During the last decade, we have seen a rapid development of neural prostheses, the systems that connect the brain to external assistive and rehabilitation devices. While this work was dominated by the research on neural prostheses that enable sensorimotor functions of the arm and hand, there has also been a growing interest in neural prostheses that restore locomotion, the ability to move in space. Brain-controlled wheelchairs and exoskeletons represent examples of such neural prostheses.The collection of articles in this Research Topic present and discuss available evidence, conceptual frameworks, neuroprosthetic designs and practical questions concerning application of neural prostheses to gait assistance and rehabilitation. The Research Topic covers a range of issues such as control schemes, robotic aspects, effectiveness, characteristics of motor performance, neural underpinnings, ethics, significance for neurological disorders, motor learning, and recovery of locomotor function. The contributions are summarized below in 7 thematic categories: (i) reviews and perspectives, (ii) animal studies, (iii) balance control, (iv) prostheses for locomotion, (v) myoelectric control, (vi) electroencephalography (EEG)-based systems for lower limb prosthesis control, and (vii) combined effects of spinal cord neuromodulation and exoskeleton gait training in paralyzed individuals.Tariq et al. discusses a number of key features of the EEG-based activity mode recognition and the potentials of EEG-based brain computer interfaces for enabling locomotion and improving its rehabilitation. The authors consider incorporation of neural technologies in various devices for locomotion, such as wearable lower-limb exoskeletons, orthoses, prostheses, wheelchairs, and assistive-robot devices. The performance of these devices could be improved by BCIs that recognize user intent and provide a communication channel. The EEG communication signals employed by these BCIs are sensorimotor rhythms, event-related potentials and visual evoked potentials. The authors develop a framework for such neural technologies and suggest using this framework for the development of the next generation of intent-based multifunctional controllers for individuals suffering from neuromotor disorders, trauma to nervous system, or limb amputation.Two review articles included in the Research Topic assess the current state of assistive devices for locomotion and their perspectives for development. The review by Bissolotti et al. discuss the limiting factors and evaluate some ethical questions regarding the domestic use of robotic exoskeletons for gait assistance in people affected by spinal cord injury (SCI). While the literature supports the effectiveness of different types of exoskeletons used in a clinical setting to treat such conditions as spasticity, balance impairment and abnormal blood pressure, multiple issues arise when such gait training systems are adapted for the home environments. These issues include high cost of the device and related inequality in the access to health care services, level of competence reached after training to use the device, risk of cardiovascular and metabolic diseases, high risk of osteoporosis of the paretic limbs, skin lesions, deep venous thrombosis and pelvic floor impairment. The article discusses the countermeasures to counteract the negative effects that could increase therapeutic efficacy and decrease inequality in the access to health care services and devices.In an opinion article, Millevolte et al. tested and demonstrated the potential for the housing and engagement of a sieve electrode within the medullary canal of long bones as part of an osseointegrated neural prosthesis. Mottaghi et al. investigated cortico-basal ganglia beta oscillations in a rat model of unilateral Parkinson's Disease (PD) and analyzed the effects of deep brain stimulation. They concluded that this model accurately represents many of the motor and electrophysiological symptoms of PD, which makes it a useful tool for pre-clinical testing of new treatments. Park et al. developed a prototype of a powered transtibial prosthesis for the use in a feline model of prosthetic gait. In this prosthesis, the linear actuator operates the prosthetic ankle joint with the control signals that emulate myoelectric activity of muscles; there is a close match between the locomotor patterns produced by the prosthesis and by cats during level walking.Several articles report testing neural technologies in animal models of locomotion. In a rabbit amputation model, Buettner et al. describe a virtual balancing apparatus that can modify gravity , damping, inertia. The apparatus can be also used to examine the effects of support surface perturbations. It may be well-suited to simulate conditions which could otherwise only be realized in space experiments and to examine the potential benefit for patients of virtual balance training. Sozzi et al. report the effects and the time-course of stabilization produced by a haptic cue provided by a walking cane. They argue that this type of haptic information has many of the features of the direct fingertip contact. They also suggest that the processing time of haptic input from a walking aid should be taken into consideration when designing prostheses for locomotion. Furthermore, Sozzi et al. assess balance improvement in subjects with low vision by adding the haptic input from a cane or fingertip. The authors discuss the ways visual and haptic information could be integrated in in the devices for balance training.Three articles address the issue of improving balance control. Malcolm et al. use a biomimetic approach to design prostheses with bi-articular actuation components. In their study, the effect of a bi-articular and spring configuration were tested that mimicked the m. gastrocnemius action; this design was compared to the mono-articular configuration and configuration without a spring. The authors discuss the specific effects of different exoskeleton configurations on metabolic cost and muscle activation that could be useful for providing customized assistance for specific gait impairments. Jayaraman et al. describe the impact of using powered knee-ankle prostheses in two transfemoral amputees. The participants gained the ability to walk with gait kinematics similar to normal gait patterns observed in a healthy limb. These results indicate that powered prosthetic components have a considerable potential to provide safe and efficient gait for individuals with above-the-knee amputation. Finally, van Dijsseldonk et al. report a framework for measuring the effects of training with the Rewalk exoskeleton on the ability to perform basic and advanced skills in people with complete spinal cord injury.Three articles analyze available evidence for using robotic devices for the benefit of patients with gait impairments. Myoelectric control of neuroprostheses for walking is a prominent theme in this Research Topic. This is a biologically inspired approach, where electromyography (EMG) feedback from lower-limb muscles assists walking in an exoskeleton or contributes to hybrid rehabilitation systems that combine functional electrical stimulation (FES) and a robotic exoskeleton.Grazi et al. report a novel assistive control strategy for a robotic hip exoskeleton that relies on the use of the gastrocnemius medialis EMG signal instead of a hip flexor muscle, to control the hip flexion torque and improve the reliability of the control system. Since the presence of moderate to severe spasticity can significantly impair gait kinematics and prevent such individuals from walking in an exoskeleton, Ekelem and Goldfarb applied peroneal stimulation (timed with the exoskeleton swing phase) to acutely suppress extensor spasticity in SCI subjects through the recruitment of the flexion withdrawal reflex. While the common peroneal stimulation had only acute effects (it did not have a significant effect on modified Ashworth scores), it suppressed extensor tone, significantly aided flexion in the hip and ankle joints and enabled improved exoskeletal walking for persons with severe spasticity.Zhang et al. propose a novel cooperative control strategy, which could realize arbitrary distribution of torque generated by functional electrical stimulation and exoskeleton. Two muscle groups (quadriceps and hamstrings) were stimulated to generate active torque for knee joint in synchrony with torque compensation from the exoskeleton. Experimental evaluation of the hybrid FES-exoskeleton system was conducted in five healthy subjects and four paraplegic patients. The system enabled cooperative control of torque distribution, trajectory tracking, and phase synchronization. Furthermore, Alibeji et al. describe a hybrid neuroprosthesis for walking that combines FES with a powered lower limb exoskeleton. This system has an electrical actuator at the hip and knee joints. The control framework mimics muscle synergy, where FES of the hamstrings and quadriceps muscle group of each leg restores walking in patients with paraplegia. The system was tested in an able-bodied subject and a patient with an incomplete SCI. Another article on myoelectric control  reports the orthotic and therapeutic effects due to continuous use of a foot drop stimulator  in children with foot drop and hemiplegia secondary to brain injury. The authors report that this treatment improves spatial gait asymmetry and increases dorsiflexion and toe displacement during swing. These are a potentially long-lasting effects.Sczesny-Kaiser et al. assess the effects and safety of body-weight supported treadmill training with the use of the HAL exoskeleton in patients with limb-girdle muscular dystrophy. All patients involved in this study benefitted from the training. Sczesny-Kaiser et al. report a crossover clinical trial comparing conventional physiotherapy and HAL supported treadmill therapy in chronic stroke patients with hemiparesis. The authors demonstrate the efficiency of individualized therapy based on this approach. Puentes et al. report the effects of HAL therapy in myelopathy  patients by performing the principal component analysis of the kinematic data. In this study, HAL therapy improved walking and gait coordination in patients by reshaping their gait pattern. Furthermore, Puentes et al. report an improvement in the intersegmental coordination (assessed by planar covariation of elevation angles) for the paretic and non-paretic side after early HAL intervention in hemiparetic stroke patients. Tan et al. show that muscle synergy analysis can be used as a tool to quantify the change and improvements in neuromuscular coordination of lateral symmetry during gait training in stroke patients with the help of the HAL exoskeleton. Finally, Shimizu et al. describe a case of voluntary ambulation triggered by upper limb activity using the HAL exoskeleton in patients with complete paraplegia after spinal cord injury. The HAL electrodes for the hip and knee flexion-extension were placed on the anterior and posterior sides of the upper limbs contralaterally corresponding to each of the lower limbs. The results suggest that an upper-limb-triggered HAL ambulation is a feasible option for rehabilitation of patients with complete quadri/paraplegia caused by chronic SCI.Several articles evaluate the efficiency of the Hybrid Assistive Limb (HAL) exoskeleton, a unique device that performs real-time collection of bioelectric signals from the patient to support and enhance voluntary gait. HAL exoskeletons are equipped with surface EMG electrodes that percutaneously detect minimal bioelectric signals generated by the patient's muscles (hip and knee flexors and extensors). Additionally, floor