A Multifunctional Therapeutic Strategy Using P7C3 as A Countermeasure Against Bone Loss and Fragility in An Ovariectomized Rat Model of Postmenopausal Osteoporosis.

By 2060, an estimated one in four Americans will be elderly. Consequently, the prevalence of osteoporosis and fragility fractures will also increase. Presently, no available intervention definitively prevents or manages osteoporosis. This study explores whether Pool 7 Compound 3 (P7C3) reduces progressive bone loss and fragility following the onset of ovariectomy (OVX)-induced osteoporosis. Results confirm OVX-induced weakened, osteoporotic bone together with a significant gain in adipogenic body weight. Treatment with P7C3 significantly reduced osteoclastic activity, bone marrow adiposity, whole-body weight gain, and preserved bone area, architecture, and mechanical strength. Analyses reveal significantly upregulated platelet derived growth factor-BB and leukemia inhibitory factor, with downregulation of interleukin-1 R6, and receptor activator of nuclear factor kappa-B (RANK). Together, proteomic data suggest the targeting of several key regulators of inflammation, bone, and adipose turnover, via transforming growth factor-beta/SMAD, and Wingless-related integration site/be-catenin signaling pathways. To the best of the knowledge, this is first evidence of an intervention that drives against bone loss via RANK. Metatranscriptomic analyses of the gut microbiota show P7C3 increased Porphyromonadaceae bacterium, Candidatus Melainabacteria, and Ruminococcaceae bacterium abundance, potentially contributing to the favorable inflammatory, and adipo-osteogenic metabolic regulation observed. The results reveal an undiscovered, and multifunctional therapeutic strategy to prevent the pathological progression of OVX-induced bone loss.

Injectable hydrogel electrodes as conduction highways to restore native pacing.

There is an urgent clinical need for a treatment regimen that addresses the underlying pathophysiology of ventricular arrhythmias, the leading cause of sudden cardiac death. The current report describes the design of an injectable hydrogel electrode and successful deployment in a pig model with access far more refined than any current pacing modalities allow. In addition to successful cardiac capture and pacing, analysis of surface ECG tracings and three-dimensional electroanatomic mapping revealed a QRS morphology comparable to native sinus rhythm, strongly suggesting the hydrogel electrode captures the deep septal bundle branches and Purkinje fibers. In an ablation model, electroanatomic mapping data demonstrated that the activation wavefront from the hydrogel reaches the mid-myocardium and endocardium much earlier than current single-point pacing modalities. Such uniform activation of broad swaths of tissue enables an opportunity to minimize the delayed myocardial conduction of heterogeneous tissue that underpins re-entry. Collectively, these studies demonstrate the feasibility of a new pacing modality that most closely resembles native conduction with the potential to eliminate lethal re-entrant arrhythmias and provide painless defibrillation.

Frailty Status Modifies the Efficacy of ICD Therapy for Primary Prevention Among Patients With HF.

BACKGROUND: Implantable cardioverter-defibrillator (ICD) therapy is recommended to reduce mortality risk in patients with heart failure with reduced ejection fraction (HFrEF). Frailty is common among patients with HFrEF and is associated with increased mortality risk. Whether the therapeutic efficacy of ICD is consistent among frail and nonfrail patients with HFrEF remains unclear. OBJECTIVES: The aim of this study was to evaluate the effect modification of baseline frailty burden on ICD efficacy for primary prevention among participants of the SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial). METHODS: Participants in SCD-HeFT with HFrEF randomized to ICD vs placebo were included. Baseline frailty was estimated using the Rockwood Frailty Index (FI), and participants were stratified into high (FI > median) vs low (FI ≤ median) frailty burden groups. Multivariable Cox models with multiplicative interaction terms (frailty × treatment arm) were constructed to evaluate whether baseline frailty status modified the treatment effect of ICD for all-cause mortality. RESULTS: The study included 1,676 participants (mean age: 59 ± 12 years, 23% women) with a median FI of 0.30 (IQR: 0.23-0.37) in the low frailty group and 0.54 (IQR: 0.47-0.60) in the high frailty group. In adjusted Cox models, baseline frailty status significantly modified the treatment effect of ICD therapy (Pinteraction = 0.047). In separate stratified analysis by frailty status, ICD therapy was associated with a lower risk of all-cause mortality among participants with low frailty burden (HR: 0.56; 95% CI: 0.40-0.78) but not among those with high frailty burden (HR: 0.86; 95% CI: 0.68-1.09). CONCLUSIONS: Baseline frailty modified the efficacy of ICD therapy with a significant mortality benefit observed among participants with HFrEF and a low frailty burden but not among those with a high frailty burden.

