White Matter Hyperintensities and Mild TBI in Post-9/11 Veterans and Service Members.

INTRODUCTION: The neurobehavioral significance of white matter hyperintensities (WMHs) seen on magnetic resonance imaging after traumatic brain injury (TBI) remains unclear, especially in Veterans and Service Members with a history of mild TBI (mTBI). In this study, we investigate the relation between WMH, mTBI, age, and cognitive performance in a large multisite cohort from the Long-term Impact of Military-relevant Brain Injury Consortium-Chronic Effects of Neurotrauma Consortium. MATERIALS AND METHODS: The neuroimaging and neurobehavioral assessments for 1,011 combat-exposed, post-9/11 Veterans and Service Members (age range 22-69 years), including those with a history of at least 1 mTBI (n = 813; median postinjury interval of 8 years) or negative mTBI history (n = 198), were examined. RESULTS: White matter hyperintensities were present in both mTBI and comparison groups at similar rates (39% and 37%, respectively). There was an age-by-diagnostic group interaction, such that older Veterans and Service Members with a history of mTBI demonstrated a significant increase in the number of WMHs present compared to those without a history of mTBI. Additional associations between an increase in the number of WMHs and service-connected disability, insulin-like growth factor-1 levels, and worse performance on tests of episodic memory and executive functioning-processing speed were found. CONCLUSIONS: Subtle but important clinical relationships are identified when larger samples of mTBI participants are used to examine the relationship between history of head injury and radiological findings. Future studies should use follow-up magnetic resonance imaging and longitudinal neurobehavioral assessments to evaluate the long-term implications of WMHs following mTBI.

Research Letter: Characterizing Lifetime Mild TBI Exposure Among Female and Male Military Service Members and Veterans in the LIMBIC-CENC Study.

OBJECTIVE: To (1) characterize lifetime mild traumatic brain injury (TBI) exposures among male and female US military service members and Veterans (SMVs) and (2) evaluate sex-related differences in mild TBI exposures. SETTING: Clinical research laboratory. PARTICIPANTS: Participants were enrolled in the ongoing Long-term Impact of Military-relevant Brain Injury Consortium-Chronic Effects of Neurotrauma Consortium (LIMBIC-CENC) Prospective Longitudinal Study. DESIGN: Cross-sectional. MAIN MEASURES: Lifetime history of mild TBI was measured via structured interview. All mild TBI characteristics were collected as part of this interview, including total lifetime number; environment (deployment vs. non-deployment); timing of injury (relative to military service and age); and mechanism of injury (blast-related vs. non-blast). RESULTS: Most participants (n = 2323; 87.5% male; 79.6% Veteran) reported ≥1 lifetime mild TBI (n = 1912; 82%), among whom, many reported ≥2 lifetime mild TBIs. Female SMVs reported fewer total lifetime mild TBIs than male participants (P < 0.001), including fewer deployment-related (P < 0.001) and non-deployment (P < 0.001) mild TBIs. There were significant sex differences for total number of mild TBIs sustained before (P = 0.005) and during (P < 0.001) military service but not after separation from military service (P = 0.99). Among participants with a lifetime history of mild TBI, female SMVs were less likely to report ≥2 mTBIs (P = 0.003); however, male SMVs were more likely to report a mild TBI during military service (P = 0.03), including combat-related mild TBI (P < 0.001) and mild TBI involving blast (P < 0.001). CONCLUSIONS: These findings inform clinical and research efforts related to mild TBI in US military SMVs. It may not be sufficient to simply measure the total number of mild TBIs when seeking to compare clinical outcomes related to mild TBI between sexes; rather, it is important to measure and account for the timing, environment, and mechanisms associated with mild TBIs sustained by female and male SMVs.

Development and validation of a stakeholder-driven, self-contained electronic informed consent platform for trio-based genomic research studies.

