ARMS2 A69S and CFH I62V was performed in all participants. Of the 155 patients , HRF was observed in 53 eyes (34.2%) and was significantly associated with type-3 MNV (p = 1.0 × 10−5) in the contralateral eye, pseudodrusen (p = 5.0 × 10−4), thinner subfoveal choroidal thickness (p = 0.013), and risk of ARMS2 A69S (p = 0.023). During follow-up (40.8 ± 17.5), 38 eyes (24.5%) developed advanced AMD. The mean time to the onset of advanced AMD was 29.8 ± 12.9 months in eyes with intermediate AMD. HRF was associated with MNV (p = 1.0 × 10−3), but not with atrophy.Hyperreflective foci (HRF) are the findings observed in optical coherence tomography (OCT) in several retinal diseases and are believed to be associated with the increased risk of atrophy in eyes with age-related macular degeneration (AMD). In this study, we investigated the clinical and genetic characteristics of intermediate AMD with HRF. We reviewed the medical charts for 155 patients with intermediate AMD, in whom macular neovascularization (MNV) was observed in the contralateral eye. The presence or absence of an HRF was evaluated using a spectral-domain OCT volume scan spanning the macular region. Patients were followed longitudinally for at least 12 months, and the maximum follow-up period was 60 months. Genotyping of  In this classification, intermediate AMD is defined as eyes with large drusen or with pigmentary abnormalities associated with at least medium druse. On another front, the AREDS classification system is a widely used classification system for AMD1. One of the major differences between the two classification systems is that the AREDS classification system includes small drusen as Level 1 AMD, whereas the Beckman Initiative regards small drusen without AMD pigmentary abnormalities as the normal aging change. In addition, the AREDS classification system evaluates the total area of the drusen, which is not included in the Beckman Initiative system.Drusen generally accumulate beneath the retinal pigment epithelium (RPE) and are hallmarks of age-related macular degeneration (AMD). As per the Beckman Initiative for Macular Research Classification Committee, drusen are categorized into small (< 63 µm), medium (63 µm ≤ and ≤ 125 µm), and large (> 125 µm) drusen2. They are believed to migrate toward the vitreous side of the retina from the RPE in eyes with early/intermediate AMD. Drusen under the HRF are more likely to collapse and develop atrophy. Several studies have demonstrated that the number and volume of HRF are associated with an increased risk of atrophy, but not macular neovascularization (MNV) in Caucasians4.Hyperreflective foci (HRF) are visualized at any retinal layer through spectral-domain/swept-source optical coherence tomography (SD/SS-OCT) in several retinal diseases and are defined as well-demarcated lesions with equal reflectivity to the RPE bands. They are sometimes detected as hyperpigmentation on color fundus photography5.The risk of AMD varies depending on the drusen type and size, and RPE abnormalities. The contralateral eye is at a high risk of developing advanced AMD. A randomized clinical trial suggested that the risk of progression from intermediate to advanced AMD increased if the patient had already developed advanced AMD in the fellow eyeIn this study, we compared the genetic and clinical characteristics of intermediate AMD with or without HRF, and longitudinally evaluated the incidence of advanced AMD using unilateral MNV cases.A total of 155 patients with intermediate AMD, who had treatment naïve MNV in the contralateral eye at baseline, were included in this study. Table p = 5.0 × 10−4 and p = 6.4 × 10−8, respectively). In addition, patients in the HRF (+) group had thinner subfoveal choroidal thickness (p = 0.013), a higher proportion of type 3 MNV (p = 1.0 × 10−5), lower proportion of PCV in the contralateral eye (p = 9.8 × 10−4), and higher risk allele frequency of ARMS2 A69S (p = 0.023) than those in HRF (−) group.Table p = 5.0 × 10−6). Of the 38 eyes with advanced AMD, 16 showed type-3 MNV, 10 showed typical neovascular AMD, 4 showed PCV, and 9 showed atrophy. One eye showed simultaneous progression to type-3 MNV and atrophy.The mean follow-up period was 40.8 ± 17.5 months. During the follow-up period, 38 eyes (24.5%) progressed from intermediate to advanced AMD in the study eye. The mean duration from the first visit to the onset of advanced AMD was 29.8 ± 12.9 months. The mean follow-up period was significantly shorter in the eyes that developed advanced AMD than that in the eyes without developing advanced AMD  eyes developed advanced AMD, including 20 MNV eyes  and 3 atrophy eyes in the HRF (+) group; and 15 (14.7%) eyes developed advanced AMD, including 9 MNV eyes , 4 atrophy eyes, and one eye with simultaneous type 3 MNV and atrophy in the HRF (−) group. The subtypes of newly-developed MNV were same as those of the contralateral eyes in 17 (85.0%) eyes in the HRF (+) group and 4 (40%) eyes in the HRF (−) group. Among 23 eyes that developed from intermediate to advanced AMD in the HRF (+) group, 18 (78.3%) eyes also showed HRF in the contralateral eye with treatment naïve MNV at baseline. However, it is difficult to differentiate accurately between HRF with RPE migration and HRF derived from lipids in exudative changes by SD/SS-OCT only. In the HRF (−) group, four (3.9%) eyes developed HRF during the study period; however, no eyes progressed to advanced AMD. During the follow-up period, no eye showed the decrease or disappearance of HRF in the HRF (+) group.p = 0.001, hazard ratio: 3.67, 95% CI 1.68–8.00), and the presence of pseudodrusen  was associated with progression to atrophy.In order to investigate the predictor of developing from intermediate to advanced AMD, we conducted Cox regression analysis. As a result, the baseline best-corrected visual acuity (BCVA), presence of pseudodrusen, and presence of HRF were associated with advanced AMD Table . Cox regp = 7.0 × 10−5, log-rank test). In contrast, the proportion of patients with progression to atrophy between the HRF (+) and HRF (−) groups was not statistically significant .Figure 4, HRF is considered as another OCT biomarker for advanced AMD.The present study attempted to characterize intermediate AMD with HRF in 155 patients with MNV versus those without HRF. Several studies have investigated OCT biomarkers as predictors of conversion from intermediate to advanced AMD and have reported that the risk of progression varies depending on the drusen type, shape, reflectivity, and internal homogeneity. In addition to drusen substructures7.In eyes with intermediate AMD, HRF may represent RPE migration because RPE has the potential to migrate when induced by cytokines and inflammatory factors in response to oxidative stress and complement activation9. However, HRF was observed in 74% (17/23) of the contralateral eyes with type-3 MNV and 50% (32/64) of eyes with pseudodrusen. HRF may be prevalent due to differences in the prevalence of these entities.In Caucasian people, HRF was observed in 41–50% of the eyes with intermediate AMD, that is higher in this study (32%)10. Corvi et al. reported that a greater CC-FD was associated with progression to complete RPE and outer retinal atrophy (cRORA) in the eyes with intermediate AMD11. Several groups have demonstrated that flow signals decreased at the choriocapillaris level, and that CC-FD areas increased in the eyes with pseudodrusen13. In the present study, both HRF and pseudodrusen increased the risk of advanced AMD. As these entities are colocalized, advanced AMD may develop through a similar pathway.Tiosano et al. recently evaluated choriocapillaris flow deficits (CC-FD) in eyes with HRF using OCT angiography. The study demonstrated that CC-FD was greater in the eyes with HRF than in those without HRF, based on 55 eyes with intermediate AMD4. Lei et al. evaluated the progression of AMD using OCT-based scoring system and reported that the presence of HRF is a risk factor for atrophy or cRORA14. Nassisi et al. quantified HRF volume in the eyes with intermediate AMD and concluded that the area of HRF correlated with a 1-year risk of progression to atrophy, but not MNV3. These studies were exclusively performed on Caucasian people and demonstrated strong association of HRF with atrophy rather than with MNV. In the present study, HRF was strongly associated with MNV but not with atrophy. This result is in contrast to those of previous studies. There are several possible explanations for this finding. First, the study eye was the contralateral eye with MNV; therefore, the study eye was more likely to develop MNV than cRORA. In the previous study aforementioned, Christenbury et al. included only one eye with category 3 AMD  and excluded eyes with category 4 AMD . Lei et al. included the patients with early AMD in one eye with or without late AMD in the fellow eye. In addition, they included not only HRF and RPD but also drusen volume and hyporeflective foci within the drusenoid lesion as risk factors. Nassisi et al. included the patients with intermediate AMD in one eye or both eyes and did not include the patients with advanced AMD in the contralateral eye. Furthermore, they assessed HRF not only qualitatively but quantitatively. These differences in the study design might have affected the results. Second, geographic atrophy/cRORA is a rare phenotype in advanced AMD in Asians than in Caucasian people15; thus, the present result may be due to differences in ethnicities.Several studies have longitudinally evaluated intermediate