Joubert syndrome and related disorders (JSRD) are rare and intractable diseases characterized by delayed psychomotor development, hypotonia and/or ataxia, and abnormal respiratory and eye movements. Cerebellar vermis agenesis and molar tooth signs are distinct on cerebral magnetic resonance imaging (MRI). Children with JSRD present with delayed psychomotor development, including intellectual disability and emotional or behavioral problems. Rehabilitation treatments are provided to promote psychomotor development. However, limited reports and evidence exist on rehabilitation treatments for children with JSRD. Three children with JSRD received rehabilitation treatment. The children received rehabilitation treatment once a week to once every one to two months at our hospital and/or other facilities. All patients received physical, occupational, and speech-language-hearing therapy, depending on their symptoms and conditions. In children with tracheostomies due to abnormal respiration, respiratory physical therapy and speech-language-hearing therapy, including augmentative and alternative communication, were needed. For hypotonia and ataxia, an orthotic intervention was considered in all three cases, and foot or ankle-foot orthoses were used in two cases. Although there is no specific or established rehabilitation method for children with JSRD, appropriate rehabilitation approaches, including physical, occupational, speech-language-hearing therapies and orthotic intervention, should be considered and provided to improve their function and expand their activity and participation. Orthotic intervention for hypotonia seems reasonable for improving gross motor development and function in children with JSRD. Joubert syndrome (JS) is a rare and intractable disease characterized by the agenesis of the cerebellar vermis, episodic hyperpnea, abnormal eye movements, ataxia, and psychomotor delay . VariousThis case presentation was approved by the Ethics Committee of Shizuoka Children’s Hospital . Written consent was obtained from the guardians for the presentation of the cases. In accordance with the JSRD guidelines in Japan , all patChild 1The patient, a three-year-old girl, was born at full term and had a normal birth weight. At four months of age, she was referred to the plastic surgery department of our hospital for polydactyly of the left upper limb . At nine months, she was referred to the Pediatric Neurology Department for developmental delay. At 10 months, she visited the rehabilitation department, and a rehabilitation intervention was initiated to promote motor development. In the same month, she underwent a cerebral MRI and was diagnosed with JS. The MRI image is shown in Figure During rehabilitation, physical therapy was administered to achieve milestones of motor development. Physical therapy was provided once a week in conjunction with a nearby hospital in her regional area. She had been prescribed a foot orthosis for hypotonia and ataxia to stabilize her ankle joints while standing and has been using it since age two. Her motor developmental milestones were as follows: head control at eight months, rolling over at 13 months, and sitting up/sitting alone at 20 months. She trained stand, walk, and climb stairs with assistance Figures , 2B and Child 2The patient, 11-year-old boy, was born at full term and had a normal birth weight. At nine months of age, he was referred to the Pediatric Neurology Department of our hospital for a second opinion on JS , especially respiratory management. In the same month, he underwent a tracheostomy and was started on mechanical ventilation at our hospital. He was discharged from our hospital, and home mechanical ventilation therapy was initiated. He underwent gastrostomy at the age of two. Despite multiple hospitalizations yearly due to respiratory infections, he was weaned off mechanical ventilation at the age of four. In the same year, he underwent fundoplication for gastroesophageal reflux. He has not been hospitalized for respiratory infections since then. The patient continued to receive home oxygen therapy. The MRI image is shown in Figure Respiratory physical therapy was the primary rehabilitation treatment. After four years of age, physical and occupational therapies were administered once every one to two months to improve motor and cognitive functions. His motor developmental milestones were as follows: head control at age three, rolling over at age three, and sitting up/sitting alone at age eight. He was prescribed a plastic ankle foot orthosis to stabilize his ankle joints during standing and walking training at the age of seven. He required assistance in standing and walking and is currently undergoing training Figures , 4B. WheChild 3The patient, 13-year-old boy, was born at full term and had a normal birth weight. At three months of age, he was referred to the Clinical Genetics and Cytogenetics Department of our hospital with suspected JS. In the same month, he underwent a tracheostomy and was started on mechanical ventilation at our hospital for a central apnea episode. Thereafter, the patient was managed at the referring hospital, and a definitive diagnosis of JS was made at another university hospital with expertise in the syndrome. He was referred to our hospital for respiratory and nutritional management, and he underwent gastrostomy at the age of four. The patient was weaned off the mechanical ventilator at age nine. The patient was not hospitalized for any respiratory infections. The patient continued to receive home oxygen therapy. The MRI images are shown in Figure He attended a regional rehabilitation facility for children with disabilities and used short-term hospitalization for intensive rehabilitation at a distant pediatric rehabilitation facility ; rehabilitation treatment was not provided at our hospital. As it had become difficult to continue attending other hospitals for rehabilitation, his guardians wanted to receive rehabilitation therapy at our hospital at the age of 10 years. With assistance, the patient was able to stand and walk. Although the tracheostomy cannula was not a speech cannula, the patient could generate a voice. No significant words were identified. He received physical therapy through a home-visit rehabilitation service once or twice a month. At our hospital, low-frequency physical and speech-language-hearing therapies are initiated every three to six months. In physical therapy, the prescription of ankle-foot orthotics was considered for the ankle joint and foot instability due to valgus foot. However, because of the improved stability due to increased muscle strength, wearing a chukka or high-cut shoes was chosen instead. In speech-language-hearing therapy, tablet devices are considered augmentative and alternative communication. However, he could express three-word sentences equivalent by gestures, and using this device was impractical. He attended a special support school and used a walker to ambulate or pedal a wheelchair to move around. The practical means of indoor and outdoor transportation is hands-in-hand walking. He was also involved in sports, such as soccer and boccia Figures , 6B. PedThe clinical features of three patients with JSRD are shown in Table There are very few reports on rehabilitation treatment for children with JSRD. Dekair et al. reported a rehabilitation treatment program for a girl with JS focusing on improving the child’s motor, language, cognitive, and social skills, including physical, occupational, and speech-language-hearing therapies; orthotic services improved her development but continued to be delayed for her age . RegardiIn JS patients, while psychomotor developmental delay and emotional or behavioral problems vary, a positive correlation between age and equivalent age on cognitive and adaptive behavior tests has been reported, indicating that children with JSRD can continue to develop gradually and acquire new skills until adulthood . AccordiAlthough there is no specific or established rehabilitation method for children with JSRD, appropriate rehabilitation approaches should be considered and provided to improve their function and expand their activity and participation. Orthotic intervention for hypotonia seems reasonable for improving gross motor development and function in children with JSRD.


Sorghum bicolor (L.) moench). Although some sorghum-related mutation databases have been published, the special SSR and SV databases still need to be constructed and updated.As an important food and cash crop, identification of DNA molecular markers is of great significance for molecular marker-assisted breeding of Sorghum . Users can query the information of related sites and primer pairs.In this study, the quality of 18 different sorghum genomes was evaluated, and two genomes were assembled at chromosome level. Through the identification and comparative analysis of SSR loci in these genomes, the distribution characteristics of SSR in the above sorghum genomes were initially revealed. At the same time, five representative reference genomes were selected to identify the structural variation of sorghum. Finally, a convenient SSR/SV database of sorghum was constructed by integrating the above results (Anyway, our research provides convenience for sorghum researchers and will play an active role in sorghum molecular marker-assisted breeding. Sorghum bicolor (L.) Moench, as an annual C4 herbaceous plant of the family poaceae, has many advantages such as drought tolerance, salt tolerance, barren tolerance, waterlogging tolerance, and strong photosynthetic ability [ ability –3. Becau ability . Diverse ability . Identif ability .Compared with restriction fragment length polymorphism (RFLP), randomly amplified polymorphic DNA (RAPD) and amplified fragment length polymorphism (AFLP), simple sequence repeat (SSR) has the advantages of wide genome distribution, simple operation, high polymorphism and co-dominant inheritance . SSR molFurthermore, with the advancement of sequencing technology, structural variation on the genome has gradually attracted the attention of more researchers. Studies have shown that although the number of structural variation (SV) is usually less than other mutation sites, it may still have an important impact on the growth and development of plants . For exaIn 2009, the first sorghum genome sequence BTx623 was successfully assembled and released, and the sequencing results showed that the size of the sorghum genome was about 730 Mb . After tAt present, the sorghum SNP database has been published and constantly updated, but the database on SSR and SV variation of sorghum is not perfect and needs to be updated , 28. In https://db.cngb.org, project accession number CNP0001440), SorGSD (http://ngdc.cncb.ac.cn/sorgsd/) and SorghumBase (https://www.sorghumbase.org).All genome and Pacbio sequencing data used in this study were collected by China National GeneBank database  to 64,667   and 24,663 (Ji2731) varied, while the number of the least GC/CG type SSRs between different genomes was only 277 (PI532566.chr) to 400 (S369-1)  to identify the structural variation of eleven sorghum varieties respectively. As shown in Fig. http://www.sorghum.top:8079/; http://43.154.129.150:8079/; http://47.106.184.91:8079/).Based on the above data, we took multiple steps to integrate and construct the first SSR and SV variation database in sorghum Fig. . The whoCase study 1, when entering the search module to query SSR, a sample name should be selected first, and then the user can further choose to search by chromosome position or by SSR length. As shown in Fig. Case study 2, given that many sorghum genome and pan-genome data have been published, researchers often need to align DNA sequences based on different genomes, so sequence alignment is provided in the Tools module. As shown in Fig. As the fifth important cereal in the world, the demand of sorghum has been increasing in recent years. In 2021 alone, China’s sorghum imports exceeded 9.4 million tons. However, unlike the sharp increase in demand, the planting area has not been significantly improved, and its molecular breeding process needs to be continuously improved and strengthened. In 2002, Sharopova  developeIn this study, we first evaluated and compared the assembly level of 20 sorghum genomes by N50 and LTR assembly index (LAI). The results showed that the assembly quality of 10 sorghum genomes reached the reference genome level . AlthougThe application of the third generation sequencing technology has promoted the discovery of plant structural variation and the research progress of functional genes. For example, Yang et al. identified 80,614 polymorphic structural variations by resequencing 521 maize germplasm ; Guo et Effective mining and utilization of large-scale sequencing data plays an important role in promoting plant breeding . Many inIn this study, we first collected 18 sorghum genomes and preliminarily evaluated their quality. Subsequently, SSR sites in different sorghum cultivars were identified and compared based on the above genome to reveal the distribution characteristics of SSR in these sorghum genome. Based on the published third-generation sequencing data and five high-quality reference genomes, the SV variation of sorghum was identified and analyzed. By integrating the above data, a SSR/SV database of sorghum was successfully constructed. The publication of these results will help relevant researchers to easily obtain relevant data to promote their research process, and will provide support for the breeding of sorghum.


