This simulation is appropriate for senior and junior emergency medicine residents.Shortness of breath is a very common presentation in the emergency department and can range from mild to severe as well as a chronic or acute onset. In sympathetic crashing acute pulmonary edema (SCAPE), patients typically present with acute onset of dyspnea occurring within minutes to hours and have significantly elevated blood pressure.1At the completion of the simulation and debriefing, the learner will be able to: 1) recognize the physical exam findings and presentation of SCAPE, 2) utilize imaging and laboratory results to further aid in the diagnosis of SCAPE, 3) initiate treatments necessary for the stabilization of SCAPE, 4) demonstrate the ability to assist with the stabilization and disposition of a patient via tele-medicine as determined by the critical action checklist and assessment tool below, 5) interpret the electrocardiogram (EKG) as atrial fibrillation with rapid ventricular response (AFRVR), and 6) recognize that SCAPE is the underlying cause of AFRVR and continue to treat the former.This simulation was performed using a high-fidelity mannequin. In order to simulate the telemedicine aspect, the learner evaluated the patient using a video conferencing interface while the two confederates were present with the high-fidelity mannequin. A debriefing session was held immediately after the simulation.The educational content was evaluated by debriefing and verbal feedback provided immediately after the case. Additionally, a survey was emailed to participants and observers of the case to provide qualitative feedback.Post-simulation feedback was overall positive with participants and observers. Participants and observers felt this was a safe and realistic simulation of SCAPE and provided them with the opportunity to practice rapid recognition and treatment of this condition.Sympathetic crashing acute pulmonary edema falls into the spectrum of acute heart failure disorders, and rapid recognition and stabilization is vital for the patient’s survival. This simulation case provided learners of all levels the chance to assess and treat a life-threatening condition with limited information in a safe and effective learning environment. The telemedicine component was used while conducting weekly didactics via zoom during the COVID-19 pandemic. Simulation is a large component of our didactic curriculum and implementing the telemedicine component into this case was worth the effort. It is important to familiarize our residents with telemedicine since we expect that it will become a larger part of the practice of emergency medicine in the future, allowing board-certified emergency medicine physicians to assist in providing care in rural emergency departments and smaller hospitals that may be staffed with less experienced providers.Medical simulation, tele-medicine, pulmonary edema, respiratory distress, cardiac emergencies, resuscitation. Learner Audience:Junior and Senior Emergency Medicine ResidentsTime Required for Implementation:Instructor Preparation: 20–30 minutesTime for case: 15 minutesTime for debriefing: 15–20 minutesRecommended Number of Learners per Instructor: 1–2Topics:Medical simulation, tele-medicine, pulmonary edema, respiratory distress, cardiac emergencies, resuscitation.Objectives:At the completion of the simulation and debriefing, the learner will be able to:Recognize the physical exam findings and presentation of SCAPE.Utilize imaging and laboratory results to further aid in the diagnosis of SCAPE.Initiate treatments necessary for the stabilization of SCAPE.Demonstrate the ability to assist with the stabilization and disposition of a patient via telemedicine as determined by the critical action checklist and assessment tool below.Interpret the electrocardiogram (EKG) as atrial fibrillation with rapid ventricular response (AFRVR).Recognize that SCAPE is the underlying cause of AFRVR and continue to treat the former.Shortness of breath and respiratory distress are common emergency department presentations. Occasionally, these symptoms are due to pulmonary edema or SCAPE, which requires rapid recognition and treatment. This case allows learners to review the presentation of SCAPE based on physical exam findings, vital signs, radiographic imaging, and laboratory results (objectives 1 and 3). The learner will then initiate medicinal and respiratory support treatments and demonstrate an understanding of the mechanism of action (objective 2). The tele-medicine format of this simulation case was chosen because our weekly didactic sessions were moved to a video conferencing format due to the COVID-19 pandemic. In our region, tele-medicine is frequently used because there are many critical access hospitals in our predominantly rural state. This case will give the learner the ability to practice telemedicine and demonstrate the ability to assist in patient resuscitation without having direct patient contact (objective 4). It will also assess their ability to interpret an EKG (objective 5), but the learner should recognize that AFRVR is being caused by SCAPE and should be treated with respiratory support and nitrates instead of rate or rhythm control medications (objective 6).Indian J Crit Care Med. 2016;20(12):719-723. doi:10.4103/0972-5229.195710Agrawal N, Kumar A, Aggarwal P, Jamshed N. Sympathetic crashing acute pulmonary edema. We recommend instructors to review current literature on the diagnosis and treatment of SCAPE as well as ACEP Clinical Guidelines on Acute Heart Failure Syndromes. Additional sources are listed in the references/suggestions section.This simulation was written to be performed during virtual didactics while using the ZOOM video conferencing platform during the COVID-19 pandemic. In order to perform the telemedicine component, a laptop was placed on a table at the foot of the mannequin’s bed. The laptop was logged into the ZOOM didactic session to allow the participant and observers to see the mannequin, cardiac monitor, and the two confederates. One second-year resident participated in the simulation case while the remainder of the residents and faculty observed. This format allowed us to demonstrate a scenario that simulates SCAPE and provides the stimulus needed during an emergent tele-medicine consult. To perform this simulation as written, we would recommend conducting the case over a video conferencing format with one to two learners and two confederates. The instructor and confederates should be with the high-fidelity mannequin and accessible over the video conference. This case could also be performed without the video conferencing format and could also be utilized as an oral board case. Learners were evaluated by the instructor(s) based on their ability to correctly diagnose and treat the patient.Participant and observer feedback was overall very positive, and they did not recommend any significant changes to the case design or format. This case was initially performed during the COVID-19 pandemic while all didactic sessions were conducted via video-conferencing. Because of this, only one junior resident was able to perform the case in the tele-medicine format during a didactic session. Of the seven responses received, one was from the participant and six were from observers. The survey was sent immediately after didactics concluded via Google Forms through the residency programs GroupMe messaging group, and all responses were anonymous. Results of the survey are below.


We study the intricate interplay between ecological and evolutionary processes through the lens of the prisoner’s dilemma game. But while previous studies on cooperation amongst selfish individuals often assume instantaneous interactions, we take into consideration delays to investigate how these might affect the causes underlying prosocial behavior. Through analytical calculations and numerical simulations, we demonstrate that delays can lead to oscillations, and by incorporating also the ecological variable of altruistic free space and the evolutionary strategy of punishment, we explore how these factors impact population and community dynamics. Depending on the parameter values and the initial fraction of each strategy, the studied eco-evolutionary model can mimic a cyclic dominance system and even exhibit chaotic behavior, thereby highlighting the importance of complex dynamics for the effective management and conservation of ecological communities. Our research thus contributes to the broader understanding of group decision-making and the emergence of moral behavior in multidimensional social systems. Selfish people always aim to maximize their well-being, which drives a formidable challenge to the evolution of cooperative behavior. Researchers remain curious to identify the necessary conditions and underlying mechanisms to obtain cooperation by natural selection. The prisoner’s dilemma game seems the best suited to address the subtleties of cooperation within groups of selfish individuals. The original version of this one-shot game consists of two rational individuals who have to decide independently to each other whether to defect or cooperate. Those selfish players’ curiosity lies in maximizing their payoff, so they always opt for defection, which promises a better return irrespective of the opponent’s chosen strategy in the classical prisoner’s dilemma game. Consequently, this mutual defection impedes the formation of a cooperative state, leading to the tragedy of the commons4, and hence, the society suffers. How to overcome this unfavorable outcome, often at odds with reality, is a basic query of the evolutionary game dynamics and evolutionary biology.The prisoner’s dilemma game5 helps in evolutionary progress. The formation of the genome from genes, multicellular organisms from single cells, helper birds assisting their parents in feeding their young6, and many more are excellent examples of cooperative enterprise. Social structures like groups and societies are examples of collaborative efforts by individuals despite cooperation always being vulnerable to exploitation by defectors. In spite of nobody knowing everything, human beings can still survive, thanks to their cooperative attitude. The large-scale collaboration among humans leads to the formation of towns, cities, states, countries, and continents. All these collective behaviors urge to determine mechanisms enforcing the appearance of cooperation in societies. A plethora of research has been conducted in the last decade recognizing several cooperation-facilitating mechanisms. The pivotal studies of Refs.9 show how nearest-neighbor interactions in spatial structure can help to sustain cooperation in iterated prisoner’s dilemma games, depending on the temptation to defect. The vital role of network topologies in flourishing a cooperative state12 has been a subject of rigorous investigation since the development of the discipline of network science. The mobility of the players13, kin selection14, reproduction restrictions15, impact of aging16 and direct and indirect reciprocity18 are all found to be highly potent promoters of cooperative behavior in the spatial prisoner’s dilemma game. People often introduce an additional strategy along with unconditional cooperation and defection. Introducing a tit-for-tat strategy19 is one of the most successful strategies for the iterated prisoner’s dilemma game for entailing cooperation. Various studies also confirm the positive role of punishment28 in elevating collaborative efforts in our society.The cooperation of simpler parts29 examined the impact of punishment on the prisoner’s dilemma game in the presence of the altruistic free space. Interestingly, although the influence of free space on emergent collective behavior36 gains well-deserved attention