Why do not we talk about MIS fellowship? A short review of the short literature.

BACKGROUND: The minimally invasive surgery (MIS) fellowship has existed for three decades and has steadily grown in both number of positions available and variety of techniques practiced. Despite continued popularity, growth, and wide breadth of surgical techniques of the MIS fellowship, publication rates in medical journals regarding these fellowships have not been as robust as one may expect. Our goal was to review the available literature on MIS fellowship. METHODS: We reviewed PubMed to search for articles pertinent for MIS fellowship. The initial search included "MIS fellowship" "minimally invasive surgery fellowship" and "laparoscopy fellowship." Articles pertaining to MIS fellowship were then reviewed by title and abstract for content. Articles were excluded from subsequent analysis if they focused on disciplines that were not direct extensions of general surgery (such as urology, gynecology, oncology). Using similar search techniques, we tabulated unfiltered publications rates specific to other major surgical fellowship disciplines. The metric articles per position was created by dividing the total number articles for each discipline by the annual fellowship positions RESULTS: An initial review of available literature produced 134 articles pertinent to MIS fellowship. Further analysis for direct relevance to MIS yielded only 58 published articles. MIS had the fewest number of publications and smallest APP, 0.7, of any of the major fellowship disciplines. CONCLUSIONS: There is a surprising dearth of material on MIS fellowship. While, MIS fellowship is a one-year experience, we have the opportunity to build on three decades of clinical experience to continue optimize the fellow experience and improve subspecialized surgical training and patient outcomes. This could be facilitated through broadened focus of inquiry and publication of findings.

Society for cardiovascular magnetic resonance recommendations for training and competency of CMR technologists.

The Society for Cardiovascular Magnetic Resonance (SCMR) recommendations for training and competency of cardiovascular magnetic resonance (CMR) technologists document will define the knowledge, experiences and skills required for a technologist to be competent in CMR imaging. By providing a framework for CMR training and competency the overarching goal is to promote the performance of high-quality CMR and to foster the increased adoption of CMR into clinical care.

The Future of Cardiac Magnetic Resonance Clinical Trials.

Over the past 2 decades, cardiac magnetic resonance (CMR) has become an essential component of cardiovascular clinical care and contributed to imaging-guided diagnosis and management of coronary artery disease, cardiomyopathy, congenital heart disease, cardio-oncology, valvular, and vascular disease, amongst others. The widespread availability, safety, and capability of CMR to provide corresponding anatomical, physiological, and functional data in 1 imaging session can improve the design and conduct of clinical trials through both a reduction of sample size and provision of important mechanistic data that may augment clinical trial findings. Moreover, prospective imaging-guided strategies using CMR can enhance safety, efficacy, and cost-effectiveness of cardiovascular pathways in clinical practice around the world. As the future of large-scale clinical trial design evolves to integrate personalized medicine, cost-effectiveness, and mechanistic insights of novel therapies, the integration of CMR will continue to play a critical role. In this document, the attributes, limitations, and challenges of CMR's integration into the future design and conduct of clinical trials will also be covered, and recommendations for trialists will be explored. Several prominent examples of clinical trials that test the efficacy of CMR-imaging guided pathways will also be discussed.

Early implementation of Fundamentals of Endoscopic Surgery training using a simulation-based mastery learning curriculum.

