Implementing the Lolli-Method and pooled RT-qPCR testing for SARS-CoV-2 surveillance in schools: a pilot project.

PURPOSE: School closures have been used as part of lockdown strategies to contain the spread of SARS-CoV-2, adversely affecting children's health and education. To ensure the accessibility of educational institutions without exposing society to the risk of increased transmissions, it is essential to establish SARS-CoV-2 testing strategies that are child-friendly, scalable and implementable in a daily school routine. Self-sampling using non-invasive saliva swabs combined with pooled RT-qPCR testing (Lolli-Method) has been proven to be a sensitive method for the detection of SARS-CoV-2. METHODS: We conducted a pilot project in Cologne, Germany, designed to determine the feasibility of a large-scale rollout of the Lolli-Method for testing without any additional on-site medical staff in schools. Over a period of three weeks, students from 22 schools were sampled using the Lolli-Method. At the end of the project, teachers were asked to evaluate the overall acceptance of the project. RESULTS: We analyzed a total of 757 pooled RT-qPCRs obtained from 8,287 individual swabs and detected 7 SARS-CoV-2 infected individuals. The Lolli-Method was shown to be a feasible and accepted testing strategy whose application is only slightly disruptive to the daily school routine. CONCLUSION: Our observations suggest that the Lolli-Method in combination with pooled RT-qPCR can be implemented for SARS-CoV-2 surveillance in daily school routine, applicable on a large scale.

Risk factors for survival following recurrence after first liver resection for colorectal cancer liver metastases.

BACKGROUND: Management of recurrence following liver resection for colorectal cancer metastases is a topic of debate. We determined risk factors for survival following recurrence after liver resection. METHODS: Long-term follow-up of patients in the PETCAM trial who had recurrence following liver resection. Risk groups were created according to their survival risk. Differences in overall survival (OS) between groups were estimated. Disease-free survival (DFS), patterns of disease recurrence and management were determined. Cox proportional hazard models, Kaplan-Meier method, and the log-rank test were used. RESULTS: Among 368 patients who underwent liver resection, 264 (72%) experienced disease recurrence (51% lung and 41% liver). Following liver resection, DFS: 17 months (95% CI, 14-19); OS: 57 months (95% CI, 46-70). In those who recurred, 120 (45%) received chemotherapy only, and 112 (42%) underwent second surgical resection. Among patients who experienced recurrence (n = 264), the high-risk group (more than one site of recurrence or disease-free duration < 5 months and node-positive disease) had median OS: 19 months (95% CI, 15-23) vs 36 months (95% CI, 30-48) for patients in the low-risk group (HR = 2.9, 95% CI, 2.2-3.9). CONCLUSION: Recurrence following liver resection is common. Following recurrence after liver resection, patients should be carefully selected for surgical re-resection based on risk factors.

Post-traumatic epilepsy associations with mental health outcomes in the first two years after moderate to severe TBI: A TBI Model Systems analysis.

PURPOSE: Research suggests that there are reciprocal relationships between mental health (MH) disorders and epilepsy risk. However, MH relationships to post-traumatic epilepsy (PTE) have not been explored. Thus, the objective of this study was to assess associations between PTE and frequency of depression and/or anxiety in a cohort of individuals with moderate-to-severe TBI who received acute inpatient rehabilitation. METHODS: Multivariate regression models were developed using a recent (2010-2012) cohort (n=867 unique participants) from the TBI Model Systems (TBIMS) National Database, a time frame during which self-reported seizures, depression [Patient Health Questionnaire (PHQ)-9], and anxiety [Generalized Anxiety Disorder (GAD-7)] follow-up measures were concurrently collected at year-1 and year-2 after injury. RESULTS: PTE did not significantly contribute to depression status in either the year-1 or year-2 cohort, nor did it contribute significantly to anxiety status in the year-1 cohort, after controlling for other known depression and anxiety predictors. However, those with PTE in year-2 had 3.34 times the odds (p=.002) of having clinically significant anxiety, even after accounting for other relevant predictors. In this model, participants who self-identified as Black were also more likely to report clinical symptoms of anxiety than those who identified as White. PTE was the only significant predictor of comorbid depression and anxiety at year-2 (Odds Ratio 2.71; p=0.049). CONCLUSIONS: Our data suggest that PTE is associated with MH outcomes 2years after TBI, findings whose significance may reflect reciprocal, biological, psychological, and/or experiential factors contributing to and resulting from both PTE and MH status post-TBI. Future work should consider temporal and reciprocal relationships between PTE and MH as well as if/how treatment of each condition influences biosusceptibility to the other condition.

