Nonpharmacological interventions to improve the cognitive function among persons with traumatic brain injury: A systematic review.

PURPOSE: The systematic review aimed to evaluate the effectiveness of nonpharmacological interventions (NPIs) for improving cognitive function among persons with traumatic brain injury. DESIGN: A systematic review. METHODS: This systematic review was registered in PROSPERO and followed the PRISMA guideline. PubMed, ScienceDirect, Scopus, SpringerLink, Wiley Online Library, JSTOR, and Taylor & Francis were systematically searched for relevant articles of peer-reviewed studies published between 2008 and 2022. Two independent researchers conducted study selection, data extraction, and data quality assessment. FINDINGS: Twenty-one studies met inclusion criteria, numbering a total of 757 participants. Six groups of NPIs were effective in improving cognitive functioning among persons with traumatic brain injury, including multimodal cognitive training, technology innovation, memory training, executive function training, physical activity, and sensory stimulation programs. Pooled evidence revealed that NPIs had a large effect on memory (d = 0.80, p < 0.05 to d = 2.03, p < 0.000), processing speed (d = 1.58, p < 0.05), and cognitive behavior (d = 1.63, p < 0.001 to d = 8.91, p 0.003). There was a medium effect on executive function (d = 0.5, p < 0.01 to d = 0.62, p < 0.05), attention (d = 0.5, p < 0.01), and intelligence (d = 0.57 to d = 0.59, p = 0.000). For visuospatial function and language, there was a significant increase post-intervention. CONCLUSION: Evidence from this systematic review indicates that NPIs, specifically the use of multimodal cognitive training and sensory stimulation programs, were effective in improving cognitive function outcomes among persons with traumatic brain injury, with medium to large effect sizes. CLINICAL RELEVANCE: Nonpharmacological interventions (NPIs) can enhance cognitive function in individuals with traumatic brain injury. These findings can guide healthcare professionals in clinical settings and support the development of technology applications for cognitive rehabilitation using NPIs.

What a Rat Race: A Case Study of Rat Bite Fever in an Emergency Department.

Rat bite fever is an acute illness caused by bacteria from rodents. In the United States, rat bite fever is considered rare; however, actual incidence is unknown because of lack of mandatory disease reporting requirements. Risk of development of rat bite fever after being bitten by a rat is approximately 10%. Early treatment is imperative as death is a potential complication. The following case study demonstrates the gravity of the syndrome.

Genetic Variability in the Iron Homeostasis Pathway and Patient Outcomes After Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND/OBJECTIVE: Iron can be detrimental to most tissues both in excess and in deficiency. The brain in particular is highly susceptible to the consequences of excessive iron, especially during blood brain barrier disruption after injury. Preliminary evidence suggests that iron homeostasis is important during recovery after neurologic injury; therefore, the exploration of genetic variability in genes involved in iron homeostasis is an important area of patient outcomes research. The purpose of this study was to examine the relationship between tagging single nucleotide polymorphisms (SNPs) in candidate genes related to iron homeostasis and acute and long-term patient outcomes after aneurysmal subarachnoid hemorrhage (aSAH). METHODS: This study was a longitudinal, observational, candidate gene association study of participants with aSAH that used a two-tier design including tier 1 (discovery, n = 197) and tier 2 (replication, n = 277). Participants were followed during the acute outcome phase for development of cerebral vasospasm and delayed cerebral ischemia (DCI) and during the long-term outcome phase for death and gross functional outcome using the Glasgow Outcome Scale (GOS; poor = 1-3). Genetic association analyses were performed using a logistic regression model adjusted for age, sex, and Fisher grade. Approximate Bayes factors (ABF) and Bayesian false discovery probabilities (BFDP) were used to prioritize and interpret results. RESULTS: In tier 1, 235 tagging SNPs in 28 candidate genes were available for analysis and 26 associations (20 unique SNPs in 12 genes) were nominated for replication in tier 2. In tier 2, we observed an increase in evidence of association for three associations in the ceruloplasmin (CP) and cubilin (CUBN) genes. We observed an association of rs17838831 (CP) with GOS at 3 months (tier 2 results, odds ratio [OR] = 2.10, 95% confidence interval [CI] = 1.14-3.86, p = 0.018, ABF = 0.52, and BFDP = 70.8%) and GOS at 12 months (tier 2 results, OR = 1.86, 95% CI 0.98-3.52, p = 0.058, ABF = 0.72, and BFDP = 77.3%) as well as rs10904850 (CUBN) with DCI (tier 2 results, OR = 0.70, 95% CI 0.48-1.02, p = 0.064, ABF = 0.59, and BFDP = 71.8%). CONCLUSIONS: Among the genes examined, our findings support a role for CP and CUBN in patient outcomes after aSAH. In an effort to translate these findings into clinical utility and improve outcomes after aSAH, additional research is needed to examine the functional roles of these genes after aSAH.

