bluuebunny/crossref_metadata_2025 huggingface dataset:
FIGURE 1 from Genome-wide p63-Target Gene Analyses Reveal TAp63/NRF2-Dependent Oxidative Stress Responses
Authors: Napoli Marco , Deshpande Avani A. , Chakravarti Deepavali , Rajapakshe Kimal , Gunaratne Preethi H. , Coarfa Cristian , Flores Elsa R.
Published: February 2024

Endogenous ∆Np63 and TAp63 bind to distinct regions throughout the genome. A, Experimental outline. WT, ΔNp63−/−, and TAp63−/− epidermal cells were isolated from embryonic day 18.5 (E18.5) embryos. RNA extracted from these cells was used for expression profiling by RNA-seq, and chromatin was used for genome-wide analysis of p63 binding to DNA by ChIP-seq. The overlap in genes identified from these analyses revealed: (i) direct p63 target genes; (ii) direct ΔNp63-specific target genes; and (iii) direct TAp63-specific target genes. B, Table summarizing the total number of peaks found through the ChIP-sequencing analysis and the relative p63 isoform responsible for the binding. C, Distribution of the ΔNp63-specific (left), common (center), and TAp63-specific (right) ChIP-seq peaks with respect to genomic landmarks. D, Nucleotide distribution in the ∆Np63-specific (top) and TAp63-specific (bottom) DNA response elements identified in the ChIP-seq peaks.
Microbiota-Based Therapeutics as New Standard-of-Care Treatment for Recurrent Clostridioides difficile Infection
Authors: Stallhofer Johannes , Steube Arndt , Katzer Katrin , Stallmach Andreas
Published: February 2024

Background: Clostridioides difficile (C. difficile) is a spore-forming bacterial species that ubiquitously exists in the environment. Colonization by C. difficile is highly prevalent in infants, while fewer than 5% of adults are asymptomatic carriers. Disruption of the microbiome, such as through antibiotic treatment, triggers the germination of bacterial spores into numerous vegetative cells. These cells then produce enterotoxins that result in watery diarrhea and colonic inflammation. If left untreated, C. difficile infection (CDI) can lead to pseudomembranous colitis with the potentially life-threatening complication of toxic megacolon. Summary: Over the past few decades, the incidence, morbidity, and mortality associated with CDIs have increased. They have emerged as the primary cause of nosocomial gastrointestinal infections in industrialized countries, posing a significant burden on healthcare systems. Despite antibiotics often being the cause of CDIs, they remain the standard treatment. However, a considerable number of patients treated with antibiotics will experience recurrent CDI (rCDI). Microbiota-based therapies targeting the core issue of CDI – antibiotic-induced dysbiosis – hold promise for rCDI treatment. While data for probiotics are insufficient, numerous studies have highlighted the effectiveness of fecal microbiota transplantation (FMT) as a safe and viable therapeutic option for rCDI. This approach is now endorsed by multiple guidelines. Nonetheless, regulatory prerequisites, such as comprehensive stool donor screening, restrict the widespread adoption of FMT beyond specialized centers. Recently, the US Food and Drug Administration has approved two commercial microbiota-based therapeutics to prevent CDI recurrence. These therapeutics are available by prescription in the USA. RBX2660 (REBYOTA™) comprises a diverse consortium of live microbes derived from human stool and is administered via enema. On the other hand, SER-109 (VOWST™) is an orally administered spore-based medication. In this review, we discuss the potential of microbiota-based treatments for rCDI against the background of medico-legal challenges associated with classical FMT. Key Messages: FMT has emerged as a highly effective cure for rCDI. Nonetheless, regulatory prerequisites and laborious preparation procedures impede its widespread use. The establishment of ready-to-use microbiota-based therapeutics in clinical practice is necessary. In the USA, the recent approval of the first two commercial medications, including a spore-based oral preparation, marks a significant step forward.
The Influence Of Public Information Systems On Auditors' Performance At KAP M. Lian Dalimunthe Dan Rekan
Authors: Abel Desiyanti Manik  , Galih Supraja
Published: February 2024

The rapid development of public information, the complexity of the nature of audit assignments, and the demands on the quality of financial statement audits require auditors to work in an audit team that is capable of working collaboratively efficiently, and effectively. One way to achieve this is through the empowerment of all public information system-based devices and electronic technology. This research presents test results of the influence of public information systems on auditor performance. The research was conducted by distributing questionnaires to auditors at KAP M. Lian Dalimunthe dan Rekan. The research results show that the information system of the public has a significant positive influence on auditor performance. Results research also found that perceived ease of use and perception of usefulness have a significant positive impact on the use of information systems public among auditors, where the perception of ease of use also influences the perception of usefulness held by auditors in system use. The complexity of the auditor's work also influences it positive implementation public information system technology by auditors.
Estimation of Right Atrial Pressure by Ultrasound-Assessed Jugular Vein Distensibility in Patients With Heart Failure
Authors: Ammirati Enrico , Marchetti Davide , Colombo Giada , Pellicori Pierpaolo , Gentile Piero , D’Angelo Luciana , Masciocco Gabriella , Verde Alessandro , Macera Francesca , Brunelli Dario , Occhi Lucia , Musca Francesco , Perna Enrico , Bernasconi Davide P. , Moreo Antonella , Camici Paolo G. , Metra Marco , Oliva Fabrizio , Garascia Andrea
Published: February 2024

BACKGROUND:

Clinical evaluation of central venous pressure is difficult, depends on experience, and is often inaccurate in patients with chronic advanced heart failure. We assessed the ultrasound-assessed internal jugular vein (JV) distensibility by ultrasound as a noninvasive tool to identify patients with normal right atrial pressure (RAP ≤7 mm Hg) in this population.