During the last few decades, the field of rehabilitation has experienced substantial development, growth, and acceptance. Rehabilitation addresses the impact of a health condition on a person's everyday life by optimizing their functioning and reducing their experience of disability. Rehabilitation expands the focus of health beyond preventative and curative care to ensure people with a health condition can remain as independent as possible and participate in education, work, and meaningful life roles . A definWe also have now a better understanding of the growing global need, demand, and recognition of rehabilitation around the world. For example, it has been estimated that 2.41 billion people in the world could benefit from rehabilitation services. This means that at least one in every three persons in the world needs rehabilitation at some point during the course of their disease or injury . This fiNotwithstanding the foregoing arguments, there continues to be a high unmet need for rehabilitation globally, with some low- and middle-income countries reporting unmet needs up to 50% of those who could benefit from rehabilitation. Rehabilitation services are not accessible to many people around the world . Many ofThe field of health policy and systems research (HPSR) seeks to understand and improve how societies organize themselves in achieving collective health goals and how different actors interact in the policy and implementation processes to contribute to policy outcomes , 11. By Supported by the recent resolution on “Strengthening rehabilitation in health systems” that has been endorsed by the World Health Assembly for the first time in the history of the World Health Organization , it is tIn 2022, the World Health Organization Rehabilitation Program established the World Rehabilitation Alliance (WRA)  to strenIn this context, the coauthors of this article on behalf of their respective academic journals express their full support for the WRA mission in general and for the specific objectives of the research workstream. In concrete terms, we commit that our journals, as much as possible, will implement one or more of the following actions: (1) invite researchers in the field of HPSR for rehabilitation to submit their manuscripts to our Journals for peer review and possible publication, (2) create a special journal section, series, or designation dedicated to HPSR for rehabilitation, (3) appoint editorial board members with expertise in HPSR for rehabilitation, and (4) disseminate research articles among funding agencies and policymakers. These actions by our academic journals will help the WRA achieve its goal of strengthening rehabilitation services for all.


Allergic rhinoconjunctivitis (ARC) and allergic rhinitis (AR) are prevalent allergic diseases. People are becoming increasingly aware of the impact of microbial disorders on host immunity and allergic diseases. Studies have demonstrated an association between allergic diseases and the microbiome, but much remains unknown. We assessed changes in the conjunctival microbiome and nasal microbiome in patients with ARC or AR.Conjunctival swabs and nasal swabs were collected from each participant for 16S rRNA amplicon sequencing. Bacterial communities were analyzed.Forty patients with ARC, 20 patients suffering from AR, and 34 healthy controls (HCs) were recruited. This study found the abundance of conjunctival microbiome in patients with ARC or AR was significantly lower than that in HCs. The diversity of conjunctival microbiome in patients with AR was significantly lower than those in the other two groups. There is no significant difference in abundance of nasal microbiome between the three groups. The diversities of nasal microbiome in patients with ARC or AR were significantly lower than that in HCs. We found significant differences in microbiota compositions in patients with ARC or AR compared with those in HCs. However, no significant difference in microbiota compositions was found between patients with ARC and patients with AR. Microbiome functions in the ARC group and AR group were also altered compared with HCs.We revealed changes in the composition and function of the conjunctival microbiome and nasal microbiome of patients with ARC or AR, which suggests that there is a relationship between allergic conditions and the local microbiome. Allergic rhinitis (AR) is an immune-mediated disease of the nose caused by hypersensitivity reactions, such as itching, sneezing, increased secretion and obstruction. Allergic conjunctivitis (AC) is an inflammatory disease of the conjunctiva caused mainly by an immunoglobulin (Ig)E-mediated mechanism . When alARC and AR are caused primarily by sensitization to specific aeroallergens, and result in local synthesis of IgE and histamine release , 5. As aThe lesion sites of ARC are ocular surface and nasal cavity. The ocular surface consists of the conjunctiva, cornea, sclera and tear film. They are continuous with the skin of the eyelid and exposed to the environment, and form the ocular surface microenvironment of the eye. A normal surface microenvironment of the eye is essential for the health of the ocular surface. Microorganisms on the ocular surface may originate from the body or external environment. Most people have a relatively stable microbial community on the ocular surface , includiThe nasal cavity is a physical transition from a space of constant contact with the outside world to a highly regulated and protected interior space, where innate microbes play a key part in health and disease. Respiratory microbiome may be the gatekeeper against respiratory pathogen colonization. It is also probable that the respiratory microbiota may participate in the maturation and maintenance of respiratory physiological and immune homeostasis . It was coagulase-negative Staphylococci, Diphtheroids, and Propionibacteria, and Streptococci  and patients suffering from ARC or AR were analyzed using 16S rRNA amplicon sequencing.The study was conducted in Tianjin TEDA Hospital . The study protocol was approved (2022-02) by the ethics committee of TEDA Hospital. All individuals provided written informed consent before participating in the study.The exclusion criteria were: (i) active ocular inflammation or dry eye; (ii) having ARC or AR along with sinusitis, nasal polyps, or non-allergic rhinitis; (iii) suffering from autoimmune disease or cancer; (iv) use of eye drops, nasal sprays, topical/systemic corticosteroids, antibiotics, or immunomodulatory medications within the previous 3 months; (v) currently pregnant or lactating; (vi) not possible (for any reason) to cooperate with the research protocol.Ninety-four participants (34 HCs and 60 patients) aged 18–60 years were recruited from Tianjin TEDA Hospital between January and March 2022. Patients whose previous test results suggested they were allergic to dust mites and/or mold were recruited.People suspected of having ARC or AR were diagnosed using the Allergic Rhinitis and its Impact on Asthma guideline  and DocuAll patients had more than two symptoms of sneezing, nasal itching, watery nasal discharge, and nasal congestion. Physical examination showed a pale nasal mucosa, edema, and watery secretions from the nose. Some patients also had ocular symptoms such as tears, itching, and redness. Mild-to-moderate hyperemia and edema were observed on the conjunctiva by examination using a slit lamp. These patients were classified as the ARC group. Those with nasal symptoms but no ocular symptoms were classified as the AR group. These 60 patients were divided into two groups: 40 with ARC and 20 with AR.Swabs were taken from the conjunctiva and nose. We sampled: 80 eyes and 80 nasal cavities of 40 patients with ARC; 40 eyes and 40 nasal cavities of 20 patients with AR; 68 eyes and 68 nasal cavities of 34 HCs.Using a sterile cotton swab, we wiped the conjunctival sac from the medial side to the lateral side of the inferior fornix (being very careful to not to touch the eyelids). This procedure was repeated thrice. Nasal samples were collected from the surface of inferior turbinate with a sterile swab under guidance by a nasal endoscope. Then, the swabs were placed in sterile tubes. Samples were stored temporarily at 0°C and then transferred to a deep freezer (−80°C) until they were sent to Novogene .® High-fidelity PCR Master Mix , each primer (0.2 μM), and target DNA (10 ng). Cycling conditions comprised an initial denaturation step at 98°C for 1 min, followed by 30 cycles at 98°C (10 s), 50°C (30 s) and 72°C (30 s), and a final extension (5 min) at 72°C. We mixed an equal volume of 1× loading buffer containing SYB green with PCR products and undertook electrophoresis on 2% agarose gel for DNA detection. PCR products were mixed in equal proportions, and the Universal DNA PCR Purification Kit  was used to purify the mixed PCR product. Following manufacturer recommendations, sequencing libraries were generated with Next Ultra DNA Library Prep Kit for Illumina . The quality of libraries was assessed on a 5400 system  and quantified by real-time PCR (1.5 nM). Finally, libraries were sequenced on a NovaSeq™ platform  and 250-bp paired-end reads. Raw data have been deposited in the National Center for Biotechnology Information Sequence Read Archive database (BioProject number: PRJNA899122).Genome-wide DNA from samples was extracted using hexadecyl trimethylammonium bromide and cetyltrimethylammonium bromide (CTAB). The concentration and purity of DNA were monitored on 1% agarose gels. According to the concentration, DNA was diluted to 1 ng/μL with sterile water. If swabs from both sides had been collected successfully, only samples with high DNA yield were collected. The V3–V4 hypervariable region of the 16S rRNA gene was amplified using the fusion primers 341F (5’-ACTCCTACGGGAGGCAGCAG-3’) and 806R (5’-GGACTACHVGGGTWTCTAAT-3’) . All PCR mixtures contained PhusionFLASH 1.2.11  is a rapFor the effective tags we obtained, denoising was undertaken with the “DADA2” module or “deblur” module in QIIME2-202006  to obtaiWe wished to analyze the uniformity, richness, and diversity of bacterial communities in a sample. Alpha diversity was calculated from seven indices in QIIME2: “Observed-OTUs”, “Chao1”, “Simpson”, “Shannon”, “Good’s coverage”, and “Pielou-e”. Two indicators were selected to determine community richness: Chao1 (Chao1 Index) and Observed-OTUs (number of observed species). Two indices were used to determine community diversity: Simpson (Simpson Index) and Shannon (Shannon Index). Good’s coverage was applied to calculate the depth of sequences. Pielou’s Evenness Index was used to calculate the evenness of a species.Beta diversity was calculated based on weighted and unweighted unifrac distances in QIIME2. Beta diversity was employed to evaluate the complexity of community composition and compare differences between samples.Cluster analysis was undertaken by applying principal component analysis. We used the “ade4” and “ggplot2” packages in R 3.5.3  to reduce the dimensionality of raw variables.Principal coordinate analysis (PCoA) was used to obtain principal coordinates and visualize sample differences in complex multidimensional data. A previously obtained matrix of weighted or unweighted unit frame distances between samples was converted into a new set of orthogonal axes in which the maximum coefficient of variation was expressed by the first principal coordinate, the second maximum coefficient by the second principal coordinate, and so on.t-test was done using R 3.5.3 to identify significantly different species at each taxonomic level. Linear discriminant analysis effect size (LEfSe) (threshold of LDA score = 4) was carried out using LEfSe 1.0 to identify biomarkers.The “adonis” and “anosim” functions in QIIME2 were employed to investigate the significance of differences in population structure between groups. The Student’s We wished to study the community function in samples and identify different community functions in different groups. Functional annotation was done using PICRUSt2 2.1.2-b. Functional differences between three groups were examined by one-way ANOVA.The study cohort comprised 40 individuals with ARC, 20 individuals with AR, and 34 HCs. There were no significant differences in age, sex, or disease course among the three groups. The characteristics and detailed demographic information of participants at baseline are presented in With respect to the conjunctival microbiome, a Venn diagram showed that 469 ASVs were shared among the three groups, whereas 14269 were unique for ARC, 3114 were unique for AR, and 15040 were specific for HCs. With regard to the nasal microbiome, a Venn diagram showed that 498 ASVs were shared among the three groups, whereas 8007 were unique for ARC, 4072 were unique for AR, and 8104 were specific for HCs  and with ARC  compared with HCs (p = 0.002) compared with HCs  and p = 0.002 vs. eye of healthy controls (HC.E))  vs. nose of healthy controls (HC.N), p = 0.918 nose of allergic rhinitis (AR.N) vs. HC.N, p = 0.691 ARC.N vs. AR.N; Observed-OTUs: p = 0.276 ARC.N vs. HC.N, p = 0.592 AR.N vs. HC.N, p = 0.675 ARC.N vs. AR.N). The Shannon Index and Simpson Index tended to be lower with ARC and AR compared with HCs .With regard to the nasal microbiome, there was no significant difference in the Chao1 Index or Observed-OTUs among the three groups (Chao1 Index: p = 0.013) and ARC group (p = 0.0293). The Simpson Index of the conjunctival microbiome was significantly higher than that of nasal microbiome of the ARC group (p = 0.001).When comparing the conjunctival microbiome and nasal microbiome of the same group, the Observed-OTUs of the conjunctival microbiome was significantly higher than that of the nasal microbiome in HCs  and between the AR group and HCs . However, there was no significant difference between the ARC group and AR group .The weighted-unifrac distance in the “anosim” package was used to ascertain significant differences in community structure between groups. There were significant differences between the ARC group and HCs . Other phyla accounting for >1% of OTUs were Firmicutes , Bacteroidota , and Actinobacteriota . Proteobacteria was more abundant in the AR group compared with the ARC group  and HCs  . Other phyla accounting for >1% of OTUs were Actinobacteriota , Cyanobacteria , Bacteroidota , and Firmicutes  (Proteobacteria (p < 0.001) and significantly higher abundance of Actinobacteriota (p < 0.05) than patients with ARC or AR.In the three groups (= 0.005) Table 2.Pseudomonas, Ralstonia, Cupriavidus, Muribaculaceae, Bacteroides, Corynebacterium, Faecalibacterium, Blautia, Prevotella, and Lactobacillus. The top-three most prevalent candidates in patients with ARC or AR were the genera Pseudomonas , Ralstonia , and Cupriavidus . However, the most abundant genus in HCs was Ralstonia (43.64%). Other genera accounting for >1% in HCs were Cupriavidus (11.16%), Pseudomonas (9.09%), Bacteroides (2.82%), Faecalibacterium (1.98%), and Blautia (1.24%). The abundance of Pseudomonas was markedly higher in the ARC group and AR group than that in HCs . The abundance of Ralstonia was markedly higher in HCs compared with that in the ARC group and AR group  , Ralstonia , Cupriavidus , Corynebacterium , and Moraxella . The most abundant genera of the nasal microbiome in HCs were Ralstonia (39.24%), Corynebacterium (9.14%), Chloroplast (7.2%), Cupriavidus (4.56%), Serratia (4.2%), Cutibacterium (2.48%), Mitochondria (2.07%), and Muribaculaceae (1.73%) (Pseudomonas was markedly higher in the ARC group and AR group than that in HCs (p < 0.001). The abundance of Ralstonia and Serratia was markedly higher in HCs compared with that in the other two groups.In the three groups (= 0.002) Table 4.We used the LEfSe algorithm to analyze the structure of the bacterial community associated with the three groups. LEfSe is a high-dimensional algorithm that uses LDA to estimate the effect of differential expression of each taxonomic unit in two groups.Pseudomonas for the ARC group and Ralstonia for HCs ”, “CDP-diacylglycerol biosynthesis II”, and “CDP-diacylglycerol biosynthesis I” were enriched significantly in the ARC group and AR group. “Aerobic respiration I (cytochrome c)”, and “pyruvate fermentation to isobutanol (engineered)” were predicted to be enriched in HCs. With regard to the nasal microbiome, among the 10 major metabolic pathways, “fatty acid salvage”, “gondoate biosynthesis (anaerobic)”, “CDP-diacylglycerol biosynthesis II”, and “CDP-diacylglycerol biosynthesis I” were enriched significantly in the ARC group and AR group. “Aerobic respiration I (cytochrome c)” and “L-tryptophan biosynthesis” were predicted to be enriched in HCs.ARC is one of the most common inflammatory disorders. Patients with AR have nasal-allergy symptoms without eye discomfort. Nevertheless, little is known about the microecological differences in the ocular surface and nasal cavity in patients with ARC or AR.The composition of the microbiota population and host–microbe interactions have key roles in inflammation. Hence, we investigated, for the first time, the microbiota in the ocular surface and nasal cavity in patients with ARC or AR.Alpha diversity indicates the average species diversity in a given sample. In the present study, the abundance of the conjunctival microbiome in the ARC group and AR group was lower than that in HCs. The diversity of the conjunctival microbiome was significantly lower in the AR group than that in the other two groups. The diversity of the nasal microbiome in the ARC group and AR group was significantly lower than that in HCs. Reduced diversity is considered to be an indicator of unhealthy microbes, and has been associated with different chronic diseases. For instance, reduced diversity of the gut microbiota has been documented in obesity and type-2 diabetes mellitus . Hence, Beta diversity denotes the ratio between regional and local species diversity. The “anosim” package revealed significant differences in the community structure of the conjunctival microbiome and nasal microbiome between HCs and patients with ARC or AR, with between-group differences being greater than within-group differences. However, there was no significant difference between the ARC group and AR group in terms of beta diversity.Proteobacteria being the most abundant, followed by Firmicutes, Bacteroidota, and Actinobacteriota. There was no significant difference in abundance between the ARC group and HCs when comparing the abundance of the four main phyla, but the AR group had significantly more Proteobacteria and significantly fewer Actinobacteriota compared with the HC group. The nasal microbiome of the three groups was enriched with Proteobacteria and Actinobacteriota, whereas HCs had significantly fewer Proteobacteria and significantly more Actinobacteriota than patients with ARC or AR. Proteobacteria was the most abundant phylum among the three groups in the conjunctiva or nasal cavity, but was less abundant in HCs than in the other two groups.We showed that the top-four rankings of the three groups for the conjunctival microbiome at the phylum level (as well as the order) were identical, with Ralstonia, Cupriavidus, Pseudomonas, Bacteroides, Faecalibacterium, Methyloversatilis, and Blautia. Genera accounting for >1% in the ARC group were Pseudomonas, Ralstonia, Cupriavidus, Muribaculaceae, Methyloversatilis, Lactobacillus, and Vibrio. Genera accounting for >1% in the AR group were Pseudomonas, Ralstonia, and Cupriavidus. Although the top-three genera accounted for an identical number of species, there were differences in relative abundance, with significantly more Pseudomonas and significantly fewer Ralstonia in the ARC group and AR group than in HCs. Among the top-10 genera in the three groups, Faecalibacterium and Prevotella were significantly less abundant and Lactobacillus was significantly more abundant in the ARC group than in HCs. The abundance of Muribaculaceae and Corynebacterium was significantly lower in the AR group than in HCs. With regard to the nasal microbiome, there was no significant difference between the ARC group and AR group, with Pseudomonas, Ralstonia, and Cupriavidus being the top-three genera. There was a significant difference between HCs and patients with ARC or AR. The abundance of Pseudomonas was significantly higher in the ARC group and AR group than in HCs. The abundance of Ralstonia and Serratia was significantly higher in HCs than in patients with ARC or AR. In the conjunctival microbiome and nasal microbiome, Pseudomonas was the most