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PurposeTo assess the pathological aging effect on caudate functional connectivity among mild cognitive impairment (MCI) participants and examine whether and how sex and amyloid contribute to this process.Materials and MethodsTwo hundred and seventy-seven functional magnetic resonance imaging (fMRI) sessions from 163 cognitive normal (CN) older adults and 309 sessions from 139 participants with MCI were included as the main sample in our analysis. Pearson's correlation was used to characterize the functional connectivity (FC) between caudate nuclei and each brain region, then caudate nodal strength was computed to quantify the overall caudate FC strength. Association analysis between caudate nodal strength and age was carried out in MCI and CN separately using linear mixed effect (LME) model with covariates (education, handedness, sex, Apolipoprotein E4, and intra-subject effect). Analysis of covariance was conducted to investigate sex, amyloid status, and their interaction effects on aging with the fMRI data subset having amyloid status available. LME model was applied to women and men separately within MCI group to evaluate aging effects on caudate nodal strength and each region's connectivity with caudate nuclei. We then evaluated the roles of sex and amyloid status in the associations of neuropsychological scores with age or caudate nodal strength. An independent cohort was used to validate the sex-dependent aging effects in MCI.ResultsThe MCI group had significantly stronger age-related increase of caudate nodal strength compared to the CN group. Analyzing women and men separately revealed that the aging effect on caudate nodal strength among MCI participants was significant only for women (left: P = 6.23 × 10−7, right: P = 3.37 × 10−8), but not for men (P > 0.3 for bilateral caudate nuclei). The aging effects on caudate nodal strength were not significantly mediated by brain amyloid burden. Caudate connectivity with ventral prefrontal cortex substantially contributed to the aging effect on caudate nodal strength in women with MCI. Higher caudate nodal strength is significantly related to worse cognitive performance in women but not in men with MCI.ConclusionSex modulates the pathological aging effects on caudate nodal strength in MCI regardless of amyloid status. Caudate nodal strength may be a sensitive biomarker of pathological aging in women with MCI.

Despite an estimated 2.8 million annual ED visits, traumatic brain injury (TBI) is a syndromic diagnosis largely based on report of loss of consciousness, post-traumatic amnesia, and/or confusion, without readily available objective diagnostic tests at the time of presentation, nor an ability to identify a patient's prognosis at the time of injury. The recognition that “mild” forms of TBI and even sub-clinical impacts can result in persistent neuropsychiatric consequences, particularly when repetitive, highlights the need for objective assessments that can complement the clinical diagnosis and provide prognostic information about long-term outcomes. Biomarkers and neurocognitive testing can identify brain injured patients and those likely to have post-concussive symptoms, regardless of imaging testing results, thus providing a physiologic basis for a diagnosis of acute traumatic encephalopathy (ATE). The goal of the HeadSMART II (HEAD injury Serum markers and Multi-modalities for Assessing Response to Trauma) clinical study is to develop an in-vitro diagnostic test for ATE. The BRAINBox TBI Test will be developed in the current clinical study to serve as an aid in evaluation of patients with ATE by incorporating blood protein biomarkers, clinical assessments, and tools to measure, identify, and define associated pathologic evidence and neurocognitive impairments. This protocol proposes to collect data on TBI subjects by a multi-modality approach that includes serum biomarkers, clinical assessments, neurocognitive performance, and neuropsychological characteristics, to determine the accuracy of the BRAINBox TBI test as an aid to the diagnosis of ATE, defined herein, and to objectively determine a patient's risk of developing post-concussive symptoms.

The guiding principle for data stewardship dictates that data be FAIR: findable, accessible, interoperable, and reusable. Data reuse allows researchers to probe data that may have been originally collected for other scientific purposes in order to gain novel insights. The current study reuses the Transforming Research and Clinical Knowledge for Traumatic Brain Injury (TRACK-TBI) Pilot dataset to build upon prior findings and ask new scientific questions. Specifically, we have previously used a multivariate analytics approach to multianalyte serum protein data from the TRACK-TBI Pilot dataset to show that an inflammatory ensemble of biomarkers can predict functional outcome at 3 and 6 months post-TBI. We and others have shown that there are quantitative and qualitative changes in inflammation that come with age, but little is known about how this interaction affects recovery from TBI. Here we replicate the prior proteomics findings with improved missing value analyses and non-linear principal component analysis and then expand upon this work to determine whether age moderates the effect of inflammation on recovery. We show that increased age correlates with worse functional recovery on the Glasgow Outcome Scale-Extended (GOS-E) as well as increased inflammatory signature. We then explore the interaction between age and inflammation on recovery, which suggests that inflammation has a more detrimental effect on recovery for older TBI patients.

Symptoms of post-traumatic stress disorder (PTSD) are common in military populations, and frequently associated with a history of combat-related mild traumatic brain injury (mTBI). In this study, we examined relationships between severity of PTSD symptoms and levels of extracellular vesicle (EV) proteins and miRNAs measured in the peripheral blood in a cohort of military service members and Veterans (SMs/Vs) with chronic mTBI(s). Participants (n = 144) were divided into groups according to mTBI history and severity of PTSD symptoms on the PTSD Checklist for DSM-5 (PCL-5). We analyzed EV levels of 798 miRNAs (miRNAs) as well as EV and plasma levels of neurofilament light chain (NfL), Tau, Amyloid beta (Aβ) 42, Aβ40, interleukin (IL)-10, IL-6, tumor necrosis factor-alpha (TNFα), and vascular endothelial growth factor (VEGF). We observed that EV levels of neurofilament light chain (NfL) were elevated in participants with more severe PTSD symptoms (PCL-5 ≥ 38) and positive mTBI history, when compared to TBI negative controls (p = 0.024) and mTBI participants with less severe PTSD symptoms (p = 0.006). Levels of EV NfL, plasma NfL, and hsa-miR-139–5p were linked to PCL-5 scores in regression models. Our results suggest that levels of NfL, a marker of axonal damage, are associated with PTSD symptom severity in participants with remote mTBI. Specific miRNAs previously linked to neurodegenerative and inflammatory processes, and glucocorticoid receptor signaling pathways, among others, were also associated with the severity of PTSD symptoms. Our findings provide insights into possible signaling pathways linked to the development of persistent PTSD symptoms after TBI and biological mechanisms underlying susceptibility to PTSD.

ObjectiveTo characterize the relationship between persistent post-traumatic headache (pPTH) and traumatic cerebrovascular injury (TCVI) in chronic traumatic brain injury (TBI). Cerebrovascular reactivity (CVR), a measure of the cerebral microvasculature and endothelial cell function, is altered both in individuals with chronic TBI and migraine headache disorder (Amyot et al., 2017; Lee et al., 2019b). The pathophysiologies of pPTH and migraine are believed to be associated with chronic microvascular dysfunction. We therefore hypothesize that TCVI may contribute to the underlying migraine-like mechanism(s) of pPTH.Materials and Methods22 moderate/severe TBI participants in the chronic stage (>6 months) underwent anatomic and functional magnetic resonance imaging (fMRI) scanning with hypercapnia gas challenge to measure CVR as well as the change in CVR (ΔCVR) after single-dose treatment of a specific phosphodiesterase-5 (PDE-5) inhibitor, sildenafil, which potentiates vasodilation in response to hypercapnia in impaired endothelium, as part of a Phase2a RCT of sildenafil in chronic TBI (NCT01762475). CVR and ΔCVR measures of each participant were compared with the individual’s pPTH severity measured by the headache impact test-6 (HIT-6) survey.ResultsThere was a moderate correlation between HIT-6 and both CVR and ΔCVR scores [Spearman’s correlation = –0.50 (p = 0.018) and = 0.46 (p = 0.03), respectively], indicating that a higher headache burden is associated with decreased endothelial function in our chronic TBI population.ConclusionThere is a correlation between PTH and CVR in chronic moderate-severe TBI. This relationship suggests that chronic TCVI may underlie the pathobiology of pPTH. Further, our results suggest that novel treatment strategies that target endothelial function and vascular health may be beneficial in refractory pPTH.

Traumatic brain injury (TBI) results in short and long-term disability neurodegeneration. Mild traumatic brain injury (mTBI) represents up to 85% of head injuries; diagnosis and early management is based on computed tomography (CT) or in-hospital observation, which are time- and cost- intensive. CT involves exposure to potentially harmful ionizing radiation and >90% of the scans are negative. Blood-brain barrier (BBB) damage is suspected pathological event post-TBI contributing to long-term sequelae and a reliable and rapid point-of-care test to screen those who can safely forego acute head CT would be of great help in evaluating patients with an acute mTBI. In this pilot study, 15 adult patients with suspected TBI (mean age = 47 years, range 18–79) and 15 control subjects (mean age = 33 years, range 23–53) were enrolled. We found that the average salivary S100B level was 3.9 fold higher than blood S100B, regardless of the presence of pathology. [S100B]saliva positively correlated with [S100B]serum (Pearson' coefficient = 0.79; p < 0.01). Salivary S100B levels were as effective in differentiating TBI patients from control subjects as serum levels (Control vs. TBI: p < 0.01; Serum ROCAUC = 0.94 and Saliva ROCAUC = 0.75). I These initial results suggest that measuring salivary S100B could represent an alternative to serum S100B in the diagnosis of TBI. Larger and confirmatory trials are needed to define salivary biomarker kinetics in relation to TBI severity and the possible roles of gender, ethnicity and age in influencing salivary S100B levels.

The neuropathology of traumatic brain injury (TB) is diverse, including primary injury to neurons, axons, glial cells, vascular structures, and secondary processes, such as edema and inflammation that vary between individual patients. Traumatic microvascular injury is an important endophenotype of TBI-related injury. We studied patients who sustained a TBI requiring ER evaluation and had an MRI performed within 48 h of injury. We classified patients into 3 groups based on their MRI findings: (1) those that had evidence of traumatic microvascular injury on susceptibility or diffusion weighted MRI sequences without frank hemorrhage [Traumatic Vascular Injury (TVI) group; 20 subjects]. (2) those who had evidence of intraparenchymal, subdural, epidural, or subarachnoid hemorrhage [Traumatic Hemorrhage (TH) group; 26 subjects], and (3) those who had no traumatic injuries detected by MRI [MRI-negative group; 30 subjects]. We then measured plasma protein biomarkers of vascular injury [von Willebrand Factor (vWF) or cellular fibronectin (cFn)] and axonal injury (phosphorylated neurofilament heavy chain; pNF-H). We found that the TVI group was characterized by decreased expression of plasma vWF (p < 0.05 compared to MRI-negative group; p < 0.00001 compared to TH group) ≤48 h after injury. cFN was no different between groups ≤48 h after injury, but was increased in the TVI group compared to the MRI-negative (p < 0.00001) and TH (p < 0.00001) groups when measured >48 h from injury. pNF-H was increased in both the TH and TVI groups compared to the MRI-negative group ≤48 h from injury. When we used the MRI grouping and molecular biomarkers in a model to predict Glasgow Outcome Scale-Extended (GOS-E) score at 30–90 days, we found that inclusion of the imaging data and biomarkers substantially improved the ability to predict a good outcome over clinical information alone. These data indicate that there is a distinct, vascular-predominant endophenotype in a subset of patients who sustain a TBI and that these injuries are characterized by a specific biomarker profile. Further work to will be needed to determine whether these biomarkers can be useful as predictive and pharmacodynamic biomarkers for vascular-directed therapies after TBI.

Mild traumatic brain injury (mTBI) presents a substantial burden to patients, families, and health care systems. Whereas, recovery can be expected in the majority of patients, a subset continues to report persisting somatic, cognitive, emotional, and/or behavioral problems, generally referred to as post-concussion syndrome (PCS). However, this term has been the subject of debate since the mechanisms underlying post-concussion symptoms and the role of pre- and post-injury-related factors are still poorly understood. We review current evidence and controversies concerning the use of the terms post-concussion symptoms vs. syndrome, its diagnosis, etiology, prevalence, assessment, and treatment in both adults and children. Prevalence rates of post-concussion symptoms vary between 11 and 82%, depending on diagnostic criteria, population and timing of assessment. Post-concussion symptoms are dependent on complex interactions between somatic, psychological, and social factors. Progress in understanding has been hampered by inconsistent classification and variable assessment procedures. There are substantial limitations in research to date, resulting in gaps in our understanding, leading to uncertainty regarding epidemiology, etiology, prognosis, and treatment. Future directions including the identification of potential mechanisms, new imaging techniques, comprehensive, multidisciplinary assessment and treatment options are discussed. Treatment of post-concussion symptoms is highly variable, and primarily directed at symptom relief, rather than at modifying the underlying pathology. Longitudinal studies applying standardized assessment strategies, diagnoses, and evidence-based interventions are required in adult and pediatric mTBI populations to optimize recovery and reduce the substantial socio-economic burden of post-concussion symptoms.

Traumatic brain injury (TBI) is a major cause of death and disability, but there are currently no therapies with proven efficacy for optimizing regeneration of repair during rehabilitation. Using standard stimulation tests, as many as 40–50% of survivors of severe TBI have deficiency of one or more pituitary hormones. Of these, the somatotropic axis is the most commonly affected, with Growth Hormone (GH) deficiency affecting ~20% of persons with severe TBI. Treatment with recombinant human Growth Hormone (rhGH) is generally effective in reversing the effects of acquired GH deficiency, but there is no evidence documenting functional or neurocognitive improvement after GH replacement in TBI patients. As a consequence, screening for GH deficiency and GH replacement when deficiency is found is not routinely performed as part of the rehabilitation of TBI survivors. Given that most of the recovery after TBI occurs within the first 6–12 months after injury and IGF-1 and GH are part of a coordinated restorative neurotrophic system, we hypothesized that patients will optimally benefit from GH therapy during the window of maximal neuroregenerative activity. We performed a Phase IIa, randomized, double-blind, placebo-controlled feasibility trial of recombinant human Growth Hormone (rhGH), starting at discharge from an inpatient rehabilitation unit, with follow up at 6 and 12 months. Our primary hypothesis was that treatment with rhGH in the subacute period would result in improved functional outcomes 6 months after injury. Our secondary hypothesis proposed that treatment with rhGH would increase IGF-1 levels and be well tolerated. Sixty-three subjects were randomized, and 40 completed the trial. At baseline, there was no correlation between IGF-1 levels and peak GH levels after L-arginine stimulation. IGF-1 levels increased after rhGH treatment, but it took longer than 1 month for levels to be higher than for placebo-treated patients. rhGH therapy was well-tolerated. The rhGH group was no different from placebo in the Disability Rating Scale, Glasgow Outcome Scale-Extended, or neuropsychological function. However, a trend toward greater improvement from baseline in Functional Independence Measure (FIM) was noted in the rhGH treated group. Future studies should include longer treatment periods, faster titration of rhGH, and larger sample sizes.

This study seeks to quantitatively assess evolution of traumatic ICHs over the first 24 h and investigate its relationship with functional outcome. Early expansion of traumatic intracranial hematoma (ICH) is common, but previous studies have focused on the high density (blood) component. Hemostatic therapies may increase the risk of peri-hematoma infarction and associated increased cytotoxic edema. Assessing the magnitude and evolution of ICH and edema represented by high and low density components on computerized tomography (CT) may be informative for designing therapies targeted at traumatic ICH. CT scans from participants in the COBRIT (Citicoline Brain Injury Trial) study were analyzed using MIPAV software. CT scans from patients with non-surgical intraparenchymal ICHs at presentation and approximately 24 h later (±12 h) were selected. Regions of high density and low density were quantitatively measured. The relationship between volumes of high and low density were compared to several outcome measures, including Glasgow Outcome Score—Extended (GOSE) and Disability Rating Score (DRS). Paired scans from 84 patients were analyzed. The median time between the first and second scan was 22.79 h (25%ile 20.11 h; 75%ile 27.49 h). Over this time frame, hematoma and edema volumes increased >50% in 34 (40%) and 46 (55%) respectively. The correlation between the two components was low (r = 0.39, p = 0.002). There was a weak correlation between change in edema volume and GOSE at 6 months (r = 0.268, p = 0.037), change in edema volume and DRS at 3 and 6 months (r = −0.248, p = 0.037 and r = 0.358, p = 0.005, respectively), change in edema volume and COWA at 6 months (r = 0.272, p = 0.049), and between final edema volume and COWA at 6 months (r = 0.302, p = 0.028). To conclude, both high density and low density components of traumatic ICHs expand significantly in the first 2 days after TBI. In our study, there does not appear to be a relationship between hematoma volume or hematoma expansion and functional outcome, while there is a weak relationship between edema expansion and functional outcome.

The microvasculature is prominently affected by traumatic brain injury (TBI), including mild TBI (concussion). Assessment of cerebral hemodynamics shows promise as biomarkers of TBI, and may help inform development of therapies aimed at promoting neurologic recovery. The objective of this study was to assess the evolution in cerebral hemodynamics observable with transcranial Doppler (TCD) ultrasound in subjects suffering from a concussion at different intervals during recovery. Pediatric subjects between the ages of 14 and 19 years clinically diagnosed with a concussion were observed at different points post-injury. Blood flow velocity in the middle cerebral artery was measured with TCD. After a baseline period, subjects participated in four breath holding challenges. Pulsatility index (PI), resistivity index (RI), the ratio of the first two pulse peaks (P2R), and the mean velocity (MV) were computed from the baseline section. The breath hold index (BHI) was computed from the challenge sections. TCD detected two phases of hemodynamic changes after concussion. Within the first 48 h, PI, RI, and P2R show a significant difference from the controls (U = −3.10; P

BackgroundNearly 5 million emergency department (ED) visits for head injury occur each year in the United States, of which

BackgroundIn November 2019, an infectious agent that caused a severe acute respiratory illness was first detected in China. Its rapid spread resulted in a global lockdown with negative economic impacts. In this regard, we expose the solutions proposed by a multinational financial institution that maintained their workers on premises, so this methodology can be applied to possible future health crisis.ObjectivesTo ensure a secure workplace for the personnel on premises employing biomedical prevention measures and computational tools.MethodsProfessionals were subjected to recurrent COVID-19 diagnostic tests during the pandemic. The sanitary team implemented an individual following to all personnel and introduced the information in databases. The data collected were used for clustering algorithms, decision trees, and networking diagrams to predict outbreaks in the workplace. Individualized control panels assisted the decision-making process to increase, maintain, or relax restrictive measures.Results55,789 diagnostic tests were performed. A positive correlation was observed between the cumulative incidence reported by Madrid’s Ministry of Health and the headcount. No correlation was observed for occupational infections, representing 1.9% of the total positives. An overall 1.7% of the cases continued testing positive for COVID-19 after 14 days of quarantine.ConclusionBased on a combined approach of medical and computational science tools, we propose a management model that can be extended to other industries that can be applied to possible future health crises. This work shows that this model resulted in a safe workplace with a low probability of infection among workers during the pandemic.

It has been two decades since biomimetic synthesis of conducting polymers were first reported, however, the systematic investigation of how catalysts influence the properties of the conducting polymers has not been reported yet. In this paper, we report a comparative study between peroxidase-like catalyst, dopants, and their effect on the properties of poly (3,4-ethylenedioxythiophene) (PEDOT), polypyrrole (PPY), and polyaniline (PANI). We also investigate the EDOT-Pyrrole and EDOT-Aniline copolymerization by enzymomimetic synthesis using two catalysts (Ferrocene and Hematin). It was found that, chemically, there are no detectable effects, only having small contributions in molar ratios greater than 0.7–0.3. Spectroscopic data provide solid evidence concerning the effect in the variation of the molar fractions, finding that, as the molar fraction of EDOT decreases, changes associated with loss of the conjugation of the structure and the oxidation state of the chains were observed. The electrical conductivity was considerably modified depending on the type of catalyst. Hematin produces conductive homopolymers and copolymers when doped with p-toluene sulfonic acid (TSA), while ferrocene produces low conductive copolymers under the same conditions. The mole fraction affects conductivity significantly, showing that as the EDOT fraction decreases, the conductivity drops drastically for both EDOT-PY and EDOT-ANI copolymers. The type of dopant also notably affects conductivity; the best values were obtained by doping with TSA, while the lowest were obtained when doping with polystyrene sulfonate (PSS). We also draw a biomimetic route to tailor the fundamental properties of conducting homopolymers and copolymers for their design and scaled-up production, as they have recently been found to have use in a broad range of applications.

Although differing in size, encoded traits, host range, and replication mechanism, both narrow-host-range theta-type conjugative enterobacterial plasmid R1 and promiscuous rolling-circle-type mobilizable streptococcal plasmid pMV158 encode a transcriptional repressor protein, namely CopB in R1 and CopG in pMV158, involved in replication control. The gene encoding CopB or CopG is cotranscribed with a downstream gene that encodes the replication initiator Rep protein of the corresponding plasmid. However, whereas CopG is an auto-repressor that inhibits transcription of the entire copG-repB operon, CopB is expressed constitutively and represses a second, downstream promoter that directs transcription of repA. As a consequence of the distinct regulatory pathways implied by CopB and CopG, these repressor proteins play a different role in control of plasmid replication during the steady state: while CopB has an auxiliary role by keeping repressed the regulated promoter whenever the plasmid copy number is above a low threshold, CopG plays a primary role by acting coordinately with RNAII. Here, we have studied the role of the regulatory circuit mediated by these transcriptional repressors during the establishment of these two plasmids in a new host cell, and found that excess Cop repressor molecules in the recipient cell result in a severe decrease in the frequency and/or the velocity of appearance of transformant colonies for the cognate plasmid but not for unrelated plasmids. Using the pMV158 replicon as a model system, together with highly sensitive real-time qPCR and inverse PCR methods, we have also analyzed the effect of CopG on the kinetics of repopulation of the plasmid in Streptococcus pneumoniae. We show that, whereas in the absence of CopG pMV158 repopulation occurs mainly during the first 45 min following plasmid transfer, the presence of the transcriptional repressor in the recipient cell severely impairs the replicon repopulation and makes the plasmid replicate at approximately the same rate as the chromosome at any time after transformation, which results in maximal plasmid loss rate in the absence of selection. Overall, these findings indicate that unrepressed activity of the Cop-regulated promoter is crucial for the successful colonization of the recipient bacterial cells by the plasmid.

Toxin–antitoxin (TA) genes were first reported in plasmids and were considered expendable genetic cassettes involved in the stable maintenance of the plasmid replicon by interfering with growth and/or viability of bacteria in which the plasmid was lost. TAs were later found in bacterial chromosomes and also in integrated mobile genetic elements; they were proposed to be involved in the bacterial response to stressful situations. At present, 100s of TAs have been identified and classified in up to six families (I to VI), with those belonging to the type II (constituted by two protein components) being the most studied. Based on well-characterized examples of several type II TAs, we discuss in this review that irrespective of their locations in plasmids or chromosomes, TAs functionally overlap as indicated by: (i) in both locations they can mediate the maintenance of genetic elements to which they are physical linked, and (ii) they can induce persistence or virulence in response to stress situations. Examples of functional confluences in homologous TA systems with different locations are also given. We also consider whether the physiological role of TAs is due to their genetic organization as operons or to their inherent properties, like the short lifespan of the antitoxin component.

Certain Salmonella enterica serovars belonging to subspecies I carry low-copy-number virulence plasmids of variable size (50-90 kb). All of these plasmids share the spv operon, which is important for systemic infection. Virulence plasmids are present at low copy numbers. Few copies reduce metabolic burden but suppose a risk of plasmid loss during bacterial division. This drawback is counterbalanced by maintenance modules that ensure plasmid stability, including partition systems and toxin-antitoxin (TA) loci. The low-copy number virulence pSLT plasmid of Salmonella enterica serovar Typhimurium encodes three auxiliary maintenance systems: one partition system (parAB) and two TA systems (ccdABST and vapBC2ST). The TA module ccdABST has previously been shown to contribute to pSLT plasmid stability and vapBC2ST to bacterial virulence. Here we describe a novel assay to measure plasmid stability based on the selection of plasmid-free cells following elimination of plasmid-containing cells by ParE toxin, a DNA gyrase inhibitor. Using this new maintenance assay we confirmed a crucial role of parAB in pSLT maintenance. We also showed that vapBC2ST, in addition to contribute to bacterial virulence, is important for plasmid stability. We have previously shown that ccdABST encodes an inactive CcdBST toxin. Using our new stability assay we monitored the contribution to plasmid stability of a ccdABST variant containing a single mutation (R99W) that restores the toxicity of CcdBST. The activation of CcdBST(R99W) did not increase pSLT stability by ccdABST. In contrast, ccdABST behaves as a canonical type II TA system in terms of transcriptional regulation. Of interest, ccdABST was shown to control the expression of a polycistronic operon in the pSLT plasmid. Collectively, these results show that the contribution of the CcdBST toxin to pSLT plasmid stability may depend on its role as a co-repressor in coordination with CcdAST antitoxin more than on its toxic activity.