METHODS:

We measured JV distensibility as the Valsalva-to-rest ratio of the vein diameter in a calibration cohort (N=100) and a validation cohort (N=101) of consecutive patients with chronic heart failure with reduced ejection fraction who underwent pulmonary artery catheterization for advanced heart failure therapies workup.

RESULTS:

A JV distensibility threshold of 1.6 was identified as the most accurate to discriminate between patients with RAP ≤7 versus >7 mm Hg (area under the receiver operating characteristic curve, 0.74 [95% CI, 0.64–0.84]) and confirmed in the validation cohort (receiver operating characteristic, 0.82 [95% CI, 0.73–0.92]). A JV distensibility ratio >1.6 had predictive positive values of 0.86 and 0.94, respectively, to identify patients with RAP ≤7 mm Hg in the calibration and validation cohorts. Compared with patients from the calibration cohort with a high JV distensibility ratio (>1.6; n=42; median RAP, 4 mm Hg; pulmonary capillary wedge pressure, 11 mm Hg), those with a low JV distensibility ratio (≤1.6; n=58; median RAP, 8 mm Hg; pulmonary capillary wedge pressure, 22 mm Hg;
P
<0.0001 for both) were more likely to die or undergo a left ventricular assist device implant or heart transplantation (event rate at 2 years: 42.7% versus 18.2%; log-rank
P
=0.034).

CONCLUSIONS:

Ultrasound-assessed JV distensibility identifies patients with chronic advanced heart failure with normal RAP and better outcomes.

REGISTRATION:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT03874312.
Proteomic Associations of NT-proBNP (N-Terminal Pro-B-Type Natriuretic Peptide) in Heart Failure With Preserved Ejection Fraction
Authors: Azzo Joe David , Dib Marie-Joe , Zagkos Loukas , Zhao Lei , Wang Zhaoqing , Chang Ching-Pin , Ebert Christina , Salman Oday , Gan Sushrima , Zamani Payman , Cohen Jordana B. , van Empel Vanessa , Richards A. Mark , Javaheri Ali , Mann Douglas L. , Rietzschel Ernst R. , Schafer Peter H. , Seiffert Dietmar A. , Gill Dipender , Burgess Stephen , Ramirez-Valle Francisco , Gordon David A. , Cappola Thomas P. , Chirinos Julio A.
Published: February 2024

Background:

NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels are variably elevated in heart failure with preserved ejection fraction (HFpEF), even in the presence of increased left ventricular filling pressures. NT-proBNP levels are prognostic in HFpEF and have been used as an inclusion criterion for several recent randomized clinical trials. However, the underlying biologic differences between HFpEF participants with high and low NT-proBNP levels remain to be fully understood.

Methods:

We measured 4928 proteins using an aptamer-based proteomic assay (SOMAScan) in available plasma samples from 2 cohorts: (1) Participants with HFpEF enrolled in the PHFS (Penn Heart Failure Study; n=253); (2) TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial) participants in the Americas (n=218). We assessed the relationship between SOMAScan-derived plasma NT-proBNP and levels of other proteins available in the SOMAScan assay version 4 using robust linear regression, with correction for multiple comparisons, followed by pathway analysis.

Results:

NT-proBNP levels exhibited prominent proteome-wide associations in PHFS and TOPCAT cohorts. Proteins most strongly associated with NT-proBNP in both cohorts included SVEP1 (sushi, von Willebrand factor type-A, epidermal growth factor, and pentraxin domain containing 1; β
TOPCAT
=0.539;
P
<0.0001; β
PHFS
=0.516;
P
<0.0001) and ANGPT2 (angiopoietin 2; β
TOPCAT
=0.571;
P
<0.0001; β
PHFS
=0.459;
P
<0.0001). Canonical pathway analysis demonstrated consistent associations with multiple pathways related to fibrosis and inflammation. These included hepatic fibrosis and inhibition of matrix metalloproteases. Analyses using cut points corresponding to estimated quantitative concentrations of 360 pg/mL (and 480 pg/mL in atrial fibrillation) revealed similar proteomic associations.

Conclusions:

Circulating NT-proBNP levels exhibit prominent proteomic associations in HFpEF. Our findings suggest that higher NT-proBNP levels in HFpEF are a marker of fibrosis and inflammation. These findings will aid the interpretation of NT-proBNP levels in HFpEF and may guide the selection of participants in future HFpEF clinical trials.
Treatment and Outcomes of Cervical Artery Dissection in Adults: A Scientific Statement From the American Heart Association
Authors: Yaghi Shadi , Engelter Stefan , Del Brutto Victor J. , Field Thalia S. , Jadhav Ashutosh P. , Kicielinski Kimberly , Madsen Tracy E. , Mistry Eva A. , Salehi Omran Setareh , Pandey Aditya , Raz Eytan ,   on behalf of the American Heart Association Stroke Council; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; and Council on Peripheral Vascular Disease
Published: February 2024

