Exploratory assessment of the effect of systemic administration of soluble glycoprotein 130 on cognitive performance and chemokine levels in a mouse model of experimental traumatic brain injury.

Uncontrolled neuroinflammation mediates traumatic brain injury (TBI) pathology and impairs recovery. Interleukin-6 (IL-6), a pleiotropic inflammatory regulator, is associated with poor clinical TBI outcomes. IL-6 operates via classical-signaling through membrane-bound IL-6 receptor (IL-6R) and trans-signaling through soluble IL-6 receptor (s)IL-6R. IL-6 trans-signaling specifically contributes to neuropathology, making it a potential precision therapeutic TBI target. Soluble glycoprotein 130 (sgp130) prevents IL-6 trans-signaling, sparing classical signaling, thus is a possible treatment. Mice received either controlled cortical impact (CCI) (6.0 ± 0.2 m/s; 2 mm; 50-60ms) or sham procedures. Vehicle (VEH) or sgp130-Fc was subcutaneously administered to sham (VEH or 1 µg) and CCI (VEH, 0.25 µg or 1 µg) mice on days 1, 4, 7, 10 and 13 post-surgery to assess effects on cognition [Morris Water Maze (MWM)] and ipsilateral hemisphere IL-6 related biomarkers (day 21 post-surgery). CCI + sgp130-Fc groups (0.25 µg and 1 µg) were combined for analysis given similar behavior/biomarker outcomes. CCI + VEH mice had longer latencies and path lengths to the platform and increased peripheral zone time versus Sham + VEH and Sham + sgp130-Fc mice, suggesting injury-induced impairments in learning and anxiety. CCI + sgp130-Fc mice had shorter platform latencies and path lengths and had decreased peripheral zone time, indicating a therapeutic benefit of sgp130-Fc after injury on learning and anxiety. Interestingly, Sham + sgp130-Fc mice had shorter platform latencies, path lengths and peripheral zone times than Sham + VEH mice, suggesting a beneficial effect of sgp130-Fc, independent of injury. CCI + VEH mice had increased brain IL-6 and decreased sgp130 levels versus Sham + VEH and Sham + sgp130-Fc mice. There was no treatment effect on IL-6, sIL6-R or sgp130 in Sham + VEH versus Sham + sgp130-Fc mice. There was also no treatment effect on IL-6 in CCI + VEH versus CCI + sgp130-Fc mice. However, CCI + sgp130-Fc mice had increased sIL-6R and sgp130 versus CCI + VEH mice, demonstrating sgp130-Fc treatment effects on brain biomarkers. Inflammatory chemokines (MIP-1ß, IP-10, MIG) were increased in CCI + VEH mice versus Sham + VEH and Sham + sgp130-Fc mice. However, CCI + sgp130-Fc mice had decreased chemokine levels versus CCI + VEH mice. IL-6 positively correlated, while sgp130 negatively correlated, with chemokine levels. Overall, we found that systemic sgp130-Fc treatment after CCI improved learning, decreased anxiety and reduced CCI-induced brain chemokines. Future studies will explore sex-specific dosing and treatment mechanisms for sgp130-Fc therapy.

Long-Term Neurodevelopmental Outcomes in Children with Gastroschisis: A Review of the Literature.

