Artificial intelligence in the diagnosis and management of arrhythmias.

The field of cardiac electrophysiology (EP) had adopted simple artificial intelligence (AI) methodologies for decades. Recent renewed interest in deep learning techniques has opened new frontiers in electrocardiography analysis including signature identification of diseased states. Artificial intelligence advances coupled with simultaneous rapid growth in computational power, sensor technology, and availability of web-based platforms have seen the rapid growth of AI-aided applications and big data research. Changing lifestyles with an expansion of the concept of internet of things and advancements in telecommunication technology have opened doors to population-based detection of atrial fibrillation in ways, which were previously unimaginable. Artificial intelligence-aided advances in 3D cardiac imaging heralded the concept of virtual hearts and the simulation of cardiac arrhythmias. Robotics, completely non-invasive ablation therapy, and the concept of extended realities show promise to revolutionize the future of EP. In this review, we discuss the impact of AI and recent technological advances in all aspects of arrhythmia care.

Scientific and Regulatory Approach to Botanical Drug Development: A U.S. FDA Perspective.

The United States FDA has received over 800 botanical investigational new drug applications (IND) and pre-IND meeting requests (PIND) in the years preceding 2018. The current data show that indications for submitted INDs cover nearly every review division of the FDA. Despite increasing global interest in the investigation of botanical mixtures as drug products, only two botanical new drug applications (NDA) have been approved in the U.S.: Veregen in 2006 and Fulyzaq (also known as Mytesi) in 2012. Given botanicals' chemical and biological complexity, efforts in characterizing their pharmacology, demonstrating therapeutic efficacy, and ensuring quality consistency remain scientific and regulatory challenges. The FDA published a revised Botanical Drug Development Guidance for Industry document in December 2016 to address developmental considerations for late-phase trials and to provide recommendations intended to facilitate botanical drug development. Herein, we present an analysis of botanical INDs showing their variety of botanical raw materials (e.g., coming from different geographic regions, single vs multiple herbs), the varied levels of previous human experience, and therapeutic areas, as well as provide an overview of experience and challenges in reviewing botanical drugs.

A New Natural Product Analog of Blasticidin S Reveals Cellular Uptake Facilitated by the NorA Multidrug Transporter.

The permeation of antibiotics through bacterial membranes to their target site is a crucial determinant of drug activity but in many cases remains poorly understood. During screening efforts to discover new broad-spectrum antibiotic compounds from marine sponge samples, we identified a new analog of the peptidyl nucleoside antibiotic blasticidin S that exhibited up to 16-fold-improved potency against a range of laboratory and clinical bacterial strains which we named P10. Whole-genome sequencing of laboratory-evolved strains of Staphylococcus aureus resistant to blasticidin S and P10, combined with genome-wide assessment of the fitness of barcoded Escherichia coli knockout strains in the presence of the antibiotics, revealed that restriction of cellular access was a key feature in the development of resistance to this class of drug. In particular, the gene encoding the well-characterized multidrug efflux pump NorA was found to be mutated in 69% of all S. aureus isolates resistant to blasticidin S or P10. Unexpectedly, resistance was associated with inactivation of norA, suggesting that the NorA transporter facilitates cellular entry of peptidyl nucleosides in addition to its known role in the efflux of diverse compounds, including fluoroquinolone antibiotics.

Design and synthesis of small molecule-sulfotyrosine mimetics that inhibit HIV-1 entry.

In the absence of a cure or vaccine for HIV/AIDS, small molecule inhibitors remain an attractive choice for antiviral therapeutics. Recent structural and functional studies of the HIV-1 surface envelope glycoprotein gp120 have revealed sites of vulnerability that can be targeted by small molecule and peptide inhibitors, thereby inhibiting HIV-1 infection. Here we describe a series of small molecule entry inhibitors that were designed to mimic the sulfated N-terminal peptide of the HIV-1 coreceptor CCR5. From a panel of hydrazonothiazolyl pyrazolinones, we demonstrate that compounds containing naphthyl di- and tri-sulfonic acids inhibit HIV-1 infection in single round infectivity assays with the disulfonic acids being the most potent. Molecular docking supports the observed structure activity relationship, and SPR confirmed binding to gp120. In infectivity assays treatment with a representative naphthyl disulfonate and a disulfated CCR5 N-terminus peptide results in competitive inhibition, with combination indices >2. In total this work shows that gp120 and HIV-1 infection can be inhibited by small molecules that mimic the function of, and are competitive with the natural sulfated CCR5 N-terminus.

