Proof Of Concept Investigation Research Articles

Automatic GAN-based MRI volume synthesis from US volumes: a proof of concept investigation

Usually, a baseline image, either through magnetic resonance imaging (MRI) or computed tomography (CT), is captured as a reference before medical procedures such as respiratory interventions like Thoracentesis. In these procedures, ultrasound (US) imaging is often employed for guiding needle placement during Thoracentesis or providing image guidance in MISS procedures within the thoracic region. Following the procedure, a post-procedure image is acquired to monitor and evaluate the patient’s progress. Currently, there are no real-time guidance and tracking capabilities that allow a surgeon to perform their procedure using the familiarity of the reference imaging modality. In this work, we propose a real-time volumetric indirect registration using a deep learning approach where the fusion of multi-imaging modalities will allow for guidance and tracking of surgical procedures using US while displaying the resultant changes in a clinically friendly reference imaging modality (MRI). The deep learning method employs a series of generative adversarial networks (GANs), specifically CycleGAN, to conduct an unsupervised image-to-image translation. This process produces spatially aligned US and MRI volumes corresponding to their respective input volumes (MRI and US) of the thoracic spine anatomical region. In this preliminary proof-of-concept study, the focus was on the T9 vertebrae. A clinical expert performs anatomical validation of randomly selected real and generated volumes of the T9 thoracic vertebrae and gives a score of 0 (conclusive anatomical structures present) or 1 (inconclusive anatomical structures present) to each volume to check if the volumes are anatomically accurate. The Dice and Overlap metrics show how accurate the shape of T9 is when compared to real volumes and how consistent the shape of T9 is when compared to other generated volumes. The average Dice, Overlap and Accuracy to clearly label all the anatomical structures of the T9 vertebrae are approximately 80% across the board.

Proposal for the use of an inhalation drug containing 2-5 oligoadenylates for treatment of COVID-19

Interferons (IFN), first described 1957 by Isaacs and Lindemann, are antiviral proteins generated in cells after viral infections. One of several interferon-induced effector mechanisms is the so called 2-5A / RNaseL system: Interferon is produced in the virus-affected cells and released. After binding to cell membrane receptors of adjacent cells, 2-5 A synthetase (oligoadenylate synthetase, OAS) is generated, attaches to dsRNA section areas of the viral RNA and catalyses the production of 2-5 oligoadenylates from ATP. In 2-5 oligoadenylates, several adenosine residues (3–4 and more) are combined via phosphodiester binding in the unusual 2′-5′ positions of the riboses. 2-5 oligoadenylates activate a RNaseL which degrades the viral RNA. Recently, characteristic gene mutations and other disturbances concerning the interferon system were detected in patients with severe COVID-19, leading to problems of 2-5 oligoadenylate synthesis and the activation of RNAseL. In order to circumvent these problems, we hypothesize that a direct application of 2-5 oligoadenylates, included in an inhalation spray, may be effective in treatment of severe COVID-19 infections of the respiratory system. In contrast to some other anti-COVID-19 drugs, oligoadenylates act inside the cells (like e.g. Paxlovid) and are therefore independent of cell surface mutations of the virus. For confirmation of our hypothesis, proof of concept investigations in vitro are suggested, before a possible clinical application can be considered.

Respiratory Rates Derived From Arterial Blood Pressure Waveforms in Telemetered Dogs.

The objective of this study was to extract low frequency respiratory "artifacts" from a standard arterial blood pressure (ABP) waveform to simultaneously derive reliable breathing rates (BR). Arterial blood pressure derived BR values were characterized against respiratory rates simultaneously obtained from the Respiratory Inductive Plethysmography (RIP) system (EMKA). Reference compounds were introduced to evaluate responsiveness of the derived measures to respiratory depressants and stimulants. Male beagle dogs (n = 3) were instrumented with minimally invasive telemetry devices for measurements of ABP and heart rate. The RIP system was utilized simultaneously to collect respiratory rate, tidal volume, and minute volume of each animal following pharmacological challenges. Early results revealed the derived BR's from ABP waveforms did not correlate well with those measured from the RIP system. Post study X-ray visualization revealed suboptimal catheter positioning, causing poor concordance of BR tallied from the ABP waveforms. Follow-up evaluations were conducted using additional animals instrumented with the ABP catheter tip placement advanced proximal to the thoracic diaphragm. Preliminary data from this subset of animals significantly improved the correlation of BR derived from ABP and respiratory rates recorded by the RIP. This proof of concept investigation was intended to evaluate an algorithm designed to extract additional data from routine cardiac waveforms. We clearly demonstrated that with optimal blood pressure catheter placement and acquisition algorithm, a reliable breathing rate can also be extracted from safety studies without the need for additional studies/animals to capture those respiratory end points.

