However, no significant difference in the overall orthodontic knowledge and skills was observed between the groups at the end of the course. Both learning methods showed moderate positive correlation between orthodontic knowledge and skills. In conclusion, virtual learning can serve as an effective alternative to traditional face-to-face learning for teaching orthodontic knowledge and skills to the dental students.A gradual transition from traditional face-to-face learning to online learning has been observed globally following the COVID-19 pandemic. The aim of the study was to compare online and traditional learning methods in relation to orthodontic knowledge and skills acquired in undergraduate courses. A quasi-experimental design was used with two consecutive year classes of 198 dental students at Jazan University, Saudi Arabia. The experimental  group of 92 students received the content of a clinical orthodontic course virtually using the Blackboard Collaborate™ platform. The control  group consisted of a previous cohort of 106 students who enrolled in the same course but received traditional classroom education. The students were evaluated through a semester, and both groups obtained the same content and exam questions. The students in the virtual group scored higher in the final theory exam than the traditional group ( It has been one hundred years since dentistry became a specialty. As dentistry evolved in the era of physics and chemistry, the initial research focused on improving materials and techniques . Since tSince the World Health Organization declared the coronavirus disease 2019 (COVID-19) outbreak a pandemic on 11 March 2020, many countries enforced lockdowns and quarantine measures to curb its spread. Consequently, there has been a general shift from traditional face-to-face instruction to online learning. Online learning/electronic (e)-learning is a type of learning environment that takes place over the internet where knowledge can be transferred and acquired virtually using multiple medias. Accessibility to information despite location, a more customized learning experience, cost-effectiveness, improved scope of learning as per individual interest, comfort and flexibility of sharing knowledge with others are some of the important benefits of this . As a reIn contrast to face-to-face education, the emergence of online education has led to student-centered approaches, in which the students can self-regulate what they study . MassiveSeveral studies have suggested that online and blended educational approaches can be compared to those of traditional classroom models ,15. The In Saudi Arabia, a study on dental students’ perceptions of online learning conducted at King Saud University showed overall positive responses regarding the usefulness of online tutorials. Moreover, few students supported the replacement of traditional lectures and live demonstrations with online tutorials, while most students preferred a combination of these teaching methods . There iThe study was conducted among the sixth-year dental students of two consecutive years at Jazan University, College of Dentistry, to compare orthodontic knowledge and skills in undergraduate courses between virtual and face-to-face traditional learning methods. The study was reviewed and approved by the Ethical Committee of Scientific Research Unit, College of Dentistry, Jazan University (Reference Number: CODJU-2014F).A quasi-experimental design was used in which a retrospective control group in the first semester of the 2019 academic year was compared to a prospective experimental group in the first semester 2020. This study used convenient sampling, and all selected students were enrolled in a two-credit clinical orthodontic I course with three contact hours per week . The clinical orthodontic I course is a 15 week-long course taught in the first semester of the last year of the six-year program of Bachelor of Dental Surgery (BDS) and includes the course learning outcomes indicated in The Blackboard Collaborate™ is an e-learning platform and a learning management system that provides various interactive learning tools, such as announcements, calendars, tasks, assessments and grading . The menThe types of educational assessments in the course were midterm and final theory examinations, objective structured clinical examination (OSCE), and a spotter examination. The midterm and final theory examinations included multiple-choice questions, whereas OSCE and the spotter examination included short essay questions. The midterm examination covered learning outcomes 1.1 and 1.2 and the final theory examination covered learning outcomes 1.2, 1.3, 2.1 and 2.2 . OSCE coThe level of knowledge among the students was assessed by combining the scores obtained in the midterm and final theory examinations. Skills acquired among the students were assessed by combining the scores of OSCE and spotter examination. In both groups, the students received the same type of evaluation methods and questions. The questions of the exams were reviewed by the exam review committee at the Preventive Dental Sciences Department, College of Dentistry, Jazan University. p-value was set at 0.05 for all tests.Data were analyzed using SPSS version 26 . A chi-squared test was used to compare the descriptive characteristics of the variables, grade point average (GPA) and the gender distribution across traditional and online learning. All variables were tested for normality using the Shapiro–Wilk test to identify any differences among the two groups. Overall differences in the course learning outcomes, including knowledge and skills, between the traditional and virtual learning methods were compared using the Mann–Whitney test. Moreover, the Spearman rho test was used to assess the correlation between the scores and the assessment methods. The A total of 198 students with a median age of 23 years (IQR: 23–24) were enrolled in the course of two consecutive years, of whom 106 students attended the traditional learning and 92 students attended the virtual learning. There was no statistical difference in terms of the students’ number and age between the groups. Males (53.54%) constituted the majority of the study students with no significant difference between the number of males and females and their distribution in traditional and virtual learning groups. The median GPA score in the virtual group was significantly higher than that in the traditional group (4.35 (IQR: 4.02–4.55) and 4.14 (IQR: 3.67–4.47), respectively) as shown in p < 0.0001) between the orthodontic knowledge and skills when the students were taught via either virtual or traditional learning methods. No statistically significant difference was found in the level of knowledge and skills between the groups. However, slightly higher knowledge and skill scores were observed in the students in the virtual learning group compared to those in the traditional group . However, the students in the virtual group scored higher in the final theory exam than the traditional group. No significant difference was noted between the two groups regarding the scores acquired on the OSCE and spotter exam (ter exam . In the virtual group, the students with high GPAs scored better in the spotter exam. Besides this, both learning methods showed a significant strong correlation between knowledge and GPA and a moderate correlation between skills and GPA . Concerning gender differences, mean scores classified by gender, learning and assessment method are shown in Most educational institutions temporarily closed following the spread of the COVID-19 pandemic. As a result, the only way to continue to provide education was via digital technology. Online learning is receiving progressive popularity in the field of dental education. This quasi-experimental study demonstrated that the virtual learning method is comparable to the traditional one in teaching orthodontic knowledge and skills in undergraduate dental courses. The results of the current study were consistent with those of other studies in the medical field, where online learning can be considered a potential method in undergraduate medical teaching . MoreoveThe COVID-19 pandemic has shown that digital technologies will play a dominant role in the future development of dental education . Some stSeveral survey studies during the pandemic have reported either positive or negative attitudes toward online teaching among different dental colleges in different countries ,31. The In addition to theoretical education, dental students must develop the clinical skills necessary to diagnose a patient’s problems and provide a suitable treatment plan . Abbasi Gormley et al. reported that undergraduate medical students considered e-learning to be just as effective as other traditional methods for the teaching of clinical skills . In the Gender differences in academic performance and self-efficacy in online-learning environments were documented. The results of our study are in line with the general trend that female students perform better than males on the online courses . AlthougThe Blackboard system provides a useful educational environment where students can interact socially and academically with each other and staff . It alsoIn this study, students were evaluated for the entire semester using routine assessment methods. This is a strength of the study, as the risk of bias related to the Hawthorne effect is neglected. However, some limitations related to the nature of a quasi-experimental study design should be acknowledged. Randomization and pure experimental design were not possible in obligatory university courses; nevertheless, two-consecutive-year students with similar demographics in the groups would reduce the selection bias.Moreover, another limitation of this study was that the learning methods were evaluated on final-year students. As the knowledge varies between academic years, using senior students could lead to bias in the study because of their knowledge and skills in orthodontics gained from other disciplines . TherefoBased on the findings of the study, I can conclude that there was no significant difference in orthodontic knowledge and skills among students irrespective of the learning methods. However, higher knowledge and skill scores were obtained for those who had received online learning. The female students in the virtual group scored higher in the final theory exam than the male students. In view of the advantage of online methods for teaching theoretical topics and its equal effectiveness in training clinical skills, it can serve as an effective alternative to traditional face to face learning.