Development of novel antibacterial agents against methicillin-resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) poses a serious threat to public health because of its resistance to multiple antibiotics most commonly used to treat infection. In this study, we report the unique ability of the cyclooxygenase-2 (COX-2) inhibitor celecoxib to kill Staphylococcus aureus and MRSA with modest potency. We hypothesize that the anti-Staphylococcus activity of celecoxib could be pharmacologically exploited to develop novel anti-MRSA agents with a distinct mechanism. Examination of an in-house, celecoxib-based focused compound library in conjunction with structural modifications led to the identification of compound 46 as the lead agent with high antibacterial potency against a panel of Staphylococcus pathogens and different strains of MRSA. Moreover, this killing effect is bacteria-specific, as human cancer cells are resistant to 46. In addition, a single intraperitoneal administration of compound 46 at 30 mg/kg improved the survival of MRSA-infected C57BL/6 mice. In light of its high potency in eradicating MRSA in vitro and its in vivo activity, compound 46 and its analogues warrant continued preclinical development as a potential therapeutic intervention against MRSA.

Formulation and characterization of curcumin loaded polymeric micelles produced via continuous processing.

A continuous processing platform was developed to produce polymeric micelles. A block copolymer of mPEG (5kD)-PCL (2kD) was used as the model drug carrier. The polymeric micelles were produced using an innovative co-axial turbulent jet with co-flow continuous technology to precisely control the physicochemical properties of the micelles. A 3 × 3 × 4 full factorial design of experiment (DoE) study was conducted to optimize the polymeric micelle processing to achieve the desired critical quality attributes such as particle size and polydispersity index (PDI). Curcumin was used as a hydrophobic model drug as polymeric micelles are traditionally used to improve solubility and chemical stability of hydrophobic drug molecules. A second DoE study was conducted to achieve maximal drug loading. The average size of the optimized curcumin-loaded polymeric micelles was 29.1 ± 0.51 d.nm with a PDI value in the range of 0.05 ± 0.02 and a maximum drug loading of 11.1 ± 0.81% (w/w). When compared to polymeric micelles prepared using a manual ethanol injection method the particle size, PDI and drug loading for curcumin-loaded polymeric micelles was 74.8 ± 8.68 d.nm, and 0.46 ± 0.12 and 8.12 ± 1.23%, respectively. These data show that the continuous processing method provided significant improvement in controlling the key quality attributes. The curcumin-loaded polymeric micelles exhibited a sustained release profile during dissolution of about 50% drug released in 12 h compared to the free drug, which was completely released within 10 h. The curcumin-loaded polymeric micelles were characterized for other key quality attributes such as critical micelle concentration (CMC), and morphology by transmission electron microscopy, X-ray powder crystallography, polarized light microscopy, and differential scanning calorimetry. A novel method for determining the CMC of the polymer was developed using dynamic light scattering (DLS). Curcumin-loaded polymeric micelles were further processed by lyophilization to prevent hydrolytic cleavage of the polymers and maintain long term stability. The current study highlighted the potential advantages of transitioning from manual batch processing to continuous processing and serves as an example of improving processing efficiency as well as product quality through utilization of advanced processing technologies.

A real-time and registration-free framework for dynamic shape instantiation.

Real-time 3D navigation during minimally invasive procedures is an essential yet challenging task, especially when considerable tissue motion is involved. To balance image acquisition speed and resolution, only 2D images or low-resolution 3D volumes can be used clinically. In this paper, a real-time and registration-free framework for dynamic shape instantiation, generalizable to multiple anatomical applications, is proposed to instantiate high-resolution 3D shapes of an organ from a single 2D image intra-operatively. Firstly, an approximate optimal scan plane was determined by analyzing the pre-operative 3D statistical shape model (SSM) of the anatomy with sparse principal component analysis (SPCA) and considering practical constraints. Secondly, kernel partial least squares regression (KPLSR) was used to learn the relationship between the pre-operative 3D SSM and a synchronized 2D SSM constructed from 2D images obtained at the approximate optimal scan plane. Finally, the derived relationship was applied to the new intra-operative 2D image obtained at the same scan plane to predict the high-resolution 3D shape intra-operatively. A major feature of the proposed framework is that no extra registration between the pre-operative 3D SSM and the synchronized 2D SSM is required. Detailed validation was performed on studies including the liver and right ventricle (RV) of the heart. The derived results (mean accuracy of 2.19 mm on patients and computation speed of 1 ms) demonstrate its potential clinical value for real-time, high-resolution, dynamic and 3D interventional guidance.