AMD. The AREDS2 Ancillary SD-OCT Study Group reported that the presence of HRF, and number and distribution of HRF are associated with an increased risk of atrophy at 2 years in eyes with intermediate AMDARMS2 (rs104909) and CFH I62V (rs800292) were associated with an increased risk of HRF with hazard ratio of 1.64 and 1.49, respectively, in the eyes with intermediate AMD16. In the present study, the hazard ratios of ARMS2 (rs10490924) and CFH I62V were 1.82 and 1.14, respectively. Based on results of previous and present studies, the risk variants of ARMS2, than of CFH, may be more strongly associated with HRF.In terms of genetic association, only one study performed a genetic analysis of HRF. In a previous study, risk variants 17.The merits of the present study are the long-term follow-up of a large number of participants. However, the present study has some limitations. First, the study was retrospective. Second, we failed to perform quantitative HRF evaluation. The information on changes in the number or distribution of HRF and the blood flow evaluation around drusen or HRF may provide some insights into the progression of advanced AMDARMS2, and progression to MNV.In summary, HRF was more frequently observed in type-3 MNV and was associated with pseudodrusen, drusenoid PED, thinner subfoveal choroidal thickness, risk variants of We retrospectively reviewed the medical charts of patients with intermediate AMD in whom MNV was observed in the contralateral eye and who visited the Macular Clinic of the Yamanashi University Hospital between March 2015 and March 2021. This retrospective study was approved by the Institutional Review Board of the University of Yamanashi and conducted in accordance with the principles of the Declaration of Helsinki. Written informed consent was obtained from all the participants before enrollment to the study.At the initial presentation, all patients underwent comprehensive ophthalmic examination, including measurement of BCVA using a Landolt chart and intraocular pressure, slit-lamp biomicroscopy with or without a 78 diopter lens with pupil dilation, fundus photography, fluorescein/indocyanine green angiography (FA/ICGA) using a confocal scanning laser ophthalmoscope , fundus autofluorescence, and near-infrared reflectance and SD-OCT using Spectralis.1.The inclusion criteria were as follows: (1) fellow eyes with intermediate AMD in patients with unilateral treatment—naive MNV, including typical neovascular AMD, polypoidal choroidal vasculopathy (PCV), and retinal angiomatous proliferation, also known as type-3 MNV; and (2) a minimum follow-up period of 12 months after the initial presentation. Intermediate AMD was diagnosed according to previously reported criteriaThe exclusion criteria were as follows: (1) previous vitrectomy and (2) other ocular abnormalities that affect the central visual field in the eyes with intermediate AMD, including glaucoma, diabetic retinopathy, and branch retinal vein occlusion.18. Briefly, HRF was evaluated as well-defined and not confluent hyperreflective lesions located at any retinal layer in the macular area20.At initial appearance, the presence or absence of an HRF was evaluated using SD-OCT. OCT scans were performed to cover the macular region using 25 horizontal B-scans spanning 20° × 25°. HRF was diagnosed according to previously published criteria21. Drusenoid pigment epithelial detachment (DPED) was defined as an aggregated or confluent soft drusen > 350 µm in diameter on SD-OCT, as previously reported22.The presence or absence of pseudodrusen was evaluated using multimodal imaging at initial presentation. The presence of pseudodrusen was defined when pseudodrusen was detected in at least one imaging modality, as previously described23. The maximum follow-up duration was 60 months.Three monthly intravitreal injections of vascular endothelial growth factor (VEGF) inhibitors, including ranibizumab or aflibercept, were administered to the contralateral eyes with MNV. Thereafter, injections were administered based on the treatment regimen. At each follow-up visit, color fundus photography and SD-OCT examination were performed in both the eyes, as performed at the initial presentation. FA/ICGA was performed to confirm the MNV subtype when intraretinal/subretinal fluid was detected on SD-OCT in the eyes with intermediate AMD. Atrophy was defined as cRORA on SD-OCT, as previously describedARMS2 A69S and CFH I62V variants. Genotyping was performed using TaqMan assays on the ABI7300/7500 Real-Time PCR System , as previously described24.At the initial appearance, peripheral blood of the participants was collected. Genomic DNA was obtained from peripheral blood using Pure Gene Isolation Kit . Genotype analyses were performed for p < 0.05 was considered to be statistically significant.Statistical analyses were performed using Statflex 7 software . The differences in categorical and continuous variables between the two groups were analyzed using the chi-square test and Mann–Whitney U test, respectively. Cox regression analyses were performed to investigate the factors associated with progression to advanced AMD. Kaplan–Meier survival analyses were also performed to evaluate the influence of HRF on progression to advanced AMD. A


Probiotics in allergic rhinitis (AR) have shown improvement in clinical and quality of life scores, whereas the role of synbiotics in the treatment of AR has been poorly investigated. The purpose of this study was to evaluate the clinical efficacy of synbiotics in children with AR.An observational, prospective cohort study of pediatric outpatients with AR from a private medical center in Peru (2021) was conducted. At baseline, patients who were prescribed synbiotics during routine and those who were not (controls) recruited and followed up on Days 30, 60, and 90 of follow‐up. Clinical efficacy was assessed with differences in Visual Analogous Scale (VAS), Total Nasal Symptom Score (TNSS), Rhinitis Control Assessment Test (RCAT), and the Pediatric Rhinoconjunctivitis Quality of Life Questionnaire (PRQLQ) scores between groups at follow‐up. Mean differences ± standard deviation (SD) and 95% confidence intervals (95% CI) are reported.n = 115), those who used synbiotics (n = 100) had significantly lower VAS , TNSS  and higher RCAT scores and PRQLQ scores  and , respectively, at Day 90 of follow‐upTwo hundred and fifteen participants were analyzed. Compared to controls  and quality of life (PRQLQ) scores of small and large sizes, respectively. These preliminary findings support the need of future trials to assess the role of synbiotics in children with AR. Our results supported a preliminary improvement in clinical scores , and a significant improvement in quality of life (PRQLQ) scores above minimal important differences. These findings show the need of conducting future trials to evaluate the efficacy of synbiotics in children with AR. In synbiotics both pre‐ and probiotics act synergistically to regulate the intestinal immune response related to allergic diseases; thus, providing a basis to be used in the prevention and treatment of AR.Several systematic reviews have shown that probiotics have a safety profile,Therefore, the purpose of this prospective observational study was to evaluate the clinical efficacy of synbiotics in children with AR in a private medical center in Lima, Peru.22.1We conducted a prospective cohort study of pediatric outpatients with AR from a private medical center located in Lima, Peru, between February 2021 and November 2021. At baseline, a group of patients receiving synbiotics (as part of their routinary care) and a group who did not (controls) were recruited; then, they were followed up monthly up to 3 months later.2.2Patients were recruited consecutively as they were identified after their routinary medical outpatient consultations. The sample size was calculated with Epidat® v.4.2, considering a potency of 80% with a minimum mean difference to detect of 1.1 for the Total Nasal Symptom Score (TNSS) between groups, a standard deviation of 2.7, and a confidence level (CI) of 95%.2.3T‐test for independent samples. The analysis was performed in the statistical software IBM SPSS version 26 with a significance level of .05.The data analysis considered the assessment of the difference in means of the result variables through the application of the 2.4The protocol of this study was approved by the Ethics Committee of the Hospital Nacional Madre Niño San Bartolomé  fructooligosaccharides 750 mg and Vitamin C 12 mg and is free of sale. Synbiotics were indicated before recruitment by the attending physician during regular medical appointments.The product of exposure was the synbiotics, we use BagoVital Inmune® that is compounded by 2.7The severity of AR symptoms, measured by changes in Visual Analogous Scale (VAS) total scores between exposure groups at follow‐up; the intensity of AR symptoms, measured by changes in total symptoms score total scores between exposure groups at follow‐up; the control of AR symptoms, measured by changes in Rhinitis Control Assessment Test (RCAT) total scores between exposure groups at follow‐up; and quality of life, measured by changes in the Pediatric Rhinoconjunctivitis Quality of Life Questionnaire (PRQLQ) total scores between exposure groups at follow‐up.33.1Data from a total of 215 participants, with a mean (SD) age of 10.4 (3.7), and 55.4% of males were analyzed  used synbiotics and 115 (53.5%) not. Compared to patients who did not use synbiotics, participants who used them had a higher proportion of males (61.0% vs. 50.4%), family history of asthma (77.0% vs. 57.4%), persistent AR (87% vs. 73.9%), and of use of inhaled corticosteroids (30.