Subsequent analysis of candidate genes that alter the misfolding of human α-synuclein (α-syn) and dopaminergic neurodegeneration, two PD pathologies, reveal that reduced expression of xdh-1, the ortholog of human xanthine dehydrogenase (XDH), is protective against α-synuclein-induced dopaminergic neurodegeneration. Further, RNAi experiments show that WHT-2, the worm ortholog of the human ABCG2 transporter and a predicted interactor of XDH-1, is the rate-limiting factor in the ADR-2, XDH-1, WHT-2 system for dopaminergic neuroprotection. In silico structural modeling of WHT-2 indicates that the editing of one nucleotide in the wht-2 mRNA leads to the substitution of threonine with alanine at residue 124 in the WHT-2 protein, changing hydrogen bonds in this region. Thus, we propose a model where wht-2 is edited by ADR-2, which promotes optimal export of uric acid, a known substrate of WHT-2 and a product of XDH-1 activity. In the absence of editing, uric acid export is limited, provoking a reduction in xdh-1 transcription to limit uric acid production and maintain cellular homeostasis. As a result, elevation of uric acid is protective against dopaminergic neuronal cell death. In turn, increased levels of uric acid are associated with a decrease in ROS production. Further, downregulation of xdh-1 is protective against PD pathologies because decreased levels of XDH-1 correlate to a concomitant reduction in xanthine oxidase (XO), the form of the protein whose by-product is superoxide anion. These data indicate that modifying specific targets of RNA editing may represent a promising therapeutic strategy for PD.Differential RNA editing by adenosine deaminases that act on RNA (ADARs) has been implicated in several neurological disorders, including Parkinson’s disease (PD). Here, we report results of a RNAi screen of genes differentially regulated in  Mitochondrial dysfunction is an important factor contributing to PD, occurring when there is an imbalance among reactive oxygen species (ROS) and antioxidants, resulting in cellular stress. Inhibition of complex I in the mitochondrial electron transport chain induces enhanced ROS generation  were used to knockdown genes in all tissues, excluding neurons, which are inherently resistant to RNAi due to low expression levels of the sid-1 gene, encoding the SID-1 dsRNA transporter needed to confer systemic RNAi sensitivity. UA196 {sid-1(pk3321);Pdat-1::sid-1, Pmyo-2::mCherry; Pdat-1::GFP, Pdat-1::α-syn} is a specialized RNAi-sensitive strain, previously generated in our lab to facilitate the knockdown of genes in dopaminergic neurons only by the selective dopaminergic expression of sid-1 in mutant animals that are otherwise depleted of sid-1 {sid-1(pk3321)} .Three stable lines of worms, overexpressing (xdh-1(ok3134)) and RB886 (adr-2(ok735)). BY250 (vtIs7[Pdat-1::GFP]), kindly provided by Randy Blakely, as well as UA457 (adr-2(ok735); ). Animals with the adr-2(ok735) mutant allele were a gift from Heather Hundley. Genetic crosses to generate new worm strains used in this study are summarized in Other strains used in this study include RB2379 C. elegans do not yet produce ovum; once ova are produced, the body wall muscles are thin and are not suitable for scoring. For each gene, two replicates of forty worms each were immobilized with 2 mM levamisole, transferred onto an agarose pad, and they were analyzed via fluorescent microscopy. The body wall muscles in the center of the worm were analyzed in all animals. The sizes of misfolded proteins were categorized as small, medium, or large, and the number of aggregates were denoted as few, multiple, or many. These categories were then quantified by multiplying by 1 for small or few, 2 for medium or multiple, and 3 for large or many to obtain a scaled score for size and number. These scores were added together to obtain an overall aggregate score, and the percent difference of each experiment compared to the empty vector (EV) control was determined.RNAi by feeding was performed, as described . BrieflyGene enrichment analysis was performed to identify tissues, phenotypes, and gene ontology (GO) terms associated with the annotations of candidate genes. All analyses were performed using the WormBase enrichment suite .dat-1::α-syn and Pdat-1::α-syn + xdh-1(ok3134)). However, for non-RNAi experiments, worms were grown on OP50-1 bacteria.RNAi by feeding was performed  in UA44 of the three stable lines of worms overexpressing xdh-1 under control of the Pdat-1 promoter in a UA44 background  were analyzed. Specifically, three replicates, consisting of 30 worms of each of three stable lines, were analyzed, as described above; however, worms were scored 4 days post hatch. This day was chosen because our neuronal PD worm models exhibit time-dependent neurodegeneration, and we have observed that enhanced neurodegeneration is best observed in younger adult worms. Data from analysis of three replicates from each of the three stable lines  on a glass coverslip. The coverslip with the worms in levamisole was inverted and placed on a 2% agarose pad attached to a microscope slide, paralyzing worms to allow for visualization. Fluorescence microscopy was performed with a Nikon Eclipse E800 epifluorescence microscope  equipped with an Endow GFP HYQ filter cube. Images were captured using a Cool Snap CCD camera  with Metamorph software .snb-1 = 99.8%, Etba-1 = 99.5%, and Eama-1 = 103.1%. The expression levels of α-syn were normalized to three reference genes: snb-1, tba-1, and ama-1. No template control (NTC) and no reverse transcriptase control (NRT) exhibited amplification. All reference genes used were analyzed by geNorm  and passed for target stability. Three independent biological replicates, with three technical replicates each, were tested for both worm strains. Data analysis was executed using the “do my qPCR calculation” web tool , and UA455 [Pdat-1::α-syn + xdh-1(ok3134)] animals seven days post hatch. An acetylated form of fluorescein that is able to diffuse into the cell was used; once in the cell, the acetate groups of this fluorescein are removed by cellular ROS, producing a fluorescent end-product  worms. An amount of ~200–250 two-day old worms were washed 3 times with 0.5× M9. Worms were frozen and thawed three times, and, subsequently, they were sonicated using an Ultrasonic Processor GEX 130PB , for three cycles of 10 s on and 30 s off at a 40% amplitude. Samples were spun down at 4 °C and 15,000× g for 10 min. An amount of 50 µL of sample was loaded into a 96-well plate. Reagents for each assay were prepared according to their respective kit . Experiments were performed according to kit instructions, and reads were taken using a Spectraax M2e Microplate Reader every 5 min for 1 h. For the XO assay, measurements were taken at 570 nm. For the uric acid assay, measurements were taken at an excitation of 550 nm and an emission of 585 nm.For both assays, RNAi by feeding of EV, For all data analyses, the mean and standard error of the mean (SEM) were determined, and the data were analyzed via the chi-square test, unpaired T test, one-way ANOVA with Tukey’s post hoc test, or two-way ANOVA with Sidak’s post hoc test . Values below 0.05 were considered significant.C. elegans neural cells in worms and (2) RNAseq of neural cells in wildtype vs. adr-2 mutant worms [adr-2 mutants because it allowed us to experimentally analyze the functional impact of editing directly by ADR-2. The editing of genes does not typically lead to a change in gene expression of the edited gene in the C. elegans neural editome; in fact, in the two previously published datasets, only four genes are edited by ADR-2 in worm neural cells, and they are also differentially regulated in neural cells of adr-2 mutants [This investigation began with the hypothesis that RNA editing by ADARs has a role in PD. In this study, we used two published gene sets: (1) sites edited in nt worms . The inv mutants . This isC. elegans mutant for adr-2; thus, expression of these genes is regulated by ADR-2 [C. elegans strain, in which α-syn and GFP are fused and co-expressed in the body wall muscle, the largest cell type in this species [F52E1.2 and fmo-5 are upregulated in the adr-2 mutant—all other genes are downregulated [An amount of 169 genes were previously reported to be up- or down-regulated in neural cells of by ADR-2 . To iden species . In suchegulated .To functionally analyze the fourteen identified candidates, a gene enrichment analysis was performed to identify highly associated biological pathways, molecular mechanisms, and phenotypes A. Of thedat-1) promoter and which allow for age- and dose-dependent analysis of neurodegeneration [papl-1, enhanced neurodegeneration, while four, xdh-1, acdh-1, pho-1, and F52E1.2, were protective when knocked down ; however, more individuals in this group displayed one degenerated neuron in comparison to the EV control. Because RNAi only leads to reduced gene expression, these data indicate that complete knockout of acdh-1 may be neuroprotective against α-syn-induced neurodegeneration.Other significant processes connected to