Stimulating and dissecting instrument for transoral endoscopic thyroidectomy: proof of concept investigation.

Intraoperative neuromonitoring (IONM) is a useful adjunct for recurrent laryngeal nerve (RLN) mapping and identification in transoral endoscopic thyroidectomy vestibular approach (TOETVA). This experimental study aimed to investigate the feasibility, safety, thresholds required of an endoscopic forceps that combine the function of surgical dissection and nerve stimulation. Prospective experimental research. TOETVA was performed in 12 piglets, i.e., 24 RLNs and 24 vagal nerves (VN). RLNs electromyography (EMG) was recorded via endotracheal surface electrodes. Baseline EMG of VN and RLN were recorded and compared by (a) percutaneously placed monopolar stimulator probe (Group I), (b) adapted Maryland endoscopic dissector applied on nerves at its tip-end (Group II) and (c) endoscopic dissector tip-lateral applied (Group III). EMG profiles, amplitude, latency, waveform, thresholds and supra-maximal stimulation (5mA) were analyzed. Application of the endoscopic device was feasible in all TOETVA and did not result in any morbidity. 24 RLNs and VNs were detected, stimulated and monitored. With increase of stimulation current, the amplitude of EMG increased, showing a dose-response curve. Mean VN stimulation thresholds were: Group I 0.28mA, Group II 0.56mA, Group III 0.58mA (P1 = 0.00, P2 = 0.00, P3 = 0.11). Minimal current to evoked a maximal VN response was: Group I 0.65mA, Group II 1.07mA and Group III 1.14mA (P1 = 0.00, P2 = 0.00, P3 = 0.48). Minimal current to evoke a RLN maximal response was Group I 0.6mA, Group II 0.95mA and Group III 1.05mA (P1 = 0.00, P2 = 0.00, P3 = 0.31). Latency values were similar to each group. Repetitive (> 10min) supra-maximal (> 5mA) electrical stimulation was safe. The application of endoscopic stimulating dissector is simple, effective and safe way to monitor both VN and RLN function during a TOETVA animal model. It provides surgeons with real-time feedback of EMG response and can be applied as a tool for RLN monitoring. Endoscopic instrument required higher current to evoke EMG response compared to hand probe stimulation. Tip-end required less current to evoke EMG response compared to tip-lateral mode of stimulation.

Proof of concept investigation of unbonded reinforcement in concrete block masonry

The use of grout in conventional reinforced masonry construction increases the cost and time of construction but allows walls subject to out-of-plane loads an enhanced ability to span between lateral support levels. An experimental investigation including a total of 21 walls was conducted in an attempt to identify potential alternatives to conventionally grouted walls. The strength and serviceability of walls containing unbonded reinforcement anchored at its ends was evaluated. All walls were two and a half blocks wide and 14 courses tall and were constructed in running bond using standard 200 mm concrete blocks. Six replicate unreinforced and partially grouted, conventionally reinforced walls served as control specimens. Walls with unbonded reinforcement were determined to be inherently stable with maximum loads approaching those of partially grouted, conventionally reinforced walls. If used in practice, these walls would need to be limited to indoor exposures due to the wide crack widths that develop.

Reactivating the Dormant Motor Cortex After Spinal Cord Injury With EEG Neurofeedback: A Case Study With a Chronic, Complete C4 Patient.

Chronic spinal cord injury (SCI) patients present poor motor cortex activation during movement attempts. The reactivation of this brain region can be beneficial for them, for instance, allowing them to use brain-machine interfaces for motor rehabilitation or restoration. These brain-machine interfacess generally use electroencephalography (EEG) to measure the cortical activation during the attempts of movement, quantifying it as the event-related desynchronization (ERD) of the alpha/mu rhythm. Based on previous evidence showing that higher tonic EEG alpha power is associated with higher ERD, we hypothesized that artificially increasing the alpha power over the motor cortex of these patients could enhance their ERD (ie, motor cortical activation) during movement attempts. We used EEG neurofeedback (NF) to enhance the tonic EEG alpha power, providing real-time visual feedback of the alpha oscillations measured over the motor cortex. This approach was evaluated in a C4, ASIA A, SCI patient (9 months after the injury) who did not present ERD during the movement attempts of his paralyzed hands. The patient performed 4 NF sessions (in 4 consecutive days) and screenings of his EEG activity before and after each session. After the intervention, the patient presented a significant increase in the alpha power over the motor cortex, and a significant enhancement of the mu ERD in the contralateral motor cortex when he attempted to close the assessed right hand. As a proof of concept investigation, this article shows how a short NF intervention might be used to enhance the motor cortical activation in patients with chronic tetraplegia.