Genetic Variation in the Vesicular Monoamine Transporter: Preliminary Associations With Cognitive Outcomes After Severe Traumatic Brain Injury.

INTRODUCTION: Traumatic brain injury (TBI) frequently results in impaired cognition, a function that can be modulated by monoaminergic signaling. Genetic variation among monoaminergic genes may affect post-TBI cognitive performance. The vesicular monoamine transporter-2 (VMAT2) gene may be a novel source of genetic variation important for cognitive outcomes post-TBI given VMAT2's role in monoaminergic neurotransmission. OBJECTIVE: To evaluate associations between VMAT2 variability and cognitive outcomes post-TBI. METHODS: We evaluated 136 white adults with severe TBI for variation in VMAT2 using a tagging single nucleotide polymorphism (tSNP) approach (rs363223, rs363226, rs363251, and rs363341). We show genetic variation interacts with assessed cognitive impairment (cognitive composite [Comp-Cog] T-scores) to influence functional cognition (functional independence measure cognitive [FIM-Cog] subscale] 6 and 12 months postinjury. RESULTS: Multivariate analyses at 6 months postinjury showed rs363226 genotype was associated with Comp-Cog (P = .040) and interacted with Comp-Cog to influence functional cognition (P < .001). G-homozygotes had the largest cognitive impairment, and their cognitive impairment had the greatest adverse effect on functional cognition. DISCUSSION: We provide the first evidence that genetic variation within VMAT2 is associated with cognitive outcomes after TBI. Further work is needed to validate this finding and elucidate mechanisms by which genetic variation affects monoaminergic signaling, mediating differences in cognitive outcomes.

Genetic variation in neuronal glutamate transport genes and associations with posttraumatic seizure.

OBJECTIVE: Posttraumatic seizures (PTS) commonly occur following severe traumatic brain injury (sTBI). Risk factors for PTS have been identified, but variability in who develops PTS remains. Excitotoxicity may influence epileptogenesis following sTBI. Glutamate transporters manage glutamate levels and excitatory neurotransmission, and they have been associated with both epilepsy and TBI. Therefore, we aimed to determine if genetic variation in neuronal glutamate transporter genes is associated with accelerated epileptogenesis and increased PTS risk after sTBI. METHODS: Individuals (N = 253) 18-75 years of age with sTBI were assessed for genetic relationships with PTS. Single nucleotide polymorphisms (SNPs) within SLC1A1 and SLC1A6 were assayed. Kaplan-Meier estimates and log-rank statistics were used to compare seizure rates from injury to 3 years postinjury for SNPs by genotype. Hazard ratios (HRs) were estimated using Cox proportional hazards regression for SNPs significant in Kaplan-Meier analyses adjusting for known PTS risk factors. RESULTS: Thirty-two tagging SNPs were examined (SLC1A1: n = 28, SLC1A6: n = 4). Forty-nine subjects (19.37%) had PTS. Of these, 18 (36.7%) seized within 7 days, and 31 (63.3%) seized between 8 days and 3 years post-TBI. With correction for multiple comparisons, genotypes at SNP rs10974620 (SLC1A1) were significantly associated with time to first seizure across the full 3-year follow-up (seizure rates: 77.1% minor allele homozygotes, 24.8% heterozygotes, 16.6% major allele homozygotes; p = 0.001). When seizure follow-up began day 2 postinjury, genotypes at SNP rs7858819 (SLC1A1) were significantly associated with PTS risk (seizure rates: 52.7% minor allele homozygotes, 11.8% heterozygotes, 21.1% major allele homozygotes; p = 0.002). After adjusting for covariates, we found that rs10974620 remained significant (p = 0.017, minor allele versus major allele homozygotes HR 3.4, 95% confidence interval [CI] 1.3-9.3). rs7858819 also remained significant in adjusted models (p = 0.023, minor allele versus major allele homozygotes HR 3.4, 95%CI 1.1-10.5). SIGNIFICANCE: Variations within SLC1A1 are associated with risk of epileptogenesis following sTBI. Future studies need to confirm findings, but variation within neuronal glutamate transporter genes may represent a possible pharmaceutical target for PTS prevention and treatment.

