Reduced dose helical CT scout imaging on next generation wide volume CT system decreases scan length and overall radiation exposure.

Purpose: Traditional CT acquisition planning is based on scout projection images from planar anterior-posterior and lateral projections where the radiographer estimates organ locations. Alternatively, a new scout method utilizing ultra-low dose helical CT (3D Landmark Scan) offers cross-sectional imaging to identify anatomic structures in conjunction with artificial intelligence based Anatomic Landmark Detection (ALD) for automatic CT acquisition planning. The purpose of this study is to quantify changes in scan length and radiation dose of CT examinations planned using 3D Landmark Scan and ALD and performed on next generation wide volume CT versus examinations planned using traditional scout methods. We additionally aim to quantify changes in radiation dose reduction of scans planned with 3D Landmark Scan and performed on next generation wide volume CT. Methods: Single-center retrospective analysis of consecutive patients with prior CT scan of the same organ who underwent clinical CT using 3D Landmark Scan and automatic scan planning. Acquisition length and dose-length-product (DLP) were collected. Data was analyzed by paired t-tests. Results: 104 total CT examinations (48.1 % chest, 15.4 % abdomen, 36.5 % chest/abdomen/pelvis) on 61 individual consecutive patients at a single center were retrospectively analyzed. 79.8 % of scans using 3D Landmark Scan had reduction in acquisition length compared to the respective prior acquisition. Median acquisition length using 3D Landmark Scan was 26.7 mm shorter than that using traditional scout methods (p < 0.001) with a 23.3 % median total radiation dose reduction (245.6 (IQR 150.0-400.8) mGy cm vs 320.3 (IQR 184.1-547.9) mGy cm). CT dose index similarly was overall decreased for scans planned with 3D Landmark and ALD and performed on next generation CT versus traditional methods (4.85 (IQR 3.8-7) mGy vs. 6.70 (IQR 4.43-9.18) mGy, respectively, p < 0.001). Conclusion: Scout imaging using reduced dose 3D Landmark Scan images and Anatomic Landmark Detection reduces acquisition range in chest, abdomen, and chest/abdomen/pelvis CT scans. This technology, in combination with next generation wide volume CT reduces total radiation dose.

Large Patent Ductus Arteriosus Masked by High Altitude Hypoxia Until Descent to Sea Level.

We present a 41-year-old female with progressive shortness of breath immediately after moving to sea level from high altitude. The patient was found to have a large PDA with systemic RV and PA pressures and pulmonary hypertension, which resolved following PDA closure.

Atypical Intrahepatic Cholestasis of Pregnancy: A Red Herring.

Intrahepatic cholestasis of pregnancy is an intrahepatic etiology of acute cholestasis commonly defined by pruritus and increased bile acids, liver transaminases, and, occasionally, bilirubin. Azathioprine is an immunosuppressive agent associated with various forms of hepatoxicity, ranging from transient rises in serum aminotransferase levels, acute cholestatic injury, and chronic hepatic injury. In this report, we present a 20-year-old pregnant woman who presented with cholestatic liver injury due to intrahepatic cholestasis of pregnancy with a clinical picture complicated by increased levels of azathioprine metabolites.

Ultra-low dose chest CT with silver filter and deep learning reconstruction significantly reduces radiation dose and retains quantitative information in the investigation and monitoring of lymphangioleiomyomatosis (LAM).