This study aimed to investigate and present a review of the literature on long-term neurodevelopmental outcomes in children with gastroschisis. Gastroschisis is the most common abdominal wall defect. Children with gastroschisis are at high risk for premature birth, intestinal failure, sepsis, and repeated anesthesia exposure, which collectively increase the risk for adverse long-term neurodevelopmental outcomes. The existing literature on neurodevelopmental outcomes is limited in number, quality, and generalizability, creating a gap in clinical knowledge and care. Five internet databases were searched by a professional research librarian: Ovid MEDLINE, Scopus, Web of Science, PsycINFO, and Cochrane Library. Included articles were (1) published in English, (2) included postneonatal hospital discharge neurodevelopmental outcomes of children with gastroschisis, and (3) included patients under the age of 18 years. No date parameters were applied. The paucity of literature on long-term neurodevelopmental outcomes in gastroschisis children has left large gaps in the body of knowledge on post-hospital care of such children. In this review, 37 articles were found evaluating neurodevelopmental outcomes in gastroschisis and, while conclusions were contradictory, the literature broadly indicated the potential for neurodevelopmental deficits in the gastroschisis pediatric population. A significant limitation of this review was the heterogeneous samples included in available literature, which confounded the ability to determine cognitive risk of gastroschisis independent of other abdominal wall defects. Findings of this review demonstrate potential risk for neurodevelopmental deficits in the pediatric gastroschisis population exist, yet additional research is needed to definitively predict the significance, type, onset, and trajectory of neurodevelopmental impairment in this population. The significant gaps in long-term outcomes data have elucidated the need for prospective, longitudinal investigation of various cognitive domains in homogenous gastroschisis populations to properly evaluate prevalence of neurodevelopmental deficits and guide recommendations for long-term clinical care. KEY POINTS: · Limited literature exists regarding long-term neurodevelopmental outcomes in gastroschisis.. · There is some evidence to suggest worse cognitive behavioral outcomes in gastroschisis over time.. · Developmental surveillance, screening, and evaluation may be beneficial for gastroschisis patients..

Temporal Profile of Serum Neurofilament Light (NF-L) and Heavy (pNF-H) Level Associations With 6-Month Cognitive Performance in Patients With Moderate-Severe Traumatic Brain Injury.

OBJECTIVE: Identification of biomarkers of cognitive recovery after traumatic brain injury (TBI) will inform care and improve outcomes. This study assessed the utility of neurofilament (NF-L and pNF-H), a marker of neuronal injury, informing cognitive performance following moderate-to-severe TBI (msTBI). SETTING: Level 1 trauma center and outpatient via postdischarge follow-up. PARTICIPANTS: N = 94. Inclusion criteria: Glasgow Coma Scale score less than 13 or 13-15 with clinical evidence of moderate-to-severe injury traumatic brain injury on clinical imaging. Exclusion criteria: neurodegenerative condition, brain death within 3 days after injury. DESIGN: Prospective observational study. Blood samples were collected at several time points post-injury. Cognitive testing was completed at 6 months post-injury. MAIN MEASURES: Serum NF-L (Human Neurology 4-Plex B) pNF-H (SR-X) as measured by SIMOA Quanterix assay. Divided into 3 categorical time points at days post-injury (DPI): 0-15 DPI, 16-90 DPI, and >90 DPI. Cognitive composite comprised executive functioning measures derived from 3 standardized neuropsychological tests (eg, Delis-Kaplan Executive Function System: Verbal Fluency, California Verbal Learning Test, Second Edition, Wechsler Adult Intelligence Scale, Third Edition). RESULTS: pNF-H at 16-90 DPI was associated with cognitive outcomes including a cognitive-executive composite score at 6 months (ß = -.430, t34 = -3.190, P = .003). CONCLUSIONS: Results suggest that "subacute" elevation of serum pNF-H levels may be associated with protracted/poor cognitive recovery from msTBI and may be a target for intervention. Interpretation is limited by small sample size and including only those who were able to complete cognitive testing.

Parallel Cerebrospinal Fluid and Serum Temporal Profile Assessment of Axonal Injury Biomarkers Neurofilament-Light Chain and Phosphorylated Neurofilament-Heavy Chain: Associations With Patient Outcome in Moderate-Severe Traumatic Brain Injury.

