Which gut microbiota interactions are present in psoriasis and how they collaborate with immune cells and influence psoriasis development via the gut-skin axis remain incompletely elucidated. In this article, we review the latest information on the unique patterns of gut microbiota and co-metabolites involved in the pathogenesis of psoriasis and attempt to explore microbial-based therapeutic targets derived from mono-and polymicrobial probiotics, fecal microbiota transplantation, pharmacomicrobiomics, and dietary interventions as diagnostic or therapeutic approaches promising to provide new options and long-term management for psoriasis.This review summarizes the potential role of gut microbes and their metabolites as novel mediators of psoriasis, including their composition and function in disease pathogenesis, progression, and management. Gut microbiota network analysis, colony construction, and  Basin vivo experiments and clinical trials demonstrated that certain common genetic and environmental factors and immune pathways might be present in psoriasis and inflammatory diseases due to intestinal dysbiosis , pharmacomicrobiomics, and dietary interventions. More importantly, we not only summarized the effective cure rate, prognosis with single or combined probiotics, and molecular mechanisms by which the gut microbiota might be engaged in drug metabolism in the treatment of psoriasis but also evaluated the effects of probiotics interacting with exogenous dietary factors on psoriasis, providing evidence for microbial immunotherapy as well as dietary interventions.2.In the human body, the skin and the intestine are the two organs with the most abundant microbiota, and the gut microbiota is involved in the occurrence and development of human systemic diseases in many ways. Many reports confirmed the close association between gut microbiota and diseases such as cancer , type 2 A strong bidirectional link between the gut and skin has been demonstrated, with many studies linking gastrointestinal health to dynamic homeostasis and heterogeneity of the skin. Patients with psoriasis have a reduced diversity of intestinal microbiota and possible dysbiosis compared to healthy controls, as evidenced by the changes in the microbiota at different levels of categorization, as detailed in P. histicola alleviates RA -23/IL-17A axis–associated cytokines and erythematous scaling lesions in the skin of IMQ-treated mice, suggesting that artificial alteration of the gut microbiota might be relevant for reducing the systemic inflammatory response in the skin of psoriasis patients (Exploring the changes and functions of the gut microbiota in psoriasis can help provide new targets for the diagnosis and treatment of psoriasis. Studies showed that helper T cells (Th17) are important mediators of intestinal epithelial barrier integrity and can drive both intestinal inflammation and extraintestinal autoimmune disease progression through the microbiota, acting as a bridge between host microbiota and immune-mediated inflammatory diseases; thus, the heterogeneity and plasticity of Th17 are expected to be a breakthrough in the mechanisms of psoriasis development and refinement of “litmus test” therapeutic strategies . For exaiates RA , and P. rthritis . Ito et ay genes . Oral adpatients .Although biologics have achieved high skin lesion clearance in psoriasis, the current process of treating psoriasis with biologics has been a source of secondary failure problems and safety issues have been a major concern for clinicians. Clinical evidence showed that IL-23 inhibitors reachive remission in patients who do not respond well to IL-17 monoclonal antibodies . Signifi3.In addition to bacteria that can influence various physiopathological processes from immune development to phenotype, mounting studies demonstrated the involvement of intestinal fungi in the regulation of immune homeostasis . Fungi aCandida albicans, worsened psoriasis-like skin inflammation by enhancing the response of Th17 cells, neutrophils, and Langerhans cells and inducing changes in the skin transcriptome of mice similar to those in lesional skin of psoriasis patients  than the general population, although the responsible mechanisms are unclear. A recent study has found that psoriasis disrupts gut microbiota, causing the production of succinate and pro-inflammatory ligands by intestinal microorganisms, which induce the proliferation and activation of colonic CX3CR1hi macrophages, ultimately exacerbating colitis . AdditioTrimethylamine (TMA) is generated from dietary carnitine and choline in fish, eggs, and beef products by intestinal microbiota choline TMA lyase. Then, TMA enters the liver via the portal circulation and is oxidized by the hepatic enzyme flavin-containing monooxygenase 3 to form TMAO . Hazen’sNew biologic treatments have recently been added to psoriasis treatment options  and higher abundance of pro-inflammatory bacteria and fungi (such as Candida spp.) compared to responders, and that response to infliximab treatment was more accurately predicted based on bacterial taxa.Methotrexate, used to treat colon cancer and psoriasis, is also used in the treatment of RA , but aboer study  comparin6.Streptococcus salivarius K-12 and that efficacy continued to improve with longer treatment duration (Bifidobacteria infantis (B. infantis) 35,624 significantly improved the progression of psoriasis and reduced the expression of C-reactive protein and tumor necrosis factor (TNF)-α, showing that the immunomodulatory effects of the microbiota in humans are not limited to the mucosal immune system but extend to the systemic immune system  in vitro. Therefore, the influence of exogenous dietary factors has to be considered while using probiotics  have certain side effects, such diet significantly reduces inflammation and is an effective means of relieving symptoms in obese psoriasis patients, possibly related to the microbiota-gut-skin axis . A Frenc8.In this article, we provided current evidence on the role of the gut microbiome and metabolites in psoriasis and discussed their potential implications for diagnosis and treatment. Significant progress has been made in characterizing the composition of gut microbes and their relevance to inflammatory diseases of the skin, as well as in resolving whether microbes interact with host cells through various small molecules and signaling peptides. Furthermore, a number of emerging microbial interventions/therapeutic strategies and protocols for their clinical application emerged. However, there are still many challenges in facing the important scientific issue of “relapse after drug withdrawal” in psoriasis. Therefore, further exploring the pathogenesis of psoriasis and screening for new targets, new candidate commensal bacteria, and their metabolite molecules that are safe and effective in prolonging the time to relapse are greatly significant.QZ and KW collected the data research from PubMed and proposed the structure of the manuscript. QZ wrote the first manuscript draft. QY and BM contributed to funding acquisition. FZ and YN had primary responsibility for the final content. All authors contributed to the article and approved the submitted version.


A code is generally defined as a system of signals or symbols for communication. Experimental evidence is synthesized for the presence and utility of such communication in heart rate variability (HRV) with particular attention to fetal HRV: HRV contains signatures of information flow between the organs and of response to physiological or pathophysiological stimuli as signatures of states (or syndromes). HRV exhibits features of time structure, phase space structure, specificity with respect to (organ) target and pathophysiological syndromes, and universality with respect to species independence. Together, these features form a spatiotemporal structure, a phase space, that can be conceived of as a manifold of a yet-to-be-fully understood dynamic complexity. The objective of this article is to synthesize physiological evidence supporting the existence of HRV code: hereby, the process-specific subsets of HRV measures indirectly map the phase space traversal reflecting the specific information contained in the code required for the body to regulate the physiological responses to those processes. The following physiological examples of HRV code are reviewed, which are reflected in specific changes to HRV properties across the signal–analytical domains and across physiological states and conditions: the fetal systemic inflammatory response, organ-specific inflammatory responses (brain and gut), chronic hypoxia and intrinsic (heart) HRV (iHRV), allostatic load , and vagotomy . Future studies are proposed to test these observations in more depth, and the author refers the interested reader to the referenced publications for a detailed study of the HRV measures involved. While being exemplified mostly in the studies of fetal HRV, the presented framework promises more specific fetal, postnatal, and adult HRV biomarkers of health and disease, which can be obtained non-invasively and continuously. Brain–body communication is accomplished via multiple routes, e.g., neural, immune, metabolic, and endocrine, and is thought to be reflected in the mathematical properties of heart rate variability (HRV). Physiologic complexity is fundamental to HRV properties. As such, HRV analysis requires comprehensive assessment via complementary mathematical estimates from different signal–analytical domains ,2. What For example, psychophysiological models of HRV have been proposed and used intensely in research ,4. Many Despite this progress in some fields, it remains striking that an overarching cohesive set of concepts has been lacking that addresses the question: How can we understand comprehensively and systematically the rich informational structure of HRV as a process-specific reflection of brain–body communication? Here, this issue is addressed by introducing and defining specifically the notion of HRV code based on a perspective from complex signals bioinformatics and rooted in a large body of experimental evidence ,9. A keyA code is generally defined as a system of signals or symbols for communication . To presBriefly, HRV contains signatures of information flow between the organs and of response to physiological or pathophysiological stimuli as signatures of states (or syndromes). HRV exhibits features of time structure, phase space structure, specificity with respect to (organ) target, and pathophysiological syndromes, as well as universality with respect to species independence . TogetheThe focus of this review is to build upon the physiological experimental evidence for the notion of the existence of such mathematically defined HRV code and to illustrate its significance. Such a notion implies that the process-specific subsets of HRV measures indirectly reflect the phase space traversal reflecting the specific information contained in the code required for the body to regulate the physiological responses to those processes. While this work focuses on the abstraction of the concept, the interested reader is referred to the cited publications for a detailed look into the HRV measures involved and their mathematical properties.This biomathematical view on HRV is novel and physiologically, translationally, and clinically relevant. After the presentation of the concept using an evidence/significance structure for each subthesis, this