Assessing patient attitudes toward genetic testing for hereditary hematologic malignancy.

Since 2003, more than 15 genes have been identified to predispose to hereditary hematologic malignancy (HHM). Although the yield of germline analysis for leukemia appears like that of solid tumors, genetic referrals in adults with leukemia remain underperformed. We assessed leukemia patients' attitudes toward genetic testing and leukemia-related distress through a survey of 1093 patients diagnosed with acute or chronic leukemia, myelodysplastic syndrome, or aplastic anemia. Principal component analysis (PCA) was used to analyze patient attitudes. Distress was measured through the Impact of Event Scale-Revised (IES-R). Exactly 19.8% of eligible respondents completed the survey. The majority reported interest in (77%) or choosing to have (78%) genetic testing for HHM. Slightly over half identified worry about cost of genetic testing (58%) or health insurance coverage (61%) as possible barriers. PCA identified relevant themes of interest in genetic testing, impact on leukemia treatment, discrimination and confidentiality, psychosocial and familial impacts, and cost of testing. The majority reported low distress. Leukemia patients report high interest in genetic testing, few barriers, and relatively low distress.

Disability education and implications for genetic counselor training.

The genetic counseling (GC) community has faced criticism about the duality of promoting patient autonomy while also advocating for individuals with disabilities. This study assessed the attitudes of the disability community and GCs to identify content that should be included in GC disability education and evaluate the landscape of GC disability education. Members of the disability community and GCs completed an electronic survey distributed through electronic listservs and partnering organizations. A total of 672 responses were analyzed from both the disability community (n = 596) and the GC community (n = 76). Members of the disability community noted differences in GC comfort level discussing different aspects of disability with GCs being perceived as being very knowledgeable about medical aspects 71% of the time versus 49% of the time when discussing social/lifestyle aspects of disability. This discordance was reflected in GCs reported comfort level in discussing medical aspects (89%) and social aspects of disability (65%) during a session. Most GC respondents (71%) felt they received adequate knowledge during their disability education and variation was reported in the execution of disability education by training programs. Disability education content recommendations from the disability community and GCs included emphasizing four key aspects of disability: medical, social/lifestyle, lived experience, and the disability rights movement. Respondents of both cohorts stressed the inclusion of and exposure to persons with disabilities in disability education to understand the lived experience of persons with disabilities. The disability community identified additional disability education content to be included such as empathy training, family hardships, and mental health. The results of this study have practice implications and provide a foundation for training expectations to ensure future GCs possess the necessary skills to improve the quality of services provided to families and persons with disabilities.

First trimester ultrasound in the age of cell-free DNA screening: What are we missing?

OBJECTIVES: To evaluate the utility of first trimester (FT) ultrasound (US) between 10 and 14 weeks gestation in identifying fetal findings that would impact clinical management. METHODS: We performed a retrospective review of FT US associated with an abnormal ICD-10 code from August 2016 to December 2018. Results of FT US, genetic testing, and management decisions were abstracted from the electronic health record. RESULTS: A total of 20,594 FT US were performed within our study period, representing 6064 unique patients. Of these, 278 ultrasounds were noted to have fetal findings (278/6064, 4.6%). The most frequent fetal findings were fetal demises (98/278, 35.3%), followed by increased NT/cystic hygroma (67/278, 24.1%), and multiple anomalies (35/278, 12.6%). There was a significant difference between the frequency of fetal findings between patients considered advanced maternal age (AMA) and those who were not (p = 0.017). However, there was no significant difference in the frequency of specific anomalies between these two groups (p = 0.103). CONCLUSION: FT US provides clinical information outside the scope of cfDNA screening in both AMA and non-AMA populations regarding viability and fetal anatomy. Earlier detection of these findings is crucial to allow for the opportunity of informed discussion of testing strategy and decision making.

Utility of expanded carrier screening in pregnancies with ultrasound abnormalities.

