IMAGINER: improving accuracy with a mixed reality navigation system during placement of external ventricular drains. A feasibility study.

OBJECTIVE: The placement of a ventricular catheter, that is, an external ventricular drain (EVD), is a common and essential neurosurgical procedure. In addition, it is one of the first procedures performed by inexperienced neurosurgeons. With or without surgical experience, the placement of an EVD according to anatomical landmarks only can be difficult, with the potential risk for inaccurate catheter placement. Repeated corrections can lead to avoidable complications. The use of mixed reality could be a helpful guide and improve the accuracy of drain placement, especially in patients with acute pathology leading to the displacement of anatomical structures. Using a human cadaveric model in this feasibility study, the authors aimed to evaluate the accuracy of EVD placement by comparing two techniques: mixed reality and freehand placement. METHODS: Twenty medical students performed the EVD placement procedure with a Cushing's ventricular cannula on the right and left sides of the ventricular system. The cannula was placed according to landmarks on one side and with the assistance of mixed reality (Microsoft HoloLens 2) on the other side. With mixed reality, a planned trajectory was displayed in the field of view that guides the placement of the cannula. Subsequently, the actual position of the cannula was assessed with the help of a CT scan with a 1-mm slice thickness. The bony structure as well as the left and right cannula positions were registered to the CT scan with the planned target point before the placement procedure. CloudCompare software was applied for registration and evaluation of accuracy. RESULTS: EVD placement using mixed reality was easily performed by all medical students. The predefined target point (inside the lateral ventricle) was reached with both techniques. However, the scattering radius of the target point reached through the use of mixed reality (12 mm) was reduced by more than 54% compared with the puncture without mixed reality (26 mm), which represents a doubling of the puncture accuracy. CONCLUSIONS: This feasibility study specifically showed that the integration and use of mixed reality helps to achieve more than double the accuracy in the placement of ventricular catheters. Because of the easy availability of these new tools and their intuitive handling, we see great potential for mixed reality to improve accuracy.

Mixed reality for spine surgery: a step into the future with a human cadaveric accuracy study.

OBJECTIVE: Current application of mixed reality as a navigation aid in the field of spinal navigation points to the potential of this technology in spine surgery. Crucial factors for acceptance include intuitive workflow, system stability, reliability, and accuracy of the method. The authors therefore aimed to investigate the accuracy of the system in visualization of anatomical structures using mixed reality in the example of pedicles of the thoracic spine in a human cadaveric study. Potential difficulties and limitations are discussed. METHODS: CT scans of a human cadaveric spinal column specimen were performed. After segmentation and import into the advanced HoloLens 2 software, the vertebrae were exposed. The vertebral arches were preserved on one side for a landmark-based surface registration, whereas pedicles were exposed on the other side in order to measure and evaluate deviation of the overlay holographs with regard to the exact anatomical structure. Accuracy was measured and statistically evaluated. RESULTS: In this work it was demonstrated that the overlay of the virtual 3D model pedicles with the real anatomical structures with anatomical landmark registration was within an acceptable surgical accuracy with the mean value of 2.1 mm (maximum 3.8 mm, minimum 1.2 mm). The highest accuracy was registered at the medial and lateral pedicle wall, and the measurement results were best in the region of the middle thoracic spine. CONCLUSIONS: The accuracy analysis for mixed reality (i.e., between the virtual and real anatomical situation of the thoracic spine) showed a very good agreement when focus was on the pedicles. This work is thus a rare proof of the precision of segmentation to the potential surgical area. The results encourage researchers to open up mixed reality technology in its development and application for spinal navigation.

Correction: The AGC protein kinase UNICORN controls planar growth by attenuating PDK1 in Arabidopsis thaliana.

[This corrects the article DOI: 10.1371/journal.pgen.1007927.].

The AGC protein kinase UNICORN controls planar growth by attenuating PDK1 in Arabidopsis thaliana.