Neurofilament-light chain (NF-L) and phosphorylated neurofilament-heavy chain (pNF-H) are axonal proteins that have been reported as potential diagnostic and prognostic biomarkers in traumatic brain injury (TBI). However, detailed temporal profiles for these proteins in blood, and interrelationships in the acute and chronic time periods post-TBI have not been established. Our objectives were: 1) to characterize acute-to-chronic serum NF-L and pNF-H profiles after moderate-severe TBI, as well as acute cerebrospinal fluid (CSF) levels; 2) to evaluate CSF and serum NF-L and pNF-H associations with each other; and 3) to assess biomarker associations with global patient outcome using both the Glasgow Outcome Scale-Extended (GOS-E) and Disability Rating Scale (DRS). In this multi-cohort study, we measured serum and CSF NF-L and pNF-H levels in samples collected from two clinical cohorts (University of Pittsburgh [UPITT] and Baylor College of Medicine [BCM]) of individuals with moderate-severe TBI. The UPITT cohort includes 279 subjects from an observational cohort study; we obtained serum (n = 277 unique subjects) and CSF (n = 95 unique subjects) daily for 1 week, and serum every 2 weeks for 6 months. The BCM cohort included 103 subjects from a previous randomized clinical trial of erythropoietin and blood transfusion threshold after severe TBI, which showed no effect on neurological outcome between treatment arms; serum (n = 99 unique subjects) and CSF (n = 54 unique subjects) NF-L and pNF-H levels were measured at least daily during Days (D) 0-10 post-injury. GOS-E and DRS were assessed at 6 months (both cohorts) and 12 months (UPITT cohort only). Results show serum NF-L and pNF-H gradually rise during the first 10 days and peak at D20-30 post-injury. In the UPITT cohort, acute (D0-6) NF-L and pNF-H levels correlate within CSF and serum (Spearman r = 0.44-0.48; p < 0.05). In the UPITT cohort, acute NF-L CSF and serum levels, as well as chronic (Months [M]2-6) serum NF-L levels, were higher among individuals with unfavorable GOS-E and worse DRS at 12 months (p < 0.05, all comparisons). In the BCM cohort, higher acute serum NF-L levels were also associated with unfavorable GOS-E. Higher pNF-H serum concentrations (D0-6 and M2-6), but not CSF pNF-H, were associated with unfavorable GOS-E and worse DRS (p < 0.05, all comparisons) in the UPITT cohort. Relationships between biomarker levels and favorable outcome persisted after controlling for age, sex, and Glasgow Coma Scale. This study shows for the first time that serum levels of NF-L and pNF-H peak at D20-30 post-TBI. Serum NF-L levels, and to a lesser extent pNF-H levels, are robustly associated with global patient outcomes and disability after moderate-severe TBI. Further studies on clinical utility as prognosis and treatment-response indicators are needed.

Differential Effects of Targeted Temperature Management on Sex-Dependent Outcomes After Experimental Asphyxial Cardiac Arrest.

Asphyxial cardiac arrest (ACA) survivors face lasting neurological disability from hypoxic ischemic brain injury. Sex differences in long-term outcomes after cardiac arrest (CA) are grossly understudied and underreported. We used rigorous targeted temperature management (TTM) to understand its influence on survival and lasting sex-specific neurological and neuropathological outcomes in a rodent ACA model. Adult male and female rats underwent either sham or 5-minute no-flow ACA with 18 hours TTM at either ∼37°C (normothermia) or ∼36°C (mild hypothermia). Survival, temperature, and body weight (BW) were recorded over the 14-day study duration. All rats underwent neurological deficit score (NDS) assessment on days 1-3 and day 14. Hippocampal pathology was assessed for cell death, degenerating neurons, and microglia on day 14. Although ACA females were less likely to achieve return of spontaneous circulation (ROSC), post-ROSC physiology and biochemical profiles were similar between sexes. ACA females had significantly greater 14-day survival, NDS, and BW recovery than ACA males at normothermia (56% vs. 29%). TTM at 36°C versus 37°C improved 14-day survival in males, producing similar survival in male (63%) versus female (50%). There were no sex or temperature effects on CA1 histopathology. We conclude that at normothermic conditions, sex differences favoring females were observed after ACA in survival, NDS, and BW recovery. We achieved a clinically relevant ACA model using TTM at 36°C to improve long-term survival. This model can be used to more fully characterize sex differences in long-term outcomes and test novel acute and chronic therapies.

Serial Measurements of Serum Glial Fibrillary Acidic Protein in Moderate-Severe Traumatic Brain Injury: Potential Utility in Providing Insights into Secondary Insults and Long-Term Outcome.