conjecture is synthesized in the conclusion section suggesting general directions for future research.HRV derived from ultrasound-based or electrocardiogram (ECG)-based sensors represents the key source of insights into prenatal, fetal, and postnatal wellbeing, development, and early detection of physiological abnormalities. There is no universally used heartbeat interval sampling method for the derivation of HRV data. In this section, it is shown that this status quo has consequences for our estimates of HRV properties, especially those relying on short-term time scales of brain–body communication reflected in HRV. An interested reader is referred to the following accompanying article .In studies on chronically instrumented fetal sheep modeling human labor  and in hFor any data capture technique following the Nyquist–Shannon sampling theorem, if the information is indeed encoded in the HRV signal, it must be sampled correctly for true representation to contain complete predictive information .In several studies using animal models and human cohorts, we made observations validating this notion. Studies in pregnant sheep demonstrate the potential to detect fetal acidemia and predict cardiovascular decompensation during labor using high-precision ECG recording of the fetal heart rate (FHR) ,17,19. AFundamentally, the temporal coding in HRV is seen as an emerging consequence of the oscillations of multiple nonlinearly coupled oscillators, together contributing to the HRV’s dynamic properties in phase space, including time .The evidence for temporal coding in HRV puts constraints on the potential for predictive utility of the low-sampling rate HRV tracking technologies such as photoplethysmography (PPG)-based wearables or ultrasound-derived fetal HRV monitors.The impact of the duration and sampling rate of ECG on the quality and physiological representativeness of the ECG-derived HRV measures has been documented in part in the studies on adult subjects (cf. ) but hasOverall, within the integrative framework of the HRV code , the proThe intrinsic limitations of the different sensor technologies must be accounted for during hardware and software stages of algorithm development with regard to their ability to adequately capture salient physiological information as well as the risk of capturing physiological artifacts at lower sampling rates ,17,35,41In “adult” HRV studies, the advent of ubiquitous wearables as consumer devices and in decentralized clinical trials makes the aspect of the HRV time structure highly relevant because, so far, the systematic studies are lacking on the impact of the sampling rates in wearables versus conventional Holter-like ECG devices for specific health monitoring purposes.The advantages of PPG-based wearables are the ease of use and versatility, as they typically double as smartwatches and have ubiquitous use. Hundreds of millions of PPG-based health trackers are already in use worldwide, and some attempts have been made, especially during the recent pandemic, to take advantage of the big data to extract some predictive information ,43,44.The key disadvantage of PPG-based wearables, and all wearables to date that are PPG-based, is their low sampling rate of physiological time series, such as beat-to-beat information and heart rate. The sampling rate differs by device, sometimes using a relatively higher, yet still physiologically insufficient, frequency internally than what is made available for analysis. Most importantly, the low sampling rate of heart rate impacts the resolution of heart rate fluctuations, as discussed above ,40. The Interestingly, very few options exist so far for consumer-grade ECG devices with a 1000 Hz sampling rate, the clinical gold standard. Some solutions do exist in sports, space, and military areas. Since this is not meant to be a review of commercial solutions available, the interested reader is left to perform a more specific search.Here, the notion of dimensionality is used as it pertains to characterizing a system’s phase space . The eviAn important and, due to its pleiotropic effects, enigmatic contributor to HRV properties is vagus nerve activity. The neuroanatomical distribution of the vagus nerve goes well beyond the well-known respiratory and cardiovascular controls as well as the more recently discovered metabolic and immunological control. The vagus nerve connects the brain with the body’s organs, in particular, the thymus, paraganglia (distributed sensor system in thorax and abdomen), liver, gastrointestinal tract, uterus, pancreatic islets, chemoreceptors sensing nutrients and related compounds , mechanosensors , temperature sensors, osmosensors, and nociceptors . In contThere is evidence that physiological predictions are possible under the assumption of HRV phase space structure. Such predictions can shed light on the complex vagal nerve’s contributions to HRV.(1)The systemic inflammatory response ,26;(2)Organ inflammatory response: brain and gut ;(3)Chronic hypoxia and intrinsic (heart) HRV (iHRV) ,51;(4)Allostatic load: physiological stress due to surgery ;(5)Vagotomy  ,25.Let us focus on the following physiological examples of HRV behavior:The cholinergic anti-inflammatory pathway (CAP) signals via the vagus nerve’s afferent branch to surveil the body’s inflammatory milieu and relay this information to the brain ,53. SimpIn contrast to the afferent and cerebral processing networks, the role of the efferent branch of the vagus nerve in the fine-grained control of inflammatory milieu under physiological and pathophysiological conditions has been studied more extensively. Underscoring its homeokinetic role, the research on the efferent branch yielded detailed insights into the anti-inflammatory, but not immunosuppressive, effects of the vagus nerve signaling on the spleen’s macrophages ,58. In pThe changes in HRV traverse a not well-understood phase space that can be, at least in part, characterized by complementary HRV measures from different signal-analytical domains . Such pIn addition to predicting inflammation, another subset of HRV measures characterizes the iHRV properties imprinted by chronic exposure to hypoxia . A complSystematic studies in various species with high semblance to human physiology, such as pigs, sheep, and non-human primates, as well as clinical studies, are needed to develop fundamental physiological and translational pathophysiological insights into HRV phase space structure.Physiological processes of special interest are sleep and exercise, with sleep being the best source of high-quality data, especially when wearables or ambient biosensors are used .Pathophysiological processes of particular interest, due to their generic nature in multiple clinical syndromes, are acute and chronic inflammation , sepsis, and hypoxia/ischemia. Due to the HRV’s potential to describe systems’ behavior at an integrative level, special attention should be paid to studies investigating multiple hits and the identification of memory signatures reflecting previous exposures ,50,62,63Such studies would account for the sympathetic and parasympathetic, especially vagal modulations of HRV as well as the more general effects of modulatory influences via intrinsic HRV, ANS, hormonal, and mechanical oscillations and entrainments via interactions with other systems . Well-deIt should be noted that the various types of devices used for acquiring HRV data influence the quality and reproducibility of the HRV metrics and machine learning models developed in such studies. This constraint is discussed in part above, in As we discussed above, for organ-specific gut and brain inflammation, no HRV measure correlated to several markers of inflammation at the same time.These organ- or target-specific observations in gut and brain inflammation suggest the possibility of identifying further target-specific HRV signatures. While the attempts to identify HRV code represent an indirect attempt to hack brain–body communication, the direct data obtained from VENG studies are also mounting to suggest the existence of a vagus code ,71,72. IIf we are to postulate code properties, target specificity must be complemented by another kind of unique encoding property: specificity to complex physiological or pathophysiological behavior or a syndrome. To that claim, let us mention once more the finding of iHRV as well as the recent findings of HRV changes in toddlers exposed to Zika during gestation and eight-year-old children with autism spectrum disorder (ASD), conduct disorder, and depression. This is discussed in the following paragraphs.Sheep fetuses exposed to chronic hypoxia in vivo and their hearts mounted in Langendorff apparatus ex vivo showed changes in cardiac activity: the beat-to-beat variability of the isolated hearts from hypoxic fetuses demonstrated the existence of a signature of such exposure .Interestingly, the mathematical properties of the HRV measures comprising this signature were also found in an independently conducted prospective study of human toddlers born without overt symptoms to mothers exposed to the Zika virus during pregnancy . Zika viIn the cohort of 68 children of eight years of age, machine learning models built from features of select HRV measures identified children from healthy, ASD, conduct disorder, and depression cohorts with the area under the receiver operating curve of more than 0.82 . The HRVThe fundamental role of the vagus nerve in ASD has been the subject of ongoing research, notably in the polyvagal theory ,34,74. TIt has been proposed that ASD represents a process defined by a set of developmental immunometabolic constraints that may explain much of its features . HRV hasMore studies are needed to connect specific VENG features with multi-dimensional HRV properties, as was attempted recently ,61,84.Further studies are needed to better understand the impact of various insults on the developmental and functional properties of individual and synchronized cardiac pacemaker cells yielding heartbeat automaticity and intrinsic variability. This will help develop a stronger causal understanding of how the various environmental exposures impact the HRV properties with regard to HRV code target specificity.Future studies should systematically investigate the relationship between HRV code and immunometabolism, especially in subjects with ASD or neurodegeneration, as these neurological conditions show altered metabolic signalling.Can this information now be used to predict trajectories toward these conditions at an earlier age so as to help commence more timely interventions? If the HRV code persists and has memory properties, this should be a reasonable expectation and tested in future studies.Another anticipated aspect of an HRV code should be its universality. The patterns of communication reflected in the HRV code should carry over between species, at least to the extent that they represent some phylogenetically preserved and functionally parsimonious solutions. That is, it seems likely that complex systems would converge onto similar, if not identical, solutions to a problem such as encoding multiorgan communication, especially when relying on a similarly implemented substrate, such as the vagus nerve. We tested this in a study on newborn piglets exposed to a sublethal dose of LPS ,85,86. WAn important aspect of the study design when investigating the universality of HRV code is the known between-subject variability of HRV measures . This caBased on the suggestions