This study aimed to evaluate the influence of different types of restorative materials and resin cements on the stress distribution in the regions of the restoration, cement layer and dental remnant in endodontically treated posterior endocrowns.A 3D finite element analysis (FEA) model of the first mandibular molar that was restored with an endocrown designed by computer-aided design (CAD) software was generated. Three kinds of restorative materials (Vita Enamic (VE), IPS e.max CAD (EMX) and Grandio blocs (GR)) and two types of cementing materials (NX3 and Maxcem Elite Chroma (MX)) were analysed with such a model. The food layer was also designed before vertical (600 N) forces were applied to simulate physiological masticatory conditions. Thermal expansion was used to simulate the polymerization shrinkage effects of cement layers. The results were obtained by colorimetric graphs of the maximum principal stress in the restoration and tooth remnant. The failure risk of the cement layer was also calculated based on the normal stress.The elastic modulus was positively correlated with the tensile stress peak values in the restoration, mainly at the intaglio surface. However, in the cervical enamel and cement layer, restorative material with a higher elastic modulus generated lower peak stress values. The cement with a higher elastic modulus resulted in higher stress peak values inside the cement layer. The combination of EMX  and NX3  in the cement layer resulted in the lowest failure risk.The ceramic material EMX with a higher elastic modulus appeared to be more effective at protecting the cement layer and residual enamel tissue. Based on the analysis of the failure risk of the cement layer, the combination of EMX and NX3 was recommended as an optional material for endocrowns for endodontically treated posterior teeth. In recent years, the development of adhesive dentistry, in conjunction with improvements in the mechanical properties of restorative materials and their manufacturing process, has enabled restorations to recover all or part of weakened tooth resistance, thus increasing the possibility of more conservative restorative procedures –3. Less Endocrowns can be made using computer-aided design/computer-aided manufacturing (CAD/CAM) technology, which minimizes clinical adjustment and defects during the manufacturing process and allows completed treatment in a single session. Recent studies have shown that the materials available for endocrowns mainly include resin composites , hybrid The reliability of adhesives is the key factor to achieve long-term satisfactory effects. Poor adhesion leads to micro-leakage, secondary caries and periodontal disease and ultimately repair failure . The sucTo evaluate the stress distribution in ETTs generated by mastication, three-dimensional finite element analysis (3D FEA) has been widely used due to its low cost and standardized parameters . TherefoA 3D CAD model of a healthy mandibular molar was built by means of a micro-computed tomography (micro-CT) scan system  and CAD software  to generate the shapes of dentin, pulp and enamel. Starting from this 3D CAD model, endocrown models of flat design preparation and restoration with different materials were created. To simulate an ETT, the root canal was filled with gutta percha 1 mm below the orifice, and the pulp chamber floor was tiled with flowable resin . The endocrown was prepared as described in our previous study : cuspal The mechanical properties of the materials and structures used in this study were determined from published values Table . All strThe colorimetric graphs in Figs. This study aimed to evaluate the stressed regions in the posterior endocrown and in the cement layer according to different restorative materials and different resin cements. The results showed that the elastic modulus of the restorative material and the resin cement can influence the stress concentration at the adhesive interface. Thus, the hypothesis was rejected.To accurately mimic the stress transmission during masticatory movement, the food layer was designed before vertical and horizontal forces were applied. Most 3D FEA studies for dental mechanical properties are carried out with three-point loading, resulting in the stress of the restoration always being concentrated on the loading point . In factFrom the colorimetric graphs, it is suggested that a higher elastic modulus of NX3 can reduce the peak stress in the prosthesis. However, the two kinds of cement had little effect on the peak value of the prosthesis, which might be the reason for the thin cement layer and the small discrepancy in the elastic modulus between NX3 and MX. Regarding the restorative material, the higher the elastic modulus was, the higher the stress concentration in the restoration. According to the manufacturer and previous studies , the biaIt is notable that some studies , 41 did Referring to Fig. Regarding the dental remnant structure, higher stress peaks concentrated in the surrounding enamel , which was the initial area where failure occurred, were observed in the materials with a lower elastic modulus (VE or GR). Due to such a stress distribution, fracture may occur in the enamel edge and propagate to the inner enamel, resulting in micro-leakage around the affected restoration . It is kWhen incorporating the analysis of stress distribution for overall structures and the failure risk assessment for the cement layer, despite all limitations of this study, the group restored with EMX and NX3 is recommended regarding endocrowns for endodontically treated posterior teeth. The results of in vitro simulation testing cannot be predictively extended to the clinical situation because this simulation study design did not consider typical factors, such as wear resistance, fatigue resistance or aesthetics. This study only analysed the stress distribution of endocrown molars under a static load at closing phase of the chewing cycle. Therefore, future studies with dynamic loading and clinical trials with long follow-up periods are indicated.


Global travel and tourism have enjoyed a significant boost due to the progress in air transport. However, the debate on air transport and the influx of foreign investments and global energy demand on economic development remains questionable. Therefore, this study is an attempt to contribute to the body of knowledge in the energy-tourism-led growth hypothesis literature. For this purpose, a novel approach to the effects of international tourism on economic growth is introduced for the Next-5 largest economies, namely  between 1990 and 2018. Empirical results reveal a positive connection between foreign direct investment and income levels, electricity production and income levels, as well as between urbanization and economic growth. Moreover, the validation of the environmental Kuznets curve and the halo effect of foreign direct investment on the environmental degradation process provides a shred of more substantial evidence and fitting environmental instruments for policymakers. The empirical results encourage sustainable economic growth in these countries, mainly through the attraction of clean and high-technology foreign investment, the increase of the share of renewable energy sources in the energy mix and the regulation in the tourism industry. The novel contribution of this study to the empirical literature is the unification in the same research of the TLGH and the EKC for the Next-5 largest economies, establishing recommendations for tourism, energy efficiency and environmental correction process. The World Travel and Tourism Council WTTC  reportedThe tourism and service industry literature has drawn particular attention to the phenomenon where tourism drives economic development  and economic growth . Among the selected variables, per capita electricity output , foreign direct investment net inflows (FDI), and finally, the share of urban population on GDP between 1990 and 2018. All these new explanatory variables are meant to facilitate the design of more suitable policy recommendations in the context of the Next-5 largest economies. These highlighted macroeconomic variables  have been neglected in the extant literature. This present study is distinct from the previous by holistically modelling the outlined variables, considering the empirical evidence of the TLGH and the EKC in the same survey. This process resonates with the need for sustainable economic growth drivers (SDG-8). Additionally, for the robustness of study coefficients and inferences, a battery of first and second-generational techniques is employed to analyse soundness.The validation of the TLGH for Next-5 largest economies implies the necessity of articulating suitable policies to promote the advanced tourism industry, promoting clean energy technologies and high tech supplementary services. This study reinforces this evidence, including the validation of the EKC hypothesis (see Appendix). This joint evidence will establish a wide range of recommendations in sustainable development, energy efficiency and environmental correction process, which has not been considered jointly in the previous empirical literature.So, our study key findings illustrate that air transportation, energy consumption (electricity), increased urban population and influx of FDI are statistically key drivers for sustainable economic growth in the Next-5 economies, validating the TLGH and energy-led growth nexus. Thus, policymakers in these economies will focus on these growth induced sectors and free productive resources to those sectors for increased and sustainable development.The paper is structured as follows: second section presents the theoretical framework, while the data and methodological process are exposed in third section. Fourth section discusses the empirical results, while fifth section concludes the review with some policy suggestions accordingly.The relevance and the determinants of economic growth and development have been studied broadly in advanced and emerging economies, being tourism one of its determinants as supported by the TLGH. The importance of tourism has grown exponentially given the multiple benefits tourism present due to employment opportunities and job creation, foreign exchange production, household income and government revenue through multiplier effects, the balance of payments improvements and growth in the number of tourism-promoted government policies  The central proposal of this study is to validate the TLGH in the Next-5 largest countries, which have not been documented in the extant literature. Additionally, to our knowledge, it has not been considered holistically in the literature. (2) The additional contribution beyond scope but the border around the careful choice of the model covariates, which aligns with the United Nations Sustainable development goals (UNSDGs) of access to energy, responsible consumption , economic growth (SDG-8) and climate change mitigation (SDG-13) in the context of the selected panel while accounting for key covariates. This contribution is supported by analysing the linkage between economic growth and carbon emissions to validate the environmental Kuznets curve (EKC) for the selected Next-5 panel  concept, where the environmental Kuznets curve (EKC) is used as a complementary analysis for the Next-5 largest economies between 1990 and 2018. Coincidentally, the investigated blocs are highly tourism destinations and thus necessitate the need to explore the role of international tourism arrival on their respective economic growth. However, the need for environmental sustainability is also investigated in an EKC framework. Hence, the empirical results will provide evidence of the positive effect of air transport as a proxy of international tourism on economic growth. This study also considers energy production, FDI and urbanization process an essential control variable for policy construction after the previous studies , where tourism is considered a catalyst for economic growth. In our study case, tourism is estimated by air transportation after the study of Balsalobre-Lorente et al. Furthermore, the theoretical underpinning of the present study draws strength to form the carbon-income function backup by the EKC concept (see Appendix). That outlines the tradeoff between economic growth (tourism development) and the quality of the environment. A holistic study of this phenomenon with key macroeconomic variables like FDI inflows and energy consumption is pertinent for policy construction for the Next-5 largest economies, which is the study’s motivation, which has not been well documented in the tourism-energy and growth literature. To check our main hypotheses, we propose Eq. This study employs the annual information Table  facilitaThe sample includes the period 1990–2018, and it is based on the fact that these countries are considered the Next-5 largest economies   of LATit on LGDPit, validating the TLGH  linkage between energy use (LELCit) and economic growth. The connection between FDI and economic growth presents a positive sign (β3 > 0), revealing that the foreign industry enhances the host economic systems  enhances economic growth (β4> 0).The econometric results evidence a direct impact  on economic growth Fig.  for the The econometric results reveal not only the validation of the TLGH for the selected Next-5 largest countries between 1990 and 2018. These results also confirm a direct impact of electricity output, FDI and urbanization on economic growth. This evidence confirms the energy-induced growth hypothesis. In other words, the economic growth of the Next-5 largest economies is positively induced by energy consumption. The energy-led growth hypothesis is insightful for the Next-5 largest economies as global energy demand increases due to international travel and interconnectedness via the FDI channel.The direct effect of FDI on income in host countries implies that these countries’ initial conditions and the nature of FDI will significantly boost domestic competitiveness, enhance skills and invariably lead to social and economic gains  in the Next-5 leading economies between 1990 and 2018. Since we confirm Chudik and Pesaran  cross-seAdditionally, electricity output, FDI and urbanization process directly impact economic growth. Following empirical results, these Next-5 leading countries’ governments need to adopt clean energy regulations to attract sustainable tourism and reduce energy dependency as conservative energy policies might hurt economic growth given the reliance of these economies on their energy sector. In other words, these countries need to consolidate the developed tourism industry, increase clean technologies and use renewable sources to avoid environmental degradation processes .The current study examines and contributes to the extant literature on the TLGH, energy-induced and FDI-growth nexus literature while accounting for macroeconomics indicators like urban population size and international travel proxy by air transport Next-5 largest economies. The positive effects of FDI on economic growth emerges from the type of FDI and positive externalities. So, policymakers need to implement measures for attracting high-tech FDI. Our empirical results confirm the advanced development phase in selected countries and how it enhances economic growth.Otherwise, budgetary effort to promote the attraction of high-tech FDI could provide additional revenues and provide social welfare schemes. These measures are prominent in developing economies where economies thrive on the primary sector, like agriculture and mining. Subsequently, the economic growth trajectory moves to the service stage evidence among developed economies, which have embraced clean technologies, emphasizing environmental consciousness for sustainable growth. However, FDI has immense benefits to the host economy. However, the development process must start from within, through a substantial investment in human capital accumulation and a significant increase in infrastructure provision. A solid basis for a diversified production system can be established, which will serve as a channel to promote technological learning and technology diffusion.Moreover, the econometric results confirm that the urbanization process enhances economic growth. Consequently, these countries need to develop strategies to promote infrastructures that attract tourism and FDI, coordinating business with local businesses. Thus, our study confirms that the tourism industry could catalyse FDI, creating new employment opportunities, generating tax revenues and gaining foreign exchange earnings. This study also advances, in the empirical literature, testing the dampening effect between FDI and air transport over economic growth in the Next-5 largest economies. The empirical evidence also confirms that air transport and subsidiary tourism-related activities intensify income levels. At this stage, policymakers need to promote suitable measures aimed to enhance the tourism industry. For instance, these countries need to promote renewable energy sources and attract foreign high-tech businesses. The reduction of dirty tourism-related activities will generate new opportunities to improve the Next-5 economies’ local business and tourism industry.Therefore, it is pertinent for future studies to consider exploring other regions or blocs using disaggregated data for emerging divides like BRICS and SSA as outcomes could differ substantially. Furthermore, future studies should focus on the analysis of trade openness and sustainable growth. The analysis of the globalization process and the impact of COVID-19 over these economies could generate relevant advances in the empirical literature.