% vs. 18.3%). The differences in the proportion of resting characteristics between exposure groups were below 10%.3.3Results of the association between synbiotics use and the outcomes of clinical efficacy are presented in Table 4Our findings in this observational cohort study showed evidence supporting the preliminary clinical benefits of add‐on treatment with synbiotics in children with AR. Among those who used synbiotics compared to controls, there was a significant improvement in quality of life (PRQLQ) scores. Differences in clinical scores of disease severity (VAS), disease control (RCAT), and intensity of symptoms (TNSS) were also significant but in less proportion. These findings may guide further assessments of the efficacy of synbiotics in children with AR.n = 152, mean age ± SD: 30.1 ± 7.6); they compared budesonide + probiotic (seven different gram‐positive organisms + fructooligosaccharide) versus budesonide + placebo, finding significantly improvements in quality of life , and clinical scores . Dehnavi et al.Streptococcus thermophilus, Bifidobacterium spp., Lactobacillus spp., and fructooligosaccharide; n = 8) versus placebo + immunotherapy (n = 9), showing no significant differences in clinical symptoms  or quality of life , but a significant decrease in interleukin‐17 levels at 6 months of follow‐up. Last, daily administration of synbiotics for 6 months  to newborn infants from pregnant mothers (who received the same probiotics before childbirth) did not reduce the incidence of allergic diseases (including AR) in an RCT from Finland (2000–2003) by Kukkonen et al.These study results contribute to the scarce previous evidence evaluating synbiotics treatment in patients with AR.Previous RCTsn = 17/22) of RCTs. Also, probiotics reduced significantly nasal and ocular symptoms score . More recent metanalysis (2022)In our study, synbiotics caused a significant improvement of clinical scores: VAS , TNSS  and RCAT scales  were significantly lower among those who received synbiotics (vs. controls). In the case of probiotics, a metanalysis (2016)A significant improvement in quality of life was associated with synbiotics in our study: PRQLQ score was significantly higher  among children who used synbiotics (vs. controls); this difference was large and above the minimal important difference of 0.5. In the case of probiotics, the same meta‐analysis (2016)However, our study has limitations related to the observational design and the prescription bias may be present since there were relevant differences between synbiotic and control groups. Additionally, even though this study has a control group a placebo effect may be present. Our findings may inform future studies to define the role of synbiotics in the context of AR.Cesar A. Galvan Calle, Cecilia Díaz Vásquez, Ricardo Muñoz Leon, Edgar E. Matos Benavides, and Alejandra V. Verde Leon were involved in the same proportion in the design of the study, collection of clinical data, redaction, and revision of the paper.Cesar Alberto Galvan Calle has received a research grant from Laboratorio Bago. Honorarios as a speaker from Laboratorio Bago and Laboratorio Mead Johnson Nutritional. The remaining authors declare no conflict of interest.Supporting information.Click here for additional data file.


Congenital or acquired atrioventricular block (AVB) is a rare disorder in the pediatric population, while celiac disease (CeD) is a common multisystemic autoimmune disorder that is characterized by intestinal manifestations as they are the typical clinical presentation. Sometimes CeD presents more complex multisystemic involvement which includes the heart. Cardiac involvement, such as dilated cardiomyopathy, myocarditis or conduction disease, have been mainly described in untreated adult patients with or without gastro-intestinal symptoms; rare cases of AVB and CeD have been also reported, particularly in association with extra-cardiac manifestations. We describe a case of a progressive acquired AVB block in a 4-year-old child, in which CeD was later diagnosed. A rapid and significantly improvement of the AVB grade has been obtained after the child started a strict gluten-free diet, and so we suggest including diagnostic exams for CeD in all of the children with acquired AVB. Atrioventricular block (AVB) is a rare conduction disorder in the pediatric population. It may occur in a structurally normal heart or in association with a congenital heart disease, and it can be congenital or acquired . The acqCeliac disease (CeD) is a common multisystemic autoimmune disorder that is characterized by inflammation and villous atrophy in the small bowel, which are triggered by gluten ingestion in genetically predisposed individuals. The typical clinical presentation of CeD is characterized by intestinal manifestations such as diarrhea, a loss of appetite, abdominal distention, bloating, constipation, abdominal pain, and weight loss. Sometimes there are extra-intestinal symptoms: the most common ones are anemia, osteoporosis, fatigue, aphthous stomatitis, headache, and reproductive disorders ,5,6,7. TCardiac involvement  has also been described in untreated adults or young adult patients with CeD . DilatedFurthermore, the data of cardiac improvement in patients who are treated with conventional therapy and a gluten-free diet (GFD) are inconclusive .We report here a case of a 4-year-old girl with CeD who developed a high-grade AVB that significantly improved after she began a strict GFD. A literature review that focuses on the association between CeD and conduction disorders is also considered.2, −0.34 z-score [A 4-year-old female  with neNo cardiac structural anomalies were found on the echocardiography. Ion disorders, previous or current infections, dysthyroidism, and anti-SSA/Ro and anti-SSB/La autoantibodies were also excluded by a blood sample test.In the next four years, a worsening of the AVB was recorded up to III-degree AVB with a narrow QRS escape rhythm also in the daytime and pauses with the longest RR interval of 5.1 s . Chronotropic incompetence  and poor exercise capacity during the treadmill stress testing additionally appeared.2, −1.39 z-score [As the AVB worsened, the 8-year-old child experienced progressively more frequent episodes of headaches and abdominal pain. She had neither diarrhea nor a significant growth failure . The blImmediately after the diagnosis, she started a strict GFD and after only 3 months, a remarkable improvement of the AVB was noticed. In the Holter monitoring, a regression of up to I-degree AVB was recorded with only brief episodes of Mobitz type 1 AVB during the nighttime . The finCeD is a complex autoimmune condition that is characterized by a specific serological and histological profile, which is triggered by gluten ingestion in genetically predisposed individuals.The estimated global prevalence of CeD is approximately 1%. CeD occurs at any age from early childhood to an adult age, with a first peak after gluten intake within the first 2 years of life and the second one in the second or third decade of life ,5,6,7. Its diagnosis remains a challenge due to its multifaceted clinical presentation and its variable age of recognition .Classically, CeD is diagnosed among children presenting gastrointestinal manifestations of it, but a more complex multisystemic involvement can be observed with neurological, psychiatric, dermatologic, ocular, musculoskeletal, endocrine, pulmonary, and reproductive manifestations . MoreoveAdditionally, a recent meta-analysis reported that adult patients having a later diagnosis of CeD, had a 38% increased risk of developing atrial fibrillation . Rare caInterestingly, our case shows some peculiarities such as the onset of the AVB (4 years old) at a young age, the absence of any other cardiac or gastroenterological involvement at the time of the diagnosis, the appearance of new symptoms, such as abdominal pain and headaches as the AVB worsened. Furthermore, our patient had a significant history of autoimmune diseases in her family (she has a father with a severe form of Crohn’s disease). Acquired AVB is a rare condition in the pediatric age, and sometimes the treatment of the primary cause determines the improvement of the conduction disorder . A challThe risk of irreversible heart damage in unrecognized patients with CeD increases with age and with the duration of gluten exposure . In our No large studies about the reversibility of cardiac events after gluten avoidance are present in the literature, and the data are discordant. Some cases report a complete or partial recovery of the cardiac involvement, while others are unresponsive to the diet . In our We presented an unusual case of an association between AVB and CeD. To the best of our knowledge, this is the first reported case in the pediatric population. Even if the data on the association between CeD and conduction disorders are rare, the hypothesis of an autoimmune reaction involving both the myocardium and the small intestine cannot be excluded. The current case is important since it provides an important insight to the clinical presentation of CD in patients of pediatric age as extra-intestinal manifestations of the cardiac involvement could be not excluded. In the children with acquired AVB who return negative results for the tests for other more frequent pathological conditions, diagnostic CeD exams should be also considered.


