Brad Kolls - Academia.edu (original) (raw)

Papers by Brad Kolls

Clinical and translational medicine, 2022

Dear Editor: This letter describes our work identifying the neuronal targets of a clinical-stage ... more Dear Editor: This letter describes our work identifying the neuronal targets of a clinical-stage stroke therapeutics CN105, and proposing a novel neuroprotective strategy involving nAChR antagonism. Stroke is a devastating disease with high morbidity and mortality. CN-105 was originally designed to mimic the anti-inflammatory activities of endogenous apolipoprotein E (apoE). Despite its proven efficacy in various animal models of brain injury and wellestablished safety profile in clinical trials,1,2 our understanding of CN-105’s mechanism of action remains incomplete. Early reports suggested that apoE-derived peptides and anumber of oligoarginine speciesmay interact directly with various neuronal targets including the nicotinic acetylcholine receptors (nAChR).3,4 The long-held view regarding nAChR was that its activation was neuroprotective, best exemplified by the cognitive-enhancing effects of nAChR agonists or positive allosteric modulators.5 One common role of nAChR, which received limited attention in stroke, is its potentiation of glutamate release at the presynaptic terminal.6 Glutamatergic neurotransmission is arguably the primary reason for the propagation of excitotoxicity in stroke.7,8 Although postsynaptic nAChR activated by ACh or nicotine could desensitize proximal NMDA receptors,9 we hypothesized that acute action of nAChR antagonist on presynaptic neurons may serve to downregulate the detrimental cascade associated with glutamate excitotoxicity. After given supratherapeutic dosing of CN-105 several orders of magnitude higher than clinical practice, Cynologous monkey exhibited symptoms of mydriasis and ptosis. A gradual recovery to normal activity took about two serum clearance half-lives of CN-105 (4 h, Table S1; Figure S1). In C57BL6 mice, CN-105 had an LD80 of 25 mg/kg (Figure 1A) with symptoms of spasm and respiratory suppression. Following intubation and mechanical ventilation, dosing of 50 mg/kg was not associated with mortality

Clinical Neurophysiology, Sep 1, 2015

Stereotactic and Functional Neurosurgery, 2022

Introduction: Stereotactic neurosurgical techniques are increasingly used to deliver biologics, s... more Introduction: Stereotactic neurosurgical techniques are increasingly used to deliver biologics, such as cells and viruses, although standardized procedures are necessary to ensure consistency and reproducibility. Objective: We provide an instructional guide to help plan for complex image-guided trajectories; this may be of particular benefit to surgeons new to biologic trials and companies planning such trials. Methods: We show how nuclei can be segmented and multiple trajectories with multiple injection points can be created through a single or multiple burr hole(s) based on preoperative images. Screenshots similar to those shown in this article can be used for planning purposes and for quality control in clinical trials. Results: This method enables the precise definition of 3-D target structures, such as the putamen, and efficient planning trajectories for biologic injections. The technique is generalizable and largely independent of procedural format, and thus can be integrated with frame-based or frameless platforms to streamline reproducible therapeutic delivery. Conclusions: We describe an easy-to-use and generalizable protocol for intracerebral trajectory planning for stereotactic delivery of biologics. Although we highlight intracerebral stem cell delivery to the putamen using a frame-based stereotactic delivery system, similar strategies may be employed for different brain nuclei using different platforms. We anticipate this will inform future advanced and fully automated neurosurgical procedures to help unify the field and decrease inherent variability seen with manual trajectory planning.

Journal of Stroke and Cerebrovascular Diseases

Informatics in Medicine Unlocked

Stroke, 2017

Background: Rapid treatment of acute ischemic stroke (AIS) is key to improving outcomes, yet pre-... more Background: Rapid treatment of acute ischemic stroke (AIS) is key to improving outcomes, yet pre-hospital transportation decisions are rarely considered. Decisions on acute care destinations for AIS patients are often poorly guided and based on patient preference. In a complex urban environments with multiple stroke centers, proper guidance these decisions may reduce delays in treatment. We hypothesize that the integration of stroke center quality metrics and traffic patterns into pre-hospital transportation of AIS patients would reduce treatment times. Methods: Travel times to Duke University Hospital (DUH) and Duke Raleigh Hospital (DRAH) from three locations (RDU airport, Falls Lake, Apex town center) were examined at 5 times of day (2AM, 8AM, 12PM, 5:30PM, 8PM) taking traffic delays into account using Google Maps estimates from historical data. Average door-to-needle times (DTN) for each hospital were obtained for the prior 6 months. The 6 month average DTN as well as individual...