Probabilistic guidance for catheter tip motion in cardiac ablation procedures.

Radiofrequency catheter ablation is one of the commonly available therapeutic methods for patients suffering from cardiac arrhythmias. The prerequisite of successful ablation is sufficient energy delivery at the target site. However, cardiac and respiratory motion, coupled with endocardial irregularities, can cause catheter drift and dispersion of the radiofrequency energy, thus prolonging procedure time, damaging adjacent tissue, and leading to electrical reconnection of temporarily ablated regions. Therefore, positional accuracy and stability of the catheter tip during energy delivery is of great importance for the outcome of the procedure. This paper presents an analytical scheme for assessing catheter tip stability, whereby a sequence of catheter tip motion recorded at sparse locations on the endocardium is decomposed. The spatial sliding component along the endocardial wall is extracted from the recording and maximal slippage and its associated probability are computed at each mapping point. Finally, a global map is generated, allowing the assessment of potential areas that are compromised by tip slippage. The proposed framework was applied to 40 retrospective studies of congenital heart disease patients and further validated on phantom data and simulations. The results show a good correlation with other intraoperative factors, such as catheter tip contact force amplitude and orientation, and with clinically documented anatomical areas of high catheter tip instability.

Aortic root dynamism, geometry, and function after the remodeling operation: Clinical relevance.

OBJECTIVES: Valve-conserving operations for aneurysms of the ascending aorta and root offer many advantages, and their use is steadily increasing. Optimizing the results of these operations depends on providing the best conditions for normal function and durability of the new root. METHODS: Multimodality imaging including 2-dimensional echocardiography, multislice computed tomography, and cardiovascular magnetic resonance combined with image processing and computational fluid dynamics were used to define geometry, dynamism and aortic root function, before and after the remodeling operation. This was compared with 4 age-matched controls. RESULTS: The size and shape of the ascending aorta, aortic root, and its component parts showed considerable changes postoperatively, with preservation of dynamism. The postoperative size of the aortic annulus was reduced without the use of external bands or foreign material. Importantly, the elliptical shape of the annulus was maintained and changed during the cardiac cycle (Δ ellipticity index was 15% and 28% in patients 1 and 2, respectively). The "cyclic" area of the annulus changed in size (Δarea: 11.3% in patient 1 and 13.1% in patient 2). Functional analysis showed preserved reservoir function of the aortic root, and computational fluid dynamics demonstrated normalized pattern of flow in the ascending aorta, sinuses of Valsalva, and distal aorta. CONCLUSIONS: The remodeling operation results in near-normal geometry of the aortic root while maintaining dynamism of the aortic root and its components. This could have very important functional implications; the influence of these effects on both early- and long-term outcomes needs to be studied further.

Experimental validation of robot-assisted cardiovascular catheterization: model-based versus model-free control.

PURPOSE: In cardiac electrophysiology, a long and flexible catheter is delivered to a cardiac chamber for the treatment of arrhythmias. Although several robot-assisted platforms have been commercialized, the disorientation in tele-operation is still not well solved. We propose a validation platform for robot-assisted cardiac EP catheterization, integrating a customized MR Safe robot, a standard clinically used EP catheter, and a human-robot interface. Both model-based and model-free control methods are implemented in the platform for quantitative evaluation and comparison. METHODS: The model-based and model-free control methods were validated by subject test (ten participants), in which the subjects have to perform a simulated radiofrequency ablation task using both methods. A virtual endoscopic view of the catheter is also provided to enhance hand-to-eye coordination. Assessment indices for targeting accuracy and efficiency were acquired for the evaluation. RESULTS: (1) Accuracy: The average distance measured from catheter tip to the closest lesion target during ablation of model-free method was 19.1% shorter than that of model-based control. (2) Efficiency: The model-free control reduced the total missed targets by 35.8% and the maximum continuously missed targets by 46.2%, both indices corresponded to a low p value ([Formula: see text]). CONCLUSION: The model-free method performed better in terms of both accuracy and efficiency, indicating the model-free control could adapt to soft interaction with environment, as compared with the model-based control that does not consider contacts.