Reduced graphene oxide coated alginate scaffolds: potential for cardiac patch application.

BACKGROUND: Cardiovascular diseases, particularly myocardial infarction (MI), are the leading cause of death worldwide and a major contributor to disability. Cardiac tissue engineering is a promising approach for preventing functional damage or improving cardiac function after MI. We aimed to introduce a novel electroactive cardiac patch based on reduced graphene oxide-coated alginate scaffolds due to the promising functional behavior of electroactive biomaterials to regulate cell proliferation, biocompatibility, and signal transition. METHODS: The fabrication of novel electroactive cardiac patches based on alginate (ALG) coated with different concentrations of reduced graphene oxide (rGO) using sodium hydrosulfite is described here. The prepared scaffolds were thoroughly tested for their physicochemical properties and cytocompatibility. ALG-rGO scaffolds were also tested for their antimicrobial and antioxidant properties. Subcutaneous implantation in mice was used to evaluate the scaffolds' ability to induce angiogenesis. RESULTS: The Young modulus of the scaffolds was increased by increasing the rGO concentration from 92 ± 4.51 kPa for ALG to 431 ± 4.89 kPa for ALG-rGO-4 (ALG coated with 0.3% w/v rGO). The scaffolds' tensile strength trended similarly. The electrical conductivity of coated scaffolds was calculated in the semi-conductive range (~ 10-4 S/m). Furthermore, when compared to ALG scaffolds, human umbilical vein endothelial cells (HUVECs) cultured on ALG-rGO scaffolds demonstrated improved cell viability and adhesion. Upregulation of VEGFR2 expression at both the mRNA and protein levels confirmed that rGO coating significantly boosted the angiogenic capability of ALG against HUVECs. OD620 assay and FE-SEM observation demonstrated the antibacterial properties of electroactive scaffolds against Escherichia coli, Staphylococcus aureus, and Streptococcus pyogenes. We also showed that the prepared samples possessed antioxidant activity using a 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging assay and UV-vis spectroscopy. Histological evaluations confirmed the enhanced vascularization properties of coated samples after subcutaneous implantation. CONCLUSION: Our findings suggest that ALG-rGO is a promising scaffold for accelerating the repair of damaged heart tissue.

Incidence, Risk Score Performance, and In-Hospital Outcomes of Postoperative Atrial Fibrillation After Cardiac Surgery.

BACKGROUND: Postoperative atrial fibrillation (POAF) frequently complicates cardiac surgery. Predicting POAF can guide interventions to prevent its onset. This study assessed the incidence, risk factors, and related adverse outcomes of POAF after cardiac surgery. METHODS: A cohort of 1,606 patients undergoing cardiac surgery at a tertiary referral center was analyzed. Postoperative AF was defined based on the Society of Thoracic Surgeons' criteria: AF/atrial flutter after operating room exit that either lasted longer than 1 hour or required medical or procedural intervention. Risk factors for POAF were evaluated, and the performance of established risk scores (POAF, HATCH, COM-AF, CHA2DS2-VASc, and Society of Thoracic Surgeons risk scores) in predicting POAF was assessed using discrimination (area under the receiver operator characteristics curve) analysis. The association of POAF with secondary outcomes, including length of hospital stay, ventilator time, and discharge to rehabilitation facilities, was evaluated using adjusted linear and logistic regression models. RESULTS: The incidence of POAF was 32.2% (n = 517). Patients who developed POAF were older, had traditional cardiovascular risk factors and higher Society of Thoracic Surgeons risk scores, and often underwent valve surgery. The POAF risk score demonstrated the highest area under the receiver operator characteristics curve (0.65), but risk scores generally underperformed. Postoperative AF was associated with extended hospital stays, longer ventilator use, and higher likelihood of discharge to rehabilitation facilities (odds ratio, 2.30; 95% CI, 1.73-3.08). CONCLUSION: This study observed a high incidence of POAF following cardiac surgery and its association with increased morbidity and resource utilization. Accurate POAF prediction remains elusive, emphasizing the need for better risk-prediction methods and tailored interventions to diminish the effect of POAF on patient outcomes.