OBJECTIVE: Explore the utility of expanded carrier screening in evaluating heritable causes of congenital anomalies detected by prenatal ultrasound. METHOD: A retrospective chart review was conducted to collect structural abnormality and genetic testing data on infants who were evaluated postnatally by a medical geneticist. These were used to determine if expanded carrier screening could have determined the etiology prior to delivery. Additionally, recessive and X-linked conditions on clinically available carrier screening panels were evaluated to determine the number of conditions associated with abnormal ultrasound findings. RESULTS: Our retrospective chart review found 222 patients with genetic etiologies, including eight unique autosomal recessive conditions and six X-linked conditions in the 23% who underwent exome sequencing. Of these 14 unique conditions detected, three were included on a list of 271 conditions for which screening was available in 2019 and five were included on a 500 condition panel available in 2020. A literature review was performed on the list of 271 conditions and 88 were reported to be associated with one or more ultrasound abnormalities. CONCLUSION: This study demonstrates limited but potential utility for expanded carrier screening to determine the underlying etiology of congenital anomalies.

Influence of genetic counselor medical history on specialty and psychosocial practice in North America.

A personal or family medical history is inherently part of a genetic counselor's life story. Yet, the degree to which this history influences counselors' clinical specialty choice and professional psychosocial practice is unexplored. A medical diagnosis may foster capacity for greater empathy, understanding, and rapport-building self-disclosure. Conversely, it could lead to disruptive countertransference, compassion fatigue, and eventually burnout. Research, however, has not specifically investigated this intersection. The aim of this study was to explore the impact of genetic counselors' personal and/or family medical history on choice of practice area and self-perceived impact on their psychosocial work within sessions. Members of the National Society of Genetic Counselors were recruited to complete an online screening survey. Of the 69 survey respondents that met inclusion criteria, 23 volunteered for and completed a telephone interview. Interview questions explored counselors' medical narratives and their consequent influence on specialty choice and clinical interaction with patients. Inductive analysis yielded nine domains within three major themes: Medical Story, Specialty Impact, and Psychosocial Influence. Participants were more likely to be attracted to a specialty possessing overlap with their medical history and attributed many of their psychosocial strengths to personal and/or family medical experiences, such as increased empathy or a more expansive scope in how they cared for patients. Many counselors, however, noted their medical history did not frequently influence their clinical practice, with most initially denying or downplaying use of self-disclosure about their history. Contradictory to their statements, the majority gave at least one example of self-disclosure, whether indirect, prompted, or direct. Importantly, almost all participants named or demonstrated countertransference. This study highlights that while medical history can be a valuable asset in providing care for patients, it requires a genetic counselor's diligent attentiveness and commitment to honest self-reflection.

Genesurance counseling: Current training practices of genetic counseling graduate programs in the United States.

In recent years, it has become apparent that patients expect genetic counselors to be able to address questions about insurance coverage for genetic testing and perform 'genesurance' tasks in and out of genetic counseling sessions. Anecdotally, many genetic counseling graduate programs have begun to incorporate genesurance training in some capacity. However, the amount, modality, and potential barriers to this training had not been previously studied; therefore, this study aimed to elucidate current graduate program practice regarding genesurance. Program Directors of Accreditation Council for Genetic Counseling (ACGC) accredited programs who had students enrolled as of July 2019 (n = 50) were recruited through the Association of Genetic Counseling Program Directors (AGCPD) listserv and invited to complete an anonymous electronic survey via Qualtrics. Program Directors (PDs) from 25 ACGC accredited programs located in the United States completed the survey and were included in the analysis, responses from two ACGC Canadian programs were excluded due to small sample size and differences in healthcare systems. Responses were analyzed using descriptive statistics and open-ended responses were coded utilizing latent qualitative content analysis. The majority of respondents from the United States, 96.0% (24/25), report incorporating genesurance training into their curriculum utilizing a variety of training modalities including classroom, clinical, and online experiences. Most (81.0%) felt their trainees were adequately or very prepared to discuss genesurance issues. Despite varied methods of teaching modalities, PDs identified barriers to providing this training, including time constraints within the curriculum, lack of interest in the subject, as well as acknowledging the constantly changing landscape of billing and insurance. Despite these barriers, a baseline understanding of the impact of insurance on offering genetic testing and insight into how insurance impacts clinical practice may be beneficial to genetic counseling trainees, as it reflects the current genetic counselor's workflow and practice patterns.