Genetic Variability and Trajectories of DNA Methylation May Support a Role for HAMP in Patient Outcomes After Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND/OBJECTIVE: Preclinical evidence suggests that iron homeostasis is an important biological mechanism following aneurysmal subarachnoid hemorrhage (aSAH); however, this concept is underexplored in humans. This study examined the relationship between patient outcomes following aSAH and genetic variants and DNA methylation in the hepcidin gene (HAMP), a key regulator of iron homeostasis. METHODS: In this exploratory, longitudinal observational study, participants with verified aSAH were monitored for acute outcomes including cerebral vasospasm (CV) and delayed cerebral ischemia (DCI) and evaluated post-discharge at 3 and 12 months for long-term outcomes of death and functional status using the Modified Rankin Scale (mRS; poor = 3-6) and Glasgow Outcome Scale (GOS; poor = 1-3). Participants were genotyped for two genetic variants, and DNA methylation data were collected from serial cerebrospinal fluid over 14 days post-aSAH at eight methylation sites within HAMP. Participants were grouped based on their site-specific DNA methylation trajectory, with and without correcting for cell-type heterogeneity (CTH), and the associations between genetic variants and inferred DNA methylation trajectory groups and patient outcomes were tested. To correct for multiple testing, an empirical significance threshold was computed using permutation testing. RESULTS: Genotype data for rs10421768 and rs7251432 were available for 241 and 371 participants, respectively, and serial DNA methylation data were available for 260 participants. Acute outcome prevalence included CV in 45% and DCI in 37.1% of the overall sample. Long-term outcome prevalence at 3 and 12 months included poor GOS in 23% and 21%, poor mRS in 31.6% and 27.3%, and mortality in 15.1% and 18.2%, respectively, in the overall sample. Being homozygous for the rs7251432 variant allele was significantly associated with death at 3 months (p = 0.003) and was the only association identified that passed adjustment for multiple testing mentioned above. Suggestive associations (defined as trending toward significance, p value < 0.05, but not meeting empirical significance thresholds) were identified between the homozygous variant allele for rs7251432 and poor GOS and mRS at 3 months (both p = 0.04) and death at 12 months (p = 0.02). For methylation trajectory groups, no associations remained significant after correction for multiple testing. However, for methylation trajectory groups not adjusted for CTH, suggestive associations were identified between cg18149657 and poor GOS and mRS at 3 months (p = 0.003 and p = 0.04, respectively) and death at 3 months (p = 0.04), and between cg26283059 and DCI (p = 0.01). For methylation trajectory groups adjusted for CTH, suggestive associations were identified between cg02131995 and good mRS at 12 months (p = 0.02), and between cg26283059 and DCI (p = 0.01). CONCLUSIONS: This exploratory pilot study offers preliminary evidence that HAMP may play a role in patient outcomes after aSAH. Replication of this study and mechanistic investigation of the role of HAMP in patient outcomes after aSAH are needed.

Psychosocial Comorbidities Related to Return to Work Rates Following Aneurysmal Subarachnoid Hemorrhage.

Purpose Ability to return to work (RTW) after stroke has been shown to have positive psychosocial benefits on survivors. Although one-fifth of aneurysmal subarachnoid hemorrhage (aSAH) survivors suffer from poor psychosocial outcomes, the relationship between such outcomes and RTW post-stroke is not clear. This project explores the relationship between age, gender, race, marital status, anxiety and depression and RTW 3 and 12 months post-aSAH. Methods Demographic and clinical variables were collected from the electronic medical record at the time of aSAH admission. Anxiety and depression were assessed at 3 and 12 months post-aSAH using the State Trait Anxiety Inventory (STAI) and Beck's Depression Inventory-II (BDI-II) in 121 subjects. RTW for previously employed patients was dichotomized into yes/no at their 3 or 12 month follow-up appointment. Results Older age was significantly associated with failure to RTW at 3 and 12 months post-aSAH (p = 0.003 and 0.011, respectively). Female gender showed a trending but nonsignificant relationship with RTW at 12 months (p = 0.081). High scores of depression, State anxiety, and Trait anxiety all had significant associations with failure to RTW 12 months post-aSAH (0.007 ≤ p ≤ 0.048). At 3 months, there was a significant interaction between older age and high State or Trait anxiety with failure to RTW 12 months post-aSAH (p = 0.025, 0.042 respectively). Conclusions Patients who are older and suffer from poor psychological outcomes are at an increased risk of failing to RTW 1-year post-aSAH. Our interactive results give us information about which patients should be streamlined for therapy to target their psychosocial needs.