Incidence and risk factors of posttraumatic seizures following traumatic brain injury: A Traumatic Brain Injury Model Systems Study.

OBJECTIVE: Determine incidence of posttraumatic seizure (PTS) following traumatic brain injury (TBI) among individuals with moderate-to-severe TBI requiring rehabilitation and surviving at least 5 years. METHODS: Using the prospective TBI Model Systems National Database, we calculated PTS incidence during acute hospitalization, and at years 1, 2, and 5 postinjury in a continuously followed cohort enrolled from 1989 to 2000 (n = 795). Incidence rates were stratified by risk factors, and adjusted relative risk (RR) was calculated. Late PTS associations with immediate (<24 h), early (24 h-7 day), or late seizures (>7 day) versus no seizure prior to discharge from acute hospitalization was also examined. RESULTS: PTS incidence during acute hospitalization was highest immediately (<24 h) post-TBI (8.9%). New onset PTS incidence was greatest between discharge from inpatient rehabilitation and year 1 (9.2%). Late PTS cumulative incidence from injury to year 1 was 11.9%, and reached 20.5% by year 5. Immediate/early PTS RR (2.04) was increased for those undergoing surgical evacuation procedures. Late PTS RR was significantly greater for individuals who self-identified as a race other than black/white (year 1 RR = 2.22), and for black individuals (year 5 RR = 3.02) versus white individuals. Late PTS was greater for individuals with subarachnoid hemorrhage (year 1 RR = 2.06) and individuals age 23-32 (year 5 RR = 2.43) and 33-44 (year 5 RR = 3.02). Late PTS RR years 1 and 5 was significantly higher for those undergoing surgical evacuation procedures (RR: 3.05 and 2.72, respectively). SIGNIFICANCE: In this prospective, longitudinal, observational study, PTS incidence was similar to that in studies published previously. Individuals with immediate/late seizures during acute hospitalization have increased late PTS risk. Race, intracranial pathologies, and neurosurgical procedures also influenced PTS RR. Further studies are needed to examine the impact of seizure prophylaxis in high-risk subgroups and to delineate contributors to race/age associations on long-term seizure outcomes.

Prognostic models for predicting posttraumatic seizures during acute hospitalization, and at 1 and 2 years following traumatic brain injury.

