Browsing by Author "Laskowitz, Daniel T"
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Item Open Access A blood-based biomarker panel to risk-stratify mild traumatic brain injury.(PloS one, 2017-01) Sharma, Richa; Rosenberg, Alexandra; Bennett, Ellen R; Laskowitz, Daniel T; Acheson, Shawn KMild traumatic brain injury (TBI) accounts for the vast majority of the nearly two million brain injuries suffered in the United States each year. Mild TBI is commonly classified as complicated (radiographic evidence of intracranial injury) or uncomplicated (radiographically negative). Such a distinction is important because it helps to determine the need for further neuroimaging, potential admission, or neurosurgical intervention. Unfortunately, imaging modalities such as computed tomography (CT) and magnetic resonance imaging (MRI) are costly and not without some risk. The purpose of this study was to screen 87 serum biomarkers to identify a select panel of biomarkers that would predict the presence of intracranial injury as determined by initial brain CT. Serum was collected from 110 patients who sustained a mild TBI within 24 hours of blood draw. Two models were created. In the broad inclusive model, 72kDa type IV collagenase (MMP-2), C-reactive protein (CRP), creatine kinase B type (CKBB), fatty acid binding protein-heart (hFABP), granulocyte-macrophage colony-stimulating factor (GM-CSF) and malondialdehyde modified low density lipoprotein (MDA-LDL) significantly predicted injury visualized on CT, yielding an overall c-statistic of 0.975 and a negative predictive value (NPV) of 98.6. In the parsimonious model, MMP-2, CRP, and CKBB type significantly predicted injury visualized on CT, yielding an overall c-statistic of 0.964 and a negative predictive value (NPV) of 97.2. These results suggest that a serum based biomarker panel can accurately differentiate patients with complicated mild TBI from those with uncomplicated mild TBI. Such a panel could be useful to guide early triage decisions, including the need for further evaluation or admission, especially in those environments in which resources are limited.Item Open Access A Randomized, Placebo-Controlled, Phase II Trial of Intravenous Allogeneic Non-HLA Matched, Unrelated Donor, Cord Blood Infusion for Ischemic Stroke.(Stem cells translational medicine, 2024-02) Laskowitz, Daniel T; Troy, Jesse; Poehlein, Emily; Bennett, Ellen R; Shpall, Elizabeth J; Wingard, John R; Freed, Brian; Belagaje, Samir R; Khanna, Anna; Jones, William; Volpi, John J; Marrotte, Eric; Kurtzberg, JoanneStroke remains a leading cause of death and disability in the US, and time-limited reperfusion strategies remain the only approved treatment options. To address this unmet clinical need, we conducted a phase II randomized clinical trial to determine whether intravenous infusion of banked, non-HLA matched unrelated donor umbilical cord blood (UCB) improved functional outcome after stroke. Participants were randomized 2:1 to UCB or placebo within strata of National Institutes of Health Stroke Scale Score (NIHSS) and study center. Study product was infused 3-10 days following index stroke. The primary endpoint was change in modified Rankin Scale (mRS) from baseline to day 90. Key secondary outcomes included functional independence, NIHSS, the Barthel Index, and assessment of adverse events. The trial was terminated early due to slow accrual and logistical concerns associated with the COVID-19 pandemic, and a total of 73 of a planned 100 participants were included in primary analyses. The median (range) of the change in mRS was 1 point (-2, 3) in UCB and 1 point (-1,4) in Placebo (P = 0.72). A shift analysis comparing the mRS at day 90 utilizing proportional odds modeling showed a common odds ratio of 0.9 (95% CI: 0.4, 2.3) after adjustment for baseline NIHSS and randomization strata. The distribution of adverse events was similar between arms. Although this study did not suggest any safety concerns related to UCB in ischemic stroke, we did not show a clinical benefit in the reduced sample size evaluated.Item Open Access Allogeneic Umbilical Cord Blood Infusion for Adults with Ischemic Stroke: Clinical Outcomes from a Phase I Safety Study.