The non-enhancing peritumoral area (NEPA) is defined as the hyperintense region in T2-weighted and fluid-attenuated inversion recovery (FLAIR) images surrounding a brain tumor. Analyses of the NEPA provide additional information to the magnetic resonance imaging (MRI) evaluation of the enhancing part of brain tumors. NEPA analyses of central nervous system malignancies with conventional and advanced MRI techniques give interesting highlights in the differential diagnosis of solid contrast-enhanced brain tumors regarding the prognostic stratification and treatment response. Considering the rapid technological changes in advanced MRI imaging, we assume that an update on this topic might be of interest. The non-enhancing peritumoral area (NEPA) is defined as the hyperintense region in T2-weighted and fluid-attenuated inversion recovery (FLAIR) images surrounding a brain tumor. The NEPA corresponds to different pathological processes, including vasogenic edema and infiltrative edema. The analysis of the NEPA with conventional and advanced magnetic resonance imaging (MRI) was proposed in the differential diagnosis of solid brain tumors, showing higher accuracy than MRI evaluation of the enhancing part of the tumor. In particular, MRI assessment of the NEPA was demonstrated to be a promising tool for distinguishing high-grade gliomas from primary lymphoma and brain metastases. Additionally, the MRI characteristics of the NEPA were found to correlate with prognosis and treatment response. The purpose of this narrative review was to describe MRI features of the NEPA obtained with conventional and advanced MRI techniques to better understand their potential in identifying the different characteristics of high-grade gliomas, primary lymphoma and brain metastases and in predicting clinical outcome and response to surgery and chemo-irradiation. Diffusion and perfusion techniques, such as diffusion tensor imaging (DTI), diffusional kurtosis imaging (DKI), dynamic susceptibility contrast-enhanced (DSC) perfusion imaging, dynamic contrast-enhanced (DCE) perfusion imaging, arterial spin labeling (ASL), spectroscopy and amide proton transfer (APT), were the advanced MRI procedures we reviewed. Conventional and advanced MRI techniques have added valuable information in the diagnosis, characterization and prognosis of brain tumors . NeverthIn this narrative review, the MRI features of NEPAs for differential diagnosis of contrast-enhanced brain lesions, prognostic evaluation and follow up of treated brain tumors are illustrated. The MRI characteristics of NEPAs are listed for both conventional MRI studies and advanced MRI techniques, including diffusion techniques, such as diffusion tensor imaging (DTI) and diffusional kurtosis imaging (DKI); perfusion-weighted imaging (PWI) techniques, such as dynamic susceptibility contrast-enhanced (DSC) perfusion imaging, dynamic contrast-enhanced (DCE) perfusion imaging and arterial spin labeling (ASL); spectroscopy; and amide proton transfer (APT).A NEPA is defined as an area with high signal intensity in MRI sequences sensitive to elevated concentrations of fluids (T2-weighted and FLAIR sequences). Two kinds of NEPA can be identified: a non-infiltrative NEPA consisting of vasogenic edema (pure edema) and an infiltrative NEPA, also characterized by the presence of infiltrative neoplastic cells; for example, in HGGs. The NEPA observed in BMs parallels the increase in extracellular fluid, leading to severe vasogenic edema. In contrast, the infiltrative edema is one of the factors responsible for HGG recurrence and tumoral spreading after apparently complete surgical resection . EngelhoThe mass-edema index has been reported to be lower in HGGs than in BMs ,13. ElseDiffusion-weighted imaging (DWI) depicts the freedom movement of water molecules in tissues. A DWI sequence is based on the incomplete rephasing of water molecules that move in the interval between the initial dephasing (the 90° radiofrequency (RF)) gradient pulse and the second rephasing (the 180° RF) gradient pulse, resulting in a loss of signal . The appSeveral studies have found significant differences in ADC values in the enhanced tumor area and in the NEPA for HGGs, BMs and PCNSL ,19,20,21−3 mm2/s at a b-value of 3000 s/mm2 [The presence of various degrees of necrosis, hemorrhages and susceptibility artifacts in both HGGs and BMs is probably responsible for the lack of differences in the intra-tumoral ADC values between the two groups of enhancing lesions . On the 00 s/mm2 .The appearance of infiltrative and vasogenic patterns for the NEPA in a patient with an HGG and BM is shown in The strength of DWI in distinguishing between enhancing CNS lesions is its availability in MRI centers: DWI is a straightforward imaging technique, it is not time-consuming, the postprocessing of data is very simple and it is routinely used even in centers that do not perform advanced imaging.Diffusion tensor imaging (DTI) can be used to measure the complex anatomical structure of white matter. DTI consists of successive DWI acquisitions with encoding in various directions in order to depict the direction and the degree of anisotropic diffusion (diffusion in which one direction is preferred) and to enable the computation of the diffusion tensor. At least six directions of diffusion encoding are needed to calculate the diffusion tensor, which is usually described in terms of three coordinate axes in which the principal axis is the direction of preferred diffusion . The maiDTI has been applied in the study of NEPAs with some contradictory findings. MD was reported to be higher and FA lower within the NEPAs of BMs when compared with NEPAs of HGGs. This can be explained by the more extensive and severe vasogenic edema surrounding cerebral metastases: the increase in extracellular fluid leads to the increase in the diffusion of water molecules in every direction (MD) and, at the same time, the decrease in the directionality (anisotropy) of water diffusion, resulting in a reduction in FA values . Neverth−6 mm2 s−1 could differentiate HGGs from BMs with sensitivity and specificity of 90 and 100% if associated with a relative cerebral blood volume (rCBV) cutoff value > 3.14. In contrast, the same DTI parameter in the tumoral-enhancing area did not show significant differences between GBM and BMs [The combination of FA and MD measurements for NEPAs using cutoff values for FA > 0.22 and MD < 143 × 10 and BMs .Diffusion kurtosis imaging (DKI) is an advanced MRI method for the analysis of diffusion attempting to account for the non-Gaussian behavior of diffusion that can better characterize the in vivo effect of the complex cytoarchitecture of organic tissue formed by various compartments, cell types and intracellular constituents ,29. DWI Both HGGs and PCNSLs are characterized by densely packed tumor cells and a small extracellular space . KurtosiDKI parameters for the tumoral solid part do not show significant differences between HGGs and solitary brain BMs; otherwise, DKI values for the NEPA are higher in HGGs than in solitary brain BMs . Tan et PWI is an advanced MRI technique that allows the assessment of neoangiogenesis in tumors. The DSC and DCE perfusion imaging techniques require the use of a contrast agent, while ASL is a non-invasive tool that can be performed without a gadolinium injection.DSC perfusion imaging is the most commonly used technique, and it relies on the measurements of the T2 MR signal during the first pass of a bolus of a paramagnetic contrast medium to provide maps of rCBV and relative cerebral blood flow (rCBF) ,36. The PWI techniques have been applied in the differential diagnosis of solitary enhancing lesions: HGGs, BMs and PCNSLs. Results from previous studies on PWI analyses in solid enhancing tumor areas of HGGs and BMs were not concordant: some studies found no significant differences in PWI values between the two ,47,48,49Analyses of MR perfusion patterns in the NEPA have shown more coherent results than those of the perfusion patterns for the enhancing tumors in the differential diagnosis of HGGs and BMs. DSC perfusion studies demonstrated that rCBV in the NEPA is higher for glioblastomas than for BMs ,49,51,52To evaluate the hypothesis of tumor infiltration beyond the NEPA, the CBV values outside—but within the region adjacent to—the peritumoral T2 hyperintensity area were assessed but did not show differences in HGGs compared to BMs ,59.In the differential diagnosis of PCNSL and other enhancing tumors, such as HGGs and BMs, a major role for the tumor core compared to the peritumoral area has been demonstrated. Neska-Matuszewska et al. proposed a two-step approach for differentiating HHGs, BMs and PCNSLs that involved placing small ROIs over several hotspots in the enhancing core of the solid tumor and the NEPA and choosing the highest rCBV value from all ROIs as the max rCBV. They used the max rCBV (max rCBV > 2.18) assessed in the tumor core to differentiate PCNSLs, which are hypoperfused, from HGGs and BMs, both hyperperfused, with an accuracy of 0.98 and the max rCBV (max rCBV above 0.98) measured in the NEPA to identify the tumor infiltration, present in HGGs but not in BMs, with an accuracy of 0.94 . HypoperDCE imaging provides a measure of vascular permeability, K-trans and Vp being the commonest parameters assessed. Very few studies have explored the NEPA with DCE imaging. K-trans measured with a 3-tesla scanner in the peritumoral area did not differ in HGGs and in BMs , probablPrevious studies have indicated that the CBF derived from ASL shows a good correlation with the CBV, the CBF derived from DSC MRI and histopathological vascular density. Additionally, ALS is less affected by a disrupted blood-brain barrier and by the underestimation of CBV values due to the leakage of gadolinium ,63. ArteIn contrast, Lin et al. found no significant differences between tumoral CBFs in HGGs and BMs, while the peritumoral CBF was higher in glioblastomas. Interestingly, they explored the gradient of CBF values within the peritumoral T2 hyperintense area from the region close to the tumor to the region distant from the tumor border, showing that the CBF gradient was able to discriminate HGGs and BMs well with a cutoff value of 1.92 mL/100 g, sensitivity of 92.86% and specificity of 100.00% . The steH-Magnetic resonance spectroscopy (H-MRS) is a non-invasive technique that provides information about the metabolic characteristics of tissue in the brain ,70. H-MRCholine (Cho) is an index of cellular proliferation and membrane turnover. Creatine (Cr) is present in metabolically active tissue and is used as a standard for calculating ratios because its peak is relatively constant. Increases in the Cho/Cr peak within tumors have been described in the NEPAs of HGGs, indicating tumor cells’ presence beyond the area with contrast enhancement, but not in the peritumoral