OBJECTIVE: Posttraumatic seizures (PTS) are well-recognized acute and chronic complications of traumatic brain injury (TBI). Risk factors have been identified, but considerable variability in who develops PTS remains. Existing PTS prognostic models are not widely adopted for clinical use and do not reflect current trends in injury, diagnosis, or care. We aimed to develop and internally validate preliminary prognostic regression models to predict PTS during acute care hospitalization, and at year 1 and year 2 postinjury. METHODS: Prognostic models predicting PTS during acute care hospitalization and year 1 and year 2 post-injury were developed using a recent (2011-2014) cohort from the TBI Model Systems National Database. Potential PTS predictors were selected based on previous literature and biologic plausibility. Bivariable logistic regression identified variables with a p-value < 0.20 that were used to fit initial prognostic models. Multivariable logistic regression modeling with backward-stepwise elimination was used to determine reduced prognostic models and to internally validate using 1,000 bootstrap samples. Fit statistics were calculated, correcting for overfitting (optimism). RESULTS: The prognostic models identified sex, craniotomy, contusion load, and pre-injury limitation in learning/remembering/concentrating as significant PTS predictors during acute hospitalization. Significant predictors of PTS at year 1 were subdural hematoma (SDH), contusion load, craniotomy, craniectomy, seizure during acute hospitalization, duration of posttraumatic amnesia, preinjury mental health treatment/psychiatric hospitalization, and preinjury incarceration. Year 2 significant predictors were similar to those of year 1: SDH, intraparenchymal fragment, craniotomy, craniectomy, seizure during acute hospitalization, and preinjury incarceration. Corrected concordance (C) statistics were 0.599, 0.747, and 0.716 for acute hospitalization, year 1, and year 2 models, respectively. SIGNIFICANCE: The prognostic model for PTS during acute hospitalization did not discriminate well. Year 1 and year 2 models showed fair to good predictive validity for PTS. Cranial surgery, although medically necessary, requires ongoing research regarding potential benefits of increased monitoring for signs of epileptogenesis, PTS prophylaxis, and/or rehabilitation/social support. Future studies should externally validate models and determine clinical utility.

IL-1ß associations with posttraumatic epilepsy development: A genetics and biomarker cohort study.

OBJECTIVE: Posttraumatic epilepsy (PTE) is a significant complication following traumatic brain injury (TBI), yet the role of genetic variation in modulating PTE onset is unclear. We hypothesized that TBI-induced inflammation likely contributes to seizure development. We assessed whether genetic variation in the interleukin-1beta (IL-1ß) gene, Il-1ß levels in cerebral spinal fluid (CSF) and serum, and CSF/serum IL-1ß ratios would predict PTE development post-TBI. METHODS: We investigated PTE development in 256 Caucasian adults with moderate-to-severe TBI. IL-1ß tagging and functional single nucleotide polymorphisms (SNPs) were genotyped. Genetic variance and PTE development were assessed. Serum and CSF IL-1ß levels were collected from a subset of subjects (n = 59) during the first week postinjury and evaluated for their associations with IL-1ß gene variants, and also PTE. Temporally matched CSF/serum IL-1ß ratios were also generated to reflect the relative contribution of serum IL-1ß to CSF IL-1ß. RESULTS: Multivariate analysis showed that higher CSF/serum IL-1ß ratios were associated with increased risk for PTE over time (p = 0.008). Multivariate analysis for rs1143634 revealed an association between the CT genotype and increased PTE risk over time (p = 0.005). The CT genotype group also had lower serum IL-1ß levels (p = 0.014) and higher IL-1ß CSF/serum ratios (p = 0.093). SIGNIFICANCE: This is the first report implicating IL-1ß gene variability in PTE risk and linking (1) IL-1ß gene variation with serum IL-1ß levels observed after TBI and (2) IL-1ß ratios with PTE risk. Given these findings, we propose that genetic and IL-1ß ratio associations with PTE may be attributable to biologic variability with blood-brain barrier integrity during TBI recovery. These results provide a rationale for further studies (1) validating the impact of genetic variability on IL-1ß production after TBI, (2) assessing genetically mediated signaling mechanisms that contribute to IL-1ß CSF/serum associations with PTE, and (3) evaluating targeted IL-1ß therapies that reduce PTE. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Genetic variation in the adenosine regulatory cycle is associated with posttraumatic epilepsy development.

