Peripheral nervous system diseases are a complex and heterogenous group of diseases affecting the different nerves with various severity and impact on quality of life. The current literature does not provide a structured guide for the rehabilitation of these conditions. We performed a lexical literature evaluation based on graph theory to clarify this topic. We performed a search on PubMed and calculated the frequencies of the words indicating rehabilitation approaches, nerves, and diseases. We found the usefulness of exercises and different physical agents, like laser and ultrasound therapy and neuromuscular stimulation vibration therapy. Orthoses are useful for entrapment, trauma, and hereditary diseases. Correct knowledge and assessment of the neuropathies are fundamental for the therapeutic decision and to guide rehabilitation. Despite the usefulness shown by the different approaches to modulating pain, improving muscle strength and endurance, and ameliorating balance and the sensory system, further studies are needed to define the best-personalized protocols. Peripheral nervous system diseases (PNDs) are a heterogeneous group of clinical conditions involving the peripheral nerves in potentially every part of the body . These cConsidering the localization, we can distinguish mononeuropathies, multineuropathies, and polyneuropathies . The monIn addition to the complex classification of PNDs, the clinical presentation is not always clear, and the symptoms and their severity can be variegated. In cases of sensory involvement, neuropathic pain, allodynia, hypoesthesia, and sometimes itch may be present . In motoConservative treatments include rehabilitation programs, which have multiple aims: increase structural restoration, ameliorate function, prevent abnormal compensation, prevent or treat pain, and improve QoL. The rehabilitation aims are guided by the International Classification of Function (ICF), which allows a classification of body and function alterations and their associations with social activity and participation . To reacThe mentioned rehabilitation approaches are not specific for each neuropathy, and, at the moment, a real identification of the most appropriate programs is not available. We performed this literature review to assess the current scientific knowledge about rehabilitation and PNDs. The aims of this review are: (1) evaluation of papers based on lexical analysis to show the relations of the words used in the papers to describe the various arguments; and (2) identification, on the basis of the current literature, of possible clinical protocols for rehabilitation of PNDs.For literature analysis, we have used PubMed and the following string: “rehabilitation AND peripheral neuropath* AND ”. The words were chosen on the basis of the experience of the authors and the availability of rehabilitation approaches routinely applied in clinical practice. The terms were linked by the Boolean operators AND and OR to define and merge the different subjects. In the string, terms identifying the common physical agents and the usual manual treatment are included. We did not use the MeSH terms in order to obtain as many results as possible. Additionally, we used the following filters: article types , and publication date (the last 10 years). The found results were exported by the in-built function of the database in a text file containing the titles, the abstracts, and the editorial information. This file was analyzed to calculate the frequency of the words from a list including the diseases, the commonly assessed nerves, and the rehabilitation techniques. The words assessed were: trauma, injury, entrapment, compression, tumor, schwannoma, neurofibroma, hereditary, inherited, Charcot–Marie–Tooth, CMT, dysimmune, immune, Guillain–Barré, GBS, polyradiculoneuropathy, CIDP, diabetic, toxic; facial district, median, ulnar, radial, peroneal, tibial, sural, femoral nerves; rehabilitation, physical agent, physical therapy, exercise, manipulation, mobilization, electrotherapy, laser therapy, magnetotherapy, ultrasound therapy, capacitive and resistive electric transfer therapy, electromagnetic stimulation, vibration therapy, extracorporeal shock wave therapy, cryotherapy, thermal therapy, and orthosis. For each time a word was present in the title or the abstract of a paper, we assigned to the relationship word-paper a value of 1, or alternatively, we assigned a value of 0. Thus, we built a rectangular matrix with the paper on one side and the words on the other side. This matrix contained the binary values 0 or 1, as above described. It was imported into the freeware software Gephi 0.10.0, which is able to process, visualize, and analyze large networks based on graph theory. The described method, a lexical network based on graph theory (LENGTH), allows the evaluation of the connections between the papers and the words, transforming them into nodes connected by the edges ,38. The To complete the literature evaluation, we have performed additional separate research on PubMed using the term “rehabilitation” linked by the operator AND to a word indicating a nerve or a disease. The results were exported and analyzed as described above. We normalized the frequency of the words for the number of papers for each nerve or disease, and we collected the data about the three most relatively frequent rehabilitation approaches for each nerve and each disease and the most relatively common nerve and disease for each rehabilitation approach. The results were summarized in a proper table.Finally, on the basis of the collected information, we developed a flowchart to recapitulate the possible clinical protocols compatible with the current literature.The search strategy initially found 345 papers. After the analysis of the titles and the abstracts, a total of 317 papers were included in the network. Among the words initially considered, only 35 were present: trauma, injury, entrapment, compression, tumor, hereditary, inherited, Charcot–Marie–Tooth, CMT, immune, Guillain–Barré, polyradiculoneuropathy, diabetic, toxic; facial, median, ulnar, radial, peroneal, tibial, sural, femoral; rehabilitation, physical agent, physical therapy, exercise, manipulation, mobilization, electrotherapy, laser therapy, ultrasound therapy, stimulation, vibration therapy, cryotherapy, and orthosis.Among the first list of rehabilitation approaches, no papers containing magnetotherapy, capacitive and resistive electric transfer therapy, extracorporeal shock wave therapy, or thermal therapy were found.Among the diseases, diabetes was the most common one, being present 254 times and in 98 papers, followed by the terms injury, toxic, compression, and immune, respectively, with a frequency of 111, 51, and 22 for compression and immune. They are present in 50, 29, 12, and 14 papers. Trauma and entrapment showed a frequency of 17 and 14, and they were present in 14 and 11 papers, respectively. The remaining diseases were mentioned less than 10 times. Considering the anatomical sites, the facial district, median, and ulnar nerves showed the highest occurrence, respectively 24, 18, and 14 times in 10, 8, and 5 papers. The radial nerve and the lower limb nerves presented a frequency from 4 to 10 times. Concerning rehabilitation approaches, exercise was the most common term and absolutely the word with the highest frequency, with a degree value of 507 and a presence in 122 papers. A high value was visible for stimulation, indicating the various forms of electromagnetic stimulation . This term was used 375 times in 117 papers. Rehabilitation and physical therapy showed a frequency of 151 and 63 times, respectively. The other words indicating rehabilitation treatments were present less than 10 times.In the network, the dimension of the papers was usually small because a paper could have only limited connections with the words, while a word could be contained in many papers. Additionally, some papers were visible on the periphery of the network, thus indicating they have only a connection with a single word. In a similar way, a few words were visible in the periphery  because they were included in a single paper. The other words presented multiple connections, being present in more papers a.Considering the classes, we found six groups of words and papers. The most populated was the group containing the terms stimulation, facial district, and femoral nerve, with 86 papers. The second group, in terms of numerosity, was the group containing polyneuropathies (immune-mediated and genetic), exercise, and electrotherapy. In the third group, trauma and injury were present, as were the terms immune, mobilization, and cryotherapy. The fourth group showed the terms diabetes and vibration therapy. In the fifth group, the other nerves were included together with compression and entrapment disease, orthosis, manipulation, and laser and ultrasound therapy. In the less populated group, we found the terms tumor and toxic in 17 papers b.The single searches combining the term rehabilitation with a nerve or a disease showed additional results . The difOur literature review shows the different approaches applicable to the different PNDs . In mostOur literature review, however, despite the high incidence of PNDs, shows a relatively low number of papers exploring their rehabilitation. This is particularly evident for traumatic nerve lesions and toxic neuropathies. Additionally, only a limited number of types of nerve tumors are explored in the literature. This result should stimulate further and larger studies to define the best rehabilitation protocols. Another important limitation of the current literature is the relative inhomogeneity of the protocols: different types of exercises with several modalities exist, as do different types of neurostimulations .Considering the methodology of lexical analysis, the inhomogeneity of the scientific interest of the different approaches and diseases is clearly visible. If diabetes and exercise are widely investigated, other common topics present very low frequencies. In particular, entrapments and traumas are scarcely represented. This result should be connected with the usual terms used to convey specific meanings. Being a lexical analysis, our analysis is determined by the words used in the different papers. This should encourage the use of the same terms to indicate the same significance across the world in order to facilitate the revision process and the data collection for generating evidence. Another utility of our lexical approach is the identification of families of words. In the graph, the strict association between diabetes and vibration therapy is well shown and confirmed by the following literature analysis. In a similar way, a close association between polyneuropathies and exercise is visible. This association is particularly interesting considering the high importance of exercise for diseases like CMT. Similarly, the nerves are strictly related to the terms entrapment and compression, which represent the most common forms of mononeuropathies. Hence, the approach can be used to facilitate an overview of the literature and depict the tendencies of the papers. Furthermore, the LENGTH approach, being based on the literature data extracted from the online database available elsewhere, is a reproducible method if the same search strategy and word identification are applied. The main limitation of the method is linked to the words themselves. The word list is decided on the basis of the authors’ experience, and the lexical analysis assesses the match of the words in the papers, thus only considering a limited number of associations and not considering all possible synonyms of the words .Finally, our entire review shows some limitations. First, we have considered a large number of common neuropathies without covering all possible PNDs. Second, in our revision, we focused on families of treatments, avoiding a deep analysis of the single approaches. For example, we did not consider the different types of laser therapy or the different parameters of electromagnetic stimulation. Additionally, a detailed characterization of the single protocols for each disorder was out of the scope of this review, which focused on the general presentation of different PNDs and their possible rehabilitation.Rehabilitation of PNDs is a complex field requiring extensive knowledge of the different neuropathies, their clinical presentation, and the methods to assess them, like EDx and imaging techniques. The protocols applicable to care for the patients are several, with different features and different aims. Drugs are used for pain management and to support patients’ functions; physical agents have a vast range of effectiveness, from pain sensation to muscle improvement; exercise aids sensory-motor restoration and the acquisition of useful strategies; and orthoses help reduce disabilities. PNDs may have different degrees of severity, but they usually negatively impact daily activity. Because of their complexity and impact, PNDs represent a real challenge for rehabilitation, which is sometimes the only effective treatment. Although the literature shows the usefulness of several approaches, the development of specific rehabilitation protocols is still ongoing, and further research is needed to identify the most appropriate treatments.