BACKGROUND: After the American Board of Surgery announcement of the Flexible Endoscopy Curriculum requirement in 2014, we implemented a dedicated endoscopy rotation at the post graduate year (PGY)2 level including a simulation curriculum for Fundamentals of Endoscopic Surgery skills. Here we evaluate the outcomes of this implementation. METHODS: Beginning in 2015, we developed a clinical endoscopy and simulation-based rotation to prepare for Fundamentals of Endoscopic Surgery testing. Originally, our curriculum was based on the published Texas Association of Surgical Skills Laboratories curriculum using the GI Mentor and transitioned to a mastery learning curriculum using the Endoscopy Training System in 2016. We evaluated the success of the curriculum in terms of first-time pass rates, training time required, and comparison to previously published benchmarks based on clinical experience. RESULTS: Since 2015, a total of 37 general surgery residents in our program were Fundamentals of Endoscopic Surgery tested (PGY2 = 24, PGY3 = 4, PGY5 = 9); 84% (31) completed the Endoscopy Training System curriculum. At the time of testing, 73% (27) had performed <25 esophagogastroduodenoscopies, and 46% had performed <25 colonoscopies. Ninety-two percent (34) spent 10 hours or less completing the curriculum. The first-time pass rate for those completing the Endoscopy Training System curriculum was 97% vs 67% for those not completing the Endoscopy Training System curriculum (P = .01). For residents completing the Endoscopy Training System curriculum, total Fundamentals of Endoscopic Surgery scores were discernibly higher (472 vs 389, P < .01), as were 3/5 task scores (Nav1 80 vs 67, P = .02; Loop2 36 vs 8, P = .02; Retro3 89 vs 71, P = .02). Despite clinical inexperience (<25 esophagogastroduodenoscopies and <50 colonoscopies), PGY2s yielded a mean score of 454 and a pass rate of 92%. This was similar to PGY5s (427, 89%; P = .3) and compares to benchmark data of endoscopists with >300 cases. CONCLUSION: Early implementation of flexible endoscopy training with a simulation-based curriculum results in Fundamentals of Endoscopic Surgery performance equal to a clinical experience not often gained during surgical residency. Often requiring <10 hours, this represents a fantastic return on investment for this training.

Piloting the FIRE: A Novel Error Management Training Simulation Curriculum for Fasciotomy Instruction.

BACKGROUND: Multiple studies have demonstrated poor performance of lower extremity fasciotomy (LEF), highlighted by missed and/or inadequately released compartments. Incorporating error management training (EMT) into surgical simulation has been promoted as a way to gain deeper understanding of procedural errors and overall performance. The purpose of this study was to evaluate LEF performance using a Fasciotomy Improvement through Recognition of Errors (FIRE) simulation training curriculum to train novice surgical trainees. METHODS: A mastery learning-based EMT curriculum was developed, and surgical residents were enrolled and pretested with a multiple-choice question (MCQ) written test, and a simulated fasciotomy using a lower leg model. Each trainee then watched a 15-minute narrated presentation followed by 2 rounds of fasciotomy error recognition and management training exercises to a mastery standard. During each round, trainees performed hands-on assessment of unique premade fasciotomy leg models containing a variable number of procedural errors. They were required to identify and propose corrective action for all errors. Serial rounds of remediation were implemented until the mastery standard was attained on both error identification rounds. All trainees were post-tested with the same MCQ and another simulated fasciotomy. RESULTS: All 14 residents had minimal experience with only 0.3 ± 0.6 fasciotomies performed prior to instruction. There were 3 ± 1.6 missed or inadequately released compartments on the pretest. Residents examined 14 ± 2.5 legs, including 2 ± 2.5 legs during remediation to attain mastery. All residents demonstrated significant improvement following the FIRE of Error curriculum for the MCQ (57% ± 16% vs 78% ± 13%; p = 0.01; Cohen's d = 1.4), fasciotomy score (10 ± 7.1 vs 28 ± 1.9; p < 0.001; Cohen's d = 3.6), and achieving a complete fasciotomy (14% ± 36% vs 93% ± 27%; p < 0.001; Cohen's d = 2.5). Only a single cumulative compartment was missed on post-testing. CONCLUSIONS: Implementation of a mastery learning-based EMT curriculum for fasciotomy simulation training results in significant improvement in fasciotomy technique without reliance on repeated procedure performance nor clinical fasciotomy exposure. This curriculum is a highly effective option for surgical trainees lacking fasciotomy training during residency.

Fact or Fiction? Practice on a Simulator is Not Required to Pass the Fundamentals of Endoscopic Surgery (FES)TM Skills Exam.