Increasingly long and complex informed consents have yielded studies demonstrating comparatively low participant comprehension and satisfaction with traditional face-to-face approaches. In parallel, interest in electronic consents for clinical and research genomics has steadily increased, yet limited data are available for trio-based genomic discovery studies. We describe the design, development, implementation, and validation of an electronic iConsent application for trio-based genomic research deployed to support genomic studies of cerebral palsy. iConsent development incorporated stakeholder perspectives including researchers, patient advocates, institutional review board members, and genomic data-sharing considerations. The iConsent platform integrated principles derived from prior electronic consenting research and elements of multimedia learning theory. Participant comprehension was assessed in an interactive teachback format. The iConsent application achieved nine of ten proposed desiderata for effective patient-focused electronic consenting for genomic research. Overall, participants demonstrated high comprehension and retention of key human subjects' considerations. Enrollees reported high levels of satisfaction with the iConsent, and we found that participant comprehension , iConsent clarity , privacy protections , and study goal explanations were associated with overall satisfaction . Although opportunities exist to optimize iConsent, we show that such an approach is feasible, can satisfy multiple stakeholder requirements, and can realize high participant satisfaction and comprehension while increasing study reach.

The Impact of Non-Pain Factors on Pain Interference Among U.S. Service Members and Veterans with Symptoms of Mild Traumatic Brain Injury.

U.S. Service members and Veterans (SM/V) experience elevated rates of traumatic brain injury (TBI), chronic pain, and other non-pain symptoms. However, the role of non-pain factors on pain interference levels remains unclear among SM/Vs, particularly those with a history of TBI. The primary objective of this study was to identify factors that differentiate high/low pain interference, given equivalent pain intensity among U.S. SM/V participating in the ongoing Long-term Impact of Military-relevant Brain Injury Consortium-Chronic Effects of Neurotrauma Consortium (LIMBIC-CENC) national multi-center prospective longitudinal observational study. An explainable machine learning was used to identify key predictors of pain interference conditioned on equivalent pain intensity. The final sample consisted of n = 1,577 SM/Vs who were predominantly male (87%), and 83.6% had a history of mild TBI(s) (mTBI), while 16.4% were TBI negative controls. The sample was categorized according to pain interference level (Low: 19.9%, Moderate: 52.5%, and High: 27.6%). Both pain intensity scores and pain interference scores increased with the number of mTBIs (p < 0.001), and there was evidence of a dose response between the number of injuries and pain scores. Machine learning models identified fatigue and anxiety as the most important predictors of pain interference, whereas emotional control was protective. Partial dependence plots identified that marginal effects of fatigue and anxiety were associated with pain interference (p < 0.001), but the marginal effect of mTBI was not significant in models considering all variables (p > 0.05). Non-pain factors are associated with functional limitations and disability experience among SM/V with an mTBI history. The functional effects of pain may be mediated through multiple other factors. Pain is a multi-dimensional experience that may benefit most from holistic treatment approaches that target comorbidities and build supports that promote recovery.

Neuropsychological Profiles of Deployment-Related Mild Traumatic Brain Injury: A LIMBIC-CENC Study.

BACKGROUND AND OBJECTIVES: Traumatic brain injury (TBI) is a concern for US service members and veterans (SMV), leading to heterogeneous psychological and cognitive outcomes. We sought to identify neuropsychological profiles of mild TBI (mTBI) and posttraumatic stress disorder (PTSD) among the largest SMV sample to date. METHODS: We analyzed cross-sectional baseline data from SMV with prior combat deployments enrolled in the ongoing Long-term Impact of Military-relevant Brain Injury Consortium-Chronic Effects of Neurotrauma Consortium prospective longitudinal study. Latent profile analysis identified symptom profiles using 35 indicators, including physical symptoms, depression, quality of life, sleep quality, postconcussive symptoms, and cognitive performance. It is important to note that the profiles were determined independently of mTBI and probable PTSD status. After profile identification, we examined associations between demographic variables, mTBI characteristics, and PTSD symptoms with symptom profile membership. RESULTS: The analytic sample included 1,659 SMV (mean age 41.1 ± 10.0 years; 87% male); among them 29% (n = 480) had a history of non-deployment-related mTBI only, 14% (n = 239) had deployment-related mTBI only, 36% (n = 602) had both non-deployment and deployment-related mTBI, and 30% (n = 497) met criteria for probable PTSD. A 6-profile model had the best fit, with separation on all indicators (p < 0.001). The model revealed distinct neuropsychological profiles, representing a combination of 3 self-reported functioning patterns: high (HS), moderate (MS), and low (LS), and 2 cognitive performance patterns: high (HC) and low (LC). The profiles were (1) HS/HC: n=301, 18.1%; (2) HS/LC: n=294, 17.7%; (3) MS/HC: n=359, 21.6%; (4) MS/LC: n=316, 19.0%; (5) LS/HC: n=228, 13.7%; and (6) LS/LC: n=161, 9.7%. SMV with deployment-related mTBI tended to be grouped into lower functioning profiles and were more likely to meet criteria for probable PTSD. Conversely, SMV with no mTBI exposure or non-deployment-related mTBI were clustered in higher functioning profiles and had a lower likelihood of meeting criteria for probable PTSD. DISCUSSION: Findings suggest varied symptom and functional profiles in SMV, influenced by injury context and probable PTSD comorbidity. Despite diagnostic challenges, comprehensive assessment of functioning and cognition can detect subtle differences related to mTBI and PTSD, revealing distinct neuropsychological profiles. Prioritizing early treatment based on these profiles may improve prognostication and support efficient recovery.