Cervical artery dissection is an important cause of stroke, particularly in young adults. Data conflict on the diagnostic evaluation and treatment of patients with suspected cervical artery dissection, leading to variability in practice. We aim to provide an overview of cervical artery dissection in the setting of minor or no reported mechanical trigger with a focus on summarizing the available evidence and providing suggestions on the diagnostic evaluation, treatment approaches, and outcomes. Writing group members drafted their sections using a literature search focused on publications between January 1, 1990, and December 31, 2022, and included randomized controlled trials, prospective and retrospective observational studies, meta-analyses, opinion papers, case series, and case reports. The writing group chair and vice chair compiled the manuscript and obtained writing group members’ approval. Cervical artery dissection occurs as a result of the interplay among risk factors, minor trauma, anatomic and congenital abnormalities, and genetic predisposition. The diagnosis can be challenging both clinically and radiologically. In patients with acute ischemic stroke attributable to cervical artery dissection, acute treatment strategies such as thrombolysis and mechanical thrombectomy are reasonable in otherwise eligible patients. We suggest that the antithrombotic therapy choice be individualized and continued for at least 3 to 6 months. The risk of recurrent dissection is low, and preventive measures may be considered early after the diagnosis and continued in high-risk patients. Ongoing longitudinal and population-based observational studies are needed to close the present gaps on preferred antithrombotic regimens considering clinical and radiographic prognosticators of cervical artery dissection.
Abstract 105: Sex Difference in Brain Energy Metabolism After Electronic Cigarette Vape Exposure May Contribute to Worsened Stroke Injury in Rats
Authors: Pradhyumnan Hari , Patel Shahil H , Raval Ami P
Published: February 2024

Introduction:
Electronic cigarettes (EC) are battery-powered nicotine delivery devices that have gained popularity as alternatives to tobacco cigarettes for young smokers and smokers trying to cease. Because of its relative novelty, our understanding about the effects of EC vaping on stroke outcome is limited. Here we aim to investigate the effects of EC on energy metabolism in the brain and on stroke outcome in animals of both sexes.

Methods:
Female and male Sprague-Dawley rats (2-3 months old; n=8) were randomly assigned to either air or EC vapor (5% nicotine Juul pods) exposure for 16 nights using the EcigAero-TM Aerosol Exposure Apparatus. After the exposure period, the rats were divided into two cohorts. The brains were collected from the first cohort of rats for unbiased metabolomic (Metabolon Inc.) or Western blot analysis. The second cohort underwent transient middle cerebral artery occlusion (tMCAO; 90 min) or sham surgery and was survived for 21 days. During the post-tMCAO/sham survival, cognition was assessed using the Morris water maze followed by brain collection for histopathological analysis.

Results:
Metabolomic analysis showed substantial changes in glycolytic metabolites in EC-exposed female rats in relation to air controls, implying altered brain energetics. In EC-exposed female animals, a significant increase (p<0.05) in glucose, glucose 6-phosphate, fructose-6-phosphate, and fructose 1-6 diphosphate was noted compared to air controls. However, such changes were not seen in EC-exposed male rats. Quantification of infarct volume demonstrated that, compared to air rats, EC-exposed rats displayed a significantly increased infarct volume in female rats while showing a trend of increase in male rats. In female rats, infarct volumes were 86 ± 19 mm
3
and 151 ± 25 mm
3
for air and EC groups, respectively, a significant difference (p<0.05). In the male rat air group, tMCAO resulted in an infarct volume of 80 ± 37 mm
3
, while EC yielded 130 ± 38 mm
3
. Behavioral testing showed worsened post-stroke cognitive outcome in EC groups compared to air groups in rats of both sexes.

Conclusion:
EC vape exposure, even for as short as two weeks, impacts glucose metabolism and worsens post-stroke cognitive deficits in female more than male rats.
Abstract 112: Assessing the Impact of the COVID-19 Pandemic on Childhood Arterial Ischemic Stroke: An Unanticipated Natural Experiment
Authors: Fullerton Heather J , Di Germanio Clara , Hills Nancy K , Beslow Lauren A , Cummings Dana D , Dlamini Nomazulu , Fox Christine K , Sun Lisa R , Norris Philip ,   and the VIPS II Investigators
Published: February 2024

Introduction:
The Vascular effects of Infection in Pediatric Stroke (VIPS II) study aimed to confirm prior findings that viral infection can trigger childhood arterial ischemic stroke (AIS). The COVID-19 pandemic developed midway through VIPS II enrollment, creating an opportunity to assess its impact.

Methods:
At 22 North American sites, we enrolled 205 children (28 days-18 years) with AIS (12/2016 - 1/2022), collected serum samples up to 7 days post-stroke, and measured clinical infection via parental interview. We defined the COVID-19 pandemic epoch as 1/2020-1/2022. We collected serum samples on 40 stroke-free controls (median [IQR] age 13.2 years [6.4, 16.5]) during the pandemic. We measured SARS-CoV2 spike IgG antibodies (present after vaccination or infection) and nucleocapsid IgG total antibodies (present after infection only; elevated for months).

Results:
The sites saw 117 AIS cases in 2019 (51 enrolled), 122 (44) in 2020, and 109 (52) in 2021. Comparing the pre-pandemic (N=105) and pandemic (N=100) cohorts, pandemic cases were less likely to report a recent infection (Table). Evidence of SARS-CoV2 infection was seen in 4 (10%) of controls and 26 (25%) of 100 pandemic cases (p=0.065); 10 of the 26 COVID positive cases reported a recent infection, and 7 of the 10 had a clinical diagnosis of COVID. Median (IQR) nucleocapsid IgG titers were 18.8 (12.0, 101) in the positive controls and 50.1 (26.9, 95.3) in the positive cases (p=0.33).