these candidates include function of the NADH dehydrogenase complex, ATP synthesis-coupled electron transport, and respirasome activity—all affiliated with the electron transport chain A. Since neration . Followiked down . RNAi taxdh-1, the ortholog of human XDH, was the most significant. Furthermore, all the genes in which a decrease in expression led to a neuronal phenotype function in enzymatic activity. Of the candidates which were neuroprotective on knockdown, xdh-1 had the strongest protective effect. Additionally, RNAi of candidate genes was performed in worms expressing α-syn and GFP, separately, in dopaminergic neurons (UA44), where knockdown occurs in all tissue types, excluding neurons  mutants displayed enhanced ROS in comparison to wildtype worms, implying that ROS reduction in the xdh-1 mutant background is α-syn specific. Since ROSs contribute to oxidative stress, mitochondrial dysfunction, and ultimately neuronal death, the decrease in ROS observed in xdh-1(ok3134) mutants could contribute to neuroprotection. xdh-1 mutant worms lacking α-syn exhibited enhanced ROS production at 2.5 h, indicating that changes in ROS production due to XDH/XO activity are α-syn specific.Although teolysis ,48. Whilotection G. The opxdh-1 expression in adr-2 mutants is due to the interaction of XDH-1 with another protein that is a substrate of ADR-2. To determine which gene is edited by ADR-2 that interacts with XDH-1, a genetic interaction network that includes 18,183 predicted interactions in C. elegans [wht-2, encoding the worm ortholog of the human ABCG2 transporter, met these criteria. Consequently, wht-2 has previously been associated with gout [wht-2 was deemed a promising link between ADR-2 and XDH-1.Although XDH-1 is downregulated in the absence of ADR-2 function, it is not edited ; thus, i elegans  was cros elegans . Specifiith gout , a condiith gout , an end-xdh-1 knockdown was completed as proof of principle—as expected, roughly double the number of worms with decreased xdh-1 expression in dopaminergic neurons had six intact neurons seven days post hatch, compared to those in the control group  can be produced at this site if electrons are delayed in the iron–sulfur clusters, or if electrons move in the reverse direction, toward complex I ,54. ROS dat-1 promoter, four presumptive modifiers of protein misfolding altered neurodegeneration: xdh-1, acdh-1, pho-1, F52E1.2, and papl-1. All these genes were protective when knocked down except papl-1, which enhanced dopaminergic neuronal cell death. Consistent with recent reports suggesting that monomeric and oligomeric α-syn is more cytotoxic than the aggregated form [xdh-1, which conferred the strongest observed effect upon knockdown, was indeed protective in our neuronal PD model. Finally, we illustrate that WHT-2, which interacts with XDH-1 and is edited by ADR-2, appears to act in the same pathway as XDH-1 to protect dopaminergic neurons from α-syn-induced neurotoxicity. Concurrent knockdown of xdh-1 and wht-2 by RNAi indicates that the neuroprotection associated with loss or absence of xdh-1 is not contingent on adr-2 expression. Thus, we propose a model in which the absence of editing leads to ineffective WHT-2 export of uric acid, which is produced by XDH-1, in turn reducing the toxicity of α-syn and protecting dopaminergic neurons from degeneration (When knocked down in the dopamine neurons of worms co-expressing α-syn and GFP under the control of the Pted form ,60, the neration .XDH, the human ortholog of XDH-1, is responsible for the breakdown of hypoxanthine to xanthine and xanthine to uric acid, the final two steps of purine catabolism. Uric acid has been associated with neuroprotection, as it serves as a scavenger of free radicals, in turn protecting against ROS. Notably, higher serum urate has been associated with lower risk of PD and slower progression of PD . AdditioC. elegans WHT-2, exports uric acid, among many other endogenous and xenobiotic substrates. Our study illustrates that RNAi of wht-2 alone and wht-2 and xdh-1 simultaneously in dopamine neurons of worm expressing α-syn and GFP leads to comparable levels of neuroprotection. Thus, it is possible that XDH-1 activity is reduced to limit uric acid production when WHT-2 is dysfunctional, to avoid the deleterious effects of hyperuricemia. Both ABCG2 and XDH inhibition have been associated with hyperuricemia and gout, providing further evidence of our hypothesis that these proteins act in the same pathway. Moreover, simultaneous RNAi of both genes did not have an additive phenotypic effect in either of our PD models—additional affirmation of this conjecture.ABCG2, the human ortholog of xdh-1 is downregulated upon loss of adr-2 in C. elegans, while wht-2 mRNA levels are not altered [Reports have indicated that the 3′ UTRs of many genes are edited by ADARs, as these regions contain Alu elements . ABCG2 i altered . Of courxdh-1 and wht-2 lead to enhanced neuroprotection and increased protein misfolding. It is possible that the intracellular elevation in uric acid is protective against dopaminergic neuronal cell death by increasing the aggregation of α-syn, the less cytotoxic form of this protein. However, whether increased misfolding is associated with enhanced or diminished disease progression remains controversial. It has been shown that soluble α-syn monomers and oligomers, which precede fibril formation, are more cytotoxic than larger inclusions due to their propensity to disrupt cell membrane permeability and promote neuroinflammation [xdh-1 was cell autonomous, and it is possible that RNAi exclusively in the body wall may yield different results. The generation of a model that expresses α-syn and GFP in the body wall muscles and is RNAi sensitive solely in the body wall muscles, in addition to more studies on the role of α-syn misfolding in PD, have the potential to resolve this issue.It is interesting that knockdown of ammation . Furtherammation . Contrasammation ,71. WhilC. elegans typically slow when they encounter a lawn of bacteria—this is known as the basal slowing response. Worms with dopaminergic neuronal loss are unable to slow in the presence of food, so they glide through the lawn [adr-2, xdh-1, and wht-2 expression are not characterized. Future studies should be conducted to connect motor and locomotive phenotypes with the results reported here. Nevertheless, it should be noted that, in contrast to other widely used worm PD models that focus on quantifying behavioral changes and/or proteostasis exclusively, the specific C. elegans α-syn model used herein has proven highly predictive of translational outcomes pertaining to human genetic findings and evaluation of chemical modifiers when neurodegeneration is the readout [This study focused on two main pathologies associated with PD: the misfolding of α-syn and progressive dopaminergic neuronal degeneration. However, this investigation does not address motor and locomotive deficits observed in PD patients . Worms hthe lawn ,74, A li readout .C. elegans. For example, it has been shown that C. elegans that lack editing by ADARs exhibit reduced chemotaxis [C. elegans is regulated by ASE sensory neurons, not dopaminergic neurons [adr-2 in the body wall—high levels of ADR-2 activity have been reported in the C. elegans nervous system specifically [adr-2 deletion in neurons and body wall muscles expressing α-syn may be an additive effect of changes in expression of all targets of ADARs—simply put, some genes may lead to enhanced neurodegeneration or misfolding, or vice versa, cumulatively leading to no net change.Notably, loss of ADR-2 activity did not impact α-syn-induced neurodegeneration. This was surprising due to evidence that aberrant ADAR activity has detrimental neurological effects across species, including emotaxis . However neurons . Since difically ,25, but xdh-1 expression. While additional work is needed to further elucidate this mechanism, the targeting of ABCG2, the human ortholog of WHT-2, by ADARs, may serve as a promising therapeutic strategy for the treatment of PD. Because ADARs modify many genes in different tissues, the targeted altering of editing or edited substrate proteins, opposed to a complete abolishment of editing, is ostensibly a better approach toward therapeutic intervention. Nonetheless, RNA editing represents an exciting area of inquiry, with substantial implications for biomedical research. The foundational studies on ADAR function in C. elegans have established this system as an exceptional model for investigation of these transformative enzymes as putative modifying factors in neurological diseases such as PD [C. elegans as a system to accelerate discovery remains largely underutilized towards translational goals, but it is expanding as an outcome of the increasingly proven preclinical utility of worm disease models [Here, we describe a functional relationship between ADR-2, WHT-2, and XDH-1 that impacts PD-associated pathologies. Further, we describe how RNA editing by ADARs affects the folding of the WHT-2 protein, presumably changing ch as PD ,23,77. Me models ,78,79.