Panicum virgatum L.) frequently suffer from unpredictable winter hardiness at more northerly sites arising from damage to rhizomes that prevent effective spring regrowth. Previously, changes occurring over the growing season in rhizomes sampled from a cold-adapted tetraploid upland cultivar, Summer, demonstrated a role for abscisic acid (ABA), starch accumulation, and transcriptional reprogramming as drivers of dormancy onset and potential keys to rhizome health during winter dormancy. Here, rhizome metabolism of a high-yielding southerly adapted tetraploid switchgrass cultivar, Kanlow—which is a significant source of genetics for yield improvement—was studied over a growing season at a northern site. Metabolite levels and transcript abundances were combined to develop physiological profiles accompanying greening through the onset of dormancy in Kanlow rhizomes. Next, comparisons of the data to rhizome metabolism occurring in the adapted upland cultivar Summer were performed. These data revealed both similarities as well as numerous differences in rhizome metabolism that were indicative of physiological adaptations unique to each cultivar. Similarities included elevated ABA levels and accumulation of starch in rhizomes during dormancy onset. Notable differences were observed in the accumulation of specific metabolites, the expression of genes encoding transcription factors, and several enzymes linked to primary metabolism.High-biomass-yielding southerly adapted switchgrasses ( Panicum virgatum L.) is a temperate, warm-season, perennial grass with good attributes as a forage, conservation, and bioenergy crop [Switchgrass . Adaptations for dormancy and onset to dormancy are accompanied by significant changes in tissue metabolism, changes in hormone levels, reordering of the transcriptome, and cessation of growth ,10,11. PPalmer et al.  developeThe major focus of this study was to discern similarities and differences in rhizome metabolism over the course of a growing season in lowland (Kanlow) and upland (Summer) cultivars of switchgrass with differences in winter survival, with an emphasis on evaluating transcriptional and metabolite changes occurring towards the end of the growing season when plants will be entering dormancy (dormancy onset), and after a killing frost when aerial portions of the plant would die or have fully senesced (dormancy). Kanlow and Summer, and hybrids between these two cultivars, continue to provide genetics for trait improvements ,14,15.ABA levels in Kanlow rhizomes were low and not significantly different for the first four sampling times, from May through August A. LevelsExpression levels of differentially expressed genes in Kanlow rhizomes encoding enzymes needed for ABA biosynthesis, ABA receptors (RCAR), select protein phosphatases 2C (PP2C), ABRE-binding factors (ABF), sucrose non-fermenting kinases (SnRKs), and select genes up/down regulated by ABA were then analyzed and compared to expression profiles previously documented in Summer rhizomes C,D.ABA2 being somewhat downregulated in November and AAO being upregulated in November. ABA levels can be modulated by biosynthetic and catabolic enzymes, and by conversion to storage forms by glycosyl transferases. ABA 8′-hydroxylases convert ABA to phaseic acid. Five copies of ABA 8′-hydroxylases were expressed in switchgrass rhizomes, with divergent expression profiles in Summer rhizomes compared to Kanlow rhizomes (Peak expression of a beta-carotene-3-hydroxylase (β-OHASE) was significantly upregulated both in Kanlow rhizomes sampled after a killing frost, and in dormant Summer rhizomes C. β-OHASrhizomes C. Three rhizomes C.The switchgrass genome contains large numbers of genes encoding RCARs, PP2Cs, and ABFs. Expression of many copies of these genes were detected in switchgrass rhizomes . RCARs w2 sensor, PP2C5 (AT2G40180) [When liganded with ABA, RCARs can form complexes with clade A PP2Cs, releasing sucrose non-fermenting1-related protein kinases 2 (SnRK2s) from inhibition by PP2Cs. Released SnRK2s subsequently activate downstream signaling that leads to ABA-induced changes in cell functions . Differe2G40180) , and conEleven and seventeen copies of ABFs and SnRKs, respectively, were differentially expressed in rhizomes. Among the eleven ABF copies with detectable expression in rhizomes, four had their highest expression in Kanlow rhizomes in November D. These In response to the increased ABA content, many genes are induced or repressed in the model plant Arabidopsis . ExpressSimilarly, among the ten most highly repressed genes in Kanlow rhizomes collected post-frost, there were some genes whose Arabidopsis orthologs respond to ABA  and others involved with disease resistance , cuticular wax synthesis (CER8), phosphate starvation response (ATPS3), cell wall elongation (BOR2), and two copies of pyruvate-Pi-dikinase D.Previously, it had been reported that sucrose content increased in Summer rhizomes at dormancy to support rhizome metabolism . To conf−1 FW) increased at each sampling date in both cultivars and was highest in rhizomes collected post killing frost in November  than the other RFOs across all sampling dates in both cultivars.The measured levels of RFOs essentially followed the expression levels of genes encoding RFO biosynthetic enzymes A. GalactMetabolite levels in rhizome extracts were quantitated using LCMS (see methods). A total of 219 metabolites were identified, with 166 metabolites being differentially abundant across all harvest dates. Multidimensional scaling (MDS) plots indicated a clear differentiation between Summer and Kanlow rhizomes in MDS1, while timepoints were segregated along MDS2 and were oriented in roughly the same pattern in the two cultivars A, indicaA heatmap of relative metabolite abundances is shown in Metabolites with higher relative enrichment in Kanlow rhizomes sampled in July included betaine aldehyde, an intermediate in glycine metabolism and a precursor for the osmoprotectant betaine; fructose-1,6-bisphosphate; sn-glycerol-3-phosphate; ribose phosphate; and 2-deoxyglucose-6-phosphate. Many of these metabolites remained at higher relative levels in Kanlow rhizomes at later sampling dates as well B.End-of-season sampling in November also suggested subtle differences in rhizome metabolism in the upland versus lowland cultivars B. SeveraAn MDS plot of transcriptomes over the course of the growing season is shown in p ≤ 0.05  or Summer (M3) rhizomes at all sampling dates B,C, withGO terms enrichment was greater at both the GO:BP and GO:MF levels in M3 as compared to M2 C, and inM4 contained 7663 genes that had strong end-of-the-year expression profiles in both cultivars and are likely linked to processes common during switchgrasses’ transition to dormancy. Notably, expression of these genes significantly increased in August and remained high through November in Summer rhizomes but did not begin to increase in expression in Kanlow until September and reached their peak expression in November E. M4 wasM5 F containAn analysis of Pearson correlations for metabolite abundances correlated with each module eigengenes identified by network analysis was performed . These cTo discern potential differences and similarities in the expression of transporter encoding genes, their abundances in individual modules were performed . Transpo+ exchangers (8), and calcium ATPase 2 . M5 only contained two transporters, one divalent anion/Na+ symporter (LSI), and one phosphate transporter (PHT). A comparison between the M2 (Kanlow) and M3 (Summer) modules indicated almost a two-fold increase in the number of annotated transporter genes in the Summer module  and one LSI were found only in M3.M1 contained a total of 117 genes encoding switchgrass transporters, of which 32 and 22 were annotated as peptide transporters (PTR) and major facilitator superfamily proteins (MFSP), respectively. M4 had fewer PTRs (6) and greater numbers of MFSP (31), Na/HM3; 103;  relativeM3; 103; . Select A total of 56 classes of genes encoding switchgrass TFs were detected within all the modules . Select M4 contained 271 genes annotated as TFs . These iM2 and M3 contained a total of 173 and 221 TFs, respectively . AlthougSwitchgrass occurs as two ecotypes, upland and lowland . The uplThe physiological basis for the differences in winter adaptations are still unclear, although a recent detailed study of cold acclimation among diverse switchgrass accessions has been performed . These aABA has important and diverse roles in controlling plant physiological processes, including dormancy ,23,24. ASucrose levels increased to a maximum with the transition to dormancy in Kanlow rhizomes, as has been reported for Summer rhizomes , althougBased on transcriptomic data, there was a clear association in the activation of RFO biosynthesis in Summer rhizomes at dormancy, which appeared to be impacted by an HSF TF . To exteOther metabolites such as amino acids, sugars, and organic acids displayed both a seasonal as well as cultivar-specific accumulation; most notably, there were greater similarities during the growth phases, especially at the June sampling date, with somewhat greater divergence at later sampling times. These changes could be a mixture of cultivar-specific metabolism ,29,30,31Network analysis identified modules with higher relative gene expression in either Kanlow or Summer rhizomes. These modules were also differentially enriched with TFs, metabolites, GO terms, and KEGG pathways. However, neither