Clinical Presentation to the Emergency Department Predicts Subarachnoid Hemorrhage-Associated Myocardial Injury.

INTRODUCTION: Aneurysmal subarachnoid hemorrhage (aSAH) is frequently seen in emergency departments. Secondary injury, such as subarachnoid hemorrhage-associated myocardial injury (SAHMI), affects one third of survivors and contributes to poor outcomes. SAHMI is not attributed to ischemia from myocardial disease but can result in hypotension and arrhythmias. It is important that emergency nurses recognize which clinical presentation characteristics are predictive of SAHMI to initiate proper interventions. The aim of this study was to determine whether patients who present to the emergency department with clinical aSAH are likely to develop SAHMI, as defined by troponin I ≥0.3 ng/mL. METHODS: This was a prospective descriptive study. SAHMI was defined as troponin I ≥0.3 ng/mL. Predictors included demographics and clinical characteristics, severity of injury, admission 12-lead electrogardiogram (ECG), initial emergency department vital signs, and pre-hospital symptoms at time of aneurysm rupture. RESULTS: Of 449 patients, 126 (28%) had SAHMI. Patients with SAHMI were more likely to report seizures and unresponsiveness with significantly lower Glasgow coma score and higher proportion of Hunt and Hess grades 3 to 5 and Fisher grades III and IV (all P < .05). Patients with SAHMI had higher atrial and ventricular rates and longer QTc intervals on initial ECG (P < .05). On multivariable logistic regression, poor Hunt and Hess grade, report of prehospital unresponsiveness, lower admission Glasgow coma score, and longer QTc interval were significantly and independently predictive of SAHMI (P < .05). DISCUSSION: Components of the clinical presentation of subarachnoid hemorrhage to the emergency department predict SAHMI. Identifying patients with SAHMI in the emergency department can be helpful in determining surveillance and care needs and informing transfer unit care. Contribution to Emergency Nursing Practice.

Prophylactic Antiepileptics and Seizure Incidence Following Subarachnoid Hemorrhage: A Propensity Score-Matched Analysis.

BACKGROUND AND PURPOSE: The utility of prophylactic antiepileptic drug (AED) administration after spontaneous subarachnoid hemorrhage remains controversial. AEDs have not clearly been associated with a reduction in seizure incidence and have been associated with both neurological worsening and delayed functional recovery in this setting. METHODS: We retrospectively analyzed a prospectively collected database of subarachnoid hemorrhage patients admitted to our institution between 2005 and 2010. Between 2005 and 2007, all patients received prophylactic AEDs upon admission. After 2007, no patients received prophylactic AEDs or had AEDs immediately discontinued if initiated at an outside hospital. A propensity score-matched analysis was then performed to compare the development of clinical and electrographic seizures in these 2 populations. RESULTS: Three hundred and fifty three patients with spontaneous subarachnoid hemorrhage were analyzed, 43% of whom were treated with prophylactic AEDs upon admission. Overall, 10% of patients suffered clinical and electrographic seizures, most frequently occurring within 24 hours of ictus (47%). The incidence of seizures did not vary significantly based on the use of prophylactic AEDs (11 versus 8%; P=0.33). Propensity score-matched analyses suggest that patients receiving prophylactic AEDs had a similar likelihood of suffering seizures as those who did not (P=0.49). CONCLUSIONS: Propensity score-matched analysis suggests that prophylactic AEDs do not significantly reduce the risk of seizure occurrence in patients with spontaneous subarachnoid hemorrhage.

Subarachnoid Hemorrhage Outcomes in an Endovascular Right of First Refusal Neurosurgical Environment.

BACKGROUND: Randomized controlled trials demonstrate that endovascular techniques yield improved outcomes compared with microsurgical approaches. However, not all patients are suitable candidates for endovascular management. This study aimed to determine if healthy patients managed microsurgically could achieve functional outcomes comparable to patients managed endovascularly. METHODS: Patients treated for ruptured aneurysmal subarachnoid hemorrhage at 2 level 1 stroke centers from January 2012 through December 2020 were retrospectively reviewed. All cases were evaluated in an endovascular right of first refusal neurosurgical environment. We collected relevant clinical and follow-up data and created a generalized linear model to identify differences between patients treated endovascularly versus microsurgically. A propensity score model accounting for these differences was used to predict patient outcomes. Functional outcomes were independently assessed using the modified Rankin Scale (mRS) with good functional outcome defined as modified Rankin Scale score <3. RESULTS: The study included 588 patients (211 microsurgical, 377 endovascular); median age was 58 years (interquartile range: 40-86 years); in-hospital mortality was 13%. Age, aneurysm size, and aneurysm location significantly predicted treatment modality (all P < 0.05). After greedy-type matching (210 microsurgical, 210 endovascular), patients managed microsurgically were less likely to be discharged home (odds ratio = 0.6, 95% confidence interval 0.4-0.9, P = 0.01). Functional differences disappeared over time; patients in the 2 treatment arms had similar functional outcomes at 3 months (odds ratio = 1.1, 95% confidence interval 0.7-1.8, P = 0.66) and 1 year after subarachnoid hemorrhage (odds ratio = 1.3, 95% confidence interval 0.8-2.1, P = 0.38). CONCLUSIONS: In an endovascular right of first refusal neurosurgical environment, practitioners can treat patients who are not good endovascular candidates microsurgically and achieve functional outcomes comparable to patients managed endovascularly.

