Haemostatic support in postpartum haemorrhage: A review of the literature and expert opinion.

Postpartum haemorrhage (PPH) remains the leading cause of pregnancy-related deaths worldwide. Typically, bleeding is controlled by timely obstetric measures in parallel with resuscitation and treatment of coagulopathy. Early recognition of abnormal coagulation is crucial and haemostatic support should be considered simultaneously with other strategies as coagulopathies contribute to the progression to massive haemorrhage. However, there is lack of agreement on important topics in the current guidelines for management of PPH. A clinical definition of PPH is paramount to understand the situation to which the treatment recommendations relate; however, reaching a consensus has previously proven difficult. Traditional definitions are based on volume of blood loss, which is difficult to monitor, can be misleading and leads to treatment delay. A multidisciplinary approach to define PPH considering vital signs, clinical symptoms, coagulation and haemodynamic changes is needed. Moreover, standardised algorithms or massive haemorrhage protocols should be developed to reduce the risk of morbidity and mortality and improve overall clinical outcomes in PPH. If available, point-of-care testing should be used to guide goal-directed haemostatic treatment. Tranexamic acid should be administered as soon as abnormal bleeding is recognised. Fibrinogen concentrate rather than fresh frozen plasma should be administered to restore haemostasis where there is elevated risk of fibrinogen deficiency (e.g., in catastrophic bleeding or in cases of abruption or amniotic fluid embolism) as it is a more concentrated source of fibrinogen. Lastly, organisational considerations are equally as important as clinical interventions in the management of PPH and have the potential to improve patient outcomes.

Epidemiology and definition of PPH worldwide.

Postpartum/peripartum hemorrhage (PPH) is an obstetric emergency complicating 1-10% of all deliveries and is a leading cause of maternal mortality and morbidity worldwide. However, the incidence of PPH differs widely according to the definition and criteria used, the way of measuring postpartum blood loss, and the population being studied with the highest numbers in developing countries. Despite all the significant progress in healthcare, the incidence of PPH is rising due to an incomplete implementation of guidelines, resulting in treatment delays and suboptimal care. A consensus clinical definition of PPH is needed to enable awareness, early recognition, and initiation of appropriate intensive treatment. Unfortunately, the most used definition of PPH based on blood loss ≥500 ml after delivery suffers from inaccuracies in blood loss quantification and is not clinically relevant in most cases, as the amount of blood loss does not fully reflect the severity of bleeding.

Embedding Weather Simulation in Auto-Labelling Pipelines Improves Vehicle Detection in Adverse Conditions.

The performance of deep learning-based detection methods has made them an attractive option for robotic perception. However, their training typically requires large volumes of data containing all the various situations the robots may potentially encounter during their routine operation. Thus, the workforce required for data collection and annotation is a significant bottleneck when deploying robots in the real world. This applies especially to outdoor deployments, where robots have to face various adverse weather conditions. We present a method that allows an independent car tansporter to train its neural networks for vehicle detection without human supervision or annotation. We provide the robot with a hand-coded algorithm for detecting cars in LiDAR scans in favourable weather conditions and complement this algorithm with a tracking method and a weather simulator. As the robot traverses its environment, it can collect data samples, which can be subsequently processed into training samples for the neural networks. As the tracking method is applied offline, it can exploit the detections made both before the currently processed scan and any subsequent future detections of the current scene, meaning the quality of annotations is in excess of those of the raw detections. Along with the acquisition of the labels, the weather simulator is able to alter the raw sensory data, which are then fed into the neural network together with the labels. We show how this pipeline, being run in an offline fashion, can exploit off-the-shelf weather simulation for the auto-labelling training scheme in a simulator-in-the-loop manner. We show how such a framework produces an effective detector and how the weather simulator-in-the-loop is beneficial for the robustness of the detector. Thus, our automatic data annotation pipeline significantly reduces not only the data annotation but also the data collection effort. This allows the integration of deep learning algorithms into existing robotic systems without the need for tedious data annotation and collection in all possible situations. Moreover, the method provides annotated datasets that can be used to develop other methods. To promote the reproducibility of our research, we provide our datasets, codes and models online.

Structure of the human NK cell NKR-P1:LLT1 receptor:ligand complex reveals clustering in the immune synapse.