module was specifically associated with a developmental transition (for example growth or dormancy), suggesting a link to cultivar-specific events, and possibly to other determining factors such as rhizome type, root, and tiller initiation.Overall, these data support a delay in the dormancy transition in the lowland cultivar Kanlow relative to the upland cultivar Summer as suggested earlier ,21. Rece2, and stored at −80 °C until analyzed. Prior to analysis, rhizomes were cryogenically ground using a SPEX 6850 Freezer Mill instrument. Aliquots of ground tissues were used for subsequent downstream analyses.Kanlow and Summer plants were raised from seeds in a greenhouse, and hand transplanted at sward densities into a field site near Mead, Nebraska, USA. Rhizomes were sampled from three individual plants (genotypes) at five time-points that approximately corresponded to spring green-up (May), rapid vegetative growth (June), transition to flowering (July), early flowering (August), seed set (September), and after a killing frost (November). Other environmental details at this field site have been provided earlier . Sampling dates and environmental conditions at this field site have been described earlier . Sampledp-value < 0.05 and a |log2 fold change| > 1.0. Co-expression analysis was done using the Weighted Gene Co-expression Network Analysis (WGCNA) package in R [RNA extraction and subsequent RNA-Seq analysis was performed as described earlier . Brieflyage in R  to creatTriplicate 50 ± 2 mg aliquots of each sample were analyzed for ABA content using mass spectrometry, essentially as described earlier ,38.Polar metabolites were extracted from 50 ± 2 mg of ground tissue in 80% methanol and analyzed by multiple reaction monitoring (LC-MRM-MS) analysis as described by Koch et al. . Metabol−1 melibiose internal standard for 90 min at 25 °C. After incubation, samples were centrifuged at 13,000× g for 10 min and multiple 50 µL aliquots of supernatant from each sample were dried in vacuo. To determine soluble sugars, two separate analyses were performed. Under the HPAEC-PAD chromatographic conditions used, galactinol eluted the earliest of the analytes of interest. Due to background signals in the injection void and the lower quantities of galactinol in the samples, quantification was not reliable. Therefore, a solid-phase extraction (SPE) was performed using monolithic aminopropyl-functionalized silica to remove background contaminants and concentrate samples for galactinol measurements.Water soluble sugars and galactinol were analyzed with high-performance anion-exchange chromatography-pulsed amperometric detection (HPAEC-PAD). Analysis of the major, extractable soluble oligosaccharide products was performed by HPAEC-PAD, due to its superior sensitivity, speed, and separation chemistry for soluble oligosaccharide components . To obtaFor WSC determination, 1000 µL of 18 MΩ water was added to one 50 µL aliquot of each sample for soluble carbohydrate analysis of the major soluble sugars . These extractable soluble sugars and oligosaccharides were determined quantitatively using HPAEC-PAD . Samples were maintained at 4 °C prior to analysis and 5 µL of the reconstituted sample was injected onto a Thermo Scientific PA-10 column (2 mm × 250 mm column) at 0.25 mL/min, running 90 mM NaOH isocratically for 30 min . The pro2 SPE spin column. Samples (500 µL) were centrifuged through the SPE-packing material at 5000 rpm for 30 s, washed with 500 µL 90% acetonitrile:water:0.1% formic acid, then eluted with 500 µL 50% acetonitrile:water:0.1% formic acid. The eluate and the combined loading and wash fractions from each sample were dried in vacuo. Samples were resuspended in 250 µL 18 MΩ water, followed by HPAEC-PAD using the conditions describe above. Galactinol was identified and quantified based on a 3-point standard curve generated from an authentic standard run several times over the course of analysis. The combined loading and wash fractions were analyzed to show that no galactinol was present in these fractions. The procedure was performed in triplicate as described for the WSC.Separate 50 µL aliquots were resuspended in 50 µL water, followed by the addition of 450 µL acetonitrile. Each sample was added to a preconditioned  MonoSpin NHw/w) were purchased from Fisher Scientific. Formic acid (for mass spectrometry) was purchased from Fluka Chemical . MonoSpin NH2 SPE spin columns were purchased from GL Sciences, Inc. .Galactinol, fructose, sucrose, raffinose, stachyose, and melibiose standards were purchased from Sigma-Aldrich Co. . Verbascose was purchased from Megazyme International Ireland Ltd. . Glucose, acetonitrile (HPLC grade), and sodium hydroxide , with mean separation done using Tukey’s HSD test. Gene ontology enrichment of co-expression modules was done using the topGO package in R with the “weight01” algorithm and “fisher” statistic. KEGG pathway enrichment of co-expression modules was done using the GeneOverlap package in R and required a KEGG pathway to have at least five member genes detected in the RNA-Seq data. Significant correlations between metabolites and co-expression module eigengenes were detected using the rcorr function in the Hmisc package in R with the Pearson correlation. Other relevant bioinformatic analyses were as described earlier ,28,39,43


Bubo virginianus) was the most common. For all owls combined admittance rates were highest in the spring, driven by an influx of juveniles . The leading cause of admittance amongst species was ‘no apparent injury’ . Where clear diagnoses could be made, the leading causes of admittances were ‘entrapment in human infrastructure’  and ‘collision with vehicles’ . While the admittance data did not reveal any cases of AR poisoning, liver screening demonstrated high incidences of AR exposure; of 53 owls screened for ARs, 50.94% (n = 27) tested positive with 18 showing exposure to multiple ARs. Brodifacoum was the most frequently detected AR  and seven owls (25.93%) tested positive within lethal ranges. Our results suggest that owls in Texas are at risk from myriad anthropogenic threats and face high exposure rates to ARs. In doing so, our results can inform conservation strategies that mitigate anthropogenic threats faced by owls in Texas and beyond.Owls (Strigiformes) provide myriad ecosystem services and are sentinels for ecosystem health. However, they are at continued risk from anthropogenic threats such as vehicle collisions, entanglement with human-made materials, and exposure to anticoagulant rodenticides (ARs), a widespread pesticide known to affect owls. Texas is an important region for numerous migratory and non-migratory owl species in the United States (US), yet assessments of threats owls face here are lacking preventing the development of informed conservation strategies. This study coupled assessment of admittance data from two wildlife rehabilitation centers in Texas with AR liver screening to (1) identify which species of owls are commonly admitted, (2) evaluate seasonality of admittance, and (3) assess causes of admittance for owls in Texas. Between 2010 and 2021, 1,620 owls were admitted into rehabilitation, representing eight species of which the Great-horned Owl ( Owls (Strigiformes) are a widespread raptorial group of birds in North America , many ofRecent attention has highlighted the potential for anticoagulant rodenticide (ARs) poisoning, a widespread issue increasingly recognized as a global conservation concern for owls to have effects at the population level . ARs areRehabilitation admittance data collected following admittance of owls into wildlife rehabilitation centers provides valuable insight into the anthropogenic threats they face. For example, previous studies using rehabilitation data suggest owls are frequently admitted following barbed-wire fence injuries and collisions with vehicles or other manmade structures –26. Conc2) within the US with a human population of 29 million  [While the rehabilitation data did not reveal any incidences of AR exposure, liver analysis suggested high AR exposure rates of owls in Texas; of the 53 owls screened for ARs, 50.94% tested positive for at least one compound while 18 (33.96%) individuals were exposed to multiple ARs. These results showcase that, in the absence of diagnostic testing, rehabilitation admittance data may underestimate rates of AR exposure. Our results of exposure to at least one AR are similar to published exposure rates for owls found dead or admitted into rehabilitation centers in North America .By coupling rehabilitation data with clinical assessments of ARs, we have expanded our understanding of threats owls face in Texas. However, we acknowledge the limitations associated with our approach. First, owls sampled from wildlife rehabilitation centers represent a nonrandom sample of the population, and thus the AR exposure rates presented are unlikely representative of population level exposure rates. Second, admittance may be biased where individual size and injury type affects the probability of detection. For example, larger species like Great-horned Owls may be more readily detected, while grounded juvenile owls in urban areas or owls hit by vehicles in areas of high traffic may be more likely to be reported than individuals persecuted away from public view. Third, our study did not consider exposure to other contaminants known to negatively affect raptors . NevertS1 Table(PDF)Click here for additional data file.