Transition from in-hospital ventilation to home ventilation: process description and quality indicators.

The current demographic development of our society results in an increasing number of elderly patients with chronic diseases being treated in the intensive care unit. A possible long-term consequence of such a treatment is that patients remain dependent on certain invasive organ support systems, such as long-term ventilator dependency. The main goal of this project is to define the transition process between in-hospital and out of hospital (ambulatory) ventilator support. A further goal is to identify evidence-based quality indicators to help define and describe this process.This project describes an ideal sequence of processes (process chain), based on the current evidence from the literature. Besides the process chain, key data and quality indicators were described in detail. Due to the limited project timeline, these indicators were not extensively tested in the clinical environment.The results of this project may serve as a solid basis for proof of feasibility and proof of concept investigations, optimize the transition process of ventilator-dependent patients from a clinical to an ambulatory setting, as well as reduce the rate of emergency re-admissions.

Polymeric microcapsules with switchable mechanical properties for self-healing concrete: synthesis, characterisation and proof of concept

Microcapsules, with sodium silicate solution as core, were produced using complex coacervation in a double, oil-in-water-in oil, emulsion system. The shell material was a gelatin–acacia gum crosslinked coacervate and the produced microcapsules had diameters ranging from 300 to 700 μm. The shell material designed with switchable mechanical properties. When it is hydrated exhibits soft and ‘rubbery’ behaviour and, when dried, transitions to a stiff and ‘glassy’ material. The microcapsules survived drying and rehydrating cycles and preserved their structural integrity when exposed to highly alkaline solutions that mimic the pH environment of concrete. Microscopy revealed that the shell thickness of the microcapsules varies across their perimeter from 5 to 20 μm. Thermal analysis showed that the produced microcapsules were very stable up to 190 °C. Proof of concept investigation has demonstrated that the microcapsules successfully survive and function when exposed to a cement-based matrix. Observations showed that the microcapsules survive mixing with cement and rupture successfully upon crack formation releasing the encapsulated sodium silicate solution.

Strategies for electrosynthesis of poly(vinylbenzyltrimethylammonium chloride) and composite films

ABSTRACTPoly(vinylbenzyl trimethyl ammonium chloride) (PVT) exhibits functional properties, which have generated interest in the fabrication of PVT and composite films. New electrochemical strategies have been utilized for the deposition of PVT-zirconia composites. The problems, related to the electrodeposition of strong polyelectrolytes, such as PVT, were addressed by the development of charge compensation mechanisms. The deposition strategies involved electrophoretic cathodic deposition (EPD) of PVT and EPD or electrochemical synthesis of zirconia. The proof of concept investigations involved deposition yield studies under different conditions, Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), differential thermal analysis (DTA), and electron microscopy studies. The electrochemical strategies can be used for electrodeposition of various composites, utilizing the properties of functional polymers and inorganic materials.

Biocompatibility and Biomechanical Effect of Single Wall Carbon Nanotubes Implanted in the Corneal Stroma: A Proof of Concept Investigation.

Corneal ectatic disorders are characterized by a progressive weakening of the tissue due to biomechanical alterations of the corneal collagen fibers. Carbon nanostructures, mainly carbon nanotubes (CNTs) and graphene, are nanomaterials that offer extraordinary mechanical properties and are used to increase the rigidity of different materials and biomolecules such as collagen fibers. We conducted an experimental investigation where New Zealand rabbits were treated with a composition of CNTs suspended in balanced saline solution which was applied in the corneal tissue. Biocompatibility of the composition was assessed by means of histopathology analysis and mechanical properties by stress-strain measurements. Histopathology samples stained with blue Alcian showed that there were no fibrous scaring and no alterations in the mucopolysaccharides of the stroma. It also showed that there were no signs of active inflammation. These were confirmed when Masson trichrome staining was performed. Biomechanical evaluation assessed by means of tensile test showed that there is a trend to obtain higher levels of rigidity in those corneas implanted with CNTs, although these changes are not statistically significant (p > 0.05). Implanting CNTs is biocompatible and safe procedure for the corneal stroma which can lead to an increase in the rigidity of the collagen fibers.