It takes two: uptake of carrier screening among male reproductive partners.

OBJECTIVE: To describe uptake of carrier screening by male reproductive partners of prenatal and preconception patients. METHODS: A retrospective database review of all prenatal and preconception patients seen for genetic counseling in Maternal Fetal Medicine clinics was performed. Descriptive statistics and chi-square analysis were used on the data set. RESULTS: Within the study period, 6087 patients were seen for genetic counseling, of whom 661 were identified as a carrier of an autosomal recessive disorder by their referring provider or genetic counselor. Despite guidelines recommending partner testing for risk clarification when a woman is known to be a carrier of an autosomal recessive condition, only 41.5% male partners elected carrier screening to clarify the couple's reproductive risk, with a majority of males (75%) having screening consecutively. Of all assessed variables, the only significant predictors of male carrier screening uptake were female parity and earlier gestational age (p < .0001, and p = .001, respectively). CONCLUSION: With less than half of male partners pursuing carrier screening when indicated, its utility becomes severely diminished. More research is needed to explore reasons why males elect or decline carrier screening.

Impacts of genesurance considerations on genetic counselors' practice and attitudes.

Genesurance counseling has been identified as an integral part of many genetic counseling sessions, but little is known about the workflow impacts and genetic counselor perceptions of genesurance-related tasks. In this study, we aimed to characterize how insurance and billing considerations for genetic testing are being incorporated into genetic counselors' practice in the United States, as well as describe current attitudes and challenges associated with their integration. An electronic survey was sent by email to members of the National Society of Genetic Counselors (NSGC). A total of 325 American Board of Genetic Counselors-certified genetic counselors who provide direct patient care in the United States for at least 50% of their time were included in data analysis. Results showed that the frequency and timing of various insurance- and billing-related tasks were not consistent among respondents, even those practicing in similar settings. Inadequate training to complete tasks was reported by 64% of respondents, and 47% reported a lack of resources from their employer and/or institution to complete genesurance tasks. Additionally, only 38% of respondents agreed that insurance- and billing-related tasks were within the scope of the genetic counseling practice, and there was little consensus on who respondents believe is the most appropriate person to complete these tasks. When asked how genesurance considerations affected job satisfaction, 85% of respondents reported a negative impact. This study found an inconsistent genesurance workflow among genetic counselors practicing in the United States, a lack of consensus on who should be responsible for genesurance tasks, several challenges associated with completing these tasks, and identifies genesurance considerations as potential risk factors for genetic counselor burnout.

Exploring experiences and expectations of prenatal health care and genetic counseling/testing in immigrant Latinas.

As the Latino population of the United States continues to increase, the specific needs of Latinos in genetic counseling continue to be unmet. Using culturally tailored genetic counseling responsive to the needs of the patient can assist in building rapport in genetic counseling sessions. We aimed to investigate the relationship between acculturation, prenatal care, genetic testing experiences, and expectations for prenatal care in an immigrant Latino population. A total of 20 Spanish-speaking, pregnant Latinas from various Latin American countries were interviewed after completing a prenatal genetic counseling session. The semi-structured phone interview included questions about the participants' experiences with genetic counseling/testing, prenatal health care in their home country, their current prenatal care in the United States, and information they felt to be important to know during their pregnancy. Although this study showed no statistically significant associations between acculturation, prenatal care, and genetic counseling/testing experiences, six significant content domains were identified as relevant to the participants. Overall, we found that immigrant Latinas desire to know prenatal risk information to help them prepare, relieve guilt, and help make screening/testing/family planning decisions. These Latinas reported the genetic counselor provided confidence, a sense of autonomy, and empowerment, for them to make their own decisions regarding prenatal screening/testing. The participants also spoke about stressors unique to the immigrant population, most notably being away from their older children and other family members. Identifying relevant factors about the lived experience of this population can help genetic counselors better address possible needs, feelings of guilt, and/or isolation and identifying women who could benefit from group-based prenatal care, support groups, or referrals to social work.