(Stem cells translational medicine, 2018-07) Laskowitz, Daniel T; Bennett, Ellen R; Durham, Rebecca J; Volpi, John J; Wiese, Jonathan R; Frankel, Michael; Shpall, Elizabeth; Wilson, Jeffry M; Troy, Jesse; Kurtzberg, JoanneStroke is a major cause of death and long-term disability, affecting one in six people worldwide. The only currently available approved pharmacological treatment for ischemic stroke is tissue plasminogen activator; however, relatively few patients are eligible for this therapy. We hypothesized that intravenous (IV) infusion of banked unrelated allogeneic umbilical cord blood (UCB) would improve functional outcomes in patients with ischemic stroke. To investigate this, we conducted a phase I open-label trial to assess the safety and feasibility of a single IV infusion of non-human leukocyte antigen (HLA) matched, ABO matched, unrelated allogeneic UCB into adult stroke patients. Ten participants with acute middle cerebral artery ischemic stroke were enrolled. UCB units were matched for blood group antigens and race but not HLA, and infused 3-9 days post-stroke. The adverse event (AE) profile over a 12 month postinfusion period indicated that the treatment was well-tolerated in these stroke patients, with no serious AEs directly related to the study product. Study participants were also assessed using neurological and functional evaluations, including the modified Rankin Score (mRS) and National Institute of Health Stroke Scale (NIHSS). At 3 months post-treatment, all participants had improved by at least one grade in mRS (mean 2.8 ± 0.9) and by at least 4 points in NIHSS (mean 5.9 ± 1.4), relative to baseline. Together, these data suggest that a single i.v. dose of allogeneic non-HLA matched human UCB cells is safe in adults with ischemic stroke, and support the conduct of a randomized, placebo-controlled phase 2 study. Stem Cells Translational Medicine 2018;7:521-529.Item Open Access Anti-inflammatory effects of progesterone in lipopolysaccharide-stimulated BV-2 microglia.(PLoS One, 2014) Lei, Beilei; Mace, Brian; Dawson, Hana N; Warner, David S; Laskowitz, Daniel T; James, Michael LFemale sex is associated with improved outcome in experimental brain injury models, such as traumatic brain injury, ischemic stroke, and intracerebral hemorrhage. This implies female gonadal steroids may be neuroprotective. A mechanism for this may involve modulation of post-injury neuroinflammation. As the resident immunomodulatory cells in central nervous system, microglia are activated during acute brain injury and produce inflammatory mediators which contribute to secondary injury including proinflammatory cytokines, and nitric oxide (NO) and prostaglandin E2 (PGE2), mediated by inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), respectively. We hypothesized that female gonadal steroids reduce microglia mediated neuroinflammation. In this study, the progesterone's effects on tumor necrosis factor alpha (TNF-α), iNOS, and COX-2 expression were investigated in lipopolysaccharide (LPS)-stimulated BV-2 microglia. Further, investigation included nuclear factor kappa B (NF-κB) and mitogen activated protein kinase (MAPK) pathways. LPS (30 ng/ml) upregulated TNF-α, iNOS, and COX-2 protein expression in BV-2 cells. Progesterone pretreatment attenuated LPS-stimulated TNF-α, iNOS, and COX-2 expression in a dose-dependent fashion. Progesterone suppressed LPS-induced NF-κB activation by decreasing inhibitory κBα and NF-κB p65 phosphorylation and p65 nuclear translocation. Progesterone decreased LPS-mediated phosphorylation of p38, c-Jun N-terminal kinase and extracellular regulated kinase MAPKs. These progesterone effects were inhibited by its antagonist mifepristone. In conclusion, progesterone exhibits pleiotropic anti-inflammatory effects in LPS-stimulated BV-2 microglia by down-regulating proinflammatory mediators corresponding to suppression of NF-κB and MAPK activation. This suggests progesterone may be used as a potential neurotherapeutic to treat inflammatory components of acute brain injury.Item Open Access Association of Early Beta-Blocker Exposure and Functional Outcomes in Critically Ill Patients With Moderate to Severe Traumatic Brain Injury: A Transforming Clinical Research and Knowledge in Traumatic Brain Injury Study.(Critical care explorations, 2023-09) Kelly-Hedrick, Margot; Liu, Sunny Yang; Temkin, Nancy; Barber, Jason; Komisarow, Jordan; Manley, Geoffrey; Ohnuma, Tetsu; Colton, Katharine; Treggiari, Miriam M; Monson, Eric E; Vavilala, Monica S; Grandhi, Ramesh; Laskowitz, Daniel T; Mathew, Joseph P; Hernandez, Adrian; James, Michael L; Raghunathan, Karthik; Goldstein, Ben; Markowitz, Amy J; Krishnamoorthy, VijayObjectives
We aimed to 1) describe patterns of beta-blocker utilization among critically ill patients following moderate-severe traumatic brain injury (TBI) and 2) examine the association of early beta-blocker exposure with functional and clinical outcomes following injury.Design
Retrospective cohort study.Setting
ICUs at 18 level I, U.S. trauma centers in the Transforming Clinical Research and Knowledge in TBI (TRACK-TBI) study.Patients
Greater than or equal to 17 years enrolled in the TRACK-TBI study with moderate-severe TBI (Glasgow Coma Scale of <13) were admitted to the ICU after a blunt TBI.Interventions
None.Measurements
Primary exposure was a beta blocker during the first 7 days in the ICU, with a primary outcome of 6-month Glasgow Outcome Scale-Extended (GOSE). Secondary outcomes included: length of hospital stay, in-hospital mortality, 6-month and 12-month mortality, 12-month GOSE score, and 6-month and 12-month measures of disability, well-being, quality of life, and life satisfaction.Main results