Conclusions:
The COVID19 pandemic
reduced
the proportion of childhood AIS cases with preceding infection, likely reflecting decreased infectious exposures while “stay at home” and masking policies were in effect. A quarter of cases in the pandemic era had positive antibodies consistent with prior SARS-CoV2 infection. Like other childhood respiratory viruses, SARS-CoV2 may act as a trigger for childhood AIS, but further investigation is needed to establish a causal role.
Abstract 113: Treatment of Tiny (≤ 3mm) Unruptured Middle Cerebral Artery Aneurysms Are Associated With High Risk of Procedural Complications: An Analysis of the Neurovascular Quality Initiative-Quality Outcomes Database
Authors: Padmanaban Varun , Harbaugh Thaddeus , Zhu Junjia , Zhou Shouhao , Ansari Sameer A , Howington Jay U , Sahlein Daniel , Tejada Juan , Wilkinson D. Andrew , Simon Scott , Cockroft Kevin M , Church Ephraim W
Published: February 2024

Introduction:
Improved imaging modalities have led to an increased detection of intracranial aneurysms, many of which are small. While studies have shown that many ruptured intracranial aneurysms are small (≤7 mm), the natural history of tiny (≤3 mm) aneurysms, particularly in certain locations such as the middle cerebral artery (MCA) is thought to be relatively benign with a reported rupture rate of less than 0.5% per year. The objective of this study is to evaluate the safety and efficacy of treatment of tiny unruptured MCA aneurysms.

Methods:
The NVQI-QOD registry was queried for patients with tiny unruptured MCA aneurysms who underwent either microsurgical or endovascular repair. Tiny size was defined as an aneurysm with a maximum dimension of ≤3 mm. Demographics, aneurysm characteristics and treatment safety were queried. Safety data included intra-operative and post-operative complications. Outcomes included modified Rankin Score (mRS) at discharge and last follow up as well as aneurysm occlusion status at discharge.

Results:
Of 670 treated, unruptured MCA aneurysms, 43 were tiny (6.4%). The mean aneurysm width was 1.9 mm with a mean patient age of 56.3 years. The median pre-operative mRS was 0 (range 0-4). The majority of patients underwent microsurgery (27/43).

The overall intra-operative complication rate was 7% (3/43) with an intra-operative rupture rate of 4.7% (2/43). The post-operative complication rate was 9.3% (4/43). New intracerebral hemorrhage occurred in 7% of patients (3/43) and unplanned return to OR occurred in 14.8% of patients who underwent microsurgery (4/27). There were no mortalities. 16.3% (7/43) of patients were discharged to inpatient rehabilitation or a skilled nursing facility. At discharge, 37 (88.1%) patients had complete aneurysm occlusion. In the subgroup of patients with recorded follow up data, only 40% (10/25) had a mRS of 0 at discharge and 40% (6/15) had an mRS of 0 at last follow up (median follow up: 165 days).

Conclusions:
Our analysis showed that treatment of tiny unruptured MCA aneurysms is associated with a high rate of complications. We suggest that many tiny, unruptured MCA aneurysms should be observed given that the morbidity associated with treatment is likely significantly higher than the risk of rupture.
Abstract 123: Emotional Prosody and Facial Expressions Differentially Augment Comprehension of Discourse for Left and Right Hemisphere Stroke Survivors
Authors: Tilton-Bolowsky Victoria , Durfee Alexandra Z , Bunker Lisa D , Hillis Argye E
Published: February 2024

Deficits in spoken discourse comprehension are common after left hemisphere (LH) and right hemisphere (RH) stroke. Thus, it is important to identify factors that facilitate comprehension and enhance communication between stroke survivors and their care partners. Emotional prosody and facial expression cues can facilitate comprehension, but this may depend on an intact RH. To determine if such cues are facilitatory to LH
and
RH stroke survivors, we compared discourse comprehension between the groups across 3 conditions. We hypothesized that RH participants would not benefit as much from these cues as LH participants due to concomitant impairments in recognition of prosody and facial expression.

We assessed 72 stroke survivors within 3 months of unilateral ischemic stroke, including 40 LH (15 female; aged 62±13 yrs) and 32 RH (17 female; aged 68±10 yrs), and 29 healthy controls (19 female; aged 72±15 yrs). Participants listened to a series of recorded spoken descriptions of scenarios and selected 1 picture from 4 to match each scenario. Targets and foils were balanced across spatial positions. Each description was presented in 3 conditions: read with neutral prosody (Trial 1), read with emotional prosody (Trial 2), and read with emotional prosody + facial expressions (Trial 3, audio + video). If 100% accuracy was achieved on a trial, the next trial was not presented. We used a Kruskal-Wallace test and paired samples
t
-tests for analyses and corrected for multiple comparisons.

Accuracy differed significantly between groups on Trial 1,
H
(2) = 26.68,
p
< .001. Controls achieved higher accuracy than LH (
p
< .01) and RH participants (
p
< .01). LH and RH participants did not differ,
p
= .51. LH participants achieved significant gains in accuracy from Trial 1 to 2 (
t
(32) = 4.16,
p
= .001) and from Trial 1 to 3 (
t
(32) = 5.49,
p
< .001), but not from Trial 2 to 3 (
t
(32) = 1.79,
p
= .08). RH participants did not achieve significant gains in accuracy from Trial 1 to 2 (
t
(23) = 1.59,
p
= .13), Trial 2 to 3 (
t
(23) = 0,
p
= 1.0), or Trial 1 to 3 (
t
(23) = 1.21,
p
= .24).

To conclude, emotional prosody and facial expressions significantly improved discourse comprehension for LH but not for RH stroke survivors. Different/additional strategies to improve discourse comprehension after RH stroke are needed.
Abstract 126: Connectome Gradient Dysfunction Contributes to White Matter Hyperintensity-Related Cognitive Decline
Authors: Yang Dan , Zhao Hui , Zhu Xiaolei , Huang Lili , Mo Yuting , Ke Zhihong , Mao Chenglu , Xu Yun
Published: February 2024

Introduction:
Although White matter hyperintensity (WMH) is closely associated with cognitive decline, the precise neurobiological mechanisms underlying this relationship are not fully elucidated. Connectome studies have identified a primary-to-transmodal gradient in functional brain networks that support the spectrum from sensation to cognition. However, whether this gradient structure is altered as WMH progresses and how this alteration is associated with WMH-related cognitive decline remain unknown.