Introduction of cell-free DNA screening is associated with changes in prenatal genetic counseling indications.

The introduction of cell-free DNA screening, or non-invasive prenatal testing (NIPT), for chromosome abnormalities has greatly impacted prenatal care since its introduction in late 2011. We aimed to evaluate the association between the introduction of cell-free DNA screening and indication and referral patterns for genetic counseling at a large US academic medical center by comparing the percentage of each counseling indication between the time period prior to the introduction of cell-free DNA screening (2006-2011) and following its introduction (2012-2016) using multivariable Poisson regression models. Genetic counseling indications for positive carrier screens, average risk patients, abnormal ultrasound findings, and family history indications were significantly higher following the introduction of NIPT while advanced maternal age and abnormal maternal serum screening indications dropped significantly. We also showed that the uptake of amniocentesis dropped significantly after the introduction of cell-free DNA screening, while chorionic villus sampling uptake increased. These results provide evidence that the introduction of new genetic screening technologies is associated with a shift in genetic counseling referral indications and an increased uptake in genetic screening. Additional research is needed to explore the impact of expanded testing options on the need for genetic counseling services.

Prenatal chromosomal microarray uptake with invasive prenatal diagnosis: How many patients take the leap?

OBJECTIVE: Characterize the uptake of chromosomal microarray analysis (CMA) among women undergoing invasive prenatal diagnosis at a large academic institution over a 4-year time period. METHODS: Retrospective database review of women who underwent invasive prenatal diagnosis via chorionic villus sampling (CVS) or amniocentesis. Entries were reviewed for demographic and clinical information. RESULTS: Nine hundred forty-six diagnostic procedures were performed at our institution over a 4-year time period including 259 CVS and 687 amniocentesis procedures. Overall, 32% elected CMA, with a significant increase in uptake over time. Women with Medicaid/CHIP insurance were more likely to elect CMA than those with private insurance (OR = 1.59, 95% CI, 1.18-2.14), while multigravida women were less likely than primigravidas to elect CMA (P = 0.003). Women with ultrasound findings were more likely to elect CMA than any other indication. Those with structural abnormalities in multiple systems (OR = 3.75, 95% CI, 1.60-8.79) or abnormalities in a single system (OR = 3.22, 95% CI, 1.47-7.05) were more likely to elect CMA than with any other types of ultrasound findings. CONCLUSION: The uptake of CMA significantly increased over a 4-year period at a large academic institution. Women with ultrasound indications, specifically structural abnormalities, are the most likely to elect CMA.

Genesurance Counseling: Patient Perspectives.

Genetic counselors (GCs) have reported an increase in discussion of insurance-related, or "genesurance," topics during genetic counseling sessions. Despite increasing frequency, there have been no studies examining patient expectations of GCs in these discussions. This study aimed to explore patient expectations of GCs in these discussions, as well as examine factors that may impact expectations. A 38-item survey was administered prior to patients receiving prenatal or cancer genetic counseling at 11 clinic sites across UTHealth, Baylor College of Medicine, and Sanford Health, with 360 responses analyzed. Key variables were analyzed using descriptive statistics, chi-square analysis, and multivariate logistic regression to assess associations between factors and control for potential confounders. Over 75% of patients expected GCs to discuss genesurance topics during a genetic counseling session. The majority of patients (78%) expected GCs to provide an estimated out-of-pocket cost, know if a test is a covered benefit (77%), and provide referral information for further questions (76%). Two additional expectations, considered to be unrealistic in most clinical settings, included expecting GCs to know the patient's specific insurance plan and coverage information (57%) and provide an exact out-of-pocket cost (41%). Ethnicity was the only significant predictor of response for these two expectations, as African Americans and Hispanics were more likely than Caucasians to have these beliefs. While the patient participants felt that GCs were primarily responsible for initiating these conversations, they also reported a personal sense of responsibility for raising questions. This study demonstrates that patients may expect GCs to address genesurance topics in a genetic counseling session, with specific expectations about the cost and coverage of genetic tests. Further studies will establish the most effective way to communicate this information to patients and examine whether and where within the scope of GC practice, genesurance discussions fall.