Of the 450 eligible participants, 57 (13%) received early beta blockers (BB+ group). The BB+ group was on average older, more likely to be on a preinjury beta blocker, and more likely to have a history of hypertension. In the BB+ group, 34 participants (60%) received metoprolol only, 19 participants (33%) received propranolol only, 3 participants (5%) received both, and 1 participant (2%) received atenolol only. In multivariable regression, there was no difference in the odds of a higher GOSE score at 6 months between the BB+ group and BB- group (odds ratio = 0.86; 95% CI, 0.48-1.53). There was no association between BB exposure and secondary outcomes.Conclusions
About one-sixth of subjects in our study received early beta blockers, and within this group, dose, and timing of beta-blocker administration varied substantially. No significant differences in GOSE score at 6 months were demonstrated, although our ability to draw conclusions is limited by overall low total doses administered compared with prior studies.Item Open Access Association of Severe Acute Kidney Injury with Mortality and Healthcare Utilization Following Isolated Traumatic Brain Injury.(Neurocritical care, 2021-01-13) Luu, David; Komisarow, Jordan; Mills, Brianna M; Vavilala, Monica S; Laskowitz, Daniel T; Mathew, Joseph; James, Michael L; Hernandez, Adrian; Sampson, John; Fuller, Matt; Ohnuma, Tetsu; Raghunathan, Karthik; Privratsky, Jamie; Bartz, Raquel; Krishnamoorthy, VijayBackground/objective
Traumatic brain injury (TBI) is a leading cause of morbidity, mortality, and disability in the USA. While cardiopulmonary dysfunction can result in poor outcomes following severe TBI, the impact of acute kidney injury (AKI) is poorly understood. We examined the association of severe AKI with hospital mortality and healthcare utilization following isolate severe TBI.Methods
We conducted a retrospective cohort study using the National Trauma Data Bank from 2007 to 2014. We identified a cohort of adult patients with isolated severe TBI and described the incidence of severe AKI, corresponding to Acute Kidney Injury Network stage 3 disease or greater. We examined the association of severe AKI with the primary outcome of hospital mortality using multivariable logistic regression models. In secondary analyses, we examined the association of severe AKI with dialysis catheter placement, tracheostomy and gastrostomy utilization, and hospital length of stay.Results
There were 37,851 patients who experienced isolated severe TBI during the study period. Among these patients, 787 (2.1%) experienced severe (Stage 3 or greater) AKI. In multivariable models, the development of severe AKI in the hospital was associated with in-hospital mortality (OR 2.03, 95% CI 1.64-2.52), need for tracheostomy (OR 2.10, 95% CI 1.52-2.89), PEG tube placement (OR 1.88, 95% CI 1.45-2.45), and increased hospital length of stay (p < 0.001).Conclusions
The overall incidence of severe AKI is relatively low (2.1%), but is associated with increased mortality and multiple markers of increased healthcare utilization following severe TBI.Item Open Access Brain Natriuretic Peptide Improves Long-Term Functional Recovery after Acute CNS Injury in Mice(2010-01) James, Michael L; Wang, Haichen; Venkatraman, Talaignair; Song, Pingping; Lascola, Christopher D; Laskowitz, Daniel TThere is emerging evidence to suggest that brain natriuretic peptide (BNP) is elevated after acute brain injury, and that it may play an adaptive role in recovery through augmentation of cerebral blood flow (CBF). Through a series of experiments, we tested the hypothesis that the administration of BNP after different acute mechanisms of central nervous system (CNS) injury could improve functional recovery by improving CBF. C57 wild-type mice were exposed to either pneumatic-induced closed traumatic brain injury (TBI) or collagenase-induced intracerebral hemorrhage (ICH). After injury, either nesiritide (hBNP) (8 μg/kg) or normal saline were administered via tail vein injection at 30 min and 4 h. The mice then underwent functional neurological testing via rotorod latency over the following 5 days and neurocognitive testing via Morris water maze testing on days 24–28. Cerebral blood flow (CBF) was assessed by laser Doppler from 25 to 90 min after injury. After ICH, mRNA polymerase chain reaction (PCR) and histochemical staining were performed during the acute injury phase (<24 h) to determine the effects on inflammation. Following TBI and ICH, administration of hBNP was associated with improved functional performance as assessed by rotorod and Morris water maze latencies (p < 0.01). CBF was increased (p < 0.05), and inflammatory markers (TNF-α and IL-6; p < 0.05), activated microglial (F4/80; p < 0.05), and neuronal degeneration (Fluoro-Jade B; p < 0.05) were reduced in mice receiving hBNP. hBNP improves neurological function in murine models of TBI and ICH, and was associated with enhanced CBF and downregulation of neuroinflammatory responses. hBNP may represent a novel therapeutic strategy after acute CNS injury.Item Open Access Changes in Informed Consent Policy and Treatment Delays in Stroke Thrombolysis.(Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association, 2020-12-18) Xu, Hanzhang; De Silva, Deidre Anne; Woon, Fung Peng; Ong, Marcus Eng Hock; Matchar, David B; Bettger, Janet Prvu; Laskowitz, Daniel T; Xian, YingObjectives