Ultrasound-Responsive Nanobubbles for Combined siRNA-Cerium Oxide Nanoparticle Delivery to Bone Cells.

This study aims to present an ultrasound-mediated nanobubble (NB)-based gene delivery system that could potentially be applied in the future to treat bone disorders such as osteoporosis. NBs are sensitive to ultrasound (US) and serve as a controlled-released carrier to deliver a mixture of Cathepsin K (CTSK) siRNA and cerium oxide nanoparticles (CeNPs). This platform aimed to reduce bone resorption via downregulating CTSK expression in osteoclasts and enhance bone formation via the antioxidant and osteogenic properties of CeNPs. CeNPs were synthesized and characterized using transmission electron microscopy and X-ray photoelectron spectroscopy. The mixture of CTSK siRNA and CeNPs was adsorbed to the surface of NBs using a sonication method. The release profiles of CTSK siRNA and CeNPs labeled with a fluorescent tag molecule were measured after low-intensity pulsed ultrasound (LIPUS) stimulation using fluorescent spectroscopy. The maximum release of CTSK siRNA and the CeNPs for 1 mg/mL of NB-(CTSK siRNA + CeNPs) was obtained at 2.5 nM and 1 µg/mL, respectively, 3 days after LIPUS stimulation. Then, Alizarin Red Staining (ARS) was applied to human bone marrow-derived mesenchymal stem cells (hMSC) and tartrate-resistant acid phosphatase (TRAP) staining was applied to human osteoclast precursors (OCP) to evaluate osteogenic promotion and osteoclastogenic inhibition effects. A higher mineralization and a lower number of osteoclasts were quantified for NB-(CTSK siRNA + CeNPs) versus control +RANKL with ARS (p < 0.001) and TRAP-positive staining (p < 0.01). This study provides a method for the delivery of gene silencing siRNA and CeNPs using a US-sensitive NB system that could potentially be used in vivo and in the treatment of bone fractures and disorders such as osteoporosis.

Potential of graphene-based nanomaterials for cardiac tissue engineering.

Cardiovascular diseases are the primary cause of death worldwide. Despite significant advances in pharmacological treatments and surgical interventions to restore heart function after myocardial infarction, it can progress to heart failure due to the restricted inherent potential of adult cardiomyocytes to self-regenerate. Hence, the evolution of new therapeutic methods is critical. Nowadays, novel approaches in tissue engineering have assisted in restoring biological and physical specifications of the injured myocardium and, hence, cardiac function. The incorporation of a supporting matrix that could mechanically and electronically support the heart tissue and stimulate the cells to proliferate and regenerate will be advantageous. Electroconductive nanomaterials can facilitate intracellular communication and aid synchronous contraction via electroactive substrate creation, preventing the issue of arrhythmia in the heart. Among a wide range of electroconductive materials, graphene-based nanomaterials (GBNs) are promising for cardiac tissue engineering (CTE) due to their outstanding features including high mechanical strength, angiogenesis, antibacterial and antioxidant properties, low cost, and scalable fabrication. In the present review, we discuss the effect of applying GBNs on angiogenesis, proliferation, and differentiation of implanted stem cells, their antibacterial and antioxidant properties, and their role in improving the electrical and mechanical properties of the scaffolds for CTE. Also, we summarize the recent research that has applied GBNs in CTE. Finally, we present a concise discussion on the challenges and prospects.

Bubble-Based Drug Delivery Systems: Next-Generation Diagnosis to Therapy.