reaction force signals could be detected caused by patient's intended weight shifts. Murphy et al. assess the benefits of using an EEG-based BCI for lower-limb prostheses. The feasibility of such systems is supported by the implementation of a reliable knee-locking switch based on a EEG rhythm-feedback training for swing phase during walking and for sitting down in a transfemoral amputee. Ortiz et al. describe a new tool based on the Stockwell transform for the analysis of the EEG signals during gait cycle. Extraction of instantaneous EEG characteristics with this method was successfully tested in healthy individuals and patients with lower limb disabilities. Mejia Tobar et al. examine the classification of ankle flexion and extension movements from cortical current sources estimated by a hierarchical variational Bayesian method they use EEG and fMRI recordings. The presented method is also applicable to real-time BCIs and has the potential to identify neural patterns to control exoskeletons, prostheses and functional electrical stimulators. Wei et al. investigate the feasibility of gait phase recognition based on EEG combined with EMG using the corticomuscular interaction analysis and the time–frequency cross mutual information method. They report good recognition for three different walking speeds and discuss a theoretical basis for gait recognition based on EEG and EMG recordings during patient rehabilitation with lower limb exoskeletons.A group of articles report and analyze the usage of EEG signals for the control of prostheses for locomotion. Gad et al. in a case study report that spinal cord stimulation combined with pharmacological treatment enhanced the level of effort and improved the coordination patterns of the lower limb muscles, resulting in a continuous stepping motion in the exoskeleton along with the improvements in autonomic functions including cardiovascular and thermoregulation. In a large cohort of SCI patients, Shapkova et al. show that percutaneous electrical stimulation of the lumbar enlargement and exoskeleton-induced walking work together well to assist walking in SCI patients. Particularly, anti-spastic stimulation at high frequency enabled individuals with severe spasticity to be able to use the exoskeleton for walking. Overall, this study showed that the 2-week intensive synergistic effect of exoskeleton-assisted walking and the simultaneous spinal cord stimulation improve gait and neurological signs in chronic SCI, including complete paralysis.Finally, a promising approach is based on neuromodulation of the spinal circuitry during walking in the exoskeleton. This method is particularly beneficial for gait rehabilitation after SCI. This approach makes use of the activation of central pattern generation circuits that largely depend on the presence of a sustained excitatory drive  combined with the over-ground step training in an exoskeleton. In particular, Taken together, this Research Topic demonstrates the growth of interest to using neural prostheses for the restoration of locomotion in patients with neurological disorders that impair gait.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.This work was supported by the Russian Science foundation Grant 21-75-30024, USA National Science Foundation (NSF) Grant # 1912557, and the Italian Ministry of Health .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Galactosialidosis (GS) is a rare inherited lysosomal storage disorder (LSD) which is characterized by a defect in the lysosomal glycoprotein catabolism. We report, for the first time, the case of a child affected by GS presenting with recurrent episodes of extensive joint inflammation in both knee joints. The aim of this case-report is to describe the clinical presentation as well as the laboratory, radiologic and microscopic features of this unique presentation of GS. Furthermore, we explore inflammatory mechanisms potentially responsible for the origination of the arthritic joint pathology observed in our patient.We describe the rare case of a 12-year-old boy diagnosed with GS (late infantile form) who presented with multiple episodes of inflammatory arthritis involving both knees; no other joints were suspected for joint inflammation. Laboratory results did not indicate an autoimmune disorder. Synovial fluid tested negative for any bacterial infection and ruled out a malignancy and crystal-induced arthritis. Microscopic examination of the synovial tissue revealed numerous foamy macrophages with extensive vacuolization, consistent with the previous diagnosis of GS. Treatment consisted of aspiration of excessive joint fluid and subsequent intra-articular injection of triamcinolonhexacetonide with excellent but transient result. Given the evidence of storage products within macrophages of the inflamed synovial tissue and the absence of other etiological clues, GS itself was considered as the primary cause for the relapsing inflammatory joint pathology. According to the restricted data on articular manifestations in GS, to date, GS cannot be linked directly to joint inflammation. Nevertheless, in several other LSDs, the accumulation of storage material has been associated with numerous osteoimmunological changes that might play a role in the pathophysiology of arthritic processes.We hypothesize that the articular build-up of GS storage products triggered systemic as well as local inflammatory processes, resulting in the extensive inflammatory joint pathology as observed in our patient. Future identification of other patients with GS is required to corroborate the existence of an arthritic clinical phenotype of GS and to assess the underlying pathophysiology. CTSA gene which is located on chromosome 20q13.1. One of the major functions of PPCA is the formation of a multienzyme complex with alpha-N-acetyl neuraminidase 1  and beta-galactosidase 1 , which ensures the stability of these enzymes and protects both glycosidases from premature proteolytic post-translational modification [Galactosialidosis  is a rare autosomal recessive lysosomal storage disorder (LSD) characterized by malfunction of the lysosomal glycoprotein degradation and subsequent intra-lysosomal accumulation of sialyloligosaccharides and glycopeptides. In GS, the primary biochemical defect is the deficiency of the lysosomal protective protein/cathepsin A (PPCA), encoded by the Here we report, for the first time, a case of a patient affected by GS who presented with severe osteoarticular manifestations as well as recurrent episodes of inflammatory arthritis in both knees. The aim of this case-report is to describe the clinical presentation as well as the laboratory, radiologic and microscopic features of this rare GS phenotype. Furthermore, we explore inflammatory mechanisms that might play a role in the pathophysiology of the arthritic joint pathology in our patient.We report a unique case of a 12-year-old boy, previously diagnosed with GS, who visited the Department of Pediatric Rheumatology with relapsing episodes of progressive swelling in the patellar region in both knees.The patient was the first child of healthy, consanguineous, parents with a Turkish ethnic background. Pregnancy and delivery were uneventful and no abnormalities were observed in the first months of life . At 17 months of age, during an admission for an upper airway infection, an enlargement of the liver, a vertebral deformity and coarsening of the facial features were noted; hence an inborn error of metabolism was suspected. Urine oligosaccharides demonstrated elevations of urinary sialyloligosaccharides and subsequent fibroblast enzyme studies revealed deficient activities of PPCA, GLB1 and NEU1, thus confirming the diagnosis of GS. Since there were no prenatal and perinatal abnormalities the patient was classified as having the late infantile form of GS. During the following years the patient developed more typical GS-related clinical characteristics. An overview of the clinical features of GS in our patient is displayed in Table At the age of 8 years, the boy presented at the Department of Orthopedic Surgery for follow-up in the management of disease-related skeletal and joint pathology  and body weight was 19 kg . Physical examination revealed warmth and severe swelling of the right knee. No other joints were suspected for arthritis. Laboratory investigations revealed no abnormalities . The initial differential diagnosis included juvenile idiopathic arthritis (JIA), infectious arthritis, reactive arthritis and malignancy.Mycobacterium tuberculosis or Borrelia spirochetes). Furthermore, the synovial fluid was not suspicious for a malignancy nor crystal-induced arthritis. Microscopic examination of the synovial tissue revealed numerous foamy macrophages with extensive vacuolization, consistent with the previous diagnosis of GS. After the exclusion of infectious arthritis and malignancy, the patient was treated with an intra-articular corticosteroid injection (triamcinolonhexacetonide 1 mg/kg). The swelling reduced significantly during follow-up and had almost disappeared entirely after 6 months.Four months after presentation to the pediatric rheumatology service, diagnostic arthroscopy of the right knee was combined with bilateral hemi-epifysiodesis . During the arthroscopy severe synovitis in the joint space of the right knee was observed. Synovial tissue and fluid were obtained and sent to the Department of Pathology and Medical Microbiology for examination. Synovial fluid assessment revealed high cellularity and mononuclear cell infiltration. Cell analysis showed a significant predominance of macrophages. Additionally, synovial fluid tested negative for any bacterial infection  and laboratory results were virtually identical to the first episode. Treatment consisted of aspiration of excessive joint fluid and subsequent intra-articular injection of triamcinolonhexacetonide, which was highly effective in all episodes, as displayed in Fig. Over the years the patient did not develop any signs suggestive of arthritis in other joints, iridocyclitis, inflammatory bowel disease or skin rashes/psoriasis.GS is a rare LSD which presents with a wide range of clinical features. The musculoskeletal system is one of the organ systems typically affected, resulting in varying degrees of musculoskeletal deformities . A few sper exclusionem [A diagnosis which could explain the clinical picture is the JIA subtype: ANA negative oligo-articular JIA. JIA is the most common acquired chronic musculoskeletal pediatric disease and defined by joint inflammation, of unknown origin, that persist for more than 6 weeks and starts before the age of 16 years . JIA is lusionem , and theAccording to the sparse literature on joint complaints in GS, to date, GS cannot be linked directly to joint inflammation. Nevertheless, disease-related arthritis has been described in several other LSDs, such as: Fabry disease MIM #301500) , Farber 1500 , FaIn this study, we report, for the first time, the case of a boy affected by GS presenting with relapsing inflammatory arthritis in both knees. Given the evidence of storage material in the inflamed synovial tissue and absence of clues typical for other potential diagnoses, GS itself is considered as the primary cause for the origination of the inflammatory arthritis. Based on the literature about joint inflammation complicating LSDs, we hypothesize that the chronic articular accumulation of GS storage products triggered dysregulation of the innate immune system, resulting in the recurrent episodes of inflammatory joint pathology in our patient. Nevertheless, future identification of other GS patients with joint inflammation is required to corroborate the existence of an arthritic clinical phenotype of GS.


Transcatheter aortic valve implantation (TAVI) has rapidly evolved to become the treatment of choice for patients with severe aortic stenosis . DespiteFirstly, 2 articles describe the rapid expansion of TAVI in the United States and the efficacy of TAVI vs. surgical aortic valve replacement (SAVR) in low to intermediate surgical risk patients.Elbaz-Greener et al. describe trends in the utilization of SAVR and TAVI over time in the United States. They illustrate how TAVI use has expanded rapidly and overtook SAVR in 2017 to become the dominant treatment choice for severe AS. Utilizing data from the largest all-payer inpatient database in the United States, they identified a weighted total of 542,734 patients who underwent SAVR. Their data shows a relatively steady trend in utilization of SAVR in AS patients during the early TAVI era (2011–2014) with a significant downward trend in the following years (2015–2017). In contrast, TAVI use increased steadily over time. In the latter period there was an increased prevalence of comorbidities in the TAVI group; however, complications and mortality rate significantly decreased over time. This is likely related to increasing operator familiarity and newer generation devices that have better profiles and outcomes. Based on the data provided in this study TAVI will continue to expand and the gap between TAVI and SAVR diverge further.In the first article, Lou et al. describe the safety and efficacy of transcatheter vs. surgical aortic valve replacement in low to intermediate surgical risk patients with primary outcome of mortality. For patients deemed at low surgical risk, TAVI was associated with a lower mortality rate at 1 year. For patients with an intermediate surgical risk, mortality rates were equivalent between groups. TAVI was associated with decreased rates of bleeding and renal failure but increased rates of reintervention and major vascular complications. Regarding myocardial infarction and stroke, rates were similar between groups. Whilst it is important to show equivalence in low-risk groups, long term data are eagerly awaited. Whilst randomized data to 8 years exists, longer-term data from multiple randomized trials in low to intermediate risk patients will be the key to lowering the age limits in recommending TAVI over SAVR  valves. Despite a reduction in valve gradients when compared to standard postdilatation, long term data are still eagerly awaited to see if it translates into improved hard endpoint outcomes.Prosthesis-patient mismatch (PPM) develops when the effective orifice area of the prosthetic valve is relatively small in relation to body size. This results in the generation of higher-than-expected gradients through normally functioning prosthetic valves and has been associated with worse outcomes . PPM hasZhang et al., provide a timely update on the safety and efficacy of a dual vs. single antiplatelet strategy post-TAVI. Twelve studies of 20,766 patients were included in their meta-analysis. Compared with single antiplatelet therapy (SAPT), post-TAVI dual antiplatelet therapy (DAPT) was associated with increased risks of major or life-threatening bleeding without additional benefits of reducing thrombotic events  and more importantly the use of guide catheter extension technology are recommended (Finally, The constellation of the above articles emphasize the growing importance and efficacy of TAVI and illustrate some of the challenges with current technology.RJ and VP wrote the editorial. AL and AC critically revised it. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The digital workflow process follows different steps for all dental specialties. However, the main ingredient for the diagnosis, treatment planning and follow-up workflow recipes is the imaging chain. The steps in the imaging chain usually include all or at least some of the following modalities: cone-beam computed tomographic data acquisition, segmentation of the cone-beam computed tomography image, intraoral scanning, facial three-dimensional soft tissue capture and superimposition of all the images for the creation of a virtual augmented model. As a relevant clinical problem, the accumulation of error at each step of the chain might negatively influence the final outcome. For an efficient digital workflow, it is important to be aware of the existing challenges within the imaging chain. Furthermore, artificial intelligence-based strategies need to be integrated in the future to make the workflow more simplified, accurate and efficient. Digital dentistry is a broader term and covers the inclusion of computer-based tools guidance for a wide variety of applications, such as, patient data collection, communication, diagnosis, treatment planning and follow-up assessment.3When trawling through advancements in dental medicine, the classical steps in conventional workflows which were once considered as the norm, such as acquiring alginate impressions, treatment planning and template designing on gypsum-based models and relying on two-dimensional (2D) images of three-dimensional (3D) dentomaxillofacial structures, are constantly being superseded by more accurate and efficient digitized approaches.4 This digitization in dental medicine has not just altered the functioning and thinking of dentists but also played an important role in improving the patients’ experience. It has had a strong impact specifically for specialties such as dental implantology, restorative dentistry, endodontics and orthodontics, by constantly aiming for and ideally delivering a more accurate treatment with improved outcomes, a reduced complication rate and better patient monitoring.5,6 Also, further advancements are being made to simplify these digital workflows.7–9The main developments in digital dentistry which have allowed most improvements in the workflows include low-dose high-resolution cone-beam computed tomography (CBCT) scanners, intraoral scanners (IOS), CAD-CAM software programs, medical 3D printers and dynamic navigation systems.10 In restorative and prosthetic dentistry, it is now possible to fabricate and provide patients with the crown and/or bridge restoration and denture through the digital workflow and additive manufacturing with a reduction in the number of visits, which once required multiple appointments using a traditional workflow.11–13 In implantology, endodontics and oral and maxillofacial surgery, digital designing of guides and templates have allowed for more precise provision of the treatment by enabling ideally a flapless insertion of dental implants.14–16 Furthermore, application of the dynamic navigation systems in the digital chain have had a strong impact in the digital world by providing clinicians a virtual environment and real-time guidance for diagnostics, treatment planning and performing both simple and complex dental procedures with a higher accuracy and precision compared to the freehand or even static guided approaches.17,18The implementation of digital workflows in conventional orthodontics has allowed fabrication of various orthodontic appliances through 3D printing, virtual planning of brackets and the possibility to review the predicted outcomes beforehand.19,20 Clinically, it is pivotal to have a precise imaging chain for the generation of a model with sufficient details of the anatomical structures in question, enabling practitioners to accurately deliver the virtual planning in reality. An inadequate virtual model might lead to an inappropriate patient assessment, flawed treatment planning and unsatisfactory clinical outcomes. Therefore, the aim of this review was to provide an evidence-based overview of the possibilities and pitfalls associated with the integration of CBCT scanning, as well as intraoral and facial soft tissue imaging for the creation of a virtual model. Furthermore, recommendations for improving the existing imaging workflows will be provided.The digital workflow process in all dental specialties follows different steps. However, the most commonly shared main component between most of the clinical diagnostic, treatment planning and follow-up workflow recipes is the imaging chain for the creation of a virtual augmented model.21–24 Later, 3D planning software programs were introduced allowing reformatting of the CT-based cross-sectional images for the visualization of bone height/width, virtual placement of dental implants and 3D simulation of the surgical procedures.25 However, the wider implementation of CT scanners for regular dental applications was impossible due to the large size and cost of the machines, high radiation exposure and risks that outweighed potential benefits. To overcome these limitations, it was in 1998, when the first CBCT device, the NewTom 9000 , was introduced in the field of dental medicine.26 Although it offered lower radiation exposure, the image quality was still not up to par to that of a CT scanner. Since then, CBCT devices have undergone multiple modifications and are now able to offer low-dose high quality images with the availability of limited field of view (FOV). The constant developments in hardware and software programs with cutting-edge reconstruction algorithms have greatly contributed towards reduction in the radiation dose using 3D imaging. However, this dose reduction is also associated with a suboptimal image quality, which might negatively influence the 3D dentomaxillofacial treatment planning.27–29The first step, which paved the way towards digitizing dental workflows was the introduction of CT scanners. With the popularization of medical-grade helical CT scanners, early applications for dental medicine became available, which included utilization of the cross-sectional images for pre-operative assessment of the jaws for endosseous implant surgery.30 The majority of the devices available offer a variable radiation dose, ranging between 10 and 1000 μSv, which corresponds to 2–200 panoramic radiographs.31–33 A limited amount of information is provided by most of the companies pertaining to the technical characteristics of the CBCT devices, such as the effective radiation dose range.34 Furthermore, a wide difference exists amongst and even within the same CBCT devices in relation to the dose depending on the technical settings, where some devices are able to provide a 3D image at a lower dose compared to others which offer a radiation level equivalent to that of a medical CT.30 Thereby, it is recommended that companies provide radiologists with all the technical parameters, so further optimization of the settings can be achieved, allowing a balance between a low radiation exposure and an optimal image quality for reconstructing an accurate virtual model. In a dental practice, an accurate virtual model is vital for establishing a definitive and objective treatment plan and follow-up assessment when using a digital workflow, which might in turn improve patient care. For instance, creating guides for a precise dental implant insertion and endodontic treatment, design and production of dental restorations, virtual orthodontic and surgical planning, transfer of planning in combined orthodontic–orthognathic and oral oncology procedures and assessing treatment outcomes by superimposing virtual models at different time points.5The most troublesome aspect in achieving an optimal accuracy of the digital workflow is the actual image acquisition, which can influence the later steps and the final outcome. Currently, approximately 279 CBCT devices exist in the market with variable technical parameters.30 It is important to realize that these features can drastically alter radiation dose exposure as well as image quality. Thus, it only makes sense that a radiologist should have a manual control over these parameters to achieve a high quality image while following the ALADAIP  principles.35Amongst the exposure parameters such as tube voltage (kV) and tube current (mA), most devices offer adjustable settings to alter these parameters depending on the task at hand while in some they are fixed.36 which needs to be explored in future studies. Another important parameter is the FOV, where agreement exists that ideally a smaller FOV should be selected to reduce radiation dose exposure to the patient.37 Although a smaller FOV is optimal for general diagnosis, a larger FOV might be indicated for using CBCT during the digital workflow related to dental implant treatment planning, since these cases require increased numbers of data points for an accurate merging, superimposition and stable placement of surgical guides. In addition, cases involving oral pathology might also require visualization through a larger FOV to include also areas of healthy bone surrounding the lesion.5Even though kV and mA are adjustable in most devices, still no clinical evidence exists related to the optimal scanning settings for reducing the influence of streak metal artifacts,33Finally, the voxel size selection also influences the image quality and radiation dose. A smaller voxel size offers higher image quality with increased radiation exposure and vice versa. Some specific workflows in which small structures such as root canals, root fracture/resorption or periodontal tissue need to be visualized optimally for treatment planning, a smaller voxel size would be more feasible.35 The guidelines should focus towards achieving a balance between low radiation dose and optimal image quality for the creation of a virtual model.All the aforementioned acquisition parameters have the ability to influence the accuracy of later steps for generating a virtual model such as segmentation and registration, which in turn can lead to a suboptimal treatment planning and outcome. Further research and formulation of guidelines is required to optimize these parameters in relation to the digital workflows. As the prior guidelines have been laid based solely on the diagnostic quality of the images without characterizing the influence of image quality on the accuracy of a digital workflow.38,39 Also, it is an indispensable step in the imaging chain allowing successful monitoring of complex maxillofacial reconstructive procedures at follow-up.40 If an accurate segmentation is not achieved, then it might negatively influence the further steps in the treatment planning phase. For instance, it could impede an accurate registration with the surface-based data, thereby resulting in an imprecise planning of surgical drilling guides for implant placement and occlusal wafers in orthognathic surgery.41,42 The segmentation quality is dependent on the CBCT parameters settings, where a smaller voxel size might improve the image quality with a better segmentation accuracy, however, requiring a higher radiation dose.33The second most critical step in the digital workflow consists of image segmentation for generating a 3D model of the anatomical region of interest. These 3D surface-rendered volumetric models are an integral part of orthodontic, oral implantology, maxillofacial surgery and guided-endodontic digital workflows for ensuring a correct diagnosis and accurate virtual treatment planning.43 These software packages utilize a sensitivity tool known as “HU” for identifying the density value of a scan and segmenting based on voxel value  which corresponds to that of the CT HUs and not the voxel values obtained from a CBCT image.33,44 For that reason, manual segmentation by an expert could be considered as a solution over thresholding-based segmentation techniques. However, it is a very subjective technique, which relies on the observer’s experience and is also time-consuming. Additionally, when transferring the CBCT data to third-party software programs for segmentation, the data export causes image degradation if data compression is performed using a suboptimal (lossy) method,33 which can further influence the segmentation and accuracy of the later steps in the digital workflow. To overcome the information loss during data export, it is advisable to either use the original data for segmentation or to apply lossless compression algorithms when data are being transferred.45,46Another common shortcoming observed with segmentation of CBCT images using semi- and fully automatic third party software programs is that the thresholding level for the automatic segmentation of these software algorithms has been originally developed for medical CT images with standardized Hounsfield units (HUs), which cannot be applied to CBCT images.47–49Recently, various artificial intelligence (AI)-based networks have been deployed to overcome errors associated with segmentation and to simplify such digital workflows. Most of these AI-based machine- or deep learning networks have been applied for segmenting the teeth and skeletal structures and have provided methods to precisely segment even in the presence of artifacts.Although, these algorithms have been deemed highly accurate and time-efficient for segmenting anatomical structures in the dentomaxillofacial region, their generalizability is still questionable. Due to the wide variety of CBCT devices offering different scanning parameters and technical settings, all these factors influence the accuracy of AI-based segmentation. For instance, as the AI-network is trained on a specific data set acquired from a single CBCT device, the segmentation outcome might be optimal for only the images acquired with the same device and settings, hence requiring further optimization.50,51 Moreover, the presence of patient motion and artifacts from restorative materials or metal including dental implants further hampers its ability to provide an accurate 3D replica of dentogingival tissue. The conventional workflows which were based on acquiring stone models for the diagnosis and treatment planning in various fields of dentistry offered the limitation of dimensional changes and mould instability due to the ongoing chemical changes within the material.3The advancements in CBCT imaging have come a long way since its initial steps in clinical practice to provide accurate bone tissue segmentation. However, it still fails to provide adequate information related to the dentogingival tissue, interocclusal relationship and bite registration.52,53 The optical impressions have offered multiple advantages when incorporated into the digital workflow by offering decreased patient discomfort, time efficiency and better communication with the patient and dental technician.54To overcome the inherent inaccuracies associated with dentogingival tissue capture using CBCT imaging and conventional impression techniques, IOS have streamlined the digital workflows by providing with a more realistic and accurate surface reproduction. Currently, the main clinical applications of IOS are designing of inlays/onlays, veneers and crowns in restorative dentistry, denture frameworks and cleft obturators in prosthodontics, rendering customized archwires, fixed and removable appliance, aligners and indirect bonding trays in orthodontics, guided-surgery in implantology and production of surgical guides and wafers in maxillofacial reconstructive procedures.52,55 However, most of this evidence has been based on justifying the accuracy for manufacturing short-span prosthesis or restorations and 3D modelling templates.56 When considering the accuracy for acquiring a full-arch impression for a long-span prosthesis, conventional impression methods still remain the clinical standard as the IOS error rises with an increase in the edentulous scanning area.57 Further research needs to be conducted to improve the precision and trueness of IOS for whole arch scanning and to observe its influence on the accuracy of designing a long-span prosthesis.At the same instance, the disadvantages of IOS cannot be ignored. To date, extensive evidence exists justifying the trueness and precision of intraoral scanning and studies have found it to be clinically satisfactory for various dental procedures.58A realistic representation of the facial soft tissue is of vital importance for an optimal treatment planning and outcome assessment in the digital workflows of orthodontics and maxillofacial reconstructive surgery. Additionally, its importance in prosthodontic, restorative and dental implantology workflows cannot be denied, where rehabilitation of the aesthetic zone is at question.33 Also, the application of stabilization aids used for CBCT imaging protocols such as chin rests or forehead restraints might further distort the surface anatomy of the facial soft tissue.51 To overcome the provision of the lack of soft tissue information acquired with CBCT devices, 3D scanners have been employed into the digital workflows such as stereophotogrammetry, laser, and structured-light systems, providing a non-ionizing method of image acquisition to create a replica of the facial soft tissue with an accurate representation of the static geometry and texture in three dimensions.59 The stereophotogrammetric devices should offer a distinct advantage over the other systems by providing a fast acquisition time, a single shot capture offering a wider coverage of the facial soft tissue of up to 360 degrees and decrease the impact of the facial movements. However, based on current evidence all 3D scanners whether stationary or portable offer the same range of accuracy without any clinically significant difference if scanning protocols are appropriately followed.60To date, CBCT-based images lack the ability to offer a diagnostically distinct 3D image of the soft tissue due to a lack of contrast resolution and texture, which limits its application in the aforementioned digital workflows for soft tissue evaluation.61 Clinically, these real-time motion imaging devices are mostly applied in the digital workflows of cleft lip and palate and orthognathic surgery for assessing the surgical outcomes in relation to the facial soft tissue symmetry by asking patients to perform certain facial expressions.62 At present, the clinical applications of 4D imaging are limited due to its high cost and time-consumption, and is mostly used for research purposes. The current digital workflows rely on the 3D devices as these are faster and clinically more acceptable in the virtual clinical evaluation phase where all steps in the workflow are static. Future studies should focus on generating a real-time 4D virtual patient, where the integration of functional and dynamic records of the soft tissue, muscle tonicity and jaw motion path might allow to establish a comprehensive 4D treatment plan especially for surgical workflows. Additionally, 4D imaging could potentially act as a valuable tool for the smile design process by adding motion to observe the virtual smile path. This would then allow an efficient and dynamic treatment planning including relevant considerations of orofacial aesthetics.63Various four-dimensional (4D) stereophotogrammetric devices are also available in the market. 4D imaging which is defined as “‘a time sequence of 3D models of facial animations” allows recording of facial dynamics.64 The image quality of the dentogingival tissue displayed on the CBCT scan and the presence of artifacts makes it difficult to segment the teeth and to plan an accurate dental procedure or design an optimal surgical guide, so it is recommended to replace the region with virtual surface data of the teeth acquired from the IOS.41 The integration of the segmented CBCT model with the intraorally scanned teeth is commonly performed by a surface matching method, where the same teeth surfaces or anatomical regions on both the CBCT and IOS are selected to perform the registration. Even while integrating the scanned teeth into the CBCT model, the influence of CBCT artifacts from restorations and orthodontic appliances makes it difficult to achieve a perfect registration.50 Some authors have recommended the application of intraoral reference devices with fiducial markers or attachment of titanium markers onto the gingiva to facilitate an accurate registration process which is a time-consuming process.51,65 Others have suggested voxel-based registration by acquiring a double scan—a low resolution CBCT of the dentoskeletal region integrated with the teeth acquired from a high resolution CBCT to obtain an augmented virtual model.66 The drawback of this method is the violation of the ALARA principle due to the increased radiation dose as well as the increased potential for doubling segmentation errors. For most digital workflows used in dental medicine today, the registration is performed with surface-based registration. This approach uses an iterative closest point (ICP) algorithm for replacing the segmented CBCT dentogingival region with the IOS image. The corresponding surfaces are selected from both images and the algorithm automatically allows superimposition based on the similar shape features.67 However, its accuracy is questionable in cases where a CBCT image consists of streak metal artefacts from orthodontics brackets, which has a deleterious effect on the segmentation process and in turn might negatively influence the superimposition accuracy.The final step in the imaging chain of the digital workflows is related to registration or superimposition of the acquired 3D images of the skeletal structures, teeth and soft tissue for the creation of a 3D virtual augmented model.68,69 At the same instance, if the CBCT scan is not followed immediately by the facial soft tissue capture or vice versa, there is a higher risk of an inaccurate registration due to the changes in the soft tissue drape with a higher potential of patient movement.51 Also, it is recommended to acquire the CBCT without a stabilization device to overcome the deformation of the soft tissue for an accurate registration, otherwise the cumulative error might increase and lead to inaccurate treatment planning. One solution to improve the accuracy of the registration could be the simultaneous capture of the CBCT image and soft tissue by placing the facial scanner in front of the patient during CBCT acquisition.70 Another alternative could be the utilization of CBCT devices integrated with a facial scanner, allowing the capture of both, CBCT and soft tissue with a single scan.71Similarly, integration of the facial soft tissue onto the CBCT data is commonly acquired with surface-based registration. The accuracy of the registration is dependent on various patient-related and image acquisition factors, such as, soft tissue and muscular apparatus changes, jaw and head movement, patient positioning and patient stabilization devices. Although, the facial soft tissue surface artifacts induced by the patient movement  during CBCT capture are minimized when using non-ionizing facial soft tissue imaging devices due to their short acquisition time. However, due to the dissimilarities between the data acquired from both devices, the issue of an accurate registration still persists.72 However, further research needs to be conducted to refine their accuracy.Lastly, even though with the introduction of state-of-art technologies, an accurate surface registration of the teeth and soft tissue onto the CBCT data is a time-consuming process, prone to error and dependent on the accuracy of the segmentation of dentoskeletal and soft tissue structures from the CBCT image. Recently, AI-based neural network algorithms have been proposed for the automatic fusion of the intraoral scan and CBCT images without any human intervention.Imaging forms the basis of all the digital workflows in dentistry. The accumulation of errors at every step of the workflow might negatively influence the treatment planning, final outcome and monitoring at follow-up. Therefore, it is important to assess the induced collective error and how it might influence the clinical efficacy of a workflow. For an efficient digital workflow, it is important to be aware of the existing challenges within the imaging chain and come up with strategies for making the workflows more simplified and efficient. Although recent technological advancements have drastically enhanced the imaging aspect of the digital workflows, there is still room for further improvement by integrating AI-based strategies. The following future possibilities should be considered to further simplify the imaging workflow and to facilitate a personalized and predictive treatment planning and outcome assessment;Development of AI-based neural-network algorithms for automatic segmentation of dentomaxillofacial structures an improved virtual diagnosis and treatment planning.Generalization of the AI segmentation techniques by standardizing scanning. parameters used, propose and agree on patient- and workflow-specific guidelines, and train AI algorithms with larger data sets to improve the precision of the segmentation in the digital workflows..Development of an automated AI-based fusion algorithm for registration of the facial soft tissue and teeth surface data onto the segmented skull without any manual intervention or dependency on the selection of the region of interest.Application of imaging-based AI algorithms for the prediction of treatment outcomes and automatic assessment of tissue healing, growth and follow-up changes.The application of these networks and state-of-art technologies will definitely add to the time-efficiency of present digital workflows and could become a clinical standard in the near future for workflows where integration of 3D images forms the basis of treatment planning and outcome assessment .


The origin of life might be sparked by the polymerization of the first RNA molecules in Darwinian ponds during wet-dry cycles. The key life-building block ribose was found in carbonaceous chondrites. Its exogenous delivery onto the Hadean Earth could be a crucial step toward the emergence of the RNA world. Here, we investigate the formation of ribose through a simplified version of the formose reaction inside carbonaceous chondrite parent bodies. Following up on our previous studies regarding nucleobases with the same coupled physico-chemical model, we calculate the abundance of ribose within planetesimals of different sizes and heating histories. We perform laboratory experiments using catalysts present in carbonaceous chondrites to infer the yield of ribose among all pentoses (5Cs) forming during the formose reaction. These laboratory yields are used to tune our theoretical model that can only predict the total abundance of 5Cs. We found that the calculated abundances of ribose were similar to the ones measured in carbonaceous chondrites. We discuss the possibilities of chemical decomposition and preservation of ribose and derived constraints on time and location in planetesimals. In conclusion, the aqueous formose reaction might produce most of the ribose in carbonaceous chondrites. Together with our previous studies on nucleobases, we found that life-building blocks of the RNA world could be synthesized inside parent bodies and later delivered onto the early Earth. Ribose was recently identified in the soluble organic matter of carbonaceous chondrites , with mesurvival of the other one, and vice versa.One of the favored theories of the origin of life relies on the finding that RNA molecules can act as both catalysts of self-replication and genetic information storage, see, e.g., ,14,15,16one pot in WLPs during wet-dry cycles (requiring specific and changing conditions with respect to temperature and pH). They added ribose without forming it in the same pot, which makes the possibility of an exogenous delivery by meteorites an intriguing hypothesis. The different pathways to nucleosides and nucleotides shown in experiments by Orgel and colleagues 3−, [HPO4]2−, and [H2PO4]− depending on pH) [In this study, we used the same model and the same initial concentrations of reactants as in our previous study for nucleobases , in whicg on pH) . Moreoveg on pH) . In addig on pH)  and catag on pH) .Thus, ribose and nucleobases  deli


In 1977 Carl Woese identified a “primary kingdom” of life which he termed Archaebacteria  of laboratory cultivation for many of them. In the Research Topic on mechanisms of preservation and change in archaeal genomes, researchers from around the world present experimental studies investigating how archaea carry out basic genetic processes. Each of the seven contributions  enlarges the basis for ongoing efforts to reconstruct the early evolution of cells and develop new methods of archaeal genetics and biotechnology.Garnier et al. provide a clear and authoritative guide to archaeal topoisomerases which they dedicate to the memory of Maria Ciaramella and her research on archaeal DNA repair. After explaining topoisomerases in mechanistic terms, the review outlines the molecular diversity and biology of the archaeal enzymes, including their significance for challenges specific to cells growing under extreme conditions .Topoisomerases, for example, support diverse DNA transactions which affect genome structure and gene expression. Wasser et al. used the technique of protoplast fusion to produce artificially heterozygous Haloferax volcanii cells, and recovered recombinants without prior genetic selection. Their results indicate that non-reciprocal recombination  is very efficient in this species and forms tracts that typically cover multiple genes.One of the processes that operates in all cells to determine genome structure is homologous recombination, which supports genome preservation through repair of double-strand breaks and accurate bypass of unrepaired damage, and genome alteration through strand or sequence transfer between non-equivalent regions of shared sequence. Archaea encode characteristically “archaeal” homologs of bacterial or eukaryotic recombination proteins, but the functional properties of recombination have been studied in relatively few archaea. Guo et al. analyzed functional properties of the Ago homolog encoded by the hyperthermophilic archaeon Ferroglobus placidus and found that relatively short guide DNAs directed the site-specific cleavage of target DNA at temperatures up to 99 C . The properties of this endonuclease shed new light on the potential roles of Ago proteins in prokaryotes and the potential uses of the archaeal enzymes in DNA or genome engineering.The value of directing natural defense systems to disrupt expression of specific genes or the genes themselves has been well-demonstrated in eukaryotic organisms by RNA interference (RNAi) and later by use of prokaryotic CRISPR-Cas proteins. Argonaute (Ago) proteins play a central role in RNAi, but homologous proteins occur in diverse bacteria and archaea. Bergsch et al. analyze an AEP that supports replication of the Sulfolobus plasmid pRN1 in order to identify how this primase enforces its characteristic 8-nt primer length . The results implicate molecular interactions among the nascent primer and multiple enzyme domains, but not the mechanisms that have been proposed previously based on study of other AEPs. This archaeal enzyme may therefore represent the first demonstration of a previously unknown strategy to define primer length.Perhaps the most basic process capable of modifying genome sequences is that of DNA replication. DNA primases are central to replication and define two major types: the DnaG  type and the AEP (archaeo-eukaryotic primase) type. Miyabayashi et al. analyzed S. acidocaldarius deletion strains and observed various phenotypes when both the PolB2 and PolB3-encoding genes were deleted. In another study, Bohall and Bell confirmed the dispensability of the two corresponding polymerases of S. islandicus and observed a similar but distinct pattern of phenotypes that included increased hydrogen peroxide survival in PolB mutants .DNA polymerases similarly represent distinct protein families distributed among cellular organisms, viruses and some plasmids. B-family members are the most common DNA polymerases among archaea, and usually include the replicative polymerases among the Sulfolobales and other crenarchaeotes. Two independent studies now confirm that the PolB2 and PolB3 polymerases of these archaea are not essential but nevertheless contribute to some aspects of DNA-damage repair or tolerance. Ahmad et al. investigated the S. islandicus and S. acidocaldarius homologs of known mismatch-specific endoncleases (EndoMS) and confirmed that both of the Sulfolobus proteins cleave duplex DNA at mismatches . Furthermore, deletion of the S. islandicus gene increased the frequency of spontaneous mutation dramatically, whereas over-expressing this gene impaired culture growth, cell division, and chromosome replication.Finally, one of the enduring mysteries of extremely thermophilic and hyper-thermophilic archaea regards the high accuracy of their genome replication despite the lack of MutS/MutL-homologous pairs, which are critical to canonical post-replicational mismatch repair Grogan, . Ahmad eAll of these articles provide valuable perspectives on genetic processes that maintain, and sometimes modify, the genomes of archaea. The questions they address relate to the molecular strategies underlying basic genetic processes, and the results they report provide new insights into functional dimensions of the evolutionary diversity that has been revealed through analyses of archaeal genomes.The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Here, we systematically interrogate the effects of grafting single-walled (SWNT) and multi-walled carbon nanotubes (MWNT) to polymer matrices by using molecular dynamics (MD) simulations. We specifically investigate key material properties that include interfacial load transfer, alteration of nanotube properties, and dispersion of nanotubes in the polymer matrix. Simulations are conducted on a periodic unit cell model of the nanocomposite with a straight carbon nanotube and an amorphous polyethylene terephthalate (PET) matrix. For each type of nanotube, either 0%, 1.55%, or 3.1% of the carbon atoms in the outermost nanotubes are covalently grafted onto the carbon atoms of the PET matrix. Stress-strain curves and the elastic moduli of nanotubes and nanocomposites are determined based on the density of covalent grafting. Covalent grafting promotes two rivalling effects with respect to altering nanotube properties, and improvements in interfacial load transfer in the nanocomposites are clearly observed. The enhanced interface enables external loads applied to the nanocomposites to be efficiently transferred to the grafted nanotubes. Covalent functionalization of the nanotube surface with PET molecules can alter the solubility of nanotubes and improve dispersibility. Finally, we discuss the current limitations and challenges in using molecular modelling strategies to accurately predict properties on the nanotube and polymers systems studied here. Over the past two decades, immense efforts have endeavored to leverage the unique properties of carbon nanotubes (CNTs) to design and manufacture multifunctional nanocomposites for vehicles, electronics, sensors, and other applications ,2,3,4. WThe issue of CNT waviness and defects arise from the intrinsic properties of CNTs, while CNT dispersion in the polymer matrix and corresponding interfacial load transfer rely on interactions among the embedded CNTs and host. Solutions to the latter two factors are important to enable the practical applications and commercialization of CNT-based nanocomposites and are often approached chemically modifying the CNT surface . Such chNonetheless, it remains uncertain whether covalent grafting is an efficient method to improve the properties of CNTs-polymer nanocomposites. This is because covalent grafting promotes two competing effects: (1) improvements to interfacial load and phonon transfer and (2) alteration of CNT properties. Usually, it is difficult to experimentally measure the alteration of CNT properties post-grafting. Moreover, precise control over the surface functionalization of CNTs and pull-out displacement of CNTs should be implemented to assess the shear strength and other interfacial properties of the grafted composite. Most of the properties of nanocomposites are readily influenced by the extent of dispersion of the embedded CNTs, or other nanofillers. Thus, some of the improvements to the properties of CNT-grafted nanocomposites may be attributed to improved dispersion and intercalation of CNT into the polymer matrix. In this case, the two rivaling factors of improved interface and CNT alteration might balance each other. Thus, establishing a theoretical background to understand and evaluate the relative dominance of these three factors in preparing CNTs-polymer nanocomposites that have high performance, is still necessary.Atomistic molecular dynamics (MD) simulations are effectively implemented to study a wide range of engineering polymer matrices and nanofillers. Thus, MD simulations are employed here to establish relationships between CNT-polymer structure and macroscopic properties. For instance, remarkable increases in the mechanical properties of nanosilica-polyimide composites have been demonstrated by using MD simulations . The motIn retrospect, enormous efforts have been dedicated to understanding the mechanical properties of CNTs and to establish the structure-to-property relationship in nanocomposites. The multi-walled (MWNT) carbon nanotubes are more popular and cost-effective than the single-walled (SWNT) carbon nanotubes, thus, studies on strengthening and optimization of the inter-tubular interaction have been performed continuously. Since individual tubes are interacting with each other through the weak van der Waals (vdW) interactions, strengthening mechanism of the MWNT can be tailored by addressing some interfacial phenomena such as defects . AccordiThe influence of covalent grafting on the interfacial properties of nanocomposites has been studied by predictive algorithms. However, computational studies into the dispersion of functionalized CNTs through the Hildebrand solubility parameter ,27 have Here, we use MD simulations to systematically investigate the alterations in functionalized CNT properties, improvement of interfacial load transfer, and dispersibility of CNTs. We then use the insights from this study to evaluate the effectiveness and benefits of covalently grafting CNTs to the polymer matrix. Both SWNT and MWNT are considered, and polyethylene terephthalate (PET) is used as an amorphous polymer matrix. Various systems are modeled, including several with increasing extents of covalent grafting from the outermost side wall of the CNTs to the carbon atoms of the PET matrix via ethyl functional groups. The transversely isotropic elastic constants of the functionalized CNTs and nanocomposites are established from stress-strain curves. Finally, the Hildebrand solubility parameter of non-functionalized and CNT-functionalized PET matrices are compared and up-to-date techniques for modeling nanocomposites with periodic molecular unit cells are discussed.Here, a SWNT with a chirality of  and a MWNT consisting of three SWNTs with chiralities of , , and  were modeled as a reinforcing phase. An amorphous PET was selected as the matrix phase. The commercially available molecular simulation program Material Studio was used for modeling molecular unit cells and geometry optimizations . A polymx-axis in a Cartesian coordinate system for the nanocomposites and nanotubes. Prior to covalently grafting the nanotubes to the matrix, nanocomposites unit cells were again optimized by the same minimization scheme. The compositions of the unit cell for all of the molecular structures are summarized in The PET matrix for the construction of nanocomposites is consists of 16 chains, each of which is polymerized by 30 ethylene terephthalate monomers. Periodic boundary conditions are also applied to the PET unit cell. The total potential energy of the PET unit cell structure is minimized by the conjugate gradient method. SWNTs and MWNTs with different numbers of surface ethyl functional groups were embedded into the PET matrix to construct the transversely isotropic nanocomposites unit cell structures, as shown in The covalent grafting process is based on a dynamic cross-linking process or virtual in-situ cross-linking process that is widely used in molecular modeling of thermoset epoxy ,32,33. FBoth an equilibration and production run were performed by using the large-scale atomic/molecular massively parallel simulator (LAMMPS) program . The opt−1 until the true strain of the structures reached 6%. In tensile deformation, atoms at the boundary of the unit cell are displaced together with the elongation of the unit cell. Therefore, the increased interatomic potential energy in the displaced atoms act as driving force to increase the internal stress of the nanocomposites. The internal pressure tensor components perpendicular to the tensile loading direction were kept at 1 atm to account for the Poisson’s effect, and the virial stress components are recorded at every 2000 steps to predict the stress-strain curves. The tensile tests were repeated three times by assigning a different random number seed for establishing the initial velocity distribution of the atoms in a unit cell. Thus, three and six stress-strain curves were obtained for the longitudinal tension and transverse tension of nanocomposites, respectively. The elongation along x-axis results in longitudinal tension and those along the y and z axes yield transverse tension. The stress-strain curves were averaged in each loading case for comparison.After equilibration, the stress-strain curves of the nanocomposites were determined in a production run. To predict the tensile stress-strain curves, each unit cell was quasi-statically elongated at a constant true strain rate of 0.0002 psxy and xz planes yield longitudinal shearing and that on the yz plane results in in-plane shearing. The shear tests were also repeated three times on each plane. The longitudinal shear stress-strain relation was averaged over six stress-strain curves and the in-plane shear stress-strain relation was averaged over three stress-strain curves. All of the tensile and shearing tests were implemented at 300 K.The shear stress-shear strain relations were determined in a similar manner. Unit cells are quasi-statically distorted at the same strain rate. NVT ensemble simulations were used to determine and monitor the shear stress components from the virial theorem at each shear strain step to complete the shear stress-shear relations. As the nanocomposite unit cell is transversely isotropic, the shearing test on the The elastic constants of SWNT and MWNT grafted at their side walls at varying numbers of sites were determined to understand the altered properties of functionalized nanotubes. As both SWNT and MWNT nanotubes have tubular structures and different spatial configurations of carbon atoms , we assume that the nanotubes are transversely isotropic ,37,38. BLE was established by the following relationship:The elastic constants of the nanotubes were determined based on the relationship between the elastic constant and strain energy density in the MM calculations. The longitudinal Young’s modulus and major Poisson’s ratio of both nanotubes were calculated from a quasi-static longitudinal tension test of the nanotube unit cell model, as shown in J is the polar moment of inertia, and L is the length of the nanotube. For the MWNT, all of the inner and outer tubes were simultaneously twisted.Nanotubes were twisted as shown in TG was obtained from the following linear elastic relationship: Both the in-plane shear modulus and in-plane bulk modulus were calculated from the in-plane projection of the carbon atoms in a periodic unit cell according to the defined in-plane strains. At each strain increment, the nanotubes were displaced, and the corresponding deformation energy density was monitored. As distinct from the longitudinal tension and twisting, geometric optimization processes were not implemented to retain the deformed configurations. The in-plane shear modulus sp3 hybridization of carbon atoms in CNTs that are bonded by ethyl functional groups. As the carbon atoms functionalized with ethyl groups for the covalent grafting are sp3 hybridized, partially double-bonded primary interaction between the functionalized carbon atoms and their neighboring atoms are degraded to the single bonds. Therefore, covalently grafted CNTs become less stiff than pristine CNTs. The alteration of nanotube properties as a result of covalent grafting presents a trade-off for improved interfacial load transfer from the PET matrix to nanotubes and vice versa. As the macroscopic properties of nanocomposites are readily influenced not only by the properties of nanotubes but also the interfacial load transfer mechanism, the results in The transversely isotropic elastic constants of SWNTs and MWNTs are listed in sp3 hybridized carbon atoms in each MWNT is lower than in SWNTs. Thus, the deformation energy density, or deformation energy and resultant elastic constants, of MWNTs are less sensitive to the number of grafting sites than those of SWNTs. Meanwhile, the SWNT is hollow and has a lower mass than MWNTs, which can be advantageous. Analysis of ijC is the engineering notation for the elastic stiffness component. The full elastic stiffness tensors of the SWNT and MWNT enable the prediction of the elastic stiffness of nanocomposites predicted from existing micromechanical models, such as the Mori-Tanaka (M-T) model, self-consistent (SC) model, double-inclusion (D-I) model, and others. In The transversely isotropic fourth-order elastic stiffness tensor can be constructed by applying the constants in sp3 hybridization of grafted carbon atoms on the nanotubes. The periodic boundary condition is applied in the longitudinal direction of the nanotubes to determine the longitudinal tension of the nanocomposites. As such, the alteration of the nanotube directly relates to the behavior of nanocomposites. As the molecular model used here includes perfectly aligned nanocomposites, the stress-strain curves shown in The transversely isotropic stress-strain curves of PET nanocomposites reinforced with either SWNTs and MWNTs are shown in In transverse tension, the transverse stress of the nanocomposites increases with the number of covalent grafting sites, as shown in The same tendencies are observed for longitudinal and in-plane shearing. Namely, the shear stress in the composites increases with increased numbers of grafting sites. There was initial residual stress at the beginning of in-plane shearing of MWNT/PET composites. Thus, the in-plane shear stress of the nanocomposites was calibrated based on the initial shear stress to enable more accurate comparisons of the evolution of shear stress with in-plane shear strain. As both longitudinal and in-plane shear moduli decrease with nanotube grafting, improvements in shear stress-shear strain relationship c,d reflef is the volume fraction of the constituent, and the subscripts p and m indicated the filler (the CNT) and matrix (the PET), respectively. The fourth-order tensor Quantitative insights into the effects of covalent grafting on the transversely isotropic Young’s moduli and shear moduli of the nanocomposites were established from the stress-strain curves, as shown in aic form ,42 as: are provided in The transverse Young’s modulus and shear moduli of the nanocomposites increase with the number of grafted sites. Notably, the MD simulation results are lower than those predicted by the M-T model for nanocomposites with non-grafted nanotubes. Even if the interphase zone forms around the nanotube, the load transfer between the interphase zone and pristine nanotubes via secondary bonding is insufficient to influence composite properties. Thus, the contribution of the interphase zone to the overall elastic moduli is not apparent. As the number of grafting sites increases, however, the trend reverses. The MD simulation results are greater than those predicted by the M-T model. The stiffness of the interphase zone becomes important because the interfacial load transfer between the nanotube and interphase zone is promoted by covalent bonds. This result also demonstrates that covalently or non-covalently grafted nanotubes, as well as nanotube surface functionalization, are important for exploiting the interphase zone to reinforce the nanocomposite. Alteration of the nanotube properties is inevitable for the covalent grafting, but the improved load transfer and participation of the interphase zone in load-bearing is anticipated to be beneficial.In order to use the CNTs for hybrid composites sensors, interfacial load transfer from matrix to CNT or vice versa is an important parameter to increase the mechanical sensing ability. In randomly dispersed CNTs percolation networks for the sensors, interfacial load transfer is mostly by the shearing between CNT and surrounding matrix. Even if polydispersed CNT microstructure was not considered in our model, we can reasonably conjecture that the covalent grafting can improve the sensing capability of CNTs-based smart composites sensors. Local stresses to the nanotubes were calculated according to the strain applied to the nanocomposites, to correlate improvements in the transverse Young’s modulus and shear moduli of nanocomposites with the interfacial load transfer in the PET-nanotube composites. 2 MPa, as shown in sp3 hybridization.For transverse tension, the stress in both nanotubes is on the order of ~10For longitudinal and in-plane shearing, the contribution of covalent grafting is clearly demonstrated. Pristine nanotubes carry almost no shear stress, with the exception of in-plane shearing for the MWNT/PET, as shown in Comparing c is the cohesive energy density, R is the gas constant, T is the temperature of the system, and mV is the molar volume of the system. Two parametric sets were prepared to understand the effects of covalently grafted PET functional groups on the solubility parameter. Specifically, one set varied the number of surface-functionalized ethylene terephthalate monomers on the outer most wall of the MWNT, and the other set varied the number of monomer groups on the grafted PET moieties. The dispersion of nanotubes in the polymer matrix is challenging to control but nonetheless important for reinforcing the composite. The contributions of covalent grafting to the dispersibility of the grafted nanotubes are studied by using the Hildebrand solubility parameter  of the nThe solubility parameter of PET-functionalized MWNTs is compared with that of pure PET in  grafted b. Thus, The improved dispersibility of MWNTs by covalent grafting prompts a reconsideration of the molecular unit cell model in sp2 hybridization occurs and the transversely isotropic elastic constants of both nanotubes decrease. This reduction demonstrates that covalent grafting of nanotubes can play a negative role.Here an MD simulation was performed to evaluate the effects of covalent grafting of nanotubes on the elastic properties of PET-nanotube nanocomposites. When SWNTs and MWNTs were covalently grafted to a PET matrix, In terms of elastic moduli, covalent grafting of nanotubes dramatically improved interfacial load transfer of nanocomposites for transverse tension and shearing. The transversely isotropic elastic moduli of nanocomposites were determined and compared with the predictions by the M-T model, which assumes perfect interfacial bonding conditions. As the extent of covalent grafting increases, the MD simulation results of transverse tension and shearing substantially increase and exceed the M-T model solution, due to the contributions of a highly densified interphase zone.Examination of the evolution of internal stress in nanotubes for tension and shearing of the nanocomposites revealed covalent grafting as a dominant factor for improved interfacial load transfer. Due to the slender configuration of the nanotube, improvements in load transfer were greater under shearing conditions. Moreover, the MWNT showed stronger intrinsic interfacial adhesion strength than the SWNT due to its robust characteristics with respect to transverse tension and in-plane shearing. Interrogations with the Hildebrand solubility parameter determined that covalent grafting enhanced the dispersibility of nanotubes in a PET matrix. Functionalizing longer and more PET to the surface of nanotubes results in greater miscibility to the PET matrix. As facile interpenetration of PET molecules into the CNTs results in the sufficient formation of a polymer sheathed zone, covalent grafting contributes to interfacial properties as well as the formation of an interphase zone.


Sensory cues provided by compression garments (CG) can improve movement accuracy and potentially reduce inter-limb balance asymmetries and the associated risk of injury. The aim of this study was to analyze the effects of CG wearing on inter-limb balance asymmetries. The hypothesis was that CG would reduce inter-limb balance asymmetries, especially in subjects with high level of asymmetries. Twenty-five sportsmen were recruited. They had to stand as motionless as possible in a one-leg stance in two postural tasks (stable and unstable), while wearing CG or not. Asymmetry indexes were calculated from center of foot pressure parameters. The effects of CG wearing were analyzed according to participants’ baseline level of asymmetry  with correlation analyses. A qualitative analysis was also performed after a dichotomization procedure to check for a specific influence of CG on the dominant and non-dominant leg. Inter-limb balance asymmetries were reduced with CG in participants with high levels of asymmetries at baseline. However, asymmetries were increased with CG in participants with low levels of asymmetries at baseline. The dominant leg was more affected by this negative effect. CG wearing could reduce inter-limb balance asymmetries and the related injury risk in subjects with high levels of inter-limb balance asymmetries at baseline. Nevertheless, CG should not be used in individuals with low baseline balance asymmetries since it can increase asymmetries in these subjects, likely by confusing and overloading the sensorimotor processing on the dominant leg. Asymmetries between two limbs are prevalent in human movement. They are characterized by a difference in performance between the right and left limbs and/or the preferential use of one side of the body  to perform a motor action . The etiInter-limb asymmetries can have a negative impact on sports performance and are associated with a high incidence of lower-limb injury, especially if asymmetries concern balance control . ActuallHence, this study was undertaken to investigate the effects of CG on inter-limb balance asymmetries in individuals with extensive experience in an asymmetric sport such as handball players. Handball is a sport involving asymmetric motor actions (lower and upper limbs) that can accentuate inter-limb asymmetries, which might negatively affect athletic performance and increase the risk of lower extremity injuries . Thus, aTwenty-five young handball players  who reported no neuromuscular problems in the past 2 years volunteered for the current study. Participants were recruited from two regional semi-professional teams. They were asked to avoid strenuous activity and the ingestion of alcohol or/and excitatory substances 24 h before the experimental session. A written informed consent was obtained from all participants before starting the experiment, which was in accordance with the Declaration of Helsinki. All procedures were approved by and performed in accordance with the relevant guidelines and regulations of the University of Pau and Pays de l’Adour Ethics Committee.® Techno Concept™, Mane, France) which sampled the displacements of the center of foot pressure  at 40 Hz. Two postural tasks were conducted: a stable task where participants stood directly on the force platform (on stable ground) with their eyes closed (while keeping their gaze straight ahead) and an unstable task where they stood with their eyes open (while looking at a fixed level target at a distance of 2 m) on a wobble board with a diameter of 40 cm and a height of 8 cm  which was placed on the force platform to generate instability. For accurate and similar feet positioning between all participants, the platform and the wobble board were marked with a central horizontal line, and participants were required to align the middle of the foot with the mark (the middle of each foot was delimited beforehand). The center of the wobble board was also aligned with the center of the force platform.Participants were asked to sway and move as little as possible when standing barefoot in a one-leg stance for 25 s on a force platform  made of 79% Polyamide and 21% Elastane, were worn by the participants . In the CG condition, calf compression sleeves  along the medio-lateral (VX) and antero-posterior (VY) axes and surface area (S: 90% confidence ellipse) . Based owith ABS: absolute value.When considering that with participants who were asked to sway as little as possible when standing upright, the lower the center of pressure parameters , the more efficient the balance control , the higThe two postural tasks (stable and unstable) were analyzed independently. Normality was tested using the Shapiro–Wilk test. As the dependent variables  did not meet the assumption of normal distribution, non-parametric Wilcoxon sign rank tests were applied to determine differences between the CG and REF conditions. The difference of each asymmetry index between the CG and REF conditions (difference = CG - REF) was also calculated to easily differentiate participants who benefit from CG wearing to reduce inter-limb balance asymmetries (negative difference) and those who do not (positive difference). Then, Spearman’s rank order correlations were undertaken between asymmetry indexes at baseline  and differences in asymmetry between the REF and CG conditions to assess whether the beneficial effects of CG in reducing inter-limb balance asymmetries was related to the participant’s inter-limb balance asymmetries at baseline.2-conformity tests were independently performed on DL and NDL data to test the null hypothesis . This qualitative analysis was performed on the whole sample and on subgroups of individuals in order to check whether individuals who benefited from CG to decrease inter-limb balance asymmetries and those who do not were differently affected by the wearing of CG on the dominant and non-dominant leg. Sub-groups were formed by distinguishing subjects in whom CG wearing had no substantial influence on asymmetry indexes , subjects in whom CG wearing markedly increased the level of asymmetry  and subjects in whom CG wearing markedly decreased the level of asymmetry . Based on previous studies about reliability of center of pressure-based postural sway measures during one-leg stance in young healthy participants, the 10% threshold was chosen to distinguish between clear and unclear changes due to measurement noise , with a an under-representation of individuals for whom CG wearing had negligible influence on the dominant-leg. When the χ2 test was applied on participants’ distribution based on VY data on the non-dominant leg, a significant difference from an equal distribution , with an over-representation of individuals for whom CG wearing had negligible influence on balance control of the non-dominant leg. Results from the Fisher’s exact test showed a significant association between subgroups of participants and CG influence on balance control on the dominant leg when participants’ distribution were based on VX (p < 0.003) and VY data (p < 0.005). Individuals in whom CG wearing markedly increased the level of asymmetry were negatively influenced by CG wearing on the dominant leg. Results from the Fisher’s exact test did not show any significant association between subgroups of participants and CG influence on balance control of the non-dominant leg.The aim of this study was to analyze the effects of CG wearing on inter-limb balance asymmetries. The hypothesis was that CG would reduce inter-limb balance asymmetries, especially in subjects with high level of asymmetries. When using a standard statistical approach with pairwise comparisons between group levels, our results showed that the wearing of CG was not associated with a significant reduction of inter-limb balance asymmetries. However, when analyzing the effect of CG wearing according to participants’ initial level of asymmetry, results from correlation analyses indicated that beneficial effects of CG in reducing inter-limb balance asymmetries were related to participant’s asymmetry levels at baseline. Only participants with high levels of inter-limb balance asymmetries at baseline benefited from CG to decrease inter-limb balance asymmetries.Inter-limb balance asymmetries are mainly related to differences in somatosensory processing between both legs originating from cerebral hemispheric asymmetry . Within When wearing CG, frictional forces that activate both slow and fast-adapting cutaneous mechanoreceptors are applied to the skin, which can improve joint position sense and balance control . In the In the present study, participants with high levels of inter-limb balance asymmetries at baseline benefited from CG wearing to reduce inter-limb balance asymmetries. However, in both the stable and unstable postural tasks, the data from the qualitative analysis about the specific influence of CG on both legs  did not A limitation of the current research is the absence of measure of the pressure exerted by the calf compression sleeves. Although compression sleeves were individually fitted by following the manufacturer’s specifications and choosing proper sizing according to individuals’ calf circumference, commercially manufactured compression garments do not provide exactly the same level of compression in all subjects. Potential differences in the pressures exerted by the CG might modulate the effects of CG on inter-limb balance asymmetries. Nevertheless, studies that have tested the effects of CG providing various compression levels on balance control did not report any significant differences attributed to the level of compression e.g., . It shouThe present study provides new insights about the influence of CG on inter-limb balance asymmetries. From a practical point of view, these results suggest that CG wearing could reduce inter-limb balance asymmetries and the related injury risk in participants with high levels of inter-limb balance asymmetries at baseline. In return, since it rather increases asymmetries in participants having low baseline balance asymmetries, CG wearing should be avoided in these participants.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the University of Pau and Adour Countries Ethics Committee. The patients/participants provided their written informed consent to participate in this study.FN, KB, and TP designed the study. KB acquired the data. FN analyzed the data and wrote the manuscript, while KB and TP revised it. All authors signed the final approval for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.