The efficacy of thrombolytic therapy with tissue plasminogen activator (tPA) is highly time dependent. Although clinical guidelines do not recommend written informed consent as it may cause treatment delays, local policy can supersede and require it. From 2014 to 2017, three out of five public hospitals in Singapore changed from written to verbal consent at different time points. We aimed to examine the association of hospital policy changes regarding informed consent on door-to-needle (DTN) times.Materials and methods
Using data from the Singapore Stroke Registry and surveys of local practice, we analyzed data of 915 acute ischemic stroke patients treated with tPA within 3 hours in all public hospitals between July 2014 to Dec 2017. Patient-level DTN times before and after policy changes were examined while adjusting for clinical characteristics, within-hospital clustering, and trends over time.Results
Patient characteristics and stroke severity were similar before and after the policy changes. Overall, the median DTN times decreased from 68 to 53 minutes after the policy changes. After risk adjustment, changing from written to verbal informed consent was associated with a 5.6 minutes reduction (95% CI 1.1-10.0) in DTN times. After the policy changed, the percentage of patients with DTN ≤60 minutes and ≤45 minutes increased from 35.6% to 66.1% (adjusted OR 1.75; 95% CI 1.12-2.74) and 9.3% to 36.0% (adjusted OR 2.42; 95% CI 1.37-4.25), respectively.Conclusion
Changing from written to verbal consent is associated with significant improvement in the timeliness of tPA administration in acute ischemic stroke.Item Open Access CN-105 in Participants with Acute Supratentorial Intracerebral Hemorrhage (CATCH) Trial.(Neurocritical care, 2021-08-23) James, Michael L; Troy, Jesse; Nowacki, Nathaniel; Komisarow, Jordan; Swisher, Christa B; Tucker, Kristi; Hatton, Kevin; Babi, Marc A; Worrall, Bradford B; Andrews, Charles; Woo, Daniel; Kranz, Peter G; Lascola, Christopher; Maughan, Maureen; Laskowitz, Daniel T; CATCH InvestigatorsBackground
Endogenous apolipoprotein (apo) E mediates neuroinflammatory responses and recovery after brain injury. Exogenously administered apoE-mimetic peptides effectively penetrate the central nervous system compartment and downregulate acute inflammation. CN-105 is a novel apoE-mimetic pentapeptide with excellent evidence of functional and histological improvement in preclinical models of intracerebral hemorrhage (ICH). The CN-105 in participants with Acute supraTentorial intraCerebral Hemorrhage (CATCH) trial is a first-in-disease-state multicenter open-label trial evaluating safety and feasability of CN-105 administration in patients with acute primary supratentorial ICH.Methods
Eligible patients were aged 30-80 years, had confirmed primary supratentorial ICH, and were able to intiate CN-105 administration (1.0 mg/kg every 6 h for 72 h) within 12 h of symptom onset. A priori defined safety end points, including hematoma volume, pharmacokinetics, and 30-day neurological outcomes, were analyzed. For clinical outcomes, CATCH participants were compared 1:1 with a closely matched contemporary ICH cohort through random selection. Hematoma volumes determined from computed tomography images on days 0, 1, 2, and 5 and ordinal modified Rankin Scale score at 30 days after ICH were compared.Results
In 38 participants enrolled across six study sites in the United States, adverse events occurred at an expected rate without increase in hematoma expansion or neurological deterioration. CN-105 treatment had an odds ratio (95% confidence interval) of 2.69 (1.31-5.51) for lower 30-day modified Rankin Scale score, after adjustment for ICH score, sex, and race/ethnicity, as compared with a matched contemporary cohort.Conclusions