IndIndMembranes play a crucial role in efficiency and longevity of flow batteries. Vanadium flow batteries suffer self-discharge and capacity fading due to crossover of electrolyte components through the membrane from one battery half-cell to the other. We consider the impact of vanadium species crossing ion exchange membranes on state of charge of the battery and we present a simple method to determine crossoverll open circuit potential measurements. State of s. State of charge for the negative and positive half-cell is simulated based on assumptions and simplifications for cation and anion exchange membranes and different crossover parameters. We introduce a crossover index “ Flow batteries gain increasing interest for the storage of renewable energies due to their independent scalability of power and capacity. The energy is stored in electrolytes containing redox active species which are reduced and oxidized, respectively charged and discharged, during operation of the battery. The battery half-cells are separated by a membrane which prevents mixing of the redox active species of the negative half-cell (NHC) and positive half-cell (PHC) electrolytes, respectively avoids short circuit of the battery. The membrane is also needed as ionic conductor and should allow transfer of ions to assure charge balance. Therewith the membrane is crucial for the efficient operation of flow batteries and should provide high ionic conductivity combined with high selectivity. Development of membranes which fit these needs is still challenging and a lot of effort is spend on research on membranes for flow battery applications.Amongst a variety of electrolyte chemistries vanadium flow batteries (VFB) are intensively studied and most common commercially applied ,2,3. VFBThe aim of this work is to study the impact of vanadium ion crossover on the SOC of the VFB and to consider and determine crossover direction as well as relative amount of crossover using half-cell open circuit potential measurements which are compared to simplified simulated case studies.Vanadium electrolytes, respectively active species of the same element, in both battery half-cells are advantageous because mixing of the half-cell electrolytes does not result in contamination of the electrolytes. Nevertheless undesirable crossover of electrolyte components, especially active vanadium species, has been observed for commercially applied membranes and results in self- discharge and capacity fading of the VFB ,5,6.The state of charge (SOC) of a battery is defined as the actual level of energy relative to its capacity and thus can be expressed by the ratio of active species to the overall vanadium concentration in each half-cell (Equations  and 4)))4)).(3)To ensure efficient charging and discharging of the battery, to avoid deep discharge and overcharge which might lead to degradation of the battery and also to develop effective operation strategies knowledge about the SOC is essential. Accurate and reliable online SOC determination is necessary to improve battery control and to achieve efficient long term operation of the system . A numbeTo enable the determination of electrolyte imbalances in earlier stage as well as to improve the accuracy of SOC calculation, the open circuit potential (OCP) of the positive half-cell (PHC) and negative half-cell (NHC) can be monitored separately ,11,14. HR is universal gas constant (R = 8.3145 J KT is temperature (in K); z is number of electrons transferred in half-cell reaction; F is Faraday constant . The connection to the potentiostat  was established via graphite bipolar  and copper plates. For all measurements, a vanadium electrolyte is used, which initially consists of 50% V®G, Hochtemperatur-Werkstoffe GmbH, 2 mm diameter, Thierhaupten, Germany). Further details can be found in previous publications [The charge and discharge experiments were performed in a VFB single cell . The membrane  was placed between two electrode felts  which may coincide or counteract.Crossover processes for different types of membranes as well as for degraded membranes and in dependence on the state of operation of the VFB have extensively been studied and complex models have been developed to unravel and predict the transport methods ,44,45,46For the theoretical determination of the SOC, concentration profiles of the four vanadium species in the respective half-cells are simulated for different case studies. A total concentration of 1.6 M vanadium per half-cell is assumed as the starting value for all case studies. The conditioning step, during which crossover can already take place, is not taken into account. For the calculation of the individual vanadium concentration profiles during cycling of the battery and the resulting SOC, further assumptions are made.Only VEach vanadium ion crossing the membrane reacts stochiometrically in the other half-cell, other side reactions or crossing of other electrolyte components, e.g., HThe amount of vanadium crossover is defined and kept constant for each cycle within the calculated charge-discharge (cd) sequences if not otherwise claimed.For charging and discharging the VFB, it is assumed that a maximum of 100% and minimum of 0% is achievable.No distinction is made between current density or thickness dependent crossover respectively between migration, electroosmotic convection and diffusion driven crossover.Water transport is neglected and a constant volume in the half-cells is assumed.Based on the resulting concentration profiles, the SOC of the respective half-cells can be calculated using Equations  and 4)..4).In order to consider the influence of crossover on the SOC, we take into account ion exchange membrane type (CEM or AEM), vanadium species which is predominantly crossing (Vmembrane . These pCEM are predominantly crossed by Vcase II) ,45. Cros [2SO4−) ,19,33,37For cases I-IV, concentration profiles of all vanadium species in both half-cells are calculated over 10 cycles see . AccordiEquation  self-disEquation  self-disrossover .IndBased on the above considerations and assumptions we suggest a simple approach to estimate net crossover direction. Using the half-cell SOC data, comparison of the SOC range for the PHC and NHC enables an unambiguous assignment of the net crossover direction. Defining a SOC progress Equation ) and NHCEquation ) as the Equation , we put For predominant crossover processes from NHC to PHC (mainly occurring using CEM) the crossover impact on the SOC of the PHC is stronger due to self-discharge. Therewith the SOC range (Equation ). For crEquation ). Since  realize .IndIndIndIndEquation  IndXovr IndIndIndIn addition to the determination of the crossover direction, also information on the relative amount of vanadium ions can be considered. Comparison of case I and II depicts a steeper slope for IndIndIndComparison of cases III and IV depicts higher The amount of vanadium ions crossing the membrane depends on membrane thickness and current density. Simplified, higher current densities as well as thinner membranes majorly promote stronger crossover and thereby higher capacity fading and stronger self-discharge. IndIndIndIndIndIndIndIndTo reveal the applicability of the crossover index, experimental data for different membranes have been collected under various conditions . Figure rossover b. In conrossover , the difIndIndIndIndThe results for IndIndIndIndIndIndIndWith membrane F-930 rfd the membrane b. DespitIndIndIndComparison of experimental results to simulated case studies reveals applicability of Crossover trough membranes employed in VFB is complex and depends on various parameters. Several detailed models have already been developed to picture and predict the crossover processes and their impact on the battery electrolyte. The dependence of crossover on various conditions makes it difficult to characterize and compare different membranes concerning their ability to diminish crossover and applicability in VFB.IndTo simplify the evaluation of membranes and to enhance the comparability of different membranes concerning crossover of vanadium ions we introduce a crossover index Considerations of the crossover index concerning applicability for the determination of crossover direction and amount based on several case studies are verified by experimental results. The results coincide with the case studies and reveal the applicability of the crossover index for comparison of membranes concerning crossover characteristics in VFB as vanadium crossover direction and relative amount. Furthermore comparison of several membranes tested under various conditions is possible without further adaption or conversion of parameters and results.


