Multimodal deep learning for personalized renal cell carcinoma prognosis: Integrating CT imaging and clinical data.

BACKGROUND AND OBJECTIVE: Renal cell carcinoma represents a significant global health challenge with a low survival rate. The aim of this research was to devise a comprehensive deep-learning model capable of predicting survival probabilities in patients with renal cell carcinoma by integrating CT imaging and clinical data and addressing the limitations observed in prior studies. The aim is to facilitate the identification of patients requiring urgent treatment. METHODS: The proposed framework comprises three modules: a 3D image feature extractor, clinical variable selection, and survival prediction. Based on the 3D CNN architecture, the feature extractor module predicts the ISUP grade of renal cell carcinoma tumors linked to mortality rates from CT images. Clinical variables are systematically selected using the Spearman score and random forest importance score as criteria. A deep learning-based network, trained with discrete LogisticHazard-based loss, performs the survival prediction. Nine distinct experiments are performed, with varying numbers of clinical variables determined by different thresholds of the Spearman and importance scores. RESULTS: Our findings demonstrate that the proposed strategy surpasses the current literature on renal cancer prognosis based on CT scans and clinical factors. The best-performing experiment yielded a concordance index of 0.84 and an area under the curve value of 0.8 on the test cohort, which suggests strong predictive power. CONCLUSIONS: The multimodal deep-learning approach developed in this study shows promising results in estimating survival probabilities for renal cell carcinoma patients using CT imaging and clinical data. This may have potential implications in identifying patients who require urgent treatment, potentially improving patient outcomes. The code created for this project is available for the public on: GitHub.

The End-to-End Molecular Communication Model of Extracellular Vesicle-Based Drug Delivery.

A closer look at nature has recently brought more interest in exploring and utilizing intra-body communication networks composed of cells as intrinsic, perfectly biocompatible infrastructures to deliver therapeutics. Naturally occurring cell-to-cell communication systems are being manipulated to release, navigate, and take-up soluble cell-derived messengers that are either therapeutic by nature or carry therapeutic molecular cargo. One example of such structures is extracellular vesicles (EVs) which have been recently proven to have pharmacokinetic properties, opening new avenues for developing the next generation biotherapeutics. In this paper, we study theoretical aspects of the EV transfer within heart tissue as a case study by utilizing an information and communication technology-like approach in analyzing molecular communication systems. Our modeling implies the abstraction of the EV releasing cells as transmitters, the extracellular matrix as the channel, and the EV receiving cells as receivers. Our results, derived from the developed analytical models, indicate that the release can be modulated using external forces such as electrical signals, and the transfer and reception can be affected by the extracellular matrix and plasma membrane properties, respectively.The presented modeling provides initial results for the EV biodistributions and contribute to avoiding unplanned administration, often resulting in side- and adverse effects.

Regional Left Ventricular Fiber Stress Analysis for Cardiac Resynchronization Therapy Response.

Cardiac resynchronization therapy (CRT) is an effective treatment for a subgroup of heart failure (HF) patients, but more than 30% of those selected do not improve after CRT implantation. Imperfect pre-procedural criteria for patient selection and optimization are the main causes of the high non-response rate. In this study, we evaluated a novel measure for assessing CRT response. We used a computational modeling framework to calculate the regional stress of the left ventricular wall of seven CRT patients and seven healthy controls. The standard deviation of regional wall stress at the time of mitral valve closure (SD_MVC) was used to quantify dyssynchrony and compared between patients and controls and among the patients. The results show that SD_MVC is significantly lower in controls than patients and correlates with long-term response in patients, based on end-diastolic volume reduction. In contrast to our initial hypothesis, patients with lower SD_MVC respond better to therapy. The patient with the highest SD_MVC was the only non-responder in the patient cohort. The distribution of fiber stress at the beginning of the isovolumetric phase seems to correlate with the degree of response and the use of this measurement could potentially improve selection criteria for CRT implantation. Further studies with a larger cohort of patients are needed to validate these results.

On the Occasion of 70th Anniversary of Life and 45 Years of Academic Work of Academician Izet Masic.