abundant genus in the ARC group and AR group, whereas Ralstonia was the most abundant genus in HCs.With respect to the conjunctival microbiome, the genera accounting for >1% in HCs were Actinobacteriota, Proteobacteria, and Firmicutes. The six genera with the highest relative abundance have been reported to be Corynebacterium, Streptococcus, Propionibacterium, Bacillus, Staphylococcus, and Ralsentia (Proteobacteria (64.4%), Firmicutes (15.5%), and Actinobacteriota (15.0%)), which have also been found to have the highest relative abundance in conjunctiva  were Ralstonia, Enterococcus, Streptococcus, Halomonas, Corynebacterium, Staphylococcus, Acinetobacter, Shewanella, Rhodococcus, and Cobetia  cells/Th2 cells are in balance. However, in patients with allergic diseases, this balance is disturbed, leading to differentiation of T cells towards Th2 cells. Several studies have linked biological disorders to the development of allergic diseases in different anatomic regions . The com species –51. Howe species , and the species . HoweverThe study has some limitations. Firstly, the Shannon curve and the species rarefaction curve showed that the samples collected are representative of the population as a whole. Further study of larger sample sizes or samples collected from different geographic groups or seasons is needed to confirm the consistency of these results. Secondly, clinical parameters included only gender, age and course of disease, and no difference was shown in each subgroup. Subtypes and severity of allergic rhinoconjunctivitis and their relationship to microbiome composition have not been collected and further analyzed. Thirdly, it is important to validate the results by different methods, for example, PCR validation of the main findings of phyla, genus, etc. Future investigations are necessary to validate the conclusions from this study.This was a preliminary study to discover if there was ecological dysregulation in patients with ARC or AR compared with HCs. By analyzing alpha diversity, beta diversity, microbiome composition, and their relative abundance, we found changes in the microbiota of the conjunctival sac and nasal cavity. Our data provide deeper understanding of the mechanism responsible for ARC and AR.https://www.ncbi.nlm.nih.gov/ accession number: PRJNA899122.Publicly available datasets were analyzed in this study. This data can be found here: The studies involving human participants were reviewed and approved by the ethics committee of TEDA Hospital . The patients/participants provided their written informed consent to participate in this study.YW designed the study, collected data, and wrote manuscripts. XL designed the study and revised the manuscript. SG performed the statistical analysis and interpretation of the results. JF collected data. All authors read and approved the final manuscript.


Rehabilomics is an important research framework that allows omics research built upon rehabilitation practice, especially in function evaluation, outcome prediction, and individualized rehabilitation. In the field of rehabilomics, biomarkers can serve as objectively measured indicators for body functioning, so as to complement the International Classification of Functioning, Disability, and Health (ICF) assessment. Studies on traumatic brain injury (TBI), stroke, and Parkinson's disease have shown that biomarkers  are correlated with diagnosis, disease severity, and prognosis. Rehabilomics also examines a wide range of individual biological characteristics in order to develop personalized rehabilitation programs. Secondary prevention and rehabilitation of stroke have already adopted a rehabilomic approach to individualize treatment programs. Mechanisms of non-pharmacological therapies are expected to be unveiled in light of rehabilomics research. When formulating the research plan, learning from established databases is recommended and a multidisciplinary collaborative team is warranted. Although still in its infancy, the advancement and incorporation of rehabilomics has the potential to make a significant impact on public health. Rehabilitation offers services for populations who differ in individual impairments, functional limitations, and response to treatments. Rehabilitation practitioners tailor programs to clients based on their specific needs, individual dysfunctions, and personal factors, thereby making standardized protocols not optimal for maximizing individual outcomes. The issue of individual variability comes to the fore when verifying the therapeutic effect of a particular intervention or clinical decision . DiffereBiomarkers are a group of objectively measured indicators of physiology, pathogenic processes, or response to treatments . In mostThe World Health Organization (WHO) proposed ICF in 2001 , which iNumerous studies have shown that serum biomarkers can predict the risk of cognitive and behavioral dysfunctions in traumatic brain injury (TBI). Serum hormones, inflammatory markers, and neurotrophic factor levels can predict fatigue , depressNotably, the biomarkers in rehabilomics are not limited to microscopic molecules such as gene expression, proteins, and metabolites. Emerging studies using medical imaging, electrophysiological indicators, and sensor data in rehabilomics have become a new research focus. Omics research based on medical imaging data is called “Radiomics” . MagnetiWith the popularization of wearable devices, digital biomarkers collected by sensors have gradually gained attention. Built-in sensors such as accelerometers and gyroscopes in mobile devices are capable of converting motion characteristics into digital signals, which can serve as quantitative surrogate indicators of diagnosis and assessment of Parkinson's disease , 26. DigRehabilomics is a biomarker-centered framework that not only complements existing evaluation metrics but also examines a wide range of individual biological characteristics to develop individualized rehabilitation programs. Taking stroke as an example, rehabilomics research has provided new insights for stroke prevention and rehabilitation. In the secondary prevention of stroke, the commonly used antiplatelet drug clopidogrel needs to be converted into its active metabolite by hepatic cytochrome p450 (CYP) to take effect, and decreased effects of clopidogrel were observed in carriers of CYP2C19 loss-of-function allele . HoweverStinear et al.  proposedDue to the modifiability of the gut microbiome, its application in rehabilitation settings has also gained research interests . MultiplWith advances in the biomedical field, rehabilomics research may contribute to the identification of non-pharmacological therapeutic mechanisms. Immune cells in the tumor microenvironment have become the basis for a new paradigm of exercise therapy for cancer. Researchers have found that voluntary movement induces an influx of immune cells into tumors and reduces tumor incidence and proliferation by more than 60% in several mouse models . The mosIn the authors' opinions, the appropriate timing for using biomarkers in clinical decision-making depends on what the specific decision is, namely diagnosis, prognosis, or treatment strategies. When examining the diagnosis, the use of biomarkers certainly is as early as possible to acquire the information needed. Likewise, the investigation of predicting function outcomes (prognosis) requires early use of biomarkers (if any), as further time since the onset of a condition introduces increasingly more factors that contribute to function. These early stages often involve rapid changes in the underlying disease processes, biomarkers may provide critical information for early diagnosis –22 and pSeveral limitations in the application of biomarkers in rehabilitation need to be considered. One limitation is the lack of specificity, as some biomarkers can be elevated or altered due to other conditions or factors, leading to false positive or false negative results. For example, heartrate variability has been associated with a number of conditions/symptoms , and mayWhen formulating a rehabilomics research plan in clincal studies, multiple issues must be considered, including (1) Construction of a research framework including a real-world cohort with the rigorous design of acquisition variables ; (2) Measurement and collection of biomarkers including genetics, epigenetics, microbiomics, metabolomics, medical imaging, and sensor data; (3) Infrastructure required for large-scale longitudinal studies and long-term follow-up information, involving the establishment and maintenance of databases; (4) Standardization of analysis workflow for informatics, including imaging information based on expertise and data characteristics. To ensure the reproducibility of rehabilomics research, three basic elements including data management, analysis process, and algorithm code need to be considered . To our The identification of rehabilitation-related biomarkers often requires the use of machine learning algorithms to establish models by screening features. Some commonly used machine learning algorithms in rehabilitation such as support vector, Random Forest Logistic Regression (LR) has been of value in rehabilitation evaluation. Toyohiro Hamaguchi et al. developed a support vector machine (SVM)-based classifier to train and test the kinematics-related parameters of peak angle and peak velocity in stroke patients with finger movements impairment. High separation accuracy was obtained when predicting the classification of paralytic movements . DomenicIn the framework of machine learning, there are generally two datasets, one is used to train the model, and the other is used to test or verify the performance of the model . Based oRehabilomics is a theranostic approach that exploits biomarkers for evaluation of rehabilitation process/outcomes, as well as for personalized treatment programs and identification of therapeutic mechanisms. Although still in its infancy, the advancement and incorporation of rehabilomics has the potential to make a significant impact on public health.WC and XZ contributed to the manuscript writing and revision. HQ conceived the study, conducted literature review, and wrote the initial draft. All authors contributed to the article and approved the submitted version.