Methods:
A total of 758 individuals with WMH were enrolled from two medical centers and one community. All these participants completed cognitive assessment and resting-state functional MRI (rs-fMRI). The functional connectome gradient was reconstructed based on rs-fMRI by using a gradient decomposition framework. Interrelations amongst regional WMH, functional gradient measures, and specific cognitive domains were explored.

Results:
The larger WMH volume, the narrower range (
r
= -0.099,
p
= 0.006) and smaller variance (
r
= -0.121,
p
< 0.001) of the primary-to-transmodal gradient, as well as the poorer executive function (
r
= -0.135,
p
= 0.001) and information processing speed (
r
= -0.224,
p
= 0.001). A narrower range (
r
= 0.131,
p
= 0.001) and smaller variance (
r
= 0.136,
p
= 0.001) of the primary-to-transmodal gradient corresponded to poorer executive function. In particular, the relationship between frontal/occipital WMH and executive function was partly mediated by gradient range/variance of the primary-to-transmodal gradient (the 95% confidence interval did not contain the value 0). WMH-related gradient alterations were associated with gene expression levels involved in the G protein-coupled receptor (GPCR) signaling pathway (FDR
q
-value < 10
-4
) and chemical synaptic transmission (FDR
q
-value < 10
-6
).

Discussion:
We found that the primary-to-transmodal gradient dysfunction contributes to WMH-related cognitive decline. The detrimental effect of frontal/occipital WMH on executive function was mediated by decreased differentiation of the connectivity pattern between the primary and transmodal areas. The neurobiological mechanisms may be related to the GPCR signaling pathway and chemical synaptic transmission.
Abstract 133: Associations of Genetically Predicted Iron Status and Ischemic Stroke Subtypes: A Mendelian Randomization Study
Authors: Barad Alexa , Xu Yaqin , Pressman Eva K , Clark Andrew G , Obrien Kimberly O
Published: February 2024

Mendelian randomization (MR) studies suggest a causal effect of Fe status on ischemic stroke (IS). It is currently unknown if these associations are confounded by pleiotropic effects of the instrumental variables (IV) on cardiovascular disease (CVD) risk factors, such as low-density lipoprotein cholesterol (LDL), diastolic blood pressure (DBP), and body mass index (BMI). We aimed to investigate the effect of iron (Fe) status on risk of IS subtypes (cardioembolic (CES), small vessel (SVS), and large artery atherosclerotic (LAS)) controlling for CVD risk factors. Fe biomarker IVs (total Fe binding capacity (TIBC), transferrin saturation (TSAT), serum Fe (SI), serum ferritin (SF)) were selected from a European GWAS (n=198K-258K) and filtered based on genome-wide significance (
P
<5e
-8
), F-statistic>10, R
2
<0.001, minor allele frequency >1%, and consistent effect direction for all Fe traits. We performed univariate two-sample MR of each Fe trait on IS subtypes from MEGASTROKE (n cases: CES=7,193; SVS =5,386; LAS= 4,373) and implemented multivariate MR conditioning on LDL, DBP, and BMI from the UK Biobank. Estimates are expressed as odds ratio [95%CI] per SD unit increase in Fe. Univariate MR showed a detrimental effect of higher Fe status on CES, no effect on SVS, and a protective effect on LAS across all Fe markers (
Figure 1
). The negative effect of Fe status on CES persisted when conditioning on LDL (TSAT: 1.17 [1.03-1.34]; TIBC: 0.84 [0.71-0.98]), DBP (TSAT: 1.15 [1.01-1.31]; TIBC: 0.82 [0.70-0.96]), or BMI (TSAT: 1.18 [1.04-1.34]; TIBC: 0.82 [0.70-0.95]) (all
P
<0.05). However, the apparent positive effect of Fe status on LAS disappeared when conditioning on CVD risk factors (
Figure 1
), particularly LDL (all
P
<0.05). Higher Fe status is associated with a greater risk of CES independent of CVD risk factors. These findings support the role of Fe status as a modifiable risk factor for CES. Future studies are needed to assess the mechanisms mediating this effect.
Abstract 143: Electronic Consultation for Outpatient Stroke/TIA Care: Are Recommendations Followed?
Authors: Williams Linda S , Odrzywoldski Karen , Kirchgassner Jessica , Chagwena Fadzai , Bastin Grace , Myers Laura J , Taylor Stanley E , Tang Qing , Daggy Joanne K , Wilkinson Jayne R
Published: February 2024

Background:
Including electronic consultations (e-consults) in addition to video visits in a teleneurology program can improve patient access and allow early recommendations (recs) to be communicated to referrers of patients with prior stroke/TIA. We sought to compare how attention to recs differed by type of teleneurology care.

Methods:
We evaluated outpatient video and e-consults for Veterans with stroke/TIA receiving care in the VA National TeleNeurology Program from 12/2022-4/2023. E-consults were completed if relevant records were available in the electronic health record (EHR). Video consults were scheduled as part of the NTNP. Clinical information, recs (categorized by type), and subsequent orders were assessed with EHR data and chart review. Rec attention was defined as ordered or completed within 60 days of a completed consult. We used two-sided two-sample t-tests, two-sample Wilcoxon rank sum tests and chi-square tests to compare demographics and rec attention rates between e-consult and video groups.