CN-105 administration represents an excellent translational candidate for treatment of acute ICH because of its safety, dosing feasibility, favorable pharmacokinetics, and possible improvement in neurological recovery.Item Open Access COVID-19-Associated Guillain-Barre Syndrome: Atypical Para-infectious Profile, Symptom Overlap, and Increased Risk of Severe Neurological Complications.(SN comprehensive clinical medicine, 2020-11-21) Kajumba, Mayanja M; Kolls, Brad J; Koltai, Deborah C; Kaddumukasa, Mark; Kaddumukasa, Martin; Laskowitz, Daniel TThe concurrence of COVID-19 with Guillain-Barre syndrome (GBS) can increase the likelihood of neuromuscular respiratory failure, autonomic dysfunction, and other life-threatening symptoms. Currently, very little is known about the underlying mechanisms, clinical course, and prognostic implications of comorbid COVID-19 in patients with GBS. We reviewed COVID-19-associated GBS case reports published since the outbreak of the pandemic, with a database search up to August 2020, including a manual search of the reference lists for additional relevant cases. Fifty-one (51) case reports of COVID-19 patients (aged 23-84 years) diagnosed with GBS in 11 different countries were included in this review. The results revealed atypical manifestations of GBS, including para-infectious profiles and onset of GBS without antecedent COVID-19 symptoms. Although all tested patients had signs of neuroinflammation, none had SARS-CoV-2 in the cerebrospinal fluid (CSF), and only four (4) patients had antiganglioside antibodies. The majority had a 1- to 10-day time interval between the onset of COVID-19 and GBS symptoms, and many had a poor outcome, with 20 out of the 51 (39.2%) requiring mechanical ventilation, and two deaths within 12 to 24 h. The atypical manifestations of COVID-19-associated GBS, especially the para-infectious profile and short time interval between the onset of the COVID-19 and GBS symptoms, increase the likelihood of symptom overlap, which can complicate the treatment and result in worsened disease progression and/or higher mortality rates. Inclusion of a neurological assessment during diagnosis of COVID-19 might facilitate timely identification and effective management of the GBS symptoms and improve treatment outcome.Item Open Access Echocardiogram Utilization Patterns and Association With Mortality Following Severe Traumatic Brain Injury(Anesthesia & Analgesia, 2020-08-12) Chen, Fangyu; Komisarow, Jordan M; Mills, Brianna; Vavilala, Monica; Hernandez, Adrian; Laskowitz, Daniel T; Mathew, Joseph P; James, Michael L; Haines, Krista L; Raghunathan, Karthik; Fuller, Matt; Bartz, Raquel R; Krishnamoorthy, VijayItem Open Access Emergency medical services use and its association with acute ischaemic stroke evaluation and treatment in Singapore.(Stroke and vascular neurology, 2020-06) Xu, Hanzhang; Xian, Ying; Woon, Fung Peng; Bettger, Janet Prvu; Laskowitz, Daniel T; Ng, Yih Yng; Ong, Marcus Eng Hock; Matchar, David Bruce; De Silva, Deidre AnneBackground
Emergency medical services (EMS) is a critical link in the chain of stroke survival. We aimed to assess EMS use for stroke in Singapore, identify characteristics associated with EMS use and the association of EMS use with stroke evaluation and treatment.Methods
The Singapore Stroke Registry combines nationwide EMS and public hospital data for stroke cases in Singapore. Multivariate regressions with the generalised estimating equations were performed to examine the association between EMS use and timely stroke evaluation and treatment.Results
Of 3555 acute ischaemic patients with symptom onset within 24 hours admitted to all five public hospitals between 2015 and 2016, 68% arrived via EMS. Patients who used EMS were older, were less likely to be female, had higher stroke severity by National Institute of Health Stroke Scale and had a higher prevalence of atrial fibrillation or peripheral arterial disease. Patients transported by EMS were more likely to receive rapid evaluation (door-to-imaging time ≤25 min 34.3% vs 11.1%, OR=2.74 (95% CI 1.40 to 5.38)) and were more likely to receive intravenous tissue plasminogen activator (tPA, 22.8% vs 4.6%, OR=4.61 (95% CI 3.52 to 6.03)). Among patients treated with tPA, patients who arrived via EMS were more likely to receive timely treatment than self-transported patients (door-to-needle time ≤60 min 52.6% vs 29.4%, OR=2.58 (95% CI 1.35 to 4.92)).Conclusions
EMS use is associated with timely stroke evaluation and treatment in Singapore. Seamless EMS-Hospital stroke pathways and targeted public campaigns to advocate for appropriate EMS use have the potential to improve acute stroke care.Item Open Access Erratum: Neuroprotective pentapeptide CN-105 improves functional and histological outcomes in a murine model of intracerebral hemorrhage.(Sci Rep, 2017-01-05) Lei, Beilei; James, Michael L; Liu, Ji; Zhou, Guanen; Venkatraman, Talaignair N; Lascola, Christopher D; Acheson, Shawn K; Dubois, Laura G; Laskowitz, Daniel T; Wang, HaichenItem Open Access Gender and age interact to affect early outcome after intracerebral hemorrhage.