An efficient cardiac mapping strategy for radiofrequency catheter ablation with active learning.

OBJECTIVE: A major challenge in radiofrequency catheter ablation procedures is the voltage and activation mapping of the endocardium, given a limited mapping time. By learning from expert interventional electrophysiologists (operators), while also making use of an active-learning framework, guidance on performing cardiac voltage mapping can be provided to novice operators or even directly to catheter robots. METHODS: A learning from demonstration (LfD) framework, based upon previous cardiac mapping procedures performed by an expert operator, in conjunction with Gaussian process (GP) model-based active learning, was developed to efficiently perform voltage mapping over right ventricles (RV). The GP model was used to output the next best mapping point, while getting updated towards the underlying voltage data pattern as more mapping points are taken. A regularized particle filter was used to keep track of the kernel hyperparameter used by GP. The travel cost of the catheter tip was incorporated to produce time-efficient mapping sequences. RESULTS: The proposed strategy was validated on a simulated 2D grid mapping task, with leave-one-out experiments on 25 retrospective datasets, in an RV phantom using the Stereotaxis Niobe® remote magnetic navigation system, and on a tele-operated catheter robot. In comparison with an existing geometry-based method, regression error was reduced and was minimized at a faster rate over retrospective procedure data. CONCLUSION: A new method of catheter mapping guidance has been proposed based on LfD and active learning. The proposed method provides real-time guidance for the procedure, as well as a live evaluation of mapping sufficiency.

Inhibition of intestinal glucose uptake by aporphines and secoaporphines.

The effects of aporphines and secoaporphines on glucose uptake by isolated intestinal brush-border membrane vesicles (BBMV) or basolateral membrane vesicles (BLMV) and glucose absorption during in situ intestinal perfusion were studied. Of the tested compounds, N-allylsecoboldine was the most potent glucose uptake inhibitor, with IC50 values of 159 microM and 121 microM, respectively, for uptake by BBMV and BLMV. While thaliporphine competitively inhibited glucose uptake by both membrane preparations, inhibition by N-allylsecoboldine was competitive using BBMV and noncompetitive using BLMV. In addition, N-allylsecoboldine significantly reduced both glucose absorption during in situ intestinal perfusion and blood glucose levels in the oral glucose tolerance test. The results demonstrate that levels of both aporphines and secoaporphines achievable by oral administration have an inhibitory effect on intestinal glucose uptake and suggest that the hypoglycemic effects of these compounds merit attention.

Spatial Orientation and Morphology of the Pulmonary Artery: Relevance to Optimising Design and Positioning of a Continuous Pressure Monitoring Device.

Personalised treatment of heart disease requires an understanding of the patient-specific characteristics, which can vary over time. A newly developed implantable surface acoustic wave pressure sensor, capable of continuous monitoring of the left ventricle filling pressure, is a novel device for personalised management of patients with heart disease. However, a one-size-fits-all approach to device sizing will affect its positioning within the pulmonary artery and its relationship to the interrogating device on the chest wall on a patient-specific level. In this paper, we analyse the spatial orientation and morphology of the pulmonary artery and its main branches in patients who could benefit from the device and normal controls. The results could optimise the design of the sensor, its stent, and importantly its placement, ensuring long-term monitoring in patient groups.

Constrained Statistical Modelling of Knee Flexion From Multi-Pose Magnetic Resonance Imaging.

Reconstruction of the anterior cruciate ligament (ACL) through arthroscopy is one of the most common procedures in orthopaedics. It requires accurate alignment and drilling of the tibial and femoral tunnels through which the ligament graft is attached. Although commercial computer-assisted navigation systems exist to guide the placement of these tunnels, most of them are limited to a fixed pose without due consideration of dynamic factors involved in different knee flexion angles. This paper presents a new model for intraoperative guidance of arthroscopic ACL reconstruction with reduced error particularly in the ligament attachment area. The method uses 3D preoperative data at different flexion angles to build a subject-specific statistical model of knee pose. To circumvent the problem of limited training samples and ensure physically meaningful pose instantiation, homogeneous transformations between different poses and local-deformation finite element modelling are used to enlarge the training set. Subsequently, an anatomical geodesic flexion analysis is performed to extract the subject-specific flexion characteristics. The advantages of the method were also tested by detailed comparison to standard Principal Component Analysis (PCA), nonlinear PCA without training set enlargement, and other state-of-the-art articulated joint modelling methods. The method yielded sub-millimetre accuracy, demonstrating its potential clinical value.