among interdisciplinary researchers, its generous contribution is often neglected from the game’s theoretical point of view. Reference29 considers the self-sacrificing contribution of free space by allowing others to replicate at the expense of its fitness. In return, free space never expects any favor from others. This inclusion of the natural instinct of free space allows them to consider an eco-evolutionary model where ecological changes and species evolution co-occur. The earlier assumption37 that evolutionary processes are much slower than ecological processes is relaxed in Ref.29. Numerous investigations43 have recently been conducted to understand the reciprocal effects of evolution and ecology. To understand how evolution influences ecology and how ecology affects evolution, scientists began studying the interaction between evolution and ecology on the same timescale51. The concept of co-evolution has also been considered in terms to depict the interactions between homogeneous and heterogeneous strategies taken by the player kinds those get useful in their evolution in the society. As ecological free space plays pivotal role in order to shower benefits in the evolution of the player populations having different actions for the dilemma, this kind of co-evolution can also be identified as eco-evolution in our study.Recently, Nag Chowdhury et al.55. A variety of natural systems requires a finite time propagation delay to materialize. The echoes in an auditorium56, the chirping of crickets57, the information flow in the nervous system58, and many other examples naturally involve a time delay parameter. Time delay is also ubiquitous in many biological processes, such as digestion59, maturation61, incubation62, and feedback63. How delay can affect collective behaviors in coupled dynamical systems72 has been investigated comprehensively. Recently, Ref.73 demonstrates the complex replicator dynamics of a delayed multigame with environmental space. How delayed distribution of continuously accumulating goods affects the evolution of cooperation in the spatial public goods games on the square lattice is revealed in Ref.74. Li et al.75 explore the bifurcation control of a fractional-order Lotka-Volterra model using delay feedback control. The profound impact of time delay on the stability of the interior equilibrium point of the pure strategy model is addressed in Ref.76. An exciting finding of Ref.77 uncovers that delay applied to the interspecific interactions can only affect the convergence time of the cooperation rate; however, the stability of the equilibrium points remains unaltered. The scenario differs in the case of delayed intraspecific interactions, where the system oscillates around the equilibrium point as the time delay period increases. Ben-Khalifa et al.78 inspect the stability of the evolutionarily stable strategy in the continuous-time replicator dynamics with random time delays.Motivated by all these studies, we wish to investigate the influence of time delays on the evolution of cooperation in the prisoner’s dilemma game by introducing additional strategies like punishment and altruistic free space. Most of the previous studies on evolutionary game dynamics assume the interactions among rational players are instantaneous. Interestingly, the significance of finite time propagation delay is enjoying widespread recognition in interdisciplinary research due to its numerous practical applicationsAll these pioneering works inspire us to study the role of time delay in spreading cooperative clusters among rational individuals. To understand how cooperation prevails in a world of selfish individuals, we consider a delayed eco-evolutionary model where free space provides unselfish benefits to all others. We update the evolutionary dynamics of the prisoner’s dilemma game by incorporating the effect of punishment and free space. The influence of time delay on the eco-evolutionary dynamics being a relatively unaddressed problem, we analyze this issue using the delayed eco-evolutionary model aimed towards resolving the dilemma raised in the prisoner’s dilemma game.R. The mutual defection yields both the player punishment P. The dealing between a cooperator and a defector gives the sucker’s payoff S to the cooperator, while the defector receives the temptation to defect T. Throughout our investigation, we maintain the ranking between the payoff as 29. This inequality of the weak prisoner’s dilemma game indicates that mutual defection always promises less payoff, as We start with the evolutionary two-strategy weak version of the prisoner’s dilemma game, where players can decide whether to cooperate mentclass2pt{minimWe further incorporate the ecological contribution of free space in the payoff matrix. Free space allows others to replicate and provide others ample opportunity to survive. Interestingly, free space never anticipates anything in return, and this selfless contribution of free space motivates us to update our payoff matrix  in the fF) seems out to be one selfless strategy to be made by any player population and on interaction with this, each population kind gets positive attributes as their benefits for replication, whereas, free space stands out to exist independently for every player kinds to shower it’s altruistic ease, without being chosen by any trait as their action in evolution. In order to showcase our dynamical system, we use the positive attributes as benefits to the competing players from this spatial free space but in game theoretic sense, free space does not act as an evolutionary move. Here, all these parameters x, y, z, and w be the respective fraction of cooperators, punishers, defectors, and free space, respectively. Hence, t based on the fitness before From the above upgraded payoff matrix  and in eWe assume all players die with a uniform rate Thus substituting Eq.  in Eq. , we obtaNote that To understand the impact of time delay in population dynamics, specifically in the context of a prisoner’s dilemma game, we present the comparative temporal behavior of variables in the presence and absence of delay in Fig. A striking difference is also observed for the subfigures  with the fixed parameter values The emergence of these oscillations hints us the spontaneous emergence of cyclic dominance among those strategies. In the following subsection, we discuss this occurrence in more detail.79 with 80 allows each strategy to dominate others for a specific time window, which is impossible if we attain steady-state dynamics. The periodic dynamics of each variable portray the coexistence of competing strategies. The maxima of each variable in the first row in Fig. We consider the same parameter values entclass1pt{minimaentclass1pt{minimaentclass1pt{minimaIn the next subsection, we will scrutinize the underlying mechanism that drives the system toward an oscillatory behavior.x remains at zero in Fig. To further study the effect of delay in our model , we keepy is vast compared to that of z  of Fig. We identify punishers overrule the defectors in the steady state regime for the chosen initial conditions and parameter values. Assuming an initial condition of  for the state variables and  for the delayed variables, we performed y and z variables in subfigures  of Fig. The first and the second largest Lyapunov exponents reveal valuable information about our system. The largest Lyapunov exponent x always remains at zero. However, the dynamics of y and z again offer a wide variety. The chaotic dynamics observed in Fig. y and z for yz plane in subfigure (i) of Fig. In spite of obtaining such captivating dynamics, we can not infer a few of these results from the biological viewpoint. The dynamics must be bounded within ; otherwise when the total population exceeds the maximum value 1, we obtain an overcrowded solution. We plot a dash-dotted horizontal line in subfigures (a) and (c) of Fig. The dynamical behavior is much more complex in the bottom panel of Fig. Figure Our proposed eco-evolutionary delay model explores various scenarios and player population diversities in society by changing the parameters in the model. The time delay parameter, 13 also found this critical value of Since punishers receive significantly higher benefits  in Fig. 46. In the future, we aim to investigate the underlying cause of this disappearance of attractors in our model. It is worth noting from an ecological perspective that the steady-state solution is now bounded within the range of . Interestingly, the cooperator’s survivability cannot be facilitated by either the temptation or delay parameter in the entire domain of analysis. Increasing the value of y and z variables oscillate with six periodic dynamics . We present the set of sub-figures (h) to describe the six-periodic oscillation among the competing population traits. Moreover, before the note of a period doubling phenomenon from periodic oscillation to bi-periodic oscillation, we also observe quasi-periodicity among punisher and defector traits, which has been marked by light grey region (I) in Fig. Figure In the upcoming subsection, we will shed light on the impact of additional system parameters on our model. Specifically, we will investigate the effects by varying two different parameters while keeping the others fixed. By doing so, we aim to uncover valuable insights into the influence of these specific parameters on our model’s behavior.In the context of our study, it becomes evident that when free space presents a more favorable opportunity for defectors, while keeping other parameter values constant, their survival becomes highly likely. In such scenarios, if the benefit induced by free space towards defectors, denoted as An analogous observation is evident when examining Fig. x, with each incremental value of In a similar vein, if we delve into the intricate interplay of free space-induced benefits towards cooperators, specifically Figure Intriguing insights into the behavior of our proposed model await us as we explore the captivating Fig. The captivating Fig. Both Figs. We maintain the parameter values at In the upcoming section, we derive the steady states and analytically determine the point of Hopf bifurcation in our model. Through rigorous analysis and numerical validation, we establish the accuracy of our findings.The extinction statePunisher and Defector-free stateCooperator and defector-free stateCooperator and punisher-free stateDefector-free statePunisher-free stateCooperator-free stateState of co-existenceThe proposed model  results Assuming By calculating the linearized version of the above system about the general steady state The characteristic equations of the linearized system  are obtaJ represents the Jacobian of the linearized system of equations. To obtain its characteristic equation, we set J. From the resulting eigenvalues, we can deduce the critical value of In this case, To simplify the transcendental equation, we make the following substitution: Using the relation in Eq. , we can m of Eq. :12\documLet us consider thatConsequently, we find the following relations,Using these two relations, we can easily concludeSince the left-hand side of Eq.  includesrite Eq.  as folloAfter performing extensive calculations, we can derive the following relationship by multiplying mentclasspt{minimaAfter substituting all the relevant terms as mentioned above, the above equation can be rewritten as:Equation  brings fBy modifying Eq. , we can from Eq. , we can In Fig. Furthermore, in Fig. Eco-evolutionary dynamics investigates how ecological and evolutionary processes interact and influence each other over time. It involves understanding the feedback loops between ecological and evolutionary processes and how they shape the dynamics of populations and communities. Ecological processes