PURPOSE: Initial work on the validity evidence used to support the Fundamentals of Endoscopic Surgery (FES) performance exam as a measure of technical competency showed a strong relationship to clinical experience. Despite this evidence, there is a perception among some program directors that the exam cannot be successfully passed without practice on a simulator. We assess the validity of this perception. METHODS: Deidentified data from the initial FES skills examination (prior to the 2014 FEC requirement) was reviewed, and 335 unique participants with reported simulation experience demographics were identified. Self reported data analyzed included gender, total clinical endoscopy procedure experience (1-150, 151-300, >300), and endoscopy simulator training hours (0, 1-5, 6-10, 11-20, >20). Final FES skills exam scores, and pass/fail designations for each participant were reported by the FES program staff. Continuous variables were compared between groups using one-way analysis of variance with post-hoc analysis where appropriate. Categorical variables were compared using Pearson Chi-Squared. The effect of variables on pass rate was assessed using univariate and multivariate logistic regression. RESULTS: Simulation training experience (SE) was categorically reported in hours(n,%): 0 (98, 29%), 1-5 (135, 40%), 6-10 (52, 16%), 11-20 (24, 7%), and >20 (26, 8%). Clinical endoscopy experience (CE), reported categorically as total cases performed (n,%), was available for 323 of 355 identified participants: 1-150 (126, 39%), 151-300 (99, 31%), >300 (98, 30%). There was no statistically discernible differences in mean FES total or task scores across the SE groups (total score 0:72 ± 15, 1-5:72 ± 13, 6-10:71 ± 14, 11-20:71 ± 16, 20:78 ± 13; p = 0.28), while both total score and task scores were discernibly higher in the more experienced CE groups (>151) compared to the least experienced group (total score; <150:67 ± 15, 151-300:75 ± 1, >300:77 ± 14; p < 0.01). Similarly, there was no statistically discernible difference in FES skills exam pass rates between SE groups (0: 80%, 1-5: 82%, 6-10: 79%, 11-20: 75%, >20: 85%; x2 = 2.5, p = 0.6), but there was a strong relationship between clinical experience and pass rate (<150: 70%, 151-300: 87%, >300: 89%; x2 = 15.8, p < 0.001). Finally, on both univariate and multivariate logistic regression, CE remained a discernible predictor of passing, even when controlling for SE (odds ratio = 2, 95% confidence interval 1.4-2.9, p < 0.001). CONCLUSIONS: FES skills examination data collected on participants completing the examination before the FEC requirement shows no demonstrable relationship with self-reported training experience on a simulator but confirms a strong relationship with clinical endoscopy experience. This lends further evidence to the validity of the FES exam as a marker of clinical endoscopic skill.

Society for Cardiovascular Magnetic Resonance (SCMR) guidance for the practice of cardiovascular magnetic resonance during the COVID-19 pandemic.

The aim of this document is to provide general guidance and specific recommendations on the practice of cardiovascular magnetic resonance (CMR) in the era of the COVID-19 pandemic. There are two major considerations. First, continued urgent and semi-urgent care for the patients who have no known active COVID-19 should be provided in a safe manner for both patients and staff. Second, when necessary, CMR on patients with confirmed or suspected active COVID-19 should focus on the specific clinical question with an emphasis on myocardial function and tissue characterization while optimizing patient and staff safety.

Fundamentals of Anorectal Technical Skills: A Concise Surgical Skills Course.