Signaling by the human C-type lectin-like receptor, natural killer (NK) cell inhibitory receptor NKR-P1, has a critical role in many immune-related diseases and cancer. C-type lectin-like receptors have weak affinities to their ligands; therefore, setting up a comprehensive model of NKR-P1-LLT1 interactions that considers the natural state of the receptor on the cell surface is necessary to understand its functions. Here we report the crystal structures of the NKR-P1 and NKR-P1:LLT1 complexes, which provides evidence that NKR-P1 forms homodimers in an unexpected arrangement to enable LLT1 binding in two modes, bridging two LLT1 molecules. These interaction clusters are suggestive of an inhibitory immune synapse. By observing the formation of these clusters in solution using SEC-SAXS analysis, by dSTORM super-resolution microscopy on the cell surface, and by following their role in receptor signaling with freshly isolated NK cells, we show that only the ligation of both LLT1 binding interfaces leads to effective NKR-P1 inhibitory signaling. In summary, our findings collectively support a model of NKR-P1:LLT1 clustering, which allows the interacting proteins to overcome weak ligand-receptor affinity and to trigger signal transduction upon cellular contact in the immune synapse.

Toward Benchmarking of Long-Term Spatio-Temporal Maps of Pedestrian Flows for Human-Aware Navigation.

Despite the advances in mobile robotics, the introduction of autonomous robots in human-populated environments is rather slow. One of the fundamental reasons is the acceptance of robots by people directly affected by a robot's presence. Understanding human behavior and dynamics is essential for planning when and how robots should traverse busy environments without disrupting people's natural motion and causing irritation. Research has exploited various techniques to build spatio-temporal representations of people's presence and flows and compared their applicability to plan optimal paths in the future. Many comparisons of how dynamic map-building techniques show how one method compares on a dataset versus another, but without consistent datasets and high-quality comparison metrics, it is difficult to assess how these various methods compare as a whole and in specific tasks. This article proposes a methodology for creating high-quality criteria with interpretable results for comparing long-term spatio-temporal representations for human-aware path planning and human-aware navigation scheduling. Two criteria derived from the methodology are then applied to compare the representations built by the techniques found in the literature. The approaches are compared on a real-world, long-term dataset, and the conception is validated in a field experiment on a robotic platform deployed in a human-populated environment. Our results indicate that continuous spatio-temporal methods independently modeling spatial and temporal phenomena outperformed other modeling approaches. Our results provide a baseline for future work to compare a wide range of methods employed for long-term navigation and provide researchers with an understanding of how these various methods compare in various scenarios.

Self-Supervised Robust Feature Matching Pipeline for Teach and Repeat Navigation.

The performance of deep neural networks and the low costs of computational hardware has made computer vision a popular choice in many robotic systems. An attractive feature of deep-learned methods is their ability to cope with appearance changes caused by day-night cycles and seasonal variations. However, deep learning of neural networks typically relies on large numbers of hand-annotated images, which requires significant effort for data collection and annotation. We present a method that allows autonomous, self-supervised training of a neural network in visual teach-and-repeat (VT&R) tasks, where a mobile robot has to traverse a previously taught path repeatedly. Our method is based on a fusion of two image registration schemes: one based on a Siamese neural network and another on point-feature matching. As the robot traverses the taught paths, it uses the results of feature-based matching to train the neural network, which, in turn, provides coarse registration estimates to the feature matcher. We show that as the neural network gets trained, the accuracy and robustness of the navigation increases, making the robot capable of dealing with significant changes in the environment. This method can significantly reduce the data annotation efforts when designing new robotic systems or introducing robots into new environments. Moreover, the method provides annotated datasets that can be deployed in other navigation systems. To promote the reproducibility of the research presented herein, we provide our datasets, codes and trained models online.

Contrastive Learning for Image Registration in Visual Teach and Repeat Navigation.

Visual teach and repeat navigation (VT&R) is popular in robotics thanks to its simplicity and versatility. It enables mobile robots equipped with a camera to traverse learned paths without the need to create globally consistent metric maps. Although teach and repeat frameworks have been reported to be relatively robust to changing environments, they still struggle with day-to-night and seasonal changes. This paper aims to find the horizontal displacement between prerecorded and currently perceived images required to steer a robot towards the previously traversed path. We employ a fully convolutional neural network to obtain dense representations of the images that are robust to changes in the environment and variations in illumination. The proposed model achieves state-of-the-art performance on multiple datasets with seasonal and day/night variations. In addition, our experiments show that it is possible to use the model to generate additional training examples that can be used to further improve the original model's robustness. We also conducted a real-world experiment on a mobile robot to demonstrate the suitability of our method for VT&R.

Evaluation of the insertion parameters and complications of the i-gel Plus airway device for maintaining patent airway during planned procedures under general anaesthesia: a protocol for a prospective multicentre cohort study.