Persons with disabilities (PWD) generally experience various barriers in using health care compared to the general population, and these problems are more worsened for those with disabilities in lower socioeconomic status. The study aimed to estimate socioeconomic inequality in using rehabilitation services (URS) in adults with disabilities in Iran.This cross-sectional study was conducted at a national level in Iran. 786 PWD (aged 18 years and older) participated in the study between September and December 2020. Socioeconomic-related inequality in URS was estimated by the Concentration Index (C). The C was decomposed to identify factors explaining the variability within the socioeconomic inequality in URS.N = 61) of the study population used rehabilitation services during the past three months. In this study, the value of the C was estimated 0.25  that shows URS was unequally distributed, and concentrated among the higher SES groups. The results of decomposition analysis indicated that the wealth index was the largest contributor (94.22%) to the observed socioeconomic inequalities in URS among PWD. Following the wealth index, Age and marital status were the major contributors to the unequal distribution of URS among the study population.In the present study 8.10% (Our findings revealed that socioeconomic inequality in using rehabilitation services was concentrated among well-off PWD. Accordingly, rehabilitation financing through appropriate mechanisms for individuals with low SES is suggested. Universal health coverage is about ensuring that all members of the population and their communities have access to promotive, preventive, curative, rehabilitative and palliative health services without suffering financial hardship. However, persons with disabilities (PWD) generally experience major obstacles to access to healthcare compared with the general population. PWD face a wide range of physical, geographical, cultural and financial barriers to health care access –3. Of thDisability is an important public health issue in Iran where about 1–4% of Iranian population live with a disability , 7. In cIn the Comprehensive Act on the Protection of the Rights of People with Disabilities (CAPRPD) in Iran 2002, disability is defined as continuous and significant physical, mental, psychological or combined disorders in health and general functioning which reduce the independence in activities of daily living. In recent decades there have been significant advances in providing rehabilitation and social services  for PWD in Iran, but they still face different obstacles to use healthcare –11.Previous studies in Iran indicate that sociocultural factors  , 12 phys“a set of interventions designed to optimize functioning and reduce disability in individuals with health conditions in interaction with their environment “ [In this article, we focus on socioeconomic inequalities in using rehabilitation services (URS) among adults with disabilities in Iran. World Health Organization defines rehabilitation as onment “ . Given tonment “ .In Iran, rehabilitation services  are provided in various settings such as inpatient setting , outpatient setting  and community-based settings (66.214 for every million people), and long-term care setting  . Also, rSome services such as occupational therapy, speech therapy, and orthotics and prosthetics are not covered by health insurance that imposes high out of pocket payments (OOP) on PWD in Iran. In addition, physiotherapy, as an essential service to improve functioning is associated with co-pay that families in lower SES groups may not afford to pay for OOP. A study by Rezaei et al. in Iran reveals that the OOP for healthcare is regressive and more concentrated in lower SES groups . The finThe samples in this observational cross-sectional study were recruited from the Iranian Society with Disabilities (ISD). The ISD is a non-governmental organization (NGO) that facilitates access to education and healthcare services for PWD in all provinces of Iran . At the PWD aged 18 years and olderPeople who were the member of ISDPeople with Iranian nationalityThe inclusion criteria in the present study consisted of:People who were reluctant to participate in the studyPeople aged under 18 yearsPeople without disabilitiesAdditionally, the exclusion criteria included:To measure socioeconomic inequalities in URS, we used a valid and reliable questionnaire developed by Karami Matin et al. in a previous study . This shGiven the pandemic of COVID-19, we decided to apply an electronic form to collect data. Thus, we sent a shared link of the electronic questionnaire via messenger applications (Telegram and WhatsApp) to the members of the ISD. We gathered data between September and December 2020.The outcome variable was a binary variable showing whether the participant used rehabilitation services during the past three months or not. Also, demographic variables , disability severity, and socioeconomic factors were included in our analysis as determinants of URS.Although income apparently is the main indicator of wealth that can be applied as a measure of economic status, it is very difficult to capture exactly . In the With regard to existing data, we used information on assets ownership , housing characteristics  and educational level of participants to develop the SES variable. Therefore, the SES indicator was created by a combination of households' assets and education levels of participants. To develop the SES indicator, we used principal components analysis (PCA) –42. ThisIn the present study, the concentration index (C) was used to measure socioeconomic related inequality in URS among the study population . The C ewhere s method :2\documeThe estimated value of the normalized C was decomposed to identify the contribution of explanatory variables to the observed socioeconomic inequality in URS . Wagstafthe C for k). If the value of the contribution of variable X is x and positive (negative), then, if the variable had no impact on URS or were equally distributed across the SES groups, inequality in URS would decrease (increase) by x%. Also, in Eq. 4, the second component, In this equation, Equation  results Regarding that URS was a binary variable, we used marginal effects derived from a logistic model as N = 493), 40.34% (N = 309), and 88.33% (N = 681) of participants were male, married and lived in the urban setting, respectively. Also, 43.88% (N = 344) of participants were covered by Social Security Insurance, and 55.75% (N = 441) had an academic degree. In the present study, 8.10%( N = 61) of the study population used rehabilitation services during the last month. Also, 46.22%( N = 348) of participants had difficulty seeing, 17.2%( N = 123) hearing, 73.05%( N = 561) walking, 39.36%( N = 447) self-caring, 29.9%( N = 211) remembering or concentrating, and 21.19%( N = 157) communicating, respectively.Regarding Table p-value = 0.025, Standard error = 0.114) that shows URS was unequally distributed, and concentrated among the higher SES groups.In this study, the value of the C was estimated 0.25  compared with low socio-economic status . There aAlso, the role of private for profit providers in providing therapies and rehabilitation services is outstanding in Iran that impose high health costs on families. Public financing for rehabilitation services is necessary to make sustainable progress towards universal health coverage. These funds need to be used effectively to assure equitable access to high-quality healthcare and financial protection for PWD. Thus, without financial access to rehabilitation services, PWD may not be able to return to work or participate in other activities of daily living.In the present study, age was the second major contributor to the socioeconomic inequality in URS. The positive contribution results from both the negative C for age groups and the negative elasticity of all measures of URS. In other words, the participants in lower age groups are more likely to be wealthy and have better access to rehabilitation services than their counterparts in higher age groups. The result implies that young people with disability are more likely to seek and access to rehabilitation services compared to those in higher age groups. A study by Maart and Jelsma indicated that PWD over 65 years old were less likely to have the medical rehabilitation that they required . Also, aIn the present study, the severity of disability was the third major contributor to the socioeconomic inequality in URS. The positive contribution is due to both the positive C for the severity of disability and the positive elasticity of all measures of URS. The finding indicates that the participants with more severe disability were more likely to be wealthy and to use rehabilitation services than the others. This result reveals that people with more severe disability probably face more unmet healthcare needs than those with a mild disability. The study by Sakellariou and Rotarou, in the United Kingdom, indicated that individuals with a severe disability were more likely to face a health problem than those with a mild disability .A study by Ahmadzadeh et al. shows that there are significant inequalities in the geographical distribution of outpatient rehabilitation services in Iran . For exaAlthough, community-based rehabilitation approach is the only main program for providing rehabilitation services in rural areas in Iran, PWD in rural settings still face barriers to access to outpatient rehabilitation services –57. ProbOverall, our findings suggest that URS is concentrated in well-off PWD. Accordingly, it seems that intersectional actions should be taken to improve financial and geographical access to rehabilitation services for PWD. Since rehabilitation services are essential for improving body function and quality of life for PWD, changing landscape of health insurance coverage is recommended to promote equality in URS. In addition, there are other factors such as treatment duration, patient satisfaction, innovation technology, cultural characteristics, availability, etc. that may affect access to rehabilitation services, and should to be addressed in the future.Coverage for therapy and rehabilitation services have received little attention over the past several decades in Iran. Studies shows that lack of insurance coverage for rehabilitation services cause lack of access or long appointment delay for PWD in Iran. Since, therapies as long term services can impose catastrophic costs on PWD and families, health policy reforms are necessary to ensure the health rights and good health of disadvantaged groups in Iran.In addition to therapy and rehabilitation services, PWD need other health services such as assistive technologies, medicines, medical visits, etc. that can exacerbate financial problems for PWD. Assistive technologies such as hearing aids, wheelchairs, orthotics and prosthetics are one of the main needs of PWD that have no insurance coverage. Regarding the role and high cost of these technologies, financial protection for PWD should be on the agenda by health policy makers.The present study had some limitations that should be considered when interpreting the results. In the present study, we used an electronic questionnaire to gather data because of the outbreak of COVID-19 pandemic in Iran. Thus, we think that people without communication tools and those with a low education level  probably have had a lower chance of participation in the study. In the light of these shortcomings, it is suggested to interpret results with caution.Also, PWD under 18 years old had not participated in the study that may affect the value of socioeconomic inequalities in access to rehabilitation services. In this study, only 3.17% of participants were above 58 years old. Regarding the high prevalence of disabilities among older people , 59, 60,In addition, a low percent of the study participants settled in rural area that may have a poorer financial and physical access to rehabilitation compared their counterparts in urban area. Our findings suggest more studies on the availability and quality of rehabilitation services in rural area in Iran. However, Ahmadzadeh et al. reveals that there is a significant difference in the distribution of outpatient rehabilitation facilities in Iran .Another limitation in the present study was related to the cross-sectional nature of the study and the lack of detailed clinical information about the disability status of the study population. Also, self-reporting of disability status was another limitation in the present study. Self-reporting is a common challenge in population studies that may cause response bias in the study. Furthermore, different factors such as geographical features, physical access, cultural factors, and availability of healthcare may contribute to inequality in access to rehabilitation services that can be investigated in future studies.Our investigation of inequalities in URS across urban and rural areas has important implications. Improving financial access to rehabilitation services especially for the lower SES groups may reduce socioeconomic-related inequalities in URS in both rural and urban areas. Second, equitable distribution of rehabilitation services need to be on the agenda by key actors to assure access to rehabilitation services for deprived populations. Interventions targeting these populations in terms of improving health outcomes can be a cost-effective strategy to reduce these health disparities.Overall, our findings revealed that socioeconomic inequalities in using rehabilitation services was concentrated among well-off PWD. Accordingly, rehabilitation financing through appropriate mechanisms for individuals with low SES is suggested.