(PLoS One, 2013) Umeano, Odera; Phillips-Bute, Barbara; Hailey, Claire E; Sun, Wei; Gray, Marisa C; Roulhac-Wilson, Briana; McDonagh, David L; Kranz, Peter G; Laskowitz, Daniel T; James, Michael LBACKGROUND: Intracerebral hemorrhage (ICH) is a common and devastating form of cerebrovascular disease. In ICH, gender differences in outcomes remain relatively understudied but have been examined in other neurological emergencies. Further, a potential effect of age and gender on outcomes after ICH has not been explored. This study was designed to test the hypothesis that age and gender interact to modify neurological outcomes after ICH. METHODS: Adult patients admitted with spontaneous primary supratentorial ICH from July 2007 through April 2010 were assessed via retrospective analysis of an existing stroke database at Duke University. Univariate analysis of collected variables was used to compare gender and outcome. Unfavorable outcome was defined as discharge to hospice or death. Using multivariate regression, the combined effect of age and gender on outcome after ICH was analyzed. RESULTS: In this study population, women were younger (61.1+14.5 versus 65.8+17.3 years, p=0.03) and more likely to have a history of substance abuse (35% versus 8.9%, p<0.0001) compared to men. Multivariable models demonstrated that advancing age had a greater effect on predicting discharge outcome in women compared to men (p=0.02). For younger patients, female sex was protective; however, at ages greater than 60 years, female sex was a risk factor for discharge to hospice or death. CONCLUSION: While independently associated with discharge to hospice or death after ICH, the interaction effect between gender and age demonstrated significantly stronger correlation with early outcome after ICH in a single center cohort. Prospective study is required to verify these findings.Item Open Access International Comparison of Patient Characteristics and Quality of Care for Ischemic Stroke: Analysis of the China National Stroke Registry and the American Heart Association Get With The Guidelines--Stroke Program.(Journal of the American Heart Association, 2018-10) Wangqin, Runqi; Laskowitz, Daniel T; Wang, Yongjun; Li, Zixiao; Wang, Yilong; Liu, Liping; Liang, Li; Matsouaka, Roland A; Saver, Jeffrey L; Fonarow, Gregg C; Bhatt, Deepak L; Smith, Eric E; Schwamm, Lee H; Prvu Bettger, Janet; Hernandez, Adrian F; Peterson, Eric D; Xian, YingBackground Adherence to evidence-based guidelines is an important quality indicator; yet, there is lack of assessment of adherence to performance measures in acute ischemic stroke for most world regions. Methods and Results We analyzed 19 604 patients with acute ischemic stroke in the China National Stroke Registry and 194 876 patients in the Get With The Guidelines--Stroke registry in the United States from June 2012 to January 2013. Compared with their US counterparts, Chinese patients were younger, had a lower prevalence of comorbidities, and had similar median, lower mean, and less variability in National Institutes of Health Stroke Scale (median 4 [25th percentile-75th percentile, 2-7], mean 5.4±5.6 versus median 4 [1-10], mean 6.8±7.7). Chinese patients were more likely to experience delays from last known well to hospital arrival (median 1318 [330-3209] versus 644 [142-2055] minutes), less likely to receive thrombolytic therapy (2.5% versus 8.1%), and more likely to experience treatment delays (door-to-needle time median 95 [72-112] versus 62 [49-85] minutes). Adherence to early and discharge antithrombotics, smoking cessation counseling, and dysphagia screening were relatively high (eg >80%) in both countries. Large gaps existed between China and the United States with regard to the administration of thrombolytics within 3 hours (18.3% versus 83.6%), door-to-needle time ≤60 minutes (14.6% versus 48.0%), deep venous thrombosis prophylaxis (65.0% versus 97.8%), anticoagulation for atrial fibrillation (21.0% versus 94.4%), lipid treatment (66.3% versus 95.8%), and rehabilitation assessment (58.8% versus 97.4%). Conclusions We found significant differences in clinical characteristics and gaps in adherence for certain performance measures between China and the United States. Additional efforts are needed for continued improvements in acute stroke care and secondary prevention in both nations, especially China.Item Open Access Intrastriatal injection of autologous blood or clostridial collagenase as murine models of intracerebral hemorrhage.