The understanding of ion dynamics in plasma applications has received significant attention. In this study, we examined these effects between He and Ar species, focusing on the Ar ion flux on the substrate. To control heterogeneous collisions, we varied the He addition rate at fixed chamber pressure and the chamber pressure at fixed Ar/He ratio in an inductively coupled Ar/He plasma source. Throughout the experiments, we maintained an electron density in the bulk plasma and plasma potential as a constant value by adjusting the RF power and applying an additional DC bias to eliminate any disturbances caused by the plasma. Our findings revealed that the addition of He enhances the Ar ion flux, despite a decrease in the Ar ion density at the plasma–sheath boundary due to the presence of He ions. Moreover, we found that this enhancement becomes more prominent with increasing pressure at a fixed He addition rate. These results suggest that the heterogeneous charge transfer collision between Ar atoms and He ions in the sheath region creates additional Ar ions, ultimately leading to an increased Ar ion flux on the substrate. This finding highlights the potential of utilizing heterogeneous charge transfer collisions to enhance ion flux in plasma processing, without the employment of additional equipment. Plasma, also known as the fourth state of matter, is an ionized gas that exhibits collective behavior and electrically quasi-neutral characteristics . It consRadical species play a dominant role in surface chemistry processes such as etching, polymerization, and oxidation on material surfaces. These radicals are primarily generated through dissociative electron impact collisions between electrons in the plasma and feedstock gases. For instance, in the plasma etching of silicon (Si) and silicon dioxide  source, the details of which have been comprehensively described elsewhere . In thisWe maintained the electron density and plasma potential at fixed values to mitigate any disturbances by plasma-induced effects such as ion flux and energy variations by plasma density and potential fluctuations, respectively. To control these parameters, we controlled both the RF power and the applied direct current (DC) bias voltage  on the copper rod depicted in For the He addition experiment, the displayed helium flow rate from the MFC controller is not accurate because the MFC used for He gas injection is optimized for Ar gas injection. Alternatively, we utilized the vacuum gauge to accurately measure the partial pressures of Ar and He gases, enabling the precise control of the small fraction of He addition ratio, typically a few percent. During the IFEDF measurement, the chamber pressure was set to 1.3 Pa (10 mTorr). However, at such low pressure, the He partial pressure fell below 0.1 Pa (1 mTorr), which was below the minimum measurement range of the vacuum gauge. To overcome this limitation, we employed an alternative method described below.Initially, Ar gas was introduced to establish a chamber pressure of 13.3 Pa (100 mTorr). Then, He gas was injected to increase the chamber pressure to approximately 0.3 Pa (2 mTorr), resulting in the total pressure of 13.6 Pa (102 mTorr). The gate valve, located beneath the pumping outlet shown in Regarding the pressure variation experiment, we adjusted the open ratio of the gate valve while maintaining a fixed gas mixture of Ar/He at a ratio of 15 to 5.To measure electron density (To sweep the voltage (V) across the Langmuir probe and measure the resulting current (I), we employed a commercial control system  and accompanying software . Since the Langmuir probe method is widely used ,40, we pThe plasma potential (As shown in E) using the following equation:To calculate the total Ar ion flux ) at a constant chamber pressure. To examine the effects of chamber pressure variation at a fixed Ar/He ratio, the IFEDF was investigated as the chamber pressure increased. Additionally, the IFEDF was examined in a pure Ar environment with the same chamber pressure variations, serving as a reference to distinguish between homogeneous and heterogeneous collision effects within the sheath. e is the elementary charge, The ion flux at the plasma–sheath boundary (PSB), velocity . In an Aelocity [ne=nAr++nequation:ΓAr+PSB=nequation:ΓAr+PSB=nThe heterogeneous ion-atom ionization between an Ar atom and a He ion is expressed as:Typically, ions can transfer only a small fraction of their kinetic energy, approximately ∼>100 eV) . ConsideOn the other hand, the heterogeneous charge transfer collision between an Ar atom and He ions is described as:d plasma . Converss) can be assumed to be constant due to the fixed The heterogeneous charge transfer can be enhanced with increasing chamber pressure. In general, the collision mean free path (e and Vp . This imIn this study, we investigated the impact of heterogeneous collisions on the Ar ion flux on the substrate. Our findings demonstrate that the addition of He gas enhances the Ar ion flux, both at a fixed chamber pressure and with increasing pressure at a fixed He addition ratio. While the quasi-neutrality condition suggests a decrease in Ar ion density with the addition of He ions, the observed increase in Ar ion flux implies the creation of Ar ions in the sheath through heterogeneous collisions. Specifically, the heterogeneous charge transfer of Ar atoms with He ions was found to significantly enhance the Ar ion flux on the substrate.In conclusion, our study provides insight into the role of heterogeneous collisions in influencing the Ar ion flux. The results highlight the importance of considering heterogeneous charge transfer processes in understanding and controlling ion fluxes in plasma systems.


We aim to determine a comprehensive set of requirements, perceptions, and expectations that people with spinal cord injury (SCI) and the clinicians in charge of their rehabilitation have regarding the use of wearable robots (WR) for gait rehabilitation.There are concerns due to the limited user acceptance of WR for gait rehabilitation. Developers need to emphasize understanding the needs and constraints of all stakeholders involved, including the real-life dynamics of rehabilitation centers.15 people with SCI, 9 without experience with WR and 6 with experience with these technologies, and 10 clinicians from 3 rehabilitation centers in Spain were interviewed. A directed content analysis approach was used.78 codes grouped into 9 categories  were expressed by at least 20% of the users interviewed, of whom 16 were not found in the literature. The agreement percentage between each group and subgroup included in the study, calculated as the number of codes that more than 20% of both groups expressed, divided over the total amount of codes any of those two groups agreed on (≥ 20%), showed limited agreement between patients and clinicians (50.00%) and between both types of patients (55.77%). The limited accessibility and availability of lower limb exoskeletons for gait rehabilitation arose in most of the interviews.The limited agreement percentage between patients and clinicians indicates that including both types of users in the design process of these technologies is important, given that their requirements are complementary. Engaging users with prior technology experience is recommended, as they often exhibit strong internal consensus and articulate well-defined requirements. This study adds up the knowledge available in the literature and the new codes found in our data, which enlighten important aspects that ought to be addressed in the field to develop technologies that respond to users’ needs, are usable and feasible to implement in their intended contexts.The set of criteria summarized in our study will be useful to guide the design, development, and evaluation of WR for gait rehabilitation to meet user’s needs and allow them to be implemented in their intended context of use.The online version contains supplementary material available at 10.1186/s12984-023-01264-y. During the last 30 years, we have witnessed an increase in the development and testing of robotic wearable (WR) exoskeletons for walking rehabilitation following spinal cord injury (SCI). The intended effect of these devices is to induce neuroplastic changes through intensive walking training , while aIn parallel, the scientific community is also becoming interested in the limitations related to users’ acceptance of WR and their interactions. Qualitative research allows exploring this phenomenon from the user’s point of view. Researchers have studied the perception of both patients and clinicians about the technologies after one session with a WR through face-to-face interviews , 7, usinTherefore, the limited clinical evidence regarding WR for gait rehabilitation, their lack of customization, and the constraints in user acceptance, arise doubts as to whether it is worth investing in these pricey technologies , since tA qualitative study using directed content analysis was conducted , followiThe initial codes and categories to implement the directed content analysis methodology were established based on a literature survey. An advanced search in the Scopus database was performed comprising the period until December 31st, 2020, using the query string “(exoskeleton) AND (user AND center* AND design) OR (perception) OR (experience) OR (perspective*)”, only research articles and reviews written in English were considered. Further selection was performed by reading the title and abstract, when necessary, to guarantee that the included articles assessed lower limb exoskeletons for gait rehabilitation in terms of the users’ perspective or experience.The National Hospital for Paraplegics (HNP) is the main monographic public hospital for intensive rehabilitation of SCI in Spain. Institute Guttmann (IG) is the main private foundation for rehabilitation of neurological injuries in the region of Catalonia. Both have vast experience in cooperating in research projects devoted to the development and evaluation of rehabilitation technologies, including lower limb exoskeletons. Spinal Cord Injury Foundation (FLM) is a private neurorehabilitation center located in Madrid, Spain, that provides integral rehabilitation, including therapy with lower limb WR, for people with SCI after their discharge from rehabilitation hospitals.Both people with SCI and clinicians were separately considered as end-users, as they might have different perspectives and requirements. In addition, and to better understand the impact of the technology on patient's expectancies, we split the SCI group within patients with and without previous experience with WR (e-SCI and n-SCI respectively). We aimed at assessing different perspectives: feedback about actual technologies and requirements that arose from experience (e-SCI and clinicians), expectations and unbiased requirements for the technologies (n-SCI), and expert advice on the requirements for the technologies to be effective as a gait rehabilitation tool (clinicians). The common exclusion criteria were inability to communicate in Spanish, inability to use to use crutches or a walker to walk with the WR, difficulties in comprehension and communication, and refusal to participate in the study. This research complied with the Declaration of Helsinki and was approved by the Institutional Review Board at the Ethics Committee of the Hospital Complex of Toledo, Spain . Informed consent was obtained from each participant.The sample size was determined following the estimates presented in , where iSimilarly, for the clinicians user group, physical medicine and rehabilitation physicians (PM&R) and physiotherapists (PT) involved with the rehabilitation of people with SCI and/or with experience in research with WR were recruited through convenience and snowball sampling techniques  between Individual, semi-structured interviews led by a theme-based interview guide with open-ended questions were used to obtain detailed descriptions of the themes previously identified in the literature , these were reviewed and corrected manually. Two authors analyzed each transcription performing deductive content analysis, following the directive content analysis approach [www.microsoft.com/microsoft-365/excel, Redmond, WA, USA). The whole codification process is shown in Fig. Verbatim transcriptions of all interviews were made using the semi-automated transcription software Amberscript , usability (17), psychology related codes (15), technical characteristics (14), activities (12), acquisition issues (4), context of use (3), development of the technologies (5), and clinical rehabilitation context (7). The full list is available in Additional file 1, usabilOur sample of primary users consisted of 15 adults with spinal cord injury 4 women, 26.67%), aged 45.5 ± 13.2 years (range 20 to 65 years), and with a median of 7.1 months since injury onset . All participants had