PURPOSE: Frequent CT scans to quantify lung involvement in cystic lung disease increases radiation exposure. Beam shaping energy filters can optimize imaging properties at lower radiation dosages. The aim of this study is to investigate whether use of SilverBeam filter and deep learning reconstruction algorithm allows for reduced radiation dose chest CT scanning in patients with lymphangioleiomyomatosis (LAM). MATERIAL AND METHODS: In a single-center prospective study, 60 consecutive patients with LAM underwent chest CT at standard and ultra-low radiation doses. Standard dose scan was performed with standard copper filter and ultra-low dose scan was performed with SilverBeam filter. Scans were reconstructed using a soft tissue kernel with deep learning reconstruction (AiCE) technique and using a soft tissue kernel with hybrid iterative reconstruction (AIDR3D). Cyst scores were quantified by semi-automated software. Signal-to-noise ratio (SNR) was calculated for each reconstruction. Data were analyzed by linear correlation, paired t-test, and Bland-Altman plots. RESULTS: Patients averaged 49.4 years and 100% were female with mean BMI 26.6 ± 6.1 kg/m2. Cyst score measured by AiCE reconstruction with SilverBeam filter correlated well with that of AIDR3D reconstruction with standard filter, with a 1.5% difference, and allowed for an 85.5% median radiation dosage reduction (0.33 mSv vs. 2.27 mSv, respectively, p < 0.001). Compared to standard filter with AIDR3D, SNR for SilverBeam AiCE images was slightly lower (3.2 vs. 3.1, respectively, p = 0.005). CONCLUSION: SilverBeam filter with deep learning reconstruction reduces radiation dosage of chest CT, while maintaining accuracy of cyst quantification as well as image quality in cystic lung disease. CLINICAL RELEVANCE STATEMENT: Radiation dosage from chest CT can be significantly reduced without sacrificing image quality by using silver filter in combination with a deep learning reconstructive algorithm. KEY POINTS: • Deep learning reconstruction in chest CT had no significant effect on cyst quantification when compared to conventional hybrid iterative reconstruction. • SilverBeam filter reduced radiation dosage by 85.5% compared to standard dose chest CT. • SilverBeam filter in coordination with deep learning reconstruction maintained image quality and diagnostic accuracy for cyst quantification when compared to standard dose CT with hybrid iterative reconstruction.

Associations Between Prior Head Injury, Physical Functioning, and Frailty in the Atherosclerosis Risk in Communities Study.

BACKGROUND: Older adults have the highest rates of head injury and are at the greatest risk for subsequent dysfunction, yet research on subsequent physical decline is limited. We sought to examine cross-sectional and prospective associations of head injury with physical functioning and frailty among older adults. METHODS: A total of 5 598 Atherosclerosis Risk in Communities Study participants from Visit 5 (2011-13) underwent assessments of physical functioning (Short Physical Performance Battery [SPPB], comprised of gait speed, chair stands, and balance) and frailty (defined using established criteria) were followed through Visit 7 (2018-19). Head injury was self-reported or based on ICD-9 codes. Adjusted linear and multinomial logistic regression models were used to estimate associations. Prospective models incorporated inverse probability of attrition weights to account for death or attrition. RESULTS: Participants were a mean age of 75 years, 58% were women, 22% were Black, and 27% had a prior head injury. Compared to individuals without head injury, individuals with head injury had worse physical functioning (SPPB total score, ß-coefficient = -0.22, 95% CI: -0.35 to -0.09) and were more likely to be pre-frail (OR = 1.19, 95% CI: 1.04 to 1.35) or frail (OR = 1.40, 95% CI: 1.08 to 1.80) compared to robust. Prospectively, head injury was associated with a 0.02 m/s greater decline (95% CI: -0.04 to -0.01) in gait speed over a median of 5 years. Among baseline robust individuals (n = 1 847), head injury was associated with increased odds of becoming pre-frail (OR = 1.32, 95% CI: 1.04 to 1.67) or frail (OR = 1.92, 95% CI: 1.05 to 3.51) compared to robust. CONCLUSIONS: Older adults with prior head injury had worse physical functioning and greater frailty at baseline and were more likely to become frail and walk slower over time, compared to individuals without head injury.

Association between structural brain MRI abnormalities and epilepsy in older adults.