Results:
Of 391 consults requested for a stroke/TIA diagnosis, 214 (55%) had a neurologist stroke/TIA diagnosis and at least one rec; 57 (27%) of these were e-consults. Patients were similar in both groups (Table); e-consults were completed faster (mean 3.9 days vs. 60.3 days). E-consults had a similar number of recs (mean 2.2 recs vs 1.9 per consult, p = 0.17) but slightly more imaging recs (0.89 vs 0.62 per consult, p = 0.04). Overall, e-consult recs were less likely to receive attention: 55% in e-consult vs 69%, p = 0.05; this gap was worst for attention to lab recs (40% vs 70%, p = 0.03).

Conclusion:
E-consults for outpatient stroke/TIA questions can improve the timeliness of care, but recs are less likely to be followed than if care is directly provided via telehealth video visits. Consideration for care models that improve communication between the neurologist and the referrer may be necessary to improve attention to consult recommendations.
Abstract 149: Different Response to Blood Pressure Reduction in Lobar and Deep Intracerebral Hemorrhage
Authors: Hawkes Maximiliano A , Clocchiatti-Tuozzo Santiago , Rivier Cyprien , Qureshi Adnan I , Matouk Charles C , Petersen Nils H , de Havenon Adam H , Sheth Kevin N , Falcone Guido J
Published: February 2024

Background:
Blood pressure (BP) reduction is associated with better neuroimaging and clinical outcomes in patients with spontaneous, non-traumatic intracerebral hemorrhage (ICH). Because this evidence comes from studies that overwhelmingly enrolled deep hemorrhages, the impact of BP reduction in patients with lobar ICH remains understudied.

Methods:
We re-analyzed data from the pivotal Antihypertensive Treatment of Acute Cerebral Hemorrhage-2 (ATACH-2) study. We included all patients with available neuroimaging data. Participants were randomized to either intensive (systolic BP target 110-139 mmHg) or standard (systolic BP target 140-179 mmHg) acute BP lowering. The main outcome measures were hematoma expansion > 6 mL in the first 24 hours (HE), poor functional outcome (3-month mRS 4-6) and renal adverse events (RAE) until day 7 or hospital discharge. We fitted multivariable logistic regression models to test for association between the intervention and our outcomes of interest. Covariates included sex, age, race and ethnicity, and baseline ICH volume.

Results:
Among 1,000 patients enrolled in ATACH-2, 875 (87.5%) with complete data were included (88.9% deep hemorrhages and 11.1% lobar hemorrhages). The baseline characteristics of the intensive and standard treatment groups remained balanced as in the original study (all comparisons p >0.05). Multivariable logistic regression showed that intensive BP reduction decreased the risk of HE (OR 0.60, 95%CI 0.39-0.90; p=0.02) and increased the risk of RAE (OR 2.53, 95%CI 1.40-4.77; p=0.003) in patients with deep, but not lobar ICH (HE, OR: 0.89; 95% CI= 0.31 - 2.52; p=0.83 and RAE, OR: 0.46; 95% CI= 0.04 - 5.10; p=0.53). Intensive BP reduction was not associated with improved mRS in either deep (OR: 0.96; 95 % CI= 0.68 - 1.37; p= 0.82) nor lobar (OR: 0.66; 95% CI= 0.16 - 2.42; p= 0.54) ICH.

Conclusion:
The impact of intensive blood pressure lowering differs in deep and lobar ICH. These results emphasize the need for a better understanding about biologic differences in ICH, which may have therapeutic implications.
Abstract 154: Clustered Vascular Endotelial Growth Factor Nanoparticles Biomaterial for the Treatment of Moyamoya Disease
Authors: Chaparro Eduardo , Erning Kevin , Fulton Amy , Mace Brian E , RITZ KENDALL , Gonzalez Luis , Segura Tatiana , Hasan David M
Published: February 2024

Introduction:
Cerebrovascular ischemia poses a substantial neurological threat due to cerebral artery constriction. Innovative solutions, such as Vascular Endothelial Growth Factor (VEGF)-infused hydrogel biomaterials, have emerged. Hydrogels, mimicking the extracellular matrix, allow controlled VEGF delivery, prompting angiogenesis, tissue repair, and enhancing conditions like moyamoya disease. This non-invasive technique carries transformative potential.

Hypothesis:
Our hypothesis postulates that hyaluronic acid (HA) gels, with or without VEGF, can augment endothelial cell quantities and blood flow in fore-brain ischemic mice.

Methods:
We divided C57/B6 mice into four groups: control, vehicle (chronic ICA occlusion and stenosis), HA gel treatment, and Cluvena (
Cl
uster
VE
GF
Na
noparticle) hydrogel treatment. Brain dissection, sectioning, and CD31 and DAPI staining were performed for cellular identification.

Results:
Following two weeks, CD31 staining unveiled diminished endothelial cell populations in ischemic animals, significantly differing from controls. HA gel effectively restored endothelial cell counts to control levels. DAPI analysis indicated ischemic animals displayed considerably fewer DAPI-stained cells, attesting to successful ischemia induction and ensuing damage. Biomaterial intervention revived cell counts, aligning with control conditions. Intriguingly, hydrogel-only treated animals closely mirrored Cluvena outcomes in CD31 counts.