First-degree atrioventricular block (AVB) may lead to complete AVB. Herein, we present a case of a complete AVB under thoracic epidural catheter infusion of ropivacaine with fentanyl in a patient with first-degree AVB and myasthenia gravis.A 74-year-old woman with first-degree AVB underwent thymectomy for myasthenia gravis. Continuous thoracic epidural catheter infusion of 0.2% ropivacaine with fentanyl was initiated at 15 min before the end of the surgery. At 9 h postoperatively, the electrocardiogram showed a 10-s-long pause due to complete AVB. Thus, a temporary pacemaker was implanted, and at 19 h postoperatively on postoperative day 1, cardiac pacing was initiated and lasted approximately 30 s. After catheter removal, she had no further episodes of complete AVB.First-degree AVB may lead to complete AVB under the influence of thoracic epidural infusion of ropivacaine in patients with myasthenia gravis. Complete atrioventricular block (AVB) is a rare occurrence that may be triggered by surgical vagal and non-surgical stimuli in addition to stimuli from myocardial ischemia and cardiac conduction anomalies .However, whether epidural anesthesia triggers complete AVB or not is not clearly indicated. To our knowledge, there has been only one case of complete AVB caused by epidural anesthesia alone, which was the first reported case in Japan .Hence, we present a case in which epidural ropivacaine infusion induced complete AVB in a patient with myasthenia gravis (MG) and first-degree AVB.A 74-year-old woman  was scheduled to undergo thoracoscopic thymectomy for MG associated with thymoma. The symptoms of MG included ptosis and muscle weakness, for which at 1.5 months preoperatively, she was administered a 1-week course of ambenonium and methylprednisolone pulse therapy that markedly improved the symptoms by the time of the surgery. She also had a history of tachyarrhythmia; however, on initiating treatment with metoprolol, the palpitations subsided and no further episodes of bradycardia or syncope occurred. Dyslipidemia was another comorbidity. Her blood test results were positive for thyroglobulin, acetylcholine receptor, and thyroid peroxidase antibodies, but no electrolyte imbalance was noted. Preoperative electrocardiogram (ECG) showed a first-degree AVB   and remifentanil (0.2–0.3 mcg/mg/min). At 15 min before the end of the surgery, thoracic epidural catheter infusion of 0.2% ropivacaine and fentanyl was initiated with an initial dose of 5 mL. No bradycardia or other arrhythmias were noted during the surgery that lasted for 3 h 52 min. The train-of-four count throughout the surgery was 0–1. Extubation was performed without difficulty. However, she complained of chills and started shivering; therefore, pethidine (35 mg) was administered. Although she was mildly sedated after pethidine administration, she did not complain of pain, and her respiratory status was stable. Therefore, she was returned to the intensive care unit after adequate observation.At 2 h postoperatively, she was awake and had no complaints of pain. However, her heart rate (HR) dropped to 15 bpm, and she suddenly became nauseous at 5 h postoperatively. After vomiting, her HR improved, and she did not lose consciousness during this episode of bradycardia. At 9 h postoperatively, severe bradycardia for 22 s with a 10-s-long pause due to complete AVB was observed on the ECG . Other factors, including first-degree AVB, MG, the toxicity of ropivacaine itself, and nausea and vomiting, must be considered.Human preganglionic sympathetic cardiac neurons originate mainly from thoracic spinal segments T1–T4 or T5 . In the First-degree AVB was considered an entirely benign condition. In fact, some reports argue that it is a misnomer as there is only delay and no actual block in the AV conduction. However, it has long been acknowledged that extreme forms of first-degree AVB  can cause symptoms because of inadequate timing of atrial and ventricular contractions, similar to the so-called pacemaker syndrome . Our patMG is known to involve other body systems including the heart. MG patients have a higher prevalence of cardiac manifestations in the presence of thymoma (10–15%) . EspeciaEpidural ropivacaine infusion has caused fluctuating arrhythmia , and ropShe frequently experienced nausea and vomiting during the bradycardia attacks, consistent with the symptoms caused by decreased cerebral blood flow. However, we cannot deny the possibility that nausea and vomiting may have stimulated the vagal afferent pathway, thus, resulting in bradycardia caused by parasympathetic excitation. Either the increased intrathoracic pressure during retching or the increased esophageal pressure during the vomiting episodes could have elicited a vagal response . A balloThis report had some limitations. We did not measure anti-Kv1.4 antibody and the blood levels of ropivacaine. If these were measured, there would have been more evidence on their impact on complete AVB. In conclusion, the risk of complete AVB should always be considered when administering epidural ropivacaine, even in asymptomatic first-degree AVB patients. Patients, especially those with MG, should be monitored accordingly.


Acute promyelocytic leukaemia (APL) is a unique subtype of acute myeloid leukaemia (AML) characterized by haematopoietic failure caused by the accumulation of abnormal promyelocytic cells in bone marrow (BM). However, indispensable BM biopsy frequently afflicts patients in leukaemia surveillance, which increases the burden on patients and reduces compliance. This study aimed to explore whether the novel circulating long noncoding RNA LOC100506453 (lnc-LOC) could be a target in diagnosis, assess the treatment response and supervise the minimal residual disease (MRD) of APL, thereby blazing a trail in noninvasive lncRNA biomarkers of APL.Our study comprised 100 patients (40 with APL and 60 with non-APL AML) and 60 healthy donors. BM and peripheral blood (PB) sample collection was accomplished from APL patients at diagnosis and postinduction. Quantitative real-time PCR (qRT–PCR) was conducted to evaluate lnc-LOC expression. A receiver operating characteristic (ROC) analysis was implemented to analyse the value of lnc-LOC in the diagnosis of APL and treatment monitoring. For statistical analysis, the Mann–Whitney U test, a t test, and Spearman’s rank correlation test were utilized.Our results showed that BM lnc-LOC expression was significantly different between APL and healthy donors and non-APL AML. lnc-LOC was drastically downregulated in APL patients’ BM after undergoing induction therapy. Lnc-LOC was upregulated in APL cell lines and downregulated after all-trans retinoic acid (ATRA)-induced myeloid differentiation, preliminarily verifying that lnc-LOC has the potential to be considered a treatment monitoring biomarker. PB lnc-LOC was positively correlated with BM lnc-LOC in APL patients, non-APL AML patients and healthy donors and decreased sharply after complete remission (CR). However, upregulated lnc-LOC was manifested in relapsed-refractory patients. A positive correlation was revealed between PB lnc-LOC and PML-RARα transcript levels in BM samples. Furthermore, we observed a positive correlation between PB lnc-LOC and BM lnc-LOC expression in APL patients, suggesting that lnc-LOC can be utilized as a noninvasive biomarker for MRD surveillance.Our study demonstrated that PB lnc-LOC might serve as a novel noninvasive biomarker in the treatment surveillance of APL, and it innovated the investigation and application of newly found lncRNAs in APL noninvasive biomarkers used in diagnosis and detection.The online version contains supplementary material available at 10.1186/s12885-022-09621-1. Acute promyelocytic leukaemia (APL) is a unique subtype of acute leukaemia characterized by balanced chromosomal ectopic t 15;17) q22; q12), leading to promyelocytic (PML) genes and retinol receptor alpha (RARα) gene fusion [5;17 , whose gene symbol is LOC100506453 and gene accession number is ENST00000424415, in BM samples from APL patients with ATRA-based targeted therapy . However4 cells and HL-60 cells) and clinical samples from patients. Moreover, therapeutic response and MRD surveillance can be accurately monitored through PB lnc-LOC detection, which is quite favourable for the noninvasive monitoring of APL. We aim to provide a novel noninvasive biomarker in the treatment surveillance of APL.In this study, we investigated lnc-LOC expression in APL by establishing a sensitive and specific TaqMan probe-based quantitative real-time PCR (qRT–PCR) and then assessed its potential value. Our data showed that after the induction of ATRA, the expression of lnc-LOC was downregulated in both APL cell lines  and non-APL cells were used for the ATRA treatment experiment. All cells were treated with a final concentration of 2 μM ATRA  or negative control dimethyl sulfoxide (DMSO)  and plated at a density of 2 × 105 cells/well in 6-well plates for 24, 48 or 72 h, respectively. Lnc-LOC and PML-RARα expression in human leukaemia cell lines or ATRA-treated APL cells was determined by qRT–PCR.The human leukaemia cell lines NB4, HL-60, THP-1, U937, K562, Kasumi-6 and HEL were purchased from the Shanghai Institution of Haematology and cultured in RPMI 1640  containing 10% foetal bovine serum  at 37 °C in a humidified 5% CO2 anticoagulant blood vessels. Approximately 2 ml BM samples and PB samples were isolated using Density Reagent  according to the manufacturer’s instructions. Total RNA was extracted from BM/PB samples or cell samples with TRIzol reagent  according to the manufacturer’s protocol, and only those that showed a ratio of A260/A280 between 1.8 and 2.0 were used in reverse transcription for cDNA [PB samples and BM samples were collected from patients and healthy donors using EDTA-Kfor cDNA . All cel−ΔΔCt method [qRT–PCR was performed with TaqMan Universal PCR Master Mix II, no UNG , and GAPDH was used as a reference for lncRNAs. After the extensive test, the final 20 μL optimized amplification system of lnc-LOC or GAPDH was as follows: 10 μL TaqMan Universal PCR Master Mix II, NO UNG (2×), 0.6 μL upstream primer (10 μM), 0.6 μL downstream primer (10 μM), 0.4 μL MGB probe (10 μM), 6.4 μL enzyme-free water, and 2 μL cDNA. Forward (F) and reverse (R) primers were synthesized by Shanghai Yiyue Biological Technology Company  as follows: lnc-LOC, lnc-LOC100506453-F GAGACCCTGGAAATAAAC, and lnc-LOC100506453-R CGATGGAATCAGTTAGAC; and GAPDH, hGAPDH-F TGCACCACCAACTGCTTAGC, and hGAPDH-R TCTTCTGGGTGGCAGTGATG. The probe sequences were as follows: lnc-LOC100506453-MGB FAM-TGGCTTCAGCGTCACCTAGT-MGB and GAPDH-MGB FAM- ACTGTGGTCATGAGTC-MGB. The PCR program was run as follows: denaturation at 95 °C for 10 min, 45 cycles of extension at 95 °C for 5 s, and 59 °C for 1 min. qRT–PCR was repeated three times. The expression level relative to the control samples was calculated by the 2MRD analysis was based on 40 BM samples collected from APL patients before and after induction therapy. qRT–PCR was used to detect PML-RARα fusion gene transcripts from all BM samples on an ABI7500 System with a TaqMan probe as previously described . AccordiP < 0.05 was considered statistically significant.SPSS 21.0 was used for statistical analysis, and graph plotting was performed using GraphPad Prism 8.01 . The nonparametric Mann–Whitney U test and a t test were performed to assess the differences in lnc-LOC expression between experimental samples and control samples. The receiver operating characteristic (ROC) curve was used to evaluate the value of lnc-LOC for APL diagnosis. Spearman’s rank correlation test and rank-sum test were performed for the correlation analysis. Based on previous studies, we explored some important lncRNAs in APL patients with ATRA-based targeted therapy through a combined computational and experimental approach . FinallyP < 0.001; Fig. P < 0.001; sensitivity = 0.975; specificity = 0.767) for distinguishing APL from healthy donors, 0.901  for distinguishing APL from non-APL AML, and 0.588  for distinguishing non-APL AML from healthy donors  (P < 0.001) or the healthy donor group (P < 0.001). Then, we analysed the correlation between PB lnc-LOC and BM lnc-LOC expression in APL at diagnosis. The results showed a positive correlation between PB lnc-LOC and BM lnc-LOC expression in APL at diagnosis  from BM samples was a dysregulated lncRNA associated with ATRA-induced APL differentiation . To inveCurrently, technological advances and analysis of biomarkers provide new methods for haematological diseases, including APL. The common identification of APL-specific genetic lesions can be made by conventional karyotyping, fluorescence in situ hybridization (FISH), or comparable nucleic acid-based techniques . HoweverlncRNAs have been demonstrated to have diverse functions in multiple biological processes and play important roles in cell differentiation and development, and it may implicate several cancers . In coloIn a previous study, early detection of APL molecular relapse using BM was the preferred approach . NeverthIn our previous study, we proved that miR-638 may be an ideal novel target for APL diagnosis and long-term surveillance . HoweverPB represents an attractive specimen source for MRD surveillance, allowing for frequent sampling attributed to easier sample collection. There are still scarce studies showing that PB lncRNAs may be detected as potential noninvasive biomarkers for leukaemia. In addition, PB lnc-LOC expression showed a significantly positive correlation with BM lnc-LOC expression, indicating lnc-LOC as a valid biomarker in noninvasive tracking for APL, which still requires multicentre validation. Therefore, our results showed the possibility of utilizing lnc-LOC as a noninvasive target for monitoring APL recurrence in patients with clinical suspicion of extramedullary relapse that may not be amenable to biopsy. In addition, many researchers have proposed that various regulatory correlations exist between lncRNAs and miRNAs. According to our previous study, lnc-LOC may change the function of miR-638 to initiate, maintain, and develop APL. Regrettably, the specific mechanism remains to be further studied. However, there are some limitations to the present study, including a relatively small sample size , individual heterogeneity, and shorter observation duration. Therefore, our results still require multicentre validation. Meanwhile, whether PB lnc-LOC can be used to predict clinical outcomes, such as the relapse rates and survival of APL patients, needs to be further studied by expanding the sample size.In conclusion, this study provides the first evidence that lnc-LOC may be a circulating biomarker for APL, including for diagnosis, treatment response, and MRD surveillance. Our study provided evidence that PB lnc-LOC could serve as a potential biomarker for APL, which set a precedent in the field of lncRNA noninvasive biomarkers of APL.Additional file 1: Supplemental Figure 1. The representative lnc-LOC and GAPDH amplification plots by qRT-PCR based on TaqMan probe. a The amplification plot of lnc-LOC from APL patients. b The amplification plot of GAPDH from APL patients. c The amplification plot of lnc-LOC from non-APL AML patients. d The amplification plot of GAPDH from non-APL AML patients. e The amplification plot of lnc-LOC from healthy donors. f The amplification plot of GAPDH from healthy donors. The x-axis represents the cycle number, and the y-axis represents the relative change in the fluorescence values. The threshold of amplification plot is set at 0.100.Additional file 2: Supplemental Figure 2. Expression of lnc-LOC in non-APL cells treated with ATRA. lnc-LOC expression in all cell lines were measured by qRT–PCR. qRT–PCR results are expressed as mean ± standard deviation.Additional file 3: Supplemental Table 1. Genetic characteristic of lnc-LOC.