Injuries to the shoulder are very common in sports that involve overhead arm or throwing movements. Strength training of the chest muscles has the potential to protect the shoulder from injury. Kinematic and kinetic data were acquired in 20 healthy subjects (age: 24.9 ± 2.7 years) using motion capture, force plates for the bench press exercises and load cells in the cable for the cable pulley exercises with 15% and 30% of body weight (BW). Joint ranges of motion (RoM) and joint moments at the shoulder, elbow and wrist were derived using an inverse dynamics approach. The maximum absolute moments at the shoulder joint were significantly larger for the cable pulley exercises than for the bench press exercises. The cable cross-over exercise resulted in substantially different joint angles and loading patterns compared to most other exercises, with higher fluctuations during the exercise cycle. The present results indicate that a combination of bench press and cable pulley exercises are best to train the full RoM and, thus, intra-muscular coordination across the upper limbs. Care has to be taken when performing cable cross-over exercises to ensure proper stabilisation of the joints during exercise execution and avoid joint overloading. Strength training plays an integral part in the prevention of and rehabilitation from injury, as well as improvement of sports performance . TherebyBench press exercises are the most popular strength exercises for developing upper body strength, especially of chest muscles . The corWhile a high number of studies have analysed muscle activity patterns during bench press exercises ,11,12,13It was previously found in professional baseball pitchers that present weakness of shoulder strength is associated with increased risk of throwing-related injuries, stressing the importance of targeted muscle strengthening plans for injury prevention . While sn = 20 was in line with similar studies that compared joint kinematics between different types of strength exercise . The sample size of Prior to data acquisition, each participant conducted a specific, five-minute warm-up session using sets of the exercises with minimal loading. Each subject received precise instructions on how to execute the exercises  according to guidelines rather than speed of execution and/or the lifting of maximum weight.To collect kinematic data of the upper extremities in all three planes of motion, a Vicon MX40 system  with 22 cameras was used. The resolution of each camera was 2353 × 1728 pixels, capturing at a frequency of 100 Hz. A skin marker set with a total of 54 markers was used, which was specifically designed for evaluating the biomechanics of the upper limbs and previously applied to strength training research . A clustThe marker trajectories from optical motion capture were tracked and labelled using Vicon Nexus 2.4  and, subsequently, exported for the analysis of joint kinematics using Matlab 2014 . Exercise cycles were separated into individual repetitions using the mean values of the z coordinates of the markers on each handle, with a minimum velocity of 30 mm/s to indicate movement for the bench press exercises and 40 mm/s for the cable pulley exercises, respectively. The positions of the glenohumeral joint centre , elbow joint centre and wrist joint centre were functionally derived based on the kinematic data from nine basic motion tasks, previously introduced by  and descThe kinematic and kinetic data from the first repetition of each exercise cycle were excluded from further analysis. Thus, five repetitions of each exercise for the right and left extremity of each subject were further processed, making a total of 200 evaluated cycles. The positions and orientations of the segments during each repetition were determined using a least-squares fit of the corresponding marker clusters . Upper labs) and their maximum (Mmax) at the shoulder, elbow and wrist during each repetition cycle were calculated using a quasi-static inverse dynamics approach based on the positions and orientation of the segments, the measured external forces and the gravitational force of the segments and handle [The joint moments , were calculated across all repetition cycles of each exercise . Joint RoMs were calculated as the difference between the maximum and minimum joint angles.Joint angles and joint moments were resampled over time, and joint moments were additionally normalised to BW. Mean maximum and mean minimum joint angles, as well as mean maximum joint moments  software. The independent variables were the four different types of strength exercises  and the two magnitudes of externally applied loads . At the wrist and the elbow joint, mean RoMs and mean Mnt in 3D .t-tests were used to analyse the significance of the differences between paired outcome variables from the four different types of strength exercises and two types of loading magnitudes. The level of significance was set at p < 0.0125 for all comparisons.Prior to statistical analysis, outcome variables were checked for normal distribution using Q–Q plots. Given normal distributions with minor deviations, parametric statistical analysis was carried out. In particular, two-sample paired max. Mean grip width was 88.7 ± 6.7 cm for the bench press exercises.All results are shown as mean ± standard deviation (SD). Positive values correspond to internal rotation, adduction or flexion angles and the corresponding MThe mean trajectories of the flexion extension and abduction-adduction joint angles and absolute moments in the shoulder joint during bench press and cable pulley exercises are shown in max at the elbow joint are given in max for the same exercise with increasing load. However, a markedly higher SD in RoM and Mmax were present for the cable pulley exercises compared to the bench press exercises, suggesting larger variations in joint motion and loading patterns subjects.The resulting flexion-extension and supination-pronation RoMs and Mmax at the wrist joint are given in max was significantly different for the cable cross-over exercise compared to all other exercises. Interestingly, no significant difference in joint RoM was found for any exercise when increasing the load from 15% to 30% BW. Increasing the load also did not result in significantly different abduction-adduction Mmax for the bench press exercises. However, a large SD in RoM and Mmax were found for all exercises, suggesting large variations in joint motion and loading patterns between subjects.The resulting flexion-extension and supination-pronation RoMs and MThe present study reports on the kinematics and kinetics of the upper limbs during four common strength exercises for chest muscles at moderate intensity. Biomechanical assessment of chest muscle strengthening exercises is important for the establishment of training guidelines to minimise injury risks, especially at the shoulder. To the authors’ knowledge, no study has previously compared upper limb kinematics and kinetics between the selected types of exercises.Biomechanically, the absolute joint moment is counterbalanced by active muscle forces which leads to a reduction of the internally applied joint moments . In resiPrevious research suggests that muscle activation patterns during the bench press exercise tend to demonstrate a specificity during moderate-intensity, non-fatiguing exercise execution ,10. TherIn order to maximise the effect of strength training, it is generally desirable to perform the exercises with a large RoM. This applies for strength training in order to improve, e.g., maximum isometric force, cross-sectional area and inter-/intra-muscular coordination ,26, as wThe key limitation of the present study is the simplified representation of the shoulder joint for biomechanical analysis. In particular, shoulder kinematics were described as the movement of the upper arm relative to the thorax without considering the intricate movement of the shoulder girdle. For small joint ranges of motion, such a simplification is considered valid. However, during the final part of the bench press exercise, protraction of the scapula is fundamental for reaching the final position of the barbell and, thus, substantially contributes to shoulder joint kinematics and RoM. Anatomically, the glenohumeral joint is a ball-and-socket joint with three rotational degrees of freedom between the scapula and the humerus, and the mobility of the shoulder complex is further increased by the sternoclavicular, acromioclavicular and scapulothoracic joints. This complex range of movement challenges the analysis of shoulder kinematics during dynamic exercises using optical motion capture because of skin movement artefacts . FurtherDetailed biomechanical analyses of both bench press and cable pulley exercises, including muscle activation patterns, muscle force estimation and internal joint loading at the shoulder joint, are recommended to gain further insights into the injury risks associated with each type of exercise. Here, a refinement of study protocol based on good practice rules for the assessment of the force–velocity relationship during strength training is advisable . In partA combination of bench press and cable pulley exercises, starting with smaller loads and guided supervision, is recommended to achieve functional training of the chest muscles to stabilise the upper limb and avoid overstressing the joint and soft tissue structures. Lower and less fluctuating joint moments during bench press exercises imply more targeted muscle strengthening with reduced need for inter-muscular control and coordination compared to cable pulley exercises. Care has to be taken when performing cable cross-over exercises to ensure proper stabilisation of the joints during exercise execution and avoid joint overloading.


Medionecrosis and medial degeneration are rare complications associated with intramural hematomas (IMHs). We present a case of a 69-year-old Asian female with an IMH with medionecrosis and medial degeneration of the aortic wall. The patient underwent successful surgical intervention, and pathological findings were significant for cystic medial degeneration of the aortic wall. Acute aortic syndromes (AAS) are a spectrum of severe aortic syndromes triggered by a rupture of the vasa vasorum which causes bleeding within the media  or permits blood to penetrate from the aortic lumen into the media layer (aortic dissection [AD]).A 69-year-old Asian female presented to a hospital with moderate chest pain that began 3 weeks prior to surgery. She was initially evaluated and managed with antihypertensive and pain medications. However, when the symptoms reoccurred as a new episode of crushing and sharp midthoracic back pain, the patient presented to a different emergency department and was transferred to the Johns Hopkins Hospital. Clinical workup included a chest computed tomography (CT) angiogram that characterized an aorta with diffuse mural thickening. The hematoma was circumferential in nature and measured 8 mm in thickness at the level of the aortic root throughout the ascending aorta, and grew to 15 mm in the descending aorta . The asA median sternotomy was performed, and once the pericardium was opened, a moderate bloody effusion was drained. The ascending aorta was visibly affected by an extensive hematoma presenting with bluish discoloration of the adventitia . The paPostoperative pathology findings revealed cystic medial degeneration of the aortic wall, characterized by elastic fiber fragmentation with the formation of mucopolysaccharide pools and medionecrosis, defined as an apparent loss of nuclei in the media . Blood IMH has an incidence of 1.2 per 100,000, making it the rarest form of AAS. Various complications can arise with IMH, such as pericardial effusions, pleural effusion, and the more serious complication of progression to an AD.Despite the physiologic difference in Type A IMH and ADs, there is no significant difference in in-hospital mortality between the two pathologies.In the presented case, medionecrosis of the medial layer highlights an atypical complication associated with IMH. The aorta is a large elastic artery with the medial layer constituting its greatest component.IMH with associated medionecrosis and medial degeneration is a type of AAS with uncommon occurrence. The ability for complicated IMHs to progress to an AD emphasizes the importance of early recognition of varied clinical presentations.