Virtual reality (VR) technology has been widely used in rehabilitation training because of its immersive, interactive, and imaginative features. A comprehensive bibliometric review is required to help researchers focus on future directions based on the new deﬁnitions of VR technologies in rehabilitation, which reveal new situations and requirements.Herein, we aimed to summarize effective research methods for and potential innovative approaches to VR rehabilitation by evaluating publications from various countries to encourage research on efficient strategies to improve VR rehabilitation.The SCIE (Science Citation Index Expanded) database was searched on January 20, 2022, for publications related to the application of VR technology in rehabilitation research. We found 1617 papers, and we created a clustered network, using the 46,116 references cited in the papers. CiteSpace V (Drexel University) and VOSviewer (Leiden University) were used to identify countries, institutions, journals, keywords, cocited references, and research hot spots.video games (2017-2021), and young adults (2018-2021).A total of 63 countries and 1921 institutes have contributed publications. The United States of America has taken the leading position in this field; it has the highest number of publications; the highest h-index; and the largest collaborative network, which includes other countries. The reference clusters of SCIE papers were divided into the following nine categories: kinematics, neurorehabilitation, brain injury, exergames, aging, motor rehabilitation, mobility, cerebral palsy, and exercise intensity. The research frontiers were represented by the following keywords: Our study comprehensively assesses the current research state of VR rehabilitation and analyzes the current research hot spots and future trends in the field, with the aims of providing resources for more intensive investigation and encouraging more researchers to further develop VR rehabilitation. In recent years, the number of people with rehabilitation needs has increased, particularly among groups of older patients, patients with disabilities, patients with chronic diseases, and patients with functional and cognitive impairments. The loss of movement, sensation, balance, and cognition, as well as other aspects, seriously affects patients’ quality of life, work, study, and social life ,2. Such With the gradual popularization of virtual reality (VR) technology, rehabilitation training systems based on VR technology have been gradually applied in sports, exercise, and functional rehabilitation for various diseases and have achieved positive effect results ,7. The cA comprehensive bibliometric review is required to help researchers focus on future directions based on the new deﬁnitions of VR technologies in rehabilitation, which reveal new situations and requirements. Although bibliometric methods have yielded positive results in a variety of ﬁelds, we found that there is still a significant gap in the research on VR rehabilitation and its development trends by using bibliometric methods.We used bibliometric methods to analyze SCIE (Science Citation Index Expanded) papers on studies related to VR rehabilitation research. Articles from different countries, regions, and research institutions were included. We identified papers in journals, gathered the top 10 citations, and enumerated how many times these citations were used. The VR rehabilitation knowledge base was analyzed by grouping authors’ co-occurring keyword networks. Burst citations were used to identify research hot spots on this topic, which could provide a useful reference for future research . These aVirtual Reality OR VR OR AR OR Augmented Reality. Further, we limited our search to original articles and reviews, and the Web of Science category Rehabilitation was selected. To determine study inclusion, the aforementioned basic information was collected from articles in the WSCC. However, the following papers were excluded: (1) irrelevant proceedings and meetings papers, (2) chapters in books, (3) duplicated articles, and (4) unpublished papers with limited information. In total, 1617 papers were included, with duplicates excluded. The search and analysis procedures are outlined in We created a clustered network, using the 46,116 references cited in 1617 published papers. The data came from the Web of Science Core Collection (WSCC), which was accessed on January 20, 2022. The search covered articles published from 2000 to 2021. The following search string, which included the search terms, was used: We defined most publication traits, including institute, country, journal, and keywords. We used Journal Citation Reports  to identify impact factors, which reflect scientific research value . All datBetween 2000 and 2021, a total of 1617 papers on VR rehabilitation were published. Emerging trends in VR rehabilitation research–related studies are outlined in The analyzed publications included contributions from a total of 63 countries and 1921 institutes. The top 10 countries and institutes are outlined in Archives of Physical Medicine and Rehabilitation was the top journal (publications: n=847), followed by Physical Therapy and Rehabilitation (publications: n=608). Among these journals, Cochrane Database of Systematic Reviews had the highest impact factor (9.266), followed by Stroke (7.914).A total of 241 journals published articles related to VR rehabilitation; the top 10 are outlined in Academic journals represent and reflect knowledge exchange in the research arena, where citing papers form a knowledge frontier and cited papers form a knowledge basis. A journal overlay dual map was assembled, as presented in Effectiveness of Virtual Reality Using Wii Gaming Technology in Stroke Rehabilitation by Saposnik et al [Stroke, was the most highly cited article (cited 58 times); the article verified the effectiveness of rehabilitation for participants with stroke by using Wii  gaming technology. Laver et al [Virtual reality for stroke rehabilitation—on 2011 [Cochrane Database of Systematic Reviews. These studies evaluated the rehabilitation impact of VR technology for patients with stroke in accordance with the status quo in different periods.A citation is a vital bibliometric indicator, with frequently cited studies greatly inﬂuencing their research areas. We list the top 10 most highly cited publications in ik et al , which wer et al ,16 publi—on 2011  and 2015In network research, betweenness centrality reflects node importance in a network; thus, a higher betweenness centrality signifies an important study . The betkinematics, cluster 1 was labeled as neurorehabilitation, cluster 2 was labeled as brain injury, cluster 3 was labeled as exergame, cluster 4 was labeled as aging, cluster 5 was labeled as motor rehabilitation, cluster 6 was labeled as mobility, cluster 7 was labeled as cerebral palsy, and cluster 8 was labeled as exercise intensity.A cocited document–centered clustering investigation was proposed to identify subnodes and connecting nodes in VR rehabilitation. To assess the scientific relevance of publications, we established a network of cocited references . The cluKeywords in similar publications were identified and processed. The top 20 keywords, which had a high link strength, are outlined in video games (2017-2021) and young adults , and Canada published the second highest number of studies . Most of the core research institutions in this field are from the United States and Israel. The US Food and Drug Administration's encouragement of digital therapy innovation is the main reason that the largest number of publications is in North American countries, led by the United States. Israel encourages entrepreneurship in the high-tech industry; as such, 4 of the top 10 universities in this field are in Israel. The most widely read journal was kinematics), cluster 1 (neurorehabilitation), cluster 2 (brain injury), cluster 3 (exergame), cluster 4 (aging), cluster 5 (motor rehabilitation), cluster 6 (mobility), cluster 7 , and cluster 8 (exercise intensity). To this end, we described VR rehabilitation research knowledge bases by using different clusters, with time considerations.In previous studies, different VR-assisted rehabilitation systems were investigated in this field, with remarkable results. As indicated in kinematics cluster, scientists designed a VR rehabilitation system based on kinematics theory to measure, monitor, and predict outcomes; they achieved good results. For example, researchers developed various VR scenes for rehabilitation training for cervical vertebrae injuries; lower limb injuries of athletes; and arm, hand, and trunk movements in patients with stroke. They proposed kinematic evaluation and measurement methods based on the VR environment [For cluster 0, the ironment -26.neurorehabilitation cluster, the research interest in VR technology for neurorehabilitation is increasing. Scientists have experimentally demonstrated the role of VR systems in neural rehabilitation and motor assistance from the perspectives of patients with impaired visuospatial perception after stroke, the augmented effect of intermittent theta burst stimulation on neurorehabilitation programs, and the use of motor imagination in brain-computer interfaces. Therefore, VR programs are considered safe and can be performed with standard neurorehabilitation protocols in patients with neurological conditions [In cluster 1, the nditions -29.brain injury cluster, scientists demonstrated the experimental results of VR training systems for patients with brain injury, for those with acute onset central nervous system damage, and for vocational rehabilitation training from both the experimental perspective and the retrospective perspective. Importantly, most patients were responsive to VR training and showed improvements in gait function, balance control, vocational rehabilitation training, and other aspects [In cluster 2, the  aspects -32.exergame cluster, McMahon et al [In cluster 3, the on et al  investigon et al , in theion et al  demonstraging cluster, several investigations concentrated on upper limb rehabilitation intervention and overall skill improvement for older patients. Molina et al [In cluster 4, the na et al  analyzedna et al ,37.motor rehabilitation cluster, scientists investigated various VR training devices. A team, for example, used VR-enhanced robot-assisted gait training to monitor the gait, motion, balance, fear of falling, and independence of 15 patients with chronic stroke. The researchers observed that cognitive performance and gait speed in tasks improved among study participants (P<.05) [In cluster 5, the  (P<.05) . Maier a (P<.05) , in theimobility cluster, researchers designed remote VR and augmented reality rehabilitation training treadmills to record training data from patients with Parkinson disease or stroke. The experimental results showed that flexibility and balance improved and that VR rehabilitation methods could provide personalized rehabilitation strategies while also improving patient participation [In cluster 6, the cipation ,41. To icipation .cerebral palsy cluster, scientists studied gait, spatial perception exercises, functional mobility, exoskeletons, visuomotor construction, and other aspects of cerebral palsy in children by using data obtained through a VR rehabilitation training system. Bimanual performance and cognitive rehabilitation gains improved significantly during gait rehabilitation [In cluster 7, the litation -45. Furtlitation .exercise intensity cluster, scientists discovered that training factors  could potentially provide training optimization stimuli. de Vries et al [For cluster 8, the es et al  identifies et al  investigKeywords represent current research issues or topical concepts, while emerging trends and research frontiers are represented by burst keywords. We used the CiteSpace program to gather burst keywords and identified 2 scientific frontier areas with the strongest citation bursts—video games (2017-2021) and young adults (2018-2021).We found that VR video games are simple and appealing to patients and therefore encourage patient participation. Measurements and assessments that were taken after testing VR video games with 12 older patients and 13 children with intellectual disabilities showed clinical improvements in motor capabilities and a positive effect on quality of life ,50. Jungyoung adult appeared between 2018 and 2021, indicating that scholars have begun to pay attention to the positive physiological, social, and psychological impacts on teenagers. Fralish et al [VR rehabilitation training research has primarily focused on sport rehabilitation aspects, such as the spine, gait, or balance, with fewer studies on teenagers when compared to studies on adults. The burst keyword sh et al , in a cash et al  proposedIn this study, we used a bibliometric analysis to objectively, comprehensively, and systematically analyze the VR rehabilitation research literature. We identified the knowledge bases, current topical hot spots, and oncoming trends in this area. In this research field, the areas with acceptable knowledge bases included kinematics, neurorehabilitation, brain injury, exergaming, aging, motor rehabilitation, mobility, cerebral palsy, and exercise intensity. We theorize that future emerging trends and frontiers will focus on video games and young adults. We also identified contemporary research topics and future trends in VR rehabilitation research and provided guidance for future research in this exciting area.Although papers that were published at different times were gathered for this study, some were not comprehensive in nature and may have introduced publication bias, thereby affecting study outcomes.Our study still has some limitations to be addressed. Although the WSCC database is reliable, other databases, such as non-English databases, should also be considered to ensure that all relevant papers are collected. Additionally, the rapid progress in the field of VR technology application limits the timeliness of this bibliometric study. Further, the VR-based rehabilitation activities we investigated included some gaming exercises, exergames, and video games that were not clearly defined. Finally, the results of the included studies only reflect current research trends in academia. In the future, VR technology is expected to be further integrated with clinical applications, which will enrich and improve the research in this subject field.


Due to various factors such as the increasing aging of the population and the upgrading of people’s health consumption needs, the demand group for rehabilitation medical care is expanding. Currently, China’s rehabilitation medical care encounters several challenges, such as inadequate awareness and a scarcity of skilled professionals. Enhancing public awareness about rehabilitation and improving the quality of rehabilitation services are particularly crucial. Named entity recognition is an essential first step in information processing as it enables the automated extraction of rehabilitation medical entities. These entities play a crucial role in subsequent tasks, including information decision systems and the construction of medical knowledge graphs.corpus in the field of rehabilitation medicine, and fine-tune Bidirectional Encoder Representation from Transformers (BERT) with the rehabilitation medicine corpus. For the rehabilitation medicine corpus, we use BERT to extract the feature vectors of rehabilitation medicine entities in the text, and use the span model to complete the annotation of rehabilitation medicine entities.In order to accomplish this objective, we construct the BERT-Span model to complete the Chinese rehabilitation medicine named entity recognition task. First, we collect rehabilitation information from multiple sources to build a corpus. The experimental results demonstrate that our method outperforms in recognizing both long medical entities and nested medical entities in rehabilitation medical texts.Compared to existing baseline models, our model achieved the highest F1 value for the named entity recognition task in the rehabilitation medicine The BERT-Span model can effectively identify and extract entity knowledge in the field of rehabilitation medicine in China, which supports the construction of the knowledge graph of rehabilitation medicine and the development of the decision-making system of rehabilitation medicine. With the steady growth of the economy and the continuous improvement of living standards, there is an escalating demand to enhance the quality of life for individuals. In addition to disease prevention, clinical treatment, and physical health care, rehabilitation medicine is receiving growing attention as a crucial approach to assist patients with disabilities in regaining their daily living abilities and enhancing their overall quality of life. According to statistics from a study by The Lancet , China hetc. These methods demonstrate excellent performance with the support of rich corpora. Nevertheless, constructing such corpora requires substantial manual effort, and the corpus-specific features pose challenges in terms of portability and generalizability. With the enhancement of computer computing power and the surge of massive data, deep learning with powerful generalization ability has gradually become a research point in the field of named entity identification.Knowledge graph, as a state-of-the-art technology, plays a pivotal role in transforming complex unstructured data into a structured “entity-relationship-entity” format . This trhttps://www.rehabsociety.org.hk/zh-hans/) and Medical Pulse (https://www.medlive.cn/), no unified research in the field of rehabilitation medicine has been found for the time being. Scattered information about rehabilitation on web pages lacks credibility, so we chose to extract reliable rehabilitation information from thesis literature and books. We first search for CNKI literature (https://www.cnki.net) and authoritative guide books to build a corpus in the field of rehabilitation medicine in a comprehensive and multifaceted way, and use the annotation consistency principle to verify the accuracy of the corpus. In terms of model selection, the BERT demonstrates robust linguistic representation and feature extraction capabilities, and Span can handle long medical entities and nested entities very well. Hence we combine the features of BERT and span to construct the BERT-Span model for the named entity recognition task in the rehabilitation domain. The experimental results indicate that the model achieves a higher F1 score in named entity identification studies in rehabilitation medicine compared to several baseline models.At present, apart from some voluntary forms of rehabilitation communities on the Internet such as, Hong Kong Society for Rehabilitation (The main contributions of this article are as follows:corpus in rehabilitation medicine.(1) In view of the complexity and diversity of rehabilitation medical texts and the remoteness of vocabulary, we have formulated corresponding annotation specifications, adopted BIO annotation method, and have formed a certain scale of (2) Combined with the results of annotation and the knowledge in the field of rehabilitation medicine, we propose the BERT-Span model that is more suitable for the task of Chinese named entity recognition in rehabilitation medicine, which fills the gap in NER in the field of rehabilitation medicine to a certain extent.corpus. Later, corpus for medical named entity recognition. Initially, convolutional neural networks (CNN), recurrent neural networks (RNN), Bi-directional long short-term memory (BiLSTM) and other basic neural networks can achieve good recognition results in NER tasks . Dong etWith the development of the research, the simple neural network model has exposed some problems. For example, global features can not be obtained, and information between long sentences is seriously missing. The concept of weight distribution in attention mechanism can effectively solve such problems. Some scholars commence adding attention mechanism to BiLSTM-CRF for named entity recognition. corpus of the same domain to pre-train word embedding and subsequently fine-tune the pre-training model of the target corpus using the model parameters obtain from the training to overcome the challenge of a small annotated corpus of Chinese clinical entities. Later, with its strong language representation ability and feature extraction ability, BERT make outstanding achievements in the field of named entity recognition  as our retrieval database. Set keywords “stroke”, “rehabilitation” and corresponding synonyms in CNKI advanced search, and select “CSSCI”, “core journals” and “CSCD” literature from 2011–2020. After manual screening, some irrelevant and repetitive literatures were removed, and 160 literatures were derived as partial data sources. Finally, a total of 10,000 corpora are collected from rehabilitation guides and CNKI literature, totaling 612,807 words.Portions of this text were previously published as part of a preprint . Stroke Since there is no unified standard for naming entity identification in the field of rehabilitation medicine, on the basis of our previous experience in entity labeling in the field of medicine and the characteristics of texts in the field of rehabilitation, we divide rehabilitation entities into: “dysfunction and performance”, “rehabilitation assessment”, “rehabilitation methods”, “rehabilitation equipment”, “body” and “drugs” six categories. Among them, the first four categories are summarized from a large number of rehabilitation literature, and the last two categories are obtained by combining the common points of rehabilitation medicine and clinical medicine.corpus, we have built a corpus in the field of rehabilitation medicine. In the context of corpus annotation, the article follows the following specifications for the annotation of four types of entities in rehabilitation medicine: non-overlapping annotation, full foreign language vocabulary not marked, and special symbols and conjunctions can be annotated.Referring to the existing medical corpus. We conduct three rounds of manual annotation and verification, and extract 500, 1,250, and 1,250 corpora respectively, until there are no entities that are difficult to regulate boundaries or ambiguous categories in the annotation process. For the 2,500 corpora in the last two rounds, we randomly select 500 corpora and submit them to the second person to label independently. The results of the two labels on the 500 corpora are compared and evaluated according to the Inter annotator Agreement (IAA) principle  pre-training technique. By employing multiple deep bi-directional Transformers, BERT generates deep bi-directional language representation vectors that capture contextual information. These vectors serve as text features and enable BERT to extract meaningful representations from the input sentences.There are a greater number of long medical entities and nested medical entities in rehabilitation medicine texts. Sequence annotation can only be assigned to the BIO tag corresponding to each token, and becomes insufficient when appearing nested entities. Some researchers propose an idea referring to machine reading comprehension (MRC) model framework technology , specifiThe Span model uses double sequence tagging in the decoding process. One sequence is used to mark the start position of all entities, and the other sequence is used to mark the end position of all entities. Two linear layers are used for decoding operations. Decoding operation using two linear layers to extract the head and tail part of the entity.Since there may be multiple entities belonging to the same category in the input text, the model will get several start indexes and end indexes simultaneously during decoding. Hence the model needs to match the decoded start index and end index appropriately. We complete the matching of the start and end index of the entities using the binary classifier. The classifier inputs the possible start and end index of the entity in the sentence and outputs 0 or 1 to indicate whether it matches or not. The formula in Span is as follows:Obtain the representation matrix E from the output of BERT, the model first predicts the probability of each token as the starting index P denotes the model prediction probability and Y is the sample label. The weighted sum of these three loss components is the final overall loss value, where α, β, and γ are the model hyperparameters. The specific formula is as follows:The loss function L consists of three parts: the entity start position loss function https://github.com/jamesXuan/BERT-Span.In this section, we compare our propose model with several baseline models and analyze the superiority of our approach from different perspectives. For our model, we try to explore the properties of entities in rehabilitation medicine texts from the perspective to further explore the performance of the model for text processing in the Chinese rehabilitation medicine domain. BERT-softmax and BERT-BiLSTM-CRF are the most widely used baseline models in the field of named entity recognition at the present time, and are also the comparison models chosen for this experiment. During the experiment, we use Adam optimizer with initial learning rate of P, recall rate R and F1 value, where, precision rate P refers to the probability of the actual correct samples among all the samples predicted to be correct; recall rate R refers to the probability of the predicted samples being correct among the actual correct samples; F1 value is the summed average of recall rate and precision rate, and the calculation formula is given in:We use the most commonly used evaluation metrics in the field of named entity recognition: precision rate corpus for the rehabilitation named entity recognition task. To mitigate the potential impact of a small dataset leading to significant experimental errors, a 5-fold cross-validation is employed.It can be seen that with the auxiliary of the pre-trained language model BERT, these models generally have better results for the recognition of named entities in rehabilitation medicine. On this basis, BiLSTM-CRF is advantageous for entity recognition compared to softmax, where the former focuses more on the global information of the sequence. BERT-BiLSTM-CRF outperforms BERT-softmax in terms of recall (R) and F1-score metrics. In addition, there are long medical entities and nested medical entities in the field of rehabilitation medicine, and CRF is difficult to distinguish them because of the limitation of its own structure and cannot play a good effect, while Span can solve this problem well, so the BERT-Span model achieves the optimal effect for the recognition of named entities in the field of rehabilitation medicine.corpus sizes on model performance. The BERT-Span model was first used to predict the annotation of 7,500 unannotated data, and a total of 2,500 manually annotated data and 7,500 model annotated data were obtained. Among the 2,500 manually labeled data, 1,250 data were randomly selected as a common test set for two sets of experiments. The first set of experiments uses the remaining 1,250 manually labeled data as the training set; the training set of the second set of experiments consists of the first training set and 7,500 model labeled data.From the table, it is clear that the performance of all three models is significantly improved after increasing the data size of the training set. In terms of F1 metrics, BERT-softmax increases by 1.7%, BERT-BiLSTM-CRF increases by 1.37%, and BERT-Span has the highest increase of 1.8%. The amount of data is still an important factor limiting the performance of the model. Notably, the BERT-Span model consistently achieves optimal performance in the named entity identification task within rehabilitation medicine, both before and after the dataset expansion.As can be seen from the table, there are considerable differences in the recognition effects of different entities. The identification accuracy of rehabilitation assessment, rehabilitation methods, rehabilitation equipment, and body was low, with F1 values below 90%, where the identification effect of rehabilitation equipment was the worst, with an F1 value of 85.29%. The recognition accuracy of dysfunction and performance, and drug entities was higher, with F1 values over 90%, and “dysfunction and performance” had the best recognition effect, with an F1 value of 93.07%.The size of the dataset and the distribution of the labels have an impact on the final prediction results of the model. Therefore, we try to explain the variability of identification results between different classes of entities in terms of these two aspects.We collated the number of each entity in the dataset, the number of low-frequency entities (the number of entity occurrences is 1), and the percentage of low-frequency entities in the total number of entities, as shown in corpus, while the two types of entities “drug” and “body” exist in clinical medicine, and they can obtain some feature information in advance. The four entities of “dysfunction and performance”, “rehabilitation assessment”, “rehabilitation methods”, and “rehabilitation equipment” exist only in the field of rehabilitation medicine and can only learn feature information during model training. Therefore, although the low frequency of “drug” is as high as 32% as the low frequency of “rehabilitation equipment”, the drug has learned some of its characteristic information in advance, so it still has a high recognition effect. It can be expected that dealing with the low-frequency word problem will have further improvement on the performance of the model.We can see that “dysfunction and performance” has the lowest percentage of low frequencies. The model can extract the feature information of these entities more accurately and give correct prediction results. The highest percentage of low frequencies for “rehabilitation equipment” indicates that most of the data of “rehabilitation equipment” entities only appear once in the data set, and the model cannot obtain their feature information well enough to give high prediction accuracy. Meanwhile, the BERT pre-training model we use is based on the general clinical medicine corpus, which solves the problem that there is no ready-made corpus available in the field of rehabilitation medicine. To avoid the influence of long medical entities and nested entities on Chinese named entity recognition in rehabilitation medicine, we proposed the Bert-Span model, using span tokens instead of traditional CRF sequence tokens. The experimental results demonstrate that the BERT-Span model is more suitable for named entity recognition studies in rehabilitation medicine compared with the BERT-Softmax and BERT-BiLSTM-CRF baseline models.Named entity recognition in rehabilitation medicine is an important step in many rehabilitation text information extraction tasks. In order to advance the research of named entity recognition in rehabilitation field, we collect data from various ways, discuss the scheme with rehabilitation physicians, and build a rehabilitation corpus, and its effectiveness on Chinese NERs from other rehabilitation datasets needs further validation. On the other hand, the performance of the model on named entity recognition tasks in other language rehabilitation domains is unclear.However, there are some limitations of our study. On the one hand, we have only validated the performance of the Chinese rehabilitation medicine named entity recognition task on a self-built In the future, we would apply our model to the actual rehabilitation medicine text annotating tasks, so as to help build the knowledge graph of rehabilitation medicine. Moreover, we plan to extend our approach to other relevant rehabilitation medicine text datasets to further validate and improve the model’s scalability and generalization capabilities.


Early surgical closure is warranted to prevent aortic valve lesion and aortic regurgitation (AR) in intracristal ventricular septal defects (icVSDs). Experiences for transcatheter device closure of icVSDs are still limited. Our objectives are to investigate AR progression following transcatheter closure of icVSDs in children and to explore the risk factors for AR progression.P = 0.001] and the ratio of pulmonary to systemic blood flows  were independent predictors for AR progression.From January 2007 to December 2017, 50 children with icVSD who had successfully undergone transcatheter closure were enrolled. With 4.0 (interquartile range: 3.0–6.2) years of follow-up, AR progression was observed in 20% (10/50) of patients after icVSD occlusion, among which 16% (8/50) remained in mild level and 4% (2/50) evolved to moderate. None progressed to severe AR. Freedom from AR progression was 84.0%, 79.5%, and 79.5% at 1, 5, and 10 years of follow-up. A multivariate Cox proportional-hazards model revealed that x-ray exposure time [hazard ratio (HR): 1.11, 95% confidence interval (CI): 1.04–1.18, Our study suggested that transcatheter closure of icVSD in children is safe and feasible in mid- to long-term follow-up. No serious AR progression occurred after icVSD device closure. Greater left-to-right shunting and longer x-ray exposure time were both risk factors for AR progression. Infundibular ventricular septal defect (VSD) is historically named as subarterial, supracristal, subpulmonic, or conal VSD –5. Due tPercutaneous transcatheter device closure has increasingly been accepted as an alternative to surgical repair in selected cases of VSD , especiaTo this day, it is technically feasible to close intracristal VSDs (icVSDs) with various devices, with reported success rates of 79%–94% –14. PeriFrom January 2007 to December 2017, 50 children (<18 years) with icVSD that were successfully closed percutaneously were enrolled in this study. Significant left-to-right shunt was the most important indications for interventional occlusion. Most of the children met at least one of the following criteria: (a) failure to thrive; (b) recurrent respiratory infections; (c) cardiomegaly on chest x-ray; (d) enlargement of left atrial and/or left ventricle on transthoracic echocardiography (TTE); (e) AVP already existed. Exclusion criteria were as follows: (a) combined with other congenital heart defects if simultaneous surgery were needed; (b) severe pulmonary artery hypertension or right to left shunt; (c) congenital aortic valve malformations, such as bicuspid aortic valve; (d) moderate-to-severe AR; (e) sepsis; (f) body weight <10 kg, and (g) contraindication to antiplatelet therapy. The study was approved by the Research Ethics Committee of the Guangdong General Hospital (No. GDREC2020213H).IcVSD was preoperatively diagnosed on TTE . In paraThe distance between VSD and right coronary cusp was determined by both TTE and angiography. A deficient rim to the aortic valve was defined as the distance <2 mm, and a sufficient rim was ≥2 mm.Multiple types of devices were used in this study. They were all modified double-disk occluders made from nitinol wire. Both symmetric and eccentric shape VSD occluders were manufactured by LifeTech Scientific, Shenzhen, China, or by Starway Medical, Beijing, China. Amplatzer Duct Occluder (ADO) I or II devices  were also used in selected cases.All patients underwent routine left and right cardiac catheterization. TTE was performed preoperatively. Left ventriculography and aortic root angiography were both performed to confirm the relationship between the aortic valve and icVSD. Thereafter, an appropriate occluder was selected according to the size and morphology of icVSD, sufficiency or deficiency of the superior rim to the aortic valve, as well as the presence or absence of AVP. Typically, the original selected size was 2–3 mm larger than the defect. If the superior rim is sufficient, the symmetric occluder was selected. Otherwise, the eccentric occluder was preferred. In very small defects, ADO II might also be an alternative. Before the release of the occluder, left ventriculography and aortic root angiography, as well as TTE, were repeated to confirm the appropriate position of the device without influence on the morphology and function of the aortic valve. TTE was also performed to monitor the whole procedure.All patients were carefully followed after occlusion. Standard 12-lead electrocardiography and TTE were regularly followed up at 1 day, 1 month, 3 months, 6 months, and 12 months after the procedure, and every 1–2 years thereafter. All patients received oral aspirin at 3–5 mg/kg per day for 6 months after the procedure.Qp/Qs), indexed pulmonary vascular resistance (PVRI), x-ray exposure time, device sizes, and device types. Device types were based on their geometric shape: (1) eccentric type: VSD occluder; (2) other types included symmetric-type VSD occluder and ADO I/II.Clinical data were collected from chart review. The first author was responsible for data acquisition (QL), including patient demographics, echocardiographic parameters, transcatheter procedural data, and other associated complications. Echocardiographic parameters included VSD size, left ventricular end-diastolic diameter (LVEDD), left ventricular ejection fraction (LVEF), the presence or absence of AVP, AR, residual shunt, and AR severity. Transcatheter procedural data included mean pulmonary arterial pressure (mPAH), pulmonary to systemic flow ratio  and 95% confidence interval (CI). P values <0.05 were defined as statistically significant. All statistical analyses were performed with SPSS 21.0 .We expressed categorical variables as percentages while continuous variables as median  or mean . Comparison of categorical variables was analyzed using the Chi-square test or Fisher's exact test. Two-sided unpaired Student’s The median follow-up durations of all icVSD children were 4.0 (IQR: 3.0–6.2) years. The follow-up rate is 98.0%, 84.0%, 84.6%, and 81.3% at 1-year, 3-year, 5-year, and 7-year periods .Qp/Qs was 1.57 (SD: 0.46). AVP was recorded in 45 (90%) patients, among whom 25 (55.6%) had both right coronary cusp prolapse (RCP) and noncoronary cusp prolapse (NCP), 14 (31.1%) had RCP only, and 6 (13.3%) had NCP only. 8.9% (4/45) of icVSD with AVP developed mild AR before occlusion. For devices used, 54.0% (27/50) were eccentric-type occluders, 36.0% (18/50) were symmetrical type, and other devices used were ADO I (4/50) and ADO II (1/50).The baseline characteristics are demonstrated in AR progression was demonstrated in Qp/Qs, the size of selected occluder, and x-ray exposure time were significantly associated with AR progression. Age or weight at presentation, AR before occlusion, VSD size by TEE, and occluder type (eccentric vs. other types) were not predictive of AR progression. A multivariate Cox proportional-hazards model revealed that x-ray exposure time  and Qp/Qs  were independent risk predictors for AR progression. Patients with exposure time longer than 20 min had almost 10-fold risk of AR progression compared with those less than 20 min    . Patient = 0.01) .Residual shunt was observed in six cases immediately after occlusion but all disappeared during follow-up. Four patients experienced transient arrhythmias  intraoperatively or postoperatively, which resolved spontaneously and did not recur. Two patients had new-onset incomplete right bundle branch block after procedure. Neither death nor surgical operation occurred due to complications following transcatheter intervention.Aortic valve lesions are common in the natural history of outlet VSDs –7, 17–20In this study, we thoroughly detected the presence of aortic valve lesions and the potential AR progression after transcatheter closure of intracristal VSDs in children in mid- to long-term follow-up. In our series, 90% of patients had AVP and four had mild AR before VSD closure, which is consistent with the notion that aortic valve lesion is common in the natural history of outlet VSDs. Several studies in pediatric cohorts with outlet VSDs suggested that the risk of evolving aortic insufficiency increases during childhood, and the peak age of the emergence of AVP and AR was between 5 and 10 years, respectively –20. TherTraditionally, open-thoracic surgery is the exclusive option for outlet VSD patients , 24. WitPrevious researchers made initial transcatheter attempts in icVSDs, with acceptable success rates and in early-to-mid-term follow-up results –14. DeviUp to date, however, data are limited with regard to the mid- to long-term results of aortic valves, and most cases included in the above studies were adults , in a relatively short follow-up period of time. Experiences in pediatric patients are scarce. Our study was the first report in children with transcatheter intervention, mostly at preschool ages. This time of point is before the peak age of the emergence of aortic valve lesions in natural history –20, whicQp/Qs, and longer x-ray exposure time. After that, we further identified that both higher Qp/Qs and longer x-ray exposure time are independent risk factors for AR progression. One explanation for these results is that the prolapsed right coronary cusp usually covers the defect, resulting in an increased measurement error, which not only affects the selection of device but also increases the procedural difficulty, especially in those with larger VSDs. On the other hand, the more difficulty we faced in the procedure, the more time of exposure was needed under fluoroscopy. Also, prolonged manipulation of catheters and guide wires around the aortic valve might increase the risk of damage to the leaflets, which could contribute to postoperative AR progression. Our results suggested that no more than 20 min of exposure time may decrease AR progression. Skilled manipulation techniques could not only reduce the x-ray radiation exposure but also reduce the risk of AR progression. When Qp/Qs > 1.8, transcatheter intervention should be performed with great caution. If guidewire tracking for intervention needs to be established several times or larger occluders need to be sequentially attempted, transcatheter intervention should be aborted and surgical thoracotomy may be considered.Up to now, no research study had reported any predictors of post-occlusion AR progression in icVSD. We first discovered that three factors are associated with AR progression after device closure: bigger occluder size used for VSD closure, Two cases in our series developed moderate AR during follow-up. They both used symmetrical type VSD occluders. This reminded us that the symmetrical occluder should be avoided in icVSD. Moreover, careful evaluation of the relationship between the occluder and aortic valve, as well as their positions and shapes, should be repeated by TTE and angiography before occluder release. We noticed that the eccentric occluder led to less structural deformity to aortic valve, although the rate of AR progression was not decreased in this group. Based on these experiences, we believe that an eccentric occluder might be more suitable for icVSD closure, which is consistent with experiences from the report of Chen et al. . RecentlIn our study, neither significant residual shunting nor severe arrhythmias were demonstrated. This is comprehensible because icVSD is anatomically in the region of muscular outlet and relatively far from the bundle of His and bundle branches. So, device-related arrhythmias were not common in transcatheter icVSD closure and could be a minor problem of concern. This is also consistent with other series that included adults –14.Our study has limitations. First, this is a single-center retrospective study with a relatively small sample in pediatric population. Comparison with surgical intervention was not performed. So, we could not know if transcatheter device closure could replace surgical repair in selected cases. Second, occluder selection was based on previous experiences extrapolated from perimembranous VSDs, and no uniform criteria were employed in our study. So, comparison between differential types of occluders was not accurate. We could not reach a conclusion as to which type of occluder is better. Further multicentered randomized controlled studies are needed to solve these questions.Our study demonstrated that the incidence of AR progression after percutaneous transcatheter device closure of icVSD in preschool pediatric patients is no higher than that in previously reported adult cohorts. The majority of AR remained unaltered at mild level and only few cases developed to moderate. No severe AR occurred and neither valvuloplasty nor valve replacement were needed during mid- to long-term follow-up. We also identified that greater left-to-right shunting and longer x-ray exposure time were both independent risk factors for post-occlusion AR progression. Our results suggested that transcatheter closure of icVSD in preschool children is safe and feasible in mid- to long-term follow-up. We recommend performing this procedure in experienced tertiary cardiac centers.


Abyssal channels are the key points controlling bottom circulation of the World Ocean. They provide meridional transport of the coldest Antarctic Bottom Water between deep-water basins influencing the meridional overturning circulation and the climate on a global scale. Here we show that the synoptic variability of deep-water flows including blocking abyssal currents between deep ocean basins is related to sea level anomalies observed over the channels. Our results demonstrate that processes at the ocean surface have a more significant connection with the bottom circulation than it was considered earlier. This study opens a discussion of the importance of mesoscale eddies and air-sea interactions on water exchange between abyssal basins, meridional heat transport in the ocean, and possible responses of the ocean to the observed sea level rise in a changing climate. Significant variability of the bottom currents at the synoptic time scale was documented almost in all studied abyssal channels12.Abyssal currents as well as their temporal variability remain the less studied part of the World Ocean circulation: they are invisible from satellites, not covered by most autonomous ocean platforms, and rarely simulated by numerical models. Thus, most studies of deep-water circulation rely on very expensive and time-consuming observations from research vessels. Unlike surface currents, the abyssal circulation is significantly influenced by bottom topography: deep-water passages, channels, troughs, and fracture zones are the key points providing the transport of Antarctic Bottom Water (AABW) between ocean basins. Monitoring of bottom currents at these key points provides data on abyssal water exchange between deep ocean basins14. This water mass occupies more than one-third of the entire volume of the World Ocean15; its northward propagation is a major component of the ocean thermohaline circulation; AABW affects the Earth climate on a global scale14. One of the most studied abyssal passages of the World Ocean is the Vema Channel connecting the Argentine and Brazil Basin in the Southwest Atlantic18  relative to the mean sea level. The mooring was deployed at the core of the abyssal flow; the LADCP data shown in Fig. 2.Despite the fact that the described idea of the relation between sea level anomalies and bottom flows is quite obvious, the spatial and temporal scales of this influence are not clear. That is why we combined daily satellite gridded altimetry maps33. The mesoscale eddies which cause the studied anomalies were quite weak. The extreme values of the sea level anomalies (− 18 and 31 cm) were low; for example, the cyclonic and anticyclonic eddies located at the Brazil-Malvinas Confluence zone at approximately 40° S, 55° W caused sea level anomalies up to 100 cm34. However, even mesoscale eddies of relatively low intensity at the entrance to the Vema Channel were related to the observed correlation.In order to evaluate spatial extents of studied sea level anomalies, the SLA maps are presented in several cases of extremely high and low velocities in the Vema Channel Fig. . In thesDirect velocity measurements carried out on moorings provide long-term velocity time series, which is important for studies of temporal variability of abyssal flows. However, the spatial resolution of such data is usually low due to high cost and logistical problems in deployment and recovery of moored deep-water stations. Comparing to the velocity measurements performed at moorings, the LADCP data provide fine cross-channel structure of the abyssal flow. Two LADCP sections across the Vema Channel on April 6, 2017 and October 26, 2018 are presented in Fig. 36. In the case of the Vema Channel, the relatively thick layer of dense AABW in the Argentine Basin and relatively thin layer of AABW in the Brazil Basin lead to the pressure difference which forces abyssal waters through the channel. It is natural to assume that variations in this pressure difference lead to variations in abyssal current velocity. Here we suggest that these abyssal pressure variations are related to sea level anomalies at the entrance to the Vema Channel. We assume that variations in the sea level over the entrance are connected with abyssal pressure variations  which are sufficient for the observed changes in abyssal velocity. Unfortunately, there are no in situ temperature and salinity data along the studied abyssal flow which provide accurate data on abyssal pressure gradient because measurements at such depths are extremely rare. However, the observed correlation between the SLA and abyssal velocity indicate that the suggested mechanism is at least not negligible and should be considered in studies of abyssal ocean variability. Moreover, our study shows the exact locations where direct temperature and salinity measurements should be made for accurate evaluation of the abyssal pressure gradient and its influence on bottom currents; we hope that this is helpful for future expeditions which are repeatedly carried out in this region (see for example a review in ref14). One of the proofs that the intense mesoscale eddies can be related to the variations in abyssal pressure field is presented in direct LADCP measurements carried out in the Brazil-Malvinas Confluence zone38. In particular, velocities in the presence of mesoscale eddies reach 50 cm/s at a depth of 3000 m and deeper indicating significant variations in abyssal pressure gradients and corresponding velocity field.The observed correlation between abyssal velocity and surface sea level anomalies does not provide a dynamical explanation of the bottom current variability itself. However, it is well-known that the along-channel pressure gradient is the main force which moves abyssal waters from one deep ocean basin to anotherThe observed correlation provides another insight to the dynamics of the abyssal flow in the channel. One can assume that there are two types of pressure gradient which affect velocity: the local cross-slope pressure gradient and bulk meridional pressure gradient along the entire channel. Our study shows that the meridional pressure gradient is more important. The local cross-channel pressure gradient could be significant in case of the geostrophic flow, where changes in the lateral pressure gradient directly affect the geostrophic velocity. However, the abyssal flow in the Vema Channel is ageostrophic which makes this effect not as important as the along-channel pressure gradient. We also calculated correlation maps between abyssal velocity and local meridional and zonal SLA gradients  to approximately 30 cm/s on average. After this fast flow forms, it possesses significant amount of kinetic energy which cannot rapidly disappear in the channel. That is why local sea level anomalies over the mooring and downstream the channel cannot change the abyssal velocity. At the same time, the sea level anomalies at the entrance to the channel are important and negative SLA can be related even to the blocking events discussed above. These blocking events should rearrange the flow in the northern Argentine Basin; however, due to low velocities and short duration of the blocking events it is unlikely that these changes are measurable. Further measurements are needed for clarification of these processes.The location of the high-correlated area is quite surprising at first glance. However, this effect may be simply explained because the area is located at the entrance to the Vema Channel where the abyssal current forms. Around this location, the velocity of abyssal flow changes from several millimeters per second . These data have a spatial resolution of 0.25° and a daily temporal resolution and includes data from all available altimeters at any given time. This product contains different types of altimetric data: Absolute Dynamic Topography (ADT), Sea Level Anomalies (SLA), and zonal and meridional components of computed surface geostrophic velocities. Though gridded altimetry data are provided with a daily resolution, the satellite revisit time is approximately 9.9 days or longer, depending on the platform. Thus, altimetry derived products do not capture SLA fluctuations typically shorter than the satellite revisit time.Data on the Sea Level Anomalies (SLA) have been taken from the satellite altimetry gridded product29. The map of correlation between the SLA and abyssal velocity time series was calculated separately for each point of the satellite altimetry grid. At each point, the Pearson correlation coefficient was calculated between 3.4-year long time series of SLA data at this point and moored velocity time series at 31.25° S, 39.32° W of the same length; the velocity data were taken from the recorder deployed at a depth of 4500 m.Velocity measurements in the abyssal ocean layer were performed at two moorings positioned 12.4 km apart. The moorings were deployed close to the eastern  and western  walls of the Vema Channel providing data on the cross-channel velocity structure. Two stages of measurements interrupted by a three-day service interval in the middle of the time series were carried out between 2003 and 2007. The total records last 3.4 years; sampling interval was set to two hours. Both acoustic current meters and Aanderaa meters with rotors were used for these measurements. A more detailed description of the data from moorings is presented in refAkademik Sergey Vavilov” of the Russian Academy of Sciences. The raw LADCP data were processed using the LDEO Software version IX.1042; the TPXO9 model43 was used for estimating the barotropic tidal velocities and subtracting of these velocities from the measured data at the moment of measurements.Distribution of meridional velocity component shown in Fig. 44. This model was adjusted for simulations in the region of the Vema Channel with high spatial resolution46. The model is based on the full system of primitive thermo-hydrodynamic equations in spherical coordinates with the hydrostatic and Boussinesq approximations. The INMOM uses a vertical coordinate σ = σ scaled by the depth of the ocean at the given point. Zero velocity and sea surface fields, and temperature and salinity fields from the climatological World Ocean Atlas were specified as initial conditions. These data were also used in a buffer zone with a width of 10 points at the liquid boundaries.Modeled bottom circulation presented in Fig. Supplementary Figures.


Developmental and epileptic encephalopathies are rare, treatment-resistant epilepsies with high seizure burden and non-seizure comorbidities. The antiseizure medication (ASM) fenfluramine is an effective treatment for reducing seizure frequency, ameliorating comorbidities, and potentially reducing risk of sudden unexpected death in epilepsy (SUDEP) in patients with Dravet syndrome and Lennox-Gastaut syndrome, among other rare epilepsies. Fenfluramine has a unique mechanism of action (MOA) among ASMs. Its primary MOA is currently described as dual-action sigma-1 receptor and serotonergic activity; however, other mechanisms may be involved. Here, we conduct an extensive review of the literature to identify all previously described mechanisms for fenfluramine. We also consider how these mechanisms may play a role in the reports of clinical benefit in non-seizure outcomes, including SUDEP and everyday executive function. Our review highlights the importance of serotonin and sigma-1 receptor mechanisms in maintaining a balance between excitatory (glutamatergic) and inhibitory (γ-aminobutyric acid [GABA]-ergic) neural networks, and suggests that these mechanisms may represent primary pharmacological MOAs in seizures, non-seizure comorbidities, and SUDEP. We also describe ancillary roles for GABA neurotransmission, noradrenergic neurotransmission, and the endocrine system . Dopaminergic activity underlies appetite reduction, a common side effect with fenfluramine treatment, but any involvement in seizure reduction remains speculative. Further research is underway to evaluate promising new biological pathways for fenfluramine. A better understanding of the pharmacological mechanisms for fenfluramine in reducing seizure burden and non-seizure comorbidities may allow for rational drug design and/or improved clinical decision-making when prescribing multi-ASM regimens. ASMs can act through different pathways and subsequently increase neuronal inhibition and/or decrease neuronal excitation. A primary mechanism of many ASMs is by sodium channel blockade and/or enhancement of neurotransmission by γ-aminobutyric acid (GABA)  . The devd (GABA) .Nonetheless, about one-third of patients with epilepsy are unable to achieve seizure control on their current ASM regimens  i.e., p. DEE canhttps://clinicaltrials.gov/ct2/show/NCT05232630) , an ASM with mechanisms of action unique among ASMs , which i5232630) .via activity at serotonin  receptors and inhibits excitatory signaling through sigma-1 (σ1)-mediated mechanisms, thereby restoring the balance between inhibition and excitation (FFA’s mechanisms of action have been studied extensively. High-dose FFA (60–120 mg/day) was originally marketed as an anti-obesity drug that reduced food intake through serotonergic activation of hypothalamic energy homeostasis circuits. With the discovery of its potent antiseizure properties , low-doscitation . Nonethecitation , includicitation  and reducitation .Since there is currently no clear, comprehensive overview regarding FFA’s pharmacological mechanisms in the literature, our aim was to concisely summarize all the known mechanisms of FFA on seizures and ancillary mechanisms that may be related to seizure control, as well as consider additional mechanisms of its observed clinical benefit in non-seizure comorbidities and survival. Our PubMed search (July 2022) retrieved 622 articles, of which 79 contained relevant information regarding the mechanisms of FFA.The proposed mechanisms of fenfluramine at the synaptic level of neurotransmission in the context of DEEs are presented in via multiple mechanisms  is a racemic mixture of levo-FFA and dextro-FFA . Both enchanisms . Dextro-chanisms . Subsequchanisms . In addichanisms .in vitro ; 2) decrease of 5-HT reuptake by inhibition of 5-HT transporters (SERT); 3) increase of release and fusion of synaptic vesicles (filled with 5-HT); 4) 5-HT increase in the synaptic cleft—via (2) and (3)—and subsequently stimulation of different 5-HT receptor subtypes and 5) direct stimulation of at least four.As summarized in a prior review , the ser5-HT receptor subtypes , which increases GABA inhibitory input and decreases glutaminergic excitatory output.in vitro and in vivo studies underlined these positive modulatory effects of FFA, which were related to their antiseizure activities (FFA has high (sub-micromolar) affinity for the σ1 receptor . Contradtivities  and potetivities . The reativities .via mediating the σ1 interaction with the NMDA receptor that leads to a dampening of calcium influx and decreasing seizure activities at glutaminergic synapses. Modulation of these calcium fluxes (in the endoplasmic reticulum via a Gq/inositolphosphate3-receptor mediated mechanism) is also under the control of serotonergic neurotransmission. σ1 receptor-client protein interactions initiate a host of signal transduction cascades, including other ion channels besides NMDA , as well as interaction with trophic factor receptors and kinases. Finally, the interaction with Rac-GTPases promotes dendritic spine formation and affects neuronal redox processes, which likely contributes to its antiseizure  . Howeverin vitro (>10 µM), dextro-FFA can stimulate alpha 1-adrenergic receptors, resulting in a metabolic shift from glucose production (gluconeogenesis) to glycose degradation (glycolysis), which is mediated by a change in glucose 6-phosphate . Selectectively , arguingectively  and ratsectively . This deectively . Of inteectively  and evenectively , there cectively . Taken tFFA targets several neuropeptides, even though the exact role of these neuro-endocrinological activities remains elusive. First, FFA increases prolactin in humans  and primSecond, 5-HT release by FFA stimulates 5-HT2C receptors in proopiomelanocortin (POMC) neurons of the hypothalamic melanocortin system that regulate energy homeostasis and feeding . The melThird, dextro-FFA specifically activates oxytocinergic and vasopressinergic neurons in the rat brain . The balFourth, Martin et al. (2022) demonstrated that positive modulation of FFA and the dextro-FFA enantiomer (but not the levo-enantiomer) on σ1 receptors reversed dizocilpine-induced amnesia in rodent models, while norfenfluramine (both dextro- and levo-isomers) acted as an antagonist at σ1 receptors . FurtherIn summary, data to date suggest that the effects of FFA on hormones associated with the HPA  or oxytocin/vasopressin are most likely to affect food intake, with only weak or speculative evidence for involvement in antiseizure properties. Neuroactive steroids  are attractive candidates for further investigation.Clinical and preclinical data support that FFA treatment may positively impact non-seizure comorbidities in addition to improving seizure control in patients with DEEs . First, Second, FFA improved everyday executive functioning, including regulation of emotions and behavior, in some patients with Dravet syndrome  and LGS Current therapeutic approaches to treating severe DEEs support targeting multiple mechanisms to optimize clinical efficacy. Rationally designed ASMs have targeted a single receptor or pathway . More re