However, the previously reported methods always involve high-temperature calcination processes which are prone to induce agglomeration of the nanostructure, leading to the attenuation of performance. In this work, Co3O4 nanowires were successfully modified by a low-temperature NH3/Ar plasma treatment, which simultaneously generated a porous structure and efficient nitrogen doping with no agglomeration. The modified N-CoOx electrode exhibited remarkable performance due to the synergistic effect of the porous structure and nitrogen doping, which provided additional active sites for faradic transitions and improved charge transfer characteristics. The electrode achieved excellent supercapacitive performance with a maximum specific capacitance of 2862 mF/cm2 and superior cycling retention. Furthermore, the assembled asymmetric supercapacitor (N-CoOx//AC) device exhibited an extended potential window of 1.5 V, a maximum specific energy of 80.5 Wh/kg, and a maximum specific power of 25.4 kW/kg with 91% capacity retention after 5000 charge–discharge cycles. Moreover, boosted hydrogen evolution reaction performance was also confirmed by the low overpotential (126 mV) and long-term stability. This work enlightens prospective research on the plasma-enhanced surface engineering strategies.Surface engineering has achieved great success in enhancing the electrochemical activity of Co Unfortunately, the efficiency of electrocatalysis is always restricted by the higher overpotential and slow kinetics in catalytic reactions [At present, the prosperity and development of human society rely on the excessive consumption of fossil fuels, which inevitably causes severe energy crises and environmental pollution ,2,3. Opteactions . Above aSince energy storage and electrocatalysis depend on the heterogeneous reactions that occur on the surface of active materials, surface engineering, including doping ,14, morp3O4, owing to its high theoretical capacity, controllable morphology and multiple valence states, has been considered as a competitive material in various fields, including energy storage, catalysis and sensing [3O4. However, the reported modification approaches always involve high-temperature calcination processes [3O4.The rare-earth oxide Co sensing ,29,30. Hrocesses ,32, whic3/Ar plasma treatment was applied to conduct surface engineering on the hydrothermally prepared Co3O4 nanowires. Taking advantage of the energetic and activated plasma, porous Co3O4 nanowires with efficient nitrogen doping were obtained at a low temperature. In order to verify the synergistic effect of etching effect and nitrogen doping, systematic characterizations, including morphology, phase, electron structure, supercapacitive behavior and hydrogen evolution reaction (HER) performance, were performed on Co3O4 nanowires before/after NH3/Ar or pure Ar plasma treatment. Furthermore, the mechanism of the superior performance is discussed. Our work provides a new idea to developing high-activity materials and might enlighten the perspective research on the synergistic effect of different surface engineering strategies.In this work, the NH3O4 nanowires and the subsequent low temperature (LT) plasma treatment, are outlined in The fabrication procedures, including hydrothermal growth of CoBefore the deposition, the Ni foam substrate (1 cm × 2 cm) was immerged in HCl (1 M) solution for 10 min to remove the oxide layer, then cleaned and ultrasonicated with acetone, ethanol, and deionized (DI) water for 15 min each. 3)2·6H2O, 0.315 g of NH4F, and 1.276 g of urea were dissolved in 59.5 mL distilled water. The whole mixture was stirred into a pellucid and uniform solution at room temperature. The obtained solution together with the dried Ni foam were transferred to a 100 mL Teflon-lined stainless-steel autoclave and heated in an electric oven at 120 °C for 5 h. After naturally cooling down to room temperature, the Ni foam was thoroughly washed with DI water under ultrasonication and dried at 70 °C for 6 h. Subsequently, the Co(OH)F nanowires were annealed in air at 350 °C for 2 h to obtain Co3O4 nanowires. The proposed synthesis reactions can be described as: Firstly, the precursor Co(OH)F nanowires were prepared on Ni foam via a facile hydrothermal method . Typical3O4 nanowires were obtained by exposing the samples to NH3/Ar (10% NH3) plasma (13.56 MHz radio frequency source). First, the Co3O4 nanowires-loaded Ni foam was set vertically in the quartz tube chamber, and then the reactor was vacuumed down to 1 × 10−5 Pa based pressure followed by flowing NH3/Ar gas to working pressure of 40 Pa. The LT plasma process was controlled by regulating the plasma power and processing time. The optimized working condition was at a power of 300 W and a pressure of 40 Pa for 6 min under NH3/Ar plasma. Herein, the Co3O4 nanowires treated at a power of 300 W with varied operation time were denoted as N/Ar-t .The N-doped Co3O4 nanowires treated under high-purity Ar plasma at 300 W for 6 min were denoted as Ar-6.As control experiments, CoThe scanning electron microscopy (SEM) was conducted on a JEOL 7800F ultra high-resolution field emission scanning electron microscope. The crystallography of the samples was determined by X-ray diffraction (XRD) which used a Rigaku D/Max-KA diffractometer with Cu Kα radiation (λ= 0.15418 nm). X-ray photoelectron spectra (XPS) measured on an Axis Supra (Kratos) using Mg Kα radiation of 1253.6 eV was to explore the chemical composition and valence of the surfaces.All electrochemical measurements were performed on the IVIUM Vertax electrochemical workstation. A series of electrochemical performance tests included cyclic voltammetry (CV), linear sweep voltammetry (LSV), galvanostatic charge-discharge (GCD), electrochemical impedance spectroscopy (EIS), electrochemical active surface areas (EASA), etc.The supercapacitor performance was studied by forming a conventional half-test cell containing a three-electrode system comprised with an as-prepared sample as the working electrode, platinum (Pt) as the counter electrode and the Hg/HGO as the reference electrode, in 6.0 M KOH aqueous electrolyte.3O4 electrode with an average mass loading of ~2 mg/cm2 worked as the cathode, while the functionalized activated carbon was used as the anode, the preparation of which was as follows. First, the commercial activated carbon was heated in 40% nitric acid at 60 °C for 3 h, and after centrifugal washing and drying, the obtained black powder was collected and named as AC-40. Then the as-prepared AC-40, carbon black and Polyvinylidene Fluoride (PVDF) at a mass ratio of 8:1:1 in N-methyl-2-pyrrolidone (NMP)were fully mixed and ground in an agate mortar. Finally, the obtained uniform slurry was evenly coated on the washed nickel foam, and then placed in a blast oven at 60 °C for 24 h.The electrochemical performance of the assembled asymmetric supercapacitor (ASC) was measured in a two-electrode system. The N-doped Co+ = q−). Therefore, the mass loading of AC-40 was calculated to be 4.74 mg using the following equation [m is the mass (g), sC is the specific capacitance (F/g) and ΔV is the potential window (V).In order to obtain the optimum device performance, the cathode and anode should achieve charge balance (qequation :(4)m+m−=3O4 electrode was also measured in the same three-electrode system as above with 1.0 M KOH (pH = 14) solution as the electrolyte. The potential measured against the Hg/HgO electrode was converted to the potential versus the reversible hydrogen electrode (RHE) according to ERHE = EHg/HgO + 0.0591 × pH + 0.098. Before the measurements, the working electrode was activated in supporting the electrolyte for 50 cycles of CV between −0.8 V and −1.5 V at scan rate of 50 mV s−1. LSV measurements were performed in the potential range of −0.8 V–−1.5 V at the scan rate of 2 mV s−1.The HER of as N-doped CoCs, mF/cm2) of the electrodes and assembled ASC devices were calculated from GCD curves according to the following equation [I, Δt, ΔV and s, refer to the constant discharge current (mA), discharge time (s), potential window (V) and the specific area (cm2), respectively.The areal capacitances (equation :(5)Cs=I E, Wh/kg) and specific power density  of the ASC devices were calculated from the discharge time obtained from the GCD plot using the following formulae [I is the discharge current (A), ∫V dt is the area under the discharge curve (Vh), m is the total mass of the active material (kg) and t is the discharge time (h) of the ASC device.The specific energy density (formulae :(6)E=I ∫3O4 nanowires were controllably treated by NH3/Ar plasma with varied operation time to yield the N-doped Co3O4 nanowires (N/Ar-t). The morphologies of the obtained N/Ar-t were investigated by SEM imaging, taking Co3O4 and pure Ar-plasma treated Co3O4 nanowires as a comparison  still maintained a compact surface structure. However, the originally straight needles gradually twisted from the tip and the surface turned rough. When the operation time was prolonged to 6 min, a rough porous structure with no obvious agglomeration and crack was obtained, which can be credited to the moderate treating time at a low temperature , respectively. No impurity peak was observed, validating the high purity of the obtained Co3O4. After plasma treatment, the XRD patterns of Ar-6 and N/Ar-6 were still mainly composed of the characteristic peaks of Co3O4, however two obvious signal peaks (marked by ♦) were recorded at around 42.5° and 61.5°, which can be indexed to the (200) and (220) of CoO (JCPDS No. 43-1004). The newly emerged peaks can be attributed to the reduction process during the plasma etching process. The identical patterns of Ar-6 and N/Ar-6 proves their consistent composition, and the absence of other peaks evinces that no cobalt nitrides were generated.The crystal phase of Co3O4, Ar-6 and N/Ar-6, the XPS experiments