(Journal of visualized experiments : JoVE, 2014-07-03) Lei, Beilei; Sheng, Huaxin; Wang, Haichen; Lascola, Christopher D; Warner, David S; Laskowitz, Daniel T; James, Michael LIntracerebral hemorrhage (ICH) is a common form of cerebrovascular disease and is associated with significant morbidity and mortality. Lack of effective treatment and failure of large clinical trials aimed at hemostasis and clot removal demonstrate the need for further mechanism-driven investigation of ICH. This research may be performed through the framework provided by preclinical models. Two murine models in popular use include intrastriatal (basal ganglia) injection of either autologous whole blood or clostridial collagenase. Since, each model represents distinctly different pathophysiological features related to ICH, use of a particular model may be selected based on what aspect of the disease is to be studied. For example, autologous blood injection most accurately represents the brain's response to the presence of intraparenchymal blood, and may most closely replicate lobar hemorrhage. Clostridial collagenase injection most accurately represents the small vessel rupture and hematoma evolution characteristic of deep hemorrhages. Thus, each model results in different hematoma formation, neuroinflammatory response, cerebral edema development, and neurobehavioral outcomes. Robustness of a purported therapeutic intervention can be best assessed using both models. In this protocol, induction of ICH using both models, immediate post-operative demonstration of injury, and early post-operative care techniques are demonstrated. Both models result in reproducible injuries, hematoma volumes, and neurobehavioral deficits. Because of the heterogeneity of human ICH, multiple preclinical models are needed to thoroughly explore pathophysiologic mechanisms and test potential therapeutic strategies.Item Open Access Neuroprotective pentapeptide CN-105 improves functional and histological outcomes in a murine model of intracerebral hemorrhage.(Sci Rep, 2016-10-07) Lei, Beilei; James, Michael L; Liu, Ji; Zhou, Guanen; Venkatraman, Talaignair N; Lascola, Christopher D; Acheson, Shawn K; Dubois, Laura G; Laskowitz, Daniel T; Wang, HaichenPresently, no pharmacological treatments have been demonstrated to improve long-term functional outcomes following intracerebral hemorrhage (ICH). Clinical evidence associates apolipoprotein E (apoE) genotype with ICH incidence and outcome. While apoE modifies neuroinflammatory responses through its adaptive role in glial downregulation, intact apoE holoprotein is too large to cross the blood-brain barrier (BBB). Therefore, we developed a 5-amino acid peptide - CN-105 - that mimics the polar face of the apoE helical domain involved in receptor interactions. In the current study, we investigated the therapeutic potential of CN-105 in a mouse model of ICH. Three doses of CN-105 (0.05 mg/kg) was administered by tail vein injection within 24 hours after ICH induction. Functional assessment showed durable improvement in vestibulomotor performance after CN-105 treatment, as quantified by increased Rotarod latencies on Days 1-5 post-ICH, and long-term improvement in neurocognitive performance, as quantified by reduced Morris water maze latencies on Days 29-32 post-ICH. Further, brain water content was significantly reduced, neuroinflammation was decreased and hippocampal CA3 neuronal survival was increased, although hemorrhage volume was not affected by CN-105. We concluded, therefore, that pentapeptide CN-105 improved short- and long-term neurobehavioral outcomes in a murine model of ICH, suggesting therapeutic potential for patients with acute ICH.Item Open Access Peak Systolic Velocity Measurements with Transcranial Doppler Ultrasound Is a Predictor of Incident Stroke among the General Population in China.(PLoS One, 2016) Wang, Hai-Bo; Laskowitz, Daniel T; Dodds, Jodi A; Xie, Gao-Qiang; Zhang, Pu-Hong; Huang, Yi-Ning; Wang, Bo; Wu, Yang-FengBACKGROUND AND OBJECTIVE: It is necessary to develop an effective and low-cost screening tool for identifying Chinese people at high risk of stroke. Transcranial Doppler ultrasound (TCD) is a powerful predictor of stroke in the pediatric sickle cell disease population, as demonstrated in the STOP trial. Our study was conducted to determine the prediction value of peak systolic velocities as measured by TCD on subsequent stroke risk in a prospective cohort of the general population from Beijing, China. METHODS: In 2002, a prospective cohort study was conducted among 1392 residents from 11 villages of the Shijingshan district of Beijing, China. The cohort was scheduled for follow up with regard to incident stroke in 2005, 2007, and 2012 by a study team comprised of epidemiologists, nurses, and physicians. Univariate and multivariate Cox proportional hazard regression models were used to determine the factors associated with incident stroke. RESULTS: Participants identified by TCD criteria as having intracranial stenosis had a 3.6-fold greater risk of incident stroke (hazard ratio (HR) 3.57, 95% confidence interval (CI) 1.86-6.83, P<0.01) than those without TCD evidence of intracranial stenosis. The association remained significant in multivariate analysis (HR 2.53, 95% CI 1.31-4.87) after adjusting for other risk factors or confounders. Older age, cigarette smoking, hypertension, and diabetes mellitus remained statistically significant as risk factors after controlling for other factors. CONCLUSIONS: The study confirmed the screening value of TCD among the general population in urban China. Increasing the availability of TCD screening may help identify subjects as higher risk for stroke.Item Open Access Postoperative changes in cognition and cerebrospinal fluid neurodegenerative disease biomarkers.(Annals of clinical and translational neurology, 2022-02) Berger, Miles; Browndyke, Jeffrey N; Cooter Wright, Mary; Nobuhara, Chloe; Reese, Melody; Acker, Leah; Bullock, W Michael; Colin, Brian J; Devinney, Michael J; Moretti, Eugene W; Moul, Judd W; Ohlendorf, Brian; Laskowitz, Daniel T; Waligorska, Teresa; Shaw, Leslie M; Whitson, Heather E; Cohen, Harvey J; Mathew, Joseph P; MADCO-PC InvestigatorsObjective