for experimental design made in An important limitation currently preventing the full translation of preclinical studies into the clinical realm is the fact that most, if not all, preclinical studies use traditional high-quality ECG electrophysiological setups, while clinical studies, except some ICU datasets, are typically relying on much lower sampling rates of heart rate  . Human cIt is exciting to consider the role of HRV metrics, across species, as part of a larger deep phenotyping effort to understand the physiology across the scales of organization, from (epi)genomic and microbiomic variability all the way to the systems level physiological variability manifested in HRV, its phylogenetically preserved, and species-specific traits ,92.This focused review is meant to generate experimentally testable hypotheses. Some future areas of interest have been highlighted throughout the review.Overall, we observed that HRV exhibits a rich spatiotemporal structure if captured at adequate temporal resolution. That is, HRV properties are phase-space- and, in particular, time-resolution-dependent. These insights inform practical considerations of data acquisition, e.g., in the choice of wearables or ambient biosensors and beat-to-beat sampling rate, and the subsequent analysis, such as the choice of HRV measures and the statistical or machine learning models to predict the outcome or classify subjects based on the outcome. Some applications of machine learning were mentioned both for prediction ,19 and cThe subsets of HRV measures relate to specific physiological responses and hence are akin to code with regard to target specificity. This has implications for HRV data interpretation and biomarker discovery using HRV technology.A fascinating question needs to be answered in future studies: after more than 50 years of studying HRV behavior under various conditions, can we bring this knowledge base together with the emerging field of bioelectronic medicine and its many promising therapeutic approaches to create a closed-loop system where HRV or VENG code hacking is used to sense the behavior of the system of interest and the vagus nerve stimulation or other bioelectronic tools are used to modify its phase space dynamics?Reproducing the above observations under different physiological conditions and in different species will help address the issue of HRV code robustness. Does the HRV code benefit from stochastic resonance ? Can thiAt last, while the above considerations are driven by the pragmatic pursuit of HRV code applications for predictive purposes of time series, there remains the big question of what HRV code really represents physiologically. We can take inspiration for conceptualizing HRV code from the brain’s default-mode network concept. . This quDoes the HRV code exhibit spontaneous intrinsic dynamics that are altered by external stimuli? It is suggested that the answer to this can already be stated in the affirmative. Progress has been made in defining the cardiac origins of HRV, arising from stochastic fluctuations of cardiac pacemaker cells’ ion channel activity, their networked synchronization, and modulation of this synchronization dynamics by the milieu intérieur and external neural and humoral inputs . Future


Obstructive sleep apnea (OSA) is characterized by repeated episodes of upper airway closure during sleep, resulting in recurrent oxyhemoglobin desaturation and sleep fragmentation . By 2020Liu et al. identified HIF1A and ATM as key genes responsible for ferroptosis during CIH using bioinformatics and animal experiments. They found that HIF1A causes increased oxidative stress and general inflammation, in addition to regulating a variety of glycolysis, proliferation, invasion, and survival genes during the hypoxic response. ATM is a type of protein kinase that is essential for both cellular inflammatory toxicity and oxidative stress-induced cell death. Central genes may be used as biomarkers and treatment targets for OSA.OSA is an individually variable disease with multiple symptoms and endogenous types. More and more studies have recognized the importance of individual differentiation and genetic heterogeneity in the management of OSA and its complications. The advent of bioinformatic methods has led to great advances in the pathophysiology and mechanisms studies of OSA. Chronic intermittent hypoxia (CIH), described as repeated hypoxia and reoxygenation, is a unique pathological mechanism of OSA that aggravates body damage. CIH can cause an increase in reactive oxygen species (ROS), which may lead to cellular ferroptosis. Based on the relationship between oxidative stress and ferroptosis, Ding et al. assessed the gene-predicted associations of OSA with type 2 diabetes (T2D), non-alcoholic fatty liver disease (NAFLD), and coronary heart disease (CHD) based on the mendelian randomization method. Outcomes excluded genetically predicted linkages of OSA with T2D, NAFLD, and CHD risk, and indicated that genes associated with obesity might obfuscate prior observations. The possibility that obesity may be a critical element in linking OSA to cardiometabolic diseases should be taken into account in subsequent clinical and scientific research studies.Cardiometabolic diseases are the most complex complication of OSA. Zong et al. reviewed the typical animal models of OSA and separately analyzed their characteristics. In specific studies, existing animal models can be selected and modified depending on the study design. Evaluating the reliability of animal models of OSA includes PSG, upper airway imaging, and electronic nasopharyngoscopy of small animals.Further studies at the genetic, molecular, and cellular levels need to be validated in animal models designed to mimic the pathophysiological characteristics of OSA patients. Cao et al. assessed the value of drug-induced sleep endoscopy (DISE), a novel technology, in predicting the prognosis of surgery in patients with OSA. They found that the lateral collapse of the velopharyngeal airway, without consideration of hypopharyngeal collapse, and minor hypopharyngeal collapse in patients with anteroposterior collapse or concentric collapse of the velopharyngeal airway may be predictive of a superior operative result. Patients with lateral velopharyngeal airway collapse and grade I glossopharyngeal airway collapse degree are suitable for velopharyngeal surgery.Continuous positive airway pressure (CPAP) and surgery, primarily uvulopalatopharyngoplasty (UPPP), are the first-line therapy for OSA and its complications. The selection and efficacy of individualized treatment for patients with OSA have always been the focus. Su et al. evaluated the impact of perioperative 1-week CPAP therapy on postoperative cardiopulmonary prognosis in patients with OSA combined with valvular heart disease. In patients undergoing CVR, the use of preoperative auto-CPAP for OSA resulted in a statistically significant reduction in mechanical ventilation time and postoperative length of stay in the ICU and hospital. However, it was not related to postoperative arrhythmias, pacemaker use, reintubation, or pneumonia. In follow-up studies, more questions need to be explored, for example, what is the appropriate length of CPAP treatment for OSA patients undergoing CVR surgery? All questions deserve in-depth research and discussion in the future.OSA is related to an increased risk of all-cause and cardiovascular mortality, as well as the incidence of postoperative cardiovascular events . OSA is Multidisciplinary, precise, and individualized treatment is the trend in OSA diagnosis and treatment. At present, the research on OSA and multi-system diseases has shown a 100 flowers and a 100 schools of thought. Innovative advances have been made in related animal experiments, bioinformatics, and clinical treatment strategies. At the same time, the new advances in mechanism and clinical research are of great significance to the updating of concepts and the improvement of clinical diagnosis and treatment techniques. In clinical work, we should pay attention to the screening of OSA-related comorbidities and take measures to reduce or mitigate the risk of the disease to improve patient satisfaction and the quality of OSA diagnosis and treatment.YS and YZ prepared the original draft. XR, XT, and TX critically reviewed and edited the manuscript. All authors have reviewed and approved the final manuscript.


Cancers entitled “Updates in thyroid surgery” is a collection of nine articles that covers a wide range of topics, providing a comprehensive picture of the latest developments in thyroid surgery. Esteemed experts in this field have critically analyzed various issues to offer new perspectives, innovative methods, and updated guidelines enhancing the surgical approach and post-operative management of patients with thyroid cancer.This Special Issue of Thyroid cancer, the most common endocrine malignancy, has been exhibiting a steady increase in incidence in the last few years . ThyroidSurgery remains the primary treatment for thyroid cancers; recent years have witnessed the development of new techniques and technologies that enable safer and more effective management . MultidiThe advancements in thyroid surgery primarily focus on surgical techniques, aiming to guarantee oncological radicality while achieving excellent aesthetic results and minimizing post-operative complications . SeveralIn addition to the most suitable approach, the use of surgical devices and technology to support surgical techniques plays a crucial role in ensuring safer surgery. Among these, intraoperative neuromonitoring has been widely employed in thyroid surgery, facilitating the early identification of recurrent laryngeal nerve injuries and improving the management of this complication . It is aOver the years, the ability to diagnose thyroid tumors early has improved more and more, enabling the selection of patients worthy of further investigations and thus increasingly limiting the number of unnecessary procedures. Advanced diagnostic tools can support specialists in patient assessment, risk stratification, and the selection of appropriate therapeutic procedures. Diagnostic imaging techniques have evolved and been refined over the years, from basic ultrasound to contrast-enhanced ultrasound (CEUS), elastosonography, and the application of artificial intelligence and machine learning for thyroid nodule characterization .The advancement of surgical techniques, continuous improvement in diagnosis and alternative or adjuvant therapies must be accompanied by a deep understanding of cancer biology. In particular, the treatment of thyroid cancer is increasingly evolving towards precision and personalized medicine, allowing therapeutic strategies to be tailored to each patient’s needs and the biological and molecular characteristics of the tumor. Extensive research is ongoing to identify specific biomarkers , geneticIn conclusion, innovations in thyroid surgery have led to significant advancements in the treatment of thyroid cancer. Minimally invasive techniques, the utilization of technologies, and the introduction of biomaterials have enhanced the safety and efficacy of surgical interventions, resulting in reduced complications and improved aesthetic outcomes. Simultaneously, innovations in diagnostic imaging and advanced imaging tools and ongoing discoveries in molecular biology have made it possible to optimize treatments, with a view to personalized therapy.


The ongoing trend towards miniaturization and increased packaging density has exacerbated the reliability problem of Au-Al heterogeneous metal bonding structures in high-temperature environments, where extreme temperatures and high current pose a serious challenge. In order to address this issue, the present study aims to investigate the electromigration reliability of Au-Al bonding by comparing the conventional heterogeneous contacts with OPM structures, which are homogeneous contacts. A novel bonding layout was developed to precisely detect the resistance and obtain stage changes in electromigration. The experimental results demonstrated that the relative resistance shift of Au-Al bonding at 250 °C was 98.7%, while CrAu and NiPdAu OPM structures exhibited only 46.1% and 2.93% shifts, which suggests that the reliability of OPM structures was improved by a factor of 2.14 and 33.6, respectively. The degradation of Au-Al bonding was attributed to the large cracks observed at the bonding interface and lateral consumption of Al elements. In contrast, OPM structures only exhibited tiny voids and maintained a better bonding state overall, indicating that homogeneous metal contacts have better immunity to electromigration. Furthermore, this study also observed the polarity effect of electromigration and analyzed the impact of NiPdAu thickness on reliability. Overall, this research provides a novel approach and an insightful theoretical reference for addressing the bottleneck of high-temperature electromigration reliability in high-temperature sensor packaging. The use of high-temperature electronic sensor devices has become increasingly prevalent in various industries, including aerospace, deep space exploration, oil well drilling, nuclear power plants, and engines. Consequently, the operating temperature has emerged as a critical factor affecting electrical performance. Despite the growing demand for devices and chips capable of stable operation at extreme temperatures of approximately 250 °C, the development and manufacture of such devices has remained a challenge, limiting progress in industrial and academic spaces ,2,3,4,5.The core predicament lies in the fact that the conventional Au-Al wire bonding relies on the contact between heterogeneous metals, which leads to weakened bond strength due to the diffusion of metal atoms into one another, eventually resulting in the creation of intermetallic compounds (IMCs) and Kirkendall voids ,8. This Significant endeavors have been undertaken to address the aforementioned challenges, with wire alloying and over-pad metallization (OPM) being the most popular approaches. In the former, Gam et al. aged alloyed Au bonding wires—Au-1 wt.% Cu wire and Au-1 wt.% Pd wire—which were bonded on Al pads. It turns out that Cu and Pd additions to the Au bonding wire slowed down interfacial reactions and crack extensions due to the formation of a Cu-rich layer and a Pd-rich layer at the interface . In a coDespite significant efforts to investigate the reliability of OPM bonding at high temperatures, there remains a knowledge gap regarding the application of OPM structures in the field of electromigration. Therefore, the principal aim of this project is to conduct experiments and simulations to examine the high-temperature electromigration reliability of Au-Al bonding structures and their optimized OPM structures, with the intention of establishing a theoretical foundation for the promotion of OPM structures in high-temperature fields. Traditionally, high-temperature aging is employed in the reliability investigations of Au-Al bonding, followed by the shear stress test, tensile test, and microscopic characterization by Energy Dispersive X-ray Spectroscopy (EDX) and Scanning Electron Microscope (SEM), but these have limitations in examining the various stages of the aging process. Moreover, current aging tests employing resistance measurements with ball on ball contact may not accurately reflect the reliability of wire bonding under electromigration conditions, as reliability of this model cannot be guaranteed . To addrIn addition, the driving mechanism of electromigration can be better understood through Finite element analysis (FEA), which exists two main analysis tools: Atomic Flux Divergence (AFD) and Atomic Density Integration (ADI). The ADI approach is based on the law of vacancy conservation and can predict the location of electromigration damage in homogeneous metals by considering the effects of the electron wind force, temperature gradient, stress gradient, and vacancy concentration gradient ,19. HoweThe high-temperature electromigration test at 250 °C was executed on both Au-Al bonding and OPM structures, which revealed a dramatic escalation in the relative resistance change in the Au-Al bonding structure after 165 h. In contrast, the NiPdAu and CrAu structures exhibited relative resistance changes of only about 2.98% and 46.7% of that of the Au-Al structure demonstrate that the utilization of homogeneous systems could significantly reinforce the reliability and longevity of bonded structures at high temperatures. SEM and EDX analyses of the aged structures revealed the development of extensive voids and cracks in the Au-Al system, which were aligned with the direction of electron movement. Conversely, the OPM structures emerged only minor voids, and the contact area was nearly completely preserved, without any crack expansion or lateral consumption of Al elements. Additionally, the impacts of current direction and the thickness of NiPdAu on the reliability of electromigration were investigated in this study, which showed that the forward current as well as the addition of the pd layer can enhance the bonding reliability to a certain extent. FEA was conducted on the complete Au-Al bond structure based on the AFD principle, and the results were consistent with both the electron wind theory and the actual situation.Various techniques have been developed for the metal coating of substrates, including sputtering, vapor deposition, electroplating, and electroless plating. To achieve the OPM structures, the vacuum magnetron sputtering process was employed in this study for metal coating. The plasmas generated by an abnormal glow discharge of dilute gas under the action of the electric field bombarded the surface of the cathode target, sputtering out the molecules, atoms, ions, and electrons on the surface of the target. The sputtered particles with certain kinetic energies were shot to the surface of the substrate in a specific direction to form a coating layer on the substrate’s surface.The test samples were prepared with a VDMOS chip, as illustrated in The test samples were packaged in Dual In-line package (DIP), with an internal cavity measuring 15.24 μm × 8.99 μm, and four VDMOS chips were included, as illustrated in Electromigration is a diffusion process that occurs when conducting electrons transfer momentum to metal film atoms under high current density-induced stress, leading to the development of open or short circuits. The primary driving forces for atomic mass movement are electron-wind-force-induced migration (EWM), temperature-gradient-induced migration (TM), and stress-gradient-induced migration (SM). The combination of related driving forces eventually results in void formation at various locations ,24,25,26Based on the COMSOL Multiphysics simulation platform, the geometric model and mesh partition of the bonded structure are illustrated in In view of the fact that temperature has a significant impact on material resistance, it is necessary to evaluate the characteristics of material resistance with respect to its linear rate of change with temperature. Additionally, in order to consider the effect of temperature on the dimensions and size of the material, it can be quantified by the coefficient of thermal expansion and elastic modulus. Accordingly, to enhance the precision of finite element simulations, it is crucial to adjust the physical parameters of materials, as presented in Electromigration, a prominent failure mechanism in heterogeneous systems, induces the movement of electrons under an electric field, resulting in the formation of IMCs that can have deleterious effects on device functionality. In such systems, the directionality of electromigration is a critical consideration due to the presence of diffusion caused by atomic chemical potentials. The polarity effect of electromigration is that the driving direction of electromigration coincides with atomic diffusion, thereby accelerating the diffusion of atoms and promoting the formation of IMCs, ultimately leading to degradation of the bonding lifetime ,33. ConvAs shown in In Aside from investigating electromigration, this study also delves into the effects of high-temperature stress on the relative resistance change in various structures, which reveal that OPM structures remain highly reliable even under such harsh conditions, as shown in To gain a comprehensive understanding of factors influencing the electromigration resistance of NiPdAu OPM structures, high-temperature storage tests were conducted on structures with varying thicknesses of 200/100/50 nm, 200/0/50 nm, and 0/100/50 nm were selected, with results shown in To further assess the reliability of the bonding structure, SEM and EDX analyses were employed to analyze the appearance and chemical composition of the Au-Al bonding interface post testing . Prior to microscopic examination, the sample was prepared via cutting. The Focused Ion Beam (FIB) technique was selected in this investigation owing to the possibility of generating brittle compounds and cracks in the samples during a prolonged aging test, thereby mitigating harm in the sample preparation process. To guarantee the precision and comprehensiveness of the analytical samples, the analysis interface was identified at the central location of the bonding, as illustrated in The SEM and EDX results of the Au-Al bonding structure, presented in the accompanying The microscopic morphology of the CrAu structure is illustrated in Although NiPd is known to enhance bond strength, it is associated with the formation of “black pads”, which are nickel surfaces that have been passivated or corroded, leading to brittle failure at the bonding contact. To address this issue, a palladium layer is applied to the underlying nickel layer before surface gold plating for NiPdAu finishes. The palladium deposit is characterized by its smooth, amorphous, and homogeneous nature, forming a dense barrier layer that effectively impedes the diffusion of underlying nickel to the gold. Although the palladium deposit in the OPM is relatively thin, measuring approximately 0.06 μm, previous research has shown no substantial degradation of the bonded structure following surface treatment, which is consistent with test results in this study . Figure In light of the comprehensive analysis, the interface of Au-Al bonding emerges as the most vulnerable and focal point of electromigration damage, whereas the neck of wire and gold finger also demonstrate the presence of electromigration damage in line with the actual situation. Furthermore, the results reveal that the distribution of atomic flux divergence, caused by various driving forces, follows the order of This study proved that the OPM structure, the contact between homogenous metals, offers more reliable resistance to electromigration in conditions of elevated temperature. This presents a significant advantage in the field of device packaging, as the traditional wire bonding process can be employed in OPM structures, thereby extending the application of wire bonding to high-temperature scenarios within a defined process window.The results obtained from the high-temperature annealing tests indicated a two-step increase in the interfacial resistance of the samples, which was primarily attributed to the existence of two distinct failure modes. By considering the same failure criteria, the lifetimes of CrAu and NiPdAu were increased by 2.14 and 33.6 times, respectively, compared to conventional bonded structures. The SEM and EDX results revealed the existence of cracks at the Au-Al bonding interface with an extension direction that is consistent with the direction of electron motion, leading to a significant rise in the interfacial resistance at later stages. Conversely, the bonding interface of the OPM structure retained a better contact state. The movement of metal atoms in the active state was propelled by electron wind forces under high temperature and high current, resulting in the formation of significant voids and cracks, which was the fundamental failure mechanism of the bonded interface. However, the OPM structure is observed to delay this process, thus increasing the high-temperature lifetime of the bonded structures. In addition, simulation results of the complete Au-Al structure indicated that the electromigration damage mainly concentrated at the interface of bonding, the junction of the finger and wire, and the neck of the wire, which was consistent with the electron wind theory and practical situations. The findings of this research, particularly in the context of high-temperature sensors, have significant reference implications for addressing the challenges associated with Au-Al bonding to enhance the packaging reliability of these devices.


Food packaging is made of four main materials, namely plastic, cardboard, glass and metals , as well as many other materials . The purpose of these materials is to ensure the protection and preservation of the product, the storage, sale and transport of foodstuffs, and communication and marketing related to the brand and regulations concerning labelling and traceability. Alongside these beneficial functions, packaging can nevertheless present a hazard to the consumer due to the existence of content/container interactions that take place, regardless of the material used, and in particular due to the fact that chemical substances can be released from the packaging when in contact with food; this is the migration phenomenon .More than 12,000 individual substances have been identified for use in the manufacture of Food Contact Materials (FCMs) , which eHowever, during the manufacturing process of the packaging or during post-treatment , chemical reactions or degradation can occur, leading to the appearance of new substances that are not predictable, often difficult to identify and for which no toxicological data are available. These are called Non-Intentionally Added Substances (NIAS). NIAS may represent a large proportion of all substances that migrate into food ,6,7 and Although Regulation 10/2011 on plastics is the only regulation that requires assurance of the health risk of NIAS, all packaging is affected by their presence, including bio-based, reusable and recycled materials, which will be increasingly present on the market in the context of the circular economy. Thus, the increased use of recycled materials and the reuse of packaging may lead to an increase in unintentionally present contaminants, which may migrate to the food and expose the consumer to a cocktail of various substances . CirculaHowever, unlike IAS, and even though plastic Regulation (EU) No 10/2011 requires a risk assessment of NIAS in the same way as IAS, this remains difficult. There is no harmonised guideline for an appropriate risk assessment, and the classical approach based on the identification and quantification of substances present in a migrate and their toxicological assessment is not conceivable due to time and cost constraints. Furthermore, technically, the chemical analysis of an extract/migrate is rarely exhaustive ,13,14.Professional associations . They applied this approach to recycled low density polyethylene (LDPE) and identified 83 substances, most of which were additives used in various plastic applications. Based on the threshold of toxicological concern approach, the authors found that the release of the identified substances did not pose a risk. Furthermore, further studies on unidentified substances and potential mixture toxicity are needed .Plant fiber/plastic composites (PPCs) are considered as an economical and environmentally friendly alternative to traditional petrochemical-based plastics for food contact products. However, Zhang and Weng pointed out that PPCs may pose food safety risks due to the migration of hazardous substances during the production process. The authors recommended that systematic research on migration methods and safety assessments are needed to address the potential safety risks of PPCs .TM, to identify DNA-reactive genotoxic substances. They found that both formats showed high concordance for mutagenic versus non-mutagenic compound classification, but the lowest effect concentrations (LEC) of the Ames MPFTM format were lower for 17 of the 21 tested known substances, indicating that this format could be preferable for the detection of complex mixtures of substances from FCM/FCA [To evaluate the safety of FCMs, it is important to exclude mutagenicity and genotoxicity in migrates but current genotoxicity assays were not enough sensitive in terms of the biological positive threshold. Rainer et al. compared two commonly used formats of the Ames test, the standard preincubation Ames test and the liquid-based Ames MPF FCM/FCA .Debon et al. proposed the high-performance thin-layer chromatography (HPTLC) coupled with the planar SOS umu-C (p-Umu-C) bioassay as a promising rapid test to detect low levels of mutagens/genotoxins in complex mixtures. An effective bioactivation protocol was developed, and all tested known mutagens could be detected at low concentrations. The threshold of detection was very low compared to regulatory bioassays currently performed, such the Ames test. The p-Umu-C bioassay may become instrumental in the genotoxicity testing of mixture, such as food packaging migrates .Finally, Marin-Kuan et al. combined both identification and testing and present a protocol combining data from analytics and bioassays for the risk assessment of packaging materials. This protocol includes guidance on sample preparation, migrant simulation, chemical analysis using liquid chromatography (LC-MS) and validated bioassays covering endocrine activity, genotoxicity and metabolism-related targets and it was tested through an inter-laboratory study on coating metal packaging materials .To conclude, these five studies illustrate the great challenges facing FCM/FCA research currently and they can be used by regulators, industry and other stakeholders to improve the safety of FCM/FCAs.Toxics for their kind invitation, and in particular Evelyn Ning and, previously, Doris Sun of the Toxics Editorial Office for their valuable and tireless support.I would like to express my gratitude to all authors for submitting their original contributions to this Special Issue and to the reviewers for their essential role in assessing the suitability of the manuscripts and improving their quality. I would like also to thank the editors of


Cell transplantation therapy using human induced pluripotent stem cell-derived neural stem/progenitor cells (hiPSC-NS/PCs) has attracted attention as a regenerative therapy for spinal cord injury (SCI), and its efficacy in treating the subacute phase of SCI has been reported in numerous studies. However, few studies have focused on treatment in the chronic phase, which accounts for many patients, suggesting that there are factors that are difficult to overcome in the treatment of chronic SCI. The search for therapeutic strategies that focus on chronic SCI is fraught with challenges, and the combination of different therapies is thought to be the key to a solution. In addition, many issues remain to be addressed, including the investigation of therapeutic approaches for more severe injury models of chronic SCI and the acquisition of practical motor function. This review summarizes the current progress in regenerative therapy for SCI and discusses the prospects for regenerative medicine, particularly in animal models of chronic SCI. Spinal cord injury (SCI) is a traumatic injury to the parenchyma of the spinal cord that results in severe physical disabilities, including permanent paralysis below the level of injury, sensory loss, and bladder dysfunction. Worldwide, the incidence of SCI is estimated to be 180,000 per year, with an estimated 3 million people suffering from the consequences of SCI. In recent years, remarkable progress in basic research has demonstrated the efficacy of regenerative medicine, such as transplantation of human induced pluripotent stem cell-derived neural stem/progenitor cells (hiPSC-NS/PCs), in many cases for the treatment of subacute SCI . Human iMost patients with SCI are already in the chronic phase. However, basic research to date has reported the efficacy of cell transplantation therapy mainly in the subacute phase, whereas cell transplantation therapy alone has not been sufficiently effective in the chronic phase ,7,9,10. The pathophysiology of the injured spinal cord changes over time after injury. First, there is mechanical injury (primary injury) due to direct external forces, such as traffic accidents and sports injuries, followed by secondary injury that extends the damage to the injured spinal cord. In this process, the blood–spinal cord barrier is disrupted, causing neuronal cell death due to oxidase induction, increased production of inflammatory cytokines due to immune cell infiltration, and local ischemia and edema due to disruption of the vascular structure. This period of intense inflammation is called the acute phase, which lasts for approximately one week after injury in the rodent model. Subsequently, during the subacute phase (1–2 weeks after injury), reactive astrocytes migrate around the injured area to surround the inflammatory cells infiltrating the injured area and prevent the damage from spreading. Eventually, glial scars and cavities are formed in the injured area, and the patient progresses to the chronic phase (6 weeks after injury), in which spinal cord function is permanently impaired, including increased axonal growth inhibitors . The envThe optimal engraftment timing of transplanted cells is an important parameter in determining treatment efficacy. It has been shown that the acute phase is not conducive to the successful engraftment of transplanted cells ,12 becauCell transplantation therapy using NS/PCs is attracting attention as a regenerative therapy for SCI . The proAs mentioned above, the microenvironment of the chronically injured spinal cord is very different from that in the subacute phase, and the spinal cord is extremely difficult to regenerate owing to various factors that inhibit axon extension and cavity formation. In particular, scarring is a major problem in cell transplantation therapy for chronic SCI because it prevents the engraftment of transplanted cells. It has been reported that the efficacy of NS/PC transplantation alone for chronic SCI is poor, and reports of cell transplantation therapy for chronic SCI have been limited to the efficacy of transplantation of NS/PCs overexpressing neurotrophin-3 (NT-3) .Recently, the efficacy of hiPSC-NS/PCs pretreated with a gamma-secretase inhibitor (GSI), which activates p38 MAPK to promote axonal regrowth, was investigated in an animal model of chronic SCI . The resRehabilitation for SCI is essential to promote the recovery of motor function, prevent joint and muscle contractures and disuse, regain activities of daily living, and restore social participation. There are numerous reports that rehabilitation improves motor function in animal models of acute and subacute SCI ,28,29,30Moreover, particularly in recent years, the concept of neurorehabilitation based on neuroscience has gained popularity, not only for the prevention of muscle strength loss but also for the promotion of plasticity of neurological function after injury, and both basic and clinical research are underway ,40. StudHowever, there are few reports on animal models of chronic SCI. Shibata et al. established a protocol for treadmill training with progressive intensity based on the overload principle . This reThe presence of glial and fibrous scars, which are unique to the injured spinal cord in the chronic phase, greatly inhibits the effectiveness of treatment. In addition, several molecules expressed in these scars have been identified as inhibitors of axonal regeneration, including chondroitin sulfate proteoglycan (CSPG)  and semaThere are many studies on ChABC, an enzyme that degrades CSPG ,47,48,49Drugs that inhibit the action of axon regeneration inhibitors alone can be effective, but their use in combination with cell transplantation and rehabilitation has been studied and will be discussed below.Rehabilitation is a widely feasible treatment in clinical practice because it is versatile and rarely ethically problematic. This concept has been termed regenerative rehabilitation and has been shown to focus on the effects of neuroplasticity from functional training through rehabilitation, increased neurotrophic factor expression from exercise therapy, and conditioning against disuse, all of which can boost the functional recovery effects of cell therapy . HoweverSome preclinical studies of combined therapy with cell transplantation and rehabilitation have focused on the subacute to late subacute phase (7 days post injury to 41 days post injury) . Keyvan-To our knowledge, there are only a few studies on the combination of NS/PC transplantation and rehabilitation in SCI, but all of them involved treating the acute to subacute phase, which corresponds to within six weeks of injury . Hwang eAlthough none had previously been validated in a chronic animal model, Tashiro et al. investigated the efficacy of rehabilitation using NS/PC transplantation and treadmill training in a mouse model of chronic SCI . The resConsidering the conversion of NS/PCs used in preclinical studies into practical cells for clinical applications, it would be useful to use hiPSC-NS/PCs for transplantation. This has great potential for the future development of regenerative medicine, not only because of fewer ethical concerns but also because it preserves the therapeutic properties of plu-ripotent stem cells . This coShibata et al. used immunodeficient NOD-SCID mice with a 70-kilodyne moderate contusion injury to the 10th thoracic spinal cord. Two groups were studied: the combination of hiPSC-NS/PC transplantation and rehabilitation group and hiPSC-NS/PC transplantation monotherapy group. The hiPSC-NS/PCs were transplanted rostrally and caudally to the lesion seven weeks after injury, the chronic phase in rodents. After eight weeks, the efficacy of the combined rehabilitation treatment, applied as quadrupedal treadmill training, was examined by comparing effects on training and histology. A standardized and qualified quadrupedal training protocol was applied . The comMany reports on combination therapy with pharmacotherapy have shown significant improvements in motor function. Glial and fibrous scars, together with the axonal growth inhibitors expressed therein, are notable inhibitory factors in the chronically injured spinal cord; therefore, they need to be addressed to improve therapeutic efficacy. As mentioned above, there have been numerous reports on combination therapy with ChABC, an enzyme that degrades CSPG—a major component of glial scars that physically inhibits axonal regeneration. It has been reported that the combined administration of ChABC and treadmill training in chronic cervical and thoracic SCI models results in axonal regeneration and recovery of motor function ,49. The On the other hand, an axonal growth inhibitor, semaphorin3A, is also attracting attention. In addition to the effect of the drug on promoting axonal growth, the semaphorin3A inhibitor, applied via a sheet-type sustained-release system, induces spinal cord plasticity and motor function recovery in combination with treadmill training in the subacute phase . It is bRecently, a combination of regenerative medicine and biomaterials has been investigated. It has been reported that combined treatment with a drug sustained-releasing collagen scaffold containing hepatocyte growth factor (HGF) and hiPSC-NS/PCs resulted in functional improvement even in chronic complete SCI . In thisThis paper reviewed the progress of basic SCI research targeting the chronic phase. While there are a variety of treatment options, the appropriate methods are highly dependent on the time since injury and the level and severity of the injury. Considering the reports to date, the combination of cell transplantation, drug therapy including biomaterials, and rehabilitation will have a remarkable therapeutic potential by acting on multiple points, such as the lesion tissue and lumbar enlargement, and could be applied to all cases of chronic SCI.Thus, there is still a long way to go to overcome chronic SCI, but steady progress is still being made. However, further progress is required.


Percutaneous thermal ablation techniques (TATs) have contributed to improving thyroid tumor management for almost twenty years. They give the opportunity to treat the thyroid nodule “in situ” while preserving the surrounding healthy thyroid tissue and the surrounding vital structures of the patient’s neck. They were initially dedicated to ablating benign thyroid tumors; yet, it has to be said that they also present a simple, safe and reliable alternative to the management of some selected differentiated thyroid cancers. They contribute to the current therapeutic de-escalation trend and can reasonably be proposed to the thyroid nodule patient, who is nowadays clearly an integral part of the therapeutic decision-making process.Participating in the evolution of medical practices is undoubtedly one of the most exciting aspects of our medical art. As a matter of fact, looking back over the past fifty years, the thyroid nodule management equation was relatively simple. The presence of a palpable neck lump invariably led to a serum TSH assessment and thyroid scintigraphy, with a non-avid thyroid nodule leading to surgery, usually a total thyroidectomy.In the case of malignant histology, surgical re-intervention and lymph node dissection 100 mCi radio-metabolic treatment with T4 withdrawal were performed.The consequence was a high curative rate and a lifelong suppressive therapy.(a)In biology, the development of US hormone assays, postoperative cancer follow-up using serum thyroglobulin level, serum calcitonin level in the detection and monitoring of medullary thyroid cancer.(b)The extraordinary advancement of multiparametric high-frequency ultrasound and the emergence of the TIRADS scoring system (Thyroid Imaging Reporting and Data System).(c)The high accuracy of fine needle aspiration cytology (FNAC) and the Bethesda System.Then, we witnessed the advent of the following events:The mutual reinforcing effect of these techniques has revolutionized our understanding of thyroid nodules. The standardization of the different TIRADS scores is currently underway, and the third edition of the Bethesda System is now available.(d)Molecular biology, including the analysis of cytological samples, has taught us about tumor-generating mechanisms and paved the way for targeted therapies. (e)Thyroid scintigraphy has become quantified, and the use of the Recombinant Human Thyrotropin (rh-TSH) has ruled out the need for withdrawal of levothyroxine, which was often poorly tolerated by the surgical patient.(f)Tyrosine kinase inhibitors (TKIs) have proven their efficacy in case of resistance to conventional treatments, and immunotherapy shows promising results.(g)Histopathology assessments have significantly evolved, and a recent update of the thyroid tumor atlas is now available.(h)Lastly, surgical techniques have become less extensive thanks to ultrasound accuracy, and alternative scar-minimizing approaches including the Robotic or Transoral Endoscopic Thyroidectomy Vestibular Approach (TOETVA).Simultaneously, prospective cohort studies have shown that treatments have been overly aggressive, and there is no benefit to survival or complications by treating all tumors with a heavy protocol .Finally, we have come to understand that the patient indeed is at the center of the debate. The patient desires to voice their own opinions, make informed choices, and retain the option to decline a lifelong medication, especially if changes in its formulation may have adverse effects on their health. The patient seeks to be recognized as an active participant in their medical journey. Therefore, a thyroid cancer patient may choose to keep the thyroid gland in place in the absence of evidence of a severe form of cancer. The patient’s satisfaction scale assessment has also become mandatory.All these elements have contributed to the current trend of therapeutic de-escalation of thyroid cancer. The sacrosanct total thyroidectomy has given way to a more limited surgical lobectomy procedure, and adjuvant radio-iodine therapy is no longer mandatory. Thus, patients are having less operations and irradiation in all cases. The scientific breakthrough of Non-Invasive Follicular Thyroid Neoplasm with Papillary like Nuclear Features (NIFT-P tumors) has reinforced this approach. Also, the experience of the thyroid carcinoma epidemic in Korea has shown the harm of overdiagnosis. Regarding the most common type of thyroid cancers, the Papillary Thyroid Micro Carcinoma (PTMC), two alternatives have thus emerged as a result: Active Surveillance (AS) and Thyroid Thermal Ablation Techniques (TATs).AS is definitely a reliable solution to be considered in patients with low-risk thyroid carcinoma. The physician should be aware of assessing a work-up of the patient’s condition  and provide biennial tumor monitoring .However, some patients struggle with the idea of being diagnosed with thyroid cancer and not receiving treatment.Thyroid Thermal Ablation TechniquesThe principle of thermal-ablation is the heating of a tissue with the aim of destroying it or limiting its growth or functional characteristics. Above 60 °C, instant cell death can be observed, followed by the creation of a vapor bubble . Currently, four techniques areavailable as follows: Laser Ablation (LA), Radiofrequency Ablation (RFA), MicroWave Ablation (MWA), and High Intensity Focused Ultrasound (HIFU). The first three techniques use a specific energy generator, a transmission cable, and an ancillary device introduced into the thyroid tissue. Regarding LA, a fiber delivering light energy is inserted into the thyroid through a Chiba needle. Considering RFA, the electrode (which can be either unipolar or bipolar) generates ionic agitation with frictional heat. MWA delivers energy, which is transmitted by an antenna, leading to an extremely rapid friction of water molecules, with a subsequent thermal heating effect and no necessity of pads. High-Intensity Focused Ultrasound (HIFU) is the only technique that does not use an emissary. Ultrasound beams are focused to heat the tissue in a target area, leading to the removal of small volume zones to be treated. Currently, it is not recommended by the medical societies as this is less effective than the other three techniques and much more expensive . In mostThis almost always regresses with medical treatment . The effThe Role of Expert Ultrasound and TAT OperatorThis is evidence that a multiparametric ultrasound is one of the foundations of this minimally invasive approach for a thyroid nodule. It serves the following purposes: the detection of non-palpable tumors, thyroid nodule characterization on B-mode, US Doppler and shear wave elastography , accurate guidance for fine-needle aspiration cytology (FNAC) and core needle biopsy of a suspicious thyroid nodule, in situ thyroglobulin/calcitonin measurement of a nodule or suspicious neck lymph node (follicular/medullary carcinomas), depiction of lymph nodes at initial work up and preoperative staging, and follow-up of treated thyroid cancers.The operator should assess the technical feasibility for thyroid thermal ablation; ideally, this should be done by the operator involved in the percutaneous procedure.Considering the oncology point of view, achieving a local curative treatment necessitates a skilled operator who will take into account not only the presence of healthy peripheral rim thyroid tissue but also apply safety margins for malignant nodule TAT. This can be done by using multiparametric ultrasound and contrast enhanced ultrasound monitoring .Obviously, the operator has to analyze the proximity of fragile structures in contact with the thyroid tumor, mainly the nerves , as well as the vascular or visceral structures (trachea and esophagus).During the Thyroid Thermal Ablation procedure (TAT), monitoring the local anesthesia needle, the hydro dissection needle, the heat device , the real-time monitoring of the ablation progress, and heat delivery quantification are of the utmost importance. Evaluating the need for hydro dissection is now of paramount importance . This prPost procedure surveillance will assess tumor evolution  and will look for lymph node involvement.As percutaneous TAT has shown high reliability and effectiveness in benign thyroid lesions, its potential was logically extended to the oncology field. It is in this way that large retrospective studies, meta-analyses, and two consensus conferences definitively provided its accurate indications and proper limitations . TherefoHowever, opinion is critical of the following cases: pT2, pT3, pT4, and N+ carcinomas, aggressive histological types such as the tall-cell variant or hobnail tumors, papillary cancers with BRAF or TERT mutations, and medullary cancers. The European Thyroid Association and Cardiovascular and Interventional Radiological Society of Europe 2021 Clinical Practice Guideline for the Use of Minimally Invasive Treatments in Malignant Thyroid Lesions have addressed the subject .Concerning the three major techniques , the results in terms of volume reduction, decrease in serum thyroglobulin level, percentage of regrowth, and occurrence of complications are very promising . The comThe patient should revisit his referring thyroidologist to be informed of the MDC conclusions, the constraints, adverse effects, and benefits of each therapeutic option, as well as the follow-up requirements for each option. Depending on the scenario, (a) in the case of active surveillance, the patient has to sign a commitment for regular US neck monitoring; (b) in the case of thermal ablation, the physician will explain the complete process to the patient, and as TAT is a relatively novel technique, the patient should not rely on social media to understand its intricacies; and (c) in the case of surgery, they should discuss the postoperative phase extensively, including the review of the case by the MDC and the potential need for a second surgery and radioiodine treatment.A summary should be provided to the patient and a duplicate sent to the primary care physician.Times have changed and responses need to be innovative. Policy choices with respect to organ function preservation and lesser complications do exist. Empowering the patient is crucial in our actual approach to care .In conclusion, in case of papillary microcarcinoma, the following reasons for considering TAT novelty include (a) satisfactory results in terms of reducing tumor volume and addressing patient concerns; (b) the lack of a scar in the neck, namely for female patients concerned about their appearance after treatment; (c) a low complication rate ; (d) a short out-patient hospital stay, thus minimizing disruption to the daily professional life; (e) a possible repeat of the procedure if needed, allowing for additional treatments or adjustments if the initial outcome is not optimal; (f) the reduced painkiller usage, indicating a relatively comfortable recovery; and (g) a better cost-effectiveness than surgical alternatives, even in an outpatient setting. In some countries, social insurance may cover the procedure’s cost, making it accessible to a broader patient population .These advantages taken together definitely make thermal ablation an attractive option for both patients and practitioners. This fits perfectly well with the current trend of patient-centered care .


The complex backgrounds of satellite videos and serious interference from noise and pseudo-motion targets make it difficult to detect and track moving vehicles. Recently, researchers have proposed road-based constraints to remove background interference and achieve highly accurate detection and tracking. However, existing methods for constructing road constraints suffer from poor stability, low arithmetic performance, leakage, and error detection. In response, this study proposes a method for detecting and tracking moving vehicles in satellite videos based on the constraints from spatiotemporal characteristics (DTSTC), fusing road masks from the spatial domain with motion heat maps from the temporal domain. The detection precision is enhanced by increasing the contrast in the constrained area to accurately detect moving vehicles. Vehicle tracking is achieved by completing an inter-frame vehicle association using position and historical movement information. The method was tested at various stages, and the results show that the proposed method outperformed the traditional method in constructing constraints, correct detection rate, false detection rate, and missed detection rate. The tracking phase performed well in identity retention capability and tracking accuracy. Therefore, DTSTC is robust for detecting moving vehicles in satellite videos. In recent years, low-orbiting video satellites have gradually become a frontier technology in the development of remote sensing because of their ability to quickly acquire high-resolution video data over large areas . CompareCompared with normal ground-based videos, satellite videos must consider their unique characteristics when detecting and tracking moving vehicles. The problems of scale variation and inter-target occlusion faced by ground-based videos have been addressed less by satellite videos . HoweverFor this reason, many scholars have proposed the use of prior road knowledge to optimize target detection algorithms ,7,8,9. DDuring the tracking phase, the focus is on correlating the detected targets between frames. Previously, data association was performed by constructing motion features ,11,12. WPrevious research has clearly shown that most algorithms suffer from three problems: ① Most algorithms construct a priori constraints considering only time domain or spatial domain information and do not fully combine the two, resulting in poor algorithm stability. ② Most algorithms are less effective in dealing with faint and small moving targets. ③ During the tracking phase, most algorithms rely excessively on deep features. Therefore, this study proposed a satellite video moving vehicle detection and tracking method based on spatiotemporal characteristic constraints called Detection and Tracking Based on Spatiotemporal Characteristics (DTSTC).The remainder of this paper is organized as follows: Traditional motion target detection can be divided into four categories: temporal difference, optical flow, background subtraction, and deep-learning-based methods . The temUsing prior road knowledge to optimize the target detection algorithm is the easiest and most effective way to remove background noise and pseudo-motion target interference. Kang et al. detected moving target regions using temporal differences, and after accumulating the moving regions to generate regions of interest, moving vehicles were detected . Lei et Current inter-frame target association methods often use target motion and appearance features. Bewley et al. used Kalman filtering (KF)  to calcuDTSTC, as proposed in this study, consists of four parts: video data pretreatment, construction of spatiotemporal constraints, moving vehicle detection, and inter-frame vehicle association . The oriAmong the existing constraint construction methods, the motion-based accumulation method is unstable and requires the accumulation of a large number of video frames. Single-frame object-oriented classification methods for extracting road masks are prone to breakage and missing detections. The method for loading existing road maps has a high memory footprint and requires significant manual labeling. Therefore, DTSTC incorporates road masks and motion heat maps to improve the robustness of the constructed constraints. The road mask in this method fully utilizes spatial domain information and can provide an improved initial value for the motion heat map. The motion heat map uses time domain information, which complements the broken and missed detection parts of the road mask. In addition, this method has a small memory footprint compared to loading an existing road network and does not require extensive manual marking.The D-LinkNet road extraction fully considers the spatial representation characteristics of roads in a single image frame, including the narrowness, connectivity, complexity, and long spans. The network also exponentially increases the perceptual field of the model using a jump connection and null convolution module, making it more capable of road extraction. Then, ResNet34  is used However, D-LinkNet only extracts the road mask using the spatial characteristics of a single frame of an image, does not take full advantage of the video data in the time domain, and cannot avoid the occurrence of broken and missing roads. Therefore, DTSTC complemented this by cumulatively generating a motion heat map using temporal differences. This temporal difference fully utilizes the target motion information between two successive frames and can effectively complement the road mask generated using only a single image frame. The specific integration of the two is shown in B and C both intersect the road mask and satisfy condition ①. The length growth rate and historical aspect ratio of connected domain A meet the threshold requirements and qualify for condition ②. In contrast, connected domain D does not meet either condition, and it is selected for elimination. The specific discriminant condition is described by Equation (3):d-th connected domain in the road mask, i-th connected domain in the motion heat map, i-th connected domain in the motion heat map, The preprocessed motion heat map was then graphically compared with the road mask, and the remaining connected domains in the motion heat map were conditionally discriminated. If these requirements were met, the domain was included in the road mask. Otherwise, the connected domains were discarded. The goodness of the discriminant condition directly determines the effectiveness and stability of the constraint construction. We combined the topological relationship between the two and the growth rate of the motion heat map and set the discriminant condition as follows: ① The motion heat map connectivity domain intersects the road mask. ② The historical aspect ratio and length growth rate of the motion heat map simultaneously satisfy the corresponding thresholds. One of these two conditions must be satisfied. Condition ① effectively raises the priority of motion targets around the road and retains their cumulative results, while suppressing them for motion targets separate from the road area. The length growth rate under condition ② can effectively identify the connected domain formed by noise and moving vehicles. The historical aspect ratio represents the aspect ratio of the connected domain during the motion accumulation process, which eliminates the effect of a surge in the length of the connected domain caused by large noise in one frame during the motion accumulation process. As shown in Moving vehicles in satellite videos are presented as faint and tiny targets, and direct detection using traditional background subtraction can result in serious under-detection. To compensate for vehicles being difficult to distinguish from the background owing to their low contrast, DTSTC optimized the KNN moving vehicle detection algorithm using the LAB color-space local contrast enhancement algorithm.Owing to the variety of colors in the background areas, the effect can be significantly reduced or even have side effects when contrast enhancement is applied to the image as a whole. We begin with the contrast enhancement within the constrained region constructed in the previous section. Specifically, the mean Subsequently, a Gaussian low-pass filter is applied to the image to obtain the filtered image L, a, and b channels are separated to obtain the three features, The low-pass filtered image is converted to the LAB color space, and the These features are fused to obtain a significant image value. The resulting highlighted moving vehicles can significantly improve the completeness of moving vehicle detection. Based on this, the KNN motion target detection algorithm was used to detect areas within the constraints, resulting in substantially improved detection results.The moving vehicles in the satellite video occupied only a few pixels and had similar shapes, colors, and other features. This results in many false matches when matching vehicles between frames using only features such as appearance and color. Vehicle motion in satellite videos can be approximated as a two-dimensional planar motion; therefore, the two-dimensional position information of moving vehicles in satellite videos is more useful for describing inter-frame vehicle association. Based on the detection of moving vehicles, this study proposed a vehicle association method that uses a combination of the relative vehicle position and historical motion information.The moving vehicle is first defined as a vector with position and velocity using a Kalman filter. The covariance matrix infers the next frame state, that is, the trajectory position of the moving vehicle, from the current frame state of the target. The Kalman filter prediction equation is given in Equation (7):m-th detection and n-th prediction frames. Finally, the Hungarian algorithm was used to obtain the optimal solution for the data association matrix to complete the inter-frame moving vehicle association.As the video contains multiple targets, data association is required to match the predicted results with the detection results of the next frame to enable vehicle tracking. For frame The degree of matching is a measure of the similarity of vehicles between frames; therefore, how well the degree of matching is constructed determines the success of the association of vehicles between frames. We fully considered the characteristics of the moving vehicles in the satellite video, integrated the features such as position and motion topology relationship, and proposed a matching degree construction method combining the intersection and merging ratio with the angular difference of motion direction. The IOU effectively describes the position relationship between the target detection and prediction frames, and the angular difference in direction of motion fully utilizes the historical position information of the target for its evaluation. As shown in Six datasets from VISO  were selP), recall (r), and F1 score (F), which are commonly used in the target detection field. This was calculated using Equation (11):To quantify the accuracy of the target detection algorithm and compare it with previous algorithms, the accuracy evaluation metrics used were the precision (IDTP), number of false tracking target identity detections (IDFP), number of missed tracking target detections (IDFN), multiple object tracking accuracy (MOTA), total number of object identity switches (IDS), and identity F1 score (IDF1). To obtain accurate precision results, the IDP, IDP, IDF, and IDS were obtained by manual counting. Among all the evaluation metrics, MOTA and IDF1 are the most important for evaluating multi-objective tracking algorithms, as shown in Equations (12) and (13), respectively:For the inter-frame association of moving vehicles, we used the number of correct tracking target identity detections , an improved mixture of Gaussian v2 (MOGv2), ViBE, the MOGv2 algorithm based on the constraints in this study (CMOGv2), the method presented in Literature 6 (MVDSV), and the method presented in Literature 8 (VOMVD).In contrast, DTSTC eliminates the influence of pseudo-motion targets and background noise with very few missed detections, as shown in P, r, and F1 score were calculated separately for each algorithm within each area. As shown in To quantify and analyze the detection results, Within Area 2, DTSTC had the highest recall and F1 scores. The accuracy was slightly lower than that of VOMVD; however, the recall was considerably higher than that of VOMVD. Comparison tests show that the accuracy of the method with constraints is considerably higher than that of the conventional method, which is analyzed because the background of Area 2 contains a large lake, and the diffuse reflection of the lake causes a lot of noise interference. The constraint effectively eliminates this type of background interference.The best results in terms of precision, recall, and F1 score were achieved in Areas 3–5. This is because there is less noise interference in these areas and a greater degree of road and vehicle disparity, providing better initial conditions for moving target detection. Spatiotemporal domain constraints build complete and contrast-enhanced assisted detection, greatly enhancing detection capabilities and enabling the robust detection of vehicles in motion satellite videos.Within Area 6, both DTSTC and CMOGv2 performed well. DTSTC was slightly less accurate than CMOGv2 in terms of detection precision. The reasons for this are as follows: On the one hand, it may be that the MOGv2 misdetection phenomenon causes it to have no misdetection noise; therefore, the phenomenon of low recall and high precision occurs. On the other hand, it may be that the contrast enhancement algorithm in DTSTC increased the influence of noise within the road, resulting in more mis-detected targets.To further validate the stability of the algorithm, By combining the results of each area detection for the satellite video data, we find that the temporal difference and MOGv2, despite maintaining a good recall rate, are subject to serious interference and have a low precision rate. Although ViBE performs more consistently, the overall precision is low, and there is significant “ghosting” and missed detections. CMOGv2 showed significant improvement in precision but still had a high rate of missed detections. Although MVDSV improves detection accuracy through heat map constraints, the recall performance is mediocre, which is probably due to the instability of the constraint construction when analyzed. The VOMVD performed well overall, but there is still room for improvement in the recall rate. In contrast, DTSTC achieved better results in terms of both detection precision and recall, with the highest F1 score. Therefore, the detection algorithm in DTSTC can also perform well in the face of the complex background and noise of satellite video data and has certain advantages in terms of robustness and applicability.To verify the effectiveness of DTSTC during the tracking phase, it was tested for four scenarios. The visualization results are shown in A small area within each area was intercepted for testing to further verify the effectiveness of the data association method. The experiments compared the CMOGv2 approach combined with the data association approach (CMOGv2_D), the detection approach combined with the SORT algorithm (C_SORT), and DTSTC. In In summary, DTSTC used in this study can effectively correlate inter-frame vehicles in satellite videos. However, tracking precision largely depends on the detection effect. Although the detection method in DTSTC has largely improved the detection precision and recall rate, the phenomenon of missed detection still exists, which leads to ID switching or missed targets in the tracking targets.Given the complex background of satellite videos, noise, and pseudo-motion targets that interfere with the detection and tracking of moving vehicles, this study proposed a method for detecting and tracking moving vehicles in satellite videos with spatiotemporal characteristic constraints (DTSTC). Compared with traditional methods, DTSTC is more robust in constructing constraints and removing background noise interference. The detection rate of moving target extraction was improved, and a significant advantage was achieved in detecting moving vehicles. DTSTC was also proven to be more stable during the tracking phase.Although DTSTC reduced the rate of missed detection of moving vehicles to a certain extent in this study, there were still missed detections of faint targets. To further improve detection precision, the incorporation of time-dimensional motion information can be considered in the detection process. In addition to the method proposed in this study, as with most current algorithms, the tracking performance depends on the detection algorithm. In the future, further consideration should be given to transferring features from the past moments of the target to the current frame, enhancing detection; thus, detection and tracking can reinforce each other and form a closed loop.


Flexible wearable sensors have garnered significant interest in the fields of human-computer interaction, materials science, and biomedicine. The remarkable progress achieved in combining flexible materials and sensor manufacturing processes has led to substantial growth in flexible wearable sensors, making it a highly attractive and rapidly evolving area of interdisciplinary research. This Special Issue aims to highlight the latest advancements, ongoing challenges, and emerging opportunities in flexible wearable sensors, encompassing both fundamental principles and practical applications. The objective of this Special Issue is to inspire the community by addressing key questions in this field, with the ultimate aim of maximizing the societal impact of flexible wearable sensors.In this Special Issue on Flexible and Wearable Sensors, we have included 25 papers, including 24 research papers, covering applications in human-computer interaction ,2,3, mecIn particular, Xue et al. proposed a frictional electromagnetic hybrid harvester with a low starting wind speed and an engineering-practical propeller design approach to achieve output power over a wide range of wind speeds . VanhalaFinally, the review articles in this issue highlight the latest advances in flexible wearable sensor devices for biomedical applications . As the It is our hope that this Special Issue on Flexible and Wearable Sensors provides readers with valuable insights into the current state of the art in this rapidly evolving research area, presenting some of the latest technologies developed in the field.