 deaths (50% of the target number of 114 events required for trial completion) had occurred. Results: The analysis was conducted on data from 120 randomized patients (62 Necu, 58 PBO). The Z-score for futility was -0.42 (prespecified boundary of -0.148 was crossed as actual score was lower). Median OS was Necu = 10.71 and PBO = 9.99 months; hazard ratio (HR) = 1.12 (favoring PBO); OS curves were intertwined. PFS was Necu = 5.52 and PBO = 6.93 months; HR = 0.97. RECIST response rates were comparable between arms: complete response, Necu = 0%, PBO = 3%; partial response, Necu = 26%, PBO = 26%; stable disease, Necu = 31%, PBO = 34%; disease control rate, Necu = 56%, PBO = 64%. The most common Grade 3+ adverse events (AEs) were neutropenia (Necu = 33%, PBO = 33%), thrombocytopenia (Necu = 27%, PBO = 5%), and anemia (Necu = 22%, PBO = 11%). There were lower rate of serious AEs with Necu (48%) vs. PBO (60%). Modest increases in APTT, AST, and ALT were noted following Necu relative to PBO. 23% of Necu and 5% of PBO patients were IgG positive with an anti-heparin/PF4 antibody titer of ≥ 0.4 at any time. There were no treatment differences for decreases in CA19.9. Conclusions: No new safety signals were observed and the toxicity profile was considered manageable; however, Necu in combination with nabP and gem did not show a sufficient level of efficacy in metastatic pancreatic cancer to warrant continued enrollment. Clinical trial information: NCT01621243.

AbstractBackgroundDifferences in the gut microbiota and breath methane production have been observed in chronic constipation, but the relationship between colonic microbiota, transit, and breath tests remains unclear.MethodsIn 25 healthy and 25 constipated females we evaluated the sigmoid colonic mucosal and fecal microbiota using 16S rRNA gene sequencing, abundance of hydrogenogenic FeFe (FeFe‐hydA) and hydrogenotrophic (methyl coenzyme M reductase A [mrcA] and dissimilatory sulfite reductase A [dsrA]) genes with real‐time qPCR assays, breath hydrogen and methane levels after oral lactulose, and colonic transit with scintigraphy.Key ResultsBreath hydrogen and methane were not correlated with constipation, slow colon transit, or with abundance of corresponding genes. After adjusting for colonic transit, the abundance of FeFehydA, dsrA, and mcrA were greater (P<.005) in colonic mucosa, but not stool, of constipated patients. The abundance of the selected functional gene targets also correlated with that of selected taxa. The colonic mucosal abundance of FeFe‐hydA, but not mcrA, correlated positively (P<.05) with breath methane production, slow colonic transit, and overall microbiome composition. In the colonic mucosa and feces, the abundance of hydrogenogenic and hydrogenotrophic genes were positively correlated (P<.05). Breath methane production was not associated with constipation or colonic transit.Conclusions & InferencesCorroborating our earlier findings with 16S rRNA genes, colonic mucosal but not fecal hydrogenogenic and hydrogenotrophic genes were more abundant in constipated vs. healthy subjects independent of colonic transit. Breath gases do not directly reflect the abundance of target genes contributing to their production.