edema of BMs ,72,73,74The NEPA was further characterized using high-field-strength 3-tesla MRI, which allows a better signal-to-noise ratio and disclosure of more metabolites ,80. BeyoIt has also been observed that the Cho/Cr peak in the peritumoral area may be affected by steroids: a reduction in the Cho/Cr peak was observed after the use of dexamethasone in low-grade gliomas (LGGs), but the changes were not significant .Amide proton transfer (APT) imaging is sensitive to the presence of amide protons in mobile proteins and peptides. APT is a chemical exchange saturation transfer (CEST) imaging technique that is based on the saturation transfer from mobile proteins and peptides to water by means of the transfer of saturated protons of the amide groups . Mobile An increased APT signal may derive from contributors other than the proliferative rate of the tumor. A high APT signal has been observed in tumoral cystic components  independWen et al. explored the peritumoral area and found that both the immediate edema  and the peripheral edema (outside the immediate edema regions) had lower APT signals than the tumor core and that of the peripheral edema was slightly lower than the immediate edema. The APT signal in the peritumoral area was higher than in the contralateral normal-appearing white matter, probably because intravascular proteins and peptides enter the extravascular space as a consequence of the increased pressure gradient from the intravascular to extravascular space due to proximity to the tumor .Additionally, absolute APT parameters  and APT values normalized for the values of the normal-appearing white matter were shown to be lower in the peritumoral edema of BMs than HGGs, with the minimum APT signal being the most accurate parameter in the differential diagnosis . In HGGsSeveral studies have reported that the best diagnostic performance is achieved when combining different advanced MRI techniques. Bauer et al. reported a high accuracy  for the association between rCBV, FA and MD measured in NEPAs in the differential diagnosis of HGGs and BMs . AdditioQualitative diagnostic algorithms and radiomic approaches have been proposed for the differential diagnosis of BMs and HGGs ,95,96,97Voicu et al. compared four algorithms evaluating both conventional qualitative MRI features and quantitative analyses of DWI and DSC PWI parameters in NEPAs. The study confirmed that, among the quantitative parameters, the mean-normalized relative CBV and the mean CBV percentage recovery in NEPAs were more accurate than the ADC in the discrimination of HGGs from BMs, with cutoffs of 1.46  and 87.5%  . The quaThe application of automated MRI pattern recognition techniques, such as support vector machine (SVM) algorithms, confirmed that the combination of advanced MRI techniques—in particular, those employing the decrease in NAA/Cr and the increase in rCBV in the peritumoral area—allowed the differentiation of glioblastomas versus metastases. Interestingly, the successive inclusion of the lipids and lactate (Lip + Lac)/Cr ratio for the NEPA in the algorithm as an additional feature decreased the performance of this approach, probably because of the absence of necrosis in this area, as confirmed by Chawla et al., who showed that peritumoral lipids and lactate did not help in the differential diagnosis of HGGs and BMs ,78.A radiomic approach based on multiparametric conventional MRI  allowed the classification of NEPAs into tumoral and nontumoral components. The machine learning algorithms were trained, tested and validated with data from NEPAs in patients with HGGs and BMs. The plasma volume (Vp) and tissue permeability (K-trans) derived from the DCE PWI were used for validation of the classification results based on the consistency with the literature data, with higher Vp and K-trans reported in tumoral NEPAs than in non-tumoral NEPAs. As expected, the radiomic analysis categorized the entire NEPA as non-tumoral in BM patients and as a mixed pattern of tumoral and non-tumoral components in HGG patients. Interestingly, in HGG patients, tumoral features were found within the NEPA adjacent to the enhancing lesion. The main limitation of this study was the absence of histological confirmation of the validation results .The parameters derived from advanced MRI techniques may also be assessed using segmentation of the tumor core and the edema. The manual segmentation of brain tumors in structural MRI images is time-consuming, laborious and needs the expertise of a neuroradiologist. Efforts have been made in achieving automatic and robust tumor segmentation. Additionally, the differences between the NEPA and the enhancing part of the tumor hinder the performance of the segmentation in MRI images. Several researchers have been tempted to employ approaches that segment the boundary of the tumor core and the NEPA, the deep learning methods being the most effective ,100. AddThe association between prognosis and the extension of NEPAs in HGG patients has been reported in some studies ,103,104,Schoenegger et al. found that extensive NEPAs in preoperative MRI correlated with poor prognosis independently of the postoperative Karnofsky performance score (KPS), age and type of tumor resection . These fIn addition, the role of NEPAs in predicting early HGG recurrence and prognosis was confirmed not only in preoperative but also in postoperative MR scans. An MRS study demonstrated that a higher Cho-NAA radio (Cho/NAA ≥ 1.31) measured in NEPAs in postoperative MRI was an independent risk factor for early recurrence. A prognostic scoring scale for GBM recurrence, including MGMT promoter methylation status, the radiation therapy and the Cho-NAA ratio in the NEPA, was proposed in order to divide patients into low-risk, moderate-risk and high-risk groups, with significant differences in the survival rates between groups . MoreoveTumor localization and tumor necrosis may influence the size of NEPAs and should be taken into account in the prognostic stratification of HGG patients: lobar superficial tumors and tumors with extensive necrosis were reported to have larger NEPAs ,117, whiIn patients with BMs, the ratio between the peritumoral edema and the tumor volume, but not the edema volume alone, was recognized as a prognostic factor for overall survival (OS) independent of other predictive factors, such as complete resection and postoperative brain irradiation .Advanced MRI techniques and multimodal MRI may assist in the in vivo assessment of tumor infiltration and the prediction of future early recurrence and survival. Multiparametric pattern analysis from clinical MRI sequences using radiomic signatures determined via machine learning methods has allowed the estimation of tumoral infiltration in NEPAs and the prediction of the rate and locations of tumor recurrence in HGG patients. The recurrent tumor region showed higher vascularity and cellularity as a radiomic signature ,123,124.Multiparametric MRI, including conventional, diffusion and perfusion imaging methods, has been applied to provide a more accurate analysis of NEPAs in terms of therapy response to bevacizumab treatment for recurrence in HGG patients . The infThe prognostic role of NEPAs in treatment response was also explored in patients with BMs. MRI features of the peritumoral areas of BMs were proposed as a new biomarker for assessing T790M mutation, a secondary mutation in the EGFR gene responsible for the resistance to therapy with tyrosine kinase inhibitors (TKIs) of the EGF receptor (EGFR) in NSCLS patients. The radiomic signatures of pre-treatment BM NEPAs, together with radiomic signatures in the tumoral area, were strongly associated with the T790M mutation status .Lastly, the extent and MRI features of NEPAs were investigated to distinguish radionecrosis from progression in BM patients. The extent of NEPAs was proposed as a potential marker of radionecrosis in patients with BMs treated with stereotactic radiosurgery: a high edema/lesion volume ratio was found to be predictive of radionecrosis as opposed to tumor recurrence . Weis etDespite the potential of conventional and advanced MRI techniques in the assessment of NEPAs in the differential diagnosis of brain tumors, some limits of the abovementioned studies should be acknowledged.These studies used different imaging acquisition parameters and forms of post-processing and analysis. Specifically, various approaches were used in the delineation of NEPAs. Some studies used manually drawn ROIs, which are poorly reproducible, while others utilized threshold-based methods. The proximity of ROIs to the tumor boundaries may also affect the results of NEPA assessment. In addition, the cutoff values previously proposed showed large overlaps between the histological subgroups and were not validated by independent external assessments or histological data. Additionally, the studies were mainly retrospective and monocentric and included small patient cohorts, with a consequent bias due to different patient selection and inclusion criteria.Additionally, other MRI techniques have rarely been used in the assessment of NEPAs and may be of interest in future studies. For example, T2 mapping/relaxometry may help in distinguishing infiltrative from non-infiltrative NEPAs: T2 relaxation time is reduced in infiltrative NEPAs compared to infiltrative NEPAs due to the presence of malignant cells. Furthermore, phase difference-enhanced imaging (PADRE) selectively enhances both paramagnetic and diamagnetic substances and allows the visualization of myelin-rich structures and veins, and it may help in the assessment of the integrity of white matter structures and vascularity in NEPAs. Nevertheless, despite their potential interest in this field, comparisons of the two kinds of NEPAs with these two techniques have scarcely been explored ,134.Future large prospective studies aiming at the standardization of MRI acquisition protocols, as recommended by imaging societies ,136, areThe study of NEPAs with conventional and advanced MR imaging techniques was shown to be helpful in discriminating HGGs, BMs and PCNSLs, as well as in predicting prognosis and treatment response, overcoming the diagnostic limits shown by the analysis of the tumor contrast-enhancing area. Advanced MRI techniques, such as PWI, DWI and MRS, are useful to distinguish infiltrative and non-infiltrative NEPAs, with infiltrative edema mainly demonstrating an increase in the perfusion parameters and Cho/Cr peak and a decrease in the NAA/Cr peak and ADC values. The accuracy of analyses increases when all these techniques are used in combination. Therefore, in the future, the radiomic evaluation of NEPAs based on multiple MRI parameters could be very useful in tumor assessment, along with large multicenter prospective studies including rigorous validation between centers and confirmation with histological data.