Multimodal treatment–induced dysphagia has serious negative effects on survivors of head and neck cancer. Owing to advances in communication technologies, several studies have applied telecommunication-based interventions that incorporate swallowing exercises, education, monitoring, feedback, self-management, and communication. It is especially urgent to implement home-based remote rehabilitation in the context of the COVID-19 pandemic. However, the optimal strategy and effectiveness of remote interventions are unclear.This systematic review aimed to examine the evidence regarding the efficacy of telerehabilitation for reducing physiological and functional impairments related to swallowing and for improving adherence and related influencing factors among head and neck cancer survivors.The PubMed, MEDLINE, CINAHL, Embase, and Cochrane Library databases were systematically searched up to July 2023 to identify relevant articles. In total, 2 investigators independently extracted the data and assessed the methodological quality of the included studies using the quality assessment tool of the Joanna Briggs Institute.A total of 1465 articles were initially identified; ultimately, 13 (0.89%) were included in the systematic review. The quality assessment indicated that the included studies were of moderate to good quality. The results showed that home-based telerehabilitation improved the safety of swallowing and oral feeding, nutritional status, and swallowing-related quality of life; reduced negative emotions; improved swallowing rehabilitation adherence; was rated by participants as highly satisfactory and supportive; and was cost-effective. In addition, this review investigated factors that influenced the efficacy of telerehabilitation, which included striking a balance among swallowing training strategy, intensity, frequency, duration, and individual motor ability; treating side effects of radiotherapy; providing access to medical, motivational, and educational information; providing feedback on training; providing communication and support from speech pathologists, families, and other survivors; and addressing technical problems.Home-based telerehabilitation has shown great potential in reducing the safety risks of swallowing and oral feeding, improving quality of life and adherence, and meeting information needs for dysphagia among survivors of head and neck cancer. However, this review highlights limitations in the current literature, and the current research is in its infancy. In addition, owing to the diversity of patient sociodemographic, medical, physiological and functional swallowing, and behavioral factors, we recommend the development of tailored telemedicine interventions to achieve the best rehabilitation effects with the fewest and most precise interventions. Head and neck cancer (HNC) was the seventh most common cancer in the world in 2020, with 932,000 new cases and 468,000 related deaths . Two-thiMoreover, the radiation-induced cascade of fibrosis and muscle atrophy in the swallowing muscle tissue ,6 can cacomfort medicine, and patients’ sense of gain comes from comfort [In recent years, owing to advances in swallowing therapy, rehabilitation exercises, and management strategies for HNC survivors, various intervention strategies have been developed to provide patients with multiple options for swallowing intervention. These interventions have been developed in close cooperation with multidisciplinary health care professionals and led by speech pathologists. However, the COVID-19 pandemic has created an urgent need for high-quality remote rehabilitation as patient safety and virus mitigation have made home-based telemedicine a priority for health care systems worldwide . The fut comfort ,15. Ther comfort ,16-18.However, given the variability in intervention designs and the diversity of web resources and support strategies for the telerehabilitation of HNC survivors, the benefits and barriers of telerehabilitation strategies remain unknown. Determining the benefits of remote rehabilitation requires not only confirming improvements in swallowing physiology and function but also the satisfaction of patients’ health information needs. The satisfaction of health information needs can relieve patients’ anxiety, fear, depression, and other emotions; improve the degree of disease knowledge; reduce disease uncertainty; increase the satisfaction of participating in treatment decision-making; and improve the treatment effect and long-term health-related quality of life. In addition, given that low adherence will exert a significant effect on the outcomes of telerehabilitation, the factors that promote and hinder patient adherence must be assessed.The aims of this review were 2-fold. First, we aimed to determine whether remote rehabilitation interventions for HNC survivors produce the expected benefits; second, we aimed to summarize the factors that influence the efficacy of telerehabilitation. Clarifying the effectiveness and factors influencing the home-based telerehabilitation model provides an evidence-based framework for the treatment and management of dysphagia in patients with HNC by speech-language pathologists and nurses and the generalizability of these results to other telemedicine services.We systematically searched the PubMed, MEDLINE, CINAHL, Embase, and Cochrane Library databases up to July 2023. The search terms included “HNC,” “remote rehabilitation,” “telemedicine,” and “dysphagia.” The search terms for each database are listed in The retrieved articles were independently screened and evaluated by WY and YD. The titles and abstracts were screened in accordance with the inclusion criteria. Studies that examined different populations, applied different interventions, or evaluated different outcomes were excluded. Moreover, duplicate reports, reviews, guidelines, opinion papers, and summaries of meetings were excluded. After identifying potentially relevant studies, the full texts were obtained and reviewed. Studies with unavailable, insufficient, or unreported information on a remote intervention were excluded. In addition, studies that did not include data on the effects of swallowing rehabilitation and its supporting factors were excluded. Any discrepancies between the 2 reviewers were resolved through discussion with MC.The systematic review included studies that met the following 4 criteria.The study population was patients diagnosed with HNC . There were no restrictions regarding cancer location or stage. We excluded patients with cognitive deficits; dysphagia of mixed etiology; severe complications ; or severe cardiac, liver, lung, or other cachexia.Interventions could be any home-based swallowing intervention (including some home exercise programs) provided remotely through information and communications technology. Relevant studies included research on evaluation, prevention, intervention, monitoring, education, and counseling provided via telephone, internet, applications, virtual reality, storage and forwarding of communications, and real-time interaction with data collected via sensors or wearable devices.The control groups included individuals in routine nursing care, basic training, or other types of interventions (not limited).The outcomes included the impact of home-based telerehabilitation on swallowing physiology and function, nutritional status, quality of life, adherence to treatment plans, and cost-effectiveness in patients with HNC or factors associated with the implementation of telerehabilitation.If the published data were insufficient, the appropriate authors were contacted and asked to provide the missing information. Differences were resolved through discussion or, when necessary, consultation with a third reviewer.Study detailsTitle, first author, year, and study typeParticipant inclusion and exclusion criteriaParticipant details: age, sex, tumor location, tumor stage, and prescribed treatmentEnrollment details: number of individuals screened, qualified, randomized, and finalized interventionsMethodological qualityA quality assessment tool from the Joanna Briggs Institute (2016)Intervention detailsTelerehabilitation or telemedicine technology, equipment, or toolsPersons involved in the intervention, intervention timing , intervention duration, and follow-up intervalType of rehabilitation exercise, exercise duration, exercise frequency, exercise intensity, and comparison of interventionsMeasurement of resultsMeasurement tools used, by whom, when, and how (in person or through information and communications technology)Main resultsPhysiology and functioning of swallowing , nutritional status, swallowing-related quality of life, swallowing-related negative emotions, satisfaction with remote rehabilitation, adherence to remote rehabilitation, and barriers and benefits of remote rehabilitationIn total, 2 reviewers used the quality assessment tool of the Joanna Briggs Institute (2016) to independently assess the methodological quality of each study, as shown in The search and selection process for the included studies is shown in Detailed results of the methodological quality assessment are presented for each included study in In this systematic review, among the 13 studies, we included 7 (54%) RCTs, 5 (38%) quasi-experimental studies, and 1 (8%) cohort study, encompassing a total of 1208 participants and 914 participants who completed their trials.The studies were conducted in the Netherlands, Denmark, Belgium, the United States, Australia, China, and Canada. All the studies 13/13, 100%) were published in English between 2014 and 2023. The sample sizes of the studies ranged from 20 to 235, and the sample size of 54% (7/13) of the studies was <100. The mean age of the participants was 57 to 65 years. Most of the participants were male, and the sex ratio was approximately 2.23:1. The tumor stages were mainly III and IV. The most common tumor site was the oropharynx, followed by the larynx. See Table S1 in 0% were pTable S2 in The types of information and communications technologies used to provide telerehabilitation interventions varied among the studies. Of the 13 studies included, 11 (85%) used asynchronous health care primarily and supplemented by synchronous health care, and 2 (15%) reported a comparison between asynchronous and synchronous telemedicine.In Tune without Cords application for customized rehabilitation regarding swallowing and lymphedema in patients with HNC and provided self-care education [Vibrent and Head and Neck Virtual Coach mobile app to provide personalized swallowing training and interactive queries to improve the adherence of patients to swallowing rehabilitation [Mobili-T for remote swallowing rehabilitation interventions and remote monitoring  [Most studies  used an application-based asynchronous remote intervention. For example, in a study that used a WeChat-based intervention, in addition to providing education and information on rehabilitation training, the members of the intervention team regularly communicated with the patients. This 2-way and internet-based communication allowed patients to accurately express their training status to better adjust exercise intensity according to the rehabilitation situation . A totalducation ,22. In tlitation ,18. Anotdevices) .Head Matters) over the internet [PREPARE) to provide swallowing and psychosocial intervention through