Hunt-Hess Score at 48 Hours Improves Prognostication in Grade 5 Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Patients with Hunt-Hess (HH)5 aneurysmal subarachnoid hemorrhage (SAH) have high mortality rates. Despite an initial moribund exam, a subset of patients progress to favorable outcomes. OBJECTIVE: To evaluate the utility of delayed HH grading to improve prognostication. METHODS: We retrospectively reviewed patients undergoing treatment of ruptured aneurysms at two level 1 stroke centers from January 2012 through December 2020. We collected relevant clinical information and developed a multivariate cox regression model to identify independent predictors of mortality. To evaluate the utility of delayed examinations in predicting outcomes, we re-assessed the HH grade at 48 hours post admission and constructed a logistic regression model with potential confounders to predict mortality. RESULTS: From 2012 to 2020, 621 patients underwent treatment for aneurysmal SAH. We identified 63 HH5 patients (10%) with a mean age of 58 years. Among these patients, the median length of stay was 14 days, with 3 patients passing away within 48 hours. The overall mortality rate was 63% at 24 months. To predict mortality, our cox regression model found only age to be significant (P = 0.002). Delayed HH grading improved prognostication at 48 hours and remained significant on multivariate analysis as a predictor of mortality (P = 0.0001). We observed a significant difference in mortality between patients HH5 and patients HH4 or lower at 48 hours (P = 0.0003). CONCLUSIONS: Delayed reassessment of HH grade 48 hours postadmission is a predictor of mortality, suggesting reassessment at 48 hours in high grade SAH leads to better prognostication.

Correlation between ED symptoms and clinical outcomes in the patient with aneurysmal subarachnoid hemorrhage.

INTRODUCTION: Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating neurologic insult often presenting to the emergency department as a headache. Recognition and prompt treatment are important to good outcomes. The purpose of this analysis was to examine the presentation of aSAH patients to the emergency department and determine whether presentation predicts length of stay or death. METHODS: This is a retrospective review of data gathered from 2 existing studies. Data from patients diagnosed with acute aSAH were reviewed for symptoms, clinical presentation, history, demographics, and laboratory results. Statistical analysis was completed by use of χ(2) and regression analysis. RESULTS: This sample of 193 adult aSAH patients confirmed headache as well as meningeal signs as the most frequent symptom on presentation to the emergency department, and this was cited as the most common reason for seeking medical treatment. Symptom presentation did not appear to affect length of stay; however, survival analysis showed that patients who presented with a Hunt and Hess grade greater than 3 along with bradycardia were 15.6 times more likely to die within the first month of aSAH. DISCUSSION: Although aSAH presentation remains the same, this analysis did find a correlation between poor clinical grade and bradycardia to be a significant predictor of death at 30 days. Additional study may help to determine whether any intervention could lessen this effect. Although patient diagnosis and referral from the community emergency department to a tertiary center were relatively quick, there was a wide window of time between patient recognition of symptoms and seeking medical treatment.

Cerebrospinal fluid 20-HETE is associated with delayed cerebral ischemia and poor outcomes after aneurysmal subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Delayed cerebral ischemia (DCI) is a major complication after aneurysmal subarachnoid hemorrhage (aSAH); it is manifested by changes in cerebral blood flow accompanied by neurological decline, and it results in long-term functional and neuropsychological impairment. Preclinical evidence has demonstrated that the arachidonic acid metabolite, 20-hydroxyeicosatetraenoic acid (20-HETE), affects cerebral microvascular tone and cerebral blood flow after aSAH. The purpose of this study was to determine whether cerebrospinal fluid 20-HETE levels were associated with DCI and long-term neuropsychological outcomes in aSAH patients. METHODS: Cerebrospinal fluid samples were collected twice daily through 14 days after hemorrhage on 108 acute, adult, aSAH patients. Samples were analyzed for 20-HETE via HPLC MSQ single quadrupole mass spectrometry. DCI was defined as the presence of impaired cerebral blood flow (angiographic vasospasm, elevated transcranial Dopplers, abnormal computed tomography or magnetic resonance perfusion scans) accompanied by neurological deterioration. Outcomes, including death and neuropsychological testing, were completed at 3 months after hemorrhage. RESULTS: Detectable 20-HETE levels were observed in 31% of patient samples and were associated with severity of hemorrhage (Hunt & Hess [HH], P=0.04; Fisher, P=0.05). Detection of 20-HETE was not associated with angiographic vasospasm (P=0.34); however, detectable 20-HETE was significantly associated with DCI (P=0.016). Our data also suggest that detectable 20-HETE was associated with decreased performance in 5 neuropsychological domains. CONCLUSIONS: These results provide the first clinical evidence that cerebrospinal fluid 20-HETE concentrations are associated with DCI and poor outcomes, and this provides impetus for future studies to elucidate the clinical utility of inhibiting 20-HETE formation as a novel therapeutic intervention in patients with aSAH.

