A longitudinal microstructural MRI dataset in healthy C57Bl/6 mice at 9.4 Tesla.

Multimodal microstructural MRI has shown increased sensitivity and specificity to changes in various brain disease and injury models in the preclinical setting. Here, we present an in vivo longitudinal dataset, including a subset of ex vivo data, acquired as control data and to investigate microstructural changes in the healthy mouse brain. The dataset consists of structural T2-weighted imaging, magnetization transfer ratio and saturation imaging, and advanced quantitative diffusion MRI (dMRI) methods. The dMRI methods include oscillating gradient spin echo (OGSE) dMRI and microscopic anisotropy (µA) dMRI, which provide additional insight by increasing sensitivity to smaller spatial scales and disentangling fiber orientation dispersion from true microstructural changes, respectively. The technical skills required to analyze microstructural MRI data are complex and include MRI sequence development, acquisition, and computational neuroimaging expertise. Here, we share unprocessed and preprocessed data, and scalar maps of quantitative MRI metrics. We envision utility of this dataset in the microstructural MRI field to develop and test biophysical models, methods that model temporal brain dynamics, and registration and preprocessing pipelines.

A systematic analysis of ultrastructural lesions in the Plasmodium coatneyi splenectomized rhesus macaque model of severe malaria.

Plasmodium falciparum remains one of the world's deadliest diseases and with ongoing concerns of evolving drug resistance, there is a need for continued refinement of the Plasmodium coatneyi infection model in macaques to study severe malaria. As such, the systemic ultrastructural lesions associated with P. coatneyi infection in splenectomized rhesus macaques was evaluated in 6 animals. Autopsy samples from multiple areas of the central nervous system (CNS), kidneys, heart, liver, and lungs of all 6 animals were processed for electron microscopy. A systematic analysis of the ultrastructural changes associated with the plasmodium was undertaken by multiple pathologists to ensure consensus. All tissues exhibited marked sequestration of infected red blood cells comprised either of cytoadherence to endothelium or rosette formation, associated with variable degrees of host cell damage in a range of tissues that in severe cases resulted in necrosis. This is the first complete systemic evaluation of ultrastructural tissue lesions in P. coatneyi-infected rhesus macaques, and the findings have important implications evaluating of the use of this model for the study of severe malaria caused by P. falciparum in humans.

Test-Retest Reproducibility of In Vivo Magnetization Transfer Ratio and Saturation Index in Mice at 9.4 Tesla.

BACKGROUND: Magnetization transfer saturation (MTsat) imaging was developed to reduce T1 dependence and improve specificity to myelin, compared to the widely used MT ratio (MTR) approach, while maintaining a feasible scan time. As MTsat imaging is an emerging technique, the reproducibility of MTsat compared to MTR must be evaluated. PURPOSE: To assess the test-retest reproducibility of MTR and MTsat in the mouse brain at 9.4 T and calculate sample sizes potentially required to detect effect sizes ranging from 6% to 14%. STUDY TYPE: Prospective. SUBJECTS: Twelve healthy C57Bl/6 mice. FIELD STRENGTH/SEQUENCE: 9.4 T; magnetization transfer imaging using FLASH-3D Gradient Echo; T2-weighted TurboRARE spin echo. ASSESSMENT: All mice were scanned at two timepoints (5 days apart). MTR and MTsat maps were analyzed using mean region-of-interest (ROIs: corpus callosum [CC], internal capsule [IC], hippocampus [HC], cortex [CX], and thalamus [TH]), and whole brain voxel-wise analysis. STATISTICAL TESTS: Bland-Altman plots were used to assess biases between test-retest measurements. Test-retest reproducibility was evaluated via between and within-subject coefficients of variation (bsCV and wsCV, respectively). Sample sizes required were calculated (significance level: 95%; power: 80%), given effect sizes ranging from 6% to 14%, using both between and within-subject approaches. Results were considered statistically significant at P ≤ 0.05. RESULTS: Bland-Altman plots showed negligible biases between test-retest sessions (MTR: 0.0009; MTsat: 0). ROI-based and voxel-wise CVs revealed high reproducibility for both MTR (ROI-bsCV/wsCV: CC-4.5/2.8%; IC-6.1/5.2%; HC-5.7/4.6%; CX-5.1/2.3%; TH-7.4/4.9%) and MTsat (ROI-bsCV/wsCV: CC-6.3/4.8%; IC-7.3/5.1%; HC-9.5/6.4%; CX-6.7/6.5%; TH-7.2/5.3%). With a sample size of 6, changes on the order of 15% could be detected in MTR and MTsat, both between and within subjects, while smaller changes (6%-8%) required sample sizes of 10-15 for MTR, and 15-20 for MTsat. DATA CONCLUSION: MTsat exhibited comparable reproducibility to MTR, while providing sensitivity to myelin with less T1 dependence than MTR. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1.

The Effect of Three-Dimensional Whole, Major, and Small Vasculature on Mouse Brain Strain Under Both Diffuse and Focal Brain Injury Loading.

Blood vessels are much stiffer than brain parenchyma and their effects in finite element (FE) brain models need to be investigated. Despite the publication of some comprehensive three-dimensional (3D) brain vasculature models, no mechanical model exists for the mouse brain vasculature. Moreover, how the vasculature affects the mechanical behavior of brain tissue remains controversial. Therefore, we developed FE mouse brain models with detailed 3D vasculature to investigate the effect of the vasculature on brain strains under both diffuse (closed-head impact) and focal injury (controlled cortical impact (CCI)) loading, two commonly laboratory models of traumatic brain injury. The effect of the vasculature was examined by comparing maximum principal strain in mouse brain FE models with and without the vasculature. On average, modeling comprehensive vasculature under diffuse injury loading reduced average brain strain predictions by 32% with nonlinear elastic properties. Nearly three-fourths of the 32% strain reduction was attributable to the effects of the major branches of the vasculature. Meanwhile, during focal open-skull CCI injury loading, the contribution of the vasculature was limited, producing a less than 5% reduction in all cases. Overall, the vasculature, especially the major branches, increased the load-bearing capacity of the brain FE model and thus reduced brain strain predictions.

ß2 Integrin CD11d/CD18: From Expression to an Emerging Role in Staged Leukocyte Migration.

CD11d/CD18 is the most recently discovered and least understood ß2 integrin. Known CD11d adhesive mechanisms contribute to both extravasation and mesenchymal migration - two key aspects for localizing peripheral leukocytes to sites of inflammation. Differential expression of CD11d induces differences in monocyte/macrophage mesenchymal migration including impacts on macrophage sub-set migration. The participation of CD11d/CD18 in leukocyte localization during atherosclerosis and following neurotrauma has sparked interest in the development of CD11d-targeted therapeutic agents. Whereas the adhesive properties of CD11d have undergone investigation, the signalling pathways induced by ligand binding remain largely undefined. Underlining each adhesive and signalling function, CD11d is under unique transcriptional control and expressed on a sub-set of predominately tissue-differentiated innate leukocytes. The following review is the first to capture the nearly three decades of CD11d research and discusses the emerging role of CD11d in leukocyte migration and retention during the progression of a staged immune response.

Test-retest reproducibility of in vivo oscillating gradient and microscopic anisotropy diffusion MRI in mice at 9.4 Tesla.

BACKGROUND AND PURPOSE: Microstructure imaging with advanced diffusion MRI (dMRI) techniques have shown increased sensitivity and specificity to microstructural changes in various disease and injury models. Oscillating gradient spin echo (OGSE) dMRI, implemented by varying the oscillating gradient frequency, and microscopic anisotropy (µA) dMRI, implemented via tensor valued diffusion encoding, may provide additional insight by increasing sensitivity to smaller spatial scales and disentangling fiber orientation dispersion from true microstructural changes, respectively. The aims of this study were to characterize the test-retest reproducibility of in vivo OGSE and µA dMRI metrics in the mouse brain at 9.4 Tesla and provide estimates of required sample sizes for future investigations. METHODS: Twelve adult C57Bl/6 mice were scanned twice (5 days apart). Each imaging session consisted of multifrequency OGSE and µA dMRI protocols. Metrics investigated included µA, linear diffusion kurtosis, isotropic diffusion kurtosis, and the diffusion dispersion rate (Λ), which explores the power-law frequency dependence of mean diffusivity. The dMRI metric maps were analyzed with mean region-of-interest (ROI) and whole brain voxel-wise analysis. Bland-Altman plots and coefficients of variation (CV) were used to assess the reproducibility of OGSE and µA metrics. Furthermore, we estimated sample sizes required to detect a variety of effect sizes. RESULTS: Bland-Altman plots showed negligible biases between test and retest sessions. ROI-based CVs revealed high reproducibility for most metrics (CVs < 15%). Voxel-wise CV maps revealed high reproducibility for µA (CVs ~ 10%), but low reproducibility for OGSE metrics (CVs ~ 50%). CONCLUSION: Most of the µA dMRI metrics are reproducible in both ROI-based and voxel-wise analysis, while the OGSE dMRI metrics are only reproducible in ROI-based analysis. Given feasible sample sizes (10-15), µA metrics and OGSE metrics may provide sensitivity to subtle microstructural changes (4-8%) and moderate changes (> 6%), respectively.

Neurite orientation dispersion and density imaging in a rodent model of acute mild traumatic brain injury.

BACKGROUND AND PURPOSE: Identification of changesin brain microstructure following mild traumatic brain injury (mTBI) could be instrumental in understanding the underlying pathophysiology. The purpose of this study was to apply neurite orientation dispersion and density imaging (NODDI) to a rodent model of mTBI to determine whether microstructural changes could be detected immediately following injury. METHODS: Fifteen adult male Wistar rats were scanned on a Bruker 9.4 Tesla small animal MRI using a multi-shell acquisition (30 b = 1000 s/mm2 and 60 b = 2000 s/mm2 ). Nine animals experienced a single closed head controlled cortical impact followed by NODDI from 1 to 4 h post injury. Region of interest analysis focused on the corpus callosum and hippocampus. A mixed analysis of variance (ANOVA) was used to determine statistically significant interactions in neurite density index (NDI), orientation dispersion index (ODI), fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity. Follow up repeated-measures ANOVAs were used to determine individual changes over time. RESULTS: NDI showed a significant increase in the hippocampus and corpus callosum following injury, while ODI showed increases in the corpus callosum. No significant changes were observed in the sham control animals. No changes were found in FA, MD, AD, or RD. Histological analysis revealed increased glial fibrillary acidic protein staining relative to controls in both the hippocampus and corpus callosum, with evidence of activated astrocytes in these regions. CONCLUSIONS: Changes in NODDI metrics were detected as early as 1 h following mTBI. No changes were detected with conventional diffusion tensor imaging (DTI) metrics, suggesting that NODDI provides greater sensitivity to microstructural changes than conventional DTI.

Repetitive mild traumatic brain injury in mice triggers a slowly developing cascade of long-term and persistent behavioral deficits and pathological changes.

We have previously reported long-term changes in the brains of non-concussed varsity rugby players using magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI) and functional magnetic imaging (fMRI). Others have reported cognitive deficits in contact sport athletes that have not met the diagnostic criteria for concussion. These results suggest that repetitive mild traumatic brain injuries (rmTBIs) that are not severe enough to meet the diagnostic threshold for concussion, produce long-term consequences. We sought to characterize the neuroimaging, cognitive, pathological and metabolomic changes in a mouse model of rmTBI. Using a closed-skull model of mTBI that when scaled to human leads to rotational and linear accelerations far below what has been reported for sports concussion athletes, we found that 5 daily mTBIs triggered two temporally distinct types of pathological changes. First, during the first days and weeks after injury, the rmTBI produced diffuse axonal injury, a transient inflammatory response and changes in diffusion tensor imaging (DTI) that resolved with time. Second, the rmTBI led to pathological changes that were evident months after the injury including: changes in magnetic resonance spectroscopy (MRS), altered levels of synaptic proteins, behavioural deficits in attention and spatial memory, accumulations of pathologically phosphorylated tau, altered blood metabolomic profiles and white matter ultrastructural abnormalities. These results indicate that exceedingly mild rmTBI, in mice, triggers processes with pathological consequences observable months after the initial injury.

Brain Metabolite Levels in Sedentary Women and Non-contact Athletes Differ From Contact Athletes.

White matter tracts are known to be susceptible to injury following concussion. The objective of this study was to determine whether contact play in sport could alter white matter metabolite levels in female varsity athletes independent of changes induced by long-term exercise. Metabolite levels were measured by single voxel proton magnetic resonance spectroscopy (MRS) in the prefrontal white matter at the beginning (In-Season) and end (Off-Season) of season in contact (N = 54, rugby players) and non-contact (N = 23, swimmers and rowers) varsity athletes. Sedentary women (N = 23) were scanned once, at a time equivalent to the Off-Season time point. Metabolite levels in non-contact athletes did not change over a season of play, or differ from age matched sedentary women except that non-contact athletes had a slightly lower myo-inositol level. The contact athletes had lower levels of myo-inositol and glutamate, and higher levels of glutamine compared to both sedentary women and non-contact athletes. Lower levels of myo-inositol in non-contact athletes compared to sedentary women indicates long-term exercise may alter glial cell profiles in these athletes. The metabolite differences observed between contact and non-contact athletes suggest that non-contact athletes should not be used as controls in studies of concussion in high-impact sports because repetitive impacts from physical contact can alter white matter metabolite level profiles. It is imperative to use athletes engaged in the same contact sport as controls to ensure a matched metabolite profile at baseline.

Longitudinal changes of brain microstructure and function in nonconcussed female rugby players.

OBJECTIVE: To longitudinally assess brain microstructure and function in female varsity athletes participating in contact and noncontact sports. METHODS: Concussion-free female rugby players (n = 73) were compared to age-matched (ages 18-23) female swimmers and rowers (n = 31) during the in- and off-season. Diffusion and resting-state fMRI (rs-fMRI) measures were the primary outcomes. The Sports Concussion Assessment Tool and head impact accelerometers were used to monitor symptoms and impacts, respectively. RESULTS: We found cross-sectional (contact vs noncontact) and longitudinal (in- vs off-season) changes in white matter diffusion measures and rs-fMRI network connectivity in concussion-free contact athletes relative to noncontact athletes. In particular, mean, axial, and radial diffusivities were increased with decreased fractional anisotropy in multiple white matter tracts of contact athletes accompanied with default mode and visual network hyperconnectivity (p < 0.001). Longitudinal diffusion changes in the brainstem between the in- and off-season were observed for concussion-free contact athletes only, with progressive changes observed in a subset of athletes over multiple seasons. Axial diffusivity was significantly lower in the genu and splenium of the corpus callosum in those contact athletes with a history of concussion. CONCLUSIONS: Together, these findings demonstrate longitudinal changes in the microstructure and function of the brain in otherwise healthy, asymptomatic athletes participating in contact sport. Further research to understand the long-term brain health and biological implications of these changes is required, in particular to what extent these changes reflect compensatory, reparative, or degenerative processes.

The Loss of ATRX Increases Susceptibility to Pancreatic Injury and Oncogenic KRAS in Female But Not Male Mice.

Background: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in North America, accounting for >30,000 deaths annually. Although somatic activating mutations in KRAS appear in 97% of PDAC patients, additional factors are required to initiate PDAC. Because mutations in genes encoding chromatin remodelling proteins have been implicated in KRAS-mediated PDAC, we investigated whether loss of chromatin remodeler ɑ-thalassemia, mental-retardation, X-linked (ATRX) affects oncogenic KRAS's ability to promote PDAC. ATRX affects DNA replication, repair, and gene expression and is implicated in other cancers including glioblastomas and pancreatic neuroendocrine tumors. The hypothesis was that deletion of Atrx in pancreatic acinar cells will increase susceptibility to injury and oncogenic KRAS. Methods: Mice allowing conditional loss of Atrx within pancreatic acinar cells were examined after induction of recurrent cerulein-induced pancreatitis or oncogenic KRAS (KRASG12D ). Histologic, biochemical, and molecular analysis examined pancreatic pathologies up to 2 months after induction of Atrx deletion. Results: Mice lacking Atrx showed more progressive damage, inflammation, and acinar-to-duct cell metaplasia in response to injury relative to wild-type mice. In combination with KRASG12D, Atrx-deficient acinar cells showed increased fibrosis, inflammation, progression to acinar-to-duct cell metaplasia, and pre-cancerous lesions relative to mice expressing only KRASG12D. This sensitivity appears only in female mice, mimicking a significant prevalence of ATRX mutations in human female PDAC patients. Conclusions: Our results indicate the absence of ATRX increases sensitivity to injury and oncogenic KRAS only in female mice. This is an instance of a sex-specific mutation that enhances oncogenic KRAS's ability to promote pancreatic intraepithelial lesion formation.

Linked MRI signatures of the brain's acute and persistent response to concussion in female varsity rugby players.

Acute brain changes are expected after concussion, yet there is growing evidence of persistent abnormalities well beyond clinical recovery and clearance to return to play. Multiparametric MRI is a powerful approach to non-invasively study structure-function relationships in the brain, however it remains challenging to interpret the complex and heterogeneous cascade of brain changes that manifest after concussion. Emerging conjunctive, data-driven analysis approaches like linked independent component analysis can integrate structural and functional imaging data to produce linked components that describe the shared inter-subject variance across images. These linked components not only offer the potential of a more comprehensive understanding of the underlying neurobiology of concussion, but can also provide reliable information at the level of an individual athlete. In this study, we analyzed resting-state functional MRI (rs-fMRI) and diffusion tensor imaging (DTI) within a cohort of female varsity rugby players (n = 52) through the in- and off-season, including concussed athletes (n = 21) who were studied longitudinally at three days, three months and six months after a diagnosed concussion. Linked components representing co-varying white matter microstructure and functional network connectivity characterized (a) the brain's acute response to concussion and (b) persistent alterations beyond clinical recovery. Furthermore, we demonstrate that these long-term brain changes related to specific aspects of a concussion history and allowed us to monitor individual athletes before and longitudinally after a diagnosed concussion.

Sox9 knockout mice have improved recovery following stroke.

The partial recovery that can occur after a stroke has been attributed to structural and functional plasticity that compensate for damage and lost functions. This plasticity is thought to be limited in part by the presence of growth inhibitors in the central nervous system. Blocking or reducing signals from inhibitors of axonal sprouting such as Nogo and chondroitin sulfate proteoglycans (CSPGs) increases post-stroke axonal sprouting and improves recovery. We previously identified the transcription factor SOX9 as a key up-regulator of CSPG production and demonstrated that conditional Sox9 ablation leads to increased axonal sprouting and improved recovery after spinal cord injury. In the present study we evaluate the effect of conditional Sox9 ablation in a transient middle cerebral artery occlusion (MCAO) model of stroke. We demonstrate that conditional Sox9 ablation leads to reduced CSPG levels, increased tissue sparing and improved post-stroke neurological recovery. Anterograde tract tracing studies demonstrate that in the Sox9 conditional knockout mice corticorubral and corticospinal projections from the contralateral, uninjured cortex increase projections to targets in the midbrain and spinal cord denervated by the injury. These results suggest that targeting SOX9 is a viable strategy to promote reparative axonal sprouting, neuroprotection and recovery after stroke.

Pathologic Thr175 tau phosphorylation in CTE and CTE with ALS.

OBJECTIVE: To investigate whether chronic traumatic encephalopathy (CTE) and CTE with amyotrophic lateral sclerosis (CTE-ALS) exhibit features previously observed in other tauopathies of pathologic phosphorylation of microtubule-associated protein tau at Thr175 (pThr175 tau) and Thr231 (pThr231 tau), and glycogen synthase kinase-3ß (GSK3ß) activation, and whether these pathologic features are a consequence of traumatic brain injury (TBI). METHODS: Tau isoform expression was assayed by western blot in 6 stage III CTE cases. We also used immunohistochemistry to analyze 5 cases each of CTE, CTE-ALS, and 5 controls for expression of activated GSK3ß, pThr175 tau, pThr231 tau, and oligomerized tau within spinal cord tissue and hippocampus. Using a rat model of moderate TBI, we assessed tau pathology and phospho-GSK3ß expression at 3 months postinjury. RESULTS: CTE and CTE-ALS are characterized by the presence of all 6 tau isoforms in both soluble and insoluble tau isolates. Activated GSK3ß, pThr175 tau, pThr231 tau, and oligomerized tau protein expression was observed in hippocampal neurons and spinal motor neurons. We observed tau neuronal pathology (fibrillar inclusions and axonal damage) and increased levels of pThr175 tau and activated GSK3ß in moderate TBI rats. CONCLUSIONS: Pathologic phosphorylation of tau at Thr175 and Thr231 and activation of GSK3ß are features of the tauopathy of CTE and CTE-ALS. These features can be replicated in an animal model of moderate TBI.

Reduced brain glutamine in female varsity rugby athletes after concussion and in non-concussed athletes after a season of play.

The purpose of this study was to use non-invasive proton magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI) to monitor changes in prefrontal white matter metabolite levels and tissue microstructure in female rugby players with and without concussion (ages 18-23, n = 64). Evaluations including clinical tests and 3 T MRI were performed at the beginning of a season (in-season) and followed up at the end of the season (off-season). Concussed athletes were additionally evaluated 24-72 hr (n = 14), three months (n = 11), and six months (n = 8) post-concussion. Reduced glutamine at 24-72 hr and three months post-concussion, and reduced glutamine/creatine at three months post-concussion were observed. In non-concussed athletes (n = 46) both glutamine and glutamine/creatine were lower in the off-season compared to in-season. Within the MRS voxel, an increase in fractional anisotropy (FA) and decrease in radial diffusivity (RD) were also observed in the non-concussed athletes, and correlated with changes in glutamine and glutamine/creatine. Decreases in glutamine and glutamine/creatine suggest reduced oxidative metabolism. Changes in FA and RD may indicate neuroinflammation or re-myelination. The observed changes did not correlate with clinical test scores suggesting these imaging metrics may be more sensitive to brain injury and could aid in assessing recovery of brain injury from concussion.

Multiparametric MRI changes persist beyond recovery in concussed adolescent hockey players.

OBJECTIVE: To determine whether multiparametric MRI data can provide insight into the acute and long-lasting neuronal sequelae after a concussion in adolescent athletes. METHODS: Players were recruited from Bantam hockey leagues in which body checking is first introduced (male, age 11-14 years). Clinical measures, diffusion metrics, resting-state network and region-to-region functional connectivity patterns, and magnetic resonance spectroscopy absolute metabolite concentrations were analyzed from an independent, age-matched control group of hockey players (n = 26) and longitudinally in concussed athletes within 24 to 72 hours (n = 17) and 3 months (n = 14) after a diagnosed concussion. RESULTS: There were diffusion abnormalities within multiple white matter tracts, functional hyperconnectivity, and decreases in choline 3 months after concussion. Tract-specific spatial statistics revealed a large region along the superior longitudinal fasciculus with the largest decreases in diffusivity measures, which significantly correlated with clinical deficits. This region also spatially intersected with probabilistic tracts connecting cortical regions where we found acute functional connectivity changes. Hyperconnectivity patterns at 3 months after concussion were present only in players with relatively less severe clinical outcomes, higher choline concentrations, and diffusivity indicative of relatively less axonal disruption. CONCLUSIONS: Changes persisted well after players' clinical scores had returned to normal and they had been cleared to return to play. Ongoing white matter maturation may make adolescent athletes particularly vulnerable to brain injury, and they may require extended recovery periods. The consequences of early brain injury for ongoing brain development and risk of more serious conditions such as second impact syndrome or neural degenerative processes need to be elucidated.

Management of Latent Tuberculosis Infection Among Healthcare Workers: 10-Year Experience at a Single Center.

BACKGROUND: The risk of infection with Mycobacterium tuberculosis among healthcare workers (HCWs) is estimated to be higher than the general population. However, HCW acceptance and compliance with available latent tuberculosis infection (LTBI) treatment regimens has been problematic. Recently, regimens have become available that might improve HCW acceptance and compliance with LTBI treatment. METHODS: A retrospective single-center review of Employee Health and Wellness Services records of all HCWs diagnosed with LTBI was conducted. HCWs diagnosed with LTBI were offered 9-month isoniazid (INH), 4-month rifampin (RIF), weekly rifapentine/isoniazid (RPT/INH) for 12 weeks, or no treatment. Acceptance, completion rates, and side effects were reported for each regimen. Comparisons of regimens were assessed using Fisher exact test. RESULTS: Between 2005 and 2014, 363 of 927 (39%) HCWs diagnosed with LTBI accepted treatment. Of 363, 202 chose INH, 106 RIF, and 55 RPT/INH. Completion rates for each regimen were 58%, 80%, and 87%, respectively. HCWs were significantly more likely to have completed treatment with RIF (P < .0001) or RPT/INH (P < .0001) than INH. Rates of discontinuation owing to side effects were 35% for INH, 21% for RIF, and 10% for RPT/INH. Discontinuation of therapy due to side effects was significantly more frequent in the INH than the RPT/INH group (P = .0042). CONCLUSIONS: Completion of RIF and RPT/INH for LTBI in an HCW population is more likely than INH. Rates of discontinuation due to side effects were lower among those taking RPT/INH. Shorter LTBI treatment regimens should be more widely considered for HCWs in the United States.

Utilization of Electronic Health Record Events to Conduct a Tuberculosis Contact Investigation in a High-Risk Oncology Unit.

OBJECTIVE To describe the utilization of electronic medical data resources, including health records and nursing scheduling resources, to conduct a tuberculosis (TB) exposure investigation in a high-risk oncology unit. SETTING A 42-bed inpatient unit with a mix of surgical and medical patients at a large tertiary-care cancer center in New York City. PARTICIPANTS High-risk subjects and coworkers exposed to a healthcare worker (HCW) with cavitary smear positive lung TB. RESULTS During the 3-month exposure period, 270 patients were admitted to the unit; 137 of these (50.7%) received direct care from the index case HCW. Host immune status and intensity of exposure were used to establish criteria for postexposure testing, and 63 patients (45%) met these criteria for first-tier postexposure testing. No cases of active TB occurred. Among coworkers, 146 had significant exposure (ie, >8 hours cumulative). In the 22-month follow-up period after the exposure, no purified protein derivative or interferon gamma release assay conversions or active cases of TB occurred among exposed HCWs or patients. CONCLUSIONS Electronic medical records and employee scheduling systems are useful resources to conduct otherwise labor-intensive contact investigations. Despite the high-risk features of our index case, a highly vulnerable immunocompromised patient population, and extended proximity to coworkers, we did not find any evidence of transmission of active or latent tuberculosis infection among exposed individuals. Infect Control Hosp Epidemiol 2017;38:1235-1239.

Investigation of the role of tyrosine kinase receptor EPHA3 in colorectal cancer.

EPH signaling deregulation has been shown to be important for colorectal carcinogenesis and genome-wide sequencing efforts have identified EPHA3 as one of the most frequently mutated genes in these tumors. However, the role of EPHA3 in colorectal cancer has not been thoroughly investigated. We show here that ectopic expression of wild type EPHA3 in colon cancer cells did not affect their growth, motility/invasion or metastatic potential in vivo. Moreover, overexpression of mutant EPHA3 or deletion of the endogenous mutant EPHA3 in colon cancer cells did not affect their growth or motility. EPHA3 inactivation in mice did not initiate the tumorigenic process in their intestine, and had no effects on tumor size/multiplicity after tumor initiation either genetically or pharmacologically. In addition, immunohistochemical analysis of EPHA3 tumor levels did not reveal associations with survival or clinicopathological features of colorectal cancer patients. In conclusion, we show that EPHA3 does not play a major role in colorectal tumorigenesis. These results significantly contribute to our understanding of the role of EPH signaling during colorectal carcinogenesis, and highlighting the need for detailed functional studies to confirm the relevance of putative cancer driver genes identified in sequencing efforts of the cancer genome.

Conditional Sox9 ablation improves locomotor recovery after spinal cord injury by increasing reactive sprouting.

The absence of axonal regeneration after spinal cord injury (SCI) has been attributed to the up-regulation of axon-repelling molecules, such as chondroitin sulfate proteoglycans (CSPGs) present in the glial scar that forms post-SCI. We previously identified the transcription factor SOX9 as a key up-regulator of CSPG production and also demonstrated that conditional Sox9 ablation leads to decreased CSPG levels and improved recovery of hind limb function after SCI. We herein demonstrate increased neural input onto spinal neurons caudal to the lesion in spinal cord injured Sox9 conditional knock out mice as indicated by increased levels of the presynaptic markers synaptophysin and vesicular glutamate transporter 1 (VGLUT1) compared to controls. Axonal sparing, long-range axonal regeneration and reactive sprouting were investigated as possible explanations for the increase in neural inputs caudal to the lesion and for the improved locomotor outcomes in spinal cord-injured Sox9 conditional knock out mice. Whereas retrograde tract-tracing studies failed to reveal any evidence for increased axonal sparing or for long-range regeneration in the Sox9 conditional knock out mice, anterograde tract-tracing experiments demonstrated increased reactive sprouting caudal to the lesion after SCI. Finally we demonstrate that application of a broad spectrum MMP inhibitor to reduce CSPG degradation in Sox9 conditional knock out mice prevents the improvements in locomotor recovery observed in untreated Sox9 conditional knock out mice. These results suggest that improved recovery of locomotor function in Sox9 conditional knock out mice after SCI is due to increased reactive sprouting secondary to reduced CSPG levels distal to the lesion.