INTRODUCTION: Supraglottic airway devices represent a less invasive method of airway management than tracheal intubation during general anaesthesia. Their continued development is focused mainly on improvements in the insertion success rate and minimalisation of perioperative and postoperative complications. The i-gel Plus is a novel, anatomically preshaped supraglottic airway device which achieves a perilaryngeal seal due to a non-inflatable cuff made of a soft thermoplastic elastomer. The purpose of this cohort study is to assess the success rate of the i-gel Plus use during elective procedures under general anaesthesia, its intraoperative performance, and the degree of postoperative complications. METHODS AND ANALYSIS: This is a multicentre, prospective, interventional cohort study. The enrolment will take place in seven centres in four European countries. We plan to enrol 2000 adult patients in total, who are scheduled for elective surgery under general anaesthesia, and with an indication for use of a supraglottic airway device for management of their airway. The study is projected to run over a period of 18 months. The primary outcome of the study is the total success rate of the i-gel Plus insertion in terms of successful ventilation and oxygenation through the device. Secondary outcomes include perioperative parameters, such as insertion time, seal/leak pressures, number of insertion attempts and postoperative adverse events and complications. Postoperative follow-up will be performed at 1 hour, 24 hours in all patients, and for selected patients at 3 and 6 months. ETHICS AND DISSEMINATION: The cohort study has received the following ethical approvals: General University Hospital Prague, University Hospital Olomouc, University Military Hospital Prague, University Hospital Barcelona, University Hospital Lodz, Antrim Area Hospital, Craigavon Area Hospital, Office for Research Ethics Committees Northern Ireland. The results will be published in peer-reviewed journals and presented at relevant anaesthesia conferences. TRIAL REGISTRATION NUMBER: ISRCTN86233693;Pre-results.

Tumor Marker B7-H6 Bound to the Coiled Coil Peptide-Polymer Conjugate Enables Targeted Therapy by Activating Human Natural Killer Cells.

Targeted cancer immunotherapy is a promising tool for restoring immune surveillance and eradicating cancer cells. Hydrophilic polymers modified with coiled coil peptide tags can be used as universal carriers designed for cell-specific delivery of such biologically active proteins. Here, we describe the preparation of pHPMA-based copolymer conjugated with immunologically active protein B7-H6 via complementary coiled coil VAALEKE (peptide E) and VAALKEK (peptide K) sequences. Receptor B7-H6 was described as a binding partner of NKp30, and its expression has been proven for various tumor cell lines. The binding of B7-H6 to NKp30 activates NK cells and results in Fas ligand or granzyme-mediated apoptosis of target tumor cells. In this work, we optimized the expression of coiled coil tagged B7-H6, its ability to bind activating receptor NKp30 has been confirmed by isothermal titration calorimetry, and the binding stoichiometry of prepared chimeric biopolymer has been characterized by analytical ultracentrifugation. Furthermore, this coiled coil B7-H6-loaded polymer conjugate activates NK cells in vitro and, in combination with coiled coil scFv, enables their targeting towards a model tumor cell line. Prepared chimeric biopolymer represents a promising precursor for targeted cancer immunotherapy by activating the cytotoxic activity of natural killer cells.

Epidural fever.

Epidural analgesia (EPA) is the most effective method of intrapartum pain relief and is considered to be very safe. Recently, it has been used in up to 34% of parturients with EPA and is also associated with maternal temperature elevations during labor. The mechanism of this epidural-associated fever remains incompletely understood. The most likely etiology seems to be non-infectious inflammation caused by an epidural catheter. However, some authors deny this association. They theorize it is caused by selection bias only, as EPA is more often required by women with more painful and prolonged or more complicated labor, where temperature elevation is due to other causes. They point out that in some studies, fever was correlated to EPA only with concurrent placental inflammation. Maternal fever, despite the cause, either infectious or non-infectious origin, carries important clinical and public health implications. Further research that evaluates maternal epidural status and its influence on maternal or neonatal fever could improve sepsis evaluation and lead to worldwide decrease of unnecessary antibio-tic exposure.

A Randomized Comparison of Non-Channeled GlidescopeTM Titanium Versus Channeled KingVisionTM Videolaryngoscope for Orotracheal Intubation in Obese Patients with BMI > 35 kg·m-2.