Stroke, 2020

Background and Purpose: The timely integration of high quality scientific evidence into daily pat... more Background and Purpose: The timely integration of high quality scientific evidence into daily patient care practices is an issue that has been around for decades. Newer research says it may take even longer for practitioners to stop unnecessary practices. What is evident is that there is a need to shorten the time from discovery to practice with an expectation of improved outcomes and control of heath care spending. Understanding the extent to which concepts (research) of stroke systems have been implemented (practice) within a region, can result in meaningful system improvement. We sought to evaluate the current state of systems in the southeastern United States to inform the development of a large-scale implementation science system of care improvement program. Methods: An 85 question, internet-based survey was developed to obtain information on current practices in sites located in the southeastern US. Data was collected in October, 2017. A total of 13 stroke centers from 3 state...

Circulation, 2015

Background: Intracranial hemorrhage (ICH) is associated with poor outcomes in patients with atria... more Background: Intracranial hemorrhage (ICH) is associated with poor outcomes in patients with atrial fibrillation (AF) treated with oral anticoagulation. Little is known about clinical characteristics and factors associated with ICH and subsequent outcomes in patients receiving apixaban. Methods: The ARISTOTLE trial randomized 18,201 patients with AF and risk of stroke to warfarin or apixaban. All ICH events were identified and adjudicated by a central committee blinded to the study treatment assignment. ICH events were analyzed in patients receiving at least one dose of study drug (N=18,140). Multivariable cox regression models were developed to identify factors associated with ICH. Results: There were 174 (1.0%) ICH events. Of those, 111 (67.7%) were intracerebral hemorrhage, 50 (30.7%) subdural hematomas, and 25 (15.3%) subarachnoid hemorrhage. Patients with ICH were older and had higher CHADS 2 score than patients without ICH. Computed tomography was used in 95.2% of patients for ...

The Journal of Neuroscience, 2002

During development, waves of activity periodically spread across retina to produce correlated act... more During development, waves of activity periodically spread across retina to produce correlated activity that is thought to drive activity-dependent ordering in optic fibers. We asked whether similar waves of activity are produced in the retina of adult goldfish during activity-dependent refinement by regenerating optic fibers. Dual-electrode recordings of spontaneous activity were made at different distances across retina but revealed no evidence of retinal waves in normal retina or during regeneration. Retinal activity was tonic and lacked the episodic bursting associated with waves. Cross-correlation analysis showed that the correlated activity that was normally restricted to near neighbors (typically seen across 100–200 μm and absent at >500 μm) was not altered during regeneration. The only change associated with regeneration was a twofold reduction in ganglion cell firing rates. Because spontaneous retinal activity is known to be sufficient to generate refinement during regene...

Journal of the American Heart Association, 2018

Background Vorapaxar, a protease‐activated receptor‐1 antagonist, is approved for secondary preve... more Background Vorapaxar, a protease‐activated receptor‐1 antagonist, is approved for secondary prevention of cardiovascular events but is associated with increased intracranial hemorrhage. Methods and Results TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) was a trial of vorapaxar versus placebo among patients with acute coronary syndrome. Strokes were adjudicated by a central events committee. Of 12 944 patients, 199 (1.5%) had ≥1 stroke during the study period (median follow‐up, 477 days). Four patients had a single stroke of unknown type; 195 patients had ≥1 stroke classified as hemorrhagic or nonhemorrhagic (165 nonhemorrhagic, 28 hemorrhagic, and 2 both). Strokes occurred in 96 of 6473 patients (1.5%) assigned vorapaxar and 103 of 6471 patients (1.6%) assigned placebo. Kaplan‐Meier incidence of stroke for vorapaxar versus placebo was higher for hemorrhagic stroke (0.45% versus 0.14% [hazard ratio, 2.74; 95% confidence interval, 1.22–6....

Clinical Neurophysiology, 2018

Scientific reports, Jan 21, 2017

At present, there are no proven pharmacological treatments demonstrated to improve long term func... more At present, there are no proven pharmacological treatments demonstrated to improve long term functional outcomes following traumatic brain injury(TBI). In the setting of non-penetrating TBI, sterile brain inflammatory responses are associated with the development of cerebral edema, intracranial hypertension, and secondary neuronal injury. There is increasing evidence that endogenous apolipoprotein E(apoE) modifies the neuroinflammatory response through its role in downregulating glial activation, however, the intact apoE holoprotein does not cross the blood-brain barrier due to its size. To address this limitation, we developed a small 5 amino acid apoE mimetic peptide(CN-105) that mimics the polar face of the apoE helical domain involved in receptor interactions. The goal of this study was to investigate the therapeutic potential of CN-105 in a murine model of closed head injury. Treatment with CN-105 was associated with a durable improvement in functional outcomes as assessed by R...