In the hilly Balkans, a folk proverb has been circulating for a long time, "It is most difficult to be a prophet in one's own village", which reflects the age-old mistrust of the population towards new ideas. This is not surprising in the least, because since the written history of the peoples of the Balkans has existed, a continuous series of conquerors and local rulers who subjugated the common folks and imposed their world view can be traced. Nevertheless, from time to time, people with great strength appear who not only break the shackles imposed by the powerful, but through their actions find a way to the souls of their compatriots and gain their unreserved trust. One of such spontaneous creators is professor Izet Masic, who achieved a miracle of medical publishing in his Sarajevo and Bosnia and Herzegovina and traced the path of medical science. There may be thousands of medical journals in the world, more or less reputable, and researchers from the Balkans can publish their work in them, but only domestic medical journals can initiate and direct domestic medical research, and educate young researchers in the right way. Professor Masic made it possible for authors from Bosnia and Herzegovina and other Balkan countries to present their results to the world and receive an incentive from impartial experts to continue their work and progress more and more by editing and publishing three domestic journals at once, which are visible in the most important world bases,. The progress in research then translated into improving medical practice and health care of the population. The following details from Professor Masic's biography tell us how this miracle happened. This year, academician Izet Masic, Editor-in-Chief of a few biomedical journals, including Acta Informatica Medica journal, celebrates his 70th birthday and also 45 years of his academic and scientific work.

Implants with Sensing Capabilities.

Because of the aging human population and increased numbers of surgical procedures being performed, there is a growing number of biomedical devices being implanted each year. Although the benefits of implants are significant, there are risks to having foreign materials in the body that may lead to complications that may remain undetectable until a time at which the damage done becomes irreversible. To address this challenge, advances in implantable sensors may enable early detection of even minor changes in the implants or the surrounding tissues and provide early cues for intervention. Therefore, integrating sensors with implants will enable real-time monitoring and lead to improvements in implant function. Sensor integration has been mostly applied to cardiovascular, neural, and orthopedic implants, and advances in combined implant-sensor devices have been significant, yet there are needs still to be addressed. Sensor-integrating implants are still in their infancy; however, some have already made it to the clinic. With an interdisciplinary approach, these sensor-integrating devices will become more efficient, providing clear paths to clinical translation in the future.

Robot-assisted magnetic capsule endoscopy; navigating colorectal inclinations.

Purpose: To investigate the interaction of a robot assisted magnetically driven wireless capsule endoscope (WCE) with colonic tissue, as it traverses the colorectal bends in the dorsal and ventral directions, relying only on the feedback from a 3D accelerometer. We also investigate the impact of shell geometry and water insufflation on WCE locomotion.Methods: A 3D printed incline phantom, lined with porcine colon, was used as the experimental platform, for controlled and repeatable results. The tilt angle of WCE was controlled to observe its influence on WCE locomotion. The phantom was placed underwater to observe the effects of water insufflation. The experiments were repeated using the two capsule shell geometries to observe the effect of shell geometry on WCE locomotion.Results: Friction between WCE and intestinal tissue increased when the tilt angle of the WCE was lower than the angle of the incline of the phantom. Increasing the WCE tilt angle to match the angle of the incline reduced this friction. Water insufflation and elliptical capsule shell geometry reduced the friction further.Conclusion: Tilting of the WCE equal to, or more than the angle of the incline improved the WCE locomotion. WCE locomotion was also improved by using elliptical capsule shell geometry and water insufflation.Abbreviations: CRC: colorectal cancer; GI: gastrointestinal; MRI: magnetic resonance imaging; WCE: wireless capsule endoscope.

Targeted Drug Delivery for Cardiovascular Disease: Modeling of Modulated Extracellular Vesicle Release Rates.

Invasive and medical therapy has led to major improvements in cardiovascular disease management, but important challenges remain open. The discovery of a nano-sized system of extracellular vesicles (EVs) is opening new possibilities for reprogramming malfunctioning cells and indicates that EVs can be employed in therapeutic biomedical applications as engineered drug vehicles. Molecular communication (MC) has applications for treating cells with directed drug delivery, employing special targeting transmembrane proteins. In this paper, we propose a novel drug delivery system for cardiovascular diseases using an EV-mediated MC platform and exemplify the potential use in hypertrophic cardiomyopathy. We utilize intracellular calcium signaling as a natural mediator of EVs released from synthetic cells and model the release rate. We propose to use the cells as a therapeutic release system with a control signal input which modulates the EVs release rate as the output signal. We also study the frequency domain of the proposed model and estimate the transfer function of the therapeutic release system model numerically where the root-mean-square error for two separate estimated output signals are 0.0353 and 0.0124. The proposed EV-mediated targeted drug delivery system can make breakthroughs in future healthcare, in cardiovascular and other diseases where targeting is required.