The aims of this paper is to search and explore publications in the field of pharmacovigilance for rare diseases and to visualize general information, research hotspots, frontiers and future trends in the field using the bibliometric tool CiteSpace to provide evidence-based evidence for scholars.We searched the Web of Science Core Collection (WoSCC) for studies related to pharmacovigilance for rare diseases, spanning January 1, 1997-October 25, 2022. CiteSpace software was utilized to discuss countries/regions, institutions, authors, journals, and keywords.After screening, a total of 599 valid publications were included in this study, with a significant upward trend in the number of publications. These studies were from 68 countries/regions with the United States and the United Kingdom making the largest contributions to the field. 4,806 research scholars from 493 institutions conducted studies on pharmacovigilance for rare diseases. Harvard University and University of California were the top two productive institutions in the research field. He Dian of the Affiliated Hospital of Guizhou Medical University and Peter G.M. Mol of the University of Groningen, The Netherlands, were the two most prolific researchers. The Cochrane Database of Systematic Reviews and the New England Journal of Medicine were the journals with the highest number of articles and co-citation frequency respectively. Clinical trial, therapy and adverse event were the top three most cited keywords.Based on keywords co-occurrence analysis, four research topics were identified: orphan drug clinical trials, postmarketing ADR surveillance for orphan drugs, rare diseases and orphan drug management, and diagnosis and treatment of rare diseases. Immune-related adverse reactions and benefit-risk assessment of enzyme replacement therapy were at the forefront of research in this field. Treatment outcomes, early diagnosis and natural history studies of rare diseases may become hotspots for future research.The online version contains supplementary material available at 10.1186/s13023-023-02915-y. The Importance of Pharmacovigilance to include “the science and activities relating to the detection, assessment, understanding, and prevention of adverse reactions or any other possible drug-related problems” [In 1974, the French first created the concept of pharmacovigilance (PV) [roblems” . Althougroblems” . Rare diroblems” , drug reroblems” , radiatiroblems” , dietaryAccording to the European Medicines Agency (EMA), there are 6,000–8,000 known rare diseases worldwide, about 80% of which are hereditary . As reseIn the case of rare diseases, traditional randomized controlled trials (RCTs) are usually not feasible with control data that may be derived from historical controls . At the In 2018, Sardella et al. [In this paper, we use the strategy of constructing a search formula to obtain the original data. Access the Web of Science Core Collection SCI-Expanded database through the official website of Guangdong Pharmaceutical University Library to search for literature. To avoid the impact of database updates, all data collection was completed on October 25, 2022. The database purchased by our unit spans the period from 1997 to the present, and the database was last updated on October 25, 2022. The data search strategy is detailed in Table CiteSpace is a software developed by Professor Chaomei Chen and his team for bibliometric research, which supports knowledge mining and visualization in databases . FirstlyThis part includes a discussion in three sections: (1) Annual trend of publications, with the aim of better analyzing the research intensity and publication trends in the field; (2) The analysis of scientific collaboration by countries/regions, institutions and authors aims to identify influential countries/regions, institutions and authors through three dimensions: macro, meso and micro, respectively; (3) Analysis of journals and co-cited journals, with the aim of identifying influential academic journals in the field.From January 1997 to October 2022, 599 articles and review articles were published in the field of pharmacovigilance for rare diseases, with an average annual volume of 23 papers. Figure In the start-up period, no more than 10 articles were published annually in this field. In 1997, only 1 paper was published on pharmacovigilance for rare diseases, an exploration of the specific side effects of the antiepileptic drug gabapentin , which wWe used CiteSpace to produce a country/region co-occurrence map Fig. . The mapGermany was the first country to explore pharmacovigilance for RDs (1997), followed by the United Kingdom, France and Spain (1998), the United States (1999), Italy (2001) and Australia (2002). It is worth noting that China research in this field started late (2012), however, China ranks sixth in terms of production. Considering a combination of volume of publications and intermediary centrality, the US and UK have contributed the most to the field of pharmacovigilance for rare diseases.A total of 493 institutions participated in studies of pharmacovigilance for RDs. The University of California (31) was the institution with the highest number of articles, followed by Harvard University (19), Duke University (12), Columbia University (12), and Mayo clinic (10) , followed by Orphanet Journal of Rare Diseases (22 articles) and Haemophilia (14 articles), meaning they had an important role in the field of pharmacovigilance for rare diseases. Table CiteSpace was used to produce a network map of co-cited journals Fig.  and idenAnalysis of keywords allows the identification of popular research field, research hotspots, the evolution of hotspots, research frontiers, and future trends . The folKeywords are a high level summary of an article’s research field, and the co-occurrence analysis of high-frequency keywords makes it possible to reveal a field’s relevant research hot spots . A keywoPharmacovigilance permeates the entire life cycle of pharmaceuticals. As delineated by the World Health Organization, the realm of pharmacovigilance encompasses every facet related to the discernment, evaluation, comprehension, and prevention of drug safety information. Consequently, data pertaining to safety and efficacy harvested during the clinical trial phase of orphan drugs constitute a crucial element in the benefit-risk assessment within pharmacovigilance for rare diseases. Presently, a plethora of orphan drugs are under the clinical trial phase, while only a minority have successfully navigated to marketing approval . The proDouble-blind, randomized controlled clinical trials stand as the canonical standard for assessing the efficacy and safety of novel pharmacological agents. Nevertheless, the stringent adherence to classical design principles may preclude many orphan drugs from obtaining marketing authorization. Legislative measures across various nations, including the Orphan Drug Act, (EC) No.141/2000, and the Orphan Drug Management System, have facilitated the relaxation of clinical trial standards for orphan drugs. Such an adjustment is aptly illustrated by the constraints imposed by the limited prevalence of many rare diseases often only affecting a few thousand individuals rendering the conventional design of large-scale trials implausible. Pivotal trials for orphan drugs may range from a mere dozen to hundreds of participants, seldom employing single-blind, double-blind, or random-assignment methodologies, and regularly relying on surrogate endpoints . FurtherThe execution of clinical trials for therapeutic agents targeting rare diseases encounters multifaceted challenges, with the quintessential dilemma residing in acquiring ample evidence to substantiate the efficacy and safety of the drugs in question. Alongside the financial burden of conducting trials and the arduous task of enlisting adept investigators, the paramount challenge remains the procurement of an adequate patient pool suffering from rare diseases . On occaAssociations dedicated to the support of patients with rare diseases may serve as invaluable assets in the recruitment of participants for clinical trials. Renowned organizations such as the National Organization for Rare Disorders (NORD) within the United States and the European Organisation for Rare Diseases (EURORDIS) facilitate outreach to the afflicted patient population. Concurrently, digital platforms, such as the website hosted by the US National Institutes of Health, proffer potential trial participants access to detailed information concerning ongoing research endeavors. Furthermore, certain pharmacological agents targeting rare diseases may have achieved extensive clinical utilization over a decade or more, including but not limited to mitotane for adrenal cortical carcinoma , tamoxifConsidering that the safety profile of an orphan drug may remain relatively uncharted at the moment of regulatory approval, the acquisition of more comprehensive efficacy and safety data becomes feasible only subsequent to its wide-scale deployment in clinical practice. As a consequence, the meticulous crafting of a prospective and highly structured post-marketing surveillance program becomes indispensable in perpetuating the continuous evaluation and validation of the safety attributes of orphan drugs.Pre-market studies of orphan drug products were conducted on a very limited scale, sometimes with only a few dozen patient volunteers enrolled in clinical trials and for short study durations. Information on certain rare adverse reactions, long-term toxicity, and effects on special populations  was often difficult to obtain in pre-marketing studies . In the Representative studies that have determined the incidence of ADR include: Bürger et al.  researchThe management of rare diseases and orphan drugs was divided into two main aspects: on the one hand, the implementation of incentive policies to stimulate the development and production of orphan drugs in the research and development phase; On the other hand, in the field of rare diseases where medical conditions were unmet, to ensure that patients can receive safe and effective pharmacological treatment to the greatest extent possible. How to ensure that patients with rare diseases had access to medicines was the focus of such research. By far the most common approaches were government imposed incentives, accelerate review and approval, and other legal regulation, along with management of patients and drugs data for precision and rational drug use.To improve the accessibility of orphan drugs and encourage orphan drugs research and development, many countries have legislated special management of orphan drugs and introduced a series of incentive policies. For example, in the United States, according to the Orphan Drug Act, the U.S. Food and Drug Administration (FDA) will provide written comments for