Elevated Axonal Protein Markers Following Repetitive Blast Exposure in Military Personnel.

Blast exposures that occur during training are common in military personnel; however, the biomarkers that relate to these subtle injuries is not well understood. Therefore, the purpose of this study is to identify the acute biomarkers related to blast injury in a cohort of military personnel exposure to blast-related training. Thirty-four military personnel who participated in the training program were included in this study. Blood samples were collected before and after repetitive blast-related training on days 2 (n = 19) and days 7 (n = 15). Serum concentration (pg/mL) of tau, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and phosphorylated tau181 (p-tau181) were measured using an ultrasensitive immunoassay platform. We observed that serum p-tau181 concentrations were elevated after exposed to repetitive blast on days 2 (z = -2.983, p = 0.003) and days 7 (z = -2.158, p = 0.031). Serum tau (z = -2.272, p = 0.023) and NfL (z = -2.158, p = 0.031) levels were significantly elevated after exposure to repetitive blasts on days 7. Our findings indicate that blast exposure affects serum biomarkers indicating axonal injury.

Extracellular Vesicle Levels of Nervous System Injury Biomarkers in Critically Ill Trauma Patients with and without Traumatic Brain Injury.

Moderate/severe traumatic brain injury (TBI) causes injury patterns with heterogeneous pathology producing varying outcomes for recovery. Extracellular vesicles (EVs) are particles containing a myriad of molecules involved in cell signaling. EVs may hold promise as biomarkers in TBI because of their encapsulation, including improved stability/decreased degradation. A subset of subjects with and without TBI from a prospective, observational trial of critically ill trauma patients were analyzed. Total EV levels of glial (glial fibrillary acidic protein; GFAP) and neuronal/axonal (ubiquitin carboxy-terminal hydrolase L1 [UCH-L1], neurofilament light chain [NfL], and total-tau) proteins were measured using single-molecule array technology. Protein levels were winsorized to address outliers and log transformed for analysis. Patients with multiple injuries (n = 41) and isolated body injury (n = 73) were of similar age and sex. Patients with multiple injuries were, as expected, more severely injured with higher Injury Severity Scores (29 [26-41] vs. 21 [14-26], p < 0.001) and lower Glasgow Coma Scale scores (12 [4-13] vs. 13 [13-13], p < 0.001). Total body EVs of GFAP, UCH-L1, and NfL were higher in those with multiple injuries (1768 [932-4780] vs. 239 [63-589], p < 0.001; 75.4 [47.8-158.3] vs. 41.5 [21.5-67.1], p = 0.03; 7.5 [3.3-12.3] vs. 2.9 [2.1-4.8], p < 0.001, respectively). There was a moderate correlation between the Head Abbreviated Injury Score and GFAP (free circulating rho = 0.62, EV rho = 0.64; both p < 0.001). Brain-derived proteins contained in EV holds promise as an informative approach to biomarker measurement after TBI in hospitalized patients. Future evaluation and longitudinal studies are necessary to draw conclusions regarding the clinical utility of these biomarkers.

Treg tissue stability depends on lymphotoxin beta-receptor- and adenosine-receptor-driven lymphatic endothelial cell responses.

Regulatory T cell (Treg) lymphatic migration is required for resolving inflammation and prolonging allograft survival. Focusing on Treg interactions with lymphatic endothelial cells (LECs), we dissect mechanisms and functional consequences of Treg transendothelial migration (TEM). Using three genetic mouse models of pancreatic islet transplantation, we show that Treg lymphotoxin (LT) αß and LEC LTß receptor (LTßR) signaling are required for efficient Treg migration and suppressive function to prolong allograft survival. Inhibition of LT signaling increases Treg conversion to Foxp3loCD25lo exTregs. In a transwell-based model of TEM across polarized LECs, non-migrated Tregs become exTregs. Such conversion is regulated by LTßR nuclear factor κB (NF-κB) signaling in LECs, which increases interleukin-6 (IL-6) production and drives exTreg conversion. Migrating Tregs are ectonucleotidase CD39hi and resist exTreg conversion in an adenosine-receptor-2A-dependent fashion. Human Tregs migrating across human LECs behave similarly. These molecular interactions can be targeted for therapeutic manipulation of immunity and suppression.