personalized self-management via coping strategies according to the chemoradiotherapy cycle [A second method involved website-based asynchronous rehabilitation interventions. A total of 15% (2/13) of the studies provided tailored interactive feedback for participants in a web multimodal guided self-help exercise program , participants were instructed, educated, encouraged, supported, and supervised by telephone as they underwent remote rehabilitation training. Another study provided participants with home-based telemedicine via video calls, including assessment and rehabilitation of swallowing and speech functions, nutrition management, and investigation of side effects after HNC treatment .SwallowIT application, and patient self-directed therapy. Compared with the clinician-guided model, swallowing effect, nutrition, and adherence were higher in the SwallowIT application than in the patient-guided group [An RCT compared 3 modes of service delivery: face-to-face therapy, the interactive ed group . Anothered group .All the included studies 13/13, 100%) administered interventions with durations of 6 to 12 weeks, and 8% (1/13) of the studies administered an intervention for up to 6 months . Of the 0% adminiAll the included studies  involved home-based remote rehabilitation. The specific intervention modules are shown in A total of 15% (2/13) of the studies assessed the safety of swallowing  in patients with HNC using subjective and objective methods involving instruments and scales. Hajdú et al  assessedIn total, 15% (2/13) of the studies used the Functional Oral Intake Scale to assess oral feeding ,29, and A total of 7 different assessment tools were used in the included studies: the MD Anderson Dysphagia Inventory ,23,26,29Hajdú et al  used theIn total, 85% (11/13) of the studies evaluated adherence to home-based swallowing telerehabilitation and investigated facilitators of and barriers to rehabilitation training -26,28,29A total of 15% (2/13) of the studies evaluated patient satisfaction using the Functional Assessment of Chronic Illness Therapy–General Treatment Satisfaction ,29,32.A cost-benefit analysis of remote swallowing rehabilitation interventions was conducted in 8% (1/13) of the studies. Jansen et al ,22 evaluThis section describes the intervention effects of home-based swallowing telerehabilitation in terms of the following 7 categories: physiology and function of swallowing, nutritional status, swallowing-related quality of life, swallowing-related negative emotions, adherence to exercise, satisfaction, and the cost-benefit breakdown.Swallowing safety mainly involves the safety of swallowing in the pharyngeal phase . Swallowing safety mainly involves the safety of swallowing in the pharyngeal phase. Swallowing in the pharyngeal phase must be safe and effective. To ensure the safety and effectiveness of swallowing after treatment, it is necessary to train the tongue, soft palate, pharyngeal wall, laryngeal muscle, thyroid cartilage, and upper esophageal sphincter to coordinate and complete swallowing. In 8% (1/13) of the studies, preventive swallowing training and progressive resistance training  were carried out during radiotherapy. The authors compared the effects of remote swallowing training mode and conventional rehabilitation after intervention. The results showed no significant differences in aspiration scores between patients with HNC in the intervention and control groups when swallowing liquids and semisolids. However, a significant difference was found in the pharyngeal residual  after 2 months of intervention . StarmerSwallowIT application intervention had the same effects in terms of reduced occurrence of aspiration when swallowing food of different consistencies [Another study compared the effects of synchronous and asynchronous remote swallowing rehabilitation. The effects of remote swallowing rehabilitation after independent training intervention were also compared. Swallowing safety was determined using the VFSS, MBS, and PAS. Face-to-face treatment and the stencies .In 31% (4/13) of the studies, the muscle groups in the maxillofacial region that participate in mouth opening and chewing were gradually relaxed, and the fibrotic muscles were slowly stretched through mouth opening training. However, even after training, the maximum mouth opening of patients with dysphagia was still decreased with increased time since treatment ,25,29. AIn total, 8% (1/13) of the studies used the mobile health swallowing system equipped with sensors and surface electromyography biofeedback devices as swallowing treatment for patients with dysphagia after HNC treatment; however, it remained unclear which exercise more effectively activated the related swallowing muscles and increased the muscle movement amplitude .Oral feeding ability is an important sign of recovery of swallowing function. The guided self-help swallowing intervention by Jansen et al  achievedIn a study comparing asynchronous and synchronous telemedicine, Wall et al  showed nSwallowing interventions can reduce the complications of malnutrition caused by delayed oral feeding. The intervention by Hajdú et al  providedPatients attach particular importance to quality of life related to dysphagia, and multiple studies have also shown that the quality of life related to swallowing function, physical functioning, and social functioning was significantly higher after home telerehabilitation in patients with HNC ,21,23,31SwallowIT application group did not change significantly at 6 weeks and 3 months after radiotherapy [Wall et al  providedotherapy .Telerehabilitation has great potential to promote patient self-management and improve adherence. The adherence rates varied widely among all the included studies, from 27% to 81.8%.In total, 38% (5/13) of the studies showed that adherence to rehabilitation interventions tended to decrease as the intervention time increased. Cnossen et al  reportedA total of 15% (2/13) of the studies investigated adherence with low-, medium-, and high-intensity rehabilitation training; adherence with low-intensity training was high, whereas adherence with medium- and high-intensity training was low ,25.The functions of web-based and offline interaction and the rich audio-video knowledge base of telerehabilitation change the traditional intervention mode, improve patients’ sense of experience, and meet the needs of patients’ health education. A total of 38% (5/13) of the studies evaluated participants’ satisfaction with swallowing rehabilitation interventions. The results all indicated that remote interventions had higher satisfaction rates and that participants supported remote medical treatment. The results of 15% (2/13) of the studies showed that participants were highly satisfied with and supportive of the therapeutic effects, treatment methods, and suggestions of telemedicine services. Participants believed that rehabilitation training improved their motivation and enabled them to cope with treatment better and faster. After training, participants reported higher satisfaction because of social and emotional support ,27,32. OCompared with traditional face-to-face follow-up, home telerehabilitation is a more efficient and low-cost approach. A study summarizing the cost and cost-effectiveness of home-based telerehabilitation in the Netherlands found that the probability of remote interventions being cost-effective was 57% to 70%. At present, the cost of intervention is relatively high because of its limitations and the low number of potential users. A cost-benefit analysis at the 6-month follow-up showed that, although the total cost for patients in the intervention group was €232 (US $255.53) higher than that for patients in the control group, the rehabilitative effect was significantly greater for those in the intervention group . TherefoThis section describes the factors influencing home-based swallowing telerehabilitation.The supporting factors of home telerehabilitation can relieve patients’ anxiety, fear, and depression; improve disease awareness; reduce disease uncertainty; and improve satisfaction with participating in treatment decision-making, thereby improving the effect of rehabilitation therapy and long-term health-related quality of life. Sociodemographic characteristicsSex, age, race, marital status, children, family support, caregiver support, and educational attainmentClinical characteristicsType of cancer, mode of treatment , stage of disease, side effects of radiotherapy , and tumor complicationsPhysiological functioningDysphagia, limited mouth opening, gavage dependence, symptoms , physical fitness, and BMIBehaviorMotor perception, motivation, confidence, motor motivation, motor history, social ability, self-management, emotional problems , smoking status, and drinking statusTechnologyApplication or internet installation issues, reasonable design, software speed, operability, cost, privacy and data security, ease of use, ease of understanding, and ease of adherenceRehabilitation processesSwallowing training type, duration of a single intervention session, intervention intensity, intervention frequency, and swallowing safety Educational contentInformation, illustrations and videos for swallowing exercises, principles of swallowing exercises, nutrition or diet, recording videos, tumor self-examination and recurrence, oral self-management, fatigue and energy management, and survival care planRemote dysphagia management is paramount for patients with HNC, family caregivers, health care providers, and health service policy makers. The effective use of home-based telemedicine interventions for dysphagia was a major concern during the COVID-19 pandemic. Our systematic review of 13 studies on home-based telerehabilitation dysphagia treatment provides an up-to-date review of the field, describing the safety, effectiveness, quality of life, and adherence regarding telerehabilitation for patients with swallowing disorders from HNC and identifying various facilitators and obstacle elements related to telerehabilitation. Owing to the limited number of studies that met the inclusion criteria, the study designs, and the methodological limitations of inconsistent measurements of results, we cannot definitively conclude that remote rehabilitation has a positive impact on patients with HNC with dysphagia. However, this systematic review provides evidence on the subject.This study indicated that home-based remote rehabilitation of patients with HNC with dysphagia may reduce the safety risks of swallowing and oral feeding, reduce malnutrition and the decline in quality of life because of delayed oral feeding, and improve the (previously low) adherence rates of rehabilitation training. Moreover, tailored rehabilitation, information provision, and behavior change strategies appeared more effective in treating dysphagia, and more pronounced improvements in swallowing and physiological function may be observed over time.Remote swallowing rehabilitation is a new mode of rehabilitation led by intelligent remote equipment and flexible participation of therapists. According to the swallowing function of patients with HNC, web-based evaluation, and push rehabilitation guidance suggestions, it supervises the rehabilitation process; records the rehabilitation data; and builds a communication, feedback, and follow-up platform among patients, their families, and