Castration-resistant prostate cancer (CRPC) is defined by resistance of the tumor to androgen deprivation therapy (ADT). Several molecular changes, particularly in the AR signaling cascade, have been described that may explain ADT resistance. The variety of changes may also explain why the response to novel therapies varies between patients. Testing the specific molecular changes may be a major step towards personalized treatment of CRPC patients. The aim of our study was to evaluate the molecular changes in the AR signaling cascade in CRPC patients. We have developed and validated several methods which are easy to use, and require little tissue material, for exploring AR signaling pathway changes simultaneously. We found that the AR signaling pathway is still active in the majority of our CRPC patients, due to molecular changes in AR signaling components. There was heterogeneity in the molecular changes observed, but we could classify the patients into 4 major subgroups which are: AR mutation, AR amplification, active intratumoral steroidogenesis, and combination of AR amplification and active intratumoral steroidogenesis. We suggest characterizing the AR signaling pathway in CRPC patients before beginning any new treatment, and a recent fresh tissue sample from the prostate or a metastatic site should be obtained for the purpose of this characterization. Castration-resistant prostate cancer (CRPC) arises when prostate cancer (PCa) progresses under castrate levels of serum testosterone which is achieved by androgen deprivation therapy (ADT) . CRPC isThe development of predictive biomarkers needs to be based on the mechanism of disease. It has been shown that several escape mechanisms underlie the emergence of CRPC. These CRPC pathways can be classified into androgen receptor (AR)-dependent and AR-independent signaling pathways. Re-activation of the AR signaling pathway is still a major cause in CRPC. Aberrations in AR dependent signaling pathways still rely on AR-mediated transactivation, and include AR mutations, AR gene amplification, expression of AR splice variants (AR-V), intratumoral steroidogenesis and AR cofactor deregulation , 8, 9. THowever, previous studies have shown that each change in the AR signaling pathway, aberrant AR or increases in intratumoral steroidogenesis enzyme, accounted for only up to 30% cases, respectively , 12. Sevvia transurethral resection of the prostate (TURP). We also used normal prostate (NP), benign prostatic hyperplasia (BPH) and primary prostate cancer without previous treatment as reference samples. These samples were obtained after radical prostatectomy for NP and PCa and TURP for BPH. The tissue specimens were snap frozen in liquid nitrogen or formalin-fixed and paraffin-embedded. Tissues containing at least 70% of tumor cells were selected after microscopic assessment of H&E-stained sections. Clinical data, such as age and previous treatment, were also collected . Prostate tissues were collected 2.All prostate (cancer) cell lines were used as previously described . All cel2O2 substrate (Immunologic) was added to the slides and incubated at room temperature for an additional 8 min. Tissue sections were counterstained slightly with hematoxylin. Slides were dehydrated and sealed with Permount Mounting Media for visualization by light microscopy. AKR1C3 data were used from a previous study  at 95°C for 10 minutes. Non-specific binding was blocked by incubating the tissue sections with 5% human serum and 1% BSA in PBS for 30 minutes. Human AR protein was detected by using the AR N-terminus antibody  and the AR C-terminus antibody . Primary antibody was incubated for 1 hour at room temperature. Poly HRP (Immunologic) secondary antibody was applied for 30 minutes at room temperature. DAB-Hus study .Genomic DNA was extracted using SDS/ProtK lysis  for 1 hour at 65°C. Samples were purified by phenol and chloroform extraction. Then DNA was ethanol precipitated, and finally dissolved in DNAse-free water. Total RNA was extracted using TRIzol reagent (Life technologies), according to the manufacturer’s instructions. The concentrations of genomic DNA and total RNA were measured on a ND-1000 Nanodrop spectrophotometer (Thermo Scientific).AR gene and for the somatic single copy gene, glyceraldehyde-3-phosphate dehydrogenase (GAPDH)  and normal female lymphocytes (AR/GAPDH ratio = 2) were used as controls in every experiment.AR amplification was measured using a modified protocol from Ottesen et al. . Briefly2O. Two µl of cDNA samples were used as a template. PCR was performed using AR exon-specific primers (® PCR Preps DNA Purification System (Promega). Purified PCR products were sequenced using AR exon-specific primers, the ABI PRISM BigDye Terminator Cycle Sequencing kit and an