Current radiologic and medication administration is systematic and has widespread side effects; however, the administration of microbubbles and nanobubbles (MNBs) has the possibility to provide therapeutic and diagnostic information without the same ramifications. Microbubbles (MBs), for instance, have been used for ultrasound (US) imaging due to their ability to remain in vessels when exposed to ultrasonic waves. On the other hand, nanobubbles (NBs) can be used for further therapeutic benefits, including chronic treatments for osteoporosis and cancer, gene delivery, and treatment for acute conditions, such as brain infections and urinary tract infections (UTIs). Clinical trials are also being conducted for different administrations and utilizations of MNBs. Overall, there are large horizons for the benefits of MNBs in radiology, general medicine, surgery, and many more medical applications. As such, this review aims to evaluate the most recent publications from 2016 to 2022 to report the current uses and innovations for MNBs.

Detection of atrial fibrillation in real world setting in patients with cryptogenic stroke and an implantable loop recorder.

INTRODUCTION: Implantable loop recorders (ILR) are used to screen for atrial fibrillation (AF) in patients with cryptogenic stroke (CS). However, there is limited real-world data regarding the long-term rate of AF detection using ILR and management consequences in patients with CS. The objective is to assess the rate of AF detection in patients with CS in a real-world study over 36 months of follow-up and its consequences on stroke prevention. METHODS: This retrospective study included patients with an ILR placed for CS at Baylor College of Medicine and Baylor St. Luke's Medical Center between January 2014 and July 2021. The primary outcome was AF detection in patients with ILR. The secondary outcome was the rate of subsequent strokes after ILR placement in patients with or without diagnosed AF. The AF detection rate in our cohort was compared to the rate in CRYSTAL-AF Trial at 36-month follow-up. The impact of AF detection on clinical management was examined. RESULTS: We identified 225 patients. 51.1% were women and 38.2% African American. Among 85 patients with ILR labeled AF, 43 patients had true AF, and 42 had incorrectly labeled AF (48.3% false positive). The estimated AF detection rate at 36 months follow-up was 28.6% (95% CI, 26.6%-30.6%). 58.1% of patients with AF were initiated on oral anticoagulation, 80.0% of whom were started on a direct oral anticoagulant. 13.8% of patients had recurrent strokes after ILR implantation; 4 of whom were diagnosed with AF. CONCLUSION: Compared to CRYSTAL-AF, the AF detection rate in our cohort is similar, but this cohort includes a higher proportion of female and African American patients. Most patients with recurrent strokes after ILR implant did not have AF during 36 months of monitoring.

Risk Stratification in Patients Who Underwent Percutaneous Left Atrial Appendage Occlusion.

Left atrial appendage occlusion (LAAO) is effective in preventing thromboembolism. Risk stratification tools could help identify patients at risk for early mortality after LAAO. In this study, we validated and recalibrated a clinical risk score (CRS) to predict risk of all-cause mortality after LAAO. This study used data from patients who underwent LAAO in a single-center, tertiary hospital. A previously developed CRS using 5 variables (age, body mass index [BMI], diabetes, heart failure, and estimated glomerular filtration rate) was applied to each patient to assess risk of all-cause mortality at 1 and 2 years. The CRS was recalibrated to the present study cohort and compared with established atrial fibrillation-specific (CHA2DS2-VASc and HAS-BLED) and generalized (Walter index) risk scores. Cox proportional hazard models were used to assess the risk of mortality and discrimination was assessed by Harrel C-index. Among 223 patients, the 1- and 2-year mortality rates were 6.7% and 11.2%, respectively. With the original CRS, only low BMI (<23 kg/m2) was a significant predictor of all-cause mortality (hazard ratio [HR] [95% CI] 2.76 [1.03 to 7.35]; p = 0.04). With recalibration, BMI <29 kg/m2 and estimated glomerular filtration rate <60 ml/min/1.73 m2 were significantly associated with an increased risk of death (HR [95% CI] 3.24 [1.29 to 8.13] and 2.48 [1.07 to 5.74], respectively), with a trend toward significance noted for history of heart failure (HR [95% CI] 2.13 [0.97 to 4.67], p = 0.06). Recalibration improved the discriminative ability of the CRS from 0.65 to 0.70 and significantly outperformed established risk scores (CHA2DS2-VASc = 0.58, HAS-BLED = 0.55, Walter index = 0.62). In this single-center, observational study, the recalibrated CRS accurately risk stratified patients who underwent LAAO and significantly outperformed established atrial fibrillation-specific and generalized risk scores. In conclusion, clinical risk scores should be considered as an adjunct to standard of care when evaluating a patient's candidacy for LAAO.