non-clinical trials and clinical trials conducted for the purpose of listing; government grants and contract funds can be used to pay for clinical trials; 50% of the clinical trial costs can be claimed as tax credits; orphan drugs will be granted a seven-year marketing exclusivity period after approval for marketing; the orphan drug approval process will be simplified and the number of clinical trial cases for new drugs will be reduced, etc. . The ActResearch on pharmaceutical treatment for rare diseases regulatory measures also continues to emerge. For example, Kesselheim et al.  comparedThe diagnosis and therapy of rare diseases has long been a challenge that has plagued the world. A survey in China in 2020 found that each rare disease patient spends an average of 4.81 years from onset to diagnosis , and mayThe time-zone map produced by CiteSpace highlights the evolutionary path of research hotspots in the field of pharmacovigilance for RDs in the temporal dimension . Based oThe first stage was 1997–2005. Figure The cluster analysis is the classification of keywords according to the degree of similarity of research topics and naming the clusters, which can reveal the research framework of a field . In the Immune checkpoint inhibitors (ICIs) have shown unprecedented efficacy in treating a wide range of rare cancers, changing the outlook for the treatment of advanced rare cancer –64. ICIsRare diseases caused by inherited metabolic disorders, such as lysosomal storage disorders, for which enzyme replacement therapy (ERT) was usually considered the standard treatment . ERT is Keyword citation burst analysis detection can identify sudden increases in keyword citation frequency within a short period of time, revealing changes in research hotspots over time, and reflecting the evolutionary trend of research hotspots . Figure The domain of pharmacovigilance in the context of rare diseases has demonstrated a marked upward trajectory in the annual volume of scholarly publications spanning the years 1997 to 2022, thereby evidencing sustained academic engagement within this specialized field. A geographical co-occurrence analysis illuminates the close collaborative ties among various nations and regions. This collaboration might be attributed to the inherently small patient population for individual rare diseases and the pronounced variability exhibited across different geographical regions . Such diAnalysis of keyword co-occurrence and clustering can elucidate current research focal points, emerging frontiers, and prevailing trends in the realm of pharmacovigilance for rare diseases. As evidenced by the recurrence of high-frequency keywords, the clinical trials of orphan drugs, post-marketing adverse drug reaction (ADR) surveillance for orphan drugs, management protocols for rare diseases and orphan drugs, as well as diagnosis and therapeutic strategies for rare diseases, constitute the principal research hotspots within this field. It is imperative to underline that this area of inquiry remains relatively uncharted and calls for more profound and dedicated exploration by scholars in the future.Through a meticulous clustering analysis of key terms, we discerned that the knowledge structure within the sphere of pharmacovigilance for rare diseases constitutes a multi-centered complex system, interconnected through various sub-domains. This intricate framework can be articulated through the following salient aspects:The pervasive issue of misdiagnosis acts as a significant barrier to timely and precise medical intervention for patients afflicted with rare diseases. Such misdiagnoses frequently culminate in erroneous medication prescriptions, consequent treatment delays, and adverse events. Minimizing the misdiagnosis rate of rare diseases and fortifying medication management practices are imperative to mitigating the incidence of adverse reactions.The purview of pharmacovigilance envelops the entire lifecycle of pharmaceuticals. During clinical trial phases, sponsors are obligated to constitute a robust pharmacovigilance system designed to assiduously amass information pertinent to drug safety and ensure the welfare of human subjects.This constitutes a vital component of pharmacovigilance and entails an exhaustive exploration of orphan drugs’ side effects and the concomitant risk factors.ERT, predicated on recombinant DNA technology, facilitates the synthesis of specific enzymes to supplement or substitute deficient enzymes in patients’ bodies for therapeutic purposes. The real-world evaluation of the benefit-risk balance of ERT pharmaceutical products has burgeoned into a cutting-edge area of focus within the pharmacovigilance domain for rare diseases.A significant portion of rare diseases manifests during childhood, with a third of afflicted children having a life expectancy not exceeding five years of age . IntensiMultiple sclerosis stands as a quintessential example of autoimmune rare diseases. The assessment of the efficacy and safety profiles of pharmaceutical interventions designed to treat multiple sclerosis continues to captivate the research interest of many scholars within this specialized field.From a temporal perspective, the evolution of research hotspots in the realm of pharmacovigilance for rare diseases can be attributed to two central phenomena: governmental facilitation through incentive structures and an intensifying focus on the safety of medical applications for rare diseases. The underpinnings of these evolving research hotspots may reside in the unique attributes of rare diseases and the concomitant reliance of pharmacovigilance endeavors on regulatory frameworks. Initially encompassing broader considerations of rare disease treatments and adverse events, research focal points have undergone a substantive refinement, focusing on specific areas such as orphan drug clinical trials, benefit-risk assessment of enzyme replacement therapy, the natural history of rare diseases, and immune-related adverse events. Of particular note, the advancement of immune checkpoint inhibitors, including PD-1/PD-L1, has indubitably propelled the field of rare diseases forward, marking immune-related adverse events as an emergent research trajectory within the pharmacovigilance sphere.Turning to the exploration of research frontiers, the real-world benefit-risk assessment of ERT has emerged as an area of concentrated academic pursuit, reflecting the consistent approval of new ERT products juxtaposed with the need for extended research into the efficacy and safety of their real-world applications. Additionally, immune-related adverse reactions stand as a burgeoning research frontier. As a revolutionary class of cancer treatment, immune checkpoint inhibitors (ICIs) have radically altered the prognosis for cancer patients. Yet, with the proliferation of ICIs in clinical contexts, the immune-related adverse events (irAEs) they engender present substantial challenges to ongoing patient care. Although irAEs are typically characterized as mild-to-moderate in severity, concurrent utilization of multiple ICIs may precipitate severe irAEs, or even fatality , 79. TheFurthermore, in terms of prevailing research trends, the compilation of clinical natural history data as historical controls within clinical trials has gained traction in the development of rare disease therapies. Despite inherent challenges in employing historical controls, the invocation of placebo treatment is regarded as ethically immoral in certain rare disease contexts lacking standard treatment modalities . ConcomiTo our knowledge, this was the first study to revealing the progress and dynamics of research in the field of pharmacovigilance for rare diseases through a bibliometric approach. This study visualizes contributors, collaborative networks, research hotspots, and future trends through CiteSpace. Scholars can quickly understand the development status of this field by reading this article, and by getting to know scholars and institutions in this field, it is expected to increase further cooperation and exchanges.There are still some limitations in this study. Literature was retrieved only from the WoS Core Collection Datebase and did not include literature from Chinese or other English databases, which may have influenced the results somewhat.This study uses CiteSpace to conduct a bibliometric analysis of the field of pharmacovigilance for rare diseases, which can help researchers identify research hotspots and frontiers. The four most compelling research hotspots are clinical trials of orphan drugs, postmarketing ADR surveillance for orphan drugs, management of rare diseases and orphan drugs, diagnosis and therapy of rare diseases. It is worth noting that the immune-related adverse events and benefit-risk assessment of enzyme replacement therapy is the frontier of research in this field. The treatment outcomes of patients with rare diseases, early diagnosis, and natural history of rare diseases are the future research trends in this field.Below is the link to the electronic supplementary material.Supplementary Material 1: S1 Appendix. A List of 599 Articles Included in this StudySupplementary Material 2: S2 Appendix. A list of abbreviations


Nanoplasmonic biosensors have a huge boost for precision medicine, which allows doctors to better understand diseases at the molecular level and to improve the earlier diagnosis and develop treatment programs. Unlike traditional biosensors, nanoplasmonic biosensors meet the global health industry’s need for low-cost, rapid and portable aspects, while offering multiplexing, high sensitivity and real-time detection. In this review, we describe the common detection schemes used based on localized plasmon resonance (LSPR) and highlight three sensing classes based on LSPR. Then, we present the recent applications of nanoplasmonic in other sensing methods such as isothermal amplification, CRISPR/Cas systems, lab on a chip and enzyme-linked immunosorbent assay. The advantages of nanoplasmonic-based integrated sensing for multiple methods are discussed. Finally, we review the current applications of nanoplasmonic biosensors in precision medicine, such as DNA mutation, vaccine evaluation and drug delivery. The obstacles faced by nanoplasmonic biosensors and the current countermeasures are discussed. Precision medicine promises to improve health by considering individual variability in genetics, environment and lifestyle . This nePrecise diagnosis is a premise for precise treatment, and to meet its requirements, detection tools need high sensitivity, specificity and rapid analysis. Most importantly, it is possible to track and quantify individual information in living cells. Nanoplasmonic sensing is a high spatial resolution optical technique based on localized surface plasmon resonance (LSPR) . Since tThe optical properties of PNPs can be modified