Using eDNA to play whack-a-mole with invasive species in green yard waste.

As large cities begin to overrun their landfill capacities, they begin to look for alternative locations to handle the waste stream. Seeing an opportunity to bring in revenue, rural communities offer to handle municipal waste in their landfills. However, many rural communities are also places of agricultural production, which are vulnerable to attacks by invasive insect species, which could be present in green yard waste, the component of municipal waste most likely to contain agriculturally harmful insect species. We used environmental DNA (eDNA) to determine whether green yard waste could be a pathway for invasive insect species to enter and establish in the landfill-receiving agricultural community. We identified several target species that could be in green yard waste coming from Vancouver, BC, Canada, to Central Washington State, USA. We sampled green yard waste from 3 sites every 2 weeks from June to October in 2019 and 2020. DNA was extracted from the nearly 400 samples and subjected to amplification with COI barcoding primers followed by sequencing to identify target insects in the samples. Sequence analyses identified 3 species from the target list: 2 species that are pests of deciduous tree fruits and a generalist root-feeding crop pest. This eDNA technique was useful in identifying potential invasive species in green yard waste and may prove to be an important tool informing policy on the movement of biological material across borders and stemming the spread of invasive species.

Prevalence of Cardiovascular Conditions After Traumatic Brain Injury: A Comparison Between the Traumatic Brain Injury Model Systems and the National Health and Nutrition Examination Survey.

BACKGROUND: The purpose of this study is to compare the prevalence of self-reported cardiovascular conditions among individuals with moderate to severe traumatic brain injury (TBI) to a propensity-matched control cohort. METHODS AND RESULTS: A cross-sectional study described self-reported cardiovascular conditions (hypertension, congestive heart failure [CHF], myocardial infarction [MI], and stroke) from participants who completed interviews between January 2015 and March 2020 in 2 harmonized large cohort studies, the TBI Model Systems and the National Health and Nutrition Examination Survey. Mixed-effect logistic regression models were used to compare the prevalence of cardiovascular conditions after 1:1 propensity-score matching based on age, sex, race, ethnicity, body mass index, education level, and smoking status. The final sample was 4690 matched pairs. Individuals with TBI were more likely to report hypertension (odds ratio [OR], 1.18 [95% CI, 1.08-1.28]) and stroke (OR, 1.70 [95% CI, 1.56-1.98]) but less likely to report CHF (OR, 0.81 [95% CI, 0.67-0.99]) or MI (OR, 0.66 [95% CI, 0.55-0.79]). There was no difference in rate of CHF or MI for those ≤50 years old; however, rates of CHF and MI were lower in the TBI group for individuals >50 years old. Over 65% of individuals who died before the first follow-up interview at 1 year post-TBI were >50 years old, and those >50 years old were more likely to die of heart disease than those ≤50 years old (17.6% versus 8.6%). CONCLUSIONS: Individuals with moderate to severe TBI had an increased rate of self-reported hypertension and stroke but lower rate of MI and CHF than uninjured adults, which may be due to survival bias.

Dim light at night shifts microglia to a pro-inflammatory state after cerebral ischemia, altering stroke outcome in mice.

Circadian rhythms are endogenous biological cycles that regulate physiology and behavior and are set to precisely 24-h by light exposure. Light at night (LAN) dysregulates physiology and function including immune response; a critical component that contributes to stroke pathophysiological progression of neuronal injury and may impair recovery from injury. The goal of this study is to explore the effects of dim LAN (dLAN) in a murine model of ischemic stroke to assess how nighttime lighting from hospital settings can affect stroke outcome. Further, this study sought to identify mechanisms underlying pathophysiological changes to immune response after circadian disruption. Male and female adult Swiss Webster (CFW) mice were subjected to transient or permanent focal cerebral ischemia, then were subsequently placed into either dark night conditions (LD) or one night of dLAN (5 lx). 24 h post-stroke, sensorimotor impairments and infarct sizes were quantified. A single night of dLAN following MCAO increased infarct size and sensorimotor deficits across both sexes and reduced survival in males after 24 h. Flow cytometry was performed to assess microglial phenotypes after MCAO, and revealed that dLAN altered the percentage of microglia that express pro-inflammatory markers (MHC II+ and IL-6) and microglia that express CD206 and IL-10 that likely contributed to poor ischemic outcomes. Following these results, microglia were reduced in the brain using Plexxikon 5622 (PLX 5622) a CSFR1 inhibitor, then the mice received an MCAO and were exposed to LD or dLAN conditions for 24 h. Microglial depletion by PLX5622 resulted in infarct sizes that were comparable between lighting conditions. This study provides supporting evidence that environmental lighting exacerbates ischemic injury and post-stroke mortality by a biological mechanism that exposure to dLAN causes a fundamental shift of activated microglial phenotypes from beneficial to detrimental at an early time point after stroke, resulting in irreversible neuronal death.

Chronic phase advances reduces recognition memory and increases vascular cognitive dementia-like impairments in aged mice.

Disrupted or atypical light-dark cycles disrupts synchronization of endogenous circadian clocks to the external environment; extensive circadian rhythm desynchrony promotes adverse health outcomes. Previous studies suggest that disrupted circadian rhythms promote neuroinflammation and neuronal damage post-ischemia in otherwise healthy mice, however, few studies to date have evaluated these health risks with aging. Because most strokes occur in aged individuals, we sought to identify whether, in addition to being a risk factor for poor ischemic outcome, circadian rhythm disruption can increase risk for vascular cognitive impairment and dementia (VCID). We hypothesized that repeated 6 h phase advances (chronic jet lag; CJL) for 8 weeks alters cerebrovascular architecture leading to increased cognitive impairments in aged mice. Female CJL mice displayed impaired spatial processing during a spontaneous alternation task and reduced acquisition during auditory-cued associative learning. Male CJL mice displayed impaired retention of the auditory-cued associative learning task 24 h following acquisition. CJL increased vascular tortuosity in the isocortex, associated with increased risk for vascular disease. These results demonstrate that CJL increased sex-specific cognitive impairments coinciding with structural changes to vasculature in the brain. We highlight that CJL may accelerate aged-related functional decline and could be a crucial target against disease progression.

The Effects of Repetitive Head Impact Exposure on Mental Health Symptoms Following Traumatic Brain Injury.

OBJECTIVE: This study aimed to characterize the types and timing of repetitive head impact (RHI) exposures in individuals with moderate to severe traumatic brain injury (TBI) and to examine the effects of RHI exposures on mental health outcomes. SETTING: TBI Model Systems National Database. PARTICIPANTS: 447 patients with moderate to severe TBI who reported RHI exposure between 2015 and 2022. DESIGN: Secondary data analysis. MAIN MEASURES: RHI exposures reported on the Ohio State University TBI Identification Method (OSU TBI-ID) were characterized by exposure category, duration, and timing relative to the index TBI. Mental health outcomes were evaluated at the 5-year follow-up assessment using the Patient Health Questionnaire-9 (PHQ-9) for depression symptoms and the Generalized Anxiety Disorder-7 (GAD-7) for anxiety symptoms. RESULTS: The majority of RHI exposures were sports-related (61.1%), followed by other causes (20.8%; including falls), repetitive violence/assault (18.8%), and military exposures (6.7%). Males predominantly reported sports and military exposures, while a larger proportion of females reported violence and falls. Sports exposures were most common before the index TBI, while exposures from falls and violence/abuse were most common after TBI. RHI exposures occurring after the index TBI were associated with higher levels of depression (ß = 5.05; 95% CI, 1.59-8.50) and anxiety (ß = 4.53; 95% CI, 1.02-8.05) symptoms than exposures before the index TBI. CONCLUSION: The findings emphasize the need to consider RHI exposures and their interaction with TBI when assessing mental health outcomes. Understanding the prevalence and challenges associated with RHI post-TBI can inform targeted interventions and improve the well-being of individuals with TBI. Preventive measures and ongoing care should be implemented to address the risks posed by RHI, particularly in individuals with prior TBI, especially surrounding fall and violence/abuse prevention.

Correction: Jannoo et al. Targeting and Sensitization of Breast Cancer Cells to Killing with a Novel Interleukin-13 Receptor α2-Specific Hybrid Cytolytic Peptide. Cancers 2023, 15, 2772.

In the original publication [...].

Tuberculosis - United States, 2023.

After 27 years of declining U.S. tuberculosis (TB) case counts, the number of TB cases declined considerably in 2020, coinciding with the COVID-19 pandemic. For this analysis, TB case counts were obtained from the National TB Surveillance System. U.S. Census Bureau population estimates were used to calculate rates overall, by jurisdiction, birth origin, race and ethnicity, and age group. Since 2020, TB case counts and rates have increased each year. During 2023, a total of 9,615 TB cases were provisionally reported by the 50 U.S. states and the District of Columbia (DC), representing an increase of 1,295 cases (16%) as compared with 2022. The rate in 2023 (2.9 per 100,000 persons) also increased compared with that in 2022 (2.5). Forty states and DC reported increases in 2023 in both case counts and rates. National case counts increased among all age groups and among both U.S.-born and non-U.S.-born persons. Although TB incidence in the United States is among the lowest in the world and most U.S. residents are at minimal risk, TB continues to cause substantial global morbidity and mortality. This postpandemic increase in U.S. cases highlights the importance of continuing to engage communities with higher TB rates and their medical providers in TB elimination efforts and strengthening the capacity in public health programs to carry out critical disease control and prevention strategies.

Outbreak of Mycobacterium orygis in a Shipment of Cynomolgus Macaques Imported from Southeast Asia - United States, February-May 2023.

Nonhuman primates (NHP) can become infected with the same species of Mycobacteria that cause human tuberculosis. All NHP imported into the United States are quarantined and screened for tuberculosis; no confirmed cases of tuberculosis were diagnosed among NHP during CDC-mandated quarantine during 2013-2020. In February 2023, an outbreak of tuberculosis caused by Mycobacterium orygis was detected in a group of 540 cynomolgus macaques (Macaca fascicularis) imported to the United States from Southeast Asia for research purposes. Although the initial exposure to M. orygis is believed to have occurred before the macaques arrived in the United States, infected macaques were first detected during CDC-mandated quarantine. CDC collaborated with the importer and U.S. Department of Agriculture's National Veterinary Services Laboratories in the investigation and public health response. A total of 26 macaques received positive test results for M. orygis by culture, but rigorous occupational safety protocols implemented during transport and at the quarantine facility prevented cases among caretakers in the United States. Although the zoonotic disease risk to the general population remains low, this outbreak underscores the importance of CDC's regulatory oversight of NHP importation and adherence to established biosafety protocols to protect the health of the United States research animal population and the persons who interact with them.

Persistent MRI Findings Unique to Blast and Repetitive Mild TBI: Analysis of the CENC/LIMBIC Cohort Injury Characteristics.

INTRODUCTION: MRI represents one of the clinical tools at the forefront of research efforts aimed at identifying diagnostic and prognostic biomarkers following traumatic brain injury (TBI). Both volumetric and diffusion MRI findings in mild TBI (mTBI) are mixed, making the findings difficult to interpret. As such, additional research is needed to continue to elucidate the relationship between the clinical features of mTBI and quantitative MRI measurements. MATERIAL AND METHODS: Volumetric and diffusion imaging data in a sample of 976 veterans and service members from the Chronic Effects of Neurotrauma Consortium and now the Long-Term Impact of Military-Relevant Brain Injury Consortium observational study of the late effects of mTBI in combat with and without a history of mTBI were examined. A series of regression models with link functions appropriate for the model outcome were used to evaluate the relationships among imaging measures and clinical features of mTBI. Each model included acquisition site, participant sex, and age as covariates. Separate regression models were fit for each region of interest where said region was a predictor. RESULTS: After controlling for multiple comparisons, no significant main effect was noted for comparisons between veterans and service members with and without a history of mTBI. However, blast-related mTBI were associated with volumetric reductions of several subregions of the corpus callosum compared to non-blast-related mTBI. Several volumetric (i.e., hippocampal subfields, etc.) and diffusion (i.e., corona radiata, superior longitudinal fasciculus, etc.) MRI findings were noted to be associated with an increased number of repetitive mTBIs versus. CONCLUSIONS: In deployment-related mTBI, significant findings in this cohort were only observed when considering mTBI sub-groups (blast mechanism and total number/dose). Simply comparing healthy controls and those with a positive mTBI history is likely an oversimplification that may lead to non-significant findings, even in consortium analyses.

Associations of Chronic Pain With Psychosocial Outcomes After Traumatic Brain Injury: A NIDILRR and VA TBI Model Systems Collaborative Project.

OBJECTIVE: To examine the differences in participation, life satisfaction, and psychosocial outcomes among individuals with traumatic brain injury (TBI) endorsing current, past, or no chronic pain. SETTING: Community. PARTICIPANTS: Three thousand eight hundred four TBI Model Systems participants 1 to 30 years of age postinjury classified into 1 of 3 groups based on their pain experience: current pain, past pain, no pain completed a Pain Survey at their usual follow-up appointment which on average was approximately 8 years postinjury. DESIGN: Multisite, cross-sectional observational cohort study. MAIN OUTCOME MEASURES: Sociodemographic and injury characteristics and psychosocial outcomes (ie, satisfaction with life, depression, anxiety, posttraumatic stress disorder [PTSD], sleep quality, community participation). RESULTS: Persons with current chronic pain demonstrated higher scores on measures of PTSD, anxiety, and depression, and the lower scores on measures of sleep quality, community participation and satisfaction with life. Those with resolved past pain had mean scores for these outcomes that were all between the current and no chronic pain groups, but always closest to the no pain group. After adjusting for sociodemographic and function in multivariate analysis, having current chronic pain was associated with more negative psychosocial outcomes. The largest effect sizes (ES; in absolute value) were observed for the PTSD, depression, anxiety, and sleep quality measures (ES = 0.52-0.81) when comparing current pain to past or no pain, smaller ES were observed for life satisfaction (ES = 0.22-0.37) and out and about participation (ES = 0.16-0.18). When comparing past and no pain groups, adjusted ES were generally small for life satisfaction, PTSD, depression, anxiety, and sleep quality (ES = 0.10-0.23) and minimal for participation outcomes (ES = 0.02-0.06). CONCLUSIONS: Chronic pain is prevalent among individuals with TBI and is associated with poorer psychosocial outcomes, especially for PTSD, depression, anxiety, and sleep disturbance. The results from this study highlight the presence of modifiable comorbidities among those with chronic pain and TBI. Persons who experience persistent pain following TBI may be at greater risk for worse psychosocial outcomes.

Characterization and Treatment of Chronic Pain After Traumatic Brain Injury-Comparison of Characteristics Between Individuals With Current Pain, Past Pain, and No Pain: A NIDILRR and VA TBI Model Systems Collaborative Project.

OBJECTIVE: To estimate the prevalence of chronic pain after traumatic brain injury (TBI) and identify characteristics that differ from those without chronic pain. SETTING: Community. PARTICIPANTS: A total of 3804 TBI Model Systems (TBIMS) participants who completed the Pain Survey at TBIMS follow-up. DESIGN: A multisite, cross-sectional observational cohort study. MAIN OUTCOME MEASURES: Functional outcomes, pain experience, and treatment. RESULTS: 46% reported current chronic pain, 14% reported past (post-injury) chronic pain, and 40% reported no chronic pain. Bivariate differences in sociodemographic and injury characteristics between the 3 pain groups were generally small in effect size, reflecting little clinical difference. However, medium effect sizes were seen for all functional outcomes, such that individuals with current chronic pain had worse functional outcomes compared with individuals in the past pain or no pain groups. Treatment utilization rates were higher for individuals with current chronic pain compared with past pain, with medical treatments being most frequently utilized. Individuals with past pain perceived more improvement with treatment than did those with current chronic pain as represented by a large effect size. CONCLUSIONS: Chronic pain affects approximately 60% of those living with TBI. The implications of chronic pain for functional outcomes support inclusion of pain metrics in prognostic models and observational studies in this population. Future research is needed to proactively identify those at risk for the development of chronic pain and determine the efficacy and access to pain treatment.

Time of day bias for biological sampling in studies of mammary cancer.

Despite its demonstrated biological significance, time of day is a broadly overlooked biological variable in preclinical and clinical studies. How time of day affects the influence of peripheral tumors on central (brain) function remains unspecified. Thus, we tested the hypothesis that peripheral mammary cancer tumors alter the transcriptome of immune responses in the brain and that these responses vary based on time of day; we predicted that time of day sampling bias would alter the interpretation of the results. Brain tissues collected at mid dark and mid light from mammary tumor-bearing and vehicle injected mice were analyzed using the Nanostring nCounter immune panel. Peripheral mammary tumors significantly affected expression within the brain of over 100 unique genes of the 770 represented in the panel, and fewer than 25% of these genes were affected similarly across the day. Indeed, between 65 and 75% of GO biological processes represented by the differentially expressed genes were dependent upon time of day of sampling. The implications of time-of-day sampling bias in interpretation of research studies cannot be understated. We encourage considering time of day as a significant biological variable in studies and to appropriately control for it and clearly report time of day in findings.

What Are the Predictors for and Psychosocial Correlates of Chronic Headache After Moderate to Severe Traumatic Brain Injury?

OBJECTIVE: Although headache (HA) is a common sequela of traumatic brain injury (TBI), early predictors of chronic HA after moderate to severe TBI are not well established, and the relationship chronic HA has with psychosocial functioning is understudied. Thus, we sought to (1) determine demographic and injury predictors of chronic HA 1 or more years after moderate to severe TBI and (2) examine associations between chronic HA and psychosocial outcomes. SETTING: Community. PARTICIPANTS: Participants in the TBI Model System (TBIMS) with moderate to severe TBI who consented for additional chronic pain questionnaires at the time of TBIMS follow-up. DESIGN: Multisite, observational cohort study using LASSO (least absolute shrinkage and selection operator) regression for prediction modeling and independent t tests for psychosocial associations. MAIN OUTCOME MEASURES: Chronic HA after TBI at year 1 or 2 postinjury and more remotely (5 or more years). RESULTS: The LASSO model for chronic HA at 1 to 2 years achieved acceptable predictability (cross-validated area under the curve [AUC] = 0.70). At 5 or more years, predictability was nearly acceptable (cross-validated AUC = 0.68), but much more complex, with more than twice as many variables contributing. Injury characteristics had stronger predictive value at postinjury years 1 to 2 versus 5 or more years, especially sustained intracranial pressure elevation (odds ratio [OR] = 3.8) and skull fragments on head computed tomography (CT) (OR = 2.5). Additional TBI(s) was a risk factor at both time frames, as were multiple socioeconomic characteristics, including lower education level, younger age, female gender, and Black race. Lower education level was a particularly strong predictor at 5 or more years (OR up to 3.5). Emotional and participation outcomes were broadly poorer among persons with chronic HA after moderate to severe TBI. CONCLUSIONS: Among people with moderate to severe TBI, chronic HA is associated with significant psychosocial burden. The identified risk factors will enable targeted clinical screening and monitoring strategies to enhance clinical care pathways that could lead to better outcomes. They may also be useful as stratification or covariates in future clinical trial research on treatments.

Relationship Between Extreme Pain Phenotypes and Psychosocial Outcomes in Persons With Chronic Pain Following Traumatic Brain Injury: A NIDILRR and VA TBI Model Systems Collaborative Project.

OBJECTIVE: To examine the relationship between extreme pain phenotypes (interference and improvement) and psychosocial outcomes among those with chronic pain after traumatic brain injury (TBI). SETTING: Community. PARTICIPANTS: In total, 1762 TBI Model Systems (TBIMS) participants 1 to 30 years postinjury reporting chronic pain. DESIGN: Multisite, cross-sectional, observational cohort study. PRIMARY MEASURES: Life satisfaction, posttraumatic stress, depression and anxiety symptoms, sleep and participation, the Brief Pain Inventory (BPI) interference scale, and the Patient's Global Impression of Change (PGIC). RESULTS: Persons in the extreme high interference phenotype (vs extreme low interference phenotype) and/or extreme no change phenotype (vs extreme improvement phenotype) had poorer psychosocial outcomes, with extreme pain interference phenotypes having a larger effect on outcomes than extreme perceived improvement phenotypes. After controlling for covariates, large effect sizes (ES) related to pain interference were observed for posttraumatic stress symptoms (ES = -1.14), sleep quality (ES = -1.10), depression (ES = -1.08), anxiety (ES = -0.82), and life satisfaction (ES = 0.76); effect sizes for participation outcomes, although significant, were relatively small (ES = 0.21-0.36). Effect sizes related to perceived improvement were small for life satisfaction (ES = 0.20) and participation (ES = 0.16-0.21) outcomes. Pain intensity was identified as a meaningful confounding factor of the relationships between extreme phenotypes and posttraumatic stress, depression, anxiety, and sleep quality. CONCLUSIONS: Examination of extreme phenotypes provides important insights into the experience of individuals living with chronic pain and TBI. Results suggest that the relationships among a variety of characteristics of the person, their experience with pain, and treatment of pain are complex. Further research is needed to better understand these complex relationships and how differences in pain interference and perceived improvement from treatment can assist in assessment and treatment of chronic pain after TBI.

Characterizing Extreme Phenotypes for Pain Interference in Persons With Chronic Pain Following Traumatic Brain Injury: A NIDILRR and VA TBI Model Systems Collaborative Project.

OBJECTIVE: To define and characterize extreme phenotypes based on pain interference for persons with chronic pain following traumatic brain injury (TBI). SETTING: Eighteen Traumatic Brain Injury Model System (TBIMS) Centers. PARTICIPANTS: A total of 1762 TBIMS participants 1 to 30 years post-injury reporting chronic pain at their most recent follow-up interview. PRIMARY MEASURES: The Brief Pain Inventory (BPI) interference scale, sociodemographic, injury, functional outcome, pain, and treatment characteristics. RESULTS: Participants were predominantly male (73%), White (75%), middle-aged (mean 46 years), and who were injured in motor vehicle accidents (53%) or falls (20%). Extreme phenotypes were identified based on upper and lower 25th percentiles to create low-interference ( n = 441) and high-interference ( n = 431) extreme phenotypes. Bivariate comparisons found several sociodemographic, injury, function, pain, and treatment differences between extreme phenotype groups, including significant differences ( P < .001) on all measures of concurrent function with those in the low-interference extreme phenotype experiencing better function than those in the high-interference extreme phenotype. Lasso regression combined with logistic regression identified multivariable predictors of low- versus high-interference extreme phenotypes. Reductions in the odds of low- versus high-interference phenotypes were significantly associated with higher pain intensity (odds ratio [OR] = 0.33), having neuropathic pain (OR = 0.40), migraine headache (OR = 0.41), leg/feet pain (OR = 0.34), or hip pain (OR = 0.46), and more pain catastrophizing (OR = 0.81). CONCLUSION: Results suggest that for those who experience current chronic pain, there is high variability in the experience and impact of pain. Future research is needed to better understand how pain experience impacts individuals with chronic pain and TBI given that pain characteristics were the primary distinguishing factors between phenotypes. The use of extreme phenotypes for pain interference may be useful to better stratify samples to determine efficacy of pain treatment for individuals with TBI.