such as competition, predation, and resource availability can drive natural selection and thus influence the evolution of traits in populations. Conversely, the traits and genetic diversity within populations can shape ecological processes and affect the structure and functioning of communities. Eco-evolutionary dynamics can have important implications for conservation biology, as changes in ecological processes or environmental conditions can alter the direction or rate of evolution and vice versa. For example, human-induced environmental changes such as habitat fragmentation or climate change can alter the selective pressures on populations, leading to changes in their evolutionary trajectory. Overall, understanding the complex interplay between ecological and evolutionary processes is crucial for understanding the functioning and resilience of ecosystems in the face of environmental change.Our present study examines the interactions and long-term effects between ecological and evolutionary processes by considering a classic game, viz. the prisoner’s dilemma. The prisoner’s dilemma is often used as a metaphor for situations in which two individuals or groups must choose between cooperation and competition and in which self-interest can lead to a suboptimal outcome for both parties. It has important applications in economics, political science, and evolutionary biology. Our study suggests free space being an ecological variable, can significantly influence the prisoner’s dilemma game’s evolutionary dynamics. Free space here acts as an individual that benefits another individual at a cost. They lose their fitness by helping others without any expectation of reward. Although this form of philanthropic activity may seem to be foolish and may raise a question on the evolutionary basis of altruism among researchers, one can still observe such altruistic behavior in a variety of forms, such as donating to charity, volunteering time to help others, or even sacrificing one’s own life to save another. Altruism can also occur in non-human species, such as when a mother animal risks her safety to protect her offspring. We incorporate this vital aspect of social behavior which has important implications for fields such as psychology, sociology, and evolutionary biology. In contrast, punishment is an effective strategy to discourage individuals from engaging in undesirable behavior by making the cost of that behavior exceed the benefit. Punishment can provide a sense of justice or closure for those harmed by the conduct and can prevent people or groups from behaving in ways that are undesirable or unacceptable. To incorporate punishment into our game, we introduce a fraction of punishers. This approach, combined with the classical prisoner’s dilemma game and two additional strategies, helps us to understand how ecological and evolutionary processes interact and impact population and community dynamics.82 and how the outcome varies for other evolutionary games84 might be fascinating. In conclusion, our analysis provides valuable insights into the complex eco-evolutionary dynamics and contributes to a better understanding of group decision-making and the emergence of moral behavior in multidimensional social systems. We hope that our study will inspire further research in this area and facilitate the development of effective strategies for managing and conserving ecological communities.However, despite making progress, we have limited knowledge of how time lag affects eco-evolutionary game dynamics. The study of dynamical systems with delay is an active research area in mathematics, physics, and engineering. It has practical applications in fields such as control theory, signal processing, and neuroscience. Through numerical simulations, we find that delay can lead to oscillation in our system, which is impossible in non-delayed cases with those sets of parameter values. The evolution of strategies depends on several factors, such as the resources punishers use to fine defectors and the charitable contribution of free space. The survival of players using different strategies also depends on the initial fraction of the population. The system can settle into various stable states, and understanding multistability can provide valuable insights into the complex behavior of our system. We derive all steady states and calculate the point of Hopf bifurcation, where the steady state loses its stability, and delay causes the system to undergo periodic oscillations. This periodic attractor enables each strategy to dominate the other in a cyclical manner under suitable circumstances. Although defection appears to be the rational choice in the classical prisoner’s dilemma game, the intricate interactions between ecological and evolutionary processes prevent any strategy from dominating the others in the long run. Our proposed eco-evolutionary model can behave like a three-species cyclic dominance system for an appropriate selection of parameters, with each species dominating and being outcompeted by the next. Following the Hopf bifurcation, the system may undergo a series of period-doubling bifurcations as the parameter value increases, resulting in a successive doubling of the period of oscillation and the emergence of chaotic behavior. However, this can lead to overcrowding and limit the biological implications of our study. Our study also has several limitations worth exploring further. Our study uses paired communications to characterize group interactions and is conducted for the prisoner’s dilemma game. Investigating the impact of higher-order interactions


Dementia is a debilitating and prevalent disorder affecting millions worldwide . The emeThe potential benefits of multi-omics analysis in dementia research are significant. Researchers can develop more targeted and effective therapies by identifying key molecular pathways and biomarkers associated with these disorders. Multi-omics analysis may also help to identify subtypes of dementia disorders, allowing for more personalized treatment approaches. For a better understanding of the complex biological processes involved in dementia, the multi-omics analysis combines data from multiple resources leading to new insights and potential treatments for this devastating disorder .This Research Topic presents eight manuscripts, consisting of five original research papers, one case report, one review, and one mini-review. The manuscripts cover a diverse range of Research Topic related to recent advances and applications of multi-omics analysis in the field of dementia and neurodegenerative disorders. These expert-contributed manuscripts provide valuable insights into the underlying molecular mechanisms of dementia-related disorders as well as new diagnostic and treatment strategies.Wang et al., examined the upregulated expression of PLAGL2 in gliomas and identified a correlation with negative clinicopathological characteristics, including tumor grade. Moreover, the investigation revealed the role of PLAGL2 as an independent prognostic indicator, not for only progression-free survival (PFS) but also overall survival (OS) in clinical glioma specimens. Therefore, findings highlight the role of PLAGL2 expression in glioma progression and suggest its potential use as a prognostic marker for diagnosis and prognosis. The study’s results could have a significant impact on the diagnosis and treatment of patients with high-grade gliomas.Alqahtani et al., examined 47 genes associated with dementia and discovered that compositional, selectional, and mutational forces affect codon usage bias (CUB). The study suggested the positive association between high GC content and elevated gene expression levels, hence favoring GC-ending codons over AT-ending codons. The behavior of the TTG codon was unique, indicating the influence of selection on codon usage. The investigation highlights the significance of selection pressure, compositional constraints, and mutational forces in finding the usage of the codon.Khandia et al., investigated the correlation between gene length and various parameters related to codon usage in genes associated with neurodegenerative disorders. The study suggests the significant correlation of gene length with codon bias and also highlights the preference for GC-ending codons over AT-ending codons. The correlation between codon usage bias and gene length varied depending on the segment size, but gene segments CUB range from 1,2002,000 bp seems to be not affected by gene length. The investigation suggests that the significance of the impact of gene length and codon usage bias can aid in gene expression modulation in cases of defective gene functioning in clinical settings.Kumari et al., in their study, investigate the changes occurring in gene expression in the temporal cortex of aged control, asymptomatic AD, and symptomatic AD individuals. They identified differentially expressed genes and performed protein-protein interaction network analysis to obtain hub genes in the network. The study highlights the changes in glutamatergic hyperexcitability at early-stage in the AsymAD group and protein synthesis impairment in the symAD group. The findings offer potential therapeutic targets for early intervention in AD.Khan et al., developed a ligand-based model using machine learning to identify effective AChE inhibitors. They trained and tested the model on experimental data and used it to screen the Maybridge chemical database, leading to the discovery of four highly effective inhibitors with superior binding affinity to a known drug. These compounds have the potential to serve as a foundation for developing anti-AD drugs.Xue Bin et al., conducted a mini-review that delved into the correlation between BDNF, mental health, and AD. The review mainly focused on the role of nutrition, lifestyle, and environment in BDNF, leading toward the contribution to AD. The review further highlighted the potential new therapeutic targets that could aid in treating neurodegenerative diseases.Tiwari and Shukla emphasizes the importance of early diagnosis of AD and the use of the latest technologies such as lipidomics and proteomics for determining the alteration in lipids and proteins level in the biological samples. These techniques could aid in halting the progression of AD and dementia, and the review highlights their potential for early diagnosis and assessment of the disease.A review article by Chen et al., reported a case of Wolfram syndrome 1 (WSF1) gene mutation that initially presented with cognitive impairment and later recurrent cerebral infarction. Brain imaging showed reduced intracranial volume, particularly in the cerebral cortex and cerebellum, and Tau protein deposition without Aβ pathology changes. The findings suggest a possible link between WFS1 and neuronal vulnerability to tau pathology and ischemic damage.The multi-omics approach extends the unique technology that broadly highlights the characterization of dementia and other neurological diseases at various biological levels. This will help in understanding in-depth disease mechanisms more widely. This approach opened a new viewpoint for the early diagnosis and treatment options for AD patients. This will also help in finding potential targets for better treatment as well as prevention for patients with AD risk or who only have AD symptoms .Conclusively, the authors and editors of this Research Topic anticipate that the Research Topic of articles will highlight the progress made in the multi-omics analysis and provide a more comprehensive understanding of the complex biological processes involved in dementia, leading to potential new treatments for the disorder. We hope that the articles will motivate, inform, and provide direction to researchers and students in the field.