OBJECTIVE: Determine if genetic variation in enzymes/transporters influencing extracellular adenosine homeostasis, including adenosine kinase (ADK), [ecto-5'-nucleotidase (NT5E), cluster of differentiation 73 (CD73)], and equilibrative nucleoside transporter type-1 (ENT-1), is significantly associated with epileptogenesis and posttraumatic epilepsy (PTE) risk, as indicated by time to first seizure analyses. METHODS: Nine ADK, three CD73, and two ENT-1 tagging single nucleotide polymorphisms (SNPs) were genotyped in 162 white adults with moderate/severe traumatic brain injury (TBI) and no history of premorbid seizures. Kaplan-Meier models were used to screen for genetic differences in time to first seizure occurring >1 week post-TBI. SNPs remaining significant after correction for multiple comparisons were examined using Cox proportional hazards analyses, adjusting for subdural hematoma, injury severity score, and isolated TBI status. SNPs significant in multivariate models were then entered simultaneously into an adjusted Cox model. RESULTS: Comparing Kaplan-Meier curves, rs11001109 (ADK) rare allele homozygosity and rs9444348 (NT5E) heterozygosity were significantly associated with shorter time to first seizure and an increased seizure rate 3 years post-TBI. Multivariate Cox proportional hazard models showed that these genotypes remained significantly associated with increased PTE hazard up to 3 years post-TBI after controlling for variables of interest (rs11001109: hazard ratio (HR) 4.47, 95% confidence interval (CI) 1.27-15.77, p = 0.020; rs9444348: HR 2.95, 95% CI 1.19-7.31, p = 0.019) . SIGNIFICANCE: Genetic variation in ADK and NT5E may help explain variability in time to first seizure and PTE risk, independent of previously identified risk factors, after TBI. Once validated, identifying genetic variation in adenosine regulatory pathways relating to epileptogenesis and PTE may facilitate exploration of therapeutic targets and pharmacotherapy development.

Factors Determining Periprocedural and Long-term Complications of High Risk Carotid Artery Stenting.

BACKGROUND AND PURPOSE: Carotid artery stenting (CAS) has been, historically, an alternative to open endarterectomy (CEA) for stroke prevention in high risk patients with carotid atherosclerosis. We sought to determine the rates of periprocedural and long-term stroke or death and the risk factors for complications after CAS in our high risk patient population. METHODS: Clinical and treatment variables of consecutive CAS procedures performed between 2002 and 2011 were analyzed. Using univariate and multivariate logistic regression analyses we examined how patient characteristics influenced outcomes and changes in modified Rankin Score (mRS). RESULTS: In 152 patients, the composite total of periprocedural death, stroke, transient ischemic attack (TIA) and myocardial infarction (MI) rate was 3.95% (6/152). Chronic kidney disease (CKD) was strongly associated with periprocedural complications (p<0.001). Coronary artery disease/peripheral vascular disease (CAD/PVD) (p=0.03), dyslipidemia (p=0.02), CKD (p=0.01), and contralateral internal carotid artery stenosis (p=0.02) were non-modifiable risk factors for mRS increase. There were 25 deaths, 8 strokes, 11 TIAs, and 1 MI (mean follow-up 38.4 months, range 0-116 months). The presence of CAD/PVD (p=0.009) and dyslipidemia (p=0.002) were significantly associated with long-term complications. CONCLUSION: CAS was performed with low periprocedural complications in high-risk patients. Our rates compare very favorably to large-scale trials that have ideal patients. This data encourages the consideration of CAS in patients considered high risk for CEA and provides possible patient characteristics (CKD) to help with periprocedural risk stratification.

IL-1ß associations with posttraumatic epilepsy development: a genetics and biomarker cohort study.