Role of endothelin-1 in human aneurysmal subarachnoid hemorrhage: associations with vasospasm and delayed cerebral ischemia.

BACKGROUND: Endothelin-1 (ET-1) is a potent vasoconstrictor implicated in the pathogenesis of vasospasm and delayed cerebral ischemia (DCI) in aneurysmal subarachnoid hemorrhage (aSAH) patients. The aim of this study was to investigate the relationship between cerebrospinal fluid (CSF) ET-1 levels and angiographic vasospasm and DCI. METHODS: Patients with aSAH were consented (n = 106). Cerebral vasospasm was determined by angiography. DCI was determined by transcranial Doppler (TCD) results and/or angiogram results with corresponding clinical deterioration. CSF ET-1 levels over 14 days after the initial insult was quantified by ELISA. ET-1 analysis included a group-based trajectory analysis and ET-1 exposure rate during 24, 48, and 72 h prior to, as well as 72 h post angiography, or clinical deterioration. RESULTS: Trajectory analysis revealed two distinct groups of subjects with 56% of patients in the low ET-1 trajectory group (mean at day 1 = 0.31 pg/ml; SE = 0.04; mean at day 14 = 0.41 pg/ml; SE = 0.15) and 44% of patients in the high ET-1 trajectory group (mean at day 1 = 0.65 pg/ml; SE = 0.08; mean at day 14 = 0.61 pg/ml; SE = 0.06). Furthermore, we observed that ET-1 exposure rate 72 h before angiography and clinical spasm was a significant predictor of both angiographic vasospasm and DCI, whereas, ET-1 exposure after angiography and clinical spasm was not associated with either angiographic vasospasm or DCI. CONCLUSION: Based on these results we conclude that ET-1 concentrations are elevated in a sub-group of patients and that the acute (72 h prior to angiography and clinical neurological deterioration), but not chronic, elevations in CSF ET-1 concentrations are indicative of the pathogenic alterations of vasospasm and DCI in aSAH patients.

Iron homeostasis pathway DNA methylation trajectories reveal a role for STEAP3 metalloreductase in patient outcomes after aneurysmal subarachnoid hemorrhage.

BACKGROUND: Following aneurysmal subarachnoid hemorrhage (aSAH), the brain is susceptible to ferroptosis, a type of iron-dependent cell death. Therapeutic intervention targeting the iron homeostasis pathway shows promise for mitigating ferroptosis and improving recovery in animal models, but little work has been conducted in humans. DNA methylation (DNAm) plays a key role in gene expression and brain function, plasticity, and injury recovery, making it a potentially useful biomarker of outcomes or therapeutic target for intervention. Therefore, in this longitudinal, observational study, we examined the relationships between trajectories of DNAm in candidate genes related to iron homeostasis and acute (cerebral vasospasm and delayed cerebral ischemia) and long-term (Glasgow Outcome Scale [GOS, unfavorable = 1-3] and death) patient outcomes after aSAH. RESULTS: Longitudinal, genome-wide DNAm data were generated from DNA extracted from post-aSAH cerebrospinal fluid (n = 260 participants). DNAm trajectories of 637 CpG sites in 36 candidate genes related to iron homeostasis were characterized over 13 days post-aSAH using group-based trajectory analysis, an unsupervised clustering method. Significant associations were identified between inferred DNAm trajectory groups at several CpG sites and acute and long-term outcomes. Among our results, cg25713625 in the STEAP3 metalloreductase gene (STEAP3) stood out. Specifically, in comparing the highest cg25713625 DNAm trajectory group with the lowest, we observed significant associations (i.e., based on p-values less than an empirical significance threshold) with unfavorable GOS at 3 and 12 months (OR = 11.7, p = 0.0006 and OR = 15.6, p = 0.0018, respectively) and death at 3 and 12 months (OR = 19.1, p = 0.0093 and OR = 12.8, p = 0.0041, respectively). These results were replicated in an independent sample (n = 100 participants) observing significant associations with GOS at 3 and 12 months (OR = 8.2, p = 0.001 and OR = 6.3, p = 0.0.0047, respectively) and death at 3 months (OR = 2.3, p = 0.008) and a suggestive association (i.e., p-value < 0.05 not meeting an empirical significance threshold) with death at 12 months (OR = 2.0, p = 0.0272). In both samples, an additive effect of the DNAm trajectory group was observed as the percentage of participants with unfavorable long-term outcomes increased substantially with higher DNAm trajectory groups. CONCLUSION: Our results support a role for DNAm of cg25713625/STEAP3 in recovery following aSAH. Additional research is needed to further explore the role of DNAm of cg25713625/STEAP3 as a biomarker of unfavorable outcomes, or therapeutic target to improve outcomes, to translate these findings clinically.