INTRODUCTION: Anorectal diseases, among the most common surgical conditions, are underrepresented in medical training. The Fundamentals of Anorectal Technical Skills course was developed to provide cost-effective formal training in diagnosis of common anorectal conditions and in commonly performed anorectal procedures using the theories of deliberative practice and perceptual and adaptive learning. MATERIALS AND METHODS: First- through third-year general surgery and internal medicine residents and third- and fourth-year medical students participated in a course consisting of didactic instruction and hands on skills stations. The course covered common anorectal conditions, including internal and external hemorrhoids, fissures, condylomata, abscesses, fistula-in-ano, rectal prolapse, pilonidal disease, pruritis ani, and anal and rectal cancer, as well as common procedures such as anoscopy, excision of thrombosed external hemorrhoids, banding of internal hemorrhoids, rigid proctoscopy, incision and drainage of an abscess, administration of local anesthesia, and reduction of rectal prolapse. Before the course, participants completed a questionnaire consisting of demographics; previous anorectal experience, as measured by procedural case volume; confidence diagnosing and treating anorectal conditions; and a clinical knowledge multiple-choice quiz. Immediately following the course, participants took an additional survey reassessing their confidence and testing their clinical knowledge. This study was granted an educational exception by the Institutional Review Board at Walter Reed National Military Medical Center. RESULTS: Forty-three learners participated in this course. Forty-six percent of participants had not participated in any anorectal cases, 26% had participated in 1 to 5 cases, 17% had participated in 6 to 10 cases, 6% had been involved with 11 to15 cases, and 6% had been involved with more than 15 cases. For learners who had no prior experience, 1 to 5 prior cases, or 6 to 10 cases, there were statistically and educationally significant increases in confidence for all diagnoses and procedures. Additionally, there were statistically and educationally significant increases between pre-course and post-course quiz scores for learners who had no prior experience (7.8 ± 2.0 vs. 11.8 ± 2.5, P < 0.01, Cohen's d = 1.8) and for those who had only participated in 1 to 5 cases (11.0 ± 3.7 vs. 14.2 ± 2.0, P = 0.04, Cohen's d = 1.1). The changes in quiz scores for learners who previously had been involved with six or more cases were not statistically significant. CONCLUSION: This course provides a cost-effective training that significantly boosts learners' confidence in diagnosis of common anorectal procedures and confidence in performance of common anorectal procedures, in addition to improving objectively measured anorectal clinical knowledge.

Incisional hernia incidence following laparotomy for combat trauma: Investigating 15 years of US war surgery.

BACKGROUND: While the incidence of incisional hernia (IH) following elective laparotomy has been well described, incidence following emergent laparotomy for combat trauma has been much less studied. This retrospective cohort investigates the latter to better describe the burden IH represents for the injured warfighter. METHODS: Data were obtained from the Expeditionary Medical Encounter Database for service members who survived a combat-related injury between January 2002 and December 2016 and underwent abdominal surgery in the first 30 days after injury. Incisional hernia diagnosis at least 30 days after injury was determined from inpatient and outpatient records in the Military Health System's Medical Data Repository.Means and SDs were reported for age and continuous Injury Severity Score, and frequency and percentages were reported for sex, branch of service, paygrade, mechanism of injury, Injury Severity Score, and maximum abdominal Abbreviated Injury Scale. Service members with and without a hernia diagnosis were compared using t test for continuous variables and χ or Fisher exact test (depending on cell size) for categorical variables.Multivariate logistic regression models were used to examine relationships between IH diagnosis and the covariates previously mentioned. Data analysis was completed using SAS software version 9.4 (SAS Institute Inc., Cary, NC). RESULTS: Of the 570 laparotomy patients, 109 (19.1%) developed IH. Of these, 58 (53%) were diagnosed within the first year after injury. An additional 21 (19%) were diagnosed within the following year, and 30 (28%) were diagnosed more than 2 years after injury. Presence of gastrointestinal injury, Abbreviated Injury Scale score of 4 and 5, and 5-year increments of age were positively associated with hernia formation. CONCLUSION: The incidence of postlaparotomy IH in combat trauma is 19.1%, a considerable source of disability for injured warfighters. Further investigation into hernia-preventive closure strategies is warranted. LEVEL OF EVIDENCE: Therapeutic study, level IV.

Aminophylline shortage and current recommendations for reversal of vasodilator stress: An ASNC information statement endorsed by SCMR.

Pharmacologic reversal of serious or intolerable side effects (SISEs) from vasodilator stress is an important safety and comfort measure for patients experiencing such effects. While typically performed using intravenous aminophylline, recurrent shortages of this agent have led to a greater need to limit its use and consider alternative agents. This information statement provides background and recommendations addressing indications for vasodilator reversal, timing of a reversal agent, incidence of observed SISE with vasodilator stress, clinical and logistical considerations for aminophylline-based reversal, and alternative non-aminophylline based reversal protocols.

Aminophylline shortage and current recommendations for reversal of vasodilator stress: an ASNC information statement endorsed by SCMR.