Tissue morphogenesis critically depends on the coordination of cellular growth patterns. In plants, many organs consist of clonally distinct cell layers, such as the epidermis, whose cells undergo divisions that are oriented along the plane of the layer. The developmental control of such planar growth is poorly understood. We have previously identified the Arabidopsis AGCVIII-class protein kinase UNICORN (UCN) as a central regulator of this process. Plants lacking UCN activity show spontaneous formation of ectopic multicellular protrusions in integuments and malformed petals indicating that UCN suppresses uncontrolled growth in those tissues. In the current model UCN regulates planar growth of integuments in part by directly repressing the putative transcription factor ABERRANT TESTA SHAPE (ATS). Here we report on the identification of 3-PHOSPHOINOSITIDE-DEPENDENT PROTEIN KINASE 1 (PDK1) as a novel factor involved in UCN-mediated growth control. PDK1 constitutes a basic component of signaling mediated by AGC protein kinases throughout eukaryotes. Arabidopsis PDK1 is implied in stress responses and growth promotion. Here we show that loss-of-function mutations in PDK1 suppress aberrant growth in integuments and petals of ucn mutants. Additional genetic, in vitro, and cell biological data support the view that UCN functions by repressing PDK1. Furthermore, our data indicate that PDK1 is indirectly required for deregulated growth caused by ATS overexpression. Our findings support a model proposing that UCN suppresses ectopic growth in integuments through two independent processes: the attenuation of the protein kinase PDK1 in the cytoplasm and the repression of the transcription factor ATS in the nucleus.

Evaluation of bismuth-based dispersion energy donors - synthesis, structure and theoretical study of 2-biphenylbismuth(iii) derivatives.

A series of 2-biphenyl bismuth(iii) compounds of the type (2-PhC6H4)3-nBiXn [n = 0 (1); n = 1, X = Cl (2), Br (3), I (4), Me (5); n = 2, X = Cl (6), Br (7), I (8)] has been synthesized and analyzed with focus on intramolecular London dispersion interactions. The library of the compounds was set up in order to investigate the Biπ arene interaction by systematic variation of X. The structural analysis in the solid state revealed that the triarylbismuth(iii) compound 1 shows an encapsulation of the metal atom but the distances between the bismuth atom and the phenyl centroids amount to values close to or larger than 4.0 Å, which is considered to be a rather week dispersion interaction. In the case of monomeric diorganobismuth(iii) compounds 2-5 the moderate crowding effectively hinders the formation of intermolecular donor-acceptor interactions, but allows for intramolecular dispersion-type interactions with the 2-biphenyl ligand. In contrast, the structures of the monoorganobismuth compounds 6-8 show the formation of Bi-XBi donor-acceptor bonds leading to the formation of 1D ribbons in the solid state. These coordination bonds are accompanied by intermolecular dispersion interactions with BiPhcentroid distances < 4.0 Å. In solution the diorganobismuth(iii) halides 2-4 show a broadening of their NMR signals (H-8, H-8' and H-9, H-9' protons of the 2-biphenyl ligand), which is a result of dynamic processes including ligand rotation. For further elucidation of these processes compounds 2, 4 and 7 were studied by temperature-dependent NMR spectroscopy. Electronic structure calculations at the density functional theory and DLPNO-coupled cluster level of theory were applied to investigate and quantify the intramolecular London dispersion interactions, in an attempt to distinguish between basic intramolecular interactions and packing effects and to shed light on the dynamic behavior in solution.

Metazoan Hsp70 machines use Hsp110 to power protein disaggregation.

Accumulation of aggregation-prone misfolded proteins disrupts normal cellular function and promotes ageing and disease. Bacteria, fungi and plants counteract this by solubilizing and refolding aggregated proteins via a powerful cytosolic ATP-dependent bichaperone system, comprising the AAA+ disaggregase Hsp100 and the Hsp70-Hsp40 system. Metazoa, however, lack Hsp100 disaggregases. We show that instead the Hsp110 member of the Hsp70 superfamily remodels the human Hsp70-Hsp40 system to efficiently disaggregate and refold aggregates of heat and chemically denatured proteins in vitro and in cell extracts. This Hsp110 effect relies on nucleotide exchange, not on ATPase activity, implying ATP-driven chaperoning is not required. Knock-down of nematode Caenorhabditis elegans Hsp110, but not an unrelated nucleotide exchange factor, compromises dissolution of heat-induced protein aggregates and severely shortens lifespan after heat shock. We conclude that in metazoa, Hsp70-Hsp40 powered by Hsp110 nucleotide exchange represents the crucial disaggregation machinery that reestablishes protein homeostasis to counteract protein unfolding stress.