Electrical Stimulation for Low-Energy Termination of Cardiac Arrhythmias: a Review.

Cardiac arrhythmias are a leading cause of morbidity and mortality in the developed world, estimated to be responsible for hundreds of thousands of deaths annually. Our understanding of the electrophysiological mechanisms of such arrhythmias has grown since they were formally characterized in the late nineteenth century, and this has led to the development of numerous devices and therapies that have markedly improved outcomes for patients affected by such conditions. Despite these advancements, the application of a single large shock remains the clinical standard for treating deadly tachyarrhythmias. Such defibrillating shocks are undoubtedly effective in terminating such arrhythmias; however, they are applied without forewarning, contributing to the patient's stress and anxiety; they can be intensely painful; and they can have adverse psychological and physiological effects on patients. In recent years, there has been interest in developing defibrillation protocols that can terminate arrhythmias without crossing the human pain threshold for energy delivery, generally estimated to be between 0.1 and 1 J. In this article, we review existing literature on the development of such low-energy defibrillation methods and their underlying mechanisms, in an attempt to broadly describe the current landscape of these technologies.

An osteogenic magnesium alloy with improved corrosion resistance, antibacterial, and mechanical properties for orthopedic applications.

The aim of this study was to develop a novel biodegradable magnesium (Mg) alloy for bone implant applications. We used scandium (Sc; 2 wt %) and strontium (Sr; 2 wt %) as alloying elements due to their high biocompatibility, antibacterial efficacy, osteogenesis, and protective effects against corrosion. In the present work, we also examined the effect of a heat treatment process on the properties of the Mg-Sc-Sr alloy. Alloys were manufactured using a metal casting process followed by heat treatment. The microstructure, corrosion, mechanical properties, antibacterial activity, and osteogenic activity of the alloy were assessed in vitro. The results showed that the incorporation of Sc and Sr elements controlled the corrosion, reduced the hydrogen generation, and enhanced mechanical properties. Furthermore, alloying with Sc and Sr demonstrated a significantly enhanced antibacterial activity and decreased biofilm formation compared to control Mg. Also, culturing Mg-Sc-Sr alloy with human bone marrow-derived mesenchymal stromal cells showed a high degree of biocompatibility (>90% live cells) and a significant increase in osteoblastic differentiation in vitro shown by Alizarin red staining and alkaline phosphatase activity. Based on these results, the Mg-Sc-Sr alloy heat-treated at 400°C displayed optimal mechanical properties, corrosion rate, antibacterial efficacy, and osteoinductivity. These characteristics make the Mg-Sc-Sr alloy a promising candidate for biodegradable orthopedic implants in the fixation of bone fractures such as bone plate-screws or intramedullary nails.

Deep Learning System for Left Ventricular Assist Device Candidate Assessment from Electrocardiograms.

Left Ventricular Assist Devices (LVADs) are increasingly used as long-term implantation therapy for advanced heart failure patients, where candidacy assessment is crucial for successful treatment and recovery. A Deep Learning system based on Electrocardiogram (ECG) diagnoses criteria to stratify candidacy is proposed, implementing multi-model processing, interpretability, and uncertainty estimation. The approach includes beat segmentation for single-lead classification, 12-lead analysis, and semantic segmentation, achieving state-of-the-art results on the classification evaluation of each model, with multilabel average AUC results of 0.9924, 0.9468, and 0.9956, respectively, presenting a novel approach for LVAD candidacy assessment, serving as an aid for decision-making.

Left Ventricular Geometry and Angiogenesis Improvement in Rat Chronic Ischemic Cardiomyopathy following Injection of Encapsulated Mesenchymal Stem Cells.

OBJECTIVE: Injection of hydrogel and cells into myocardial infarction (MI) patients is one of the emerging treatment techniques, however, it has some limitations such as a lack of electromechanical properties and neovascularization. We investigated the therapeutic potential of new electroactive hydrogel [reduced graphene oxide (rGO)/Alginate (ALG)] encapsulated human bone marrow mesenchymal stem cells (BMSCs). MATERIALS AND METHODS: The experimental study involved ligating the left anterior descending coronary artery (LAD) in rat models of chronic ischemic cardiomyopathy. Echocardiograms were analyzed at 4 and 8 weeks after MI treatment. In the eighth week after injection in the heart, the rats were sacrificed. Histological and immunohistochemical analyses were performed using Hematoxylin and Eosin (H and E) staining, Masson's trichrome staining and anti-CD31 antibody to analyze tissue structure and detect neovascularization. RESULTS: In comparison to the control and other treatment groups, MSCs encapsulated in rGO-ALG showed significant improvements in fractional shortening (FS), ejection fraction (EF), wall thickness and internal diameters (P<0.05). The morphological observation showed several small blood vessels formed around the transplantation site in all treated groups especially in the MSC-ALG-rGO group 8 weeks after the transplantation. Also, Masson's trichrome staining indicated an increased amount of collagen fibers in rGO-ALG-MSC. Microvessel density was significantly higher using MSC-ALG-rGO compared to controls (P<0.01). CONCLUSION: This study demonstrates that intramyocardial injection of rGO/ALG, a bio-electroactive hydrogel, is safe for increasing LV function, neovascularization, and adjusting electrical characteristics following MI. The results confirm ALG promising capability as a natural therapeutic for cardiac regeneration.

Biodegradable Mg-Sc-Sr Alloy Improves Osteogenesis and Angiogenesis to Accelerate Bone Defect Restoration.

Magnesium (Mg) and its alloys are considered to be biodegradable metallic biomaterials for potential orthopedic implants. While the osteogenic properties of Mg alloys have been widely studied, few reports focused on developing a bifunctional Mg implant with osteogenic and angiogenic properties. Herein, a Mg-Sc-Sr alloy was developed, and this alloy's angiogenesis and osteogenesis effects were evaluated in vitro for the first time. X-ray Fluorescence (XRF), X-ray diffraction (XRD), and metallography images were used to evaluate the microstructure of the developed Mg-Sc-Sr alloy. Human umbilical vein/vascular endothelial cells (HUVECs) were used to evaluate the angiogenic character of the prepared Mg-Sc-Sr alloy. A mix of human bone-marrow-derived mesenchymal stromal cells (hBM-MSCs) and HUVEC cell cultures were used to assess the osteogenesis-stimulating effect of Mg-Sc-Sr alloy through alkaline phosphatase (ALP) and Von Kossa staining. Higher ALP activity and the number of calcified nodules (27% increase) were obtained for the Mg-Sc-Sr-treated groups compared to Mg-treated groups. In addition, higher VEGF expression (45.5% increase), tube length (80.8% increase), and number of meshes (37.9% increase) were observed. The Mg-Sc-Sr alloy showed significantly higher angiogenesis and osteogenic differentiation than pure Mg and the control group, suggesting such a composition as a promising candidate in bone implants.

Prevalence and characteristics of ponticulus posticus and its association with cervicogenic headache and migraine: A lateral cephalometric study.