Conclusions:
Therapeutic angiogenic biomaterials, whether incorporating VEGF or not, hold significant potential for ischemic conditions. Cluvena efficiently reinstated endothelial cell numbers, thus unveiling potential therapeutic avenues for moyamoya, an ischemic disease with related neurological disorders or symptoms. This minimally-invasive strategy bears the promise of revolutionizing the field of brain ischemic condition therapeutics.
Abstract 155: Critical Care Decisions After Large Core Cerebral Infarctions:
A Secondary Analysis From the SELECT2 Trial
Authors: Kasner Scott E , DeGeorgia Michael , Burkhardt Jan-Karl , Abraham Michael G , Chen Michael , Hussain Muhammad S , Ortega-Gutierrez Santiago , Hu Yin , Bambakidis Nicholas C , Pujara Deep , Shaker Faris , Blackburn Spiros , Moussa Rami B , Churilov Leonid , Xiong Wei , Opaskar Amanda , Al-Shaibi Faisal , Duncan Kelsey R , Johns Hannah , Sundararajan Sophia , Sitton Clark W , Sila Cathy A , Furlan Anthony J , Mendes Pereira Vitor , Hill Michael D , Grotta James C , Ribo Marc , Hassan Ameer E , Campbell Bruce , Sarraj Amrou ,   The SELECT2 Investigators
Published: February 2024

Background/hypothesis:
The SELECT2 trial randomly assigned patients with LVO and large ischemic cores to either endovascular thrombectomy (EVT) or medical management (MM). This population is at high risk for cerebral edema and other complications, often leading to critical decisions about decompressive hemicraniectomy (DHC) or early withdrawal of care (WOC). We hypothesized that patients initially treated with EVT were more likely to get life-sustaining care regardless of recanalization success, presumably because initial treatment with EVT led toward an expectation of aggressive care, while those treated with MM expected futility.

Methods:
We analyzed the full SELECT2 study population using the as-treated principle, comparing the use of DHC and early (within 7 days from randomization) transition to comfort measures/WOC. We also compared these decisions based on recanalization success in those receiving EVT. We further tested baseline characteristics for association with these outcomes.

Results:
Patients treated with EVT were as likely to undergo DHC (aRR:1.19 [0.75-1.88], p=0.46) or WOC (aRR:0.94 [0.66-1.34], p=0.72) as those given MM (Table). Time to DHC was also similar (EVT 47[19-74] vs. MM 36[27-61] hours, p=0.95). Patients with successful (mTICI≥2b) recanalization were numerically less likely to undergo DHC than those with unsuccessful (TICI 0-2a) recanalization (aRR:0.66 [0.33-1.3], p=0.23), while WOC was similar (Table). Larger estimated core volumes were associated with both DHC and WOC, with DHC used more in younger and WOC more in older patients.

Conclusions:
In the SELECT2 trial of patients with large infarct cores, DHC was performed in ~1 in 6 and WOC in ~1 in 5, without an observed difference based on treatment with EVT or MM. The similar distribution of decisions to proceed with DHC or to change goals of care to acute palliative measures provides reassurance that the overall trial outcomes were not biased by open-label treatment allocation.
Abstract 19: Von Willebrand Factor Deficiency Improves Long Term Stroke Outcomes in Mice With Respiratory Infections
Authors: Patel Rakesh B , Jha Abhishek B , Kumskova Mariia , Leira Enrique C , Gurung Prajwal , Chauhan Anil K
Published: February 2024

Background:
Preceding respiratory tract infections (RTI) due to bacteria or virus has been linked to an increasing risk of stroke likely by potentiating an inflammatory immune response, endothelial dysfunction, platelet activation, and coagulopathy. Von Willebrand factor (VWF) plays a crucial role in hemostasis and thrombosis by promoting platelet adhesion to the subendothelial matrix and factor VIII stabilization. VWF activity is regulated by the protease ADAMTS13. Prior population-based studies suggest increased VWF levels and reduced ADAMTS13 activity as independent risk factors for stroke; however, a causal role of the VWF/ADAMTS13 axis in RTI-mediated stroke exacerbation is not investigated yet.

Objective:
To determine the causal role of the VWF/ADAMTS13 axis in a mouse model of preceding RTI and ischemic stroke.

Methods:
Wild-type (WT) mice were infected intranasally with sub-lethal doses of
S. aureus
or vehicle on days 0, 2, and 5. On day 6, infection was measured in the lungs (MRI), brain, and blood. VWF levels and ADTMTS13 activity were quantified by ELISA in the plasma on day 6 post-infection. In another set of experiments, on day 6 post-infection
S. aureus
-infected WT,
Vwf
-/-
,
Adamts13
-/-
mice were subjected to transient (30 min) middle cerebral artery ischemia using a filament model. Functional outcomes (modified neurological severity score, rota-rod, corner, novel object recognition, and wire-hanging test) were measured in the same cohort of mice up to 4 weeks. Controls were mock-infected WT mice.

Result:
We demonstrate that a sustained
S. aureus
infection localized to lungs in WT mice, increases plasma VWF levels (~2-fold) and reduces ADAMTS13 activity that were associated with larger infarcts and worsened long-term functional outcomes (P<0.05 vs. mock-infected mice).
S. aureus
infected VWF-deficient mice exhibited reduced infarcts and better long-term functional outcomes (P <0.05 vs.
S. aureus
infected WT). In contrast,
S. aureus
infected ADAMTS13-deficient mice exhibited larger infarcts and worse long-term functional outcomes (P <0.05 vs.
S. aureus
infected WT).

Conclusion:
In a model of respiratory tract infection during the week preceding stroke, VWF has a causal role in worsening stroke outcomes while ADAMTS13 is protective.
Abstract 23: Results of CRISP2: CTP and CTA Assessment of Collaterals Predicts Inter-Hospital Infarct Growth
Authors: Wouters Anke , Seners Pierre , Yuen Nicole , Mlynash Michael , Heit Jeremy J , Kemp Stephanie M , Christensen Soren , Albers Gregory W , Lemmens Robin , Lansberg Maarten G
Published: February 2024

Background:
Acute ischemic stroke patients with a large vessel occlusion (LVO) who present in a primary stroke center (PSC) without endovascular treatment capability, are often transferred to a comprehensive stroke center (CSC) for thrombectomy. CRISP2 was a prospective NIH funded multi-center study that aimed to determine characteristics associated with infarct growth during inter-hospital transfer.