Evolution around the Red Sea: Systematics and biogeography of the agamid genus Pseudotrapelus (Squamata: Agamidae) from North Africa and Arabia.

Since the Oligocene, regions adjacent to the Red Sea have experienced major environmental changes, from tectonic movements and continuous geological activity to shifting climatic conditions. The effect of these events on the distribution and diversity of the regional biota is still poorly understood. Agamid members of the genus Pseudotrapelus are diurnal, arid-adapted lizards distributed around the Red Sea from north-eastern Africa, across the mountains and rocky plateaus of the Sinai and Arabian Peninsulas northwards to Syria. Despite recent taxonomic work and the interest in the group as a model for studying biogeographic and diversity patterns of the arid areas of North Africa and Arabia, its taxonomy is poorly understood and a comprehensive phylogeny is still lacking. In this study, we analyzed 92 Pseudotrapelus specimens from across the entire distribution range of the genus. We included all known species and subspecies, and sequenced them for mitochondrial (16S, ND4 and tRNAs) and nuclear (MC1R, c-mos) markers. This enabled us to obtain the first time-calibrated molecular phylogeny of the genus, using gene trees, species trees and coalescent-based methods for species delimitation. Our results revealed Pseudotrapelus as a monophyletic genus comprised of two major clades and six independently evolving lineages. These lineages correspond to the five currently recognized species and a sixth lineage relating to the synonymized P. neumanni. The subspecific validity of P. sinaitus werneri needs further assessment as it does not form a distinct cluster relative to P. s. sinaitus. The onset of Pseudotrapelus diversification is estimated to have occurred in Arabia during the late Miocene. Radiation has likely resulted from vicariance and dispersal events due to the continued geological instability, sea level fluctuations and climatic changes within the region.

Antimicrobial Efficacy of a Historical High-Frequency Plasma Apparatus in Comparison With 2 Modern, Cold Atmospheric Pressure Plasma Devices.

BACKGROUND: Today, highly sophisticated devices deliver cold atmospheric pressure plasma (CAPP) with a multitude of bioactive properties, opening the window to a new medical field: plasma medicine. Different techniques to create the optimal plasma device for different medical indications are currently being explored. However, even a 100 years ago, CAPP was briefly used in the related form of high-frequency therapy. The objective of our study was to compare historic with modern techniques regarding antimicrobial efficacy. METHODS: First, 26 different clinical isolates of relevant wound pathogens were treated in vitro with a historic violet wand (VW) and 2 modern plasma sources (kINPen 09 and dielectric barrier discharge [DBD]) and the obtained inhibition areas (IAs) were compared. Second, a biofilm model was used to compare biofilm inactivation by VW, DBD, ethanol, and polyhexanide treatment. RESULTS: DBD with the largest electrode produced the largest IAs. VW showed results similar to 2 different modes of the kINPen 09. IAs of VW were enlargeable by attaching a larger electrode. Against biofilms, VW was less effective than DBD but more effective than ethanol 70% and polyhexanide. CONCLUSION: The proven antimicrobial efficacy of VW may encourage the development of new, potent plasma devices based on the very simple and inexpensive technique of the historic high-frequency apparatus.

NextLens-The Next Generation of Surgical Navigation: Proof of Concept of an Augmented Reality System for Surgical Navigation.

Objective The aim of this work was the development of an augmented reality system including the functionality of conventional surgical navigation systems. Methods An application software for the Augmented Reality System HoloLens 2 from Microsoft was developed. It detects the position of the patient as well as position of surgical instruments in real time and displays it within the two-dimensional (2D) magnetic resonance imaging or computed tomography (CT) images. The surgical pointer instrument, including a pattern that is recognized by the HoloLens 2 sensors, was created with three-dimensional (3D) printing. The technical concept was demonstrated at a cadaver skull to identify anatomical landmarks. Results With the help of the HoloLens 2 and its sensors, the real-time position of the surgical pointer instrument could be shown. The position of the 3D-printed pointer with colored pattern could be recognized within 2D-CT images when stationary and in motion at a cadaver skull. Feasibility could be demonstrated for the clinical application of transsphenoidal pituitary surgery. Conclusion The HoloLens 2 has a high potential for use as a surgical navigation system. With subsequent studies, a further accuracy evaluation will be performed receiving valid data for comparison with conventional surgical navigation systems. In addition to transsphenoidal pituitary surgery, it could be also applied for other surgical disciplines.