therapists. For patients, the use of telerehabilitation time is flexible, free, and convenient for family supervision to ensure that the scheduled swallowing training movements are accurately repeated, reduce injury and human error, avoid the delay of treatment caused by inconvenient travel and regional restrictions, and reduce the economic burden. For rehabilitation therapists, remote rehabilitation can be realized from “one to one” to “one to many,” and it can also make more patients participate, thereby facilitating the collection of follow-up data.This study shows that home-based remote swallowing rehabilitation therapy can effectively improve the swallowing and dietary function of patients with HNC and support their nursing and psychological needs. Notably, all studies in this review were based on the remote treatment mode of asynchronous telemedicine. Although there is a certain gap between the remote treatment mode and the “one-to-one” rehabilitation mode of therapists, there was no significant difference between the treatment effect and conventional rehabilitation treatment. However, whether remote swallowing rehabilitation can be an effective alternative to traditional rehabilitation in clinical practice needs to be evaluated in the long term, and future research still needs to continue to improve remote rehabilitation.The Hajdú et al  RCT of hImproved swallowing function is essential to restore oral feeding. The importance of combining dietary intake and swallowing training was supported by 15% (2/13) of the studies, in which maintaining an oral diet during multimodal therapy was a powerful predictor of long-term functional swallowing ,35. AnotIn the process of swallowing function diagnosis and treatment, patients with HNC need timely, long-term, and strong health information support and guidance. Comprehensive, accurate, and systematic assessment of the health information needs of patients with HNC is the first step toward providing individualized and targeted professional information support. It is also an important basis for constructing information support strategies based on the real needs of patients. Home-based telerehabilitation enables patients to receive services that provide higher motivation, informational content, support, and encouragement  and to iSynchronous telemedicine also plays an important role in planning and implementing dysphagia treatment and involves incorporating the underlying etiology based on swallowing anatomy or physiological damage obtained through a comprehensive clinical or instrumental assessment  and making decisions regarding personalized swallowing and oral dysphagia management. For example, there is the absence of one factor in swallowing and the compensation for another factor to achieve safe and effective swallowing. Remote VFSS assessments have been repeatedly demonstrated to be safe, effective, and reliable compared with traditional on-site swallowing assessments ,41. StudHNC, as a complex chronic disease, urgently requires the self-monitoring of disease changes, changes in unhealthy lifestyles, and rehabilitation exercises after chemotherapy or radiotherapy. Increasing patients’ adherence and supporting patients’ self-management are of great significance for improving patients’ health outcomes, improving quality of life, and reducing medical costs. The results of this study showed that, although the swallowing rehabilitation adherence in patients with HNC with telerehabilitation was improved compared with standard rehabilitation, it also decreased significantly with the treatment time, indicating that patients still lack the necessary confidence or skills to actively manage the disease. The reasons are analyzed as follows. First, influenced by the traditional medical concept, most patients are still overdependent on medical staff after discharge. Second, the chronic side effects caused by radiotherapy, such as cancer-related fatigue, pain, difficulty in opening the mouth, and head and neck fibrosis, were gradually aggravated, and the patients’ knowledge of disease treatment and nursing was insufficient.This study aimed to identify methods for improving adherence to telerehabilitation. It is recommended to design a tailor-made telemedicine service to solve personalized dysphagia functional problems and address health-related risk behaviors and psychological problems  to ensure adherence to rehabilitation  and meetAn interesting comparison of synchronous and asynchronous telemedicine showed that the app group had the lowest adherence rate of the 3 service models. The reason is that the elements in the app were not compelling enough and the design was not convenient enough. Therefore, the perceived usefulness and comfort of the website or app are important factors affecting participants’ acceptance of and adherence to home-based telerehabilitation and were also found to be positive supportive factors for older people to receive home-based telemedicine services .Age, gender cognition, motivation, physical mobility, and sensory and perceptual function are important factors influencing remote swallowing rehabilitation. For older individuals, the ability to understand and use is limited. When individualizing the rehabilitation program, it is necessary to further confirm the practicality of the intervention and design an appropriate application program interface and function and consider font and color contrast or sensitivity, among other things. Younger patients placed more emphasis on the social and emotional domains  than older patients . As the Studies have emphasized the importance of biofeedback and social engagement. When biofeedback is combined with swallowing training, feedback, or education, it may lead to enhanced improvements in patient adherence ,47. ThisTherefore, future high-quality research can identify motivations for participants to persist in rehabilitation according to age, sex, disease status (new diagnosis or recurrence), treatment duration, radiotherapy duration, radiotherapy side effects, swallowing practice demonstration, and other aspects using websites or applications and provide information for personalized dysphagia management and support. According to the survey results of this study, we recommend that swallowing function should first be assessed through face-to-face or synchronous telemedicine  and swallowing training suitable for patients (such as strengthening hyoid muscle group training) should be formulated according to the assessment results. It is then recommended to build a synchronous and asynchronous home-based rehabilitation mode. The main functions are intelligent questions and answers , light consultations, health education video columns, remote audio- and videoconference, and manual appointment services. As for rehabilitation training, it is recommended that preventive low-intensity training targeting the muscles involved in swallowing injury be carried out before rehabilitation therapy and continue for 3 months after the end of treatment. During this period, speech therapists regularly assess swallowing function, make individualized adjustments, and guide intervention. Moreover, in the design of remote intervention applications, combining the gamification of exercise, robot equipment, virtual reality equipment, biofeedback systems, smart home systems, and social engagement can motivate patients to actively complete rehabilitation training and create a virtuous cycle that improves functionality and adherence to rehabilitation. However, rehabilitation technology is still in the initial stage of development, and further research on the effectiveness and safety of these rehabilitation technologies for the population with HNC is needed.Our systematic review comprehensively examined the impact of home-based teleintervention in the population with HNC dysphagia as well as the evidence for facilitators of favorable outcomes. It summarized the safety, effectiveness, and adherence regarding remote interventions in patients with HNC with dysphagia as well as the related barriers and facilitators. However, we acknowledge that our systematic review has some limitations. First, although 2 researchers separately conducted the literature search and extraction, we admit that it is possible that we overlooked some relevant studies. Second, the form of home-based remote intervention used in the included studies was mainly asynchronous telemedicine rather than synchronous telemedicine; in addition, the intervention content, training duration, training intensity, and evaluation indicators of the family-based remote interventions used in the studies differed. This heterogeneity among studies is a general limitation of other systems used to evaluate swallowing rehabilitation. In addition, not all the studies reported swallowing clinical findings and cost follow-up data; the studies mostly focused on the feasibility and implementation of remote interventions, which may have led to the limited impact reflected on the population with HNC dysphagia.By demonstrating the effectiveness of telerehabilitation interventions, this study can inform public policy development and reduce current barriers to better support the population with HNC.Rapid clinical transformation of technological innovation can be achieved through cross-disciplinary and cross-clinical cooperation and targeted remote rehabilitation systems . These can be tailored to different populations; swallowing training can be adjusted to suit individual needs; and training  can be formulated to suit the current motor ability, performance, and preferences of individuals. Interactive internet-based feedback improved patient self-management and rehabilitation adherence, and educational resources and training samples met the information needs of patients with HNC and their caregivers, thereby maximizing the effectiveness and acceptability of remote swallowing rehabilitation.High-quality, systematic, rigorously designed, randomized multicenter studies are needed to assess the rehabilitation effects of different or combined remote rehabilitation methods in patients with HNC and explore the balance among training duration, effectiveness, and adherence to provide stronger evidence in support of remote intervention. In addition, qualitative interviews or longitudinal follow-up can be conducted in the future, focusing on interviewing and documenting the practical problems and experiences of different patients to study adherence management and its influencing factors in depth and focusing on patient self-efficacy, educational information, behavioral skills, and psychosocial rehabilitation, including the caregivers of patients, to promote the development of telemedicine.Home-based telerehabilitation has shown great potential in reducing the safety risks of swallowing and oral feeding, improving quality of life and adherence, and meeting the information needs for dysphagia in patients with HNC. The lack of standardization across methods and metrics limits our understanding. Therefore, future research needs to deeply explore the intervention effects of different remote interventions in the prevention of dysphagia in patients with HNC; adopt tailored telemedicine interventions ; and increase sample sizes to implement long-term intervention studies, achieve optimal recovery, and maximize adherence to home-based training programs.