Methods:
Data from patients with an anterior circulation LVO transferred to two CSCs were collected. A CT perfusion (CTP) was obtained at the PSC followed by an MRI at the CSC, before consideration of thrombectomy. The inter-hospital infarct growth rate was defined as the difference between the co-registered infarct volumes on MRI and CTP, divided by the time between the two scans. Multivariable logistic regression was used to determine characteristics associated with fast inter-hospital progression, defined as a growth rate ≥ 5ml/h. The hypoperfusion intensity ratio (HIR) was calculated automatically from the CTP, while the Tan collateral score was visually rated on baseline CT angiography.

Results:
A total of 183 patients, of whom 45% were fast progressors, were included. Baseline characteristics are presented in

Table 1

. An HIR ≥0.40 identified fast infarct growth with a sensitivity of 0.76 (95%CI 0.65-0.84) and a specificity of 0.55 (95%CI 0.44-0.65), whereas for Tan 0-1 sensitivity was 0.37 (95%CI 0.27-0.48) and specificity 0.93 (95%CI 0.86-0.97). In multivariable models, baseline core volume and poor collaterals defined as either an HIR ≥ 0.40 (aOR = 2.18 (95%CI 1.10-4.42); p = 0.03) or a Tan score of 0-1 (aOR = 4.74 (95%CI 1.90-13.07); p=0.001), remained independently associated with fast infarct growth.

Conclusion:
An HIR ≥ 0.40 is a predictor of fast inter-hospital infarct growth with high sensitivity and a Tan score of 0-1 predicts fast growth with high specificity. These are promising imaging markers for patient selection in future neuroprotective trials.
Abstract 32: Escape Room Activity Improves Nurses’ Knowledge of Stroke Clinical Practice Guidelines
Authors: Kramer Siena , Martin Michael , Skeels Katelyn
Published: February 2024

Background:
Patients receiving care from stroke specialized nurses have better outcomes. In 2021, the American Heart Association/American Stroke Association (AHA/ASA) published updates to the Comprehensive Nursing Care Scientific Statements providing new evidence and best nursing practices in stroke care. Nursing leadership at a Comprehensive Stroke Center identified this as an opportunity to utilize the Nursing Care Scientific Statements and other AHA/ASA stroke clinical practice guidelines (CPG) to optimize stroke program education and improve quality of nursing care.

Purpose:
The purpose of this study was to determine whether an escape room activity significantly increases knowledge of stroke CPGs and best nursing care practices and to assess nurses’ confidence in their application when compared to viewing online modules alone.

Methods:
Based on a literature review and learning needs assessment, nine escape room puzzles were developed spanning the continuum of stroke care. Each puzzle required the application of a CPG or scientific statement to a patient scenario. A variety of materials were used to develop the puzzles, including black lights, locks, jigsaw puzzles, and a custom learning environment in EPIC. Participants submitted a pre- and post-survey to capture qualitative and quantitative data regarding the nurse’s knowledge of and confidence in applying stroke CPGs and best practices. A paired two-sided T-test was conducted using a confidence interval of 95% and sample size of 75 to determine whether the post-survey increase in nurse knowledge and confidence was significant.

Results:
For all five Likert items, the p-value was less than 0.05, indicating a statistically significant improvement in nurses’ knowledge of and confidence in applying stroke CPGs and best practices. The qualitative data demonstrated a learner preference for the interactive nature of the escape room and the teamwork and critical thinking that it fostered.

Conclusion:
In conclusion, there was a statistically significant increase in nurse confidence and knowledge of comprehensive nursing stroke care and stroke CPGs after the escape room intervention. This suggests that escape room activities can be an effective way to develop clinical knowledge in stroke nursing.
Abstract 35: Integrating Clinical Trials Into Comprehensive Stroke Education for Inpatient Nurses
Authors: Gieseke Jessica , Nierengarten Elizabeth , Tessmer Megan , Staloch Jessica , Halverson Megan , Sansgaard Lisa , Streib Christopher D , Staugaitis Abbey
Published: February 2024

Introduction:
A major challenge in the implementation of clinical trials is the lack of integration of research into the clinical practice of frontline staff. The University of Minnesota partnered with the M Health Fairview (MHFV) System to incorporate stroke clinical trials into the annual comprehensive stroke education courses. While not required by the stroke accreditation curriculum standards, embedding research topics into ongoing stroke education is a novel practice that broadly increases awareness of clinical research with the frontline staff caring for stroke patients.

Methods:
In 2019, the comprehensive stroke class was updated to include a section for stroke trials. The research topics include: a brief description of study team roles, an overview of the impact of clinical trials on EBP, results for published trials, updates on current clinical trials, and the impact on nursing workflow. The number of attendees for each session from 2019-June 2023 were recorded along with anonymous comments about the presentation. The total number of subjects enrolled in acute, inpatient, and outpatient stroke trials in MHFV were compiled.

Results:
The comprehensive stroke class was attended by MHFV nurses 1,667 times. Interest in research was noted 77 times in the comments and research was ranked 3rd “most interesting” topic presented in 2019. A total of 276 patients were enrolled in stroke research in that timeframe.

Conclusion:
While no direct correlation can be drawn to trial enrollment, the volume of learners demonstrates broad dissemination of stroke trials information to frontline staff caring for stroke patients and the collection of positive feedback shows an interest in the topic. Incorporating clinical trials education into established comprehensive stroke education increases awareness of clinical trials and facilitates integration of research into clinical workflows with a higher acceptance of clinical trial efforts by frontline staff.