were implemented correspondingly. The XPS survey spectra . The 2p1/2 and 2p3/2 peaks of pristine Co3O4 are located at 795.12 eV and 779.76 eV, respectively (1/2 and 2p3/2 peaks in the Co 2p spectra of Ar-6 and N/Ar-6 present an obvious shift towards high binding energy (BE). In order to get a more accurate assessment, each Co 2p spectrum was further decomposed into six peaks , which demonstrate that the peak shift of 2p1/2 and 2p3/2 is due to the different Co3+/Co2+ ratio on the surface layer. The Co3+ accounts for a substantial part in Co3O4, while Ar-6 and N/Ar-6 are mainly made up of Co2+. The higher concentration of Co2+ can be ascribed to the preferred etching effect on lighter O element, which is in consistent with the detection of CoO by XRD analysis. O 1s core level spectra of all samples can be fitted into three distinct peaks at 529.53, 531.19 and 532.75 eV  at 64 mA/cm2, exceeding those of some previously reported nickel foam-based Co3O4 electrodes, such as ZnO/Co3O4 (1135 mF/cm2 at 1 mA/cm2) [3O4 (814 mF/cm2 at 1 mA/cm2) [3O4/NiO (2352 mF/cm2 at 1 mA/cm2) [3O4/Mn2O3 (1762 mF/cm2 at 1 mA/cm2) [3O4 (680 mF/cm2 at 1 mA/cm2) [3O4 (1720 mF/cm2 at 2 mA/cm2) [3O4 (956 mF/cm2 at 2 mA/cm2) [3O4 (1183 mF/cm2 at 2/3 mA/cm2) [2. As shown in The specific capacitances of N/Ar-6 electrode under diverse current densities were calculated from the GCD curves d and the mA/cm2) , Co3O4 ( mA/cm2) , Co3O4/N mA/cm2) , Co3O4/M mA/cm2) , Co3O4 ( mA/cm2) , ZnO@Co3 mA/cm2) , Co3O4 ( mA/cm2) , nitroge mA/cm2) . The lon2 to 32 mA/cm2 , confirming its good rate capability. The cycling performance was also investigated by running charge/discharge cycling at a current density of 8 mA/cm2 using GCD method  [3O4 (60.8 Wh/kg at 5.8 kW/kg) [3O4 nanorod (34.1Wh/kg at 4 kW/kg) [3O4@C nanofiber (37.75 Wh/kg at 1.8 kW/kg) [3O4 nanosphere  [3O4 nanoplate (66.1 Wh/kg at 1.652 kW/kg) [3O4 nanosheet  [In order to evaluate the feasibility of our constructed N/Ar-6//AC-40 asymmetric device, the power density and energy density calculated through Equations (6) and (7) were compared with other Co5 kW/kg) , Co-Co3O8 kW/kg) , Co3O4 n4 kW/kg) , Co3O4@C8 kW/kg) , Cl-dope2 kW/kg) , Co3O4 n2 kW/kg) , and Co33O4 and Ar-6 electrodes were also measured under the same conditions. As presented in 3O4 nanowires improved the performance since Co3O4 is a catalytic active material for HER electrocatalysis. Notably, the plasma treatment further boosted the performance. Especially for the N/Ar-6 electrode, the lowest overpotential (at the current density of 10 mA/cm2) of about 126 mV (vs. RHE) was obtained, which compares favorably to pure Co3O4 (263 mV vs. RHE) and Ar-6 (165 mV vs. RHE). To further perceive the reaction kinetics of the electrodes, Tafel plots (3O4 (227 mV/dec) and Ar-6 (143 mV/dec), elucidating the favorable kinetics for HER on the N/Ar-6 electrode. The electrochemical stability, which is an important criterion in evaluating the HER performance of the catalysts in practical applications, was studied using chronopotentiometry at constant current densities of 10, 20 and 30 mA/cm2. As shown in 2, respectively, which is apparently lower than the potential of Co3O4 and Ar-6 at the same current density.The electrocatalytic capability of the N/Ar-6 electrode toward HER was assessed by linear sweep voltammetry (LSV), whereas for comparison, pure Coel plots b were co3/Ar plasma treatment mainly works on Co3O4 nanowires in three aspects: (1) producing a porous surface and increasing the active surface area; (2) generating oxygen vacancies on the surface layer; (3) injecting nitrogen dopant into Co3O4 lattice. Since the first two aspects mainly originate from the etching effect of plasma and can be accomplished in a pure Ar atmosphere, the Ar-6 electrode was applied as the control group in exploring the relationship between structure and performance.According to the previous results, the NH3O4, Ar-6 and N/Ar-6 electrodes were studied to verify the influence of etching and nitrogen doping. The CV curves of all electrodes were recorded in the non-faradic regions (0.05 V–0.15 V) under different scan rates (4–14 mV/s), as depicted in 2) possesses a higher EASA than Co3O4 (slope = 222.43 mF/cm2), indicating that the etching effect of plasma produced a higher surface area and abundant active sites. The highest slope (435.98 mF/cm2) achieved by the N/Ar-6 electrode corroborates the important role of nitrogen doping in activating reaction sites.First, the electrochemical active surface areas (EASA) of Co3O4, Ar-6 and N/Ar-6 was calculated to be 2.16, 1.94 and 1.73 Ω, respectively. The slight decrease indicates that Rs is not sensitive to the plasma treatment since it is mainly composed of bulk phase resistance  and interfacial resistance between active materials and current collector, which is well protected from plasma. However, the charge-transfer resistance (Rct) was greatly affected by the plasma treatment, as demonstrated by the distinct size of the semicircles. The Rct for Co3O4, Ar-6 and N/Ar-6 was determined to be 38.96, 5.90 and 3.64 Ω, respectively. The sharp drop of Rct for both N/Ar-6 and Ar-6 implies that the superior electron transfer kinetics is mainly induced by oxygen vacancies. A further slight decrease in Rct for N/Ar-6 indicates that the nitrogen incorporation into the Co3O4 lattice also facilitates the electron transfer.Furthermore, the EIS measurement was performed in a three-electrode system to study the electron/ion transfer behavior. The Nyquist plots in the high-frequency range are illustrated in 3O4 nanowires were assembled on Ni foam by the hydrothermal method and surface-modified by NH3/Ar plasma treatment. Comparative analyses were conducted on pristine Co3O4, Ar-6 and N/Ar-6. N/Ar-6 outperformed all the other samples and exhibited the superior supercapacitive and electrocatalytic performance, which should be accredited to the synergistic effects of plasma etching and nitrogen doping, offering copious active reaction sites and favoring the electron transfer kinetics. Our low-temperature modification method and relevant investigation of the synergistic effect of etching and nitrogen doping provides the necessary experimental and theoretical foundation for the future design of convenient, low-cost and high-performance electrochemical devices.In summary, Co


Recent studies on consumer behaviors showed that the role of neuroscientific tools in increasing the knowledge of the neural mechanism is involved in the decision and emotional processes . NeuromaNowadays, consumers’ needs are not only related to the product/service as such but also to the associated buying experience that must be enchanting, captivating, and fascinating . VirtualIn defining AR, scholars argue that it is somehow related to VR because of its immersivity: in both cases, users feel telepresence, namely, the sensation to be present in an environment that is real, with the possibility to respond, and control and act on the experience they are living . VR scenEven though VR and AR are similarly evolving in both the theoretical models and applicative examples , they stConsidering these elements, we argue the importance of deepening the role of AR in the emotional response of consumers to a product and to an experience that is closer to reality. Together with the mentioned engagement the combination of real objects with virtual elements matching the physical environment  and redrConsidering the characteristics of the associated media , AR can via VR experience. Considering the possibility of highly simulating the real environment through AR technology, it is important to also focus on neuromarketing tools to capture emotional responses in AR situations. This is particularly important as little has been done in AR with neuromarketing techniques, also with the understanding of the AR features in consumer behavior (As mentioned, the VR experience has already been investigated through neuromarketing techniques. A study by behavior . As for behavior . Some tobehavior . In addibehavior . Skin cobehavior . Heart rbehavior . Finallybehavior .It is important to consider the nature of AR and the exposure to specific visual stimuli that could engage but also ask for an effort of adaptation that can change the human’s sensitivity and sensorial perception . TherefoNeuromarketing tools have been already used within the immersive VR technology through devices applied to the head and the hands to record consumers’ responses and changes in muscle control over a long time. This was possible since VR involves the sensorimotor system more than other stimuli, with the potential of increased realistic psychological and behavioral responses . Recent This article aimed to focus on the importance of deepening the role of AR in the emotional response of consumers to a product and an experience through specific tools, such as neuromarketing techniques, considering that AR could be closer to reality than other simulated situations. If VR has already been investigated, AR should be deepened by scholars, researchers, and companies for them to offer reliable answers on consumer behavior in augmented situations.These considerations can be useful in tracing a roadmap for future research in the neuromarketing and AR fields. Neuromarketing studies could include AR as an alternative experimental environment, while AR could consider the benefits of the neuromarketing tools .Augmented Reality technologies will directly mediate the interaction between the brain and the real world, as well as the effort in adaptation and perception of risks, including cognition, memory, and decision-making . In thisVR, MB, and MZ wrote the first draft and each section of the manuscript, contributed to the manuscript’s final writing and revision, read, and approved the submitted version. All authors contributed to the article and approved the submitted version.