a diagnosis of SCI with various degrees of impairment to walk, different etiologies of the injury , and a variety of injury classification : five PM&R and five PT. Average age was 41.8 ± 12.7 y.o. (range 26 to 62 years), and had on average 12.2 ± 10.6 years of experience working with SCI (range 2 to 30 years)  were not previously identified in the literature . This analysis showed that patients and clinicians agreed on 50.00% of the codes, n-SCI and e-SCI agreed on 55.77% of the codes, clinicians and e-SCI agreed on 45.83% of the codes and lastly, clinicians and n-SCI agreed on 45.45% of the codes.N). Some codes in the figures have a sign (*) at the end, representing that some users that talked about the same code but with a different perspective from the other users; these cases are detailed in the description of the corresponding figure.To visualize the codes expressed by at least 20% of clinicians or people with SCI, we use column charts showing the relative frequency of each group that referred to each code. Figures for each category are comprised within Figs. In this category, two out of the four new codes that emerged were related to negative aspects such as 40% of the patients having fears about using exoskeletons or 50% of the clinicians and 22.20% of n-SCI having reasons to reject their use. Examples of the fears are: falling, damaging the device, “doing it wrong”, and hurting one-self and affecting body parts that are currently healthy. Patients’ reason not to use the technologies is that for their recovery and independence it is better to do all the activities they can without the exoskeleton, and they need to know their capabilities at the end of their sub-acute rehabilitation to assess if an exoskeleton is needed. For clinicians the reasons include: the need to adapt to a new technology that could be complex to use, lack of trust towards technologies due to the fear that they will replace physiotherapists in their workplace, having to lift and move heavy devices, and believing that traditional therapy is better than robot-assisted therapy.Through qualitative research, we managed to determine a comprehensive set of requirements, perceptions, and expectations that people with spinal cord injury and the clinicians in charge of their rehabilitation have for the design of lower limb wearable exoskeletons for gait rehabilitation. To our knowledge, this is the first research comparing the expectations of people with SCI without experience in the use of exoskeletons versus the requirements of experienced users, and most importantly, the first study that aims to summarize a comprehensive list of criteria for the design of these technologies, encompassing the knowledge available in the literature and allowing new criteria to emerge from our own data. Both the criteria summarized in our study and the additional ones from literature , shows even though less clinicians than patients were interviewed, they agreed on more codes in interviews that were almost 1/3In relation to intergroup agreement rates, the agreement percentage among both types of patients (55.77%) demonstrates the contrast between the expectations from n-SCI and the “down-to-earth” requirements from e-SCI, and therefore, the complementarity of their requirements. Indeed, including both types of patients in this study and people with injuries of different severity was aimed at seeking requirements representative of the heterogeneous SCI population. Similarly, the intergroup agreement percentage of 50.0% between patients and clinicians indicates that including both type of users in the design process of these technologies is a must, given that their requirements are complementary. As shown in our results, both patients and clinicians agree on the importance of involving both types of users in the design and development of lower limb wearable exoskeletons, and they are motivated and willing to participate in these processes , 58. TheWith respect to the agreement intragroup see Fig. , cliniciThe new codes found in our data are one of the most important contributions of our paper. Considering the use of lower limb exoskeletons in rehabilitation settings, it is very important for PT that the devices have manageable weights and are easy to handle and move around, to not to increase the physical burden during therapy due to the manipulation of the device. All three groups agreed on the relevance of having devices that can be fit to different bodies and functionally adapted according to the patient needs, since these needs differ from user to user due to their specific impairment, and also evolve along therapy. Overall, there is a lack of scientific evidence to identify the specific population that can benefit from each technology depending on its features, as well as regarding the specific protocols that allow to optimize their use as rehabilitation devices .Mostly clinicians and some e-SCI demand an improvement in the interaction of the device with the surroundings through sensors that help the device to automatically adapt to different scenarios, and an improvement in the interaction of the device with the person wearing it by closing the control loop through biofeedback and intention detection to move the exoskeleton. The latter is key to enhance neuroplasticity in robotic-assisted gait rehabilitation . To thesIt is also very important to understand the fears that SCI people have regarding the use of these devices, because they ought to be addressed during the design of the technologies and when training the users, to allow them to trust the device and have a smooth interaction. Similarly, it is imperative to address clinicians’ concerns regarding the perceived threat of exoskeletons for walking rehabilitation through education. Exoskeletons for gait rehabilitation are not meant to replace physiotherapists, instead, they are meant to be a new tool to assist clinicians for physical therapy, exactly like the healthcare workers of our study expressed. Previous experiences with similar technologies, including for example the Lokomat, can show clinicians that these devices allow to provide intensive rehabilitation reducing the physical burden that PT have in traditional therapy, allowing them to (1) invest the time in more observation and evaluation of the progress of patients, (2) have more time available to design better therapy plans for patients and (3) have objective data regarding the patient movement and evolution, provided by the devices.All types of users interviewed in this study suggest an increase in funding for lower limb exoskeletons, mostly because they consider these technologies are still under development. Nonetheless, currently there are six (6) devices CE marked, and there are at least four times more devices in different development stages , most ofThe complete set of criteria summarized in our study, encompassing both the knowledge available in the literature and the new criteria that emerged from our own data, will be useful to guide developers of WR for gait rehabilitation in the design, development and evaluation of their technologies, to make sure the efforts invested in the field lead to technologies that respond to the needs and expectations of their end users and are feasible to implement in their intended context of use. Additionally, we emphasize the need to implement User-centered design and usability evaluation in the field, in line with the findings of this study.Qualitative research, due to its emphasis on in-depth understanding and context-specific insights, does not lend itself to statistical generalization of findings to the broader population . NeverthA potential limitation to the generalizability of the results is that the data collection was held in Spain, a country with a public health system. This could represent cultural differences in some of the expectations of users from other countries without a public health system, particularly those regarding the accessibility of the technologies and the constraints to effectively implement the technologies in clinical rehabilitation settings. Nevertheless, we consider user’s requirements in 6 out of the 9 categories presented in our study  are most likely preserved within people with a spinal cord injury regardless their country of residence, since their demands depend more on the functional limitations caused by the injury and the intrinsic condition of being humans interacting with a robotic device than by cultural expectations.Both the chronicity and injury severity differences between the subgroups of people with SCI are another limitation of this study, since they could have influenced the perspectives of the users interviewed. As indicated in the manuscript, the subjects were recruited through criterion and convenience sampling techniques, therefore, despite the research team sought for heterogeneity and managed to have both complete and incomplete SCI subjects in both patients’ subgroups, a more balanced sample was not feasible to be recruited for this study. Requirements of incomplete and complete SCI are indeed complementary instead of equivalent. The formers use WR for gait rehabilitation as tools to improve their ability to walk whereas the latter use them for gait rehabilitation mostly due to the physical and psychological benefits that these technologies represent, but not to improve their ability to walk. This is why it was imperative to gather insights in both subgroups and in the whole study from both types of subjects, to effectively summarize a comprehensive set of requirements from a heterogeneous sample of SCI subjects.Regarding the chronicity of the injury, the marked difference is due to the type of centers where each subgroup was recruited. One is meant for subacute inpatient rehabilitation while the other is for chronic rehabilitation after discharge from the first institution. The research team aimed to recruit both subgroups only from HNP but there were no experienced subjects in the institution, given that no active or recent research was ongoing with WR devices for gait rehabilitation due to the pandemic. Therefore, an alternative center with people with SCI with experience in the use of these technologies had to be included in the study, and due to proximity, cultural, and convenience reasons, the FLM was the institution reached to recruit the e-SCI sample. In spite of this limitation, the authors consider that the chronicity of the injury could possibly affect mostly the expectations expressed between the acute and the beginning of the subacute phase of the injury, with respect to the chronic phase, because SCI subjects are reaching the plateau of their gait rehabilitation by the end of the subacute period of their injury (6 months approximately), where the enhanced period of neuroplasticity is over. Taking this into account, the average time since injury of the n-SCI is by the end of the subacute period, and therefore, no massive differences are estimated between the expectations of these subjects and the ones expressed by the e-SCI. The time undergone in intensive rehabilitation is also essential to understand the rehabilitation goals of each subject with the specific characteristics of their injury and their maximum expected recovery. Therefore, while undergoing the subacute period, people with an SCI learn to understand their injury and adapt their lives while seeking the maximum possible rehabilitation, where the WR for gait rehabilitation could help.The research team was aware of these limitations regarding the differences in severity and chronicity of the injuries and decided to provide and analyze the overall requirements of SCI subjects as a whole and the subgroup statistics separately, to make both results available to developers and researchers in the field. In this way, this limitation does not affect the requirements summarized for the whole group of people with SCI.People with spinal cord injury and the clinicians in charge of their rehabilitation are stakeholders of exoskeletons with complimentary design requirements, thus, both must be involved in designing technologies that are usable, respond to users’ needs and that are feasible to implement in their intended contexts, because currently, there is limited accessibility and availability of lower limb exoskeletons for gait rehabilitation. This can be achieved through implementing User-centered design during the development of these technologies: users interviewed are motivated to participate in the developments and they agreed on the relevance of being involved. We provide a comprehensive set of requirements, perceptions, and expectations of these users for the design of lower limb wearable exoskeletons for gait rehabilitation that can serve as a starting point for developers.Additional file 1: Semi-structured interview guide.Additional file 2: Full list of codes found in the study and in the literature survey.