This work presents a novel framework for web-based environment-aware rendering and interaction in augmented reality based on WebXR and three.js. It aims at accelerating the development of device-agnostic Augmented Reality (AR) applications. The solution allows for a realistic rendering of 3D elements, handles geometry occlusion, casts shadows of virtual objects onto real surfaces, and provides physics interaction with real-world objects. Unlike most existing state-of-the-art systems that are built to run on a specific hardware configuration, the proposed solution targets the web environment and is designed to work on a vast range of devices and configurations. Our solution can use monocular camera setups with depth data estimated by deep neural networks or, when available, use higher-quality depth sensors  that provide a more accurate perception of the environment. To ensure consistency in the rendering of the virtual scene a physically based rendering pipeline is used, in which physically correct attributes are associated with each 3D object, which, combined with lighting information captured by the device, enables the rendering of AR content matching the environment illumination. All these concepts are integrated and optimized into a pipeline capable of providing a fluid user experience even on middle-range devices. The solution is distributed as an open-source library that can be integrated into existing and new web-based AR projects. The proposed framework was evaluated and compared in terms of performance and visual features with two state-of-the-art alternatives. Augmented reality (AR) consists in augmenting the real world with virtual layers of information . Since iWhile all AR systems need pose tracking to align virtual content with the environment, most systems still do not possess the capability of dynamically adjusting content to their surroundings, limiting the immersion of the AR application, an essential factor for the effectiveness of these systems as discussed by .Environment awareness in AR systems is an important step not only from an interactive and immersive perspective but also to improve usability, for example by adjusting fonts or content colour to improve readability based on the environment, as studied by .The computing power of mobile devices has improved significantly over the last decade and these devices have become the most common scenario for AR applications. Currently, mobile devices have powerful systems on a chip (SoC) that contain motion sensors capable of good position and orientation tracking, which, paired with modern visual camera systems composed of multiple image sensors, make smartphones a natural fit for AR experiences.Although smartphones are the most common type of devices used for AR, advanced features and more precise tracking are available on dedicated wearable devices, such as Microsoft HoloLens 2 , Magic LTo accelerate the development of AR applications, vendors have introduced dedicated APIs  that simplify the integration of advanced hardware features that provide details about the environment in which the user is located .Web-powered AR offers the capability of a setupless experience, without the need to download and install applications while offering developers the possibility of developing cross-platform AR experiences. Using modern application programming interfaces (API) , web-based AR experiences can achieve performance close to native applications, while being faster to develop due to the simplified nature of the web ecosystem.WebXR  is a webWith the rise in real-time collaborative AR experiences, the usage of web technologies has become more relevant as they allow for cross-platform communication and collaboration from a single application. Works such as the ones proposed by  or 14],,14], wheIn this document, a novel framework for environment-aware AR applications based on WebXR is presented. The novelty of this work stems from the integration of many state-of-the-art concepts in AR such as occlusion rendering, environment lighting, shadows, and physics interaction between virtual and real objects into a single performant pipeline.The solution uses physically based shading, combined with environment information that results in the rendering of 3D objects that are consistent with the real-word surroundings as demonstrated in This work was motivated by the lack of cross-device AR solutions that provide environment-aware rendering and physics for AR. Current solutions for cross-device AR  are limited to basic AR functionalities such as tracking and scene alignment .The rest of the paper is structured as follows: Traditional AR applications require previous knowledge of the environment or the usage of discrete markers to align the virtual information with real-world images and provide adequate tracking between the virtual and real worlds.The search for solutions capable of mapping and recognizing the environment for AR applications has been a topic of research for as long as the AR term has existed; an early solution for environment interaction in AR with depth estimation from a stereo camera was presented in .In 2014, Google introduced the Tango SDK, used to build AR devices equipped with depth sensors and motion tracking, capable of obtaining a detailed 3D mapping of the environment using simultaneous location and mapping (SLAM) algorithms. This innovative platform kickstarted the growth in mobile environment-aware AR and opened new possibilities regarding environment tracking and geometry occlusion between real and virtual worlds ,18.In 2017, Apple introduced a concurrent to Google Tango, the ARKit, which used the already existing hardware of iPhone and iPad devices for environment tracking, depth sensing, and lighting information.In 2018, an efficient algorithm for the densification of depth points obtained from monocular visual feature tracking integrated into a SLAM process using deep neural networks (DNN) capable of running in real time was proposed by . It prodIn the same year, Google introduced a new API for AR applications named ARCore. As its counterpart (Apple ARKit), ARCore could run on already available smartphones by using DNN to densify depth data obtained from a single camera alongside with phone position and orientation provided by the inertial measurement unit (IMU). It was also compatible with dedicated depth hardware such as time-of-flight (ToF) cameras that can provide more precise depth information. Alongside with device tracking and environment geometry information, ARCore also introduced the possibility of obtaining lighting information, image tracking, human face recognition, and mechanisms for real-time collaborative AR among devices by sharing environment features across devices .Although ARCore and ARKit proposed similar functionality, there were differences in their technical approach that were investigated by ,22, wherIn 2020, a solution for environment-aware AR named DepthLab  was intrAlso in 2020, Apple introduced solid-state Light Detection and Ranging (LIDAR) technology in smartphones. LIDAR provides high-accuracy dense depth data without the need for additional processing from DNN, improving both performance and quality of the depth information. Two examples of applications using this solution are Snapchat, which provides accurate geometry occlusion and relighting of a real world image, and Polycam, which uses the geometry provided from the LIDAR to perform a 3D reconstruction using SLAM.The web environment offers one of the most complete toolsets for Graphical User Interface (GUI) development with the possibility of developing complex 3D systems using WebGL.AR.js was the first framework widely adopted for web AR targeting smartphone devices with marker-based tracking. This approach requires the usage of markers such as QRCode, Aruco, or pretrained images to track the environment using the device camera.The usage of markers with data storage also provides context for the AR system . Without markers, AR systems must rely on object detection and classification techniques that can be computationally expensive for mobile devices.With the introduction of the first versions of WebXR, markerless web-based AR solutions have started to appear in scientific works and commercial applications. However, while WebXR provides the required technology to implement AR experiences, the inherent limitation of the web environment regarding data bandwidth and the complexity of leveraging the high-performance functionality still impose a barrier for fully featured experiences leading to badly implemented solutions, as studied in .In 2020, a solution for AR interaction with point cloud data using three.js and WebXR for environment tracking and interaction was proposed, providing a limited but performant example of a web application .The real-time realistic rendering of virtual images has been a research topic widely explored over the years from simulation applications, gaming systems, and even industrial applications. In the last few years, we observed an exponential increase in the processing capabilities of graphics hardware. Ray tracing is now a viable solution for hybrid rasterized systems in desktop computers and gaming consoles allowing the simulation of paths of light. Low-power mobile devices are now also capable of realistically rendering images using techniques that were previously not feasible such as physically based rendering (PBR) or the usage of advanced screen-space effects .AR realistic rendering techniques have been constrained by the lack of environment information  and limitations in performance. In 2003, image-based lighting (IBL)  was intrIn 2019, DeepLight , a DNN-bFor the implementation of the solution, the three.js graphics library and the JavaScript programming language were selected. The three.js library was chosen based on its rendering capabilities with PBR and WebGL 2.0 support and on its popularity to increase the reach of the solution proposed to researchers and developers. Three.js has a much larger community of users when compared to the closest competitors Babylon.js and Play Canvas.For GUI elements, the “dom-overlay” functionality, which allows the integration of document object model (DOM) elements in the AR scene, was used to implement an abstraction layer that projected and aligned these elements into the 3D scene using CSS transforms extracted from the camera projection model. These elements could also be used in 2D for on-screen user inputs and information.For the development and tests, a Xiaomi Mi 10 Lite 5G (M2002J9G) smartphone  was selected as a representation of a middle-range device that supports ARCore depth functionality. The device was equipped with a Qualcomm 765G SOC and 6 GB of RAM using the operating system Android 10. The code was tested using Chrome 88.0.4324.68. Models used for testing were obtained from the Khronos Group glTF 2.0 sample repository.In this section, the object-picking module of the solution used for interaction with the 3D virtual environment from a 2D screen points using the “hit-test” functionality of WebXR is presented. The hit-test system assumed that all interactions were performed over plane surfaces; it was capable of handling multiple planes simultaneously and provided the normal of the plane surface. The API received a ray described by its origin and direction vector and responded with the estimated distance to a real-world surface, if any. Points obtained from the hit-test were stored internally by the API as environment anchors used to realign the scene when the tracking was lost, ensuring the objects placed in the scene were always correctly realigned after tracking problems.The object placement mechanism was used to introduce virtual 3D objects using a position calculated from the hit-test result. The solution allowed the user to select screen-space points for which the origin and direction of the ray were calculated based on the device position (obtained from tracking) and the camera projection characteristics.Object picking could be combined with dedicated controllers using the Gamepad API and motion-sensing-enabled controllers  to further improve immersion. Using the object placement module, we also implemented sample measurement tools to evaluate distances, angles, and areas using the GUI toolkit.The accuracy of the tracking solution provided by the API was analysed in depth by , where tIn this section, a Graphics Processing Unit (GPU) based solution for object occlusion is presented. The quality of the depth data available depends on the system configuration and sensors existing on the device. The approach used allowed for high-precision depth data when available, by integrating the raw depth data into the rendering pipeline. The