OBJECTIVE: Posttraumatic epilepsy (PTE) is a significant complication following traumatic brain injury (TBI), yet the role of genetic variation in modulating PTE onset is unclear. We hypothesized that TBI-induced inflammation likely contributes to seizure development. We assessed whether genetic variation in the interleukin-1beta (IL-1ß) gene, IL-1ß levels in cerebrospinal fluid (CSF) and serum, and CSF/serum IL-1ß ratios would predict PTE development post-TBI. METHODS: We investigated PTE development in 256 Caucasian adults with moderate-to-severe TBI. IL-1ß tagging and functional single nucleotide polymorphisms (SNPs) were genotyped. Genetic variance and PTE development were assessed. Serum and CSF IL-1ß levels were collected from a subset of subjects (n = 59) during the first week postinjury and evaluated for their associations with IL-1ß gene variants, and also PTE. Temporally matched CSF/serum IL-1ß ratios were also generated to reflect the relative contribution of serum IL-1ß to CSF IL-1ß. RESULTS: Multivariate analysis showed that higher CSF/serum IL-1ß ratios were associated with increased risk for PTE over time (p = 0.008). Multivariate analysis for rs1143634 revealed an association between the CT genotype and increased PTE risk over time (p = 0.005). The CT genotype group also had lower serum IL-1ß levels (p = 0.014) and higher IL-1ß CSF/serum ratios (p = 0.093). SIGNIFICANCE: This is the first report implicating IL-1ß gene variability in PTE risk and linking (1) IL-1ß gene variation with serum IL-1ß levels observed after TBI and (2) IL-1ß ratios with PTE risk. Given these findings, we propose that genetic and IL-1ß ratio associations with PTE may be attributable to biologic variability with blood-brain barrier integrity during TBI recovery. These results provide a rationale for further studies (1) validating the impact of genetic variability on IL-1ß production after TBI, (2) assessing genetically mediated signaling mechanisms that contribute to IL-1ß CSF/serum associations with PTE, and (3) evaluating targeted IL-1ß therapies that reduce PTE.

Cardiovascular effects, pharmacokinetics and cross-reactivity in digitalis glycoside immunoassays of an antidiarrheal uzara root extract.

Uzara glycosides (UG) extracted from Xysmalobium undulatum are used for treating non-specific diarrhea.Cross-reactivity has been described for UG in digitalis glycoside assays but digitalis-like cardiac effects are controversially discussed. Therefore, we performed a randomized, singleblind cross-over study in 18 healthy volunteers receiving a commercially available Uzara product (Uzara® Lösung N, Stada AG, Bad Vilbel, Germany (ULN)), digoxin (1 mg, i.v., positive control) and placebo in double-dummy technique. Pharmacodynamic effects were quantified by means of ECG and impedance cardiography (ICG). After oral administration of ULN, main metabolites were determined using HPLC-MS/MS and digitalis-like serum levels (DLSL) were measured in two digitoxin and digoxin assays, respectively. In comparison to placebo, ULN did not change significantly any PD parameters whereas digoxin altered significantly area under the effect curve of several ECG and ICG parameters, respectively. Since some serum levels of three ULN ingredients (uzarin, uzarigenin and xysmalorin) were below LLQ, PK analyses could only be performed for allouzarigenin and revealed a marked inter-individual variability. Therefore, median values (min; max) were calculated as follows: Cmax = 0.39 (0.15; 1.81) ng/ml, tmax = 7.0 (3.0; 36.0) h, T1/2 = 5.2 (0.8; 23.6) h, AUC0-36h = 4.2 (0.8; 11.1) ng/ml×h, AUC0-∞ = 5.8 (1.8; 13.1) ng/ml×h. DLSL reached Cmax of 28 ng/ml and 1,980 ng/ml for digoxin and digitoxin, respectively. We could not observe significant cardiovascular pharmacodynamic effects after oral administration of the recommended single dose of Uzara extract to healthy volunteers. However, considerable DLSL could be detected, proving cross-reactivity of uzara components with the conventional digitalis assays used. However, none of the metabolites we had suspected to be the cause for the crossreactivity could be identified in reasonable quantities.

Top 10 Research Priorities for U.S. Military En Route Combat Casualty Care.