The ringing of a bell has become an honored and cherished tradition in the realm of cancer survivorship care. As a medical student, I was initially unaware of this practice, but I have since gained a profound appreciation for its deep significance and emotional potency. Through the act of ringing the bell, patients who have successfully completed their cancer treatment are able to mark the end of a gruelling journey, while also heralding the start of a new and hopeful chapter in their lives. In recent years, the tradition of bell ringing has become a beloved and celebrated custom in the world of oncology and cancer survivorship care. The concept is rooted in the notion that when a patient successfully completes their cancer treatment, they are invited to ring a bell to symbolize the end of their battle and the beginning of their journey as a triumphant cancer survivor . As a meWith each tug, the sound of the bell filled the air, reverberating with a power that spoke to the strength and resilience of the human spirit. In that moment, I realized that the act of ringing the bell was not just a simple tradition, but a profound and deeply meaningful symbol of hope and triumph over adversity. It was a reminder that even in the darkest moments, there is always the potential for light and the possibility of a brighter tomorrow. The ringing of the bell was a testament to the indomitable spirit and steadfast resilience of cancer patients, a reminder of the unwavering support they receive from their loved ones and the dedicated healthcare professionals. Yet, it was also a poignant reminder of the profound emotional toll that cancer takes on individuals and their families, a bittersweet reminder that each ring of the bell encapsulates a singular and intensely personal odyssey of anguish, trepidation, and optimism.As I watched the middle-aged woman triumphantly ring the bell, I couldn't help but think of the countless others still undergoing treatment, looking on with both hope and longing. For those in the midst of their cancer journey, witnessing the bell ringing ceremony can be a source of both inspiration and pain, as they are reminded of the difficult road ahead, yet also filled with a sense of hope that one day, they too will ring that bell. Conversely, the bell ringing ceremony can also be a double-edged sword, evoking both hope and fear. It serves as a stark reminder of the challenges that lie ahead and it can be a painful reminder of the struggles they are still facing.Nevertheless, the need for cancer having an outlet to help them cope with the physical and emotional challenges of their disease is heavily recognized. Much of the research on this topic focuses on this outlet being present during the cancer journey but starting the cancer-free journey also requires adequate support and resources to help survivors navigate their new normal . The rin


Asthma is a chronic lung disease that primarily affects the lower respiratory tract in more than 300 million people worldwide. Asthma is often triggered by exposure to certain substances or conditions, such as allergens or cold air. The overreaction to the allergens causes inflammation and narrowing of the airway, which leads to episodic or persistent symptoms including shortness of breath, nocturnal cough, chest tightness, and wheezing.in vivo.Recently, significant progress has been made in understanding AR development. Miki et al have successfully identified the LIGHT-LTβR non-canonical nuclear factor-κB (NF-κB) signaling pathway as the direct regulator of airway smooth muscle hyperresponsiveness (AHR) and AR pathogenesis in severe asthma.in vitro, indicating potential myofibroblast contamination in ASM cell culture in certain in vitro studies.This finding shed light on potential strategies for AR targeting asthma treatment. For instance, candidates for drug screening include inhibitors that block the LIGHT-LTβR interaction or the non-canonical NF-κB signaling in ASM cells. However, more investigation is needed to validate whether AR development is dependent on the same signaling pathway in humans. In addition, apart from ASM cells, airway myofibroblasts are also implicated in AR. Myofibroblasts are essential for inflammation and repair. With characteristics of both fibroblasts and smooth muscle cells, myofibroblasts are difficult to identify due to the lack of a specific cell marker, which is also why they have been overlooked in most asthma studies. It is also known that myofibroblasts can secrete cytokines and promote AR, and can be formed from various cell types, including local fibroblasts, smooth muscle cells, and epithelial cells. ASM cells can develop a myofibroblast-like cell type when cultured There is no conflict of interest to declare.


Background: Augmented reality (AR) is a novel technology with many applications in medical education. Perhaps one of the most beneficial potential applications is to enable better clinical access for students; however, there is limited research into this use. The purpose of this mixed-methods feasibility study was to evaluate the applicability and acceptability of AR in undergraduate and early postgraduate medical education.Methods: Single-group quasi-experimental study design was developed for critical care-themed simulation teaching delivered using Microsoft HoloLens . Post-test questionnaires were completed including a validated adapted immersive experience questionnaire (AIEQ) and an abridged intrinsic motivation inventory (AIMI). The AIMI focused on the domains of ‘interest and enjoyment’, and ‘value and usefulness’. Following the teaching, focus group interviews with thematic analysis were conducted to evaluate participants’ experiences with AR.Results: All 15 participants (100%) completed the AIEQ and AIMI. Co-located airway teaching  was reported as having a moderate level of user immersion (median 72) and a high level of user enjoyment and value (median 52). Thematic analysis revealed four key themes: visual conceptualization for learning, accessibility, varied immersion, and future application. Conclusions: Remote simulation for the management of airways in critical care was found to be acceptable and afforded a high level of enjoyment and value. Similarly, this was reflected in the thematic analysis. However, immersion was rated variably in both AIEQ and thematic analysis. The challenges identified with the application of AR included technical infrastructure and patient consent. AR-enabled education benefits are relevant to a number of clinical teaching areas. DefinitionsAugmented reality (AR) is defined as a technology that allows virtual elements to be superimposed onto the user’s perspective of their surroundings. This can be further subdivided into “pass-through AR” where real-world images are captured on camera and displayed by screen to the user (eg. smartphone AR applications/some head-mounted displays (HMDs); and “see-through AR” where the real world is viewed directly through the visor of the HMD with overlaid virtual elements displayed concurrently .Development of ARForays into AR date back to the 1960s , but iniA pilot study in anatomy training using HoloLens demonstrated significant potential for medical education , and CasThree integrative reviews have suggested that there has been a lack of learning theory behind its use -7, despiAR in medical educationAR has an increasing role in medical education with various functions, including creating an immersive environment and authentic participatory reality , and intAR also fosters a safe environment to make and learn from errors . This isAn extensively evaluated area of AR application is teaching procedural skills, at both the undergraduate and postgraduate levels. AR was found to standardise performance and ensure fewer procedural errors in a study comparing conventional and AR methods of teaching extracorporeal membrane oxygenation (ECMO) cannulation . Gerup eLearning OpportunityPotentially one of the most beneficial applications for AR in medical education is to enable better clinical access for students. Using the technology for “a remote access mixed reality teaching ward round”, Bala et al. showed in their proof-of-concept study how AR may be used to deliver more equitable, standardised, insightful and enjoyable clinical teaching for those traditionally hard-to-access areas . There iCurrent medical students have been significantly affected by the lack of clinical exposure during the coronavirus disease 2019 (COVID-19) pandemic, which has exacerbated the perceived inequality of learning opportunities between, or even within, cohorts. Students themselves are often keen to drive forward innovative learning methods, even more so with the disruption of COVID-19 [When fully utilised, clinical placement promotes situated learning, where students engage with the team, its culture, norms, and practices in a two-way relationship. They progress to becoming legitimate peripheral participants in that area . HoweverAR could be used to provide an alternative to in-person clinical placement, through an interactive, point-of-view, virtual graphic-enhanced, live feed of simulated or real clinical scenarios. In this way it would build on its accepted social constructivist merits as a more knowledgeable educator enables learners to build on their prior theoretical knowledge, applying it to practice: clinical scenarios ,22.Taking an experiential view of learning, AR could be instrumental in the “re-learning” of ideas, previously learnt in the classroom, but now experienced in (augmented) reality. This mode of learning could better reflect the real world in which ideas are applied, emphasising the crucial two-way relationship between the person and their environment . With thResearch aimThis feasibility study has been designed to evaluate the potential utility and acceptability of AR in undergraduate and early postgraduate medical education for clinical areas that are harder to gain exposure to. Our study uses simulation to demonstrate this. Furthermore, using validated measures we aim to capture the user experience of AR as a tool for evaluation.ParticipantsConvenience sampling occurred at the research institution and 15 participants were recruited: this included 13 senior clinical medical students at United Kingdom (UK) universities and two newly qualified doctors. Participants’ age range was 22 to 36, with 10 females and five males. All participants had previous simulation experience. Written consent was obtained at enrolment, and this was stored securely in line with the General Data Protection Regulations United Kingdom (GDPR).Eligibility and exclusion criteriaCriteria were set to promote the inclusion of those wishing to gain education in critical care. However, to preserve study group homogeneity, an exclusion criterion of SettingThis was a single site  and a single group study. The teaching session used the high-fidelity, purpose-built simulation suite and a neighbouring seminar room in the education centre.Study processThe 15 participants were divided into two groups, with two smaller group teaching sessions delivered on separate dates by the same facilitators. Both groups received the same 20-minute critical care-themed teaching session delivered using Microsoft HoloLens (2nd generation), an AR HMD, with Microsoft Remote Assist, Microsoft Teams, and Microsoft PowerPoint. The session content was created in-house by the authors, and reviewed by a senior anaesthetist before implementation.In the session, the demonstrator wore the Microsoft HoloLens Figure , 4. ThesA technician was present in the simulation suite to help the demonstrator with technical aspects of the teaching session, such as finding and positioning equipment.Outcome measuresQuantitative Data and Statistical Analysis PlanQuantitative data was collected through