In patients with traumatic brain injury (TBI), serum biomarkers may have utility in assessing the evolution of secondary brain injury. A panel of nine brain-injury- associated biomarkers was measured in archived serum samples over 10 days post-injury from 100 patients with moderate-severe TBI. Among the biomarkers evaluated, serum glial fibrillary acidic protein (GFAP) had the strongest associations with summary measures of acute pathophysiology, including intracranial pressure (ICP), cerebral perfusion pressure (CPP), and brain tissue pO2 (PbtO2). Group based trajectory (TRAJ) analysis was used to identify three distinct GFAP subgroups. The low TRAJ group (n = 23) had peak levels of 9.4 + 1.2 ng/mL that declined rapidly. The middle TRAJ group (n = 48) had higher peak values (31.5 + 5.0 ng/mL) and a slower decline over time. The high TRAJ group (n = 26) had very high, sustained peak values (59.6 + 12.5 ng/mL) that even rose among some patients over 10 days. Patients in the high TRAJ group had significantly higher mortality rate than patients in low and middle TRAJ groups (26.9% vs. 7.0%, p = 0.028). The frequency of poor neurological outcome (Glasgow Outcome Score Extended [GOS-E] 1-4) was 88.5% in the high TRAJ group, 54.2% in the middle TRAJ group, and 30.4% in the low TRAJ group (p < 0.001). ICP was highest in the high TRAJ group (median 17.6 mm Hg), compared with 14.4 mmHg in the low and 15.9 mm Hg in middle TRAJ groups (p = 0.002). High TRAJ patients spent the longest time with ICP >25 mm Hg, median 23 h, compared with 2 and 6 h in the low and middle TRAJ groups (p = 0.006), and the longest time with ICP >30 mm Hg, median 5 h, compared with 0 and 1 h in the low and middle TRAJ groups, respectively (p = 0.013). High TRAJ group patients more commonly required tier 2 or 3 treatment to control ICP. The high TRAJ group had the longest duration when CPP was <50 mm Hg (p = 0.007), and PbtO2 was <10 mm Hg (p = 0.002). Logistical regression was used to study the relationship between temporal serum GFAP patterns and 6-month GOS-E. Here, the low and middle TRAJ groups were combined to form a low-risk group, and the high TRAJ group was designated the high-risk group. High TRAJ group patients had a greater chance of a poor 6-month GOS-E (p < 0.0001). When adjusting for baseline injury characteristics, GFAP TRAJ group membership remained associated with GOS-E (p = 0.003). When an intensive care unit (ICU) injury burden score, developed to quantify physiological derangements, was added to the model, GFAP TRAJ group membership remained associated with GOS-E (p = 0.014). Mediation analysis suggested that ICU burden scores were in the causal pathway between TRAJ group and 6-month mortality or GOS-E. Our results suggest that GFAP may be useful to monitor serially in moderate-severe TBI patients. Future studies in larger cohorts are needed to confirm these results.

Temporal Profiles of P-Tau, T-Tau, and P-Tau:Tau Ratios in Cerebrospinal Fluid and Blood from Moderate-Severe Traumatic Brain Injury Patients and Relationship to 6-12 Month Global Outcomes.