INTRODUCTION: Within the Military Health System, the process of transporting patients from an initial point of injury and throughout the entire continuum of care is called "en route care." A Committee on En Route Combat Casualty Care was established in 2016 as part of the DoD Joint Trauma System to create practice guidelines, recommend training standards, and identify research priorities within the military en route care system. MATERIALS AND METHODS: Following an analysis of currently funded research, future capabilities, and findings from a comprehensive scoping study, members of a sub-working group for research identified the top research priorities that were needed to better guide evidence-based decisions for practice and policy, as well as the future state of en route care. RESULTS: Based on the input from the entire committee, 10 en route care research topics were rank-ordered in the following manner: (1) medical documentation, (2) clinical decision support, (3) patient monitoring, (4) transport physiology, (5) transfer of care, (6) maintaining normothermia, (7) transport timing following damage control resuscitation or surgery, (8) intelligent tasking, (9) commander's risk assessment, and (10) unmanned transport. Specific research questions and technological development needs were further developed by committee members in an effort to guide future research and development initiatives that can directly support operational en route care needs. The research priorities reflect three common themes, which include efforts to enhance or increase care provider capability and capacity; understand the impact of transportation on patient physiology; and increase the ability to coordinate, communicate, and facilitate patient movement. Technology needs for en route care must support interoperability of medical information, equipment, and supplies across the global military health system in addition to adjusting to a dynamic transport environment with the smallest possible weight, space, and power requirements. CONCLUSIONS: To ensure an evidence-based approach to future military conflicts and other medical challenges, focused research and technological development to address these 10 en route care research gaps are urgently needed.

Mindfulness and Executive Functions: Making the Case for Elementary School Practice.

This study explores the use of mindfulness school-based intervention program in an elementary school. Mindfulness training is an accepted and effective didactic approach to improve the executive functions (EFs) of elementary school students. This study aimed to evaluate the effects of the Mind Yeti program on the executive functions of elementary school students. A diverse sample of third, fourth, and fifth grade elementary school students (n = 177) participated in their natural classroom setting, with six sessions per week for six weeks. Students self-reported their EFs on the Executive Function Student Questionnaire (EFSQ) pre- and posttest. Paired-sample t-tests indicated that students significantly improved on the three of the six EFs examined. Additionally, students in fifth grade responded better to Mind Yeti than students in third grade. Results were consistent with the hypothesis, suggesting that Mind Yeti is an appropriate and effective intervention for improving the EFs of students.

Variability with Astroglial Glutamate Transport Genetics Is Associated with Increased Risk for Post-Traumatic Seizures.

Excitotoxicity contributes to epileptogenesis after severe traumatic brain injury (sTBI). Demographic and clinical risk factors for post-traumatic seizures (PTS) have been identified, but genetic risk remains largely unknown. Thus, we investigated whether genetic variation in astroglial glutamate transporter genes is associated with accelerated epileptogenesis and PTS risk after sTBI. Adults (n = 267) 18-75 years old were assessed over a three-year period post-TBI. Single nucleotide polymorphisms (SNPs) throughout the SLC1A2 and SLC1A3 genes were assayed. Kaplan-Meier estimates and log-rank statistics were used to compare seizure frequencies by genotype. Multivariate Cox proportional hazards regression was used to estimate hazard ratios (HRs) for genotypes significant in Kaplan-Meier analyses. Thirty-nine tagging SNPs were examined (SLC1A2: n = 21, SLC1A3: n = 18). PTS developed in 57 (21.4%) individuals. Of those with PTS, n = 20 (35.7%) had an immediate/early seizure within the first seven days, and n = 36 (64.3%) had a late seizure occurring between eight days and three years post-TBI. When adjusting for multiple comparisons, rs4869682 genotypes (SLC1A3, GG vs. T-carriers) were associated with time to first seizure (p = 0.003). Median time until first seizure was 20.4 days for individuals with a GG genotype and 44.8 days for T-carriers. After adjusting for covariates, rs4869682 GG-homozygotes had a 2.05 times increased PTS risk versus T-carriers (aHR = 2.08, 95% confidence interval: 1.20, 3.62, p = 0.009). Variation within SLC1A3 is associated with accelerated epileptogenesis and clinical PTS development after sTBI. Future studies should validate these findings and examine how genetic variation at rs4869682 may be a target for PTS prevention and treatment.

Probabilistic Matching Approach to Link Deidentified Data from a Trauma Registry and a Traumatic Brain Injury Model System Center.