Cytokine Profiles Differentiate Symptomatic from Asymptomatic PTSD in Service Members and Veterans with Chronic Traumatic Brain Injury.

Traumatic brain injuries (TBI) and posttraumatic stress disorder (PTSD) are commonly observed comorbid occurrences among military service members and veterans (SMVs). In this cross-sectional study, SMVs with a history of TBI were stratified into symptomatic and asymptomatic PTSD groups based on posttraumatic stress checklist-civilian (PCL-C) total scores. Blood-based biomarkers were assessed, and significant differential markers were associated with scores from multiple neurobehavioral self-report assessments. PCL-C cutoffs were total scores >50 (PTSD symptomatic) and <25 (asymptomatic). Cytokines IL6, IL8, TNFα, and IL10 were significantly elevated (p < 0.05−0.001) in the TBI+/PTSD symptomatic group compared to the TBI+/asymptomatic group. Cytokine levels of IL8, TNFα, and IL10 were strongly associated with PCL-C scores (0.356 < r > 0.624 for all, p < 0.01 for all), while TNFα and IL10 were additionally associated with NSI totals (r = 0.285 and r = 0.270, p < 0.05, respectively). This is the first study focused on PTSD symptom severity to report levels of circulating pro-inflammatory IL8, specifically in SMVs with TBI. These data suggest that within the military TBI population, there are unique cytokine profiles that relate to neurobehavioral outcomes associated with TBI and PTSD.

Extracellular vesicle neurofilament light is elevated within the first 12-months following traumatic brain injury in a U.S military population.

Traumatic brain injury (TBI) can be associated with long-term neurobehavioral symptoms. Here, we examined levels of neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in extracellular vesicles isolated from blood, and their relationship with TBI severity and neurobehavioral symptom reporting. Participants were 218 service members and veterans who sustained uncomplicated mild TBIs (mTBI, n = 107); complicated mild, moderate, or severe TBIs (smcTBI, n = 66); or Injured controls (IC, orthopedic injury without TBI, n = 45). Within one year after injury, but not after, NfL was higher in the smcTBI group than mTBI (p = 0.001, d = 0.66) and IC (p = 0.001, d = 0.35) groups, which remained after controlling for demographics and injury characteristics. NfL also discriminated the smcTBI group from IC (AUC:77.5%, p < 0.001) and mTBI (AUC:76.1%, p < 0.001) groups. No other group differences were observed for NfL or GFAP at either timepoint. NfL correlated with post-concussion symptoms (rs = - 0.38, p = 0.04) in the mTBI group, and with PTSD symptoms in mTBI (rs = - 0.43, p = 0.021) and smcTBI groups (rs = - 0.40, p = 0.024) within one year after injury, which was not confirmed in regression models. Our results suggest the potential of NfL, a protein previously linked to axonal damage, as a diagnostic biomarker that distinguishes TBI severity within the first year after injury.

Sex Differences in Behavioral Symptoms and the Levels of Circulating GFAP, Tau, and NfL in Patients With Traumatic Brain Injury.