Comparison between cold plasma, electrochemotherapy and combined therapy in a melanoma mouse model.

The study was undertaken to compare antitumor efficacy of electrochemotherapy (ECT) with cold plasma therapy (CP) in a melanoma mouse model. After melanoma implantation into the flank of C57BL/6N mice, CP by two different plasma sources (APPJ and DBD) was applied directly to the tumor surface. ECT was performed with bleomycin intravenously at a field strength of 1000 V/cm without or combined with CP. Primary endpoints were tumor growth acceleration (TGA), daily volume progression (DVP) and survival after treatment. Both plasma sources as single treatment showed a significant TGA delay, which proved less effective than ECT. CP (APPJ) combined with ECT (ECJ) significantly improved per cent mouse survival, with significant superiority compared with ECT. Plasma therapy alone albeit less effective seems a potential alternative to ECT in patients with melanoma and can be applied manifold in a session without general anaesthesia. Accordingly, CP alone and combined with ECT may serve as new option in palliative skin melanoma therapy.

Triple swabbing allows sensitive MRSA detection in dermatologic patients of a university tertiary care hospital.

BACKGROUND: To optimize preventive measures to control MRSA, we investigated retrospectively the suitability of a multiple site screening model and the optimal sampling technique to detect MRSA in a university-based phlebology and skin cancer center in Germany. PATIENTS AND METHODS: During 4.5 years samples of 3 712 inpatients in a dermatologic department were analyzed for MRSA by conventional microbiologic cultures and in parallel by PCR. Samples were taken from nares, wounds and skin lesions. RESULTS: MRSA was detected in 60 inpatients (1.6%). 268 of 7 269 (3.7%) samples at admission and during hospital stay were found positive ñ 96 (35.8%) of these were swabs of nares, 59 (22.0%) surveillance swabs, 53 (19.8%) wound swabs and 42 (15.7%) from other dermatologic lesions. Twenty-five of 60 patients (41.7%) were found positive only in the nares, 10 (16.7%) patients only in wounds and 4 (6.7%) patients only in lesions. 166 (61.9%) of all positive culture samples became positive 24 hours after cultivation, 86 (32.1%) after 48 hours, and 16 (6.0%) after 72 hours. CONCLUSIONS: Highest sensitivity to detect MRSA can be reached by combining three swabs: nares, wounds and skin lesions (ìtriple-testî). Culture of screening specimens for 72 hours is recommended.

Development of 3D printed patient-specific skull implants based on 3d surface scans.

Sometimes cranioplasty is necessary to reconstruct skull bone defects after a neurosurgical operation. If an autologous bone is unavailable, alloplastic materials are used. The standard technical approach for the fabrication of cranial implants is based on 3D imaging by computed tomography using the defect and the contralateral site. A new approach uses 3D surface scans, which accurately replicate the curvature of the removed bone flap. For this purpose, the removed bone flap is scanned intraoperatively and digitized accordingly. When using a design procedure developed for this purpose creating a patient-specific implant for each bone flap shape in short time is possible. The designed skull implants have complex free-form surfaces analogous to the curvature of the skull, which is why additive manufacturing is the ideal manufacturing technology here. In this study, we will describe the intraoperative procedure for the acquisition of scanned data and its further processing up to the creation of the implant.

Development of an individual helmet orthosis for infants based on a 3D scan.