Background: Ponticulus posticus (PP) (arcuate foramen) is an abnormal bony bridge in the posterior arch of the atlas, which could possibly cause certain complications such as headache. Our goal was to assess the prevalence and size of PP on lateral cephalometric radiographs and its relationships with cervicogenic headache and migraine. Materials and Methods: This cross-sectional study was a descriptive-analytical type and was performed in Isfahan Azad Dental University. Lateral cephalometric radiographs of 150 patients referred to the radiology department were selected to assess the prevalence and size of the anomaly. A checklist was prepared to evaluate cervicogenic headache and migraine among patients. Results: Our sample consisted of 97 females and 53 males with an age range between 5 and 56 years. The prevalence of PP was 21.3% (12% complete and 9.3% incomplete), and an insignificant difference was noted between the prevalence of complete and incomplete foramen (P > 0.05). The prevalence of foramen was higher in women (59.4%), but it was not significant. The mean width of complete foramen was 6.40 mm, and the mean heights in individuals with complete and incomplete foramen were 4.71 and 4.84 mm, respectively. Among patients with the anomaly, 43.8% had cervicogenic headache and 9.4% had migraine. There was a significant association between the presence of foramen and both types of headaches (P < 0.05). However, there was no significant correlation between the shape of anomaly and the presence of cervicogenic headache and migraine (P > 0.05). Conclusion: Our study showed a high prevalence of PP and its significant association with cervicogenic headache and migraine.

Systematic review on the application of 3D-bioprinting technology in orthoregeneration: current achievements and open challenges.

BACKGROUND: Joint degeneration and large or complex bone defects are a significant source of morbidity and diminished quality of life worldwide. There is an unmet need for a functional implant with near-native biomechanical properties. The potential for their generation using 3D bioprinting (3DBP)-based tissue engineering methods was assessed. We systematically reviewed the current state of 3DBP in orthoregeneration. METHODS: This review was performed using PubMed and Web of Science. Primary research articles reporting 3DBP of cartilage, bone, vasculature, and their osteochondral and vascular bone composites were considered. Full text English articles were analyzed. RESULTS: Over 1300 studies were retrieved, after removing duplicates, 1046 studies remained. After inclusion and exclusion criteria were applied, 114 articles were analyzed fully. Bioink material types and combinations were tallied. Cell types and testing methods were also analyzed. Nearly all papers determined the effect of 3DBP on cell survival. Bioink material physical characterization using gelation and rheology, and construct biomechanics were performed. In vitro testing methods assessed biochemistry, markers of extracellular matrix production and/or cell differentiation into respective lineages. In vivo proof-of-concept studies included full-thickness bone and joint defects as well as subcutaneous implantation in rodents followed by histological and µCT analyses to demonstrate implant growth and integration into surrounding native tissues. CONCLUSIONS: Despite its relative infancy, 3DBP is making an impact in joint and bone engineering. Several groups have demonstrated preclinical efficacy of mechanically robust constructs which integrate into articular joint defects in small animals. However, notable obstacles remain. Notably, researchers encountered pitfalls in scaling up constructs and establishing implant function and viability in long term animal models. Further, to translate from the laboratory to the clinic, standardized quality control metrics such as construct stiffness and graft integration metrics should be established with investigator consensus. While there is much work to be done, 3DBP implants have great potential to treat degenerative joint diseases and provide benefit to patients globally.

RT-RCG: Neural Network and Accelerator Search Towards Effective and Real-time ECG Reconstruction from Intracardiac Electrograms.

There exists a gap in terms of the signals provided by pacemakers (i.e., intracardiac electrogram (EGM)) and the signals doctors use (i.e., 12-lead electrocardiogram (ECG)) to diagnose abnormal rhythms. Therefore, the former, even if remotely transmitted, are not sufficient for doctors to provide a precise diagnosis, let alone make a timely intervention. To close this gap and make a heuristic step towards real-time critical intervention in instant response to irregular and infrequent ventricular rhythms, we propose a new framework dubbed RT-RCG to automatically search for (1) efficient Deep Neural Network (DNN) structures and then (2) corresponding accelerators, to enable Real-Time and high-quality Reconstruction of ECG signals from EGM signals. Specifically, RT-RCG proposes a new DNN search space tailored for ECG reconstruction from EGM signals, and incorporates a differentiable acceleration search (DAS) engine to efficiently navigate over the large and discrete accelerator design space to generate optimized accelerators. Extensive experiments and ablation studies under various settings consistently validate the effectiveness of our RT-RCG. To the best of our knowledge, RT-RCG is the first to leverage neural architecture search (NAS) to simultaneously tackle both reconstruction efficacy and efficiency.