Toward real-time polyp detection using fully CNNs for 2D Gaussian shapes prediction.

To decrease colon polyp miss-rate during colonoscopy, a real-time detection system with high accuracy is needed. Recently, there have been many efforts to develop models for real-time polyp detection, but work is still required to develop real-time detection algorithms with reliable results. We use single-shot feed-forward fully convolutional neural networks (F-CNN) to develop an accurate real-time polyp detection system. F-CNNs are usually trained on binary masks for object segmentation. We propose the use of 2D Gaussian masks instead of binary masks to enable these models to detect different types of polyps more effectively and efficiently and reduce the number of false positives. The experimental results showed that the proposed 2D Gaussian masks are efficient for detection of flat and small polyps with unclear boundaries between background and polyp parts. The masks make a better training effect to discriminate polyps from the polyp-like false positives. The proposed method achieved state-of-the-art results on two polyp datasets. On the ETIS-LARIB dataset we achieved 86.54% recall, 86.12% precision, and 86.33% F1-score, and on the CVC-ColonDB we achieved 91% recall, 88.35% precision, and F1-score 89.65%.

Continuous Estimation of Acute Changes in Preload Using Epicardially Attached Accelerometers.

OBJECTIVE: A miniaturized accelerometer can be incorporated in temporary pacemaker leads which are routinely attached to the epicardium during cardiac surgery and provide continuous monitoring of cardiac motion during and following surgery. We tested if such a sensor could be used to assess volume status, which is essential in hemodynamically unstable patients. METHODS: An accelerometer was attached to the epicardium of 9 pigs and recordings performed during baseline, fluid loading, and phlebotomy in a closed chest condition. Alterations in left ventricular (LV) preload alter myocardial tension which affects the frequency of myocardial acceleration associated with the first heart sound ( fS1). The accuracy of fS1 as an estimate of preload was evaluated using sonomicrometry measured end-diastolic volume (EDV[Formula: see text]). Standard clinical estimates of global end-diastolic volume using pulse index continuous cardiac output (PiCCO) measurements (GEDV[Formula: see text]) and pulmonary artery occlusion pressure (PAOP) were obtained for comparison. The diagnostic accuracy of identifying fluid responsiveness was analyzed for fS1, stroke volume variation (SVV[Formula: see text]), pulse pressure variation (PPV[Formula: see text]), GEDV[Formula: see text], and PAOP. RESULTS: Changes in fS1 correlated well to changes in EDV[Formula: see text] ( r2=0.81, 95%CI: [0.68, 0.89]), as did GEDV[Formula: see text] ( r2=0.59, 95%CI: [0.36, 0.76]) and PAOP ( r2=0.36, 95%CI: [0.01, 0.73]). The diagnostic accuracy [95%CI] in identifying fluid responsiveness was 0.79 [0.66, 0.94] for fS1, 0.72 [0.57, 0.86] for SVV[Formula: see text], and 0.63 (0.44, 0.82) for PAOP. CONCLUSION: An epicardially placed accelerometer can assess changes in preload in real-time. SIGNIFICANCE: This novel method can facilitate continuous monitoring of the volemic status in open-heart surgery patients and help guiding fluid resuscitation.

Optimal pacing sites in cardiac resynchronization by left ventricular activation front analysis.

Cardiac resynchronization therapy (CRT) can substantially improve dyssynchronous heart failure and reduce mortality. However, about one-third of patients who are implanted, derive no measurable benefit from CRT. Non-response may partly be due to suboptimal activation of the left ventricle (LV) caused by electrophysiological heterogeneities. The goal of this study is to investigate the performance of a newly developed method used to analyze electrical wavefront propagation in a heart model including myocardial scar and compare this to clinical benchmark studies. We used computational models to measure the maximum activation front (MAF) in the LV during different pacing scenarios. Different heart geometries and scars were created based on cardiac MR images of three patients. The right ventricle (RV) was paced from the apex and the LV was paced from 12 different sites, single site, dual-site and triple site. Our results showed that for single LV site pacing, the pacing site with the largest MAF corresponded with the latest activated regions of the LV demonstrated during RV pacing, which also agrees with previous markers used for predicting optimal single-site pacing location. We then demonstrated the utility of MAF in predicting optimal electrode placements in more complex scenarios including scar and multi-site LV pacing. This study demonstrates the potential value of computational simulations in understanding and planning CRT.

Theoretical Aspects of Resting-State Cardiomyocyte Communication for Multi-Nodal Nano-Actuator Pacemakers.

The heart consists of billions of cardiac muscle cells-cardiomyocytes-that work in a coordinated fashion to supply oxygen and nutrients to the body. Inter-connected specialized cardiomyocytes form signaling channels through which the electrical signals are propagated throughout the heart, controlling the heart's beat to beat function of the other cardiac cells. In this paper, we study to what extent it is possible to use ordinary cardiomyocytes as communication channels between components of a recently proposed multi-nodal leadless pacemaker, to transmit data encoded in subthreshold membrane potentials. We analyze signal propagation in the cardiac infrastructure considering noise in the communication channel by performing numerical simulations based on the Luo-Rudy computational model. The Luo-Rudy model is an action potential model but describes the potential changes with time including membrane potential and action potential stages, separated by the thresholding mechanism. Demonstrating system performance, we show that cardiomyocytes can be used to establish an artificial communication system where data are reliably transmitted between 10 s of cells. The proposed subthreshold cardiac communication lays the foundation for a new intra-cardiac communication technique.

Wide Frequency Characterization of Intra-Body Communication for Leadless Pacemakers.

Leadless Cardiac Pacemakers (LCP) have the potential to revolutionize Cardiac Rhythm Management (CRM). Current LCPs can only pace a single location of the heart limiting their use to patients requiring single-chamber stimulation. A Multi-node system of synchronized LCPs could be used in a significantly larger patient population. Synchronization using standard communication techniques involves high power consumption decreasing the longevity of the device. In this work, we investigate Galvanic Intra Body Communication (IBC) as a method to synchronize multi-node LCP systems. First, an accurate computational torso model was used for quasi-static simulations to estimate channel pathloss in the frequency range [40 kHz-20 MHz]. The model was then verified with in-vivo measurements using a novel experimental setup, where two LCP devices were placed in the right atrium, right ventricle and left ventricle. All channels involved in a potential multi-node LCP system were characterized. The orientation of the transducers relative to each other had a great impact on the results, with the attenuation level ranging between 55 dB and 70 dB between the best and worst orientations. The best results were achieved in the MHz range. Coupled with the fact that it does not require additional electrodes, this study suggests Galvanic IBC be superior to conventional communication methods for LCP devices. This analysis defines a methodology for galvanic IBC channel characterization for LCP systems, which is an important step for the design of efficient transceivers for IBC applications. More experiments with larger datasets are needed to bring this method to practice.

Multisite pacing and myocardial scars: a computational study.

Cardiac resynchronization therapy (CRT) is a frequently effective treatment modality for dyssynchronous heart failure, however, 30% of patients do not respond, usually due to suboptimal activation of the left ventricle (LV). Multisite pacing (MSP) may increase the response rate, but its effect in the presence of myocardial scars is not fully understood. We use a computational model to study the outcome of MSP in an LV with scars in two different locations and of two different sizes. The LV was stimulated from anterior, posterior and lateral locations individually and in pairs, while a septal stimulation site represented right ventricular (RV) pacing. Intraventricular pressures were measured, and outcomes evaluated in terms of maximum LV pressure gradient (dP/dtmax)- change compared to isolated RV pacing. The best result obtained using various LV pacing locations included a combination of sites remote from scars and the septum. The highest dP/dtmax increase was achieved, regardless of scar size, using MSP with one pacing site located on the LV free wall opposite to the scar and one site opposite to the septum. These in silico modelling results suggest that making placement of pacing electrodes dependent on location of scarring, may alter acute haemodynamics and that such modelling may contribute to future CRT optimization.

Guidelines for Editing Biomedical Journals: Recommended by Academy of Medical Sciences of Bosnia and Herzegovina.

BACKGROUND: Enormous number of medical journals published around the globe requires standardization of editing practice. OBJECTIVE: The aim of this article was to enlist main principles of editing biomedical scientific journals adopted at annual meeting of Academy of Medical Sciences of Bosnia & Herzegovina (AMSB&H). METHODS: The evidence for writing this Guideline was systematically searched for during September 2020 in the PUBMED and GOOGLE SCHOLAR databases. The inclusion criteria were: original studies, systematic reviews, invited expert opinions, guidelines and editorials. The exclusion criteria were narrative reviews and uninvited opinion articles. The retrieved evidence was analyzed by members of the AMSB&H, then discussed at 2020 annual meeting of the AMSB&H and adopted by nominal group technique. RESULTS: In total 14 recommendations were made, based on A to C class of evidence. The editors should educate potential authors and instruct them how to structure their manuscript, how to write every segment of the manuscript, and take care about correct use of statistical tests. Plagiarism detection softwares should be used regularly, and statistical and technical editing should be rigorous and thorough. International standards of reporting specific types of studies should be followed, and principles of ethical and responsible behavior of editors, reviewers and authors should be published on the journal's web site. The editors should insist on registration of clinical studies before submission, and check whether non-essential personal information is removed from the articles; when essential personal information has to be included, an article should not be published without signed informed consent by the patient to whom these information relate. CONCLUSIONS: Principles of editing biomedical scientific journals recommended in this guideline should serve as one of the means of improving medical journals' quality.

Balkan Clinical Research Registry: Established by Academy of Medical Sciences of Bosnia and Herzegovina.

BACKGROUND: From 2013 the World Medical Association's Declaration of Helsinki explicitly requires pre-registration of a study involving human subjects. The registration gives a chance for improvement of design and avoidance of bias. OBJECTIVE: The aim of this article was to describe process of bearing decision to create regional registry of clinical studies for Balkan countries. METHODS: After finding relevant studies about research registries and designing the concept and structure of future regional registry an article was published in IJBH journal. The article was than used as basis for discussion at 2020 meeting of Academy of Medical Sciences of Bosnia and Herzegovina (AMSBH), and final decision was made by the Academy to create the research registry. RESULTS: Regional registry of clinical studies will be under the auspices of AMSBH and web-based, with the option of online registration of new studies. The data required to be entered in the moment of registration relate to key elements of research plan: topic, variables, sample, type of the study and the study population. After applying for registration of a clinical study, the authors will soon receive the review made by the AMSBH expert committee. The application could be accepted, rejected or returned for major or minor revision. After an application is accepted, it will be deposited in the searchable database and given the registration number. CONCLUSION: The AMSBH's decision to create the regional registry of clinical studies will satisfy needs of researchers from Balkan countries in the first place, who share cultural and lingual similarities. It will also help with increasing standards of clinical research in the region.

Improving Automatic Polyp Detection Using CNN by Exploiting Temporal Dependency in Colonoscopy Video.

Automatic polyp detection has been shown to be difficult due to various polyp-like structures in the colon and high interclass variations in polyp size, color, shape, and texture. An efficient method should not only have a high correct detection rate (high sensitivity) but also a low false detection rate (high precision and specificity). The state-of-the-art detection methods include convolutional neural networks (CNN). However, CNNs have shown to be vulnerable to small perturbations and noise; they sometimes miss the same polyp appearing in neighboring frames and produce a high number of false positives. We aim to tackle this problem and improve the overall performance of the CNN-based object detectors for polyp detection in colonoscopy videos. Our method consists of two stages: a region of interest (RoI) proposal by CNN-based object detector networks and a false positive (FP) reduction unit. The FP reduction unit exploits the temporal dependencies among image frames in video by integrating the bidirectional temporal information obtained by RoIs in a set of consecutive frames. This information is used to make the final decision. The experimental results show that the bidirectional temporal information has been helpful in estimating polyp positions and accurately predict the FPs. This provides an overall performance improvement in terms of sensitivity, precision, and specificity compared to conventional false positive learning method, and thus achieves the state-of-the-art results on the CVC-ClinicVideoDB video data set.

Energy-efficiency of Cardiomyocyte Stimulation with Rectangular Pulses.