Heart rate variability as a potential indicator of positive valence system disturbance: A proof of concept investigation

One promising avenue toward a better understanding of the pathophysiology of positive emotional disturbances is to examine high-frequency heart rate variability (HRV-HF), which has been implicated as a potential physiological index of disturbances in positive emotional functioning. To date, only a few psychopathology relevant studies have systematically quantified HRV-HF profiles using more ecologically valid methods in everyday life. Using an experience-sampling approach, the present study examined both mean levels and intra-individual variability of HRV-HF – as well as comparison measures of cardiovascular arousal, sympathetic activity, and gross somatic movement – in everyday life, using ambulatory psychophysiological measurement across a six-day consecutive period among a spectrum of community adult participants with varying degrees of positive valence system disturbance, including adults with bipolar I disorder (BD; n=21), major depressive disorder (MDD; n=17), and healthy non-psychiatric controls (CTL; n=28). Groups did not differ in mean HRV-HF, but greater HRV-HF instability (i.e., intra-individual variation in HRV-HF) was found in the BD compared to both MDD and CTL groups. Subsequent analyses suggested that group differences in HRV-HF variability were largely accounted for by variations in clinician-rated manic symptoms. However, no association was found between HRV-HF variability and dimensional measures of positive affectivity. This work provides evidence consistent with a quadratic relationship between HRV-HF and positive emotional disturbance and represents a valuable step toward developing a more ecologically valid model of positive valence system disturbances and their underlying psychophysiological mechanisms within an RDoC framework.

Topological changes of the effective connectivity during the working memory training.

Working memory (WM) refers to the retention of information over a short period of time. Accumulated evidence showed that training WM would lead to beneficial effects in untrained tasks, which could be attributed to the strengthening of the functional connections between brain regions through repeated training task. In this proof of concept investigation, we applied a graph theoretical approach to analyze the early changes of functional connectivity from two subjects undergoing a spatial n-back WM training task for three continuous days. A significant decreased clustering coefficient and normalized shortest path length was revealed, suggesting a reduced local efficiency with an increased global efficiency after WM training. Our findings thereby provide insightful implications for understanding the mechanisms of brain dynamics in cognitive training.

Toward Identification of Molecules in Ill-Defined Hydrocarbons Using Infrared, Raman, and Nuclear Magnetic Resonance (NMR) Spectroscopy

The molecular composition of heavy oil and bitumen is critical for process design calculations and for the selection of production and refining processes, reaction schemes, and conditions that optimize their economic value. These materials remain ill-defined on a molecular basis. For example, diverse molecular structures have been proposed for asphaltenes on the basis of the same physical samples and analytical data [1H and 13C nuclear magnetic resonance (NMR) spectroscopy, mass spectroscopy, and elemental composition]. Molecule construction algorithms appear under constrained by these analytical data, particularly at the molecular subunit length scale (e.g., naphthenic and aromatic groups and aliphatic chains) from both an identification and a mass balance perspective. In this work, we address whether spectral data can provide additional constraints at this length scale that reduces the ambiguity of outcomes from molecule construction algorithms, by making use of spectral data for possible subunits. In this proof of concept investigation, infrared (IR), Raman, and 1H and 13C NMR spectra were computed using density functional theory (DFT) and the B3LYP/6-311G basis set. The molecular subunits present in more than 20 large molecules were probed by spectral subtraction based on spectral contributions from a library of small molecules, because it is at this length scale that the greatest uncertainty in molecule identification and construction algorithms appears to arise. Spectral subtraction using 1H NMR spectroscopy failed to identify molecular subunits in any of the more than 20 large molecules evaluated. 13C NMR spectroscopy identified only 3 large molecules. In contrast, joint use of IR and Raman spectroscopy identified more than 75% of the aromatic subunits present, and naphthenic and aromatic subunits were discriminated. Aliphatic chain length remained poorly defined, and the resulting molecule compositions are qualitative. It is expected that the results of this work will inform molecule construction and identification algorithms for ill-defined hydrocarbons.

Chronic stroke recovery after combined BCI training and physiotherapy: A case report

A case of partial recovery after stroke and its associated brain reorganization in a chronic patient after combined brain computer interface (BCI) training and physiotherapy is presented. A multimodal neuroimaging approach based on fMRI and diffusion tensor imaging was used to investigate plasticity of the brain motor system in parallel with longitudinal clinical assessments. A convergent association between functional and structural data in the ipsilesional premotor areas was observed. As a proof of concept investigation, these results encourage further research on a specific role of BCI on brain plasticity and recovery after stroke.

Oncolytic gene therapy for canine cancers: teaching old dog viruses new tricks

The use of viruses to treat cancer has been studied for decades. With the advancement of molecular biology, viruses have been modified and genetically engineered to optimize their ability to target cancer cells. Canine viruses, such as distemper virus and adenovirus, are being exploited for the treatment of canine cancer as the dog has proven to be a good comparative model for human cancer research and proof of concept investigations. In this review, we introduce the concept of oncolytic viruses and describe some of the preliminary attempts to use oncolytic viruses for the treatment of canine cancer.