Engineering performance of tungsten network reinforced copper matrix composites synthesized by selective laser melting and infiltration.

To solve poor engineering performance of copper-tungsten alloys operated at high temperatures, 3D network tungsten frameworks were prepared using a selective laser melting (SLM) process, and then copper was melted and diffused into these tungsten network structures to form copper matrix composites with different copper contents (i.e. Cu-10vol%W and Cu-30vol%W). Their mechanical/electrical properties and arc ablation performance were characterized. Results showed the obtained CuW composites were dense with good interfacial bonding, and the connected Cu phases formed a heat conduction channel and improved electrical and thermal conductivities of the composites. Electrical conductivities of Cu-30W and Cu-10W composites were 44.7% and 80.3% IACS, and their thermal conductivities at 25°C were 247.5 and 375.4 W/(m·K), respectively. The W-skeleton grid structure in the composites showed enhanced effects on impact toughness and anti-friction/wear resistance. Tensile strengths of Cu-30W and Cu-10W composites measured at 300°C were 95 MPa and 135 MPa, and their impact toughness values were 11.25 and 15.25 J/cm2, respectively. For the arc ablation performance, the copper phase of CuW composite was identified as the key influencing phase, whereas the W skeleton effectively hindered the spread of arc spots, inhibited quick melting of copper phases, and played effective support and protection functions.

W network reinforced Cu matrix composites were prepared by combining 3D printing technology and fusion technology, which significantly improved the thermal and mechanical properties of Cu matrix composites. We find that the interconnected Cu phases improves the thermal properties of the composites, and the mesh W skeleton improves the mechanical properties.

Identification of genes with oscillatory expression in glioblastoma: the paradigm of SOX2.

Quiescence, a reversible state of cell-cycle arrest, is an important state during both normal development and cancer progression. For example, in glioblastoma (GBM) quiescent glioblastoma stem cells (GSCs) play an important role in re-establishing the tumour, leading to relapse. While most studies have focused on identifying differentially expressed genes between proliferative and quiescent cells as potential drivers of this transition, recent studies have shown the importance of protein oscillations in controlling the exit from quiescence of neural stem cells. Here, we have undertaken a genome-wide bioinformatic inference approach to identify genes whose expression oscillates and which may be good candidates for controlling the transition to and from the quiescent cell state in GBM. Our analysis identified, among others, a list of important transcription regulators as potential oscillators, including the stemness gene SOX2, which we verified to oscillate in quiescent GSCs. These findings expand on the way we think about gene regulation and introduce new candidate genes as key regulators of quiescence.

Medical Device Advances in the Treatment of Glioblastoma.

Despite decades of research and the growing emergence of new treatment modalities, Glioblastoma (GBM) frustratingly remains an incurable brain cancer with largely stagnant 5-year survival outcomes of around 5%. Historically, a significant challenge has been the effective delivery of anti-cancer treatment. This review aims to summarize key innovations in the field of medical devices, developed either to improve the delivery of existing treatments, for example that of chemo-radiotherapy, or provide novel treatments using devices, such as sonodynamic therapy, thermotherapy and electric field therapy. It will highlight current as well as emerging device technologies, non-invasive versus invasive approaches, and by doing so provide a detailed summary of evidence from clinical studies and trials undertaken to date. Potential limitations and current challenges are discussed whilst also highlighting the exciting potential of this developing field. It is hoped that this review will serve as a useful primer for clinicians, scientists, and engineers in the field, united by a shared goal to translate medical device innovations to help improve treatment outcomes for patients with this devastating disease.

What is the association of renin-angiotensin-aldosterone system inhibitors with COVID-19 outcomes: retrospective study of racially diverse patients?