by changing their composition, shape and size, and different PNPs can be applied to different situations. Nanoparticles of gold (Au), silver (Ag), and copper (Cu) serve as typical plasmonic materials, which have significant light absorption capabilities in the visible region . Due to In this review, we describe the principles of nanoplasmonic biosensors, discuss the use of nanoplasmonic biosensors combined other detection tools and research progress in precision medicine in recent years, and provide an outlook on the challenges and future development of nanoplasmonic biosensors .in situ detection of important substances in living organisms, which poses new requirements for biosensing. In recent years, the rapid development of nanotechnology has provided new opportunities. Nanophotonics-based LSPR sensing enables ultramicroscopic structures, and this combination of the unique optical and electronic properties of nanomaterials has led to a wide range of applications in medical diagnosis and treatment, molecular biology and cell biology  and LSPR are caused by the interaction of light with metal surfaces. When light travels through a dielectric (such as air or water) to a metal surface and interacts with certain metals (such as Au), collective oscillations of electrons in the conductive band take place at the metal-dielectric interface . If the Most of the LSPR sensing is performed on gold nanoparticles (AuNPs) or silver nanoparticles (AgNPs). AuNPs and AgNPs are widely used because of the strong fluorescence quenching, resonance and oxidation resistance. . Most imThere are various sensing detection principles based on LSPR, among which the typical types are the use of LSPR absorbance as a readout signal, resonance shifts resulting from local variations in refractive index (refractive index sensing) and field-enhanced characteristic optical radiation  .Shigella. They utilized coatings of nanomaterials and molybdenum disulfide (MoS2) to help excite localized plasma excitations.Nanoparticles utilizing LSPR absorbance as a readout signal are typically small in size, they are more stable in buffer, and shorten the time to detection. The extinction of nanoparticles is usually monitored by chromaticity change or UV-vis spectroscopy . reporteAccording to the Mie theory, the plasma resonance frequency of noble metal nanoparticles frequency is closely related to the refractive index of the surrounding medium . The scain vitro based on Raman spectroscopy. Instead of using plasma nanoparticles to enhance the intrinsically weak Raman signal as described previously, this system is quantified by the pure Raman signal intensity of the TMB. Still, it can be seen that the development of low-cost and portable systems is the direction of SERS device development. However, logical multiplex assays with more than three biomarkers remain challenging , recombinase polymerase amplification (RPA) and helicase-dependent amplification (HDA), etc . The entThe application of nanoplasmonic in isothermal amplification is extensive and effective. Because nanoplasmonic significantly increases the sensitivity to isothermal amplification. But traditional isothermal amplification requires purification of nucleic acids and gel electrophoresis, and although the amplification time is shortened, the results show that it takes a significant amount of time. Researchers expected to take advantage of the fast speed of isothermal amplification by combining it with nanoplasmonic and using fluorescence microscopy for simple measurements. However, the overflow of nucleic acids during isothermal amplification and the lack of the complex laboratory equipment remain pressing issues.Recent advances in Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and CRISPR associated (Cas) enzymes have exposed the distinctive incidental DNase activities of Cas . The widIn recent years, although different methods for detecting DNA mutations such as SPR and SERS have also been developed, these methods require expensive equipment and do not allow for point of care (POC) applications . Zhou e developeBesides that, the nanoplasmonic also plays a role in virus detection by enhancing color development , describin situ detection. With high sensitivity and accuracy, the characteristics of both are well complemented. It is exciting to note that in addition to diagnostic advances, the synergy of nanoplasmonic and Cas-led gene editing in therapeutic approaches has also yielded good results, which is driving the development of precision medicine.Nanoplasmonic is integrated with CRISPR may be the future trend of development. Firstly, compared to the traditional CRISPR strategy of signal amplification with the help of amplification, which is prone to aerosol contamination, nano-plasma combination achieves enhanced sensitivity under no amplification by a different way. Secondly, traditional nano-plasma sensing usually requires the use of precision and complex instruments, while CRISPR systems have great potential for visualization and Enzyme-linked immunosorbent assay (ELISA) is a comprehensive technique that combines the immune reaction of antigens and antibodies with the efficient catalytic reaction of enzymes. A common feature of nanomaterials is the high specific surface, which has enabled the immobilization of probes and enhanced detection performance through increased sensitivity . ExploriPlasmodium falciparum lactate dehydrogenase (PfLDH), specifically and ultrasensitively in whole blood (4 pg/mL In the early diagnosis of hepatitis C virus (HCV) infection, the detection sensitivity was much better than that of commercial ELISA kits. And the 83.3% positivity rate of the plasmonic nanoplatform was higher than the 53.3% of ELISA. Plasmonic nanostructures are candidates for extending fluorescence detection limits to femtomolar levels and beyond.le blood . The biole blood , designeNaked-eye detection, without any optical readout device, is another advantage of this sensing approach, which significantly reduces the cost of analysis and makes it feasible in resource-limited settings. Although the emerging plasmonic ELISA is a candidate diagnostic due to its unprecedented sensitivity and ease of handling, unimodal colorimetric readouts that rely primarily on the monodisperse or aggregated state of Au or Ag nanoparticles remain limited in clinical applications due to uncertain experimental and environmental factors leading to poor accuracy.The future direction of nanoplasmonic biosensors relies on fast, sensitive, and fielded strategies that are not only useful for achieving single-molecule sensitivity in vitro bioassays and revealing molecular interactions within organisms, but are also suitable for large-scale applications. This requires the cross-application of multiple technologies and continuous improvement of detection devices to complement the obvious shortcomings of biosensors, thus showing greater potential for integration, portability, and standardization in nanoplasmonic biosensors. Surprisingly, with the advancement of biocompatible and long-term stable nanomaterials, tracking single target molecules will finally open new paths for precision diagnostics and therapeutics.2) next-generation fast liquid sensor. However, due to the oversimplified nature of most optical architectures, miniaturized systems are usually far less capable than equivalent systems in desktop labs . In recent years, advances in LOC technology have facilitated advances in miniaturized bioanalytical equipment . Hinkov presentetop labs  developeAlthough LOC has made substantial progress in improving detection throughput, reducing cost and time, and simplifying operation, the improvement of sensitivity in the integration of nanoplasmonic on microfluidic chips is still not negligible . produceGenetic diagnosis (such as DNA mutations) for precise prevention and treatment presupposes the ability to accurately determine individual genetic information, thus genetic diagnosis is the foundation of precision medicine . CurrentScientists believe that identifying specific point mutations, deficiencies and nucleic acid modifications is becoming increasingly important as many sequences are confirmed as clinical biomarkers . Gene muIn addition to high-precision detection of single-base mutations, because nanopores are sensitive to small changes in local refractive index, novel nanopore-based sequencing has been developed to open up new avenues for high-throughput nucleic acid sequencing . Arif E.The diagnosis of cancer biomarkers is essential to achieve early disease prevention, monitoring progression and effectiveness of therapeutic interventions. Plasmonic sensors have demonstrated a wide array of analytical abilities, ranging from fast colorimetric readings generation to single molecule sensitivity at ultra-low sample volumes, which has allowed them to be increasingly explored in cancer biomarkers . A largeThe spread and proliferation of viruses has emerged as a risk to global biosecurity, with the current COVID-19 pandemic as an example. SARS-CoV-2 is an RNA virus that can be transmitted not only by inhalation of viral particles in droplets discharged into the air, but also by aerosols carrying viral droplets that can survive for up to 3 h, and by daily personal contact with contaminated surfaces . The higNanoplasmonic have antiviral activity against former coronaviruses and numerous other kinds of viruses, and by studying the photoelectric and chemical characteristics of plasmonic nanoparticles showing surface plasmon resonance effects, they may offer novel perspectives to combat COVID-19 as a drug carrier that is part of an effective therapy for early detection. On the one hand, it is based on the detection of metal surfaces. For example , developIn terms of external conditions, existing personal protective equipment can actually be an effective measure to restrain the spreading of SARS-CoV-2, but there is no inherent antimicrobial effect can only temporarily protect the user . TherefoAlthough the COVID-19 vaccine has significantly transformed the struggle against pandemics, for many people there is hesitation to get vaccinated . DetectiDue to the expanding imaging and diagnostic capabilities of nanoplasmonic biosensors in response to exterior stimulation, they are already being explored for on-demand drug detection , drug reThe number of nanomedicines currently available to patients is much lower than predicted by the field, in part because of the translational gap between animal and human studies . OvercomIn conclusion, the introduction of nanoplasmonic developed for specific patient populations can accelerate clinical translation. Advances in genome sequencing and biomarker diagnostics permit suitable choices for the treatment of patient-specific diseases, as mentioned earlier. The development of drug delivery for precision medicine should