Blood, Jun 29, 2017

We investigated the frequency and characteristics of intracranial hemorrhage (ICH), factors assoc... more We investigated the frequency and characteristics of intracranial hemorrhage (ICH), factors associated with risk of ICH, and outcomes post-ICH overall and by randomized treatment. We identified patients in ARISTOTLE with ICH who received ≥1 dose of study drug (n=18,140). ICH was adjudicated by a central committee. Cox regression models were used to identify factors associated with ICH. ICH occurred in 174 patients; most ICH events were spontaneous (71.2%) versus traumatic (28.8%). Apixaban resulted in significantly less ICH (0.33%/year), regardless of type and location, than warfarin (0.80%/year). Independent factors associated with increased risk of ICH were enrollment in Asia or Latin America, older age, prior stroke/transient ischemic attack, and aspirin use at baseline. Among warfarin-treated patients, the median (25th, 75th) time from most recent international normalized ratio (INR) to ICH was 13 (6, 21) days. Median INR prior to ICH was 2.6 (2.1, 3.0); 78.5% of patients had a ...

Nursing Critical Care, 2011

8 l Nursing2011CriticalCare l Volume 6, Number 6 www.nursing2011criticalcare.com LLas Vegas. It w... more 8 l Nursing2011CriticalCare l Volume 6, Number 6 www.nursing2011criticalcare.com LLas Vegas. It was hot. It was dry. My daughter, Natalie, had decided that getting married in Las Vegas was lucky, and she choose July 7, 2007 (7/7/07) as the luckiest day to get married. This unique idea was shared by just over 3,000 other couples. As we rode from our hotel to the chapel, Natalie informed me that after the wedding, she was going to celebrate by playing roulette. As any good father would, I cautioned against this, but she insisted that she had a system. In fact, she said she’d tested this system yesterday (without playing her money) and after four spins, betting only on red or black, she would already have quadrupled her money. Unfortunately, she was a newlywed with no money of her own. So she offered me an opportunity. She’d play roulette with my money, and we’d split the winnings. She pleaded, “Daddy, with just one spin of the wheel, we could double our money.” Yup, they always call you daddy when they want something...and when did my life savings become “our money”? Readers, would you take this bet? Let’s assume that there are two options to every spin of the roulette wheel: The ball may land on red or it may land on black. Would you trust Natalie’s system and bet your life savings on one spin of the wheel? As nurses, we essentially gamble with our patients’ health: We bet that a patient will do better if we administer certain medications. What’s the level of evidence that we, as nurses, require before we reject the idea that our patient has just as good a chance at recovering even if we don’t give them the medication? I made the decision that before I took my money to the table, I should design an experiment to test the accuracy of Natalie’s system. The roulette wheel has two options (red or black)—a dichotomous response—the same as tossing a coin. I could test the hypothesis that the system was better than just taking a chance by testing its ability to correctly predict the outcome of a coin toss. In scientific terms, the null hypothesis is that Natalie’s system is no different than chance and chance alone. You may recognize the form for expressing the null and alternate hypotheses from previous courses in nursing research. • The null hypothesis (HO): System = chance • The alternate hypothesis (HA) System > chance. I took a quarter out my pocket, tossed it high into the air, and asked Natalie, “Heads or tails?” As I tossed the coin for the first time, I knew that on each toss, two results were possible: Natalie could be right (R), or she could be wrong (W). In The first toss you see that if the coin is heads and her “system” predicts heads, then she’s right (R), and if the “system” predicts tails, she’s wrong (W). Most people correctly identify that Natalie has a 50/50 chance of being right. Mathematically we can express this as probability (P). With one toss of the coin, the probability of being right is equal to the probability of being wrong. Understanding P values

American Journal of Hematology, 2002

We report herein a case of Factor XIII deficiency that remained undiagnosed until 2 years of age.... more We report herein a case of Factor XIII deficiency that remained undiagnosed until 2 years of age. Part of the delay in diagnosis was a consequence of testing that was performed on a blood sample obtained after plasma transfusion therapy for a life‐threatening bleeding episode. Due to insufficient family follow‐up after discharge from the hospital, the diagnosis was delayed 1 year until the child was rehospitalized and a pre‐transfusion plasma sample was tested. The commonly accepted approach of using only a qualitative test for the diagnosis of factor XIII deficiency is challenged by this case report. Am. J. Hematol. 71:328–330, 2002. © 2002 Wiley‐Liss, Inc.

Communications Biology

The underlying etiologies of seizures are highly heterogeneous and remain incompletely understood... more The underlying etiologies of seizures are highly heterogeneous and remain incompletely understood. While studying the unfolded protein response (UPR) pathways in the brain, we unexpectedly discovered that transgenic mice (XBP1s-TG) expressing spliced X-box–binding protein-1 (Xbp1s), a key effector of UPR signaling, in forebrain excitatory neurons, rapidly develop neurologic deficits, most notably recurrent spontaneous seizures. This seizure phenotype begins around 8 days after Xbp1s transgene expression is induced in XBP1s-TG mice, and by approximately 14 days post induction, the seizures evolve into status epilepticus with nearly continuous seizure activity followed by sudden death. Animal death is likely due to severe seizures because the anticonvulsant valproic acid could significantly prolong the lives of XBP1s-TG mice. Mechanistically, our gene profiling analysis indicates that compared to control mice, XBP1s-TG mice exhibit 591 differentially regulated genes (mostly upregulate...