OBJECTIVE: To describe the clinical outcomes of COVID-19 in a racially diverse sample from the US Southeast and examine the association of renin-angiotensin-aldosterone system (RAAS) inhibitor use with COVID-19 outcome. DESIGN, SETTING, PARTICIPANTS: This study is a retrospective cohort of 1024 patients with reverse-transcriptase PCR-confirmed COVID-19 infection, admitted to a 1242-bed teaching hospital in Alabama. Data on RAAS inhibitors use, demographics and comorbidities were extracted from hospital medical records. PRIMARY OUTCOMES: In-hospital mortality, a need of intensive care unit, respiratory failure, defined as invasive mechanical ventilation (iMV) and 90-day same-hospital readmissions. RESULTS: Among 1024 patients (mean (SD) age, 57 (18.8) years), 532 (52.0%) were African Americans, 514 (50.2%) male, 493 (48.1%) had hypertension, 365 (36%) were taking RAAS inhibitors. During index hospitalisation (median length of stay of 7 (IQR (4-15) days) 137 (13.4%) patients died; 170 (19.2%) of survivors were readmitted. RAAS inhibitor use was associated with lower in-hospital mortality (adjusted HR, 95% CI (0.56, (0.36 to 0.88), p=0.01) and no effect modification by race was observed (p for interaction=0.81). Among patients with hypertension, baseline RAAS use was associated with reduced risk of iMV, adjusted OR, 95% CI (aOR 0.58, 95% CI 0.36 to 0.95, p=0.03). Patients with heart failure were twice as likely to die from COVID-19, compared with patients without heart failure. CONCLUSIONS: In a retrospespective study of racially diverse patients, hospitalised with COVID-19, prehospitalisation use of RAAS inhibitors was associated with 40% reduction in mortality irrespective of race.

Unravelling the potential of graphene in glioblastoma therapy.

Glioblastoma multiforme (GBM) is one of the most malignant types of central nervous system tumours. Despite advances in treatment modalities, it remains largely incurable with an extremely poor prognosis. Treatment of GBM is associated with several difficulties such as the risk of damaging healthy brain tissues during surgery, drug resistance and inadequate drug delivery across the blood brain barrier. The new nanomaterial graphene, has recently attracted great attention due to its unique physico-chemical characteristics, good biocompatibility, specific targeting and small size. Starting from simple drug delivery systems, the application of graphene-based nanomaterials has been extended to a versatile platform of multiple therapeutic modalities, including immunotherapy, gene therapy, photothermal therapy and photodynamic therapy. Graphene-based materials can also be engineered to integrate multiple functions into a single platform for combination therapy for enhanced anticancer activity and reduced side effects. This review aims to discuss the state-of-the-art applications of graphene-based materials in GBM diagnosis and therapy. In addition, future challenges and prospects regarding this promising field are discussed, which may pave the way towards improving the safety and efficacy of graphene-based therapeutics.

Enhancing therapeutic efficacy of in vivo platelet-targeted gene therapy in hemophilia A mice.

Our previous studies demonstrated that intraosseous (IO) infusion of lentiviral vectors (LVs) carrying a modified B domain-deleted factor VIII (FVIII) transgene driven by a megakaryocyte-specific promoter (GP1Bα promoter; G-F8/N6-LV) successfully transduced hematopoietic stem cells (HSCs) to produce FVIII stored in the platelet α-granules. Platelet FVIII corrected the bleeding phenotype with limited efficacy in hemophilia A (HemA) mice with and without preexisting anti-FVIII inhibitors. The present study sought to further enhance the therapeutic efficacy of this treatment protocol by increasing both the efficiency of LV transduction and the functional activity of platelet FVIII. A combined drug regimen of dexamethasone and anti-CD8α monoclonal antibody enhanced the percentage of transduced bone marrow and HSCs over time. In G-F8/N6-LV-treated HemA mice, significant improvement in phenotypic correction was observed on day 84. To improve platelet FVIII functionality, genes encoding FVIII variant F8X10K12 with increased expression or F8N6K12RH with increased functional activity compared with F8/N6 were incorporated into LVs. Treatment with G-F8X10K12-LV in HemA mice produced a higher level of platelet FVIII but induced anti-FVIII inhibitors. After treatment with combined drugs and IO infusion of G-F8/N6K12RH-LV, HemA mice showed significant phenotypic correction without anti-FVIII inhibitor formation. These results indicate that new human FVIII variant F8/N6K12RH combined with immune suppression could significantly enhance the therapeutic efficacy of in vivo platelet-targeted gene therapy for murine HemA via IO delivery. This protocol provides a safe and effective treatment for hemophilia that may be translatable to and particularly beneficial for patients with preexisting inhibitory antibodies to FVIII.

CD4+ T cells engineered with FVIII-CAR and murine Foxp3 suppress anti-factor VIII immune responses in hemophilia a mice.