Hematopoietic stem cell transplantation (HSCT) represents the only curative treatment option for numerous hematologic malignancies. While the influence of donor age and the composition of the graft have already been examined in clinical and preclinical studies, little information is available on the extent to which different hematological subpopulations contribute to the dynamics of the reconstitution process and on whether and how these contributions are altered with age. In a murine model of HSCT, we therefore simultaneously tracked different cultivated and transduced hematopoietic stem and progenitor cell (HSPC) populations using a multicolor-coded barcode system (BC32). We studied a series of age-matched and age-mismatched transplantations and compared the influence of age on the reconstitution dynamics. We show that reconstitution from these cultured and assembled grafts was substantially driven by hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs) independent of age. The reconstitution patterns were polyclonal and stable in all age groups independently of the variability between individual animals, with higher output rates from MPPs than from HSCs. Our experiments suggest that the dynamics of reconstitution and the contribution of cultured and individually transduced HSPC subpopulations are largely independent of age. Our findings support ongoing efforts to expand the application of HSCT in older individuals as a promising strategy to combat hematological diseases, including gene therapy applications. Since the first successful hematopoietic stem cell transplantation (HSCT) in 1957 . Since dSimilar questions are raised in the context of gene therapeutic applications, in which ex vivo cultured and transduced hematopoietic stem and progenitor cells (HSPCs) are transferred back to the same patient via autologous transplantations. This greatly expanding field will target an increasing number of diseases and also be applicable to older patients, for whom optimal conditioning is required.Besides the influence of donor and recipient age, the cell source ), mobilized peripheral blood stem cells, and umbilical cord blood) and the composition of the graft have an impact on the success of HSCTs. The surface marker CD34 is used to enrich for HSCs; however, the CD34 protein is expressed not only on HSCs but also on a variety of different progenitor cells ,15. WhilIn recent years, the development of genetic barcodes as a means of cellular labeling has revolutionized clonal tracking ,18, espe+ cell population, similarly to a standard human transplantation setting ..6 cells We performed ddPCR on DNA from the BM in a duplex reaction by simultaneously amplifying the Y chromosome and a reference gene (erythropoietin receptor). The analyses were performed using QX100  according to the manufacturer’s instructions, with the primer and probes shown in https://cran.r-project.org/web/packages/vegan/index.html, last access 28 January 2022).The genetic barcodes were extracted from gDNA and amplified via PCR as described earlier ,40. In bIn summary, our approach documents the feasibility of individual marking and parallel transplantation of four distinct HSPC subpopulations to follow their contribution to reconstitution after HSCT. In our murine transplantation experiments, we focused on the first reconstitution phase up to 16 weeks post transplantation, in which we could not see any profound impact of donor or recipient age. We detected the same kinetics as described for HSCTs in murine or human CD34 xenograft experiments ,30 or inOur experimental approach closely mimics an autologous transplantation setting in which the transduced cells need to achieve a sustained contribution in the particular recipient. Such settings become increasingly important in the context of gene therapeutic applications ,72. Newe


Nutrients focuses on the effects of diet on brain function with a special emphasis on epileptic disorders. Altering the diet to treat epilepsy dates back to circa 400 B.C., and the classical ketogenic diet has been utilized since the 1920s. Numerous biochemical changes occur in the brain in response to the ketogenic diet, but how the diet works at a cellular and molecular level remains an enigma. Likewise, there is much to be learned regarding how other diets such as the Atkins diet or plant-based diets affect brain function and the development of seizures. As the use of these diets gain popularity, it is of vital importance to understand their acute and long-term effects on the brain as well as identify their bioactive components. Often, patients resort to natural products and dietary interventions as a means to relieve disease symptoms. Unlike pharmaceutical drugs, which must be proven safe and effective for their intended use before marketing, the FDA does not guarantee the biological activity or purity of dietary supplements. Herbal and vitamin products are sold over the counter and can interact with prescription drugs. We invited review and original research articles that described advances in the field of diet and epileptic disorders for this Special Issue entitled, “Diet in the Treatment of Epilepsy: What We Know So Far”. Epilepsy afflicts 0.5–1% of the world population with a lifetime incidence of 1–3%. A third of patients are resistant to pharmacological therapy. Following are two review articles providing a thorough background on the state of the art of ketogenic diet therapies and five original research manuscripts describing recent diet and dietary supplement findings in animal and human models of epilepsy.This Special Issue for Zarnowska reviews the therapeutic use of the ketogenic diet in refractory epilepsy. The classic ketogenic diet, which mimics starvation, has been utilized for a century to treat epilepsy . The keyVerrotti and colleagues review the evidence-based literature in regard to the use of high-fat diets in the treatment of epilepsy with a focus on the classic ketogenic diet as well as some popular high-fat diet variants including the modified Atkins diet, low glycemic index diet and medium-chain triglyceride diet, which are less restrictive and more palatable . The autPasca and colleagues contribute a communication article on family experiences regarding classic ketogenic diet managements under acute medical conditions as assessed by a web-based survey . Survey Hung and colleagues examined serum acylcarnitine and amino acid profiles in response to ketogenic diet therapy in pediatric drug-resistant epilepsy . Their sBrunner and colleagues tested the efficacy of uridine and exogenous ketone supplements in decreasing bilateral, synchronous, spontaneous spike-wave discharges in Wistar Albino Glaxo/Rijswijk rats (WAG/Rij), a model of human absence epilepsy . After iChang and colleagues conducted a prospective, open, cohort, pilot study of the effect and tolerability of add-on multivitamin therapy in patients with intractable focal epilepsy . SpecifiWestmark and colleagues contribute a survey-based study to this Special Issue regarding associations between caregiver-reported use of soy-based infant formula and disease comorbidities in their children with fragile X syndrome . FragileOverall, these studies describe exciting new findings in the field of nutrition and epileptic disorder research at preclinical, translational and clinical levels while highlighting the need for increased attention to and resources for the study of dietary effects on neurological outcomes. As evidence-based medicine moves into the realm of personalized medicine, it is imperative to understand the effects of environmental factors including diet on disease outcomes. Please enjoy our collection.


Energy dispersive X-ray (EDX) analysis was performed to investigate the mass percentage of calcium (Ca) and phosphorous (P) in the surface enamel. Ultrastructural aberrations of surface enamel were observed in the test group teeth. Additionally, prism perforations were seen at the junction of rod and inter-rod enamel and the prisms were loosely packed. An even aprismatic layer of surface enamel was evident in the control group teeth. There was a statistically significant difference (p < 0.05) of Ca and P mass percentage between the test and control group teeth. The mean mass percentage rates of Ca and P were 33.75% and 16.76%, respectively. A poor surface characteristic and elemental composition of the enamel surface of primary teeth is observed in diabetic children. Therefore, appropriate caries preventive measures are mandatory to maintain the structural integrity of the tooth in these patients.Diabetes affects the developing enamel by altering the mineralization process, which can have a detrimental effect on oral health. The objectives of this study were to examine the ultrastructure and composition of surface enamel in primary teeth of diabetic children and its clinical implications. Hundred extracted primary teeth from diabetic children (Test group:  Type 1 Diabetes (T1D) is a common chronic disorder, caused due to the destruction of insulin-producing pancreatic beta cells. The destruction of beta cells is attributed to autoimmune-mediated pathology affecting the production of insulin necessary for glucose metabolism. Juvenile diabetes (JD) is a type of T1D occurring in children before the age of 15 years, which accounts for five to ten percent of all diabetes cases worldwide . StudiesIn experimental animals, T1D is known to affect the mineralization process and alter the morphological features of enamel, thereby increasing its susceptibility to caries . The detEnergy Dispersive X-ray (EDX) analysis of enamel of diabetes-induced rats has shown a reduction in the concentration of calcium (Ca) and phosphorous (P) ,17. Low The effect of diabetes on enamel ultrastructure, to date, has been tested only on rodents. None of the previous studies have examined the ultrastructure and composition of enamel in human primary teeth of diabetic children. Therefore, the objectives of this study were to analyze the structural properties of surface enamel in primary teeth of diabetic children. The study also aimed to assess any changes in the elemental composition in the same teeth. The clinical significance of the ultrastructural and compositional changes and the preventive measures to reduce caries risk in these patients were also explored. This prospective study was carried out over a period of 19 months between 2018 and 2020 in the Aseer Dental Center and Pediatric Dental Clinics of King Khalid University College of Dentistry. Before commencing the study, ethical approval was obtained from the King Khalid University College of Dentistry Institutional Review Board with approval letter number SRC/ETH/2016-17/049. Informed consent from the parents was obtained for each child included in the study.The study subjects were screened on the basis of the American Academy of Pediatric Dentistry Caries Risk Assessment Tool to make sure the biological, social, protective and clinical factors were similar for both the test and control groups . In totaSimultaneously, 50 primary teeth of healthy children matching the age of the test group and fulfilling the inclusion criteria were used as the control group. The reason for tooth extraction in the study samples was either pre-shedding mobility or retaining the primary tooth.After extraction, the teeth were disinfected with formalin, coded, and stored in normal saline at room temperature during the collection period. Prior to SEM imaging, the teeth were washed with fresh normal saline solution and pat-dried with sterile cotton gauze. The crown surface was subjected to SEM analysis using a JEOL JSM-636OLA Analytic Scanning Electron Microscope  with backscatter electron mode. The SEM was operated at a voltage between 15 and 25kV. The scanning site was standardized for all of the teeth samples by focusing on the mid-labial/buccal aspect of the crown. The