be a highly customizable process. Such well-designed methods enable the pharmacokinetics of therapeutic agents to be tuned to meet solubility, delivery or biodistribution requirements.Nanoplasmonic in SPR and LSPR imaging are applied to microscopic imaging techniques in biology and biochemistry to improve key properties of fluorescence imaging (such as sensitivity and resolution) . SPR andin vitro and in vivo bioimaging due to their ultra-sensitivity, specificity, multiplicity, biocompatibility and photostability  and analyzes their existing advantages and shortcomings. The second part reports on the integration of multiple technologies, including integrated isothermal amplification, CRISPR/Cas, lab on a chip and ELISA, which help to bridge the gaps of individual technologies. Based on the current situation, POC testing is more appropriate for these sensors than large-scale testing, although micro and portable sensors are appearing. In the final section we discuss the applications and trends of nanoplasmonic biosensors in precision medicine. In particular, the continuing COVID-19 pandemic has highlighted the need to find fast and reliable sensors. In fact, in a sense, virus pandemics and insurmountable cancers are driving the field of precision medicine sensing, especially plasmonic technology, as the requirement for rapid, dependable, mobile and inexpensive sensors becomes essential.Despite the rapid development of nanoplasmonic with controlled optical properties, their large-scale utilization in medicine is still limited, probably due to i) the relatively high price of precious metals, ii) the low yield of materials with excellent properties, iii) the need for precise fabrication methods to control different sizes and morphologies, iv) the unclear biological toxicity in physiological environments, and v) the complex matrix identification capabilities in complex matrices. In most applications, the optical properties of nanoplasmonic are strongly dependent on size, morphology, and interactions with each other, so care must be taken to adapt fabrication techniques to achieve well-controlled and highly productive plasmas with various structures. In order to be stable in maintaining optical properties, polymers and inorganic coatings have been successfully used with many effective surface modification strategies that contribute to chemical and biological stability. However, issues such as long-term biocompatibility and specific cytotoxic residues of nanoplasmonic under pathological conditions remain a challenge for clinical practice.Several issues need to be addressed in nanoplasmonic integration technology. The first is the integration of nanoplasmonic biosensors with sample pre-processing units (such as separation and purification of samples) for eventual practical applications in POC as well as cost-effective sensors for mass production, and more ideally will be used to deliver advanced nanoplasmonic technology from the laboratory to the bedside. As a result, the need for plasma coupled to microfluidics for sample collection and processing will continue to grow. With development it can be expected that mobile and economical biosensors will be available. Secondly, while nanoplasmonic biosensors are very promising for detecting the redox activity of individual proteins or enzymes, they still face challenges due to the limitations of current amplification strategies. The application of nanopores will not only be applied to commercial DNA sequencing, but will also contribute to the study of protein binding and enzyme reaction kinetics.In conclusion, nanoplasmonic biosensors have achieved significant advances and have shown sufficient sensitivity to observe even single molecular binding events. The quantification of biomolecular interactions at the single molecule level greatly expands the scope of biosensor and analytical techniques and allows access to potential heterogeneity in molecular properties. This heterogeneity may arise from the existence of various species in the sample or the presence of distinct conformations of the same species. However, transforming these encouraging advances in science to biosensor devices for daily life will require additional work on many aspects. The next-generation of nanoplasmonic technology will move out of the laboratory and translate into smart POC diagnostics that will shape the future of precision medicine.


Attention Deficit Hyperactivity Disorder (ADHD) is a common developmental disorder affecting 5-7% of adults and children. We surveyed the literature to examine ADHD through three pillars: developmental characteristics, symptomatology, and treatment strategies. Firstly, in terms of developmental characterstics, early life stress may increase the risk of developing ADHD symptoms according to animal models’ research. Secondly, the current core symptoms of ADHD are comprised of inattention, hyperactivity, and impulsivity. However, the up-to-date literature indicates individuals with ADHD experience emotional and sensory dysregulation as well, which early-life stress may also increase the risk of. Finally, we discuss the therapeutic benefits of methylphenidate on both the current core ADHD symptoms and the sensory and emotional dysregulation found in those with ADHD. In summation, we surveyed the recent literature to analyze (i) the potential role of early-life stress in ADHD development, (ii) the involvement of emotional and sensory dysregulation in ADHD symptomatology and finally, (iii) the therapeutic intervention with methylphenidate, aiming to reduce the potential effect of early life stress in ADHD, and mainly emotional and sensory dysregulation. The apparent but currently less recognized additional symptoms of emotional and sensory dysregulation in ADHD call for further investigation of these possible causes and thus increasing treatments efficacy in individuals with ADHD. Attention Deficit Hyperactivity Disorder (ADHD) is a common developmental disorder suggested to be caused by a delay in brain maturation , affectiThe core symptomatology of ADHD comprises of inattention, hyperactivity, and impulsivity, thus forming three subtypes of ADHD according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) . While iPharmacological strategies for treating ADHD symptoms include methylphenidate (MPH), being one of the most common treatments. This review focuses on MPH specifically since it has a low addictive potential , a shortTherefore, this review (August 2019 through August 2022) is conducted on three pillars: Developmental characteristics, Symptomatology, and Treatment strategies. Within developmental characteristics, the role of early life stress on the development of ADHD-like symptoms will be discussed. The specific symptoms themselves will then be discussed in the Symptomatology sections, exploring the currently accepted ADHD symptoms , as well as the proposed additional symptoms of ADHD . Finally, after discussing the way these symptoms develop and the subtleties of the Symptomatology, we will discuss how MPH mitigates ADHD symptoms, including the potential additional ADHD symptoms of sensory and emotional dysregulation. Through this discussion of Developmental Characteristics, Symptomatology, and Treatment strategies, we can follow the line of how early life stress may increase the risk of ADHD symptoms, and how certain ADHD symptoms, particularly emotional and sensory dysregulation, may give rise to the higher order symptoms of impulsivity, hyperactivity, and inattention, and how application of MPH can prevent these symptoms, respectively.Thus, we aim to understand nuances of the developmental risks, the role of sensory and emotional dysregulation on symptoms, and treatments of ADHD by considering the National Institute of Health’s call to approach a more dimensional diagnostic process for mental health concerns. Furthermore, by understanding the neurophysiological and behavioral symptoms of the disorder and determining the dis-/similarities between ADHD and emotional and sensory dysregulation, we may suggest differential and more accurate treatments of the disorders.In regards to methodology, we conducted the review between August 2017 through August 2022, as mentioned, through Google Scholar and Pubmed. A limitation worth mentioning is a large subset of these publications were gathered prior to the recent Pubmed website update, meaning some of our citations may not be available through Pubmed currently.Neglect, deprivation, abuse, and trauma may intensify the risk of ADHD development . The strThe potential role of early-life trauma on the development of inattention and hyperactivity, symptoms typically associated with ADHD, may be mitigated through environmental factors. Environmental factors like emotionally supportive parenting in childhood and early adolescence correlated with a reduction of emotional dysregulation symptoms in individuals with ADHD . ParentsEarly life stress not only correlates with the typical ADHD symptoms of impulsivity, hyperactivity, and inattention, as above-mentioned, but, according to animal models research, may intensify anxiety-like behaviors in a rat model of “emotional dysregulation” . EmotionADHD has a high comorbidity with a variety of mental disorders, like the previously mentioned generalized anxiety disorder, leading to the exclusion of emotional dysregulation as a direct feature of ADHD, and consider it a manifestation of a comorbid disorder. However, emotional dysregulation has been found in ADHD with no comorbidities, and emotional dysregulation symptoms respond to common ADHD treatments . EmotionHypothetically, emotional dysregulation may induce some of the classical symptoms of ADHD, like impulsivity and inattention. The dysregulation of emotion would make paying attention more difficult and would also increase the likelihood of impulsive behavior. This hypothesis is mirrored in data of ADHD individuals, as impulsivity and hyperactivity predict the severity of emotional dysregulation in ADHD individuals . Some stSimilar to emotional dysregulation, early life stress correlates with increased sensory dysregulation in adolescents as well . Both chThis sensory dysregulation, found in those with ADHD, seems to be tied to emotional dysregulation as well, as pain sensitivity in children with ADHD was recently shown to be associated with the severity of emotional dysregulation . This reNeurologically, these disruptions in the processing of somatosensation found in ADHD may be related to disruptions in disruptions in central nervous system inhibitory systems . The senMethylphenidate (MPH) is one of most commonly prescribed ADHD medications and is highly efficacious in treating ADHD symptoms . MPH preBoth acute and chronic MPH administration increases activity in the Ventral Tegmental Area (VTA) and Locus Coeruleus (LC) . Acute MAcute MPH has