OBJECTIVE: There is no civilian traumatic brain injury database that captures patients in all settings of the care continuum. The linkage of such databases would yield valuable insight into possible care interventions. Thus, the objective of this article is to describe the creation of an algorithm used to link the Traumatic Brain Injury Model System (TBIMS) to trauma data in state and national trauma databases. DESIGN: The TBIMS data from a single center was randomly divided into two sets. One subset was used to generate a probabilistic linking algorithm to link the TBIMS data to the center's trauma registry. The other subset was used to validate the algorithm. Medical record numbers were obtained and used as unique identifiers to measure the quality of the linkage. Novel methods were used to maximize the positive predictive value. RESULTS: The algorithm generation subset had 121 patients. It had a sensitivity of 88% and a positive predictive value of 99%. The validation subset consisted of 120 patients and had a sensitivity of 83% and a positive predictive value of 99%. CONCLUSIONS: The probabilistic linkage algorithm can accurately link TBIMS data across systems of trauma care. Future studies can use this database to answer meaningful research questions regarding the long-term impact of the acute trauma complex on health care utilization and recovery across the care continuum in traumatic brain injury populations.

Visual Priming Enhances the Effects of Nonspatial Cognitive Rehabilitation Training on Spatial Learning After Experimental Traumatic Brain Injury.

Previous work demonstrates that spatial (explicit) and nonspatial (implicit) elements of place learning in the Morris water maze (MWM) task can be dissociated and examined in the context of experimental traumatic brain injury (TBI). Providing nonspatial cognitive training (CT) after injury can improve place learning compared with untrained controls. In the present study, we hypothesized that brief exposure to extra-maze cues, in conjunction with CT, may further improve MWM performance and extra-maze cue utilization compared with CT alone. Adult male Sprague-Dawley rats (n = 66) received controlled cortical impact (CCI) injury or sham surgery. Beginning day 8 postsurgery, CCI and sham rats received 6 days of no training (NT) or CT with/without brief, noncontextualized exposure to extra-maze cues (BE and CT, respectively). Acquisition (days 14-18), visible platform (VP; day 19), carryover (CO; days 20-26), and periodic probe trials were performed. Platform latencies, peripheral and target zone time allocation, and search strategies were assessed. CCI/BE rats had shorter acquisition trial latencies than CCI/NT (P < .001) and tended to have shorter latencies than CCI/CT rats (P < .10). Both BE and CT reduced peripheral zone swimming for CCI rats versus CCI/NT. CCI/BE animals increased spatial swim strategies from day 14 to day 18 relative to CCI/CT and showed similar swim strategy selection to the Sham/NT group. These data suggest that visual priming improves initial place learning in the MWM. These results support the visual priming response as another clinically relevant experimental rehabilitation construct, to use when assessing injury and treatment effects of behavioral and pharmacological therapies on cognition after TBI.

Brain venular pattern by 7T MRI correlates with memory and haemoglobin in sickle cell anaemia.

Sickle cell anaemia (SCA) is a hereditary hemoglobinopathy characterised by extensive vascular dysfunction that stems from inflammation, thrombosis and occlusion of post-capillary venules. Cognitive impairment is a neurological complication of SCA whose pathogenesis is unknown. We hypothesised that cerebral venular abnormalities are linked to cognitive impairment in SCA. Thus, we employed 7T magnetic resonance imaging (MRI) to examine the association between venular density and cognitive function in homozygous SCA. We quantified the density of total, long, and short venules in pre-defined regions of interest between the frontal and occipital cornu on each hemisphere. Cognitive function was assessed using the Hopkins Verbal Learning Test - Revised (HVLT-R) test of learning and memory. Patients (n=11) were compared with race, age and gender-equated controls (n=7). Compared to controls, patients had an overall venular rarefaction, with significantly lower density of long venules and greater density of short venules which was inversely related to HVLT-R performance and haemoglobin. To our knowledge, this is the first 7T MRI study in SCA and first report of associations between cerebral venular patterns and cognitive performance and haemoglobin. Future studies should examine whether these novel neuroimaging markers predict cognitive impairment longitudinally and are mechanistically linked to severity of anaemia.