enamel was visualized under the microscope, and the images were saved in jpg file format. Ultrastructural characterization of enamel prisms and crystal deposition pattern of the enamel surface was determined by detailed visual examination of the images in Windows Microsoft Office Picture Manager Software . t-test using STATA Version 9.2. The statistical significance was set at 5%. The clinical significance of the study findings was interpreted based on the outcomes of previous reports on altered enamel in primary teeth.Following SEM imaging, enamel surface composition analysis was performed in the same areas of the crown using EDX Spectrometry. The same SEM unit  was used to record the mass percentage rates of Ca and P. The mean mass percentage rates of Ca and P in the test and control groups were statistically analyzed by independent Ultrastructural aberrations were observed in the SEM images of the enamel surface of teeth in the test group. An uneven aprismatic layer A,C with t-test was applied. There was a statistically significant difference (p < 0.05) in the mass percentage of Ca and P between test and control groups  crystals. Similar changes are reported in the experimental research on Wistar rats with artificially induced diabetes, where the changes in enamel and its mechanical features are comparable ,17. MetaWhile amelogenesis taking place under the influence of JD is a significant event, several other factors collectively may lead to defects in the enamel. For example, the lack of proper proteinases activity can affect amelogenesis and lead to loosely packed prisms in mature enamel. The development of enamel begins with high protein content and ends in high mineral content , with moThe other common ultrastructural defect observed in the SEM images of diabetic primary teeth was an uneven aprismatic layer with surface perforations. The normal surface of enamel exhibits an even, highly mineralized aprismatic or prismless layer formed by the shortened ameloblast in the late secretory stage of amelogenesis, as evident from the control samples. Kodaka et al.  categoriIn our study, the mass percentage of Ca and P in the test group teeth were significantly lower than the control group teeth. According to experimental data, the disturbance in homeostasis in diabetes causes dyselectrolytemia and transmineralization leading to changes in the mineral components of bone and teeth . During In short, we report defects in the enamel surface of primary teeth in diabetic children, akin to the defects reported by several studies on diabetes-induced experimental rats. Abnormal ameloblast activity appears to be the prime reason for the changes observed in the enamel surface. The following two hypotheses may be indicative of the changes brought about by the ameloblasts. The effect of hyperglycemia on the mineralization leads to a low concentration of Ca and P in the mature enamel. Decreased levels of Ca and P could be a direct reason for the enamel defects. The work of Atar et al.  supportsIn addition to the impact on elemental composition, the influence of oxidative stress on the expression of MMP-20 and KLK4 during the secretory stage can lead to impaired development of HAP crystals in the rod and inter-rod enamel. The exact effect of diabetes on MMP-20 and KLK4 is still unreported, however, our assumption in this regard is based on the literature published by Bartlett JD .Dental Caries is the most significant threat that can be caused due to defects observed in the surface enamel of diabetic children. Defective surface increases the risk of acid dissolution of surface enamel, leading to caries. Special caries prevention protocol seems mandatory to maintain caries-free teeth in the already compromised oral condition of diabetic children. By special prevention protocol, we mean steps that are specific to high caries risk children, such as the use of topical remineralizing agents including fluorides, and active measures by parents and oral health professionals aimed at maintaining the non-cariogenic oral environment and monitoring possible caries development.Considering the results of this study alongside the data available regarding the enamel of T1D teeth we recommend the following measures to reduce the risk of caries in diabetic children.Primary teeth of diabetic children should be screened for macroscopic deficiencies as soon as they erupt.Diabetic children should be considered high caries risk children and they should be clinically monitored every three months.Primary and secondary prevention protocols specific to the teeth of diabetic children should be developed and implemented to curtail the initiation of dental caries.The parents of diabetic children should be made aware of the increased risk of dental caries and its consequences at an early stage.The parents should be educated to ensure these children maintain good oral hygiene and a healthy non-cariogenic diet.Finally, parents should be counseled to help maintain healthy blood glycemic levels to prevent the undesired oral and systemic consequences of diabetes.Poor ultrastructural surface characteristics of enamel surface are observed in primary teeth of diabetic children. Abnormal amelogenesis activity in primary teeth of diabetic children seems to be the cause of these defects in the enamel surface. The defects make the enamel more prone to acid dissolution, thus increasing caries risk. Therefore, appropriate caries preventive measures are mandatory to maintain the structural integrity of enamel in these patients.


The journal retracts the article, Effects of a Single Dose of Ivermectin on Viral and Clinical Outcomes in Asymptomatic SARS-CoV-2 Infected Subjects: A Pilot Clinical Trial in Lebanon , cited aFollowing publication, the authors contacted the editorial office regarding an error between files used for the statistical analysis.Adhering to our complaints procedure, an investigation was conducted that confirmed the error reported by the authors.This retraction was approved by the Editor in Chief of the journal.The authors agreed to this retraction.


Passive movement is an important mean of rehabilitation for stroke survivors in the early stage or with greater paralysis. The upper extremity robot is required to assist therapists with passive movement during clinical rehabilitation, while customizing is one of the crucial issues for robot-assisted upper extremity training, which fits the patient-centeredness. Robot-assisted teaching training could address the need well. However, the existing control strategies of teaching training are usually commanded by position merely, having trouble to achieve the efficacy of treatment by therapists. And deficiency of flexibility and compliance comes to the training trajectory. This research presents a novel motion control strategy for customized robot-assisted passive neurorehabilitation. The teaching training mechanism is developed to coordinate the movement of the shoulder and elbow, ensuring the training trajectory correspondence with human kinematics. Furthermore, the motion trajectory is adjusted by arm strength to realize dexterity and flexibility. Meanwhile, the torque sensor employed in the human-robot interactive system identifies movement intention of human. The goal-directed games and feedbacks promote the motor positivity of stroke survivors. In addition, functional experiments and clinical experiments are investigated with a healthy adult and five recruited stroke survivors, respectively. The experimental results present that the suggested control strategy not only serves with safety training but also presents rehabilitation efficacy. New advances in technology and an increased upper extremity motor dysfunction lead to widespread adoption of robots in clinical rehabilitation poststroke. Robotic devices for upper extremity rehabilitation have the potential to deliver highly repetitive, task oriented, intensive, and quantifiable neurorehabilitation , which iThe rapid development of many robotic devices has been seen during the past two decades. And the devices fall into two main classes: robots developed to compensate for lost skills (assisted devices) and robots designed to recover lost function by training (therapy devices) . The maiThe aim of designs is not to realize a brand novel robot for stroke survivors but to fill an existing gap that customizes robot-assisted passive movement. Intending to make the passive movement patterns customized on the residual functional ability and embedded in therapist's track, the paper analyzes the design of the upper extremity robot with human-robot system and teaching training mechanism. Besides, functional and clinical experiments were conducted to verify the effectiveness and efficacy of proposed teaching training mechanisms.Thus, the research presents a novel motion control strategy for robot-assisted passive neurorehabilitation exercise. The teaching training is developed to assist therapists with customized smoothing passive movement, based on the judgment of residual function and desired training trajectory by therapists.FELXO-Arm1 system manufactured by Shanghai Electric GeniKIT Medical Science and Technology Co., Ltd., of China is an exoskeleton robot that is kinematic equivalent to the human limb . In ordeDuring rehabilitation training, the active joints consisting of motor and gear provide additional assistance to participants, with the encoder measuring joint angular information and the torque sensor obtaining human-robot interactive torque. We can develop different motion control algorithms to adapt different training modes based on the mechanical structure.According to training requirement of upper extremity rehabilitation robot, the power unit on the sagittal plane of the joint is made up by a Maxon EC motor and a Harmonic Drive harmonic gear, which can provide additional 46 Nm and 13 Nm assistive torque to the shoulder and elbow joints, respectively. During training, the activity information of each degree of freedom (such as angle and angular velocity) can be measured corresponding to the encoder to control the active joint or saved in memory. The human-robot interactive force obtained by the torque sensor can be used to identify the movement intention of patient, which can improve the control precision of robot.Our upper extremity robot has the ability to enable a strict application of motor learning principles known as stroke rehabilitation paradigms –17, whicg stands for the acceleration of gravity; m1 represents the mass of shoulder module of robot and the shoulder of the patient. d1 is the length from the shoulder rotation center to center of mass, l1 is the length of upper arm of robot, and q1 is the shoulder angle. In the same way, m2, d2, l2, and q2 represent the same values of the elbow joint.According to the Lagrange method, the above dynamic model could be analyzed and presented in mathematical expression as the following equation:τ1 and τ2 represent the driving moment of the shoulder and elbow, respectively.τ =  is the joint torque vector, q =  is the joint angular position vector, M(q) is the inertia matrix, q) is the grabity vector, B is the viscous friction vector, and D is the dynamic friction vector. τm is the torque generated by the motor; τh is the interaction torque vector.The torque control based on the position control is the global scheme of a robot controller. The robot completes the tracking of desired trajectory by introducing the feedforward controller and enhancing with a proportional differential controller. The Lagrange method-based human-robot coupling dynamical model in equation  is rewrie(t) = q(t) − qd(t), KP and KD are proportional and differential coefficients of the proportional differential controller; the inverse dynamic term, B and D in equation . Each survivor undergoes one session in passive training of the shoulder and elbow, 30 min per session, one training day. The program also included two-hour daily (5 days a week) sessions of physical and occupational therapy based on the paretic extremity rehabilitation and, if necessary, half an hour of speech therapy 5 times a week. Motor impairment was measured using the active range of motion (AROM) of the shoulder and elbow and the upper limb Fugl-Meyer  AssessmeThe Fugl-Meyer scale measured the ability to move paretic arm, which is a global evaluation scale for impairment in stroke patients. Fugl-Meyer SEC includes items related to the movements of shoulder and elbow and the coordination. Each item is rated on a 3-point scale .Demographics and clinical characteristics of five stroke survivors are presented in All survivors regained an increased Fugl-Meyer SEC score after teaching training. Subject 1 improved in flexor and extensor synergy of the upper extremity. Subjects 2 and 4 improved in flexor and extensor synergy, movement combing, and out of synergy. Subject 3 was without improvement in extensor synergy for the ceiling effect. Subject 5 remained powerless in movement combining and out of synergy , while sThe AROM of the shoulder  and elbow (flexion and extension) are displayed in The artificial intelligence and the technological revolution seem to indicate a greater artificial cognitive agents in our clinical practice, especially in rehabilitation poststroke. Robot-assisted therapy for upper extremity rehabilitation with effective scientific protocol achieves motor function recovery. Passive training with the upper extremity robot is crucial for stroke survivors with greater impairment of the upper extremity who have difficulty moving actively and even at the early stage. In the investigation, a control strategy with the teaching training mechanism was proposed to realize customized passive neurorehabilitation exercise, serving with safety and efficacy robot-assisted motion. The teaching training was developed to assist therapists by supplying customized passive training, ensuring coordination and smoothness of upper extremity motor. Meanwhile, the robot-assisted teaching training offers passive training sufficiently and alleviates the shortage of therapists.The teaching trajectory motion keeps shoulder and elbow movements synchronized and coordination during the course of repeated movements, resolved with position and torque controlling simultaneously. Meanwhile, the model of the human-robot system is adopted to extract special points, avoiding the violation of upper extremity normal movement. Furthermore, the subject could resist the detailed movement by arm strength to realize the flexibility and plasticity of movement, with no need to follow the trajectory strictly.The functional experiments and clinical experiments were schemed and investigated with a healthy adult and five recruited stroke survivors, respectively. In the functional experiment, the repetitive passive training effectively inhibits the formation of joint adhesions, inducing the impairment of range of joint movement. In addition, the teaching training showed a smooth and coordinating curve based on the Bobath approach. The trajectory is used to suppress abnormal pattern by correcting the upper extremity flexor spasticity, while improving joint mobility and activities of daily living. During clinical experiments, the upper extremity function was evaluated by the Fugl-Meyer SEC and AROM of the shoulder and elbow. The improvement of upper extremity functional evaluation by the Fugl-Meyer SEC unfolds the restoration of the upper extremity function by robot-assisted teaching training. However, not all subjects achieve remission on the AROM of the shoulder and elbow, especially in extension. The outcomes are coinciding with the impairment of stroke. The experimental results showed that the suggested control strategy not only serves with safe teaching training but also presents rehabilitation efficacy. Due to the small sample size, the result should be cautiously considered.Therefore, the developed teaching training mechanism played an important role to serve subjects with customized training, as closely as what the therapist did. The trajectory is made by therapists based on the residual function, ensuring adherence to the principle of human kinematics. Future models should be updated according to the clinical demands. Beyond the shoulder and elbow joints, the wrist and fingers are a nonnegligible fraction of the upper extremity function. A robot integrating shoulder, elbow, wrist, and fingers with human anatomy mechanics is indispensable in clinical rehabilitation. So it is worth investigating in future studies. On top of this, the customization of active and assistive models during robot-assisted training is equally important, which makes the robot an ideal therapist. And further study will investigate the rehabilitation efficacy with controlled experiments.


Epigenetic drug discovery field has evidenced significant advancement in the recent times. A plethora of small molecule inhibitors have progressed to clinical stage investigations and are being explored exhaustively to ascertain conclusive benefits in diverse malignancies. Literature precedents indicates that substantial amount of efforts were directed towards the use of epigenetic tools in monotherapy as well as in combination regimens at the clinical level, however, the preclinical/preliminary explorations were inclined towards the identification of prudent approaches that can leverage the anticancer potential of small molecule epigenetic inhibitors as single agents only. This review article presents an update of FDA approved epigenetic drugs along with the epigenetic inhibitors undergoing clinical stage investigations in different cancer types. A detailed discussion of the pragmatic strategies that are expected to steer the progress of the epigenetic therapy through the implementation of emerging approaches such as PROTACS and CRISPR/Cas9 along with logical ways for scaffold fabrication to selectively approach the enzyme isoforms in pursuit of garnering amplified antitumor effects has been covered. In addition, the compilation also presents the rational strategies for the construction of multi-targeting scaffold assemblages employing previously identified pharmacophores as potential alternatives to the combination therapy. Genome refers to the complete set of genetic information in the form of nucleotide sequence inside the DNA, whereas the epigenome refers to complex modifications inside the genomic DNA . In simpEpigenetic mechanisms regulate gene transcription and genomic stability and maintain normal cell growth, development, and differentiation –10. As sThough epigenetics is a key component of an organism’s normal development, from embryonic development through adulthood, epigenetic dysregulation can significantly contribute to the origin and progression of human diseases such as cancer, cardiovascular diseases, metabolic diseases and neurological diseases. Extensive explorations conducted to enhance the understanding of the epigenome reveals that localised differences existing in epigenetic states of normal and disease tissues can be utilized as disease biomarkers –26.Literature precedents indicate that all the three families of epigenetic proteins—readers, writers, and erasers are druggable targets. This disclosure coupled with the improved understanding of epigenetics in diverse complications dramatically spurred and expedited the translational investigation of the epigenetic inhibitors. In particular, exhaustive investigations predominantly on small-molecule inhibitors were carried out at the clinical level and the subsequent efforts have culminated in the identification of efficacious inhibitors, with some of them being used in the clinic currently. To add on, the preclinical and preliminary studies have also comprehensively explored the epigenetic tools (DNMT/HDAC/LSD1/DOT1L/BET/EZH2 inhibitors) in pursuit of leveraging enhanced antiproliferative effects. Albeit the clinical stage investigations have been appropriately directed towards the evaluation of the epigenetic inhibitors as single agents, a significant proportion of the efforts is also covered by the studies inclined towards the utilization of the epigenetic tools as a part of combination regimens. This information raises a critical question regarding the therapeutic credibility of some of the epigenetic inhibitors as single agents to attain conclusive benefits in cancer. The doubts are further strengthened by the fact that only seven drugs have approved till date despite the epigenetic targets being at the forefront of the strategized explorations. Nevertheless, the medicinal chemist at the preclinical/preliminary level has been quite proficient to employ rational drug design approaches to maximize the benefits of the predefined pharmacophore models of the epigenetic targets. Indeed, the preclinical/preliminary findings (section) bears a relatively higher degree of fascination for the researchers as efforts invested have not just been confined to elucidate the mechanistic insights responsible for exerting antitumor effects via inhibition of the epigenetic targets, rather the chemist has looked beyond this strategy to attain favourable effects via degradation of the proteins also (PROTACS). Sagaciously evidenced on the literature precedential basis, degradation of the target proteins can be achieved at low exposures by PROTACs (protein degraders) owing to their catalytic mode of action and this emerging approach is likely to steer the wheels of the drug discovery field towards the class of degraders bearing appropriately installed epigenetic tools in the near future. For the selective targeting, the concept of antibody–drug conjugates have also attracted the eyeballs of the researchers working in the field of epigenetic inhibitors. This strategy of targeted drug delivery is anticipated to overcome the issue of systemic toxicity and narrow therapeutic window that limits the clinical use of the available epigenetic inhibitors. CRISPR/Cas9-based strategies to target the cancerous epigenetic regulators also represent an emerging potential approach that is being foreseen as a tool to correct genetic mutations. Other than this, the approach of multitarget assemblage construction has continued garnering significant attention to extract enhanced antitumor effects via concomitant inhibition of the biochemically correlated targets and is also conceived to be one of the preferred futuristic strategies as a potential alternative to the combination therapy. To sum up, it is highly likely that the ship of epigenetic inhibitors will sail through the implementation of the aforementioned approaches.Despite the significant promise demonstrated by the aforementioned strategies, there is no denying the fact that the conventional approaches will continue receiving tantamount attention of the research groups for the development of new inhibitors. Fragment stitching approach on existing drugs coupled with lead modification studies ascertaining the impact of scaffold installation, regiovariation, bioisosteric replacement, structure simplification approach, structure rigidification approach and other subtle structural variations on the activity profile exemplifies some of these potential approaches.In light of the current scenario and the amount of efforts currently being invested in this field, it is highly likely that this decade might evidence the therapeutic growth of a handful of epigenetic drugs presently undergoing efficacy and safety evaluations at the clinical level and many new agents might enter the clinic. This review article presents an update of FDA approved epigenetic drugs along with the epigenetic inhibitors undergoing clinical stage investigations. The compilation also encompasses a detailed discussion of the rational strategies that can prove to be instrumental in the