Traumatic brain injury (TBI) can initiate progressive injury responses, which are linked to increased risk of neurodegenerative diseases known as "tauopathies." Increased post-TBI tau hyperphosphorylation has been reported in brain tissue and biofluids. Acute-to-chronic TBI total (T)-tau and phosphorylated (P)-tau temporal profiles in the cerebrospinal fluid (CSF) and serum and their relationship to global outcome is unknown. Our multi-site longitudinal study examines these concurrent profiles acutely (CSF and serum) and also characterizes the acute- to-chronic serum patterns. Serial serum and CSF samples from individuals with moderate-to-severe TBI were obtained from two cohorts (acute, subacute, and chronic samples from University of Pittsburgh [UPitt] [n = 286 unique subjects] and acute samples from Baylor College of Medicine [BCM] [n = 114 unique subjects]) and assayed for T-tau and P-tau using the Rolling Circle Amplification-Surround Optical Fiber ImmunoAssay platform. Biokinetic analyses described serum T-tau and P-tau temporal patterns. T-tau and P-tau levels are compared with those in healthy controls (n = 89 for both CSF and serum), and univariate/multivariable associations are made with global outcome, including the Disability Rating Scale (DRS) and the Glasgow Outcome Scale-Extended (GOS-E) scores at 3 and 6 months post-TBI (BCM cohort) and at 6 and 12 months post-TBI (UPitt cohort). For both the UPitt and BCM cohorts, temporal increases in median serum and CSF T-tau and P-tau levels occurred over the first 5 days post-injury, while the initial increases of P-tau:T-tau ratio plateaued by day 4 post-injury (UPitt: n = 99, BCM: n = 48). Biokinetic analyses with UPitt data showed novel findings that T-tau (n = 74) and P-tau (n = 87) reached delayed maximum levels at 4.5 and 5.1 days, while exhibiting long serum half-lives (152 and 123 days), respectively. The post-TBI rise in acute (days 2-6) serum P-tau (up to 276-fold) far outpaced that of T-tau (7.3-fold), leading to a P-tau:T-tau increase of up to 267-fold, suggesting a shift toward tau hyperphosphorylation. BCM analyses showed that days 0-6 mean CSF T-tau and P-tau levels and P-tau:T-tau ratios were associated with greater disability (DRS) (n = 48) and worse global outcome (GOS-E) (n = 48) 6 months post-injury. Days 0-6 mean serum T-tau, P-tau, and P-tau:T-tau ratio were not associated with outcome in either cohort (UPitt: n = 145 [DRS], n = 154 [GOS-E], BCM: n = 99 [DRS and GOS-E]). UPitt multivariate models showed that higher chronic (months 1-6) mean P-tau levels and P-tau:T-tau ratio, but not T-tau levels, are associated with greater disability (DRS: n = 119) and worse global outcomes (GOS-E: n = 117) 12 months post-injury. This work shows the potential importance of monitoring post-TBI T-tau and P-tau levels over time. This multi-site longitudinal study features concurrent acute TBI T-tau and P-tau profiles in CSF and serum, and also characterizes acute-to-chronic serum profiles. Longitudinal profiles, along with no temporal concordance between trajectory groups over time, imply a sustained post-TBI shift in tau phosphorylation dynamics that may favor tauopathy development chronically.

Factors Associated with Hospital Readmission One Year Post-Discharge in Infants with Gastroschisis.

INTRODUCTION: Gastroschisis is the most common congenital abdominal wall defect with a rising prevalence. Infants with gastroschisis are at risk for multiple complications, leading to a potential increased risk for hospital readmission after discharge. We aimed to find the frequency and factors associated with an increased risk of readmission. METHODS: A retrospective analysis of infants born with gastroschisis between 2013 and 2019 who received initial surgical intervention and follow-up care in the Children's Wisconsin health system was performed. The primary outcome was the frequency of hospital readmission within 1 year of discharge. We also compared maternal and infant clinical and demographic variables between those readmitted for reasons related to gastroschisis, and those readmitted for other reasons or not readmitted. RESULTS: Forty of 90 (44%) infants born with gastroschisis were readmitted within 1-year of the initial discharge date, with 33 (37%) of the 90 infants being readmitted due to reasons directly related to gastroschisis. The presence of a feeding tube (p < 0.0001), a central line at discharge (p = 0.007), complex gastroschisis (p = 0.045), conjugated hyperbilirubinemia (p = 0.035), and the number of operations during the initial hospitalization (p = 0.044) were associated with readmission. Maternal race/ethnicity was the only maternal variable associated with readmission, with Black race being less likely to be readmitted (p = 0.003). Those who were readmitted were also more likely to be seen in outpatient clinics and utilize emergency healthcare resources. There was no statistically significant difference in readmission based on socioeconomic factors (all p > 0.084). CONCLUSION: Infants with gastroschisis have a high hospital readmission rate, which is associated with a variety of risk factors including complex gastroschisis, multiple operations, and the presence of a feeding tube or central line at discharge. Improved awareness of these risk factors may help stratify patients in need of increased parental counseling and additional follow-up.