Traumatic brain injury (TBI) affects millions of Americans each year and has been shown to disproportionately impact those subject to greater disparities in health. Female sex is one factor that has been associated with disparities in health outcomes, including in TBI, but sex differences in biomarker levels and behavioral outcomes after TBI are underexplored. This study included participants with both blunt and blast TBI with majority rating their TBI as mild. Time since injury was 5.4 (2.0, 15.5) years for females and 6.8 (2.4, 11.3) years for males. The aim of this cross sectional study is to investigate the relationship between postconcussive, depression, and post-traumatic stress disorder (PTSD) symptoms, as well as health related quality of life (HRQOL), and the levels of glial fibrillary acidic protein (GFAP), total tau (t-tau), neurofilament light chain (NfL), and ubiquitin C-terminal hydrolase-L1 (UCH-L1). Behavioral outcomes were evaluated with the Neurobehavioral Symptom Inventory (NSI), Patient Health Questionnaire-9 (PHQ-9), PTSD Checklist- Civilian Version (PCL-C), short form (SF)-36, and plasma levels of total tau, GFAP, NfL, and UCHL-1 measured with the Simoa-HDX. We observed that females had significantly higher levels of GFAP and tau (ps < 0.05), and higher PHQ-9 scores, NSI total scores, NSI- vestibular, NSI-somatosensory, NSI-affective sub-scale scores (ps < 0.05)), than males. In addition, females had lower scores in HRQOL outcomes of role limitations due to emotional problems, vitality, emotional well-being, social functioning, and pain compared to males (ps < 0.05). Correlation analysis showed positive associations between levels of tau and the NSI-total and NSI-cognitive sub-scale scores (ps < 0.05) in females. No significant associations were found for NfL or GFAP with NSI scores. For female participants, negative correlations were observed between tau and NfL concentrations and the SF-36 physical function subscale (ps < 0.05), as well as tau and the social function subscale (p < 0.001), while GFAP levels positively correlated with role limitations due to emotional problems (p = 0.004). No significant associations were observed in males. Our findings suggest that sex differences exist in TBI-related behavioral outcomes, as well as levels of biomarkers associated with brain injury, and that the relationship between biomarker levels and behavioral outcomes is more evident in females than males. Future studies are warranted to corroborate these results, and to determine the implications for prognosis and treatment. The identification of candidate TBI biomarkers may lead to development of individualized treatment guidelines.

Survival Rates and Biomarkers in a Large Animal Model of Traumatic Brain Injury Combined With Two Different Levels of Blood Loss.

INTRODUCTION: The pathology resulting from concurrent traumatic brain injury (TBI) and hemorrhagic shock (HS; TBI+HS) are leading causes of mortality and morbidity worldwide following trauma. However, the majority of large animal models of TBI+HS have utilized focal/contusional injuries rather than incorporating the types of brain trauma (closed-head injury caused by dynamic acceleration) that typify human injury. OBJECTIVE: To examine survival rates and effects on biomarkers from rotational TBI with two levels of HS. METHODS: Twenty-two sexually mature Yucatan swine (30.39 ±â€Š2.25 kg; 11 females) therefore underwent either Sham trauma procedures (n = 6) or a dynamic acceleration TBI combined with either 55% (n = 8) or 40% (n = 8) blood loss in this serial study. RESULTS: Survival rates were significantly higher for the TBI+40% (87.5%) relative to TBI+55% (12.5%) cohort, with the majority of TBI+55% animals expiring within 2 h post-trauma from apnea. Blood-based neural biomarkers and immunohistochemistry indicated evidence of diffuse axonal injury (increased NFL/Aß42), blood-brain barrier breach (increased immunoglobulin G) and inflammation (increased glial fibrillary acidic protein/ionized calcium-binding adaptor molecule 1) in the injured cohorts relative to Shams. Invasive hemodynamic measurements indicated increased shock index and decreased pulse pressure in both injury cohorts, with evidence of partial recovery for invasive hemodynamic measurements in the TBI+40% cohort. Similarly, although both injury groups demonstrated ionic and blood gas abnormalities immediately postinjury, metabolic acidosis continued to increase in the TBI+55% group ∼85 min postinjury. Somewhat surprisingly, both neural and physiological biomarkers showed significant changes within the Sham cohort across the multi-hour experimental procedure, most likely associated with prolonged anesthesia. CONCLUSION: Current results suggest the TBI+55% model may be more appropriate for severe trauma requiring immediate medical attention/standard fluid resuscitation protocols whereas the TBI+40% model may be useful for studies of prolonged field care.