ANGPT1 methylation and delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage patients.

Background: Delayed cerebral ischemia (DCI) is a common secondary complication and an important cause of disability and mortality among patients who survive aneurysmal subarachnoid hemorrhage (aSAH). Knowledge on DCI pathogenesis, risk factors, and biomarkers are essential for early detection and improved prognosis. To investigate the role of DNA methylation in DCI risk, we conducted an epigenome-wide association study (EWAS) in 68 patients followed up to 1 year after the initial aneurysm rupture. Blood samples were collected within 48 h post hemorrhage and used for DNA methylation profiling at ~ 450k CpG sites. A separate cohort of 175 patients was sequenced for the top CpG sites from the discovery analysis for a replication of the EWAS findings. Results: EWAS did not identify any epigenome-wide significant CpGs. The top signal, cg18031596, was annotated to ANGPT1, a gene with critical functions in angiogenesis after vascular injury. Post hoc power calculations indicated a well-powered discovery analysis for cg18031596. Analysis of the replication cohort showed that four out of the five CpG sites sequenced at the ANGPT1 locus passed a Bonferroni-adjusted significance threshold. In a pooled analysis of the entire sample, three out of five yielded a significant p-value, and the top association signal (p-value = 0.004) was seen for a CpG that was not originally measured in the discovery EWAS. However, four ANGPT1 CpG sites had an opposite effect direction in the replication analysis compared to the discovery EWAS, marking a failure of replication. We carefully examined this observed flip in directions and propose several possible explanations in addition to that it was a random chance that ANGPT1 ranked at the top in the discovery EWAS. Conclusions: We failed to demonstrate a significant and consistent effect of ANGPT1 methylation in DCI risk in two cohorts. Though the replication attempt to weaken the overall support of this gene, given its relevant function and top rank of significance in the EWAS, our results call for future studies of larger aSAH cohorts to determine its relevance for the occurrence of DCI.

Predictors of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage: a cardiac focus.

BACKGROUND: Myocardial injury after aneurysmal subarachnoid hemorrhage (aSAH) is associated with poor outcomes. Delayed cerebral ischemia (DCI) is also a complication of aSAH. We sought to determine whether (1) DCI could be predicted by demographics, aSAH severity/aneurysm location, or aSAH-associated myocardial injury (SAHMI), and (2) DCI is associated with increased mortality after aSAH. METHODS: Prospective longitudinal study of 149 aSAH subjects with definitive DCI evaluation, age 18-75 years, Hunt and Hess (HH) ≥ 3, and/or Fisher ≥ 2, and admitted to the Neurovascular ICU. DCI was defined by the presence of neurological deterioration accompanied by evidence of abnormal cerebral blood flow. RESULTS: Subjects were 48% DCI(+) and 52% DCI(-). DCI(+) subjects had more severe aSAH [HH (P = 0.002), Fisher (P = 0.004), admission Glasgow Coma Scale (P = 0.018)]. More DCI(+) subjects had pulmonary congestion than DCI(-) subjects (63 vs. 39%, P = 0.003). On echocardiogram, cardiac output (CO, liters per minute [LPM]) was significantly higher in DCI(+) than in DCI(-) subjects (6 ± 2 vs. 5 ± 1 LPM; P = 0.015). Multivariate analysis identified CO and Fisher grade as independent predictors of DCI (P = 0.02, 0.019). For each 1 LPM increase in CO, the odds of DCI increased by 1.5 (95% CI: 1.1-2.1). Fisher grade 4 increased the odds of DCI by 6.5 compared to Fisher grade 2 (95% CI: 1.6-25.8). After controlling for Fisher grade, CO remained an independent predictor of DCI (P = 0.02). Three-month mortality rate was not significantly different between DCI groups, P = 0.786. CONCLUSION: Elevated CO and Fisher grade are predictors of DCI after aSAH. However, prevention of DCI may not decrease mortality.