OBJECTIVE: To determine the association between brain MRI abnormalities and incident epilepsy in older adults. METHODS: Men and women (ages 45-64 years) from the Atherosclerosis Risk in Communities study were followed up from 1987 to 2018 with brain MRI performed between 2011 and 2013. We identified cases of incident late-onset epilepsy (LOE) with onset of seizures occurring after the acquisition of brain MRI. We evaluated the relative pattern of cortical thickness, subcortical volume, and white matter integrity among participants with incident LOE after MRI in comparison with participants without seizures. We examined the association between MRI abnormalities and incident LOE using Cox proportional hazards regression. Models were adjusted for demographics, hypertension, diabetes, smoking, stroke, and dementia status. RESULTS: Among 1251 participants with brain MRI data, 27 (2.2%) developed LOE after MRI over a median of 6.4 years (25-75 percentile 5.8-6.9) of follow-up. Participants with incident LOE after MRI had higher levels of cortical thinning and white matter microstructural abnormalities before seizure onset compared to those without seizures. In longitudinal analyses, greater number of abnormalities was associated with incident LOE after controlling for demographic factors, risk factors for cardiovascular disease, stroke, and dementia (gray matter: hazard ratio [HR]: 2.3, 95% confidence interval [CI]: 1.0-4.9; white matter diffusivity: HR: 3.0, 95% CI: 1.2-7.3). INTERPRETATION: This study demonstrates considerable gray and white matter pathology among individuals with LOE, which is present prior to the onset of seizures and provides important insights into the role of neurodegeneration, both of gray and white matter, and the risk of LOE.

Selective head cooling in the acute phase of concussive injury: a neuroimaging study.

Introduction: Neurovascular decoupling is a common consequence after brain injuries like sports-related concussion. Failure to appropriately match cerebral blood flow (CBF) with increases in metabolic demands of the brain can lead to alterations in neurological function and symptom presentation. Therapeutic hypothermia has been used in medicine for neuroprotection and has been shown to improve outcome. This study aimed to examine the real time effect of selective head cooling on healthy controls and concussed athletes via magnetic resonance spectroscopy (MRS) and arterial spin labeling (ASL) measures. Methods: 24 participants (12 controls; 12 concussed) underwent study procedures including the Post-Concussion Symptom Severity (PCSS) Rating Form and an MRI cooling protocol (pre-cooling (T1 MPRAGE, ASL, single volume spectroscopy (SVS)); during cooling (ASL, SVS)). Results: Results showed general decreases in brain temperature as a function of time for both groups. Repeated measures ANOVA showed a significant main effect of time (F = 7.94, p < 0.001) and group (F = 22.21, p < 0.001) on temperature, but no significant interaction of group and time (F = 1.36, p = 0.237). CBF assessed via ASL was non-significantly lower in concussed individuals at pre-cooling and generalized linear mixed model analyses demonstrated a significant main effect of time for the occipital left ROI (F = 11.29, p = 0.002) and occipital right ROI (F = 13.39, p = 0.001). There was no relationship between any MRI metric and PCSS symptom burden. Discussion: These findings suggest the feasibility of MRS thermometry to monitor alterations of brain temperature in concussed athletes and that metabolic responses in response to cooling after concussion may differ from controls.

Treatment of hypokalemia with amiloride unmasked hypercalcemia and hyperparathyroidism: A case report.

Colonic pseudo-obstruction, also called Ogilvie's syndrome, occurs due to impaired intestinal propulsion, and may be caused by electrolyte imbalances such as hypokalemia and some endocrine disorders such as hyperparathyroidism. Secretory diarrhea due to intestinal pseudo-obstruction can cause hypokalemia. Diuretics such as amiloride can be used to treat hypokalemia, however in this case, treatment with amiloride induced hypercalcemia and unmasked hyperparathyroidism. A 73-year-old female with a history of hypertension and parathyroid adenoma presented with recurrent colonic pseudo-obstruction and chronic hypokalemia. Her hypokalemia was treated with amiloride, causing hypercalcemia of 14.4 mg/dL, elevated PTH, and altered mental status. Amiloride was subsequently discontinued with improvement in her symptoms, and her hyperparathyroidism was treated with cinacalcet. To our knowledge, this is the first report of amiloride unmasking hyperparathyroidism and inducing hypercalcemia.