Although protein replacement therapy provides effective treatment for hemophilia A patients, about a third of severe patients develop neutralizing inhibitor antibodies to factor VIII. Adoptive transfer of regulatory T cells (Tregs) has shown promise in treating unwanted immune responses. In previous studies, transferred polyclonal Tregs ameliorated the anti-factor VIII immune responses in hemophilia A mice. In addition, factor VIII-primed Tregs demonstrated increased suppressive function. However, antigen-specific Tregs are a small fraction of the total lymphocyte population. To generate large numbers of factor VIII-specific Tregs, the more abundant murine primary CD4+ T cells were lentivirally transduced ex vivo to express Foxp3 and a chimeric antigen receptor specific to factor VIII (F8CAR). Transduced cells significantly inhibited the proliferation of factor VIII-specific effector T cells in suppression assays. To monitor the suppressive function of the transduced chimeric antigen receptor expressing T cells in vivo, engineered CD4+CD25+Foxp3+F8CAR-Tregs were sorted and adoptively transferred into hemophilia A mice that are treated with hydrodynamically injected factor VIII plasmid. Mice receiving engineered F8CAR-Tregs showed maintenance of factor VIII clotting activity and did not develop anti-factor VIII inhibitors, while control CD4+T cell or PBS recipient mice developed inhibitors and had a sharp decrease in factor VIII activity. These results show that CD4+ cells lentivirally transduced to express Foxp3 and F8CAR can promote factor VIII tolerance in a murine model. With further development and testing, this approach could potentially be applied to human hemophilia patients.

Controlling Drug Absorption, Release, and Erosion of Photopatterned Protein Engineered Hydrogels.

A protein-engineered triblock copolymer hydrogel composed of two self-assembling domains (SADs) has been fabricated by a photoactivatable diazirine group followed by ultraviolet (UV)-mediated crosslinking. The photocrosslinkable protein polymer CEC-D has been patterned into various features including different micrometer-scale stripes by using lithographic techniques. The patterned hydrogels are important for encapsulation of small molecules where a photopatterned fraction of 50% is optimal for maximum absorption. Stripe-patterned CEC-D100-100 exhibits slightly lower swelling ratios, an 8.9 times lower erosion profile, and a 2.6-fold higher drug release compared to the unpatterned hydrogel control, CEC-D0. Our studies demonstrate the potential of photocrosslinkable protein polymer hydrogels to be used as scaffolds for therapeutic delivery of small molecules. Through photolithographic techniques on the protein hydrogel, a variety of functionalities can be achieved by patterning different features enabling the mimicry of biological systems.

Pre-emptive intrathecal vancomycin therapy reduces external ventricular drain infection: a single centre retrospective case-control study.

OBJECTIVES: External ventricular drain (EVD)-related infection is a significant source of morbidity in neurosurgical patients. Recently, there has been a drive to adopt new catheters with bactericidal properties to reduce infection rates. We propose that the use of standard catheters combined with pre-emptive intrathecal vancomycin (ITV) 10 mg daily provides an effective alternative. DESIGN: Retrospective study of all patients with EVDs between 2010 and 2012, comparing infection rates in those who did and did not receive pre-emptive ITV. All EVDs were of the standard silicon catheter type. CSF infection was defined, as per Centre for Disease Control (CDC) guidelines, as clinical suspicion ± positive CSF gram stain/culture or leucocytosis. Infection rates were compared using Pearson's chi-squared test. RESULTS: 262 EVDs were included in the study, of which 111 were managed with pre-emptive ITV. The infection rate was 2.7% in the vancomycin group and 11.9% in the control group (p<.01). There were no cases of vancomycin-resistant infection in either group. CONCLUSION: The use of pre-emptive ITV is associated with a significantly lower EVD infection rate. This compares favourably with those reported in the literature for bactericidal catheters.

Dopamine Activation Preserves Visual Motion Perception Despite Noise Interference of Human V5/MT.

UNLABELLED: When processing sensory signals, the brain must account for noise, both noise in the stimulus and that arising from within its own neuronal circuitry. Dopamine receptor activation is known to enhance both visual cortical signal-to-noise-ratio (SNR) and visual perceptual performance; however, it is unknown whether these two dopamine-mediated phenomena are linked. To assess this, we used single-pulse transcranial magnetic stimulation (TMS) applied to visual cortical area V5/MT to reduce the SNR focally and thus disrupt visual motion discrimination performance to visual targets located in the same retinotopic space. The hypothesis that dopamine receptor activation enhances perceptual performance by improving cortical SNR predicts that dopamine activation should antagonize TMS disruption of visual perception. We assessed this hypothesis via a double-blinded, placebo-controlled study with the dopamine receptor agonists cabergoline (a D2 agonist) and pergolide (a D1/D2 agonist) administered in separate sessions (separated by 2 weeks) in 12 healthy volunteers in a William's balance-order design. TMS degraded visual motion perception when the evoked phosphene and the visual stimulus overlapped in time and space in the placebo and cabergoline conditions, but not in the pergolide condition. This suggests that dopamine D1 or combined D1 and D2 receptor activation enhances cortical SNR to boost perceptual performance. That local visual cortical excitability was unchanged across drug conditions suggests the involvement of long-range intracortical interactions in this D1 effect. Because increased internal noise (and thus lower SNR) can impair visual perceptual learning, improving visual cortical SNR via D1/D2 agonist therapy may be useful in boosting rehabilitation programs involving visual perceptual training. SIGNIFICANCE STATEMENT: In this study, we address the issue of whether dopamine activation improves visual perception despite increasing sensory noise in the visual cortex. We show specifically that dopamine D1 (or combined D1/D2) receptor activation enhances the cortical signal-to-noise-ratio to boost perceptual performance. Together with the previously reported effects of dopamine upon brain plasticity and learning (Wolf et al., 2003; Hansen and Manahan-Vaughan, 2014), our results suggest that combining rehabilitation with dopamine agonists could enhance both the saliency of the training signal and the long-term effects on brain plasticity to boost rehabilitation regimens for brain injury.