In cardiac pacemaker design, energy expenditure is an important issue. This work aims to explore whether varying stimulation pulse configuration is a viable optimization strategy for reducing energy consumption by the pacemaker. A single cardiomyocyte was used as an experimental model. Each cardiomyocyte was stimulated with different stimulation protocols using rectangular waveforms applied in varying number, in short succession. The amplitude, the width of each pulse, and the interval between consecutive pulses were modified. The application of multiple pulses in a short sequence led to a reduction of the threshold voltage required for stimulation when compared to a single pulse. However, none of the employed multi-pulse sequences reduced the overall energy expenditure of cell stimulation when compared to a single pulse stimulation. Among multiple pulse protocols, a combination of two short pulses (1 ms) separated with a short interval (0.5 ms) had the same energy requirements as a single short pulse (1 ms), but required the application of significantly less voltage. While increasing the number of consecutive pulses does not reduce the energy requirements of the pacemaker, the reduction in threshold voltage can be considered in practice if lower stimulation voltages are desired.

Dynamic gravity compensation does not increase detection of myocardial ischemia in combined accelerometer and gyro sensor measurements.

Previous studies have shown that miniaturised accelerometers can be used to monitor cardiac function and automatically detect ischemic events. However, accelerometers cannot differentiate between acceleration due to motion and acceleration due to gravity. Gravity filtering is essential for accurate integration of acceleration to yield velocity and displacement. Heart motion is cyclic and mean acceleration over time is zero. Thus, static gravity filtering is performed by subtracting mean acceleration. However, the heart rotates during the cycle, the gravity component is therefore not constant, resulting in overestimation of motion by static filtering. Accurate motion can be calculated using dynamic gravity filtering by a combined gyro and accelerometer. In an animal model, we investigated whether increased accuracy using dynamic filtering, compared to using static filtering, would enhance the ability to detect ischemia. Additionally, we investigated how well the gyro alone could detect ischemia based on the heart's rotation. Dynamic filtering tended towards lower sensitivity and specificity, using receiver operating characteristics analysis, for ischemia-detection compared to static filtering (area under the curve (AUC): 0.83 vs 0.93, p = 0.125). The time-varying gravity component indirectly reflects the heart's rotation. Hence, static filtering has the advantage of indirectly including rotation, which alone demonstrated excellent sensitivity to ischemia (AUC = 0.98).

Mechanism of Abnormal Septal Motion in Left Bundle Branch Block: Role of Left Ventricular Wall Interactions and Myocardial Scar.

OBJECTIVES: This study sought to investigate how regional left ventricular (LV) function modifies septal motion in left bundle branch block (LBBB). BACKGROUND: In LBBB, the interventricular septum often has marked pre-ejection shortening, followed by immediate relengthening (rebound stretch). This motion, often referred to as septal flash, is associated with positive response to cardiac resynchronization therapy (CRT). METHODS: In 10 anesthetized dogs, we induced LBBB by radiofrequency ablation and occluded the circumflex (CX) (n = 10) and left anterior descending (LAD) (n = 6) coronary arteries, respectively. Myocardial dimensions were measured by sonomicrometry and myocardial work by pressure-segment length analysis. In 40 heart failure patients with LBBB, including 20 with post-infarct scar and 20 with nonischemic cardiomyopathy, myocardial strain was measured by speckle-tracking echocardiography and myocardial work by pressure-strain analysis. Scar was assessed by cardiac magnetic resonance imaging with late gadolinium enhancement. RESULTS: During LBBB, each animal showed typical septal flash with pre-ejection shortening and rebound stretch, followed by reduced septal systolic shortening (p < 0.01). CX occlusion caused LV lateral wall dysfunction and abolished septal flash due to loss of rebound stretch (p < 0.0001). Furthermore, CX occlusion restored septal systolic shortening to a similar level as before induction of LBBB and substantially improved septal work (p < 0.001). LAD occlusion, however, accentuated septal flash by increasing rebound stretch (p < 0.05). Consistent with the experimental findings, septal flash was absent in patients with LV lateral wall scar due to lack of rebound stretch (p < 0.001), and septal systolic shortening and septal work far exceeded values in nonischemic cardiomyopathy (p < 0.0001). Septal flash was present in most patients with anteroseptal scar. CONCLUSIONS: LV lateral wall dysfunction and scar abolished septal flash and markedly improved septal function in LBBB. Therefore, function and scar in the LV lateral wall should be taken into account when septal motion is used to evaluate dyssynchrony.