Associations Between Head Injury and Subsequent Risk of Falls: Results From the Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND AND OBJECTIVES: Falls are a leading cause of head injury among older adults, but the risk of fall occurring after a head injury is less well-characterized. We sought to examine the association between head injury and subsequent risk of falls requiring hospital care among community-dwelling older adults. METHODS: This analysis included 13,081 participants in the Atherosclerosis Risk in Communities Study enrolled in 1987-1989 and followed through 2019. The association of head injury (time-varying exposure, self-reported and/or ICD-9/10 code identified) with the risk of subsequent (occurring >1-month after head injury) falls requiring hospital care (ICD-9/10 code defined) was modeled using Cox proportional hazards regression. Secondary analyses included Fine and Gray proportional hazards regression to account for the competing risk of death, analysis of head injury frequency and severity, and formal testing for interaction by age, sex, and race. Models were adjusted for age, sex, race/center, education, military service, alcohol consumption, smoking, diabetes, hypertension, and psychotropic medication use. RESULTS: The mean age of participants at baseline was 54 years, 58% were female, 28% were Black, and 14% had at least one head injury occurring over the study period. Over a median 23 years of follow-up, 29% of participants had a fall requiring medical care. In adjusted Cox proportional hazards models, individuals with head injury had 2.01 (95% CI 1.85-2.18) times the risk of falls compared with individuals without head injury. Accounting for the competing risk of mortality, individuals with head injury had 1.69 (95% CI 1.57-1.82) times the risk of falls compared with individuals without head injury. We observed stronger associations among men compared with women (men: hazard ratio [HR] = 2.60, 95% CI 2.25-3.00; women: HR = 1.80, 95% CI 1.63-1.99, p-interaction <0.001). We observed evidence of a dose-response association for head injury number and severity with fall risk (1 injury: HR = 1.68, 95% CI 1.53-1.84; 2+ injuries: HR = 2.37, 95% CI 1.92-2.94 and mild: HR = 1.97, 95% CI 1.78-2.18; moderate/severe/penetrating: HR = 2.50, 95% CI 2.06-3.02). DISCUSSION: Among community-dwelling older adults followed over 30 years, head injury was associated with subsequent falls requiring medical care. We observed stronger associations among men and with increasing number and severity of head injuries. Whether older individuals with head injury might benefit from fall prevention measures should be a focus of future research.

Climate Spaces and Cliffs: A Novel Bovine Thermodynamic and Mass Balances Model.

The effects of climate change on animals are typically viewed in terms of survivability and wellbeing. In this study, we broaden that purview to include climate impacts on reproductive capability. There are not only climate spaces for daily function, but climate cliffs that represent reproductive failures in the face of climate warming. This alternative focus suggests that climate warming challenges may be more immediate and profound than initially imagined. This research describes a state-of-the-art mechanistic model, Dairy Niche Mapper (DNM), and independent validation tests. Where test data are absent, the calculated results are consistent with expected responses. Simulations of metabolic chamber conditions reveal the local steady-state impacts of climate and animal variables on milk production capacity, metabolic rate, food consumption and water needs. Simulations of a temperature humidity index (THI) show strengths and limitations of that approach. Broader time- and spatial-scale calculations applied in the western and eastern halves of the northern hemisphere identify current and future monthly latitudinal climate change impacts on milk production potential, feed and water needs in dairy cows of different sizes. Dairy Niche Mapper (DNM) was developed from a broadly tested mechanistic microclimate-animal model, Niche Mapper (NM). DNM provides an improved quantitative understanding of the complex nonlinear interactions of climate variation and dairy bovine properties' effects on current and future milk production, feed and water needs for grazing and confinement dairy operations. DNM outputs include feasible activity times, milk production and water and feed needs of different-sized Holstein cows on high-grain (confinement feeding) versus high-forage (grazing feeding) diets at three arbitrary north latitudes, 12°, 30° and 60°, for North and Central America and for Asia. These three latitudes encompass current northern hemisphere bovine production environments and possible future production locations. The greatest impacts of climate change will be in the low elevations in tropical and subtropical regions. Global regions above 30° and below 60° latitude with reliable rainfall will be least affected by current projected levels of climate change. This work provides the basis for computational animal design for guiding agricultural development via breeding programs, genetic engineering, management options including siting or the manipulation of other relevant environmental and animal variables.

Spatiotemporal profile of atrophy in the first year following moderate-severe traumatic brain injury.