test device used a monocular depth estimation provided by the AR Core obtained using a DNN-based algorithm  with a rThe rendering pipeline for the geometry occlusion is presented in The depth data were provided as an array of 16-bit depth values, efficiently stored in a WebGL texture using the luminance alpha mode, which allowed for two 16-bit unsigned byte colour channels, exactly matching the size of the input data. The depth data provided were not normalized by default so the depth buffer coordinates may not correspond to screen-space coordinates. To convert from depth buffer coordinates, a normalization matrix was provided by the API that had to be applied to correct the screen coordinates.The resolution of the depth data could be different from the screen resolution depending on the system. In the used test scenario, the depth resolution of To reuse the existing materials from the three.js library, we analysed how the materials shaders were built from the material description. The shaders were built from a set of OpenGL Shading Language (GLSL) shader chunks, and each material had its own shader program, which, after being compiled, was managed by the internal renderer of the library.The shader code generated could be accessed from the “onBeforeCompile” call-back executed before the GLSL code was compiled, where the code for the depth occlusion was injected into the existing shader code. In that phase, uniform variables could be registered, specifically, the depth texture shared between all shaders, the normalization matrix, and the screen size. These uniforms were mapped from their JavaScript attribute name to the shader code exactly and had to be managed manually to prevent memory leaks.To blend the result between virtual environments and real-work images, a preprocessing step was applied to prevent the overdraw of fragments that would be latter discarded. To ensure no loss in precision, we compare the depth data encoded in data texture against the projected vertices z passed to the fragment shader. This approach avoided the truncation of the precision of the depth data to match the depth buffer accuracy.The screen-space depth coordinates were obtained through the rectification matrix to reconstruct the 16-bit depth value from the two 8-bit components, obtaining the original depth value in millimetres. Any fragments that had a lower depth value, meaning that they were further away from the projection origin than the real-world surface, were discarded from the result before any additional processing was performed.Combining real and virtual objects using the method proposed provided visually accurate results, where it was possible to distinguish the separation between real and virtual objects across their borders as shown in For some scenarios, it was possible to observe some inconsistencies due to errors in the depth data observed with virtual objects placed behind objects with holes, translucid objects, or with the presence of highlights and reflective surfaces and moving objects. This section describes how the solution uses lighting information and PBR rendering to provide a consistent shading appearance with the environment. PBR rendering consists in using physical models to calculate lighting in 3D-rendered scenes, instead of using a visually obtained approximation to model light interaction with surfaces. The idea is that instead of tweaking materials to “look good” under specific lighting, a material can be created that will react correctly according to calibrated lighting scenarios. In practice, this gives a more accurate and realistic-looking result than the Lambert or Blinn–Phong  models.Bidirectional reflectance distribution functions (BRDF)  define hThe “lighting-estimation” module of WebXR provides light intensity, the direction of the main light source, and a cube-map texture of the environment surroundings. These data are obtained from a device’s light sensor and camera.To access lighting data, a light probe was used to query the direction of the main light source as well as environment light information provided as a set of spherical harmonics (SH)  at each SH encode lighting conditions in spherical functions that are then projected into frequency space and represented by 9 coefficients. It is an alternative representation to a full cube map that uses less memory and is effective for scenarios where high-frequency details are not required. The API provides a set of SH coefficients for each RGB colour channel.The three.js library has a PBR rendering implementation based on the model described in . The SH The 3D models used in the framework must contain all the required physical attributes of their surfaces encoded into textures. Using the lighting information, the framework provided a solution for casting AR shadow between 3D objects and the ground planes. The technique described in Planes found were used to render shadows using shadow maps  cast froThe usage of shadow maps presents some limitations: it is not possible to have partial light occlusion from translucid objects, shadows are projected for a finite area, and the number of lights casting shadows must be limited, since computational cost and memory increase exponentially with the number of lights in the scene. Numeric precision limitation may also cause a shimmering effect commonly known as “shadow acne”, that was studied and addressed in .To ensure good performance, shadow maps are typically rendered with a resolution considerably lower than the expected shadow pixel density in the screen space and to improve their perceived quality, a filtering method can be used. We tested 3 different algorithms for shadow map filtering: percentage-closer shadows (PCS) , variancTo evaluate the performance and quality of the shadow-mapping mechanism based on its resolution and filtering algorithm, we tested multiple configurations and measured the performance for each one, and we selected a shadow area of To provide an interaction between virtual and real world objects, depth information was used to create a simplified model of the real environment that was combined with the virtual scene object for the physics simulation.For the physics simulation, the cannon.js rigid body physics engine was used. It was selected based on its performance through the usage of the SPOOK stepper  combinedThe process for the physics simulation is represented in The voxel occupancy grid consisted of a dense voxel volume that could be expanded dynamically as required. Voxel size should be adapted to the precision required. For the implementation, we selected empirically a voxel size of 5 cm. Voxels stored a weight value, which was compared against a threshold value to decide if the voxel was occupied by a real-work object or not.wV is the voxel weight, sU is the update speed, from 0 to 1, and tH is the depth hit result with values 0 or 1.Equation  represenThe depth was projected into a 3D space; each point had to hit a voxel in the grid; if not, the voxel grid needed to be expanded. For each point, all voxels close to the camera had a reduction in occupancy weight and the voxel hit by the point had its weight increased. Voxels outside of the view were not updated. To handle virtual objects and maintain a good computational performance of the physics simulation, simplified convex hulls were generated for each object geometry using the quick-hull algorithm .Information from the probabilistic voxel model and convex hulls were provided to the physics engine, which updated the simulation state and the position of virtual objects before rendering each frame.www.github.com/tentone/enva-xr (accessed on 12 February 2023).The solution presented is distributed openly as a library and focuses on providing an abstraction layer for web AR with fallbacks available for non-AR devices. The code is available on GitHub at The solution takes care of all initialization code required, so that developers can focus on the application development. The “ARApp” object provides access to all the features presented in the document. It checks for the existence of all WebXR features required in the device and manages the rendering of 3D objects and the physics simulation.The features of the system can be toggled trough flags and developers can provide 3D objects to the “scene” attribute of the application instance. A state update of 3D objects can be performed in the “onFrame” method called before rendering each frame.To evaluate the performance of the framework, a simple implementation using only the environment-tracking functionality without any lighting or geometry effect was considered as a baseline, similarly to the solution proposed by .A 3D model of an antique camera available under MIT’s permissive license was used; this model is shown in No optimizations were used during the tests and each group of entities used its own textures and geometries that were replicated in memory. All objects were placed under direct visibility, otherwise the framework would remove them from rendering. The device was placed on a fixed stand during the tests to ensure that the tracking process was under similar conditions.Incremental tests were performed for each of the features proposed with different number of objects; for each scenario, the average, minimum, and maximum values were measured. We tested a baseline approach only with environment tracking , a geomeA significant variation between minimum and maximum frame times could be observed. In the complete system test , we obseFor the most complex scenario, the device ran out of memory for more than 112 entities, caused by the quantity of texture data required for the textures and geometries. In a real scenario, this situation could be easily avoided by compressing and sharing the resources across the multiple entities that can be implemented in the solution.All tests were repeated by measuring only the rendering time of the solution proposed without accounting for the WebXR overhead, considering only the time required to update the data structures and render an image to the screen. The results are presented in In a device using a dedicated depth solution this value is expected to be the major penalty introduced by the platform, easily allowing high-end devices to sustain higher frame rates.To understand better how the WebXR API impacted performance, a new test, independent from the framework, was prepared, evaluating the times for each one of the WebXR API modules necessary to access information used by the framework. Each feature was tested separately, and the results are presented in The results suggested that no specific feature of the API imposed a higher performance limitation as the performance was similar independently of the features in use. A big gap between minimum and maximum values was observed, confirming again the substantial variation in processing time of the API.For comparison of the approach presented, we selected two solutions: DepthLab and MyWebAR. DepthLab uses the AR Core API and can be considered a representative of the state-of-art in mobile augmented reality . MyWebARDepthLab version 1.0.5 and the device presented in Although surface lighting used a similar technique with PBR materials, the proposed solution lacked environment maps, relying instead on a simplified spherical harmonics (SH) model, which, although not as detailed, provided a better consistency, as observed when comparing the results from Shadows were also obtained using different techniques; the proposed approach used shadow maps projected over planar surfaces with soft filtering, whereas the solution by  used harThe results obtained with the DepthLab solution also presented some issues as seen in For the physics interaction, the solution presented combined a voxel occupancy grid approach, which was built and updated as a simplified but dynamic model of the environment with a simplified hull for the virtual objects and which allowed the physics simulation to run even for elements outside of the viewport.The approach presented in DepthLab used a closed triangulated mesh updated in real time from the depth data available in the viewport, which did not cope well with physics elements leaving the screen space or interacting with the surface. In contrast, the proposed solution a updatedMyWebAR is a web-based commercial solution for AR experiences. It supports different types of AR projects based on image tracking, QR codes, and SLAM. For comparison, we created a SLAM project. In SLAM projects, MyWebAR can use WebXR to track the environment similarly to the solution presented.In This paper presented a framework for environment-aware AR application based on the WebXR API providing a consistent and performant package paving the way for the