Cancer Smart Nanomedicine”, we have gathered high-quality contributions related to the fascinating field of nanomedicine. The Special Issue contains eight articles, namely four research articles and four reviews. The complete description of each study and the main results are presented in the full manuscripts and readers are cordially invited to explore the contents in detail.In this Special Issue entitled “In the manuscript authored by Klebowski et al., the authors provide scientific proof related to bimetallic palladium–platinum nanoparticles with different nanostructures to improve the effectiveness of therapy, while reducing the necessary total dose of the radiation used. In this study, the authors provide evidence about the design and development of nanomaterials to modulate their radiosensitizing potential and enhance the effectiveness of cancer therapeutics .In the manuscript written by Jugel et al., the authors detail how they developed cyclodextrein-modified poly(propylene imine) nanocarriers modified to specifically target minicircle DNA, targeting tumor cells. The authors found long-term expression of a therapeutic p53 gene in tumor cells .The work of Katifelis et al. tested whether the developed nanoparticles, composed of gold and silver, could induce programmed cell death over other pathways, despite apoptosis. The authors demonstrated that necroptosis and pyroptosis occurred, and therefore the nanoparticles induced promising anticancer effects. These exciting aspects warrant further research .The manuscript of Lafuente-Gómez details the development of a smart gemcitabine delivery system based on magnetic nanoparticles for the treatment of pancreatic cancer. The developed formulation proved to prevent the unspecific binding of proteins, reduced the cytotoxic effect of the drug in non-cancerous cells, and improved internalization in pancreatic cancer cells, and its activity was synergistically enhanced in combination with magnetic hyperthermia .The review of Wahnou et al. highlights the potential use of natural compounds with anticancer properties as potential therapeutic agents for the treatment of various cancers, including colorectal cancer. This manuscript provides a comprehensive review about the potential use of nanoparticles to overcome the pharmacokinetic obstacles of polyphenols as anticancer drugs .The review written by Dissanayake et al. provides an overview of the recent progress toward the use of nanotherapeutics for the treatment of metastatic breast cancer. In this review, the authors discuss in detail how nanotechnology can be used in combination with existing treatments .The review written by Chuang et al. describes the functions of exosomal long non-coding RNAs, sponging, and exosomal processing in anticancer processes. This review also discusses future directions regarding the application of natural products in the regulation of non-coding RNA-loaded exosomes .The review written by Ghidini et al. highlights the most recent developments in the field of nanomedicine RNA-associated therapies for the treatment of cancer. The ongoing clinical trials using RNA-loaded nanoparticles for cancer therapy are also described, with some promising formulations in phase I and II .


Volume II of Reducing the harm of medication–recent trends in pharmacovigilance. Ramírez et al. . In 2017, the World Health Organization (WHO) launched the third global health challenge, Drugs Without Harm, to achieve a reduction in harm related to iatrogenic drugs by 50% in 5 years. In this Research Topic, our objective was to evaluate strategies to improve the safety in the use of medicines to achieve this objective.This Research Topic is the Khan et al. performed a semi-structured exploratory interview with stakeholders to assess their perceptions of the current adverse drug reactions (ADR) reporting system and to identify pharmacovigilance policy issues and effective coordination issues in Pakistan. The results obtained are similar to those of other low- and middle-income countries that identify the lack of a regulatory framework as the main gap in the reporting system for ADRs. These findings highlight differences compared to the pharmacovigilance systems of high-income countries. Rehman et al. performed a survey to determine the perception and effects of intervention on patients regarding ADRs in public hospitals in Islamabad revealed that most of the participants were interested in medical consultation for medication use; some were willing to report ADRs in the future and called for the establishment of a hospital-level pharmacovigilance system. Pakistan felt the need for an effective and robust pharmacovigilance system after one of the deadliest medication-related tragedies that caused more than 300 deaths in 2012. The country established its national pharmacovigilance system center in 2015 and joined the WHO International Drug Program Monitoring in 2018 as a full member. Khan et al. in a descriptive cross-sectional study conducted by providing a questionnaire administered by an interviewer from the pharmacovigilance system through a convenience sampling method using the Indicator-Based Pharmacovigilance Assessment Tool concluded that despite receiving funding from the Global Fund, none of the National Public Health Programs have pharmacovigilance system centers or associated activities. A two-phase strategy is proposed encompassing non-financial and financial interventions to improve pharmacovigilance system systems at the national, provincial, Public Health Programs and hospital levels.A set of standards, regulations, guidelines and standard operating procedures constitute the fundamental basis of an efficient pharmacovigilance system as part of health policies. Several nations implemented pharmacovigilance systems in the early 1960s and continually introduce new legislation to strengthen their existing medication safety systems. However, the development and implementation of pharmacovigilance systems is very uneven throughout the world. Tang et al., using system organ classes and preferred terms from the Medical Dictionary of Regulatory Activity, analyzed the adverse reaction signals of ticagrelor and clopidogrel.The databases of adverse event reporting systems are public tools available on the web that provide access to search for information related to adverse events in humans. FDA Adverse Event Reporting System (FAERS) is a public web-based tool providing access to search for information related to human adverse events reported to the FDA by the pharmaceutical industry, healthcare providers and consumers. This type of database with all its limitations  offers interested parties stakeholders possibilities for signals mining of possible adverse reactions of many medications. A FAERS-based study was conducted to compare adverse reaction reports and bleeding signals for ticagrelor and clopidogrel. Valdés-Garicano et al. retrospectively evaluated the performance of a proactive pharmacovigilance system using laboratory alerts as a method to detect serious ADRs using hyponatremia and rhabdomyolysis as case studies. The authors found moderate sensitivity and high specificity for both ADRs.Most hospitals participate in pharmacovigilance through spontaneous reporting systems. However, spontaneous reporting systems have limitations, such as the difficulty of recognizing ADRs, the uncontrolled nature of the reporting method, and underreporting. For these reasons, retrospective and prospective surveillance methods are considered more effective than spontaneous reporting systems. in vitro tests that are safe for patients. Two papers addressed the use of in vitro tests in the identification of the culprit medication involved in hypersensitivity ADRs. Bellon et al. carried out a case-control study to evaluate the diagnostic tools in medication induced eosinophilia and systemic symptoms (DRESS) induced by vancomycin in Spanish cases. The evaluation included causality algorithms, the lymphocyte transformation test, and HLA testing. The results confirmed the association of the HLA-A*32:01 risk allele with vancomycin-induced DRESS and support lymphocyte transformation test as a reliable tool for determining vancomycin sensitization. Elzagallaai et al. evaluated the lymphocyte toxicity assay to diagnose and capture a serum sickness-like reaction due to ß-lactam antibiotics. The authors found that there was a significant concentration-dependent increase in cell death in cells isolated from patients compared to cells from healthy controls. The results of both studies suggest that in vitro tests could play a role in the diagnosis of hypersensitivity ADRs.Diagnosis of delayed-type ADRs is complex and is usually done after recovery. The ADR study includes medical history, causality algorithms, skin tests, and suspected medication rechallenge tests, and helps to identify the immunological mechanisms and culprit medications involved. The identification of the guilty medication is of great importance in the diagnosis, allowing an adequate management of the patient and avoiding a possible re-exposure in the future with serious consequences. The diagnosis based on the clinical history is especially difficult and in many cases it is not easy to establish an accurate time sequence between the administration of the medication and the onset of adverse symptoms. The information that skin tests can provide in the diagnosis of immune-mediated ADRs is limited because their sensitivity and specificity depend on the medication and the clinical manifestations, and their sensitivity is low. Therefore, the gold standard for confirming the diagnosis of severe ADRs and identifying the culprit medication is re-exposure to the suspected medications. However, it raises serious ethical concerns in severe ADRs. One of the approaches that has been explored to improve the diagnosis of ADRs is Taylor et al. have developed two tools to identify patient, medication, and emergency department (ED) presentation related predictors for MRPs across the continuum of ED care that may require specialist input to identify, manage or prevent. These screening tools were applied (or implemented) at and during the ED presentation (Presentation Tool), and shortly after emergency department or short-stay unit (SSU) discharge (Discharge Tool). Preliminary scoring cutoffs and associated screening tool performance have been proposed. The authors state that MRP predictors are readily available at the bedside and can be used to detect patients at increased risk on presentation to the ED and upon discharge from the ED or SSU at community.The search for predictors of medication-related problems (MRPs) is an approach that may improve current knowledge regarding the prediction of adverse drug events. Wang et al. evaluated potentially hazardous drug-drug interactions (DDIs) associated with prescribed oral antineoplastic agents in tertiary care teaching hospital settings without computerized DDI detection programs. Potentially hazardous DDI associated with oral antineoplastic agents were analyzed by using the United States Food and Drug Administration-approved labeling. Nearly 300 DDIs were identified in about 14,000 enrolled patients, with proton pump inhibitors, dexamethasone, and fluoroquinolones being the most frequently dangerous DDIs involved with oral antineoplastic agents. Multivariate analysis revealed younger age, increasing number of medications, and targeted therapy-treated patients were the main risk factors for a DDI. In the other study with cancer patients Tian et al. evaluated the use of potentially inappropriate medication in elderly patients seen in tertiary hospital outpatients with cancer with multimorbidity according to Chinese Geriatrics Association criteria, American Geriatrics Society (AGS)/Beers criteria and the Screening Tool for Prescribing for the Elderly (STOPP) and the Screening Tool to Alert the Right Treatment (START) criteria. The authors found a high prevalence of PIM use in older Chinese cancer outpatients with multimorbidity and low to moderate concordance among the three criteria used. The low concordance between the different criteria highlights the need to develop special PIM detection criteria for older cancer patients.Potentially inappropriate medicines (PIMs) are a major concern in pharmacovigilance and are a well-known public health problem. In this volume, two papers related to potentially inappropriate medication in cancer patients were presented. China is currently the country with the largest population of elderly people with cancer in the world, and cancer, as a chronic disease, places a heavy burden on the elderly. Older cancer patients may suffer from a higher rate of comorbidity, frailty, and geriatric syndrome, putting them at high risk for polypharmacy and PIM use. In the multicenter cross-sectional study, Yang et al. conducted a cross-sectional survey for pediatricians and guardians of children with tic disorders in Myanland, China, Macao, and Hong Kong to analyze information on physician behavior and medication choices and on the Guardians’ knowledge of tic disorder, medical treatment behaviors, and medication. Options and needs. The study revealed that pediatricians in China often follow clinical guidelines when selecting tic disorder medications, but rarely consider guardians’ preferences, highlighting a gap in treatment optimization. In addition, the patients’ guardians lack sufficient knowledge about tic disorders and medication options, requiring more physician-initiated dialogue.Evidence-based medicine integrates clinical experience and patient values and aims to use the best evidence to make decisions about the care of individual patients. The patients’ values, which reflect their subjective cognition and demand, have been proposed to be considered as a reliable clinical guide. In the case of pediatric patients, their guardians are responsible for their values. Jang et al. proposed that RWE has the potential to provide evidence for future regulatory decision-making in an environment where RCTs cannot be performed. Its objective was to investigate to what extent the safety of empagliflozin from the RWE study in Korea is different from that of the RCT emulating the design of a foreign RCT. The results of their study suggest that RWE emulating foreign RCTs has the potential to provide evidence for future regulatory decision-making.Randomized Controlled Trials (RCTs) are considered the most scientifically rigorous method for regulatory decision making. However, real-world evidence (RWE) is playing an increasing role in healthcare decisions. RWE enables monitoring of post-marketing safety and the assessment of comparative treatment effectiveness, which can be of utmost importance to develop guidelines and decision support tools for use in clinical practice. in vitro tests in the diagnosis of ADRs. Current methods of diagnosis of severe ADRs, often rare medication hypersensitivity reactions by frequency and mechanism, lack clear diagnostic criteria. Given their safety and good predictive value, lymphocyte transformation test and lymphocyte toxicity assay in vitro tests have great potential to be a useful diagnostic tool for severe ADRs. On the other hand, the implementation of tools to reduce potentially dangerous medications in older patients with cancer, drug interactions and inappropriate medications is urgently needed. The electronic medical record has proven to be more useful for evaluating problems already detected, allowing the implementation of prevention and early detection tools that minimize the risk of ADR. The use of large automated databases, including demographic data, diagnoses, procedures, and medication use, can generate real-world evidence (RWE) about the benefits and risks of medications and could even emulate a randomized clinical trial (RCT) with the advantages of providing longer follow-ups of patients with less exclusion criteria and higher external validity. However, RWE-based studies are more prone to systematic errors than RCTs which should be taken into account when assessing causal inference medication. For all these reasons, it is necessary to have a critical mass of specialists for the early detection, diagnosis and management of ADRs who, in collaboration with the authorities and patients, develop and implement the tools that make it possible to reduce severe medication-related harm.We appreciate the good acceptance of Reducing the Harm of Medication - Recent Trends in Pharmacovigilance series as shown by the interesting contributions to its two volumes. As in the first volume, we make some suggestions to encourage future Pharmacovigilance activities. The first is based on the need for continuous improvement of pharmacovigilance systems, and on the positive involvement of patients in spontaneous reporting systems of possible ADRs. Public adverse event reporting databases  make it easier for researchers with data mining skills to use these tools to generate new medication safety signals. As we already said in the first volume, it is necessary to improve diagnostic tools, causality algorithms and other


The utilization of quick compression-sensed magnetic resonance imaging results in an enhancement of diffusion imaging. Wasserstein Generative Adversarial Networks (WGANs) leverage image-based information. The article presents a novel G-guided generative multilevel network, which leverages diffusion weighted imaging (DWI) input data with constrained sampling. The present study aims to investigate two primary concerns pertaining to MRI image reconstruction, namely, image resolution and reconstruction duration. The implementation of simultaneous k-q space sampling has been found to enhance the performance of Rotating Single-Shot Acquisition (RoSA) without necessitating any hardware modifications. Diffusion weighted imaging (DWI) is capable of decreasing the duration of testing by minimizing the amount of input data required. The synchronization of diffusion directions within PROPELLER blades is achieved through the utilization of compressed k-space synchronization. The grids utilized in DW-MRI are represented by minimal-spanning trees. The utilization of conjugate symmetry in sensing and the Partial Fourier approach has been observed to enhance the efficacy of data acquisition as compared to unaltered k-space sampling systems. The image’s sharpness, edge readings, and contrast have been enhanced. These achievements have been certified by numerous metrics including PSNR and TRE. It is desirable to enhance image quality without necessitating any modifications to the hardware. Diffusion magnetic resonance imaging enables the analysis of brain tissue structure at a significantly smaller scale than what can be achieved through empirical voxel resolution when collecting data on water molecule activity in the brain. The effectiveness of this instrument is restricted by various hindrances such as spatial resolution, acquisition time, and potential distortions caused by motion. Super-Resolution Reconstruction has undergone significant development and rigorous testing over the course of the last twenty years. Notwithstanding the advancements made, there remain numerous unresolved issues. Certain entities are subject to regular simplification. Scientists commonly aim to optimize the inter-frame motion scheme. The commonly employed global motion estimation algorithm, which is defined manually, fails to consider the potential motion trajectories that may arise within sets of frames. The algorithm presented in this study integrates discrete dense displacement sampling into its framework, thereby facilitating the deformable registration of high-resolution images. The efficacy of Super-Resolution Reconstruction (SRR) has been evidenced in various medical imaging modalities, including Functional MRI (fMRI) as cited in references ,2, as weThe persuasive argument put forth by the authors suggests that residual learning techniques have the potential to improve the effectiveness of said algorithms. By employing a modified optimization technique that involves eliminating unnecessary modules from conventional residual networks, additional improvements have been attained . FurtherZhang in  providedThe efficacy of employing a Generative Adversarial Network (GAN) architecture for motion correction is predicated on its established capacity to tackle concerns associated with image restoration and facilitate Magnetic Resonance Imaging (MRI) reconstruction. The above-mentioned capability is attributed to its proficiency in generating high-quality images, as evidenced by the reference . The GANThe primary cause of image deformations in Magnetic Resonance Imaging (MRI) is the in-plane motion of the patient. However, this motion can also be utilized as a significant advantage for super-resolution. The tasks of image registration and motion artifact removal are complex and are elaborated upon in The authors proposed a method for accelerating data acquisition through the use of a rotating single-shot acquisition (RoSA) procedure with model-free reconstruction, based on the observed correlation. The crux of this algorithm involves acquiring a solitary blade for each diffusion direction in a single shot. The RoSA technique utilizes similarities that are apparent in diffusion weighted contrast for the purpose of image reconstruction. Therefore, it is necessary to utilize a subset of diffusion weighted (DW) data that has diffusion directions in proximity to the DW image under examination. It is assumed that DW scans that are adjacent exhibit a significant correlation coefficient. The modification of the highly constrained back-projection (HYPR) reconstruction procedure was undertaken for the purpose of reconstructing the RoSA images. The HYPR method is a standard non-iterative reconstruction technique utilized in subsampled radial acquisition for time-resolved MRI. According to reference , this teIn the meantime, RoSA has demonstrated its effectiveness by permitting high acceleration rates, namely . In thisDW image similarities are ignored by several approaches, including ,25,26,27The framework algorithm exhibits comprehensiveness with respect to the reconstruction procedure of DW images, sampling schemes of raw data, synchronization of k-q spaces, deblurring, denoising, motion estimation, and ultimately, the reconstruction of super-resolution images.A new GAN-based super-resolution image reconstruction model for DW-MR images is presented.The algorithm extracts image features at different scales. Other authors usually simplify this issue.At various scales, the algorithm extracts visual characteristics. This topic is often simplified by other authors.The technique uses different preprocessing phases for deblurring and denoising layers.The method uses a DW image reconstruction approach based on convolutional neural networks to rebuild low quality images from very sparse k-q spaces.The scheme uses the compressed sensing architecture to focus on reducing acquisition times.The procedure nests the author’s deformable motion estimation procedure as its reconstruction layer.The main contributions of this work are:The utilization of algorithms in compressed sensing requires the acquisition of samples that are entirely random. Subsampling at a rate lower than the Nyquist frequency can lead to the occurrence of aliasing artifacts, thereby necessitating the need to prevent such an occurrence. The model mentioned previously, as referenced in , facilitThe Poisson-disc sampling methodology generates a dense arrangement of points that are spaced apart by a predetermined minimum distance, resulting in a more naturalistic configuration. This methodology satisfies all necessary requirements, including the absence of coherence and the specified spacing among specimens. Moreover, it ensures the requisite noise characteristics. The concept of sampling low-frequency components at a higher sampling frequency is proposed by the author, as these components are considered to possess significant information.According to Otazo et al. , it is rTheoretical enhancement of temporal efficiency is the aim of the integration of the Partial Fourier concept with compressively-sensed data, as proposed in . The optOn the premise that the subject transitions among obtained k-q-space structural components, the subsequent subgroup is linked to patient motion that may be rectified and integrated into a super-resolution algorithm as its fundamental feature, as illustrated in The low-resolution DW image reconstruction algorithm commences by utilizing k-q-spaces that are highly compressed. The non-uniform fast Fourier transform (NUFFT) is utilized due to the presence of irregular sampling schemes. The subsequent phase utilizes the zero-filling (ZF) methodology.The technique of zero-filling is commonly employed for the purpose of increasing the dimensions of the image matrix along the phase-encoded direction. In the context of 2D imaging, the observed rise in matrix size pertains to the “within-plane” dimension, wherein the pixel count escalates from 256 to 512. The utilization of ZIP in 3D imaging can enhance the perceived resolution in the slab-select direction by employing the “through-plane” approach, resulting in an increase from 64 to 128 slices. The benefits are observed only during the initial doubling of the matrix size, beyond which no further advantage is obtained. While the process of zero-filling does not introduce any additional information to the original raw data, it can enhance the perceived spatial resolution of the resulting image by mitigating the effects of partial volume artifacts. The process of zero filling serves as a means of signal interpolation between adjacent voxels, resulting in a more uniform and less granular visual representation of the image.The convolutional recurrent neural network architecture is utilized in the proposed algorithm for MR image reconstruction. This approach enables the reconstruction of high quality images from highly undersampled k-space data by jointly exploiting the dependencies of the utilized sequences.The architecture under consideration incorporates the framework of conventional iterative algorithms, adeptly representing the repetition of the iterative reconstruction phases through the utilization of recurrent hidden connections across said iterations. Furthermore, the acquisition of spatio-temporal dependencies is achieved through the utilization of bidirectional recurrent hidden connections across temporal sequences.Subsequently, a correction in k space is required. The utilization of the inverse non-fast Fourier transform is aimed at generating a sequence of rectified k spaces. Ultimately, a collection of low-resolution diffusion weighted images is obtained through the utilization of an image reconstruction technique that employs the non-uniform fast Fourier transform (NUFFT) as its fundamental component. This study examines the alterations made to the motion effects in order to facilitate the reconstruction of super-resolution magnetic resonance images. Moreover, the registration algorithm exhibits a high degree of precision and effectively mitigates problems related to in-plane and out-of-plane motion.The implementation of multiple frames of images demonstrates temporal correlation between frames, thereby augmenting the information contained within each individual frame. Therefore, it is essential to consider both precision and uniformity simultaneously. Achieving this objective typically involves two primary approaches: motion compensation and super-resolution restoration . The notThe efficacy of employing a Generative Adversarial Network (GAN) architecture for motion correction is predicated on its demonstrated capacity to mitigate challenges associated with image restoration and facilitate Magnetic Resonance Imaging (MRI) reconstruction. The aforementioned capability is attributed to its proficiency in generating high-quality images, as evidenced by the reference . The GANy and x represent the graphical representations that have undergone motion distortion and those that have been rectified for it, respectively. The encoder block, excluding the central layer, is composed of five convolutional layers and includes n features. The structural design of the decoder blocks displays resemblances to that of the encoder blocks, with the exception being the utilization of transposed convolutions instead of convolutional layers. The implementation of image registration technology involves the calculation of spatial transformation parameters through an image registration methodology, as described in reference [The symbols eference . FollowiThe module responsible for registration produces several sets of results, which are subsequently combined with the objective frames denoted by eference  to implec  in terms of absolute magnitude. The study of Generative Adversarial Network (GAN) has gained significant prominence in recent times, owing to its complex and challenging nature [Increasing the number of network layers leads to a corresponding rise in the number of features. The decrease in the number of feature dimensions can be ascribed to the declining magnitude of the convolutional kernel. Two modifications were implemented to address the suboptimal reconstruction outcomes of the SRGAN and to surmount the challenges encountered during the network’s training and convergence. The omission of the g nature .The focug nature . The obsThe algorithm commences by reconstructing a set of low-resolution DWI images from a cluster of highly sparse k-q spaces, as cited in the The effectiveness of creating a confrontation network through the utilization of the Wasserstein distance is augmented by a particular attribute, as evidenced by the WGAN . The defw is subject to an update process that is restricted to a range of values between c. The technique mentioned above is utilized to emphasize the significance of the gradient update generator and mitigate the possibility of the vanishing gradient phenomenon. The function represented by the symbol The equation mentioned above employs the mathematical notation With each increment of the variable The function that measures the loss of the discriminator during training, denoted as The principal aim of this methodology is to enhance the training process of the generator, denoted as The neural network underwent a training procedure utilizing the parameter identified as terature  states tW by H by C for an image with C color channels, and C, respectively.The present study employs a loss function denoted as enced in .(7)IG=lN denotes the quantity of target images. The symbols The provided equation concerns the reconstruction of the generator of the discriminator, which is symbolized as The reduction in PSNR and SSIM metrics has been attributed to the smoothing effect of the reconstructed image through the utilization of the GAN architecture, as reported in the reference . The autThe aforementioned equation illustrates the outcome of the application of the registration network on the image denoted as Based on the outcomes of the experiment, the weight coefficient for RLT, denoted by the variable The efficacy of the motion estimation in the network, which utilizes a multi-scale methodology, has been established in conventional techniques, as indicated by prior research . The proThe notation The sequential arrangement of the images is under observation. The diagram illustrated in S, and the pair-wise regularization cost denoted by m.The current investigation utilizes an algorithm to derive a spanning tree that exhibits the lowest collective edge costs. The nodes denoted by the symbol The aforementioned cost function provides an estimation of the similarity of pixels between two compared images. This term remains unaffected by the displacements exhibited by its adjacent entities. The utilization of the parameter noted as   noise is to enhance the quality of the diagnostic image that has been negatively impacted by noise, leading to an improved image. The variable The mapping function y, while the variable The function x and y as two separate samples originating from two distinct data distributions. The distributions in question refer to the probability distribution of the noisy image, which is represented as f.From a statistical perspective, it is possible to consider The utilization of Generative Adversarial Networks (GANs) has been widespread across multiple domains, such as image super-resolution, image modality transformation, and image synthesis. The domains mentioned above have been thoroughly investigated, as evidenced by the extant literature ,52,53. TThe expression presented denotes the loss function employed for the denoising layer:The ultimate element of the equation denotes a gradient penalty term, where the penalty parameter is denoted by the symbol The Mean Squared Error (MSE) loss function is a frequently utilized approach in tasks that involve modifications at the pixel level. The primary objective is to minimize the disparities between the genuine depiction and the generated representation on a pixel-by-pixel basis. The aforementioned computation can be derived utilizing the subsequent methodology:o, p, and r. Recent research has indicated that the Mean Squared Error (MSE) loss function can lead to a noteworthy improvement in the peak signal-to-noise ratio. The envisaged result of this methodology is a decrease in precision, specifically in relation to frequently recurring particulars, which could significantly affect clinical diagnosis [The dimensions of the image are represented by the variables iagnosis .The proposed loss function can effectively tackle the issue by integrating a perceptual loss, as mentioned in references ,51,54. Ug, h, and i. The present study employs the pre-existing VGG-19 neural network [The variable  network  to extraThe generator denoted by eference . Pan andeference . The afoThe diagram illustrating the structure of the RED-WGAN model proposed can be found in The effectiveness of the algorithm was assessed through the analysis of in vivo patient cases and phantom data. The MATLAB software was utilized for conducting all trials and investigations. The objective of the assessments was to assess the effectiveness of super-resolution image reconstruction through the utilization of compressed input. An additional aim was to assess the efficacy of the MR sampling technique. This study involved the analysis of both in vivo and phantom data. The simulation results are illustrated in 10−5 .The present study incorporates the technique of compressed-sensing with super-resolution image reconstruction for application in Magnetic Resonance Imaging scanners. The utilization of phantom data has been employed to expose the inverse challenges associated with compressed sensing in the context of magnetic resonance imaging (MRI). The utilization of sparse projections has been observed in the retrieval of Shepp–Logan phantom data, as depicted in This study employs various descriptors, namely, the hybrid L-BFGS-B and cat swarm optimisation (HLCSO), sum of squared differences on entropy images, MIND , and self-similarity context (SSC).The assessment of motion estimating algorithms has employed Target Registration Error (TRE) as a metric.N denotes the quantity of landmarks that have been manually marked according to the recommendations of medical professionals. The study aimed to evaluate the effectiveness of the the WGAN-based deformable motion registration algorithm by comparing it to several image registration techniques in order to identify the most successful approach. The statistical analysis was performed on each of the registration algorithms listed by utilizing the mean and standard deviation. (std). The variable The limitations of medical imaging modalities, such as low spatial resolution, weak contrast, visual noise scattering, and blurring caused by the complexity of internal body tissues, can have a substantial impact on the accuracy of medical diagnosis. The text outlines a number of improvements that are purported to be advantageous in augmenting the quality of images while simultaneously minimizing scanning durations. Despite the presence of motion distortions, the algorithm that has been suggested effectively mitigates artifacts that are caused by data that has been highly undersampled. The algorithm presented in this study integrates an effective highly sparse acquisition strategy, namely, partial Fourier and Poisson Disc sampling, with super-resolution reconstruction to yield superior outcomes. The outcome is an improvement in the quality of dMR images and a decrease in time complexity. Furthermore, the augmentation of sampling for high-frequency components results in an improvement of edge depiction. The aforementioned methodology has the potential to be executed on dMR scanners without necessitating any alterations to the hardware. Therefore, it is apparent that the algorithm that has been implemented has the capability to generate images that are improved and more accurate. This study investigates the viability of a newly proposed DW-MRI algorithm, which aims to enable rapid and effective high-resolution diffusion imaging. The algorithm in question, known as RoSA, operates by selecting a single compressively sensed rotating blade of a PROPELLER in each diffusion direction. Moreover, the utilization of the resemblances among contiguous DW images constitutes a pivotal facet of the method’s execution. The short-axis EPI readout model has retained the advantages of short-axis EPI with regards to distortion reduction and significant improvement in resolution along the phase-encoding direction as a result of T2 decay.Improving spatial resolution yields clear advantages for both clinical diagnosis and fundamental research. Early detection of soft tissue abnormalities is possible. Furthermore, as a result of the reduction in movement aberrations, the algorithm has the capacity to augment the perceptibility of white matter tractography, as well as the trajectory of nerve fibers in close proximity to neoplasms. In comparison to T1/T2-weighted imaging, which generally offers isotropic resolutions of 1.0 mm or more for complete brain coverage, diffusion MRI is constrained by either excessively large voxel sizes or insufficient coverage. The proposed algorithm offers a major advantage in terms of enhancing image resolution and reducing examination time, in comparison to existing solutions. The aforementioned outcome is attained by means of amalgamating super-resolution image reconstruction, accurate motion estimation, and capitalizing on the similarity in the sequence of diffusion weighted (DW) images of neighboring diffusion directions. The efficacy of the algorithm was evaluated through a range of studies carried out under varied circumstances, wherein the quantity of PROPELLER blades, overall diffusion directions, and window dimensions were altered within the range of 5 to 40. In addition, the existence of off-resonance artifact is commonly acknowledged as a significant obstacle to EPI-based acquisition protocols. The implementation of improved sampling techniques has led to the reduction of aberrations and the mitigation of motion-induced distortions.The enhanced precision of tissue demarcation heightens the probability of arriving at a precise clinical diagnosis, for reasons that are self-evident. This mode entails certain financial considerations that necessitate attention. Hence, it is yet to be ascertained whether the increased procurement expenses associated with DW-MRI would be rationalized in the foreseeable future. The objective of this study was to showcase the capabilities of integrating various methodologies to enhance DW-MRI images, while simultaneously preserving a swift acquisition rate. As per anticipated outcomes, the algorithm put forth has the potential to enhance image resolution without necessitating any alterations to the hardware. Moreover, this approach has the potential to mitigate motion distortions while compromising on resolution. Preliminary trial data can serve as a valuable source of background information that may aid in the reduction of examination duration. The utilization of motion estimation algorithm can significantly reduce the presence of image artifacts in diagnostic imaging, thus enhancing the probability of an accurate diagnosis.Please refer to The average peak signal-to-noise ratio (PSNR) is computed by utilizing various method outputs and ground truth images. The simulation was conducted on one hundred occasions. To ensure the statistical reliability of quality measurements, the PSNR calculation procedure was replicated for every simulation case and subsequently averaged. It is noteworthy that the most favorable outcomes were achieved utilizing a compression ratio of 50%. This implies that a further reduction in the overall quantity of input samples leads to a slight improvement in the peak signal-to-noise ratio (PSNR), as evidenced by the data presented in The study conducted a comparison between the proposed algorithm’s robustness and other existing image resolution enhancement algorithms, namely, bicubic spline interpolation, Yang’s N-R-M-3D  (3DKR) aCompressed sensing (CS) theory provides a feasible approach to reconstructing signals with sparsity by projecting them onto a linear subspace of low dimensionality. This methodology exhibits significant potential owing to the theoretical assurances it offers. The methodology employed in this study involves the integration of Generative Adversarial Networks (GANs) in the image domain, along with k-space corrections. Generative Adversarial Networks (GANs) are accountable for encoding prior knowledge that is specific to images. Hence, it is imperative to establish a spurious linkage between the input and output strata of Generative Adversarial Networks (GANs). Possible areas for future research include enhancing reconstruction algorithms and refining raw data sampling schemes.


Editorial on the Research TopicInsights in pediatric gastroenterology, hepatology and nutrition: 2022The world of pediatric gastroenterology, hepatology and nutrition continues to expand and evolve over time: 2022 was no exception. Advances included diagnostic approaches, understanding of disease and new therapies. This research topic (RT) aimed to include some of these.Inflammatory bowel disease (IBD) beginning in childhood is typically more severe and more extensive than onset in adults . This isBorowitz provided a focused review of the epidemiology of IBD. As outlined in this review, there are a number of key aspects that likely contribute together to the onset of disease. These include environmental factors, diet, the host microbiome, triggering infections, immune responses and at risk genes. Whilst more is known about these variables, the cause of IBD has not yet been delineated. Further advances may follow clear, focused and detailed epidemiology studies.Sun et al. explored the some of the relationships between vitamin D in a systematic review. In the 16 studies that met inclusion criteria, the authors determined that there was no difference between vitamin D levels in children with IBD and controls without IBD. The data arising from these reports indicated that vitamin D supplementation can improve disease activity. Further studies focused on vitamin D in children with IBD are required: these could focus further on these relationships, the optimal dosage regimen to maintain vitamin D sufficiency and the treatment target.Vitamin D is one environmental factor of increasing interest to the epidemiology, pathogenesis and management of IBD . Sun et Tabari et al., in a third article focusing on IBD in children, compared imaging findings with clinical features in a group of children with fistulising Crohn disease (CD). Thirty-six of the 60 children included were shown to have one or more abscesses associated with their perianal fistula. Magnetic resonance imaging (MRI) findings associated with abscess formation were the length of the fistula tract, and the presence of multiple external openings or multiple fistulae.Lorton et al. reported on the development and assessment of a new passive driver for the application of MR elastography in children. The authors determined that their novel driver was considered to be more comfortable and provided enhanced imaging outputs. Further assessment leading to the use of such advances should lead to increased use of MR elastography.The use of MRI for assessment of hepatic fibrosis (MR elastography) has been considered more recently . Lorton Feng et al. described the development of a novel scoring system to enable clinicians to differentiate acute liver failure (ALF) due to Wilson disease from ALF due to other causes. When the use of this scoring system was applied in a cohort of 58 children a cut-off score of ≥6.5 (out of a maximum of 13) provided sensitivity of 91.7% and specificity of 97.8% to identify those with WD (p < 0.0001). Inclusion of age further enhanced the utility of the scoring system. This tool now needs further validation in other cohorts with greater patient numbers.In a second manuscript that focused on an aspect of liver disease in children, Kroger et al. evaluated the causes and outcomes of non-atrophic duodenal changes in 315 children from a consecutive cohort of 1,107 children undergoing upper gastrointestinal endoscopy in one centre in Finland. There was an association between the finding of non-atrophic changes and anemia, blood loss and abnormal celiac serology tests. The authors showed that, after excluding the subgroup with potential celiac disease, the remainder had good long-term outcomes.Borowitz reviewed the literature relating to this condition and noted increasing numbers of children being diagnosed in several countries. The authors also highlighted a number of gaps in the literature including the variety of scoring systems used and the lack of long-term outcome data.The final manuscript included in this RT provided an overview of the some-times controversial area of ankyloglossia  . BorowitTogether these seven reports covered some interesting aspects relevant to the field of pediatric gastroenterology. From these works, a number of questions arise. Hopefully these publications might help to trigger further endeavours that might answer some of the questions posed, and lead on to enhanced management and patient outcomes.