Traumatic brain injury (TBI) triggers progressive neurodegeneration resulting in brain atrophy that continues months-to-years following injury. However, a comprehensive characterization of the spatial and temporal evolution of TBI-related brain atrophy remains incomplete. Utilizing a sensitive and unbiased morphometry analysis pipeline optimized for detecting longitudinal changes, we analyzed a sample consisting of 37 individuals with moderate-severe TBI who had primarily high-velocity and high-impact injury mechanisms. They were scanned up to three times during the first year after injury (3 months, 6 months, and 12 months post-injury) and compared with 33 demographically matched controls who were scanned once. Individuals with TBI already showed cortical thinning in frontal and temporal regions and reduced volume in the bilateral thalami at 3 months post-injury. Longitudinally, only a subset of cortical regions in the parietal and occipital lobes showed continued atrophy from 3 to 12 months post-injury. Additionally, cortical white matter volume and nearly all deep gray matter structures exhibited progressive atrophy over this period. Finally, we found that disproportionate atrophy of cortex along sulci relative to gyri, an emerging morphometric marker of chronic TBI, was present as early as 3 month post-injury. In parallel, neurocognitive functioning largely recovered during this period despite this pervasive atrophy. Our findings demonstrate msTBI results in characteristic progressive neurodegeneration patterns that are divergent across regions and scale with the severity of injury. Future clinical research using atrophy during the first year of TBI as a biomarker of neurodegeneration should consider the spatiotemporal profile of atrophy described in this study.

Elevated renal afferent nerve activity in a rat model of endothelin B receptor deficiency.

Renal nerves have been an attractive target for interventions aimed at lowering blood pressure; however, the specific roles of renal afferent (sensory) versus efferent sympathetic nerves in mediating hypertension are poorly characterized. A number of studies have suggested that a sympathoexcitatory signal conveyed by renal afferents elicits increases in blood pressure, whereas other studies identified sympathoinhibitory afferent pathways. These sympathoinhibitory pathways have been identified as protective against salt-sensitive increases in blood pressure through endothelin B (ETB) receptor activation. We hypothesized that ETB-deficient (ETB-def) rats, which are devoid of functional ETB receptors except in adrenergic tissues, lack appropriate sympathoinhibition and have lower renal afferent nerve activity following a high-salt diet compared with transgenic controls. We found that isolated renal pelvises from high salt-fed ETB-def animals lack a response to a physiological stimulus, prostaglandin E2, compared with transgenic controls but respond equally to a noxious stimulus, capsaicin. Surprisingly, we observed elevated renal afferent nerve activity in intact ETB-def rats compared with transgenic controls under both normal- and high-salt diets. ETB-def rats have been previously shown to have heightened global sympathetic tone, and we also observed higher total renal sympathetic nerve activity in ETB-def rats compared with transgenic controls under both normal- and high-salt diets. These data indicate that ETB receptors are integral mediators of the sympathoinhibitory renal afferent reflex (renorenal reflex), and, in a genetic rat model of ETB deficiency, the preponderance of sympathoexcitatory renal afferent nerve activity prevails and may contribute to hypertension.NEW & NOTEWORTHY Here, we found that endothelin B receptors are an important contributor to renal afferent nerve responsiveness to a high-salt diet. Rats lacking endothelin B receptors have increased afferent nerve activity that is not responsive to a high-salt diet.

Structural brain network deviations predict recovery after traumatic brain injury.

OBJECTIVE: Traumatic brain injury results in diffuse axonal injury and the ensuing maladaptive alterations in network function are associated with incomplete recovery and persistent disability. Despite the importance of axonal injury as an endophenotype in TBI, there is no biomarker that can measure the aggregate and region-specific burden of axonal injury. Normative modeling is an emerging quantitative case-control technique that can capture region-specific and aggregate deviations in brain networks at the individual patient level. Our objective was to apply normative modeling in TBI to study deviations in brain networks after primarily complicated mild TBI and study its relationship with other validated measures of injury severity, burden of post-TBI symptoms, and functional impairment. METHOD: We analyzed 70 T1-weighted and diffusion-weighted MRIs longitudinally collected from 35 individuals with primarily complicated mild TBI during the subacute and chronic post-injury periods. Each individual underwent longitudinal blood sampling to characterize blood protein biomarkers of axonal and glial injury and assessment of post-injury recovery in the subacute and chronic periods. By comparing the MRI data of individual TBI participants with 35 uninjured controls, we estimated the longitudinal change in structural brain network deviations. We compared network deviation with independent measures of acute intracranial injury estimated from head CT and blood protein biomarkers. Using elastic net regression models, we identified brain regions in which deviations present in the subacute period predict chronic post-TBI symptoms and functional status. RESULTS: Post-injury structural network deviation was significantly higher than controls in both subacute and chronic periods, associated with an acute CT lesion and subacute blood levels of glial fibrillary acid protein (r = 0.5, p = 0.008) and neurofilament light (r = 0.41, p = 0.02). Longitudinal change in network deviation associated with change in functional outcome status (r = -0.51, p = 0.003) and post-concussive symptoms (BSI: r = 0.46, p = 0.03; RPQ: r = 0.46, p = 0.02). The brain regions where the node deviation index measured in the subacute period predicted chronic TBI symptoms and functional status corresponded to areas known to be susceptible to neurotrauma. CONCLUSION: Normative modeling can capture structural network deviations, which may be useful in estimating the aggregate and region-specific burden of network changes induced by TAI. If validated in larger studies, structural network deviation scores could be useful for enrichment of clinical trials of targeted TAI-directed therapies.

The mRNA Vaccine Technology Era and the Future Control of Parasitic Infections.

Despite intensive long-term efforts, with very few exceptions, the development of effective vaccines against parasitic infections has presented considerable challenges, given the complexity of parasite life cycles, the interplay between parasites and their hosts, and their capacity to escape the host immune system and to regulate host immune responses. For many parasitic diseases, conventional vaccine platforms have generally proven ill suited, considering the complex manufacturing processes involved and the costs they incur, the inability to posttranslationally modify cloned target antigens, and the absence of long-lasting protective immunity induced by these antigens. An effective antiparasite vaccine platform is required to assess the effectiveness of novel vaccine candidates at high throughput. By exploiting the approach that has recently been used successfully to produce highly protective COVID mRNA vaccines, we anticipate a new wave of research to advance the use of mRNA vaccines to prevent parasitic infections in the near future. This article considers the characteristics that are required to develop a potent antiparasite vaccine and provides a conceptual foundation to promote the development of parasite mRNA-based vaccines. We review the recent advances and challenges encountered in developing antiparasite vaccines and evaluate the potential of developing mRNA vaccines against parasites, including those causing diseases such as malaria and schistosomiasis, against which vaccines are currently suboptimal or not yet available.

In vivo editing of the pan-endothelium by immunity evading simian adenoviral vector.

Biological applications deriving from the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 site-specific nuclease system continue to impact and accelerate gene therapy strategies. Safe and effective in vivo co-delivery of the CRISPR/Cas9 system to target somatic cells is essential in the clinical therapeutic context. Both non-viral and viral vector systems have been applied for this delivery matter. Despite elegant proof-of-principle studies, available vector technologies still face challenges that restrict the application of CRISPR/Cas9-facilitated gene therapy. Of note, the mandated co-delivery of the gene-editing components must be accomplished in the potential presence of pre-formed anti-vector immunity. Additionally, methods must be sought to limit the potential of off-target editing. To this end, we have exploited the molecular promiscuities of adenovirus (Ad) to address the key requirements of CRISPR/Cas9-facilitated gene therapy. In this regard, we have endeavored capsid engineering of a simian (chimpanzee) adenovirus isolate 36 (SAd36) to achieve targeted modifications of vector tropism. The SAd36 vector with the myeloid cell-binding peptide (MBP) incorporated in the capsid has allowed selective in vivo modifications of the vascular endothelium. Importantly, vascular endothelium can serve as an effective non-hepatic cellular source of deficient serum factors relevant to several inherited genetic disorders. In addition to allowing for re-directed tropism, capsid engineering of nonhuman primate Ads provide the means to circumvent pre-formed vector immunity. Herein we have generated a SAd36. MBP vector that can serve as a single intravenously administered agent allowing effective and selective in vivo editing for endothelial target cells of the mouse spleen, brain and kidney. DATA AVAILABILITY: The data that support the findings of this study are available from the corresponding author upon reasonable request.

Head Injury and Long-term Mortality Risk in Community-Dwelling Adults.

Importance: Head injury is associated with significant short-term morbidity and mortality. Research regarding the implications of head injury for long-term survival in community-dwelling adults remains limited. Objective: To evaluate the association of head injury with long-term all-cause mortality risk among community-dwelling adults, with consideration of head injury frequency and severity. Design, Setting, and Participants: This cohort study included participants with and without head injury in the Atherosclerosis Risk in Communities (ARIC) study, an ongoing prospective cohort study with follow-up from 1987 through 2019 in 4 US communities in Minnesota, Maryland, North Carolina, and Mississippi. Of 15 792 ARIC participants initially enrolled, 1957 were ineligible due to self-reported head injury at baseline; 103 participants not of Black or White race and Black participants at the Minnesota and Maryland field centers were excluded due to race-site aliasing; and an additional 695 participants with missing head injury date or covariate data were excluded, resulting in 13 037 eligible participants. Exposures: Head injury frequency and severity, as defined via self-report in response to interview questions and via hospital-based International Classification of Diseases diagnostic codes (with head injury severity defined in the subset of head injury cases identified using these codes). Head injury was analyzed as a time-varying exposure. Main Outcomes and Measures: All-cause mortality was ascertained via linkage to the National Death Index. Data were analyzed between August 5, 2021, and October 23, 2022. Results: More than one-half of participants were female (57.7%; 42.3% men), 27.9% were Black (72.1% White), and the median age at baseline was 54 years (IQR, 49-59 years). Median follow-up time was 27.0 years (IQR, 17.6-30.5 years). Head injuries occurred among 2402 participants (18.4%), most of which were classified as mild. The hazard ratio (HR) for all-cause mortality among individuals with head injury was 1.99 (95% CI, 1.88-2.11) compared with those with no head injury, with evidence of a dose-dependent association with head injury frequency (1 head injury: HR, 1.66 [95% CI, 1.56-1.77]; 2 or more head injuries: HR, 2.11 [95% CI, 1.89-2.37]) and severity (mild: HR, 2.16 [95% CI, 2.01-2.31]; moderate, severe, or penetrating: HR, 2.87 [95% CI, 2.55-3.22]). Estimates were similar by sex and race, with attenuated associations among individuals aged 54 years or older at baseline. Conclusions and Relevance: In this community-based cohort with more than 3 decades of longitudinal follow-up, head injury was associated with decreased long-term survival time in a dose-dependent manner, underscoring the importance of measures aimed at prevention and clinical interventions to reduce morbidity and mortality due to head injury.

Longitudinal Abnormalities in White Matter Extracellular Free Water Volume Fraction and Neuropsychological Functioning in Patients with Traumatic Brain Injury.

Traumatic brain injury is a global public health problem associated with chronic neurological complications and long-term disability. Biomarkers that map onto the underlying brain pathology driving these complications are urgently needed to identify individuals at risk for poor recovery and to inform design of clinical trials of neuroprotective therapies. Neuroinflammation and neurodegeneration are two endophenotypes potentially associated with increases in brain extracellular water content, but the nature of extracellular free water abnormalities after neurotrauma and its relationship to measures typically thought to reflect traumatic axonal injury are not well characterized. The objective of this study was to describe the relationship between a neuroimaging biomarker of extracellular free water content and the clinical features of a cohort with primarily complicated mild traumatic brain injury. We analyzed a cohort of 59 adult patients requiring hospitalization for non-penetrating traumatic brain injury of all severities as well as 36 healthy controls. Patients underwent brain magnetic resonance imaging (MRI) at 2 weeks (n = 59) and 6 months (n = 29) post-injury, and controls underwent a single MRI. Of the participants with TBI, 50 underwent clinical neuropsychological assessment at 2 weeks and 28 at 6 months. For each subject, we derived a summary score representing deviations in whole brain white matter extracellular free water volume fraction (VF) and free water-corrected fractional anisotropy (fw-FA). The summary specific anomaly score (SAS) for VF was significantly higher in TBI patients at 2 weeks and 6 months post-injury relative to controls. SAS for VF exhibited moderate correlation with neuropsychological functioning, particularly on measures of executive function. These findings indicate abnormalities in whole brain white matter extracellular water fraction in patients with TBI and are an important step toward identifying and validating noninvasive biomarkers that map onto the pathology driving disability after TBI.

Dynamic contrast enhanced MRI for characterization of blood-brain-barrier dysfunction after traumatic brain injury.

BACKGROUND AND PURPOSE: Dysfunction of the blood-brain-barrier (BBB) is a recognized pathological consequence of traumatic brain injury (TBI) which may play an important role in chronic TBI pathophysiology. We hypothesized that BBB disruption can be detected with dynamic contrast-enhanced (DCE) MRI not only in association with focal traumatic lesions but also in normal-appearing brain tissue of TBI patients, reflecting microscopic microvascular injury. We further hypothesized that BBB integrity would improve but not completely normalize months after TBI. MATERIALS AND METHODS: DCE MRI was performed in 40 adult patients a median of 23 days after hospitalized TBI and in 21 healthy controls. DCE data was analyzed using Patlak and linear models, and derived metrics of BBB leakage including the volume transfer constant (Ktrans) and the normalized permeability index (NPI) were compared between groups. BBB metrics were compared with focal lesion distribution as well as with contemporaneous measures of symptomatology and cognitive function in TBI patients. Finally, BBB metrics were examined longitudinally among 18 TBI patients who returned for a second MRI a median of 204 days postinjury. RESULTS: TBI patients exhibited higher mean Ktrans (p = 0.0028) and proportion of suprathreshold NPI voxels (p = 0.001) relative to controls. Tissue-based analysis confirmed greatest TBI-related BBB disruption in association with focal lesions, however elevated Ktrans was also observed in perilesional (p = 0.011) and nonlesional (p = 0.044) regions. BBB disruption showed inverse correlation with quality of life (rho = -0.51, corrected p = 0.016). Among the subset of TBI patients who underwent a second MRI several months after the initial evaluation, metrics of BBB disruption did not differ significantly at the group level, though variable longitudinal changes were observed at the individual subject level. CONCLUSIONS: This pilot investigation suggests that TBI-related BBB disruption is detectable in the early post-injury period in association with focal and diffuse brain injury.

Spatially resolved whole transcriptome profiling in human and mouse tissue using Digital Spatial Profiling.

Emerging spatial profiling technology has enabled high-plex molecular profiling in biological tissues, preserving the spatial and morphological context of gene expression. Here, we describe expanding the chemistry for the Digital Spatial Profiling platform to quantify whole transcriptomes in human and mouse tissues using a wide range of spatial profiling strategies and sample types. We designed multiplexed in situ hybridization probes targeting the protein-coding genes of the human and mouse transcriptomes, referred to as the human or mouse Whole Transcriptome Atlas (WTA). Human and mouse WTAs were validated in cell lines for concordance with orthogonal gene expression profiling methods in regions ranging from ∼10-500 cells. By benchmarking against bulk RNA-seq and fluorescence in situ hybridization, we show robust transcript detection down to ∼100 transcripts per region. To assess the performance of WTA across tissue and sample types, we applied WTA to biological questions in cancer, molecular pathology, and developmental biology. Spatial profiling with WTA detected expected gene expression differences between tumor and tumor microenvironment, identified disease-specific gene expression heterogeneity in histological structures of the human kidney, and comprehensively mapped transcriptional programs in anatomical substructures of nine organs in the developing mouse embryo. Digital Spatial Profiling technology with the WTA assays provides a flexible method for spatial whole transcriptome profiling applicable to diverse tissue types and biological contexts.