Numerous investigators have theorized that postoperative changes in Alzheimer's disease neuropathology may underlie postoperative neurocognitive disorders. Thus, we determined the relationship between postoperative changes in cognition and cerebrospinal (CSF) tau, p-tau-181p, or Aβ levels after non-cardiac, non-neurologic surgery in older adults.Methods
Participants underwent cognitive testing before and 6 weeks after surgery, and lumbar punctures before, 24 h after, and 6 weeks after surgery. Cognitive scores were combined via factor analysis into an overall cognitive index. In total, 110 patients returned for 6-week postoperative testing and were included in the analysis.Results
There was no significant change from before to 24 h or 6 weeks following surgery in CSF tau (median [median absolute deviation] change before to 24 h: 0.00 [4.36] pg/mL, p = 0.853; change before to 6 weeks: -1.21 [3.98] pg/mL, p = 0.827). There were also no significant changes in CSF p-tau-181p or Aβ over this period. There was no change in cognitive index (mean [95% CI] 0.040 [-0.018, 0.098], p = 0.175) from before to 6 weeks after surgery, although there were postoperative declines in verbal memory (-0.346 [-0.523, -0.170], p = 0.003) and improvements in executive function (0.394, [0.310, 0.479], p < 0.001). There were no significant correlations between preoperative to 6-week postoperative changes in cognition and CSF tau, p-tau-181p, or Aβ42 changes over this interval (p > 0.05 for each).Interpretation
Neurocognitive changes after non-cardiac, non-neurologic surgery in the majority of cognitively healthy, community-dwelling older adults are unlikely to be related to postoperative changes in AD neuropathology (as assessed by CSF Aβ, tau or p-tau-181p levels or the p-tau-181p/Aβ or tau/Aβ ratios).Trial registration
clinicaltrials.gov (NCT01993836).Item Open Access RECOVER-NEURO: study protocol for a multi-center, multi-arm, phase 2, randomized, active comparator trial evaluating three interventions for cognitive dysfunction in post-acute sequelae of SARS-CoV-2 infection (PASC).(Trials, 2024-05) Knopman, David S; Laskowitz, Daniel T; Koltai, Deborah C; Charvet, Leigh E; Becker, Jacqueline H; Federman, Alex D; Wisnivesky, Juan; Mahncke, Henry; Van Vleet, Thomas M; Bateman, Lucinda; Kim, Dong-Yun; O'Steen, Ashley; James, Melissa; Silverstein, Adam; Lokhnygina, Yuliya; Rich, Jennifer; Feger, Bryan J; Zimmerman, Kanecia OBackground
Post-acute sequelae of SARS-CoV-2 infection (PASC) symptoms have broad impact, and may affect individuals regardless of COVID-19 severity, socioeconomic status, race, ethnicity, or age. A prominent PASC symptom is cognitive dysfunction, colloquially referred to as "brain fog" and characterized by declines in short-term memory, attention, and concentration. Cognitive dysfunction can severely impair quality of life by impairing daily functional skills and preventing timely return to work.Methods
RECOVER-NEURO is a prospective, multi-center, multi-arm, phase 2, randomized, active-comparator design investigating 3 interventions: (1) BrainHQ is an interactive, online cognitive training program; (2) PASC-Cognitive Recovery is a cognitive rehabilitation program specifically designed to target frequently reported challenges among individuals with brain fog; (3) transcranial direct current stimulation (tDCS) is a noninvasive form of mild electrical brain stimulation. The interventions will be combined to establish 5 arms: (1) BrainHQ; (2) BrainHQ + PASC-Cognitive Recovery; (3) BrainHQ + tDCS-active; (4) BrainHQ + tDCS-sham; and (5) Active Comparator. The interventions will occur for 10 weeks. Assessments will be completed at baseline and at the end of intervention and will include cognitive testing and patient-reported surveys. All study activities can be delivered in Spanish and English.Discussion
This study is designed to test whether cognitive dysfunction symptoms can be alleviated by the use of pragmatic and established interventions with different mechanisms of action and with prior evidence of improving cognitive function in patients with neurocognitive disorder. If successful, results will provide beneficial treatments for PASC-related cognitive dysfunction.Trial registration
ClinicalTrials.gov NCT05965739. Registered on July 25, 2023.