The musculoskeletal system is an essential part of the human body that is responsible for providing support, movement, and protection. The system is composed of bones, muscles, and connective tissues that work together in a complex manner to facilitate the functioning of the body. Over the years, extensive research has been conducted to understand the biomechanical and biochemical regulation of this system, and how these processes are interrelated. The 2017 Global Burden of Disease Study reports that the burden of musculoskeletal disorders accounts for 5.6% of lost years of “healthy” life worldwide . This ReChing et al. focused on simulating the mechanical and recurrent sprain injuries in chronic ankle instability (CAI) patients, and established a new ankle instability model with multiple ankle injuries using a self-designed machine to sprain the ankle with a controlled inversion angle and speed. This model provided a better understanding of the mechanical factors that contribute to ankle instability, and highlighted that multiple mechanical sprains are a good model for investigating the mechanisms of CAI induced by recurrent sprain injuries. Li et al. explored the biomechanical analysis of oblique-pulling manipulation in treating sacroiliac joint (SIJ) dysfunction. This study showed that pubic symphysis is essential to restrict SIJ motion, and the oblique-pulling manipulation could cause a weak nutation and separation of SIJ. The study highlighted the effects of stretching and loosening of surrounding ligaments in treating SIJ dysfunction. Han et al. performed the biomechanical and clinical study of rod curvature in single-segment posterior lumbar interbody fusion. This study evaluated the effect of rod contouring on single-segment posterior lumbar interbody fusion using the finite element method and retrospective study. The findings of the study have significant implications for the design of spinal implants and the treatment of spinal disorders. Zhang et al. evaluated the biomechanical effects of a novel anatomic titanium mesh cage for single-level anterior cervical corpectomy and fusion using finite element analysis. This study demonstrated the potential benefits of this implant in decreasing the risks of titanium mesh cage subsidence, instrument-related complications, and adjacent segment degeneration after surgery. The study highlighted the importance of biomechanical regulation in the design of cervical spinal implants. Zou et al. focused on the distal humeral trochlear geometry associated with the spatial variation of the dynamic elbow flexion axis. They investigated the relationship between distal humeral trochlear geometry and in vivo spatial variation of the dynamic flexion axis. By studying 10 healthy subjects, they found that medial and lateral trochlear sizes could be the key parameters affecting the elbow joint flexion function, highlighting the potential for designing custom implants to improve joint function. Wen et al. explored the relationship between bearing extrusion and postoperative persistent pain in Oxford unicompartmental knee arthroplasty. The study evaluated the biomechanical factors that contribute to bearing extrusion and postoperative pain in patients with knee arthroplasty, highlighting the improvement in bearing movement trajectory in potential beneficial treatment of knee disorders. Wang et al. investigated the biomechanical relationship between posterosuperior rotator cuff tear (PSRCT) size and shoulder abduction function using cadaveric shoulders. These biomechanical testing suggested that the weight-bearing ability of the shoulder significantly decreased as PSRCT progressed. Chang et al. compared the muscle activation patterns and spinal kinematics between the hand-foot kneeling (HFK) position used in the traditional Chinese exercise Wuqinxi and the four-point hand-knee kneeling (HKK) position commonly used for core stabilization exercises. This study suggested that HFK was more effective for strengthening abdominal muscles, while HKK was more effective for strengthening lumbar muscles and increasing spine mobility, providing evidence for selecting specific exercises and developing individualized training programs.Several factors influence the biomechanical regulation of the musculoskeletal system, including muscle strength, muscle flexibility, joint stability, and joint range of motion (ROM). By understanding these factors, researchers can develop interventions to improve the overall function of the musculoskeletal system. Orth et al. evaluated the use of novel mineral-coated microparticles for spatiotemporal controlled delivery of VEGF and BMP-2, which showed great potential to improve bone healing in atrophic non-unions by promoting angiogenesis and osteogenesis as well as reducing early osteoclast activity. Ran et al. described a new method for bone preparation in total knee arthroplasty using an ultra-pulsed CO2 laser osteotomy system, which was shown to preserve natural bone structure and improve cell adhesion compared to traditional mechanical saws. This study suggested the promising application of ultra-pulsed CO2 laser in total knee arthroplasty (TKA) bone preparation, offering non-invasive bone cutting and long-term biological fixation. Besides these original articles, Wang et al. reviewed the application of iron oxide nanoparticles for bone regeneration in recent years, and outlined the mechanisms of iron oxide nanoparticles in bone tissue regeneration in detail based on the physicochemical properties, structural characteristics and safety of iron oxide nanoparticles. This review demonstrated the potential of these nanoparticles in enhancing bone growth and regeneration, highlighting the importance of biochemical regulation in the treatment of bone disorders.Another exciting area of research that is highlighted in this Research Topic is the use of novel materials and technologies for the treatment of musculoskeletal disorders. For instance, Zheng et al. demonstrated that activating the Sirt1-autophagy signaling network through the pulsed electromagnetic field (PEMF) therapy can alleviate intervertebral disc degeneration, thereby protecting extracellular matrix (ECM) and reducing intervertebral disc (IVD) degeneration. This finding highlights the critical role of Sirt1-dependent autophagy signaling pathway in ECM protection, and the establishment of therapeutic effect of PEMF on IVD degeneration.Biochemical regulation, on the other hand, is controlled by various hormones, signaling pathways and growth factors, including VEGF, BMP-2, P1NP, and HbA1c. These substances play a crucial role in regulating the growth, development, and maintenance of the musculoskeletal system. For instance, Jia et al. focused on the prediction of femoral strength based on bone density and biochemical markers in elderly men with type 2 diabetes mellitus, which illustrated the interplay between biomechanical and biochemical regulation in the treatment of musculoskeletal disorders.Recent research has focused on the interplay between biomechanical and biochemical regulation of the musculoskeletal system. It has been discovered that mechanical loading can influence the expression of certain genes that regulate muscle growth and repair. Furthermore, biochemical signals can also affect the biomechanical properties of the musculoskeletal system, including the stiffness and strength of bone and connective tissue. For example, Jeong et al. evaluated the optimal surgical plan for the treatment of extraocular muscle damage in thyroid eye disease patients based on finite element analysis. This study highlighted the potential benefits of using finite element model in designing surgical interventions to reduce damage to the extraocular muscle during treatment strategies. Similarly, Jia et al. focused on the prediction of femoral strength based on bone density and biochemical markers in elderly men with type 2 diabetes mellitus. This study showed how computational models can be used to assess the risk of bone fractures and guide clinical decision-making. Wang et al. investigated the biomechanical effects of medial meniscus radial tears on the knee joint during gait using a finite element model. This study demonstrated that radial tears with larger widths could lead to high stress concentrations, contributing to a better understanding of meniscal tear-induced biomechanical changes during human activities and potential surgical guidance of meniscectomies and the prophylaxis and treatment of OA. Fang et al. used computational kinematic simulations to investigate the effect of different rotational alignments of the tibial component on knee kinematics after total knee arthroplasty. The results showed that moderate external rotation of the tibial component generated more natural knee kinematics than internal rotation or neutral position of the tibial component. Pei et al. investigated the kinematic and biomechanical effects of spinal distraction surgery in children with early onset scoliosis using 3D finite element analysis. This study revealed that traditional bilateral fixation can cause spinal re-imbalance and unexpected cervical lordosis and lateral displacement, and that more attention should be paid to spinal kinematic and biomechanical changes, providing a better understanding of spinal distraction surgery. Wu et al. proposed a principal-strain criterion to evaluate the safety of the fixation construct in cervical kyphosis correction and validates it against a retrospective case of anterior cervical discectomy fusion (ACDF), using finite element model. This study suggested that the ACDF restricted the ROM of cervical segments and lent stability to vertebra fusion, and the shape of the anterior cervical plate conforming to the curvature of the vertebra and screws fully inserted into vertebrae reduced the deformation concentration around the screw trajectories. Zeng et al. used finite element analysis to investigate the stability of internal fixation systems in different subtypes of Schatzker II fracture of the tibial plateau, and found that the use of fillers at the defect site can effectively reduce stress concentration of the implant and loss of the collapsed block, providing good stability for the fracture. This study highlighted finite element analysis as a powerful tool to help improve clinical outcomes.Another fascinating aspect of this Research Topic is the use of computational models to gain insight into the biomechanical and biochemical regulation of the musculoskeletal system. In conclusion, the articles in this Frontiers Research Topic provide valuable insights into the biomechanical and biochemical regulation of the musculoskeletal system. The studies highlight the mechanical, biochemical factors, and the complex interplay between them in the maintenance of musculoskeletal health and the development of musculoskeletal disorders. The findings of these studies have important implications for the development of new treatments and therapies for musculoskeletal disorders, as well as for the design of prosthetics and orthotics. The use of novel materials, technologies, and computational models is also an exciting area of research that has the potential to revolutionize the field of musculoskeletal biomechanics. Overall, the articles in this Research Topic represent a significant contribution to the field of bioengineering and biotechnology and will be of great interest to researchers, clinicians, and engineers working in this area. The primary challenges within the field of Biomechanical and Biochemical Regulation of the Musculoskeletal System involve deciphering the mechanisms behind musculoskeletal injuries and diseases, enhancing prevention and treatment approaches, and investigating the interplay between mechanical forces and biochemical signaling pathways. In order to tackle these Research Topic, future studies will employ cutting-edge imaging, computational modeling, molecular biology methods, clinical trials, and interdisciplinary partnerships.