An early childhood skull deformity can have long-term health and aesthetic consequences for the growing toddler. Individual helmet therapy aims at a healthy growth of the skull shape, although not every helmet shape guarantees an optimal result. To ensure an optimal fit, a scanning procedure based on a hand-held surface scanner was evaluated.The new helmet orthosis has an inner layer adapted to the shape of the head, which can be exchanged depending on the growth stage without changing the outer layer.In collaboration with surgeons and engineers, a new helmet orthosis concept was developed that is intended to offer improvements in wearing comfort, overall weight, fit and user-friendliness compared to conventional systems. In the course of the development process and in constant exchange with parents, a multi-layer helmet system with generous perforations was created using additive manufacturing processes. The new helmet shape promises easier handling, especially through the closure system.The helmet shape developed in this study is of high quality, especially in terms of fitting accuracy. Unpleasant perspiration is significantly reduced. The integration of the closure as a direct component of the helmet represents a secure closure option.

A new concept for expansion screws on the cervical spine using shape memory alloy - a feasibility study.

BACKGROUND: In general, sufficient anchoring of screws in the bone material ensures the intended primary stability. METHODS: Shape memory materials offers the option of using temperature-associated deformation energy in a targeted manner in order to do justice to the special situation of osteoporotic bones or the potential lack of anchoring. An expansion screw was developed that takes this possibility and these requirements into account. Using finite element analysis, the variability of screw configuration and actuator was assessed from shape memory. In particular, the dimensioning of the screw slot, the actuator length and the actuator diameter as well as the angle of attack in relation to the intended force development were considered. RESULTS: As a result of the finite element analysis, a special configuration of expansion screw and shape memory element could be found. Accordingly, with an optimal screw diameter of 4 mm, an actuator diameter of 0.8 mm, a screw slot of 7.8 mm in length and an angle of attack of 25 degrees, the best compromise between individual components and high efficiency in favor of maximum strength can be predicted. CONCLUSION: Shape memory material offers the possibility of using completely new forms of power development. By skillfully modifying the mechanical and shape memory elements, their interaction results in a calculated development of force in favor of a high primary stability of the screw material used. Activation by means of body temperature is a very elegant way of initializing the intended locking and screw strength.

Development of a 3D-printed, patient-specific stereotactic system for bihemispheric deep brain stimulation.

The aim of the project was to develop a patient-specific stereotactic system that allows simultaneous and thus time-saving treatment of both cerebral hemispheres and that contains all spatial axes and can be used as a disposable product. Furthermore, the goal was to reduce the size and weight of the stereotactic system compared to conventional systems to keep the strain on the patient, who is awake during the operation, to a minimum. In addition, the currently mandatory computed tomography should be avoided in order not to expose the patient to harmful X-ray radiation as well as to eliminate errors in the fusion of CT and MRI data.3D printing best meets the requirements in terms of size and weight: on the one hand, the use of plastic has considerable potential for weight reduction. On the other hand, the free choice of the individual components offers the possibility to optimize the size and shape of the stereotactic system and to adapt it to the individual circumstances while maintaining the same precision. The all-in-one stereotactic system was produced by means of the Multi Jet Fusion process. As a result, the components are highly precise, stable in use, lightweight and sterilizable. The number of individual components and interfaces, which in their interaction are potential sources of error, was significantly reduced. In addition, on-site manufacturing leads to faster availability of the system.Within the project, a patient-specific stereotaxy system was developed, printed, and assembled, which enables the execution of deep brain stimulation via only three bone anchors located on the skull. Pre-developed MRI markers, which can be screwed directly onto the bone anchors via the sleeves, eliminate the need for a CT scan completely. The fusion of the data, which is no longer required, suggests an improvement in target accuracy.

Mechanistic assessment and ablation of left ventricular assist device related ventricular tachycardia in patients with severe heart failure.