Understanding recruitment and retention in neurological research.

Cognitive deficits in participants and the abrupt and traumatic way in which many neurological conditions present are two examples of the unique challenges in recruiting and retaining participants with neurological injury for research studies. The purpose of this investigation was to identify obstacles to recruitment and retention in three ongoing research studies. These studies involve persons with neurological disorders across the continuum of care, from those newly diagnosed and with emergent presentation to those with more established chronic neurological conditions. For this analysis, we evaluated the effectiveness of the strategies employed to improve participation rates. The first study was a project funded by the National Institutes of Health designed to identify biomarkers of vasospasm in persons (n = 496) with aneurysmal subarachnoid hemorrhage who presented to the neurovascular intensive care unit (National Institute of Nursing Research, R01 NR004339). The purpose of the second study was to examine biobehavioral interactions in family caregivers (n = 59) of persons with a primary malignant brain tumor recruited in the community setting. The third project involved recruiting persons (n = 1,019) within an outpatient neurosurgical center to participate in a research registry. To determine differential effectiveness of strategies, consent and attrition rates were calculated at serial points over time in three studies, and recruitment and retention strategies were compared. Sentinel time points in participants' disease trajectories played a key role in determining whether those who were approached to participate gave consent and were retained, particularly in the studies involving persons with aneurysmal subarachnoid hemorrhage (consent = 85%; retention = 89%) and persons with primary malignant brain tumors and their caregivers (consent = 68%; retention = 83%). In addition, several specific recruiter and interviewer training techniques were associated with higher recruitment and retention. Targeted strategies to improve participation rates are vital for neuroscience nurses involved in any aspect of clinical research, including those who conduct studies, assist with data collection, and recruit potential participants.

Psychometric Properties of the Patient Assessment of Own Functioning Inventory Following Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND AND PURPOSE: The purpose of this study was to examine the psychometric properties of the Patient Assessment of Own Functioning Inventory (PAOFI) following aneurysmal subarachnoid hemorrhage (aSAH). METHODS: The PAOFI was completed by 182 participants 3 months after verified aSAH. Exploratory factor analysis was used to evaluate the underlying factor structure of the PAOFI and reliability and concurrent validity were evaluated for each subscale. RESULTS: A three-factor structure accounted for 58.9% of the extracted variance. Cronbach's alpha coefficients for extracted factors ranged from .867 to .924. The PAOFI subscales demonstrated concurrent validity with neuropsychological tests measuring similar constructs. CONCLUSION: There is evidence of reliability and validity of the PAOFI following aSAH. Further studies are needed to confirm these results.

Methylation Data Processing Protocol and Comparison of Blood and Cerebral Spinal Fluid Following Aneurysmal Subarachnoid Hemorrhage.

One challenge in conducting DNA methylation-based epigenome-wide association study (EWAS) is the appropriate cleaning and quality-checking of data to minimize biases and experimental artifacts, while simultaneously retaining potential biological signals. These issues are compounded in studies that include multiple tissue types, and/or tissues for which reference data are unavailable to assist in adjusting for cell-type mixture, for example cerebral spinal fluid (CSF). For our study that evaluated blood and CSF taken from aneurysmal subarachnoid hemorrhage (aSAH) patients, we developed a protocol to clean and quality-check genome-wide methylation levels and compared the methylomic profiles of the two tissues to determine whether blood is a suitable surrogate for CSF. CSF samples were collected from 279 aSAH patients longitudinally during the first 14 days of hospitalization, and a subset of 88 of these patients also provided blood samples within the first 2 days. Quality control (QC) procedures included identification and exclusion of poor performing samples and low-quality probes, functional normalization, and correction for cell-type heterogeneity via surrogate variable analysis (SVA). Significant differences in rates of poor sample performance was observed between blood (1.1% failing QC) and CSF (9.12% failing QC; p = 0.003). Functional normalization increased the concordance of methylation values among technical replicates in both CSF and blood. SVA improved the asymptotic behavior of the test of association in a simulated EWAS under the null hypothesis. To determine the suitability of blood as a surrogate for CSF, we calculated the correlations of adjusted methylation values at each CpG between blood and CSF globally and by genomic regions. Overall, mean within-CpG correlation was low (r < 0.26), suggesting that blood is not a suitable surrogate for global methylation in CSF. However, differences in the magnitude of the correlation were observed by genomic region (CpG island, shore, shelf, open sea; p < 0.001 for all) and orientation with respect to nearby genes (3' UTR, transcription start site, exon, body, 5' UTR; p < 0.01 for all). In conclusion, the correlation analysis and QC pipelines indicated that DNA extracted from blood was not, overall, a suitable surrogate for DNA from CSF in aSAH methylomic studies.