an adapted immersive experience questionnaire (AIEQ) and an abridged intrinsic motivation inventory (AIMI). The AIMI focused on the domains of interest and enjoyment, and value and usefulness. Both the AIEQ and AIMI were adapted from research by Jacobs and Rigby, who have explored validation in these immersion and motivation surveys for healthcare education .socstatistics.com) were used.Items on each questionnaire were Likert-scaled, and the maximal Likert score for each item was five. Likert-scaled data was assumed to be continuous. The AEIQ included 21 items, the AIMI domain of interest and enjoyment included seven items, and the AIMI domain of value and usefulness had five items. Following a validation study of the AIMI for the clinical teaching environment , this stQualitative DataIn addition, five small group semi-structured interviews were conducted for hybrid thematic analysis. Groups were sized at three to four participants and within each group, all participants were in a similar year of study or grade. Interviews were conducted by two authors (OG and JF), transcribed verbatim , and independently coded by each author . An open coding method was used and codes were collated into themes and reviewed by the three co-authors together . Following this, the final thematic schema was developed , and this was reviewed by fellow author CJ. This thematic analysis process was based on Braun and Clarke’s six-step approach .Ethical approvalEthical approval was given by the Swindon Academy Medical Education Research Committee in November 2021 .AIEQ and AIMIA test for normality demonstrated non-normally distributed data and scores were reported as medians. The AIEQ was scored as previously described, and the total immersion (TI) score was the sum of the AIEQ items. The AIEQ median score was 72.00 IQR 16.5). The median SRI score was 6.00 (IQR 3). A high correlation existed between the TI score and the SRI . The median score for the AIMI domain of interest and enjoyment was 28.00 (IQR 7.5). The median score for the AIMI domain of value and usefulness was 24.00 (IQR 4). Descriptive findings of both the AIEQ and AIMI findings have been illustrated in Table . The medThematic analysisThe main thematic analysis findings have been highlighted below, broken down into key themes. Within these themes, details and quotes have been provided to give context. Four key themes were identified.Theme 1: Ability to Visualise Difficult ConceptsInterviewees felt the HoloLens was able to improve the ability to visualise difficult concepts. It is able to overlay annotated diagrams into the same visual field as the simulation scenario, and this can help improve learner understanding.…really helpful to have the theoretical and the practical applications happening simultaneously…""They are able to see physiology, pharmacology and anatomy embedded into a live clinical situation, and can clarify understanding through two-way questioning. Interviewees noted that having theory and practice run simultaneously, rather than separately, was beneficial to their learning. Equally, they felt it made it more memorable."It puts what you would have learnt on paper…suxamethonium is this and it acts in this way…but actually seeing it being used is much more memorable."Often, medical education is split into two dichotomous stages: preclinical and clinical education. Preclinically, learners are repeatedly overwhelmed with seemingly abstract concepts, and this can seem far removed from clinical medicine. Interviewees identified the Microsoft HoloLens as a useful bridging adjunct, helping to convert preclinical concepts into practice. They stated that it would be useful before going onto the wards."…converting all the theory of what we had learnt before into something practical...that would have been super useful before going onto the wards..."Theme 2: ImmersionInterviewees also commented on immersion, which was rated variably. This was similar to the AIEQ. Some found it very immersive and said it was perhaps as close to in-person teaching as you could possibly get because it was able to transfer high levels of fidelity and realism."…seeing someone in front of you, that’s immersive…and that is as close to real life as we could realistically get, I think.""I didn’t find it that immersive because…you haven’t got your own headset…"Theme 3: AccessibilityA further theme that emerged from the thematic analysis was accessibility. The HoloLens would improve access to teaching because learners could log in to Microsoft Teams remotely and partake in the session. It would still retain its interactivity, provided learners had access to a microphone. Many interviewees linked this potential to improving accessibility to the COVID-19 pandemic: they could learn at home and wouldn’t have to compromise on session quality."Everyone in the room is experiencing the same thing. In big group teaching often there is a crowd of people and you can’t actually see what you are meant to be seeing."In addition, interviewees noted the teaching session could be scaled up easily, and a large number of learners could attend. Although they felt this may not be as personal, they did feel it would help with teaching standardisation."It is quite good in democratising the experience, that different medical students have."Moreover, the thematic analysis revealed that many interviewees recognised the application of the HoloLens in limited exposure clinical areas. For instance, in large group teaching, learners may be crowded around a bedspace trying to see a procedure, yet because of the number of learners they are unable to see anything. In fact, in any limited space area, they thought the HoloLens would be beneficial, and they gave examples including intensive care, surgery and obstetrics.“(on future applications) clinically, I just think of any…clinical area where there is limited space or limited access."The reason behind this benefit was almost entirely attributed to the point-of-view camera angles, which provide the same visuals for both the demonstrator and learner. In some circumstances, namely surgery, interviewees believed it could even replace in-person teaching, which can be too difficult to access. However, one interviewee did express concern about the idea that in-person teaching may be reduced due to improved teaching technology.Theme 4: FutureThe final theme encompassed future challenges with the HoloLens. Interviewees felt that if it was used in the ward on real patients, the headset would be jarring and odd for them. Patient perception was not the only barrier to ward transition, and consent and confidentiality issues were also identified."It’d probably be quite jarring for the patient to have their doctor be wearing that headset and videoing hand movements that they can’t see what’s going on."In addition, there are further considerations that interviewees thought should be recognised. These included training clinicians and/or learners to wear the headset, refinements in the AR functionality and calibration of the hardware, and system improvements such as improved internet connectivity.The aim of this study was to explore the application of AR in undergraduate (and early postgraduate) medical education for limited exposure clinical areas.High-scoring Likert items in the AIMI indicate participants believe that AR has interest, enjoyment, value and usefulness as an educational tool. Positive personal experiences with AR have already been documented in medical education. Aebersold et al. found participants enjoyed AR and thought its application was useful when trying to place a nasogastric tube , and BorThe intrinsic motivation inventory domains scored highly; previous technology-enhanced “participatory simulations” were shown to be highly intrinsically motivating with two different types of technology (basic and more advanced) . WhetherHowever, immersion (defined by the connection to the AR world), was a much more variable entity: in both the AIEQ and thematic analysis there were conflicting opinions. In educational environments, it has been proposed that immersion can enhance learning through perspective, situated experience and skill transfer . Yet, reIt is still useful, however, to try and understand the reasons behind the variable immersion experienced by participants’ in this study. A reality-virtuality continuum helps delineate between AR and VR, with MR as an overarching definition . In a coIn addition, all our participants watched the augmented session from the same room, and at times our graphics became pixelated because of connectivity. Not only may this have negatively affected immersion, but also the phenomenon of place illusion, which can be both limited and linked by immersion. Place illusion is the sense of being in a place you know you are not, and uses a cave analogy to explain this: two gamers may both be immersed in a virtual reality cave, but if one goes near the walls of the cave and the visuals become pixelated, place illusion may break . Both imThe benefit of AR in improving access to learning opportunities seemed important to participants. A study of anatomy learning recognised the ability of AR teaching to be used remotely . A collaLimitationsThis is a feasibility study and thus, by definition, it is small-scale and designed to give preliminary results, which requires caution in interpreting the findings. The study was a single group without a comparison, leaving the AIEQ and AIMI vulnerable to bias. Additionally, the AIMI Likert scale was amended to 5 points from 7, which impacts the validity and reliability of comparison with other AIMI-based studies. However, limiting the response anchors to five can improve measuring the experience by participants and this aligns both measures to the response scale . Moreover, only one topic was covered in the teaching session. Although it did represent a limited exposure clinical scenario and allowed for teaching on anatomy, physiology, and pharmacology with AR supplementation, if participants had an already established interest (or disinterest) in the topic it could have influenced the outcomes and acceptability. Future work to compare different educational settings, content and reality-virtuality type would benefit the medical education community in appraising the utility of immersive technology; for instance, a follow-up study comparing an AR headset to a virtual reality (VR) headset . Much of the data from other studies on AR in medical education similarly follows a feasibility or pilot study design. Currently, there is very little comparison of AR (including HMDs) to conventional methods, particularly in teaching locations that are hard to access.Participants were not able to wear the Microsoft HoloLens in this study because we wanted the demonstrator to share and explain their point-of-view; this allowed the expert to guide them through the simulation. Moreover, considerable training and experience are needed to operate the Microsoft HoloLens, and we only had one headset. Additional headsets would incur a significant cost. In this feasibility study, we have shown that using AR to teach medical concepts in limited exposure clinical areas is perceived as valuable and useful by learners, with particular strengths in improving equality of access to the clinical learning environment and bridging the theory to clinical practice gap.Participants found this mode of teaching interesting and enjoyable but rated the immersive experience variably. They outlined several challenges for the future development of AR in medical education such as the technical infrastructure needed and issues around patient consent and perception of AR devices. There is a growing framework linking AR with learning theory in the literature, and this work contributes to this and provides future avenues for research.