Aims: Left-ventricular-assist-devices (lvad) are an established treatment for patients with severe heart failure with reduced ejection fraction (HF) and reduce mortality. However, HF patients have significant substrate for ventricular tachycardia (VT) and the lvad itself might be pro-arrhythmogenic. We investigated the mechanism of VT in lvad-patients in relation to the underlying etiology and provide in silico and ex-vivo data for ablation in these HF patients. Methods and Results: We retrospectively analyzed invasive electrophysiological (EP) studies of 17 patients with VT and lvad. The mechanism of VT was determined using electroanatomical, entrainment and activation time mapping. Ischemic cardiomyopathy was present in 70% of patients. VT originated from the lvad region in >30%. 1/6 patients with VT originating from the lvad region had episodes before lvad implantation, while 7/11 patients with VT originating from other regions had episodes before implantation. Number and time of radiofrequency (RF)-ablation lesions were not different between VTs originating from the lvad or other regions. Long-term freedom from VT was 50% upon ablation in patients with VT originating from the lvad region and 64% if ablation was conducted in other regions. To potentially preemptively mitigate lvad related VT in patients undergoing lvad implantation, we obtained in silico derived data and performed ex-vivo experiments targeting ventricular myocardium. Of the tested settings, application of 25 W for 30 s was safe and associated with optimal lesion characteristics. Conclusion: A significant percentage of patients with lvad undergoing VT ablation exhibit arrhythmia originating in close vicinity to the device and recurrence rates are high. Based on in silico and ex-vivo data, we propose individualized RF-ablation in selected patients at risk for/with lvad related VT.

Cold plasma is well-tolerated and does not disturb skin barrier or reduce skin moisture.

BACKGROUND: Cold plasma, a new treatment principle in dermatology based on ionic discharge delivering reactive molecular species and UV-light, exhibits strong antimicrobial efficacy in vitro and in vivo. Before implementing plasma as new medical treatment tool, its safety must be proven, as well as assessing skin tolerance and patient acceptance. PATIENTS AND METHODS: We investigated the plasma effects of three different plasma sources (pulsed, non-pulsed atmospheric pressure plasma jet (APPJ) and a dielectric barrier discharge (DBD)) on the transepidermal water loss (TEWL) and skin moisture after treating the fingertips of four healthy male volunteers. RESULTS: TEWL values were reduced by pulsed APPJ and DBD by about 20% but increased after non-pulsed APPJ by 5-20%. TEWL values normalized 30 min after all forms of plasma treatment. Skin moisture was increased immediately and 30 min after treatment with pulsed APPJ but was not affected by non-pulsed APPJ and DBD. CONCLUSIONS: All plasma treatments were well-tolerated and did not damage the skin barrier nor cause skin dryness. Cold plasma fulfils basic recommendations for safe use on human skin and as future option may serve as the first physical skin antiseptic.

Cytopathic effects of the cytomegalovirus-encoded apoptosis inhibitory protein vMIA.

Replication of human cytomegalovirus (CMV) requires the expression of the viral mitochondria-localized inhibitor of apoptosis (vMIA). vMIA inhibits apoptosis by recruiting Bax to mitochondria, resulting in its neutralization. We show that vMIA decreases cell size, reduces actin polymerization, and induces cell rounding. As compared with vMIA-expressing CMV, vMIA-deficient CMV, which replicates in fibroblasts expressing the adenoviral apoptosis suppressor E1B19K, induces less cytopathic effects. These vMIA effects can be separated from its cell death-inhibitory function because vMIA modulates cellular morphology in Bax-deficient cells. Expression of vMIA coincided with a reduction in the cellular adenosine triphosphate (ATP) level. vMIA selectively inhibited one component of the ATP synthasome, namely, the mitochondrial phosphate carrier. Exposure of cells to inhibitors of oxidative phosphorylation produced similar effects, such as an ATP level reduced by 30%, smaller cell size, and deficient actin polymerization. Similarly, knockdown of the phosphate carrier reduced cell size. Our data suggest that the cytopathic effect of CMV can be explained by vMIA effects on mitochondrial bioenergetics.

Fast filtration for metabolome sampling of suspended animal cells.

A new method for sampling suspended animal cells by fast filtration is presented that allows rapid quenching of cellular metabolism and efficient separation of the cells from culture medium. Compared to sampling with a microstructure heat exchanger or centrifugation without prior quenching, the adenylate energy charge and the measured concentrations especially of metabolites with a high turnover rate or of metabolites early in metabolic pathways were substantially higher. No leakage of ATP from the cells was observed when using iso-osmotic NaCl solution in the washing step. The combination of fast filtration and cold methanol extraction is therefore suitable for intracellular metabolomic studies of suspended animal cell cultures and superior to other methods currently applied.