Using Machine Learning to Examine Suicidal Ideation After Traumatic Brain Injury: A Traumatic Brain Injury Model Systems National Database Study.

OBJECTIVE: The aim of the study was to predict suicidal ideation 1 yr after moderate to severe traumatic brain injury. DESIGN: This study used a cross-sectional design with data collected through the prospective, longitudinal Traumatic Brain Injury Model Systems network at hospitalization and 1 yr after injury. Participants who completed the Patient Health Questionnaire-9 suicide item at year 1 follow-up ( N = 4328) were included. RESULTS: A gradient boosting machine algorithm demonstrated the best performance in predicting suicidal ideation 1 yr after traumatic brain injury. Predictors were Patient Health Questionnaire-9 items (except suicidality), Generalized Anxiety Disorder-7 items, and a measure of heavy drinking. Results of the 10-fold cross-validation gradient boosting machine analysis indicated excellent classification performance with an area under the curve of 0.882. Sensitivity was 0.85 and specificity was 0.77. Accuracy was 0.78 (95% confidence interval, 0.77-0.79). Feature importance analyses revealed that depressed mood and guilt were the most important predictors of suicidal ideation, followed by anhedonia, concentration difficulties, and psychomotor disturbance. CONCLUSIONS: Overall, depression symptoms were most predictive of suicidal ideation. Despite the limited clinical impact of the present findings, machine learning has potential to improve prediction of suicidal behavior, leveraging electronic health record data, to identify individuals at greatest risk, thereby facilitating intervention and optimization of long-term outcomes after traumatic brain injury.

Abdominal Wall Defects: A Review of Current Practice Guidelines.

The 2 most common congenital abdominal wall defects are gastroschisis and omphalocele. Gastroschisis is a defect in the abdominal wall with exposed abdominal contents. Mortality rates are low but lengths of stay are often prolonged by bowel dysmotility and other intestinal abnormalities in complicated cases. Omphalocele is a defect through the umbilical cord with herniated abdominal contents covered by a sac. It is associated with other genetic abnormalities and other anomalies that can lead to significant morbidity and mortality. Prenatal diagnosis in both conditions allows for improved prenatal consultation and coordinated perinatal care to improve clinical outcomes.

Developing a National Trauma Research Action Plan: Results from the long-term outcomes research gap Delphi survey.

BACKGROUND: In the National Academies of Sciences, Engineering, and Medicine 2016 report on trauma care, the establishment of a National Trauma Research Action Plan to strengthen and guide future trauma research was recommended. To address this recommendation, the Department of Defense funded the Coalition for National Trauma Research to generate a comprehensive research agenda spanning the continuum of trauma and burn care. We describe the gap analysis and high-priority research questions generated from the National Trauma Research Action Plan panel on long-term outcomes. METHODS: Experts in long-term outcomes were recruited to identify current gaps in long-term trauma outcomes research, generate research questions, and establish the priority for these questions using a consensus-driven, Delphi survey approach from February 2021 to August 2021. Panelists were identified using established Delphi recruitment guidelines to ensure heterogeneity and generalizability including both military and civilian representation. Panelists were encouraged to use a PICO format to generate research questions: Patient/Population, Intervention, Compare/Control, and Outcome model. On subsequent surveys, panelists were asked to prioritize each research question on a 9-point Likert scale, categorized to represent low-, medium-, and high-priority items. Consensus was defined as ≥60% of panelists agreeing on the priority category. RESULTS: Thirty-two subject matter experts generated 482 questions in 17 long-term outcome topic areas. By Round 3 of the Delphi, 359 questions (75%) reached consensus, of which 107 (30%) were determined to be high priority, 252 (70%) medium priority, and 0 (0%) low priority. Substance abuse and pain was the topic area with the highest number of questions. Health services (not including mental health or rehabilitation) (64%), mental health (46%), and geriatric population (43%) were the topic areas with the highest proportion of high-priority questions. CONCLUSION: This Delphi gap analysis of long-term trauma outcomes research identified 107 high-priority research questions that will help guide investigators in future long-term outcomes research. LEVEL OF EVIDENCE: Diagnostic Tests or Criteria; Level IV.