WITHDRAWN: Editorial of special issue Computing and Visualisation for Intravascular Imaging.

The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.compmedimag.2014.01.001. The duplicate article has therefore been withdrawn.

Emerging robotic platforms for minimally invasive surgery.

Recent technological advances in surgery have resulted in the development of a range of new techniques that have reduced patient trauma, shortened hospitalization, and improved diagnostic accuracy and therapeutic outcome. Despite the many appreciated benefits of minimally invasive surgery (MIS) compared to traditional approaches, there are still significant drawbacks associated with conventional MIS including poor instrument control and ergonomics caused by rigid instrumentation and its associated fulcrum effect. The use of robot assistance has helped to realize the full potential of MIS with improved consistency, safety and accuracy. The development of articulated, precision tools to enhance the surgeon's dexterity has evolved in parallel with advances in imaging and human-robot interaction. This has improved hand-eye coordination and manual precision down to micron scales, with the capability of navigating through complex anatomical pathways. In this review paper, clinical requirements and technical challenges related to the design of robotic platforms for flexible access surgery are discussed. Allied technical approaches and engineering challenges related to instrument design, intraoperative guidance, and intelligent human-robot interaction are reviewed. We also highlight emerging designs and research opportunities in the field by assessing the current limitations and open technical challenges for the wider clinical uptake of robotic platforms in MIS.

A general framework for context-specific image segmentation using reinforcement learning.

This paper presents an online reinforcement learning framework for medical image segmentation. The concept of context-specific segmentation is introduced such that the model is adaptive not only to a defined objective function but also to the user's intention and prior knowledge. Based on this concept, a general segmentation framework using reinforcement learning is proposed, which can assimilate specific user intention and behavior seamlessly in the background. The method is able to establish an implicit model for a large state-action space and generalizable to different image contents or segmentation requirements based on learning in situ. In order to demonstrate the practical value of the method, example applications of the technique to four different segmentation problems are presented. Detailed validation results have shown that the proposed framework is able to significantly reduce user interaction, while maintaining both segmentation accuracy and consistency.

Learning-based modeling of endovascular navigation for collaborative robotic catheterization.

Despite rapid growth of robot assisted catheterization in recent years, most current platforms are based on master-slave designs with limited operator-robot collaborative control and automation. Under this setup, information concerning subject specific behavior and context-driven manoeuvre is not re-utilized for subsequent intervention. For endovascular catheterization, the robot itself is designed with little consideration of underlying skills and associated motion patterns. This paper proposes a learning-based approach for generating optimum motion trajectories from multiple demonstrations of a catheterization task such that it can be used for automating catheter motion within a collaborative setting. Motion models are generated from experienced manipulation of a catheterization procedure and replicated using a robotic catheter driver to assist inexperienced operators. Catheter tip motions of the automated approach are compared against the manual training sets for validating the proposed framework. The results show significant improvements in the quality of catheterization, which facilitate the design of hands-on collaborative robots that make full use of the natural skills of the operators.

Motion-adapted catheter navigation with real-time instantiation and improved visualisation.

The improvements to catheter manipulation by the use of robot-assisted catheter navigation for endovascular procedures include increased precision, stability of motion and operator comfort. However, navigation through the vasculature under fluoroscopic guidance is still challenging, mostly due to physiological motion and when tortuous vessels are involved. In this paper, we propose a motion-adaptive catheter navigation scheme based on shape modelling to compensate for these dynamic effects, permitting predictive and dynamic navigations. This allows for timed manipulations synchronised with the vascular motion. The technical contribution of the paper includes the following two aspects. Firstly, a dynamic shape modelling and real-time instantiation scheme based on sparse data obtained intra-operatively is proposed for improved visualisation of the 3D vasculature during endovascular intervention. Secondly, a reconstructed frontal view from the catheter tip using the derived dynamic model is used as an interventional aid to user guidance. To demonstrate the practical value of the proposed framework, a simulated aortic branch cannulation procedure is used with detailed user validation to demonstrate the improvement in navigation quality and efficiency.