SNTF immunostaining reveals previously undetected axonal pathology in traumatic brain injury

Diffuse axonal injury (DAI) is a common feature of severe traumatic brain injury (TBI) and may also be a predominant pathology in mild TBI or “concussion”. The rapid deformation of white matter at the instant of trauma can lead to mechanical failure and calcium-dependent proteolysis of the axonal cytoskeleton in association with axonal transport interruption. Recently, a proteolytic fragment of alpha-II spectrin, “SNTF”, was detected in serum acutely following mild TBI in patients and was prognostic for poor clinical outcome. However, direct evidence that this fragment is a marker of DAI has yet to be demonstrated in either humans following TBI or in models of mild TBI. Here, we used immunohistochemistry (IHC) to examine for SNTF in brain tissue following both severe and mild TBI. Human severe TBI cases (survival <7d; n = 18) were compared to age-matched controls (n = 16) from the Glasgow TBI archive. We also examined brains from an established model of mild TBI at 6, 48 and 72 h post-injury versus shams. IHC specific for SNTF was compared to that of amyloid precursor protein (APP), the current standard for DAI diagnosis, and other known markers of axonal pathology including non-phosphorylated neurofilament-H (SMI-32), neurofilament-68 (NF-68) and compacted neurofilament-medium (RMO-14) using double and triple immunofluorescent labeling. Supporting its use as a biomarker of DAI, SNTF immunoreactive axons were observed at all time points following both human severe TBI and in the model of mild TBI. Interestingly, SNTF revealed a subpopulation of degenerating axons, undetected by the gold-standard marker of transport interruption, APP. While there was greater axonal co-localization between SNTF and APP after severe TBI in humans, a subset of SNTF positive axons displayed no APP accumulation. Notably, some co-localization was observed between SNTF and the less abundant neurofilament subtype markers. Other SNTF positive axons, however, did not co-localize with any other markers. Similarly, RMO-14 and NF-68 positive axonal pathology existed independent of SNTF and APP. These data demonstrate that multiple pathological axonal phenotypes exist post-TBI and provide insight into a more comprehensive approach to the neuropathological assessment of DAI

Team Approach Or Individual Approach: A Statistical Analysis Of The Impact Of Socioeconomic Heterogeneity On Students Preference In Writing Term Papers In Management Courses

The purpose of this paper is to examine students preference in writing term papers in management courses. Specifically, students attitudes and preferences toward the choices, i.e., whether it is written as an individual effort, or as a team effort, are examined. These choices (individual approach, team approach, freedom of choice and indifferent) are then tested against a set of socioeconomic factors to see if there are significant relationships among the variables. The paper reports the empirical findings of the study

Template-Stripped Multifunctional Wedge and Pyramid Arrays for Magnetic Nanofocusing and Optical Sensing

We present large-scale reproducible fabrication of multifunctional ultrasharp metallic structures on planar substrates with capabilities including magnetic field nanofocusing and plasmonic sensing. Objects with sharp tips such as wedges and pyramids made with noble metals have been extensively used for enhancing local electric fields via the lightning-rod effect or plasmonic nanofocusing. However, analogous nanofocusing of magnetic fields using sharp tips made with magnetic materials has not been widely realized. Reproducible fabrication of sharp tips with magnetic as well as noble metal layers on planar substrates can enable straightforward application of their material and shape-derived functionalities. We use a template-stripping method to produce plasmonic-shell-coated nickel wedge and pyramid arrays at the wafer-scale with tip radius of curvature close to 10 nm. We further explore the magnetic nanofocusing capabilities of these ultrasharp substrates, deriving analytical formulas and comparing the results with computer simulations. These structures exhibit nanoscale spatial control over the trapping of magnetic microbeads and nanoparticles in solution. Additionally, enhanced optical sensing of analytes by these plasmonic-shell-coated substrates is demonstrated using surface-enhanced Raman spectroscopy. These methods can guide the design and fabrication of novel devices with applications including nanoparticle manipulation, biosensing, and magnetoplasmonics

Transcutaneous electrical nerve stimulation using an LTP-like repetitive stimulation protocol for patients with upper limb complex regional pain syndrome: A feasibility study

Introduction This feasibility study aimed to (i) develop a clinical protocol using a long-term potentiation-like repetitive stimulation protocol for transcutaneous electrical nerve stimulation in patients with upper limb complex regional pain syndrome and (ii) develop a research protocol for a single-blind randomised controlled trial investigating the efficacy of transcutaneous electrical nerve stimulation for complex regional pain syndrome. Methods This small-scale single-blind feasibility randomised-controlled trial planned to randomise 30 patients with upper limb complex regional pain syndrome to either a variant of transcutaneous electrical nerve stimulation or placebo transcutaneous electrical nerve stimulation for three weeks. Stimulation comprised 20 pulses over 1 s with a non-stimulation interval of 5 s, a so-called repetitive electrical stimulation protocol following the timing of long-term potentiation. Pain, function and body image were measured at baseline, post-treatment and at three months follow-up. At three months, participants were invited to one-to-one interviews, which were analysed thematically. Results A transcutaneous electrical nerve stimulation protocol with electrodes applied proximal to the area of allodynia in the region of the upper arm was developed. Participant concordance with the protocol was high. Recruitment was below target (transcutaneous electrical nerve stimulation (n = 6), placebo (n = 2)). Mean (SD) pain intensity for the transcutaneous electrical nerve stimulation group on a 0 to 10 scale was 7.2 (2.4), 6.6 (2.8) and 7.8 (1.9), at baseline, post-treatment and at three-month follow-up, respectively. Qualitative data suggested that some patients found transcutaneous electrical nerve stimulation beneficial, easy to use and were still using it at three months. Conclusion Patients tolerated transcutaneous electrical nerve stimulation well, and important methodological information to facilitate the design of a large-scale trial was obtained (ISRCTN48768534). </jats:sec

Extubation and Weaning: Implementing a Standard Weaning Protocol

Purpose The purpose of this project is to determine if implementation of a standardized weaning protocol on mechanically ventilated patients affects reintubation rates and decreases adverse outcomes

Mechanical disruption of the blood-brain barrier following experimental concussion

Although concussion is now recognized as a major health issue, its non-lethal nature has limited characterization of the underlying pathophysiology. In particular, potential neuropathological changes have typically been inferred from non-invasive techniques or post-mortem examinations of severe traumatic brain injury (TBI). Here, we used a swine model of head rotational acceleration based on human concussion to examine blood–brain barrier (BBB) integrity after injury in association with diffuse axonal injury and glial responses. We then determined the potential clinical relevance of the swine concussion findings through comparisons with pathological changes in human severe TBI, where post-mortem examinations are possible. At 6–72 h post-injury in swine, we observed multifocal disruption of the BBB, demonstrated by extravasation of serum proteins, fibrinogen and immunoglobulin-G, in the absence of hemorrhage or other focal pathology. BBB disruption was observed in a stereotyped distribution consistent with biomechanical insult. Specifically, extravasated serum proteins were frequently observed at interfaces between regions of tissue with differing material properties, including the gray–white boundary, periventricular and subpial regions. In addition, there was substantial overlap of BBB disruption with regions of axonal pathology in the white matter. Acute perivascular cellular uptake of blood-borne proteins was observed to be prominent in astrocytes (GFAP-positive) and neurons (MAP-2-positive), but not microglia (IBA1-positive). Parallel examination of human severe TBI revealed similar patterns of serum extravasation and glial uptake of serum proteins, but to a much greater extent than in the swine model, attributed to the higher injury severity. These data suggest that BBB disruption represents a new and important pathological feature of concussion

Deep-diving beaked whales dive together but forage apart

Funding: Data collection and analysis were performed with funds from the U.S. Office of Naval Research (ONR), the US National Oceanographic Partnership Program (NOPP), the US Strategic Environmental Research Development Program (SERDP) and the Spanish Government National Projects CETOBAPH (CGL2009-13112) and DEEPCOM (CTM2017-88686-P). J.A.T. is currently the recipient of a FPU Doctoral Scholarship (FPU16/00490) from the Spanish Ministry of Universities. M.J. is supported by the Aarhus University Research Foundation and the EU H2020 research and innovation programme under Marie Skłodowska-Curie grant 754513. P.A. is funded by an Agustín de Bethencourt fellowship from the Cabildo Insular de Tenerife and NAS by a Ramón y Cajal fellowship from the Spanish Government. V.E.W. is funded by a University of Auckland Doctoral Scholarship. C.J.P.G. is partially funded by the Ministry of Science and Innovation (MICINN) of Spain under Grant PID2019-110442GB-I00. T.A.M. thanks partial support from CEAUL (funded by FCT - Fundação para a Ciência e a Tecnologia, Portugal, through the project UIDB/00006/2020).Echolocating animals that forage in social groups can potentially benefit from eavesdropping on other group members, cooperative foraging or social defence, but may also face problems of acoustic interference and intra-group competition for prey. Here, we investigate these potential trade-offs of sociality for extreme deep-diving Blainville′s and Cuvier's beaked whales. These species perform highly synchronous group dives as a presumed predator-avoidance behaviour, but the benefits and costs of this on foraging have not been investigated. We show that group members could hear their companions for a median of at least 91% of the vocal foraging phase of their dives. This enables whales to coordinate their mean travel direction despite differing individual headings as they pursue prey on a minute-by-minute basis. While beaked whales coordinate their echolocation-based foraging periods tightly, individual click and buzz rates are both independent of the number of whales in the group. Thus, their foraging performance is not affected by intra-group competition or interference from group members, and they do not seem to capitalize directly on eavesdropping on the echoes produced by the echolocation clicks of their companions. We conclude that the close diving and vocal synchronization of beaked whale groups that quantitatively reduces predation risk has little impact on foraging performance.PostprintPeer reviewe

Cryptotephra preserved in Lake Suigetsu (SG14 core) reveals the eruption timing and distribution of ash fall from Japanese volcanoes during the Late-glacial to early Holocene

Long sedimentary successions extracted for palaeoclimate research regularly preserve volcanic ash (tephra) fall from explosive eruptions and are increasingly used to elucidate the timing and scale of past events. This study investigates the non-visible tephra (cryptotephra) layers preserved in the annually laminated and intensively 14 C dated sediments of Lake Suigetsu (SG14 core), Japan. The cryptotephra investigations reported here focus on the Late-glacial to early Holocene sediments that were deposited between two visible tephra layers, the Ulleungdo (U)-Oki (10.2 ka) and the Sambe ‘Sakate’ (19.6 ka), and consequently span an interval of abrupt climate change making any newly identified cryptotephra layers invaluable chrono-stratigraphic markers. Using major and trace element volcanic glass compositions the cryptotephra are used to assign provenance to chrono-stratigraphically relevant eruption units. Five new cryptotephra layers are identified within this time interval. Three cryptotephra layers are from Kyushu volcanoes (SG14-1337 and SG14-1554 [Sakurajima]; and SG14-1806 [Kirishima]), all of which offer important chronological constraints on archaeological (Jomon) cultural transitions in southern Japan during the last termination. Another cryptotephra (SG14-1579), is assigned to activity on Niijima Island providing the first known distal occurrence and age of the eruption. Finally, the SG14-1798 cryptotephra precisely dated at 16,619 ± 74 IntCal20 yrs BP (2σ) is linked to Asama (As) volcano and more precisely the later phases of the As-YKU eruption. This discovery greatly expands the distribution of ash fall from this multi-phased eruption at Asama volcano, which affected an area in the region of 120,000 km2. Refining the timing of the eruption and the distribution of As-YKU ash fall is important as it offers an excellent chrono- and climato45 stratigraphic marker suitable for assessing spatial variability in environmental response to past climate change during the termination of the last glacial

Competing risk bias in prognostic models predicting hepatocellular carcinoma occurrence: impact on clinical decision making

Existing models predicting hepatocellular carcinoma (HCC) occurrence do not account for competing risk events and, thus, may overestimate the probability of HCC. Our goal was to quantify this bias for patients with cirrhosis and cured hepatitis C. We analyzed a nationwide cohort of patients with cirrhosis and cured hepatitis C infection from Scotland. Two HCC prognostic models were developed: (1) a Cox regression model ignoring competing risk events and (2) a Fine-Gray regression model accounting for non-HCC mortality as a competing risk. Both models included the same set of prognostic factors used by previously developed HCC prognostic models. Two predictions were calculated for each patient: first, the 3-year probability of HCC predicted by model 1 and second, the 3-year probability of HCC predicted by model 2. The study population comprised 1629 patients with cirrhosis and cured HCV, followed for 3.8 years on average. A total of 82 incident HCC events and 159 competing risk events (ie, non-HCC deaths) were observed. The mean predicted 3-year probability of HCC was 3.37% for model 1 (Cox) and 3.24% for model 2 (Fine-Gray). For most patients (76%), the difference in the 3-year probability of HCC predicted by model 1 and model 2 was minimal (ie, within 0 to ±0.3%). A total of 2.6% of patients had a large discrepancy exceeding 2%; however, these were all patients with a 3-year probability exceeding >5% in both models. Prognostic models that ignore competing risks do overestimate the future probability of developing HCC. However, the degree of overestimation—and the way it is patterned—means that the impact on HCC screening decisions is likely to be modest