Pharmacologic reversal of serious or intolerable side effects (SISE) from vasodilator stress is an important safety and comfort measure for patients experiencing such effects. While typically performed using intravenous aminophylline, recurrent shortages of this agent have led to a greater need to limit its use and consider alternative agents. This information statement provides background and recommendations addressing indications for vasodilator reversal, timing of a reversal agent, incidence of observed SISE with vasodilator stress, clinical and logistical considerations for aminophylline-based reversal, and alternative non-aminophylline based reversal protocols.

Association of Unrecognized Myocardial Infarction With Long-term Outcomes in Community-Dwelling Older Adults: The ICELAND MI Study.

Importance: Cardiac magnetic resonance (CMR) imaging can identify unrecognized myocardial infarction (UMI) in the general population. Unrecognized myocardial infarction by CMR portends poor prognosis in the short term but, to our knowledge, long-term outcomes are not known. Objective: To determine the long-term outcomes of UMI by CMR compared with clinically recognized myocardial infarction (RMI) and no myocardial infarction (MI). Design, Setting, and Participants: Participants of the population-based, prospectively enrolled ICELAND MI cohort study (aged 67-93 years) were characterized with CMR at baseline (from January 2004-January 2007) and followed up for up to 13.3 years. Kaplan-Meier time-to-event analyses and a Cox regression were used to assess the association of UMI at baseline with death and future cardiovascular events. Main Outcomes and Measures: The primary outcome was all-cause mortality. Secondary outcomes were a composite of major adverse cardiac events (MACE: death, nonfatal MI, and heart failure). Results: Of 935 participants, 452 (48.3%) were men; the mean (SD) age of participants with no MI, UMI, and RMI was 75.6 (5.3) years, 76.8 (5.2) years, and 76.8 (4.7) years, respectively. At 3 years, UMI and no MI mortality rates were similar (3%) and lower than RMI rates (9%). At 5 years, UMI mortality rates (13%) increased and were higher than no MI rates (8%) but still lower than RMI rates (19%). By 10 years, UMI and RMI mortality rates (49% and 51%, respectively) were not statistically different; both were significantly higher than no MI (30%) (P < .001). After adjusting for age, sex, and diabetes, UMI by CMR had an increased risk of death (hazard ratio [HR], 1.61; 95% CI, 1.27-2.04), MACE (HR, 1.56; 95% CI, 1.26-1.93), MI (HR, 2.09; 95% CI, 1.45-3.03), and heart failure (HR, 1.52; 95% CI, 1.09-2.14) compared with no MI and statistically nondifferent risk of death (HR, 0.99; 95% CI, 0.71-1.38) and MACE (HR, 1.23; 95% CI, 0.91-1.66) vs RMI. Conclusions and Relevance: In this study, all-cause mortality of UMI was higher than no MI, but within 10 years from baseline evaluation was equivalent with RMI. Unrecognized MI was also associated with an elevated risk of nonfatal MI and heart failure. Whether secondary prevention can alter the prognosis of UMI will require prospective testing.

Prevalence and prognosis of unrecognized myocardial infarction determined by cardiac magnetic resonance in older adults.

CONTEXT: Unrecognized myocardial infarction (MI) is prognostically important. Electrocardiography (ECG) has limited sensitivity for detecting unrecognized MI (UMI). OBJECTIVE: Determine prevalence and mortality risk for UMI detected by cardiac magnetic resonance (CMR) imaging or ECG among older individuals. DESIGN, SETTING, AND PARTICIPANTS: ICELAND MI is a cohort substudy of the Age, Gene/Environment Susceptibility-Reykjavik Study (enrollment January 2004-January 2007) using ECG or CMR to detect UMI. From a community-dwelling cohort of older individuals in Iceland, data for 936 participants aged 67 to 93 years were analyzed, including 670 who were randomly selected and 266 with diabetes. MAIN OUTCOME MEASURES: Prevalence and mortality of MI through September 1, 2011. Results reported with 95% confidence limits and net reclassification improvement (NRI). RESULTS: Of 936 participants, 91 had recognized MI (RMI) (9.7%; 95% CI, 8% to 12%), and 157 had UMI detected by CMR (17%; 95% CI, 14% to 19%), which was more prevalent than the 46 UMI detected by ECG (5%; 95% CI, 4% to 6%; P < .001). Participants with diabetes (n = 337) had more UMI detected by CMR than by ECG (n = 72; 21%; 95% CI, 17% to 26%, vs n = 15; 4%; 95% CI, 2% to 7%; P < .001). Unrecognized MI by CMR was associated with atherosclerosis risk factors, coronary calcium, coronary revascularization, and peripheral vascular disease. Over a median of 6.4 years, 30 of 91 participants (33%; 95% CI, 23% to 43%) with RMI died, and 44 of 157 participants (28%; 95% CI, 21% to 35%) with UMI died, both higher rates than the 119 of 688 participants (17%; 95% CI, 15% to 20%) with no MI who died. Unrecognized MI by CMR improved risk stratification for mortality over RMI (NRI, 0.34; 95% CI, 0.16 to 0.53). Adjusting for age, sex, diabetes, and RMI, UMI by CMR remained associated with mortality (hazard ratio [HR], 1.45; 95% CI, 1.02 to 2.06, absolute risk increase [ARI], 8%) and significantly improved risk stratification for mortality (NRI, 0.16; 95% CI, 0.01 to 0.31), but UMI by ECG did not (HR, 0.88; 95% CI, 0.45 to 1.73; ARI, -2%; NRI, -0.05; 95% CI, -0.17 to 0.05). Compared with those with RMI, participants with UMI by CMR used cardiac medications such as statins less often (36%; 95% CI, 28% to 43%, or 56/157, vs 73%; 95% CI, 63% to 82%, or 66/91; P < .001). CONCLUSIONS: In a community-based cohort of older individuals, the prevalence of UMI by CMR was higher than the prevalence of RMI and was associated with increased mortality risk. In contrast, UMI by ECG prevalence was lower than that of RMI and was not associated with increased mortality risk. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01322568.

Phase 1b randomized study of antidote-controlled modulation of factor IXa activity in patients with stable coronary artery disease.

BACKGROUND: Whether selective factor IXa inhibition produces an appropriate anticoagulant effect when combined with platelet-directed therapy in patients with stable coronary artery disease is unknown. REG1 consists of RB006 (drug), an injectable RNA aptamer that specifically binds and inhibits factor IXa, and RB007 (antidote), the complementary oligonucleotide that neutralizes its anti-IXa activity. METHODS AND RESULTS: We evaluated the safety, tolerability, and pharmacodynamic profile of REG1 in a randomized, double-blind, placebo-controlled study, assigning 50 subjects with coronary artery disease taking aspirin and/or clopidogrel to 4 dose levels of RB006 (15, 30, 50, and 75 mg) and RB007 (30, 60, 100, and 150 mg). The median age was 61 years (25th and 75th percentiles, 56 and 68 years), and 80% of patients were male. RB006 increased the activated partial thromboplastin time dose dependently; the median activated partial thromboplastin time at 10 minutes after a single intravenous bolus of 15, 30, 50, and 75 mg RB006 was 29.2 seconds (25th and 75th percentiles, 28.1 and 29.8 seconds), 34.6 seconds (25th and 75th percentiles, 30.9 and 40.0 seconds), 46.9 seconds (25th and 75th percentiles, 40.3 and 51.1 seconds), and 52.2 seconds (25th and 75th percentiles, 46.3 and 58.6) (P<0.0001; normal 25th and 75th percentiles, 27 and 40 seconds). RB007 reversed the activated partial thromboplastin time to baseline levels within a median of 1 minute (25th and 75th percentiles, 1 and 2 minutes) with no rebound increase through 7 days. No major bleeding or other serious adverse events occurred. CONCLUSIONS: This is the first experience of an RNA aptamer drug-antidote pair achieving inhibition and active restoration of factor IXa activity in combination with platelet-directed therapy in stable coronary artery disease. The preliminary clinical safety and predictable pharmacodynamic effects form the basis for ongoing studies in patients undergoing elective revascularization procedures.

Age-related vascular stiffness and left ventricular size after myocardial infarction.

Aortic stiffness increases with age and may contribute to adverse remodeling after myocardial infarction (MI). The authors examined whether vascular stiffness affects left ventricular (LV) size after MI using contrast-enhanced cardiac magnetic resonance imaging. Despite similar infarct sizes, patients aged 60 years or older (n=30) had a lower ejection fraction (42+/-15 vs 53+/-11%, P<.01) and greater end-systolic volume index (75+/-47 vs 44+/-18 mL/m(2), P<.01) than younger patients (n=19). As infarct size increased, LV end-systolic volumes (P<.0001) and ejection fraction (P<.0001) in the older participants were progressively greater. Participants with greater aortic stiffness had greater end-systolic volume indices (P<.0001) and lower ejection fraction (P<.0001) with increasing infarct size. Using multivariate analysis, MI size (P<.001) and aortic distensibility (P=.02) were significant predictors of end-systolic volume index. Older patients have increased LV size after MI compared with younger patients, possibly related to age-related decreases in aortic distensibility affecting LV remodeling.

First-in-human experience of an antidote-controlled anticoagulant using RNA aptamer technology: a phase 1a pharmacodynamic evaluation of a drug-antidote pair for the controlled regulation of factor IXa activity.

BACKGROUND: Selectivity, titratability, rapidity of onset, and active reversibility are desirable pharmacological properties of anticoagulant therapy administered for acute indications and collectively represent an attractive platform to maximize patient safety. A novel anticoagulation system (REG1, Regado Biosciences), developed using a protein-binding oligonucleotide to factor IXa (drug, RB006) and its complementary oligonucleotide antidote (RB007), was evaluated in healthy volunteers. The primary objective was to determine the safety profile and to characterize the pharmacodynamic responses in this first-in-human study. METHODS AND RESULTS: Regado 1a was a subject-blinded, dose-escalation, placebo-controlled study that randomized 85 healthy volunteers to receive a bolus of drug or placebo followed 3 hours later by a bolus of antidote or placebo. Pharmacodynamic samples were collected serially. Subject characteristics were the following: median age, 32 years (interquartile range, 23 to 39 years); female gender, 35%; and median weight, 79 kg (interquartile range, 70 to 87 kg). No significant differences were found in median hemoglobin, platelet, creatinine, or liver function studies. There were no significant bleeding signals associated with RB006, and overall, both drug and antidote were well tolerated. One serious adverse event, an episode of transient encephalopathy, occurred in a subject receiving the low intermediate dose of RB006. The subject's symptoms resolved rapidly, and no further sequelae occurred. A predictable dose-pharmacodynamic response, reflected in activated partial thromboplastin time measurements, was seen after administration of the bolus of drug, with a clear correlation between the peak posttreatment activated partial thromboplastin time and post hoc weight-adjusted dose of drug (correlation coefficient, 0.725; P<0.001). In subjects treated with drug, antidote administration reversed the pharmacological activity of the drug, with a rapid (mean time, 1 to 5 minutes across all dose levels) and sustained return of activated partial thromboplastin time to within the normal range. The activated clotting time followed a similar anticoagulant response and reversal pattern. As anticipated, prothrombin time remained unchanged compared with baseline. CONCLUSIONS: These observations represent a first-in-human experience of an RNA aptamer and its complementary oligonucleotide antidote used as an anticoagulant system. The findings contribute to an emerging platform of selective, actively reversible anticoagulant drugs for use among patients with thrombotic disorders of the venous and arterial circulations.

Prognosis of negative adenosine stress magnetic resonance in patients presenting to an emergency department with chest pain.

OBJECTIVES: This study was designed to determine the diagnostic value of adenosine cardiac magnetic resonance (CMR) in troponin-negative patients with chest pain. BACKGROUND: We hypothesized that adenosine CMR could determine which troponin-negative patients with chest pain in an emergency department have coronary artery disease (CAD) or future adverse cardiac events. METHODS: Adenosine stress CMR was performed on 135 patients who presented to the emergency department with chest pain and had acute myocardial infarction (MI) excluded by troponin-I. The main study outcome was detecting any evidence of significant CAD. Patients were contacted at one year to determine the incidence of significant CAD defined as coronary artery stenosis >50% on angiography, abnormal correlative stress test, new MI, or death. RESULTS: Adenosine perfusion abnormalities had 100% sensitivity and 93% specificity as the single most accurate component of the CMR examination. Both cardiac risk factors and CMR were significant in Kaplan-Meier analysis (log-rank test, p = 0.0006 and p < 0.0001, respectively). However, an abnormal CMR added significant prognostic value in predicting future diagnosis of CAD, MI, or death over clinical risk factors. In receiver operator curve analysis, adenosine CMR was a more accurate predictor than cardiac risk factors (p < 0.002). CONCLUSIONS: In patients with chest pain who had MI excluded by troponin-I and non-diagnostic electrocardiograms, an adenosine CMR examination predicted with high sensitivity and specificity which patients had significant CAD during one-year follow-up. Furthermore, no patients with a normal adenosine CMR study had a subsequent diagnosis of CAD or an adverse outcome.