Proceedings of the Second Curing Coma Campaign NIH Symposium: Challenging the Future of Research for Coma and Disorders of Consciousness.

This proceedings article presents actionable research targets on the basis of the presentations and discussions at the 2nd Curing Coma National Institutes of Health (NIH) symposium held from May 3 to May 5, 2021. Here, we summarize the background, research priorities, panel discussions, and deliverables discussed during the symposium across six major domains related to disorders of consciousness. The six domains include (1) Biology of Coma, (2) Coma Database, (3) Neuroprognostication, (4) Care of Comatose Patients, (5) Early Clinical Trials, and (6) Long-term Recovery. Following the 1st Curing Coma NIH virtual symposium held on September 9 to September 10, 2020, six workgroups, each consisting of field experts in respective domains, were formed and tasked with identifying gaps and developing key priorities and deliverables to advance the mission of the Curing Coma Campaign. The highly interactive and inspiring presentations and panel discussions during the 3-day virtual NIH symposium identified several action items for the Curing Coma Campaign mission, which we summarize in this article.

Controversies in Fetal Surgery: Prenatal Repair of Myelomeningocele in the Modern Era.

Fetal surgery is a constantly evolving field that showed noticeable progress with the treatment of myelomeningocele (MMC) using prenatal repair. Despite this success, there are ongoing questions regarding the optimal approach for fetal myelomeningocele repair, as well as which patients are eligible. Expansion of the inclusion and exclusion criteria is an important ongoing area of study for myelomeningocele including the recent Management of Myelomeningocele Plus trial. The significant personal and financial burden required of families seeking treatment has likely limited its accessibility to the general population.

Relations Among Suicidal Ideation, Depressive Symptoms, and Functional Independence During the 10 Years After Traumatic Brain Injury: A Model Systems Study.

OBJECTIVE: To investigate relative causality in relations among suicidal ideation (SI), depressive symptoms, and functional independence over the first 10 years after traumatic brain injury (TBI). DESIGN: Prospective longitudinal design with data collected through the Traumatic Brain Injury Model Systems (TBIMS) network at acute rehabilitation hospitalization as well as 1, 2, 5, and 10 years after injury. SETTING: United States Level I/II trauma centers and inpatient rehabilitation centers with telephone follow-up. PARTICIPANTS: Individuals enrolled into the TBIMS National Database (N=9539) with at least 1 SI score at any follow-up data collection (72.1% male; mean age, 39.39y). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Patient Health Questionnaire-9 and FIM at years 1, 2, 5, and 10 post injury. RESULTS: A cross-lagged panel structural equation model, which is meant to indirectly infer causality through longitudinal correlational data, suggested that SI, depressive symptoms, and functional independence each significantly predicted themselves over time. Within the model, bivariate correlations among variables were all significant within each time point. Between years 1 and 2 and between years 2 and 5, depressive symptoms had a larger effect on SI than SI had on depressive symptoms. Between years 5 and 10, there was reciprocal causality between the 2 variables. Functional independence more strongly predicted depressive symptoms than the reverse between years 1 and 2 as well as years 2 and 5, but its unique effects on SI over time were extremely marginal or absent after controlling for depressive symptoms. CONCLUSIONS: A primary goal for rehabilitation and mental health providers should be to monitor and address elevated symptoms of depression as quickly as possible before they translate into SI, particularly for individuals with TBI who have reduced functional independence. Doing so may be a key to breaking the connection between low functional independence and SI.

Identifying group-based patterns of suicidal ideation over the first 10 years after moderate-to-severe TBI.

OBJECTIVE: To identify group-based patterns in suicidal ideation (SI) over the first 10 years after traumatic brain injury (TBI). METHODS: Participants included 9539 individuals in the TBI Model Systems National Database who responded to Patient Health Questionnaire-9 Item 9 assessing SI at 1, 2, 5, and/or 10 years post-injury. A k-means cluster analysis was conducted to determine group-based patterns of SI, and pre-injury variables were compared with ANOVAs and chi-square tests. RESULTS: SI and attempts decreased over time. Four group-based patterns emerged: Low, increasing, moderate, and decreasing SI. The low SI group comprised 89% of the sample, had the highest pre-injury employment, fewer mental health vulnerabilities, least severe injuries, and were oldest. The increasing SI group had the most severe TBIs, were youngest, and disproportionately Black or Asian/Pacific Islander. CONCLUSION: These findings reinforce the importance of mental health and suicide risk assessment during chronic recovery from TBI.

Placental Location in Maternal-Fetal Surgery for Myelomeningocele.

INTRODUCTION: Uterine incision based on the placental location in open maternal-fetal surgery (OMFS) has never been evaluated in regard to maternal or fetal outcomes. OBJECTIVE: The aim of this study was to investigate whether an anterior placenta was associated with increased rates of intraoperative, perioperative, antepartum, obstetric, or neonatal complications in mothers and babies who underwent OMFS for fetal myelomeningocele (fMMC) closure. METHODS: Data from the international multicenter prospective registry of patients who underwent OMFS for fMMC closure (fMMC Consortium Registry, December 15, 2010-June 31, 2019) was used to compare fetal and maternal outcomes between anterior and posterior placental locations. RESULTS: The placental location for 623 patients was evenly distributed between anterior (51%) and posterior (49%) locations. Intraoperative fetal bradycardia (8.3% vs. 3.0%, p = 0.005) and performance of fetal resuscitation (3.6% vs. 1.0%, p = 0.034) occurred more frequently in cases with an anterior placenta when compared to those with a posterior placenta. Obstetric outcomes including membrane separation, placental abruption, and spontaneous rupture of membranes were not different among the 2 groups. However, thinning of the hysterotomy site (27.7% vs. 17.7%, p = 0.008) occurred more frequently in cases of an anterior placenta. Gestational age (GA) at delivery (p = 0.583) and length of stay in the neonatal intensive care unit (p = 0.655) were similar between the 2 groups. Fetal incision dehiscence and wound revision were not significantly different between groups. Critical clinical outcomes including fetal demise, perinatal death, and neonatal death were all infrequent occurrences and not associated with the placental location. CONCLUSIONS: An anterior placental location is associated with increased risk of intraoperative fetal resuscitation and increased thinning at the hysterotomy closure site. Individual institutional experiences may have varied, but the aggregate data from the fMMC Consortium did not show a significant impact on the GA at delivery or maternal or fetal clinical outcomes.

Neutrophil-to-Lymphocyte Ratios and Infections after Traumatic Brain Injury: Associations with Hospital Resource Utilization and Long-Term Outcome.

Traumatic brain injury (TBI) induces immune dysfunction that can be captured clinically by an increase in the neutrophil-to-lymphocyte ratio (NLR). However, few studies have characterized the temporal dynamics of NLR post-TBI and its relationship with hospital-acquired infections (HAI), resource utilization, or outcome. We assessed NLR and HAI over the first 21 days post-injury in adults with moderate-to-severe TBI (n = 196) using group-based trajectory (TRAJ), changepoint, and mixed-effects multivariable regression analysis to characterize temporal dynamics. We identified two groups with unique NLR profiles: a high (n = 67) versus a low (n = 129) TRAJ group. High NLR TRAJ had higher rates (76.12% vs. 55.04%, p = 0.004) and earlier time to infection (p = 0.003). In changepoint-derived day 0-5 and 6-20 epochs, low lymphocyte TRAJ, early in recovery, resulted in more frequent HAIs (p = 0.042), subsequently increasing later NLR levels (p ≤ 0.0001). Both high NLR TRAJ and HAIs increased hospital length of stay (LOS) and days on ventilation (p ≤ 0.05 all), while only high NLR TRAJ significantly increased odds of unfavorable six-month outcome as measured by the Glasgow Outcome Scale (GOS) (p = 0.046) in multivariable regression. These findings provide insight into the temporal dynamics and interrelatedness of immune factors which collectively impact susceptibility to infection and greater hospital resource utilization, as well as influence recovery.