Videolaryngoscopes may improve intubating conditions in obese patients. A total of 110 patients with a body mass index > 35 kg∙m-2 were prospectively randomized to tracheal intubation using non-channeled Glidescope Titanium or channeled King Vision videolaryngoscope. The primary outcome was the time to tracheal intubation. Secondary outcomes included: total success rate, number of attempts, the quality of visualization, peri-procedural and post-proceduralcomplications. Time to the first effective breath was shorter with the King Vision (median; 95% CI)-36; 34-39 s vs. 42; 40-50 in the Glidescope group (p = 0.007). The total success rate was higher in the Glidescope group-100% vs. 89.1% (p = 0.03). There was a higher incidence of moderate and difficult laryngoscopy in the King Vision group. No difference was recorded in first attempt success rates, total number of attempts, use of additional maneuvers, intraoperative trauma, or any significant decrease in SpO2 during intubation. No serious complications were noted and the incidence of postoperative complaints was without difference. Although tracheal intubation with King Vision showed shorter time to the first breath, total success was higher in the Glidescope group, and all but one patients where intubation failed with the KingVision were subsequently intubated with the Glidescope.

Natural Killer Cell Activation Receptor NKp30 Oligomerization Depends on Its N-Glycosylation.

NKp30 is one of the main human natural killer (NK) cell activating receptors used in directed immunotherapy. The oligomerization of the NKp30 ligand binding domain depends on the length of the C-terminal stalk region, but our structural knowledge of NKp30 oligomerization and its role in signal transduction remains limited. Moreover, ligand binding of NKp30 is affected by the presence and type of N-glycosylation. In this study, we assessed whether NKp30 oligomerization depends on its N-glycosylation. Our results show that NKp30 forms oligomers when expressed in HEK293S GnTI- cell lines with simple N-glycans. However, NKp30 was detected only as monomers after enzymatic deglycosylation. Furthermore, we characterized the interaction between NKp30 and its best-studied cognate ligand, B7-H6, with respect to glycosylation and oligomerization, and we solved the crystal structure of this complex with glycosylated NKp30, revealing a new glycosylation-induced mode of NKp30 dimerization. Overall, this study provides new insights into the structural basis of NKp30 oligomerization and explains how the stalk region and glycosylation of NKp30 affect its ligand affinity. This furthers our understanding of the molecular mechanisms involved in NK cell activation, which is crucial for the successful design of novel NK cell-based targeted immunotherapeutics.

Video Laryngoscopic Intubation Using the King VisionTM Laryngoscope in a Simulated Cervical Spine Trauma: A Comparison Between Non-Channeled and Channeled Disposable Blades.

Videolaryngoscopes may reduce cervical spine movement during tracheal intubation in patients with neck trauma. This manikin study aimed to compare the performance of disposable non-channeled and channeled blades of the King Vision™ videolaryngoscope in simulated cervical spine injury. Fifty-eight anesthesiologists in training intubated the TruMan manikin with the neck immobilized using each blade in a randomized order. The primary outcome was the time needed for tracheal intubation, secondary aims included total success rate, the time required for visualization of the larynx, number of attempts, view of the vocal cords, and subjective assessment of both methods. Intubation time with the channeled blade was shorter, with a median time of 13 s (IQR 9-19) vs. 23 s (14.5-37.5), p < 0.001, while times to visualization of the larynx were similar in both groups (p = 0.54). Success rates were similar in both groups, but intubation with the non-channeled blade required more attempts (1.52 vs. 1.05; p < 0.001). The participants scored the intubation features of the channeled blade significantly higher, while visualization features were scored similarly in both groups. Both blades of the King Vision™ videolaryngoscope are reliable intubation devices in a simulated cervical spine injury in a manikin model when inserted by non-experienced operators. The channeled blade allowed faster intubation of the trachea.

Publisher Correction: Production of recombinant soluble dimeric C-type lectin-like receptors of rat natural killer cells.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Cellular Localization of Carbonic Anhydrase Nce103p in Candida albicans and Candida parapsilosis.

Pathogenic yeasts Candida albicans and Candida parapsilosis possess a ß-type carbonic anhydrase Nce103p, which is involved in CO2 hydration and signaling. C. albicans lacking Nce103p cannot survive in low CO2 concentrations, e.g., in atmospheric growth conditions. Candida carbonic anhydrases are orthologous to the Saccharomyces cerevisiae enzyme, which had originally been detected as a substrate of a non-classical export pathway. However, experimental evidence on localization of C. albicans and C. parapsilosis carbonic anhydrases has not been reported to date. Immunogold labeling and electron microscopy used in the present study showed that carbonic anhydrases are localized in the cell wall and plasmatic membrane of both Candida species. This localization was confirmed by Western blot and mass spectrometry analyses of isolated cell wall and plasma membrane fractions. Further analysis of C. albicans and C. parapsilosis subcellular fractions revealed presence of carbonic anhydrases also in the cytosolic and mitochondrial fractions of Candida cells cultivated in shaken liquid cultures, under the atmospheric conditions.