a higher efficacy in treating attentional symptoms than impulsive symptoms . ThroughChronic MPH administration increases neuroplasticity in a variety of brain regions  and upreAfter MPH treatment, adolescents with ADHD report improved quality of life . RegardiThe current core ADHD symptoms are comprised of inattention, hyperactivity, and impulsivity . DespiteEmotional and sensory dysregulation may give rise to the current core symptoms of ADHD, which in turn induce higher order, classical symptoms. For instance, dysregulated emotions and improperly processed sensory input is quite distracting of itself. Sensorimotor gating is a preconscious regulator of attention, and is why the pre-pulse inhibition of startle is often impaired in disorders with attentional abnormalities , and visOn the treatment end, we conclude that MPH mitigates ADHD symptoms once they have developed. Acute and chronic MPH administration has beneficial effects on ADHD symptomatology . Acute aThese results lead us to conclude that: (i) developmental stress may correlate with an increased risk of ADHD development, potentially mediated by the increase of sensory and emotional dysregulation; (ii) This increased sensory and emotional dysregulation give rise to the ‘classical’ ADHD symptoms of inattention, impulsivity, and hyperactivity. These symptoms may be diagnosed through (iii) objective, physiological means, and finally (iv) mitigated with MPH application, and, following further research, possibly also by treatments aimed at these dysregulation processes. To properly further aid ADHD individuals, further research is required to better define causes, symptoms and preventative techniques. Further research is also needed to determine the role of early-life stress effects on the development of ADHD, particularly as there is limited clinical evidence for the causative role of early-life stress on ADHD development. This creates a limitation within our review paper, as the lack of research limits the potential number of references. A deeper investigation into the additional suggested symptoms of ADHD  beyond the current core symptoms of impulsivity, hyperactivity, and inattention, bares an important potential in improving both ADHD diagnosis  and treatment.In sum, better ADHD treatment strategies may be achieved by the inclusion of further research on (i) developmental stress on ADHD development, (ii) emotional and sensory dysregulation as potential ADHD additional symptoms, and finally (iii) the effects MPH on emotional and sensory dysregulation in ADHD populations. This new and comprehensive prism could lead to new tools for diagnosing and treating individuals with ADHD.AG surveyed the literature, drafted the manuscript, and co-wrote the conclusion. AA conceptualized the manuscript, co-wrote the conclusion, and edited previous versions into the final one. Both authors contributed to the article and approved the submitted version.


Power transformers are essential apparatuses used to transfer electrical energy from one voltage-level circuit to another. For reliable systems, preventive maintenance of the transformers is required to ensure good services of all mechanical, electrical, and insulation parts. Oil-immersed paper is most often used for transformer insulation. To ensure such good insulation performance and for assessing insulation conditions, advanced transformer sensing, monitoring, and effective assessment techniques are required. This paper introduces an effective technique for assessing the insulation conditions in power transformers, which are crucial for ensuring reliable energy transfer. The method utilizes advanced transformer sensing and monitoring, focusing on oil-immersed paper insulation commonly used in transformers. The technique employs dielectric response sensing, obtained from frequency-domain spectroscopy tests, to estimate degrees of polymerization (DP) and percentages of moisture content (PMCs) in the oil-immersed paper insulation. These parameters are well-known indicators of insulation performance. The approach is based on the weighted k-nearest neighbor regression, using a database of dielectric loss factors at low frequency and oil conductivities. To overcome limited data availability, linear interpolation and extrapolation techniques are applied to enlarge the database. Experimental verification and comparison with a previously developed method demonstrate the proposed technique’s superiority in accuracy and complexity. The maximum deviations of DP and PMC in the validation cases are 6.2% and 18.7%, respectively. In addition, to evaluate the validity of our proposed method in the case of a real power transformer, a comparative analysis of the DP and PMC values determined by the proposed method with those obtained through a previously developed and complicated approach was performed. The predicted results indicate that the DP and PMC values of the oil-immersed insulation fall within the ranges of 800 to 1000 and 1.5 to 2.0, respectively, which agree with the results determined by the complicated approach and closely align with real conditions. By offering a reliable and advanced means of assessing insulation conditions, this technique contributes to the preventive maintenance and overall efficiency of power transformers. Sustainability drives manufacturers to consider long-term environmental, social, and human impacts. Transformers, essential for electrical systems, can enhance sustainability through strategic design and maintenance modifications to reduce energy losses and environmental effects. Digitalization and condition-based lifecycle management  improve Not only are advanced transformer sensing and monitoring required for transformer asset management, but also effective assessment techniques. Operators may optimize their maintenance planning and spending by keeping a close check on the most critical transformer components. According to CIGRE research , transfoOil-immersed cellulose-based paper is utilized in various applications in the electrical and industrial sectors due to its unique characteristics, providing notable advantages for high-voltage apparatus insulation, including exceptional dielectric strength, elevated thermal stability, effective electrical insulation, resilience against environmental factors, and a long lifespan. Typically employed for insulating cellulose-based materials, mineral or transformer oil serves a dual role as a vital liquid insulation and a medium for heat dissipation in high-voltage equipment. However, with time, insulation degradation can transpire due to various factors. Historically, replacing used transformer oil was common, but this practice entailed environmental risks and financial burdens. Presently, transformer oil reclamation technologies introduce an efficient and sustainable solution. The reclamation process rejuvenates used oil, restoring its dielectric performance, prolonging its service life, and curbing toxic waste and emissions. This approach aligns with environmental responsibility and cost-effectiveness in high-voltage equipment maintenance. The reconditioning procedure mitigates degradation and acidic components in the oil, increasing oxidation stability, while diminishing gas solubility and water content. It effectively eliminates sediment from insulation and transformer windings, thereby reducing dissipation factor and losses, ultimately significantly elongating the transformer’s lifespan. Accurate data, encompassing dissolved gases, moisture content, and the degree of polymerization of cellulose-based paper, assume pivotal importance for the condition-based upkeep of power transformers.The aging process of oil-immersed paper insulation refers to the gradual transformation that occurs in the insulation material over time due to a combination of environmental, thermal, chemical, and electrical stresses. The aging of oil-immersed paper is a complex and multifaceted phenomenon driven by various physical and chemical processes. When subjected to prolonged exposure to heat and oxygen, the cellulose molecules in the paper insulation undergo degradation. This degradation process results in the breakdown of cellulose molecules into smaller fragments and the release of functional groups, leading to the formation of polar groups. Simultaneously, the degree of polymerization decreases, causing the long polymer chains of cellulose to shorten. As aging progresses, it introduces impurities into both the paper insulation and the insulating oil. These impurities may originate from environmental contaminants or arise as breakdown byproducts from the insulation material itself. Aging also induces physical changes in the paper insulation, making it more porous. This increased porosity enables the paper to absorb moisture from the surrounding environment. Consequently, the moisture content within the paper rises, culminating in a higher dielectric loss factor. Furthermore, the aging process releases breakdown byproducts into the insulating oil, thereby contaminating it. Contaminated oil exhibits elevated electrical conductivity, which compromises its insulating properties. This elevated conductivity can increase the risk of electrical breakdown within the equipment, negatively impacting its performance and safety. Additionally, aging may release furanic compounds into the oil, further exacerbating the reduction in oil conductivity and contributing to an increase in the dielectric loss factor. These intricate processes collectively characterize the aging of oil-immersed paper, which can detrimentally affect the performance and longevity of electrical equipment.The severity of the process depends on the level of thermal stress, oxidation, hydrolysis, chemical reactions, and electrical stress. This process predominantly affects the degradation of physical properties of the paper, i.e., loss in flexibility and change in dielectric constant, reduction in dielectric strength, increase in dielectric loss, and increase in conductivity of oil and paper insulation. Therefore, the degree of polymerization (DP) and percentage of moisture content (PMC) play important roles in the evaluation of the aging and remaining life of the oil-immersed paper insulation.For preventive maintenance of high-voltage (HV) apparatuses including power transformers, it is well known that condition-based maintenance is more realistic, economical, and effective than time-based maintenance. Thus, it is necessary to appropriately assess the insulation conditions of the HV equipment for management of the condition-based maintenance ,2,3,4,5.