Kalev Freeman

Alterations in cardiac adrenergic signaling and calcium cycling differentially affect the progression of cardiomyopathy.

The medical treatment of chronic heart failure has undergone a dramatic transition in the past decade. Short-term approaches for altering hemodynamics have given way to long-term, reparative strategies, including beta-adrenergic receptor (betaAR) blockade. This was once viewed as counterintuitive, because acute administration causes myocardial depression. Cardiac myocytes from failing hearts show changes in betaAR signaling and excitation-contraction coupling that can impair cardiac contractility, but the role of these abnormalities in the progression of heart failure is controversial. We therefore tested the impact of different manipulations that increase contractility on the progression of cardiac dysfunction in a mouse model of hypertrophic cardiomyopathy. High-level overexpression of the beta(2)AR caused rapidly progressive cardiac failure in this model. In contrast, phospholamban ablation prevented systolic dysfunction and exercise intolerance, but not hypertrophy, in hypertrophic cardiomyopathy mice. Cardiac expression of a peptide inhibitor of the betaAR kinase 1 not only prevented systolic dysfunction and exercise intolerance but also decreased cardiac remodeling and hypertrophic gene expression. These three manipulations of cardiac contractility had distinct effects on disease progression, suggesting that selective modulation of particular aspects of betaAR signaling or excitation-contraction coupling can provide therapeutic benefit.

Requirements and Definitions in Conflict of Interest Policies of Medical Journals

CONTEXT Conflicts of interest (COIs) may influence medical literature. However, it is unclear whether medical journals have consistent policies for defining and soliciting COI disclosures. OBJECTIVE To determine the prevalence of author COI policies, requirements for signed disclosure statements, and variability in COI definitions among medical journals. DESIGN A cross-sectional survey of Instructions for Authors and manuscript submission documents, including authorship responsibility forms, for high-impact medical journals across 35 subject categories available from March through October 2008. MAIN OUTCOME MEASURE Presence of language referring to COI disclosure in the Instructions for Authors or manuscript submission documents. RESULTS Of 256 journals, 89% had author COI policies. Fifty-four percent required authors to sign a disclosure statement, and 77% provided definitions of COI. Most definitions were limited to direct financial relationships; a minority of journals requested disclosure of other potential conflicts such as personal relationships (42%), paid expert testimony (42%), relationships with other organizations (26%), or travel grants (12%). The prevalence of policies varied by subject category: all internal medicine, respiratory medicine, and toxicology journals studied had comprehensive COI definitions, with 19 of these 24 journals requiring signed disclosure attestations. In contrast, 6 of 19 geriatrics, radiology, and rehabilitation journals requested author COI disclosure. Most journals that officially endorsed International Committee of Medical Journal Editors guidelines had COI policies (68/69), compared with 84% of journals not endorsing the guidelines (158/187). CONCLUSIONS In 2008, most medical journals with relatively high impact factors had author COI policies available for public review. Among journals, there was substantial variation in policies for solicitation of author COIs and in definitions of COI.

Traumatic Brain Injury Disrupts Cerebrovascular Tone Through Endothelial Inducible Nitric Oxide Synthase Expression and Nitric Oxide Gain of Function

Background Traumatic brain injury (TBI) has been reported to increase the concentration of nitric oxide (NO) in the brain and can lead to loss of cerebrovascular tone; however, the sources, amounts, and consequences of excess NO on the cerebral vasculature are unknown. Our objective was to elucidate the mechanism of decreased cerebral artery tone after TBI. Methods and Results Cerebral arteries were isolated from rats 24 hours after moderate fluid‐percussion TBI. Pressure‐induced increases in vasoconstriction (myogenic tone) and smooth muscle Ca2+ were severely blunted in cerebral arteries after TBI. However, myogenic tone and smooth muscle Ca2+ were restored by inhibition of NO synthesis or endothelium removal, suggesting that TBI increased endothelial NO levels. Live native cell NO, indexed by 4,5‐diaminofluorescein (DAF‐2 DA) fluorescence, was increased in endothelium and smooth muscle of cerebral arteries after TBI. Clamped concentrations of 20 to 30 nmol/L NO were required to simulate the loss of myogenic tone and increased (DAF‐2T) fluorescence observed following TBI. In comparison, basal NO in control arteries was estimated as 0.4 nmol/L. Consistent with TBI causing enhanced NO‐mediated vasodilation, inhibitors of guanylyl cyclase, protein kinase G, and large‐conductance Ca2+‐activated potassium (BK) channel restored function of arteries from animals with TBI. Expression of the inducible isoform of NO synthase was upregulated in cerebral arteries isolated from animals with TBI, and the inducible isoform of NO synthase inhibitor 1400W restored myogenic responses following TBI. Conclusions The mechanism of profound cerebral artery vasodilation after TBI is a gain of function in vascular NO production by 60‐fold over controls, resulting from upregulation of the inducible isoform of NO synthase in the endothelium.

Cardiac Reactive Oxygen Species After Traumatic Brain Injury

BACKGROUND Cardiovascular complications after traumatic brain injury (TBI) contribute to morbidity and mortality and may provide a target for therapy. We examined blood pressure and left ventricle contractility after TBI, and tested the hypothesis that β-adrenergic blockade would decrease oxidative stress after TBI. MATERIAL AND METHODS Rodents received fluid-percussion injury or sham surgery, confirmed with magnetic resonance imaging (MRI) and histopathology. We followed recovery with sensorimotor coordination testing and blood pressure measurements. We assessed left ventricular ejection fraction using ECG-gated cardiac MRI and measured myocardial reactive oxygen species (ROS) with dihydroethidium. We randomized additional TBI and sham animals to postoperative treatment with propranolol or control, for measurement of ROS. RESULTS Blood pressure and cardiac contractility were elevated 48 h after TBI. Myocardial tissue sections showed increased ROS. Treatment with propranolol diminished ROS levels following TBI. CONCLUSIONS TBI is associated with increased cardiac contractility and myocardial ROS; decreased myocardial ROS after β-blockade suggests that sympathetic stimulation is a mechanism of oxidative stress.

Cognitive Improvement after Mild Traumatic Brain Injury Measured with Functional Neuroimaging during the Acute Period.

Functional neuroimaging studies in mild traumatic brain injury (mTBI) have been largely limited to patients with persistent post-concussive symptoms, utilizing images obtained months to years after the actual head trauma. We sought to distinguish acute and delayed effects of mild traumatic brain injury on working memory functional brain activation patterns < 72 hours after mild traumatic brain injury (mTBI) and again one-week later. We hypothesized that clinical and fMRI measures of working memory would be abnormal in symptomatic mTBI patients assessed < 72 hours after injury, with most patients showing clinical recovery (i.e., improvement in these measures) within 1 week after the initial assessment. We also hypothesized that increased memory workload at 1 week following injury would expose different cortical activation patterns in mTBI patients with persistent post-concussive symptoms, compared to those with full clinical recovery. We performed a prospective, cohort study of working memory in emergency department patients with isolated head injury and clinical diagnosis of concussion, compared to control subjects (both uninjured volunteers and emergency department patients with extremity injuries and no head trauma). The primary outcome of cognitive recovery was defined as resolution of reported cognitive impairment and quantified by scoring the subject’s reported cognitive post-concussive symptoms at 1 week. Secondary outcomes included additional post-concussive symptoms and neurocognitive testing results. We enrolled 46 subjects: 27 with mild TBI and 19 controls. The time of initial neuroimaging was 48 (+22 S.D.) hours after injury (time 1). At follow up (8.7, + 1.2 S.D., days after injury, time 2), 18 of mTBI subjects (64%) reported moderate to complete cognitive recovery, 8 of whom fully recovered between initial and follow-up imaging. fMRI changes from time 1 to time 2 showed an increase in posterior cingulate activation in the mTBI subjects compared to controls. Increases in activation were greater in those mTBI subjects without cognitive recovery. As workload increased in mTBI subjects, activation increased in cortical regions in the right hemisphere. In summary, we found neuroimaging evidence for working memory deficits during the first week following mild traumatic brain injury. Subjects with persistent cognitive symptoms after mTBI had increased requirement for posterior cingulate activation to complete memory tasks at 1 week following a brain injury. These results provide insight into functional activation patterns during initial recovery from mTBI and expose the regional activation networks that may be involved in working memory deficits.

Airway, breathing, computed tomographic scanning: duplicate computed tomographic imaging after transfer to trauma center.

BACKGROUND Trauma patients imaged at community hospitals often receive duplicate computed tomographic (CT) imaging after transfer to regional trauma centers (RTCs). CT scanning is expensive, is resource intensive, and has acknowledged radiation risk to the patient. The objective of this study was to review and evaluate the frequency, indications, impact on patient management, as well as associated radiation and charges for duplicate CT imaging of trauma patients transferred to our RTC from outside hospitals (OSH). METHODS Patients transferred to our RTC between September 2009 and August 2010 were evaluated prospectively. The OSH patients’ charts and provider interviews were used to determine the reasons for repeated scans. The primary outcome was frequency of duplicate CT scan, defined as a repeated CT image of the same body part within 24 hours. The reason for duplicate imaging and impact on patient management was categorized. Radiation exposure and charges for duplicate scans were also determined. RESULTS Of the 185 patients transferred to our facility, 177 were eligible. CT examinations at the OSH were performed on 137 patients (77%). A duplicate CT examination occurred in 38 patients (28%). The most common reason for duplicate CT scanning was lack of thin-section multiplanar data, on images sent via CD-ROM (37%). There was a change in management in 16 patients (42%). The patients with duplicate scanning received a median of 10.2 mSv (interquartile range, 6.6–15.7 mSv) of additional radiation, with a median charge of

Clinical assessment of trauma-induced coagulopathy and its contribution to postinjury mortality: A TACTIC proposal.

409 (interquartile range,

TACTIC: Trans-Agency Consortium for Trauma-Induced Coagulopathy

307–

Promoting tobacco cessation utilizing pre-health professional students as research associates in the emergency department

734). CONCLUSION More than one third of duplicated scans performed on transferred trauma patients were potentially avoidable, primary owing to inadequate transfer of data from the OSH CT scan. The capacity of a single CD-ROM is insufficient to contain full imaging data from a trauma scan, and establishing direct links to imaging data from OSHs would decrease the number of repeated CT scans performed on transferred trauma patients. LEVEL OF EVIDENCE Care management study, level III.

Prevention of treatment-related fluid overload reduces estimated effective cost of prothrombin complex concentrate in patients requiring rapid vitamin K antagonist reversal

T concept of impaired coagulation following injury has been the subject of scientific investigation for a century, but defining the responsible mechanisms to guide precisionevidence management for distinct phenotypes remains elusive. In 2010, the National Institutes of Health (NIH), recognizing the ongoing knowledge gaps in the diagnosis and management of coagulopathy associated with severe injury, organized a workshop and arrived at a consensus to name this phenomenon trauma-induced coagulopathy (TIC). The common denominator of TIC-related research has been a laboratory-based strategy for quantifying and stratifying TIC. While detailed analyses of laboratory data related to TIC have been correlated with outcomes, there is a spectrum of coagulopathic phenotypes, and investigative efforts have been limited by the lack of (1) a standardized clinical scoring system for coagulopathy and (2) criteria for determining whether coagulopathy impacted postinjury mortality, that is, are they dying because they are bleeding or bleeding because they are dying. Rather remarkably, resuscitation strategies have emerged to treat a condition that remains a vague clinical entity that is presently defined by subjective surgeon assessment and blood product/transfusion requirements. Although clinical scoring systems for disseminated intravascular coagulopathy in sepsis exist, to date, no consensus statement regarding the clinical presentation of TIC has emerged. Standardized scoring systems for key clinical definitions, which can be quantified, validated, and tested for interrater reliability, are critical to progress in challenging clinical entities. As an example, there was little progress in understanding the fundamental mechanisms of multipleorgan failure (MOF) until a standard definition was developed. In recognition of the significance of TIC as a clinical problem, the NIH has funded the Trans-Agency Consortium for Trauma-Induced Coagulopathy (TACTIC) through the National Heart, Lung, and Blood Institute. TACTIC represents a consortium of investigators who have partnered in a collaborative effort between the NIH and the Department of Defense to investigate the problemof coagulopathy after trauma, ranging from large-scale clinical research studies at multiple sites to basic mechanistic laboratory investigations. In designing amulticenter study, it immediately became apparent that the lack of a unifying clinical definition of coagulopathy severity presents a major barrier to communication between investigators at various sites. Furthermore, interpretation of ongoing laboratory testing of coagulation should be compared in real timewith clinical assessment of hemostasis. Finally, evidence exists to suggest that coagulopathy is, in part, driven by the anatomic location aswell asmechanismof injury results in distinguishable phenotypes of TIC.As such, a robust scoring system to quantify the severity of coagulation disturbance, taking into account important clinical variables, is needed. Quantification of impaired hemostasis and bleeding due to coagulation disturbance as opposed to surgical bleeding (uncontrolled arterial or venous disruption) is, at times, challenging and at risk ofmisclassification. To address the potentially subjective nature of this assessment and to provide a balanced assessment, we propose to use a scoring system designed around a 5-point Likert scale (definitive positive, positive, possible positive, equivocal, and negative) to stratify the level of observer confidence in each assigned score. Such a stratified scheme prohibits calculation of sensitivity and specificity (no dichotomized results), and likelihood ratios will need to be used instead. Even though this is more complex, it better reflects the use of clinical scoring systems. We therefore propose the following quantitative scoring system for TIC (Table 1). One goal of the system is to differentiate injuries requiring hemostasis, which are not complicated by a coagulopathy (mechanical bleeding alone) versus mechanical bleeding from injuries compounded by biologic coagulopathy. Through the use of this system, we are attempting to distinguish between bleeding severity resulting from injury alone, that is, controllable with pressure or suturing/stapling versus bleeding, which persists due to a coagulopathy. Thus, to score higher than I for coagulopathy, the trauma surgeon must conclude that the bleeding is not simply due to a severe injury requiring ordinary hemostatic intervention. In addition, to facilitate coagulation research, we propose to further subclassify bleeding according to the source of bleeding. A modifier is included to denote themechanism of injury, namely (p) for penetrating or (b) for blunt. The location of the patient when the score is calculated is to be indicated in parenthesis as the emergency department (ED), operating room (OR), or intensive care unit (ICU).A series of example cases with the corresponding scores are included in Table 2.We suggest that the score be determined by the attending trauma surgeon immediately after achieving surgical hemostasis or at the earliest feasible time point so as to best achieve an early CURRENT OPINION