Disruption of the dimerization interface of the sensing domain in the dimeric heme-based oxygen sensor AfGcHK abolishes bacterial signal transduction.

The heme-based oxygen sensor protein AfGcHK is a globin-coupled histidine kinase in the soil bacterium Anaeromyxobacter sp. Fw109-5. Its C-terminal functional domain exhibits autophosphorylation activity induced by oxygen binding to the heme-Fe(II) complex located in the oxygen-sensing N-terminal globin domain. A detailed understanding of the signal transduction mechanisms in heme-containing sensor proteins remains elusive. Here, we investigated the role of the globin domain's dimerization interface in signal transduction in AfGcHK. We present a crystal structure of a monomeric imidazole-bound AfGcHK globin domain at 1.8 Å resolution, revealing that the helices of the WT globin dimer are under tension and suggesting that Tyr-15 plays a role in both this tension and the globin domain's dimerization. Biophysical experiments revealed that whereas the isolated WT globin domain is dimeric in solution, the Y15A and Y15G variants in which Tyr-15 is replaced with Ala or Gly, respectively, are monomeric. Additionally, we found that although the dimerization of the full-length protein is preserved via the kinase domain dimerization interface in all variants, full-length AfGcHK variants bearing the Y15A or Y15G substitutions lack enzymatic activity. The combined structural and biophysical results presented here indicate that Tyr-15 plays a key role in the dimerization of the globin domain of AfGcHK and that globin domain dimerization is essential for internal signal transduction and autophosphorylation in this protein. These findings provide critical insights into the signal transduction mechanism of the histidine kinase AfGcHK from Anaeromyxobacter.

Production of recombinant soluble dimeric C-type lectin-like receptors of rat natural killer cells.

Working at the border between innate and adaptive immunity, natural killer (NK) cells play a key role in the immune system by protecting healthy cells and by eliminating malignantly transformed, stressed or virally infected cells. NK cell recognition of a target cell is mediated by a receptor "zipper" consisting of various activating and inhibitory receptors, including C-type lectin-like receptors. Among this major group of receptors, two of the largest rodent receptor families are the NKR-P1 and the Clr receptor families. Although these families have been shown to encode receptor-ligand pairs involved in MHC-independent self-nonself discrimination and are a target for immune evasion by tumour cells and viruses, structural mechanisms of their mutual recognition remain less well characterized. Therefore, we developed a non-viral eukaryotic expression system based on transient transfection of suspension-adapted human embryonic kidney 293 cells to produce soluble native disulphide dimers of NK cell C-type lectin-like receptor ectodomains. The expression system was optimized using green fluorescent protein and secreted alkaline phosphatase, easily quantifiable markers of recombinant protein production. We describe an application of this approach to the recombinant protein production and characterization of native rat NKR-P1B and Clr-11 proteins suitable for further structural and functional studies.

The influence of mode of anaesthesia for caesarean delivery on neonatal Apgar scores in the Czech Republic and Slovakia: secondary analysis of the results of an international survey in 2015.

AIMS: The purpose of this international survey was to describe the impact of current practices and techniques of caesarean section on the neonatal Apgar score in the Czech Republic (CZE) and Slovakia (SVK). METHODS: All Czech and Slovak departments that provide obstetric anaesthesia were invited to participate in a one-month (November 2015) prospective study that monitored in details all peripartum anaesthetic practices, delivered by anaesthesiologists. Participating centers recorded all data on-line in the CLADE-IS database (Masaryk University, CZE). RESULTS AND DISCUSSIONS: We collected data of 10119 women who delivered 10226 newborns. A caesarean section was recorded in 25.1% of deliveries (CZE 23.2%; SVK 30%). General anaesthesia was used for caesarean section in 37.5% of the cases (CZE 40%, SVK 33%). There was no statistically significant difference in the Apgar score lower than 7 in the 1, 5 or 10 min in groups of general and regional anaesthesia for caesarean section, when only elective sections of in-term babies with birth weight over 2500 g were analyzed. We found no statistically significant differences in the Apgar score in newborns of women intubated for caesarean section in rocuronium (n=21; 2.2%) and suxamethonium (n=889; 93%). CONCLUSION: We found no difference in neonatal outcomes in groups of general and regional anaesthesia for caesarean section when only out-of-risk newborns were analyzed. The risk factors were identified as follows: an acute caesarean section, preterm babies, birth weight less than 2 500 g, born in perinatological center and multiple pregnancy - second baby. TRIAL REGISTRATION: ClinicalTrials.gov (ID: NCT02380586) https://clinicaltrials.gov/ct2/show/NCT02380586.