−3 Hz to 103 Hz. The development of the database involves time-consuming preparation of test sample materials and conducting of experiments. Therefore, a small database can be developed in practice. This aspect can pose challenges and inconveniences in practical applications.The DP tester based on viscosity testing and the moisture tester using Karl Fischer titration are utilized to determine the DP and PMC, respectively, of the test sample of oil-immersed paper insulation . It is hTo address the drawback in the previously developed technique , a new aAs mentioned in the Introduction section, the fundamental concept underlying the proposed method for predicting the degree of polymerization (DP) and percentage of moisture content (PMC) is based on the aging process of the oil-immersed paper insulation. The development of the proposed method is composed of three parts, i.e., the selection of the input data in the prediction model, data preparation, and the prediction model based on an adaptive k-nearest neighbor regression. The descriptions of these parts of the proposed method are provided in this section.−3 Hz and 10−1 Hz and oil conductivity.The prediction model for DP and PMC relies on insights from the aging process to guide the selection of crucial input parameters that must exhibit a robust correlation with DP and PMC. Similarly, the choice of input parameters for the estimating model, aimed at predicting DP and PMC in oil-impregnated paper insulation, draws upon well-established research findings. Specifically, it has been observed that both moisture and aging significantly influence the dielectric loss factor within the low-frequency range, as illustrated in The loss tangent is obtained through frequency domain spectroscopy (FDS), which measures complex capacitance and can be utilized to calculate the loss tangent by exposing the material to alternating electric fields across different frequencies. This reveals the material’s ability to store electrical energy under an electric field, offering insights into its behavior at various frequencies. The equivalent circuit and test configuration schematic for the FDS test on a power transformer are illustrated in Some experiments on samples of oil-immersed paper insulations were performed by accelerating thermal aging with a temperature of 130 °C. Then the samples were exposed to the air to absorb the moisture, and the moisture was determined utilizing the gained weight, measured using a precision electronic scale. The oil temperature was carefully maintained at 30 °C during both the FDS test and the measurement of oil conductivity. This implies that the test temperature for the loss tangent curve of oil-immersed insulation within the oil remained at approximately 30 °C. The FDS tests of the samples were performed, oil conductivities were measured, loss tangents were calculated, and DP and PMC were measured. The above experimental scheme is illustrated in In practice, it is feasible to construct limited databases containing loss tangents and oil conductivities. However, certain prediction models demand substantial data to attain satisfactory accuracy, necessitating effective data normalization and enhancement techniques. In this paper, the k-nearest neighbor regression is applied for the prediction model because it has been recognized as essential for achieving such accuracy.In this study, data from a total of 24 laboratory samples were gathered. We employed a straightforward validation set approach to assess the performance of our prediction model. Of these, the dataset of twenty laboratory cases was employed for the construction of the prediction model, and the corresponding results are detailed in It is noticed that the loss tangent and oil conductivity in To achieve practical and effective data enhancement, the linear relations of such parameters are required. Therefore, the natural logarithms of the loss tangents and the oil conductivities are utilized as the input parameters of the prediction model. The input parameters and the required and predicted parameters (DP and PMC) are found to have close linear relationships, as shown in ix, maxx, and minx are the considered, maximum, and minimum values of the input parameter, respectively, and nix is the normalized parameter.The data preparation is composed of two processes. The first is data normalization. The input data are prepared by taking the natural logarithm of the low-frequency dielectric loss factors and the oil conductivities. Then, these input parameters are normalized by (1) to balance the effects of the different input data scales, where In this paper, the k-nearest neighbor (kNN) regression method was applied to predict the DP and PMC. A weak point of this method is that it yields an average value in the vicinity of the analyzed data point. The output values for points situated near the dataset’s boundaries tend to exhibit pronounced deviations. To illustrate this, consider the test sample outlined in Linear interpolation and extrapolation are foundational mathematical techniques with distinct roles in the realm of data analysis. Interpolation comes into play when the objective is to estimate values that fall between two well-established data points. It operates on the fundamental assumption that a linear relationship exists between these data points, meaning that the change in the dependent variable can be accurately predicted based on the changes in the independent variable within the known data range. Utilizing this assumption, interpolation calculates intermediate values, effectively connecting the dots along a straight line or linear curve. In contrast, extrapolation ventures beyond the known data points to predict values outside this established range. It extrapolates the linear trend identified within the provided data range, postulating that the same linear relationship persists beyond these bounds. While it also relies on the linear relationship assumption, extrapolation extends this assumption to make forecasts and estimations for values that lie beyond the observed data range.From the original dataset  size of In the prediction model, the adaptive k-nearest neighbor (kNN) regression is applied to predict the DP and PMC using the enhanced database. A brief history and details of the kNN regression are presented in this subsection.d are not considered in the prediction model. In the kNN classification, the predicted result (x) can be classified in the class of the blue square. In the kNN regression, the predicted result (x) is an average value in the specified area, and it can be calculated by (2).The kNN algorithm was invented by Evelyn Fix and Joseph Hodges in 1951  and exteIn this research endeavor, we employ an adaptive approach centered on the k-nearest neighbor (kNN) regression technique to predict two critical parameters: the degree of polymerization (DP) and the percentage of moisture content (PMC). Our prediction model is primarily driven by two input parameters, which are the average value derived from two fundamental attributes: the low-frequency loss tangent and the oil conductivity. A distinctive feature of our proposed method lies in its adaptive nature. Specifically, it entails a straightforward yet effective strategy for the selection of the parameter of k in the kNN algorithm. Instead of employing a fixed k value, our approach adaptively determines ‘k’ from the pool of data points with distances smaller than three times the minimum distance of the input data. This dynamic selection ensures that the nearest neighbors considered for prediction are not only close in proximity but are also highly relevant to the specific context.Based on the description of the development of the prediction model, the visual representation of the model’s structure is presented in −3 to 103 Hz and the oil conductivity).It is noticed that the proposed method can predict the DP and PMC of the enlarged database very precisely, because when the proposed method is employed to predict the parameters of the database, d equals zero, k equals one, and the results match perfectly with the parameters of the enlarged data. The proposed method is superior to the previously developed method  because To validate the proposed method, the remaining four sets of experimental data from the test samples . refT stands for the reference temperature of 318.15 K, while the test temperature is denoted T.In the real case, the temperature during the measurement of FDS and oil conductivity may differ from the temperature of the test samples. However, it is possible to apply a temperature correction factor , as descThis correction factor can be directly multiplied with the average loss factor and oil conductivity  to conveTo evaluate the validity of our proposed method, a comparative analysis of the DP and PMC values determined by the proposed method with those obtained through a previously developed and complicated approach with the temperature correction factor  was perfIn this research, a precise model was developed to predict the degree of polymerization (DP) and the percentage of moisture content (PMC) in oil-immersed paper insulation. Although substantial DP and moisture variations within transformers are observed in practical scenarios, the proposed method still offers an alternative approach that is explicitly tailored to assessing the average degree of polymerization (DP) and percentage of moisture content (PMC) across the entire oil-immersed insulation within high-voltage equipment. These averaged parameters serve as valuable indicators for evaluating the overall insulation conditions.To enhance the available data, techniques involving linear interpolation and extrapolation were employed. The proposed approach utilizes an adaptive k-nearest neighbor regression, utilizing only two input parameters, namely the low-frequency loss tangent and oil conductivity, to predict DP and PMC. In this study, a straightforward validation set approach was employed to assess the performance of our prediction model.The results indicate that the proposed method consistently aligns with the expanded dataset and corroborates other experimental findings. Notably, this method achieves these outcomes with the use of only two parameters, yet retains superior accuracy compared to the previously developed model, which relied on four parameters for prediction. The maximum deviations of DP and PMC in the validation cases are 6.2% and 18.7%, respectively. In addition, a comparative analysis of the DP and PMC values determined by the proposed method with those obtained through a previously developed and complicated approach was performed in the case of a real power transformer. The predicted results indicate that the DP and PMC values of the oil-immersed insulation agree with the results determined by the complicated approach and closely align with real conditions.Based on these findings, it can be concluded that the proposed method presents an attractive approach for assessing the condition of oil-immersed paper insulation. Its ability to accurately predict DP and PMC with a reduced number of parameters enhances its practicality and usefulness.