creation of complex AR applications that can better reflect changes in the environment.The novelty and a most significant advantage of the proposed approach resulted from the integration of multiple state-of-the-art AR features into a single performant package  were in a proposal state, and their implementation was subject to changes in future releases of the Chrome web browser.The framework presented is intended to be used by other developers and researchers. It allows users to quickly create a web AR application capable of environment interaction with minimal code required for setup.While the WebXR API specification is still under development, it already offers a significant toolset for environment-aware mixed reality. The performance instability of the WebXR API probably caused by the unpredictability of the SLAM process used to build the environment model, poses some challenges for consistent performance in more complex AR applications, which was also observed in .To further enhance the results of the work presented, real-time reflections could be introduced using environment cube-map information. It was not possible to integrate this feature because the API provided it as a preallocated WebGL texture that we were not able to integrate into the three.js rendering pipeline. An alternative algorithm for occlusion could be used to improve the visual fidelity of the solution; for instance, in Throughout the development of the proposed framework, it was noticed that memory limitations arose quickly, which was expected considering the complexity of the SLAM process used internally by ARCore to keep track of the device position and environment anchors.To reduce the memory used for textures, which represent the largest chunk of memory, GPU-compressed formats should be used whenever possible and are supported by the proposed framework. To ensure compatibility with vendor-specific formats, the approach proposed by  provides


Glioma is a group of tumors that originate from glial cells within the central nervous system and comprise 27% of all tumors and 80% of malignant tumors. With remarkable progress in surgical practices, chemotherapy, and radiation therapy, patients with glioma are experiencing greater survival times, which means they need more rehabilitative care. In fact, people with this condition may experience a variety of symptoms that can affect their functions and drastically reduce their quality of life. In fact, patients suffering from glioma has a distinctive symptom complex highlighting the requirement for customized care. Growing evidence shows that rehabilitation therapy can improve the functional prognosis and quality of life of glioma patients. However, there is limited evidence of the success of rehabilitation protocols designed specifically for individuals with glioma. It is essential to determine the most comprehensive rehabilitation programs as well as the sufficient resources, dosage, and duration. The goal of this mini-review was to classify and map rehabilitation interventions used to treat multiple disabling sequalae in individuals affected by glioma. We aim to provide a comprehensive overview of the rehabilitation protocols used for this population, so that clinicians have a guide to support treatment and an inspiration for further research. This document is intended to be a reference point for professionals involved in the management of adult patients with gliomas. Further exploration is needed to form improved care models for recognizing and addressing functional restrictions in this population. They can be divided into two main groups: diffuse gliomas, which infiltrate their surroundings, and those with a more circumscribed growth pattern . The WorPatients diagnosed with glioma have specific functional impairments and restrictions in physical activity, making them a distinct patient population. They experience many symptoms that affect their neurological functions and quality of life. A recent review  reveals The purpose of rehabilitation is to effectively improve the motor, consciousness and psychology of glioma patients . The guiTo accurately assess the issues and plan effective interventions, a range of factors needed to be considered and only a multidisciplinary approach could ensure that each person can receive support tailored to their individual physical, sensory, cognitive, psychological and social needs. Preliminary research suggests that rehabilitation can reduce disability in glioma patients, by improving both functional abilities and cognitive functioning compared to standard care. A recent meta-analysis  indicateTo date, there is limited evidence of the success of rehabilitation programs designed specifically for individuals with glioma. The impact of multidisciplinary treatment was examined by a Cochrane Review completed in 2013, although no RCTs could be included due to the difficulties in locating high-quality research. The twelve lower-quality observational studies included led the authors to draw the following conclusions: interdisciplinary rehabilitation is not detrimental and may even improve disability and quality of life . A few yThis mini-review is not intended to be a comprehensive review of the available literature on glioma tumor rehabilitation as it serves as a guide for clinicians to support treatment and facilitate further research. We aim to offer a comprehensive overview of the rehabilitation protocols used for this population.2.2.1.References for this review were obtained by searching the online databases PUBMED, CINAHL, Web of Science, Cochrane, and Scopus until November 2022. Search terms included: brain, glioma, rehabilitation, intervention with the Boolean operator “AND” to narrow results and connect terms. We considered articles published after the year 2000 and papers printed in or translated into English. Only observational studies and randomized control trials were included. Some of the references were not found through online databases, but rather through reference lists of other articles.The raw search of the databases yielded a total of 164 articles, then an initial filtering within the same databases by document type  and a subsequent filtering of duplicate articles, left 31 unique articles. These 31 articles were subjected to a review of titles and abstracts, leaving 29 articles as candidates for assessment for eligibility. Only 13 articles met the inclusion criteria with 16 articles being excluded. To ensure the homogeneity of the study population, we excluded 6 papers that reported on various brain tumor types, such as meningiomas, metastases, and other tumors, besides glioma  checklist to capture intervention descriptions. This checklist included categories such as “brief name”, “why”, “what ”, “what (procedures)”, “who provided”, “how”, “where”, “when and how much”. The TIDieR checklist is designed to ensure that authors provide enough detail for others to replicate their interventions.Data extracted are summarized in 2.2.Motor deficits associated with brain tumors can vary greatly and include focal deficits such as hemiparesis/plegia with spasticity, gait impairment, ataxia, and incoordination. These impairments depend on the location and extent of the tumor or its treatment, and may affect different muscles or limbs . PatientFive studies were included: two RCTs and three observational studies that examined inpatient, outpatient, and home-based rehabilitation for benign and malignant brain tumors. Different grades of brain tumors were included in all studies. The timing of the rehabilitation varied from study to study—from early after surgery to weeks after the completion of proper management. Rehabilitation protocols usually include physical therapy, occupational therapy, psychological support, and cognitive therapies.Yu et al.  in a retTay et al.  providedHansen et al.  conducteGehring et al.  recently2.3.Cognitive dysfunctions are common and debilitating consequences of brain tumors that affect patients' quality of life and daily functioning. The causes of these impairments are complex and depend on tumor characteristics, such as type, location, size, and edema, as well as on the involvement of neural pathways. The most frequently affected cognitive domains are attention (30%) and working memory (20%), followed by visual memory (14%), verbal memory (13%), information processing speed (11%), and executive functioning (8%) . The preThis mini-review included two studies with a focus on cognitive rehabilitation, one randomized control trials and one observational study.Gehring et al.  exploredHassler et al.  in a pil3.The studies reviewed explore protocols of various rehabilitation interventions for glioma patients. Rehabilitation protocols typically include physical therapy, occupational therapy, psychological support, and cognitive therapies, and the timing of the rehabilitation can vary from early after surgery to weeks after the completion of proper management. The interventions included inpatient, outpatient, and home-based rehabilitation, with varying exercises and therapy components.The studies showed that rehabilitation can lead to improvements in motor function, cognition, activities of daily living, and quality of life, with some studies also demonstrating improvements in physical fitness and cognitive performance. However, it is important to note that the timing, intensity, and duration of rehabilitation may influence its effectiveness. Some studies showed mixed results, highlighting the need for further research in this area. Overall, rehabilitation interventions can play an important role in improving the outcomes and well-being of patients with brain tumors. It is important for healthcare providers to consider rehabilitation as part of the comprehensive care for these patients and to tailor the interventions to individual needs and circumstances. Infact, the interventions with the most successful outcomes were those that included personalized exercise prescriptions, individualized training, and adherence strategies such as monitoring training data and regular guidance from a physiotherapist.As for the cognitive rehabilitation protocol, the two studies included in this mini-review provide valuable insights into the effectiveness of cognitive rehabilitation interventions for patients with gliomas. Gehring et al. highlights the potential benefits of early cognitive rehabilitation interventions for patients with gliomas in remission; while Hassler et al.'s pilot study also showed promising results, indicating that group training sessions targeting attention and memory skills can lead to improvements in cognitive function, particularly in perception, concentration, and retentiveness. Overall, these studies suggest that cognitive rehabilitation interventions can significantly contribute to improvement in the quality of life of patients with gliomas and should be further explored in larger and more rigorous studies.It is noteworthy that some studies were excluded because they included other patients besides gliomas. However, they are still relevant for glioma rehabilitation and may offer useful insights. So, we summarized their findings in the discussion section and provided detailed information about their protocols in the Regarding the physical rehabilitation a study by Yoon et al.  investigConcerning cognitive rehabilitation, we discovered five studies that incorporated glioma patients as well as those with other brain tumor types. For instance, Zucchella et al.  demonstr4.This review shows that rehabilitation interventions, such as physical and cognitive therapies, can enhance quality of life and function in glioma patients. Rehabilitation is a safe, feasible, and well-tolerated option that should be considered for glioma patients. However, more studies are required to clarify the rehabilitation effects on glioma patients, such as finding the best rehabilitation models, assessing motor and cognitive outcomes, choosing the appropriate physical activity strategies, evaluating the long-term training effects, and measuring the influence of motor and cognitive rehabilitation on patient daily life and caregivers. New approaches such as neuromodulation have been proposed as a new strategy to increase the safety of brain tumor resection, promote cortical reorganization and accelerate functional recovery after surgery , 37. InvSS, SF: concept and design. SS: drafting and reviewing the manuscript. SF: literature analysis and manuscript revision. NC, RP, PF and AS: technical support and study supervision. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.https://www.frontiersin.org/articles/10.3389/fsurg.2023.1137516/full#supplementary-material.The Supplementary Material for this article can be found online at: