Active learning-based STEM education for in-person and online learning.

The COVID-19 global pandemic has forced the higher education sector to transition to an uncharted remote-learning format. This offers an opportunity to adopt active learning, which increases students' performance compared to lectures, narrows achievement gaps for underrepresented students, and promotes equity and inclusivity, as the basis of STEM education.

Volumetric Analysis: Effect on Diagnosis and Management of Indeterminate Solid Pulmonary Nodules in Routine Clinical Practice.

OBJECTIVE: To evaluate the effect of volumetric analysis on the diagnosis and management of indeterminate solid pulmonary nodules in routine clinical practice. METHODS: This was a retrospective study with 107 computed tomography (CT) cases of solid pulmonary nodules (range, 6-15 mm), 57 pathology-proven malignancies (lung cancer, n = 34; metastasis, n = 23), and 50 benign nodules. Nodules were evaluated on a total of 309 CT scans (average number of CTs/nodule, 2.9 [range, 2-7]). CT scans were from multiple institutions with variable technique. Nine radiologists (attendings, n = 3; fellows, n = 3; residents, n = 3) were asked their level of suspicion for malignancy (low/moderate or high) and management recommendation (no follow-up, CT follow-up, or care escalation) for baseline and follow-up studies first without and then with volumetric analysis data. Effect of volumetry on diagnosis and management was assessed by generalized linear and logistic regression models. RESULTS: Volumetric analysis improved sensitivity (P = 0.009) and allowed earlier recognition (P < 0.05) of malignant nodules. Attending radiologists showed higher sensitivity in recognition of malignant nodules (P = 0.03) and recommendation of care escalation (P < 0.001) compared with trainees. Volumetric analysis altered management of high suspicion nodules only in the fellow group (P = 0.008). κ Statistics for suspicion for malignancy and recommended management were fair to substantial (0.38-0.66) and fair to moderate (0.33-0.50). Volumetric analysis improved interobserver variability for identification of nodule malignancy from 0.52 to 0.66 (P = 0.004) only on the second follow-up study. CONCLUSIONS: Volumetric analysis of indeterminate solid pulmonary nodules in routine clinical practice can result in improved sensitivity and earlier identification of malignant nodules. The effect of volumetric analysis on management recommendations is variable and influenced by reader experience.

Pathological Slow-Wave Activity and Impaired Working Memory Binding in Post-Traumatic Amnesia.

Associative binding is key to normal memory function and is transiently disrupted during periods of post-traumatic amnesia (PTA) following traumatic brain injury (TBI). Electrophysiological abnormalities, including low-frequency activity, are common following TBI. Here, we investigate associative memory binding during PTA and test the hypothesis that misbinding is caused by pathological slowing of brain activity disrupting cortical communication. Thirty acute moderate to severe TBI patients (25 males; 5 females) and 26 healthy controls (20 males; 6 females) were tested with a precision working memory paradigm requiring the association of object and location information. Electrophysiological effects of TBI were assessed using resting-state EEG in a subsample of 17 patients and 21 controls. PTA patients showed abnormalities in working memory function and made significantly more misbinding errors than patients who were not in PTA and controls. The distribution of localization responses was abnormally biased by the locations of nontarget items for patients in PTA, suggesting a specific impairment of object and location binding. Slow-wave activity was increased following TBI. Increases in the δ-α ratio indicative of an increase in low-frequency power specifically correlated with binding impairment in working memory. Connectivity changes in TBI did not correlate with binding impairment. Working memory and electrophysiological abnormalities normalized at 6 month follow-up. These results show that patients in PTA show high rates of misbinding that are associated with a pathological shift toward lower-frequency oscillations.SIGNIFICANCE STATEMENT How do we remember what was where? The mechanism by which information (e.g., object and location) is integrated in working memory is a central question for cognitive neuroscience. Following significant head injury, many patients will experience a period of post-traumatic amnesia (PTA) during which this associative binding is disrupted. This may be because of electrophysiological changes in the brain. Using a precision working memory test and resting-state EEG, we show that PTA patients demonstrate impaired binding ability, and this is associated with a shift toward slower-frequency activity on EEG. Abnormal EEG connectivity was observed but was not specific to PTA or binding ability. These findings contribute to both our mechanistic understanding of working memory binding and PTA pathophysiology.

Task-based differences in brain state dynamics and their relation to cognitive ability.

Transient patterns of interregional connectivity form and dissipate in response to varying cognitive demands. Yet, it is not clear how different cognitive demands influence brain state dynamics, and whether these dynamics relate to general cognitive ability. Here, using functional magnetic resonance imaging (fMRI) data, we characterised shared, recurrent, global brain states in 187 participants across the working memory, emotion, language, and relation tasks from the Human Connectome Project. Brain states were determined using Leading Eigenvector Dynamics Analysis (LEiDA). In addition to the LEiDA-based metrics of brain state lifetimes and probabilities, we also computed information-theoretic measures of Block Decomposition Method of complexity, Lempel-Ziv complexity and transition entropy. Information theoretic metrics are notable in their ability to compute relationships amongst sequences of states over time, compared to lifetime and probability, which capture the behaviour of each state in isolation. We then related task-based brain state metrics to fluid intelligence. We observed that brain states exhibited stable topology across a range of numbers of clusters (K = 2:15). Most metrics of brain state dynamics, including state lifetime, probability, and all information theoretic metrics, reliably differed between tasks. However, relationships between state dynamic metrics and cognitive abilities varied according to the task, the metric, and the value of K, indicating that there are contextual relationships between task-dependant state dynamics and trait cognitive ability. This study provides evidence that the brain reconfigures across time in response to cognitive demands, and that there are contextual, rather than generalisable, relationships amongst task, state dynamics, and cognitive ability.

Lifelong Association of Disorders Related to Military Trauma with Subsequent Parkinson's Disease.

BACKGROUND: Trauma-related disorders such as traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) are emerging as risk factors for Parkinson's disease (PD), but their association with development of PD and independence from comorbid disorders remains unknown. OBJECTIVE: To examine TBI and PTSD related to early trauma in military veterans using a case-control study. METHODS: PD was identified by International Classification of Diseases (ICD) code, recurrent PD-specific prescriptions, and availability of 5+ years of earlier records. Validation was performed by chart review by a movement disorder-trained neurologist. Control subjects were matched 4:1 by age, duration of preceding health care, race, ethnicity, birth year, and sex. TBI and PTSD were identified by ICD code and onset based on active duty. Association and interaction were measured for TBI and PTSD with PD going back 60 years. Interaction was measured for comorbid disorders. RESULTS: A total of 71,933 cases and 287,732 controls were identified. TBI and PTSD increased odds of subsequent PD at all preceding 5-year intervals back to year -60 (odds ratio range: 1.5 [1.4, 1.7] to 2.1 [2.0, 2.1]). TBI and PTSD showed synergism (synergy index range: 1.14 [1.09, 1.29] to 1.28 [1.09, 1.51]) and additive association (odds ratio range: 2.2 [1.6, 2.8] to 2.7 [2.5, 2.8]). Chronic pain and migraine showed greatest synergy with PTSD and TBI. Effect sizes for trauma-related disorders were comparable with established prodromal disorders. CONCLUSIONS: TBI and PTSD are associated with later PD and are synergistic with chronic pain and migraine. These findings provide evidence for TBI and PTSD as risk factors preceding PD by decades and could aid in prognostic calculation and earlier intervention. © 2023 International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Aciclovir-induced neurotoxicity.

Aciclovir-induced neurotoxicity results from the accumulation of aciclovir and its metabolite 9-carboxymethoxymethylguanine (CMMG). It occurs predominantly in older patients with impaired renal function and is characterised by a combination of confusion and psychiatric changes. Seizures, myoclonus and dysarthria may also occur. Critically, peritoneal dialysis has little effect on reversing the toxic effects of aciclovir. We describe a woman in her 70s with renal failure who developed confusion and seizures after receiving aciclovir. She was ultimately diagnosed with aciclovir-induced neurotoxicity, confirmed by an elevated serum CMMG concentration. This condition is likely to be underdiagnosed and the neurologist's primary challenge is differentiating aciclovir-induced neurotoxicity from viral encephalitis.

Destruction complex dynamics: Wnt/ß-catenin signaling alters Axin-GSK3ß interactions in vivo.

The central regulator of the Wnt/ß-catenin pathway is the Axin/APC/GSK3ß destruction complex (DC), which, under unstimulated conditions, targets cytoplasmic ß-catenin for degradation. How Wnt activation inhibits the DC to permit ß-catenin-dependent signaling remains controversial, in part because the DC and its regulation have never been observed in vivo Using bimolecular fluorescence complementation (BiFC) methods, we have now analyzed the activity of the DC under near-physiological conditions in Drosophila By focusing on well-established patterns of Wnt/Wg signaling in the developing Drosophila wing, we have defined the sequence of events by which activated Wnt receptors induce a conformational change within the DC, resulting in modified Axin-GSK3ß interactions that prevent ß-catenin degradation. Surprisingly, the nucleus is surrounded by active DCs, which principally control the degradation of ß-catenin and thereby nuclear access. These DCs are inactivated and removed upon Wnt signal transduction. These results suggest a novel mechanistic model for dynamic Wnt signal transduction in vivo.

Abnormal dorsal attention network activation in memory impairment after traumatic brain injury.

Memory impairment is a common, disabling effect of traumatic brain injury. In healthy individuals, successful memory encoding is associated with activation of the dorsal attention network as well as suppression of the default mode network. Here, in traumatic brain injury patients we examined whether: (i) impairments in memory encoding are associated with abnormal brain activation in these networks; (ii) whether changes in this brain activity predict subsequent memory retrieval; and (iii) whether abnormal white matter integrity underpinning functional networks is associated with impaired subsequent memory. Thirty-five patients with moderate-severe traumatic brain injury aged 23-65 years (74% males) in the post-acute/chronic phase after injury and 16 healthy control subjects underwent functional MRI during performance of an abstract image memory encoding task. Diffusion tensor imaging was used to assess structural abnormalities across patient groups compared to 28 age-matched healthy controls. Successful memory encoding across all participants was associated with activation of the dorsal attention network, the ventral visual stream and medial temporal lobes. Decreased activation was seen in the default mode network. Patients with preserved episodic memory demonstrated increased activation in areas of the dorsal attention network. Patients with impaired memory showed increased left anterior prefrontal activity. White matter microstructure underpinning connectivity between core nodes of the encoding networks was significantly reduced in patients with memory impairment. Our results show for the first time that patients with impaired episodic memory show abnormal activation of key nodes within the dorsal attention network and regions regulating default mode network activity during encoding. Successful encoding was associated with an opposite direction of signal change between patients with and without memory impairment, suggesting that memory encoding mechanisms could be fundamentally altered in this population. We demonstrate a clear relationship between functional networks activated during encoding and underlying abnormalities within the structural connectome in patients with memory impairment. We suggest that encoding failures in this group are likely due to failed control of goal-directed attentional resources.

CRS Diabetes: An Effective Model for Improving Family Medicine Resident Knowledge, Competence, and Performance in Diabetes Care.

The Chief Residents Summit on Intensifying Diabetes Management, now in its 15th year, has resulted in real-world improvements in patient outcomes and has shown itself to be an effective model for teaching diabetes to family medicine residents. This article describes the program and the evidence supporting its effectiveness.

Onset of Skin, Gut, and Genitourinary Prodromal Parkinson's Disease: A Study of 1.5 Million Veterans.

BACKGROUND: Prodromal Parkinson's disease of skin, genitourinary, and gastrointestinal systems offers a unique window for understanding early disease pathogenesis and developing disease modifying treatments. However, prior studies are limited by incomplete timing information, small sample size, and lack of adjustment for known confounders. Verifying prodromal timing and identifying new disorders in these accessible organs is critically important given their broad use. OBJECTIVE: We aimed to measure onset timing for gastrointestinal, genitourinary, and skin disorders in a large, nationwide clinically characterized cohort of 1.5 million participants. METHODS: Patients with Parkinson's disease (n = 303,693) were identified using diagnostic codes in the medical records database of the United States Veterans Affairs healthcare system and were compared 4:1 with matched controls. Disorder prevalence and estimated onset times were assessed for 20 years preceding diagnosis. RESULTS: The earliest significantly increased prodromal disorders were gastroesophageal reflux, sexual dysfunction, and esophageal dyskinesia at 17, 16, and 15 years before diagnosis. Estimated onset times for each disorder occurred 5.5 ± 3.4 years before the first measured increase. The earliest estimated onset times were smell/taste, upper gastrointestinal tract, and sexual dysfunction at 20.9, 20.6, and 20.1 years before diagnosis. Onset times for constipation and urinary dysfunction were notably longer by 7 and 9 years compared to prior studies in sleep disorder patients. Dermatophytosis and prostatic hypertrophy were identified as new high prevalence prodromal disorders. CONCLUSIONS: Gastrointestinal, genitourinary, and skin disorders manifest decades before diagnosis of Parkinson's disease, reiterating their potential as sites for developing early diagnostic testing and understanding pathogenesis.

Small bowel hemorrhage from check point inhibitor enteritis: a case report.

BACKGROUND: There is rising utilization of immune checkpoint inhibitors (ICI) for a growing number of metastatic malignancies. While gastrointestinal side effects of ICI are common, isolated ICI-induced enteritis leading to small bowel hemorrhage is rare. CASE PRESENTATION: A 71-year-old man with a previously resected right colon adenocarcinoma on atezolizumab and recently treated Clostridioides difficile presented with acute on chronic abdominal pain and non-bloody diarrhea. A CT scan revealed enteritis of the duodenum and jejunum without colitis. Initial endoscopic work-up revealed many clean-based non-bleeding duodenal ulcers to the third portion of the duodenum and normal rectosigmoid mucosa. The patient initially improved on steroids but was readmitted on day after discharge with hematochezia and hemorrhagic shock. Repeat CT showed improvement in enteritis; however, repeat push enteroscopy revealed multiple duodenal and jejunal ulcers, two with visible vessels requiring endoscopic intervention. He continued to have significant hemorrhage requiring transfusions despite IV methylprednisolone. Conventional angiogram revealed multiple sites of active extravasation, and he underwent small bowel resection and subsequent IR embolization due to persistent bleeding. He was then started on infliximab 10 mg/kg with resolution of his small bowel hemorrhage and diarrhea. CONCLUSIONS: Severe isolated ICI-enteritis is rare and can lead to clinically significant gastrointestinal hemorrhage. Patients with severe ICI-enteritis on endoscopy should be carefully monitored for steroid refractory disease for consideration of step-up therapy such as infliximab.

Distinct patterns of structural damage underlie working memory and reasoning deficits after traumatic brain injury.

It is well established that chronic cognitive problems after traumatic brain injury relate to diffuse axonal injury and the consequent widespread disruption of brain connectivity. However, the pattern of diffuse axonal injury varies between patients and they have a correspondingly heterogeneous profile of cognitive deficits. This heterogeneity is poorly understood, presenting a non-trivial challenge for prognostication and treatment. Prominent amongst cognitive problems are deficits in working memory and reasoning. Previous functional MRI in controls has associated these aspects of cognition with distinct, but partially overlapping, networks of brain regions. Based on this, a logical prediction is that differences in the integrity of the white matter tracts that connect these networks should predict variability in the type and severity of cognitive deficits after traumatic brain injury. We use diffusion-weighted imaging, cognitive testing and network analyses to test this prediction. We define functionally distinct subnetworks of the structural connectome by intersecting previously published functional MRI maps of the brain regions that are activated during our working memory and reasoning tasks, with a library of the white matter tracts that connect them. We examine how graph theoretic measures within these subnetworks relate to the performance of the same tasks in a cohort of 92 moderate-severe traumatic brain injury patients. Finally, we use machine learning to determine whether cognitive performance in patients can be predicted using graph theoretic measures from each subnetwork. Principal component analysis of behavioural scores confirm that reasoning and working memory form distinct components of cognitive ability, both of which are vulnerable to traumatic brain injury. Critically, impairments in these abilities after traumatic brain injury correlate in a dissociable manner with the information-processing architecture of the subnetworks that they are associated with. This dissociation is confirmed when examining degree centrality measures of the subnetworks using a canonical correlation analysis. Notably, the dissociation is prevalent across a number of node-centric measures and is asymmetrical: disruption to the working memory subnetwork relates to both working memory and reasoning performance whereas disruption to the reasoning subnetwork relates to reasoning performance selectively. Machine learning analysis further supports this finding by demonstrating that network measures predict cognitive performance in patients in the same asymmetrical manner. These results accord with hierarchical models of working memory, where reasoning is dependent on the ability to first hold task-relevant information in working memory. We propose that this finer grained information may be useful for future applications that attempt to predict long-term outcomes or develop tailored therapies.

Diffuse axonal injury predicts neurodegeneration after moderate-severe traumatic brain injury.

Traumatic brain injury is associated with elevated rates of neurodegenerative diseases such as Alzheimer's disease and chronic traumatic encephalopathy. In experimental models, diffuse axonal injury triggers post-traumatic neurodegeneration, with axonal damage leading to Wallerian degeneration and toxic proteinopathies of amyloid and hyperphosphorylated tau. However, in humans the link between diffuse axonal injury and subsequent neurodegeneration has yet to be established. Here we test the hypothesis that the severity and location of diffuse axonal injury predicts the degree of progressive post-traumatic neurodegeneration. We investigated longitudinal changes in 55 patients in the chronic phase after moderate-severe traumatic brain injury and 19 healthy control subjects. Fractional anisotropy was calculated from diffusion tensor imaging as a measure of diffuse axonal injury. Jacobian determinant atrophy rates were calculated from serial volumetric T1 scans as a measure of measure post-traumatic neurodegeneration. We explored a range of potential predictors of longitudinal post-traumatic neurodegeneration and compared the variance in brain atrophy that they explained. Patients showed widespread evidence of diffuse axonal injury, with reductions of fractional anisotropy at baseline and follow-up in large parts of the white matter. No significant changes in fractional anisotropy over time were observed. In contrast, abnormally high rates of brain atrophy were seen in both the grey and white matter. The location and extent of diffuse axonal injury predicted the degree of brain atrophy: fractional anisotropy predicted progressive atrophy in both whole-brain and voxelwise analyses. The strongest relationships were seen in central white matter tracts, including the body of the corpus callosum, which are most commonly affected by diffuse axonal injury. Diffuse axonal injury predicted substantially more variability in white matter atrophy than other putative clinical or imaging measures, including baseline brain volume, age, clinical measures of injury severity and microbleeds (>50% for fractional anisotropy versus <5% for other measures). Grey matter atrophy was not predicted by diffuse axonal injury at baseline. In summary, diffusion MRI measures of diffuse axonal injury are a strong predictor of post-traumatic neurodegeneration. This supports a causal link between axonal injury and the progressive neurodegeneration that is commonly seen after moderate/severe traumatic brain injury but has been of uncertain aetiology. The assessment of diffuse axonal injury with diffusion MRI is likely to improve prognostic accuracy and help identify those at greatest neurodegenerative risk for inclusion in clinical treatment trials.

EEG, MEG and neuromodulatory approaches to explore cognition: Current status and future directions.

Neural oscillations and their association with brain states and cognitive functions have been object of extensive investigation over the last decades. Several electroencephalography (EEG) and magnetoencephalography (MEG) analysis approaches have been explored and oscillatory properties have been identified, in parallel with the technical and computational advancement. This review provides an up-to-date account of how EEG/MEG oscillations have contributed to the understanding of cognition. Methodological challenges, recent developments and translational potential, along with future research avenues, are discussed.

AAV diffuses across zona pellucida for effortless gene delivery to fertilized eggs.

Gene delivery to fertilized eggs is often the first step in creation of transgenic animals, CRISPR knock-out, or early developmental studies. The zona pellucida, a hardened glycoprotein matrix surrounding the mammalian fertilized eggs, often complicates gene delivery by forming a barrier against transfection reagents and viruses. High efficiency techniques to perforate or penetrate the zona allow for access and gene delivery to fertilized eggs. However, these techniques often rely on highly skilled technologists, are costly, and require specialized equipment for micromanipulation, laser perforation, or electroporation. Here, we report that adenoassociated viruses (AAVs) with serotypes 1 or DJ can efficiently diffuse across the zona to deliver genes without any manipulations to fertilized eggs. We observe lowered rates of embryo development after treatment of embryos with all AAV serotypes. However, we were able to reduce adverse effects on embryo development by exposing embryos to AAVs at later stages of in vitro development. AAVs have low immune response and do not incorporate into their host chromosomes to cause insertional mutations. Hence, AAVs can serve as a highly effective tool for transient delivery of genes to fertilized mammalian eggs.

Stratifying drug treatment of cognitive impairments after traumatic brain injury using neuroimaging.

Cognitive impairment is common following traumatic brain injury. Dopaminergic drugs can enhance cognition after traumatic brain injury, but individual responses are highly variable. This may be due to variability in dopaminergic damage between patients. We investigate whether measuring dopamine transporter levels using 123I-ioflupane single-photon emission computed tomography (SPECT) predicts response to methylphenidate, a stimulant with dopaminergic effects. Forty patients with moderate-severe traumatic brain injury and cognitive impairments completed a randomized, double-blind, placebo-controlled, crossover study. 123I-ioflupane SPECT, MRI and neuropsychological testing were performed. Patients received 0.3 mg/kg of methylphenidate or placebo twice a day in 2-week blocks. Subjects received neuropsychological assessment after each block and completed daily home cognitive testing during the trial. The primary outcome measure was change in choice reaction time produced by methylphenidate and its relationship to stratification of patients into groups with normal and low dopamine transporter binding in the caudate. Overall, traumatic brain injury patients showed slow information processing speed. Patients with low caudate dopamine transporter binding showed improvement in response times with methylphenidate compared to placebo [median change = -16 ms; 95% confidence interval (CI): -28 to -3 ms; P = 0.02]. This represents a 27% improvement in the slowing produced by traumatic brain injury. Patients with normal dopamine transporter binding did not improve. Daily home-based choice reaction time results supported this: the low dopamine transporter group improved (median change -19 ms; 95% CI: -23 to -7 ms; P = 0.002) with no change in the normal dopamine transporter group (P = 0.50). The low dopamine transporter group also improved on self-reported and caregiver apathy assessments (P = 0.03 and P = 0.02, respectively). Both groups reported improvements in fatigue (P = 0.03 and P = 0.007). The cognitive effects of methylphenidate after traumatic brain injury were only seen in patients with low caudate dopamine transporter levels. This shows that identifying patients with a hypodopaminergic state after traumatic brain injury can help stratify the choice of cognitive enhancing therapy.

Plasma concentrations of itraconazole following a single oral dose in juvenile California sea lions (Zalophus californianus).

The objective of this study was to establish a single-dose pharmacokinetic profile for orally administered itraconazole in California sea lions (Zalophus californianus). Twenty healthy rehabilitated juvenile California sea lions were included in this study. Itraconazole capsules were administered orally with food at a target dose of 5-10 mg/kg. Blood samples were collected from each animal at 0 hr and at two of the following timepoints: 0.5, 1, 2, 4, 6, 8, 12, 24, 48, and 72 hr. Quantitative analysis of itraconazole in plasma samples was performed by high-performance liquid chromatography. An average maximum concentration of 0.22 µg/ml ± 0.11 was detected 4 hr after administration. The average concentration fell to 0.12 µg/ml ± 0.11 by 6 hr and 0.02 µg/ml ± 0.02 at 12 hr. At no point did concentrations reach 0.5 µg/ml, the concentration commonly accepted for therapeutic efficacy. While this formulation was well tolerated by the sea lions, oral absorption was poor and highly variable among individuals. These data indicate that a single oral dose of itraconazole given as a capsule at 5-10 mg/kg, under the conditions used in this study, does not achieve therapeutic plasma concentrations in California sea lions.

EVALUATION OF LOCALIZED INFLAMMATORY REACTIONS SECONDARY TO INTRAMUSCULAR INJECTIONS OF ENROFLOXACIN IN STRIPED BASS (MORONE SAXATILIS).

Enrofloxacin is a fluoroquinolone widely used in animals including fish. Intramuscular (IM) injection of enrofloxacin is a feasible and efficacious option for drug delivery. In many species IM injection has been associated with injection site reactions and increases in serum muscle enzymes. Injection site reactions have not been well characterized in fish. Three groups of striped bass (Morone saxatilis) received an IM injection of enrofloxacin 2.27% in the right epaxial musculature 24, 48, or 96 hr prior to evaluation. Mean dose was 7.69 mg/ kg (6.14-9.69 mg/kg). The 24- and 48-hr groups received an injection of equal-volume 0.9% saline in the left epaxial musculature. A corresponding noninjected tissue sample was designated in the left epaxial musculature from each fish of the 96-hr group. Fish were euthanized and injection sites and noninjection control sites were evaluated grossly and histologically. Grades 1-4 were assigned to samples, with grade 1 corresponding to normal tissue and grades 2, 3, and 4 corresponding to mild, moderate, and severe inflammation and/or necrosis respectively. Externally, all control and injection sites appeared visually unremarkable. On cut surface, epaxial muscle of the enrofloxacin-injected tissue appeared moderately to severely hemorrhagic compared to saline and noninjected tissue, which was normal or mildly hemorrhagic. Histologically, eight of eight noninjected tissues were grade 1. For saline-injected tissues, 14 of 16 tissues were grade 2 and 2 samples were grade 3 when 24- and 48-hr groups were combined. For enrofloxacin-injected tissues, 8 of the 8 24-hr samples were grade 3 and 16 of the 16 48- and 96-hr samples were grade 4. These data show that IM injection of enrofloxacin 2.27% is associated with severe hemorrhage, necrosis, and inflammation in striped bass, and may negatively affect animal welfare.

Spatial patterns of progressive brain volume loss after moderate-severe traumatic brain injury.

Traumatic brain injury leads to significant loss of brain volume, which continues into the chronic stage. This can be sensitively measured using volumetric analysis of MRI. Here we: (i) investigated longitudinal patterns of brain atrophy; (ii) tested whether atrophy is greatest in sulcal cortical regions; and (iii) showed how atrophy could be used to power intervention trials aimed at slowing neurodegeneration. In 61 patients with moderate-severe traumatic brain injury (mean age = 41.55 years ± 12.77) and 32 healthy controls (mean age = 34.22 years ± 10.29), cross-sectional and longitudinal (1-year follow-up) brain structure was assessed using voxel-based morphometry on T1-weighted scans. Longitudinal brain volume changes were characterized using a novel neuroimaging analysis pipeline that generates a Jacobian determinant metric, reflecting spatial warping between baseline and follow-up scans. Jacobian determinant values were summarized regionally and compared with clinical and neuropsychological measures. Patients with traumatic brain injury showed lower grey and white matter volume in multiple brain regions compared to controls at baseline. Atrophy over 1 year was pronounced following traumatic brain injury. Patients with traumatic brain injury lost a mean (± standard deviation) of 1.55% ± 2.19 of grey matter volume per year, 1.49% ± 2.20 of white matter volume or 1.51% ± 1.60 of whole brain volume. Healthy controls lost 0.55% ± 1.13 of grey matter volume and gained 0.26% ± 1.11 of white matter volume; equating to a 0.22% ± 0.83 reduction in whole brain volume. Atrophy was greatest in white matter, where the majority (84%) of regions were affected. This effect was independent of and substantially greater than that of ageing. Increased atrophy was also seen in cortical sulci compared to gyri. There was no relationship between atrophy and time since injury or age at baseline. Atrophy rates were related to memory performance at the end of the follow-up period, as well as to changes in memory performance, prior to multiple comparison correction. In conclusion, traumatic brain injury results in progressive loss of brain tissue volume, which continues for many years post-injury. Atrophy is most prominent in the white matter, but is also more pronounced in cortical sulci compared to gyri. These findings suggest the Jacobian determinant provides a method of quantifying brain atrophy following a traumatic brain injury and is informative in determining the long-term neurodegenerative effects after injury. Power calculations indicate that Jacobian determinant images are an efficient surrogate marker in clinical trials of neuroprotective therapeutics.

Dopaminergic abnormalities following traumatic brain injury.

Traumatic brain injury can reduce striatal dopamine levels. The cause of this is uncertain, but is likely to be related to damage to the nigrostriatal system. We investigated the pattern of striatal dopamine abnormalities using 123I-Ioflupane single-photon emission computed tomography (SPECT) scans and their relationship to nigrostriatal damage and clinical features. We studied 42 moderate-severe traumatic brain injury patients with cognitive impairments but no motor parkinsonism signs and 20 healthy controls. 123I-Ioflupane scanning was used to assess dopamine transporter levels. Clinical scan reports were compared to quantitative dopamine transporter results. Advanced MRI methods were used to assess the nigrostriatal system, including the area through which the nigrostriatal projections pass as defined from high-resolution Human Connectome data. Detailed clinical and neuropsychological assessments were performed. Around 20% of our moderate-severe patients had clear evidence of reduced specific binding ratios for the dopamine transporter in the striatum measured using 123I-Ioflupane SPECT. The caudate was affected more consistently than other striatal regions. Dopamine transporter abnormalities were associated with reduced substantia nigra volume. In addition, diffusion MRI provided evidence of damage to the regions through which the nigrostriatal tract passes, particularly the area traversed by dopaminergic projections to the caudate. Only a small percentage of patients had evidence of macroscopic lesions in the striatum and there was no relationship between presence of lesions and dopamine transporter specific binding ratio abnormalities. There was also no relationship between reduced volume in the striatal subregions and reduced dopamine transporter specific binding ratios. Patients with low caudate dopamine transporter specific binding ratios show impaired processing speed and executive dysfunction compared to patients with normal levels. Taken together, our results suggest that the dopaminergic system is affected by a moderate-severe traumatic brain injury in a significant proportion of patients, even in the absence of clinical motor parkinsonism. Reduced dopamine transporter levels are most commonly seen in the caudate and this is likely to reflect the pattern of nigrostriatal tract damage produced by axonal injury and associated midbrain damage.