Effect of the novel direct factor Xa inhibitor DX-9065a on thrombin generation and inhibition among patients with stable atherosclerotic coronary artery disease.

INTRODUCTION: Thrombin, a pluripotential effector enzyme with prothrombotic, proinflammatory, and mitogenic properties, plays a pivotal role in the pathobiology and clinical expression of atherothrombotic coronary artery disease. Existing anticoagulant drugs have not been shown to attenuate thrombin generation or activity consistently. We sought to investigate the effect of DX-9065a on thrombin generation and inhibition in patients with stable CAD. DX-9065a is a small-molecule, synthetic, direct inhibitor of factor Xa. MATERIALS AND METHODS: Peripheral venous blood samples were collected serially during and after administration of either placebo or 1 of 4 weight-adjusted regimens of DX-9065a, in 73 patients with stable CAD participating in the XaNADU-1B study. RESULTS AND CONCLUSIONS: At baseline, the median (25th, 75th) prothrombin activation fragment 1.2 (F1.2) level was 2.56 (2.05, 3.20) nmol/L, and the median d-dimer level was 0.26 (0.19, 0.38) microg FEU/L. There were significant relationships between measured plasma DX-9065a concentrations and both F1.2 (4.9% decrease for each doubling of DX-9065a) (P<0.0001) and d-dimer (5.5% decrease for each doubling of DX-9065a) (P=0.001). F1.2 was suppressed (below baseline) at 96 h after administration of DX-9065a. Coronary thrombotic events did not occur during or after study drug administration. DX-9065a, the first in a class of small-molecule, direct, selective and reversible factor Xa inhibitors, reduces thrombin generation and fibrin formation among patients with stable CAD. The effect is concentration-dependent and persists for at least 96 h following drug cessation, without biochemical or clinical evidence of rebound.

Separation of single-walled carbon nanotubes on silica gel. Materials morphology and Raman excitation wavelength affect data interpretation.

In this report, procedures are discussed for the enrichment of single-walled carbon nanotube (SWNT) types by simple filtration of the functionalized SWNTs through silica gel. This separation uses nanotube sidewall functionalization employing two different strategies. In the first approach, a crude mixture of metallic and semiconducting SWNTs was heavily functionalized with 4-tert-butylphenyl addends to impart solubility to the entire sample of SWNTs. Two major polarity fractions were rapidly filtered through silica gel, with the solvent being removed in vacuo, heated to 700 degrees C to remove the addends, and analyzed spectroscopically. The second approach uses two different aryldiazonium salts (one with a polar grafting group and one nonpolar), appended selectively onto the different SWNTs by means of titration and monitoring by UV analysis throughout the functionalization process. The different addends accentuate the polarity differences between the band-gap-based types permitting their partial separation on silica gel. Thermal treatment regenerated pristine SWNTs in enriched fractions. The processed samples were analyzed and characterized by Raman spectroscopy. A controlled functionalization method using 4-fluorophenyl and 4-iodophenyl addends was performed, and XPS analyses yielded data on the degree of functionalization needed to affect the van Hove singularities in the UV/vis/NIR spectra. Finally, we demonstrate that relative peak intensity changes in Raman spectra can be caused by morphological changes in SWNT bundling based on differing flocculation or deposition methods. Therefore a misleading impression of separations can result, underscoring the care needed in assessing efficacies in SWNT enrichment and the prerequisite use of multiple excitation wavelengths and similar flocculation or deposition methods in comparative analyses.