Neurocardiac Injury Assessed by Strain Imaging Is Associated With In-Hospital Mortality in Patients With Subarachnoid Hemorrhage.

OBJECTIVES: This study sought to test the hypothesis that speckle tracking strain echocardiography can quantify neurocardiac injuries in patients with aneurysmal subarachnoid hemorrhage (SAH), which is associated with worse clinical outcome. BACKGROUND: SAH may be a life-threatening disease associated with variable degrees of neurocardiac injury. Strain imaging has the potential to detect subtle myocardial dysfunction which is additive to conventional measurements. METHODS: A total of 255 consecutive patients were prospectively enrolled with acute SAH, who were admitted to the intensive care unit with echocardiography studies within 72 h. Left ventricular (LV) and right ventricular (RV) strains were acquired from standard apical views. Abnormal LV global longitudinal strain (GLS) and RV free-wall strain were pre-defined as <17% and <23% (absolute values), respectively. RESULTS: Performing LV GLS was feasible in 221 patients (89%) 53 ± 10 years of age, 71% female, after excluding those with previous cardiac disease. Abnormal LV GLS findings were observed in 53 patients (24%) and were associated with worse clinical severity, including a Hunt-Hess grade >3 (34% vs. 15%; p = 0.005) and biomarker evidence of neurocardiac injury and higher troponin values (1.50 [interquartile range (IQR): 0.01 to 3.87] vs. 0.01 [IQR: 0.01 to 0.22] ng/ml; p < 0.001). A reverse Takotsubo pattern of segmental strain was observed in 49% of patients (apical sparing and reduced basal strain). Importantly, LV GLS was more strongly associated with in-hospital mortality than left ventricular ejection fraction (LVEF), even after adjusting for clinical severity (odds ratio [OR]: 3.11; 95% confidence interval [CI]: 1.12 to 8.63; p = 0.029). RV strain was measured in 159 subjects (72%); abnormal RV strain was added to LV GLS for predicting in-hospital mortality (p = 0.007). CONCLUSIONS: Neurocardiac injury can be detected by LV GLS and RV strain in patients with acute SAH. LV GLS was significantly associated with in-hospital mortality. RV strain, when available, added prognostic value to LV GLS. Abnormal myocardial strain is a marker for increased risk of in-hospital mortality in SAH and has clinical prognostic utility.

Elevated cardiac troponin I and relationship to persistence of electrocardiographic and echocardiographic abnormalities after aneurysmal subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Cardiac injury persistence after aneurysmal subarachnoid hemorrhage (aSAH) is not well described. We hypothesized that post-aSAH cardiac injury, detected by elevated cardiac troponin I (cTnI), is related to aSAH severity and associated with electrocardiographic and structural echocardiographic abnormalities that are persistent. METHODS: Prospective longitudinal study was conducted of patients with aSAH with Fisher grade >or=2 and/or Hunt/Hess grade >or=3. Serum cTnI was collected on Days 1 to 5; cohort dichotomized into peak cTnI >or=0.3 ng/mL (elevated) or cTnI <0.3 ng/mL. Relationships among cTnI and aSAH severity, 12-lead electrocardiography early (or=7 days), Holter monitoring on Days 1 to 5, and transthoracic echocardiogram (left ventricular ejection fraction and regional wall motion abnormalities) early (Days 0 to 5) and late (Days 5 to 12) were evaluated. RESULTS: Of 204 subjects, 31% had cTnI >or=0.3 ng/mL. cTnI >or=0.3 ng/mL was incrementally related to aSAH severity by admission symptoms (Hunt/Hess P=0.001) and blood load (Fisher P=0.028). More patients with cTnI >or=0.3 ng/mL had prolonged QTc on early (63% versus 30%, P<0.0001) and late electrocardiography (24% versus 7%, P=0.024). On Holter monitoring, more patients with cTnI >or=0.3 ng/mL had ventricular tachycardia/fibrillation (22% versus 9%, P=0.018) but not atrial fibrillation/flutter (P=0.241). Cardiac troponin I >or=0.3 ng/mL was associated with both early ejection fraction <50% (44% versus 5%, P<0.0001) and regional wall motion abnormalities (44% versus 4%, P<0.0001). Regional wall motion abnormalities predominated in basal and midventricular segments and persisted to some degree in 73% of patients affected, whereas ejection fraction <50% persisted in 59% of patients affected. CONCLUSIONS: Cardiac injury is incrementally worse with increasing aSAH severity and associated with persistent QTc prolongation and ventricular arrhythmias. Regional wall motion abnormalities and depressed ejection fraction persist to some degree in the majority of those affected.