development of new inhibitors. The covered literature in this review indicates that the future attempts in the epigenetic drug discovery filed needs to headed in the following directions: (i) explorations of natural product based libraries for the development of non-nucleoside based DNMT inhibitors (ii) initiation of parallel programs on non-metal chelating type HDAC inhibitors as well as anilides to transpose the focus from hydroxamic acid type scaffolds owing to the pharmacological liabilities associated with latter class (iii) exhaustive studies needs to be conducted to ascertain the expression level of epigenetic enzymes in diverse malignancies (iv) fabrication of selective isoform inhibitors of HDAC to extract amplified anticancer effects despite of the fact that the clinical success, till date, have only been attained through pan HDAC inhibitors (v) exploration of additional structural templates other than the framework of tranylcypromine to expand the size of LSD1 inhibitors pipeline (vi) design of dual EZH1/EZH2 inhibitors in view of the fact EZH1, complements EZH2 in mediating H3K27 methylation and is also endowed with HMT activity. (vii) Expanding the size of the libraries of DOT1L inhibitors (viii) utilization of the existing chemical architectures of BET and HDAC inhibitors in the PROTAC model and antibody–drug conjugate model (ix) explorations of combination of epigenetic inhibitors with immunotherapy..) and noncoding RNAs are the major epigenetic mechanisms that control gene activity leading to a number of complex cancers  . In anotg/m2/day  , an oral DNA-demethylating drug has demonstrated stability in acidic environments as well as aqueous solutions. Despite being a potential DNMT inhibitor, its clinical translation has been hindered by the limited bioavalability in (< 7%) and primates (< 1%) along with high dose requirements in millimolar concentrations. , 114.Risk of mutagenicity and genomic instability associated with the use of nucleoside DNMT inhibitors  has led P = 0.27). Moreover, the study indicated substantial benefits in context of PFS . E. E309]. Epigenetic drug discovery field, at present, is flooded with numerous agents that have shown promise at preclinical or early stage clinical level. An obvious step forward to extract the benefits of these inhibitors is their installation in the PROTAC model as ligands for the target protein Fig. . Most clOnce each component of the PROTAC model is finalized, a site of tetheration on the ligand for the target protein and ligand for E3 ligase is identified either through the previously established structure activity relationship or through the docking study of the ligand with in the active site of target protein. Forth this, a synthetic route is proposed that requires an in-depth knowledge of classical organic chemistry concepts. For the tetheration of components, click chemistry , organometallic chemistry  and amide coupling methodologies  have been most exhaustively utilized. In comparison to other therapeutic modalities, PROTAC offers significant advantages such as elimination of target proteins, good oral availability, ease of attaining high potency/selectivity at nonomolar or even picomolar concentrations and high tissue penetration –311, 313More recently, epigenetic inhibitors have garnered significant attention of researchers in pursuit of degrading the target protein and this has led to the initiation of several explorations for the development of epigenetic inhibitor installed PROTACs Fig. . Some of75 that demonstrated striking selectivity as well as potency and selectivity for the HDAC6 degradation, clearly evidenced with the upregulated levels of HDAC6. The PROTAC also demonstrated promising antiproliferative effects in multiple myeloma cells . T. T359]. The surface recognition part has also demonstrated scope for structural alteration to afford a transposition in the pattern of inhibitory effects from pan-HDAC inhibition to selective isoform inhibitors of the enzyme. For example, a study focusing on the structural alteration of PXD-101 reported that conferring few degrees of rigidity to the surface recognition part (CAP) via placement of bicyclic ring (Azaindoles) in the chemical architecture of PXD-101 instilled a transposition in inhibitory effects from pan-HDAC inhibition to selective HDAC6 inhibition. Fig.  360]FigFig360]FiCAP and Linker modification On similar lines, the linker part has also demonstrated significant accommodative ability and several functionalities have been employed for the design of HDAC inhibitor. Digging the structural architecture of FDA approved inhibitors viz. Vorinostat, belinostat and panabinostat reveals that each of the structure comprises of different type of a linker  yet exerts pan-HDAC inhibition. However, utilization of the same linker of SAHA with an altered CAP construct  leads to two selective HDAC6 inhibitors namely ACY-1215 378]These aforementioned studies provide a strong rational to extend this concept to the targeted delivery of epigenetic inhibitors that, in turn, can demonstrate fruitful results in cancer by exerting epigenetic modulation at a much safer dose in comparison to standard epigenetic inhibitors based therapeutic tools. In this context, it appears logical to dig the preclinical pipeline of the epigenetic inhibitors and select some candidates that could not advance to the clinical stage investigation owing to the toxicity related hindering factors. Once selected, their accommodation in ADC model should be attempted.Designing the CRISPR/Cas9-based strategies to target the cancerous epigenetic regulators in a more specific manner is an emerging potential approach that has garnered tremendous interest in the recent past as a tool to correct genetic mutations. CRISPR-based epigenome editors (CRISPR epi-editors) consist of dCas9 and epigenetic effector  –382 and Significant advancement has been made in the field of the epigenetic drug discovery in the last decade. All the major classes of the epigenetic tools have received considerable attention. In context of the DNMT inhibitors, the FDA approved DNMT inhibitors 5-azacytidine and decitabine were exhaustively explored in AML and MDS at the clinical level and optimistic results were attained particularly in combination therapy. Other than the FDA approved nucleoside based DNMT inhibitors, guadecitabine, a dinucleotide antimetabolite of a decitabine linked via phosphodiester bond to guanosine and 5-fluoro-2′-deoxycytidine (FdCyd) also demonstrated promise and are likely to be the subjects of number of investigations in diverse cancer types in the near future. In addition, non-nucleoside prototypes namely curcumin, hydralazine, procainamide, disulfiram, SGI-1027 and ((-)-epigallocatechin-3-gal were evidenced to be endowed with interesting antitumor profiles. In light of the current trends in medicinal chemistry, it appears that the balance in context of the future research will be tilted towards the natural product based non-nucleoside inhibitors owing to the beneficial trends evidenced with curcumin coupled with the fact that the chemical architecture of this phytoconstituent comprises of several sites accessible to generate an appropriate sized structure pool. For the EZH2 inhibitory field, several drug candidates are undergoing clinical stage evaluation with GSK126, GSK343, CPI-205, ZLD1039, PF-06821497, UNC1999 representing a few of them. It is noteworthy to mention that the clinical success of tazemetosat has brought the spotlight on EZH2 as a potential target for the design of cancer therapeutics. The studies conducted also indicates that significant benefits can be attained through the simultaneous inhibition of EZH1/EZH2 and thus the dual targeting of the aforementioned is likely to be explored more comprehensively. Moreover, the synergistic effects anticipated to be attained through the combination of EZH2 inhibitors with immunotherapy or chemotherapy are also likely to be evaluated. In context of the preliminary/preclinical exploration, the chemical architectures of tazemetostat offer several sites for chemical alterations that can be exploited to create library of new inhibitors. The area of development of DOT1L inhibitors have relatively received less attention in comparison to the other epigenetic tools and pinometostat, a potent and selective small molecule DOT1L inhibitor, stands as the only DOT1L inhibitor that has been a subject of significant clinical attention. In this context, there is an urgent need to load the armoury of the DOT1L inhibitors with new entries that can maximize the therapeutic benefits of inhibiting this epigenetic target in cancer. HDAC inhibitors as small molecule inhibitors have always been at the forefront of investigations and a number of inhibitors belonging to this class of hydroxamic acids and anilides were tested in diverse malignancies both as single agents as well as the part of combination regimens. While these two classes are expected to continue being evaluated clinically as well as preclinically, it is also anticipated that some initiatives will be taken to probe the candidature of the non-metal chelating class of HDAC inhibitors as a potential therapeutic weapon in cancer. A complete profiling of TMP-269, prototype non-metal chelating HDAC inhibitor, might open an avenue for the construction of similar scaffolds. As the non-metal chelating class is expected to be relatively free of the pharmacological liabilities of the metal chelating class of HDAC inhibitors, safer therapeutics can be established via furnishment of agents that binds weakly with the metals but relies on interactions from other parts of the pharmacophore to afford acceptable levels of isoform inhibition. Progress in the field of LSD1 inhibitors has basically relied on the fragment stitching approach on the chemical architecture of tranylcypromine to access new frameworks capable of producing antiproliferative effects. OPY-1001, IMG-7289, GSK-2879552 and ORY-2001 are the tranylcypromine based LSD1 inhibitors that are undergoing clinical stage investigation in different cancer types. Futuristic attempts are likely to be directed towards the hydrazide type LSD1 inhibitors owing to the striking antitumor potential demonstrated by SP-2509. OTX-015, CPI-0610, BMS-986158, GSK525762, INCB054329, INCB057643, ODM-207, RO-6870810, BAY1238097, CC-90010, AZD-5153, PLX-51107, SF-1126 represents the BET inhibitors in various phases of clinical evaluation. It is quite hopeful that a comprehensive profiling of these BET inhibitors might yield a cancer therapeutic in the longer run. In addition, some preclinical studies have excellently utilized the BET inhibitory scaffolds for installation in the PROTACS model. The optimistic activity profile of the BET inhibitor based degraders can also spur numerous investigations in this direction. To sum up, the armoury of clinical and preclinical epigenetic inhibitors is filled with numerous candidates, however, conclusive benefits can only be ascertained after the completion of all the phases of the clinical trials.Overall, the findings covered in this perspective present recent advances in the field of epigenetic drug discovery. It is apparent that future research will include parallel programs aimed at the completion of the ongoing clinical studies, initiation of new clinical trials and development of new inhibitors. In addition, numerous brain storming sessions involving expertise of interdisciplinary teams composed of chemist, biologist, and formulation chemist along with researchers well versed with computational aspects of drug design needs to be conducted. Such programs can identify the hurdles and the hindering factors that have halted the clinical growth of several inhibitors of the epigenetic targets and present logical ways to strengthen the candidature of epigenetic targets in context of capacity to generate single target agents.