Eye Movements during Auditory Attention Predict Individual Differences in Dorsal Attention Network Activity.

The neural mechanisms supporting auditory attention are not fully understood. A dorsal frontoparietal network of brain regions is thought to mediate the spatial orienting of attention across all sensory modalities. Key parts of this network, the frontal eye fields (FEF) and the superior parietal lobes (SPL), contain retinotopic maps and elicit saccades when stimulated. This suggests that their recruitment during auditory attention might reflect crossmodal oculomotor processes; however this has not been confirmed experimentally. Here we investigate whether task-evoked eye movements during an auditory task can predict the magnitude of activity within the dorsal frontoparietal network. A spatial and non-spatial listening task was used with on-line eye-tracking and functional magnetic resonance imaging (fMRI). No visual stimuli or cues were used. The auditory task elicited systematic eye movements, with saccade rate and gaze position predicting attentional engagement and the cued sound location, respectively. Activity associated with these separate aspects of evoked eye-movements dissociated between the SPL and FEF. However these observed eye movements could not account for all the activation in the frontoparietal network. Our results suggest that the recruitment of the SPL and FEF during attentive listening reflects, at least partly, overt crossmodal oculomotor processes during non-visual attention. Further work is needed to establish whether the network's remaining contribution to auditory attention is through covert crossmodal processes, or is directly involved in the manipulation of auditory information.

Yawning as a presenting symptom of Chiari malformation Type I: report of 2 cases.

Yawning is thought to be a behavior regulated by the brainstem. Although excessive yawning has been reported in brainstem strokes, demyelination, and tumors, the cases presented here are the first reports of excessive yawning in patients with Chiari malformation Type I (CM-I). The authors believe that brainstem compression at the craniocervical junction and ensuing edema were implicated in this curious symptomatology. They describe excessive yawning as a presenting feature of CM-I in 2 adolescent females. The presentation was acute in the first case and more chronic in the second. Both patients underwent foramen magnum decompression, which resulted in complete cessation of the excessive yawning.

Surgical and Biomechanical Perspectives on Osteoarthritis and the ACL Deficient Knee: A Critical Review of the Literature.

This review was undertaken to better understand the debate regarding the issue of osteoarthritis associated with anterior cruciate ligament (ACL) injuries, from a surgical and biomechanical standpoint. Much of the current debate focuses on contributory surgical factors and their relative roles in increasing or decreasing the risk of future osteoarthritis development, primarily highlighting the controversy over whether reconstructive surgery itself is necessarily protective. This review addresses the evolution of ACL reconstruction techniques over time, and with a view to thoroughly examine the role of surgery, outcome differences in procedural technique are reviewed, with a focus on open versus arthroscopic methods, graft choice and the use of a double versus single bundle reconstruction technique. Moreover, other potentially important contributory factors are identified and discussed, such as intrinsic biomechanical alterations sustained at the time of initial injury, and how these may have a more significant role with regard to future osteoarthritic changes in the knee than previously attributed.

Structure and process of infrared hot electron transistor arrays.

An infrared hot-electron transistor (IHET) 5 × 8 array with a common base configuration that allows two-terminal readout integration was investigated and fabricated for the first time. The IHET structure provides a maximum factor of six in improvement in the photocurrent to dark current ratio compared to the basic quantum well infrared photodetector (QWIP), and hence it improved the array S/N ratio by the same factor. The study also showed for the first time that there is no electrical cross-talk among individual detectors, even though they share the same emitter and base contacts. Thus, the IHET structure is compatible with existing electronic readout circuits for photoconductors in producing sensitive focal plane arrays.