ABI PRISM 3730 automated DNA Analyzer (Applied Biosystems).Two micrograms of TRIzol-extracted RNA was DNase-I-treated and cDNA was synthesized using random hexamer primers and SuperScript II-MMLV reverse transcriptase (Life Technologies). The RT-reaction (30 µl) was diluted 4 times in HAR Amplification). Crossing-point (Cp) values were determined using the LightCycler 480 SW 1.5 software (Roche). HPRT expression was used for normalization. Relative gene expression levels were calculated according to the model described by Pfaffl  and 2 µl cDNA as a template. RNA not subjected to reverse transcriptase was used as a negative control for PCR amplification. Gene-specific primers used are listed in y Pfaffl .Comparison of AR protein levels with other patient characteristics were analyzed using Fisher’s exact test. The mRNA expression levels were analyzed using non parametric Mann-Whitney U test. Correlation of mRNA levels were analyzed using non parametric Spearman’s rho test. SPSS version 22 software was used for statistical analysis; p values < 0.05 were considered as statistically significant.In this study, we evaluated 23 CRPC patients from whom fresh frozen and FFPE tissues were available for analysis. Various different treatments were used for advanced PCa before CRPC developed. Detailed patient characteristics are described in We used an AR N-terminus-specific antibody to determine AR protein levels in patient samples. Most of the patients 20/23) had strong AR expressions, 4 patients had intermediate AR levels, whilst only 1 patient had low/no AR expression . We vali/23 had sIn a previous study, we determined AKR1C3 enzyme levels as a marker for active intratumoral steroidogenesis. High AKR1C3 expression was only observed in a subgroup of patients (~30%)  for patients that had received pure antiandrogen treatment . We also did not find any mutation in the non-LBD domains of the AR.AR mutation analysis revealed that only one CRPC patient had a mutation (T868A) in the AR LBD, similar to the AR mutation in LNCaP cells. This patient had intermediate AR protein expression. We extended the AR mutation analysis to the entire AR gene . Even though, the half-life of AR-Vs is shorter than AR-FL, AR-Vs are more resistant to AR degradation process . Perhapsi.e. AR and AR-V expression, AR gene amplification and mutation, and AKR1C3 protein expression, in CRPC specimens. In our study, we found heterogeneity in the AR signaling pathway changes, and no single prominent alteration was found  AR targeting treatments (Due to the high frequency of (re-)activated AR signaling in our patients, we suggest performing an initial assessment of AR activity in CRPC patients before giving additional treatment  activated in the majority of CRPC patients. We suggest performing AR signaling profiling analysis before providing further treatment to CRPC patients.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by Local Ethical Committee of the Radboud University Medical Center (RUMC). The patients/participants provided their written informed consent to participate in this study.All authors listed have made a substantial, direct, and intellectual contribution to the work, and approved it for publication.This work was supported by the Prostate Research Organizations-Network of Early Stage Training (PRO-NEST) project funded by the European Commission . The authors would also like to thank Universitas Indonesia for funding this research through Hibah Kolaborasi Riset Internasional Tahun 2019 grant with contract number NKB-1919/UN2.R3.1/HKP.05.00/2019.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Allergic rhinitis (AR) is an inflammatory disorder of the nose caused by immunoglobulin E (IgE)-mediated immune response to allergens. Apart from the typical symptoms of sneezing, itching, rhinorrhea, and nasal congestion, behavioral complications were also reported to be associated with the progression of AR, such as cognitive deficits, mood changes, memory decline, attention deficiency, poor school performance, anxiety, and depression. Recent human studies have suggested that alterations in brain function caused by allergen exposure may precipitate high levels of anxiety and emotional reactivity in asthma patients. But until now, there is no direct evidence of the relationship between brain activity and allergic rhinitis.z conversion of ALFF (zALFF) in 20 patients with AR and 20 age- and sex-matched healthy controls (HCs) using the rs-fMRI data.Resting-state functional magnetic resonance imaging (rs-fMRI) was used to excavate whether there remain functional changes of brain activity in AR patients. We measured the amplitude of low-frequency fluctuation (ALFF) and the Compared with healthy controls, AR patients exhibited lower ALFF values in the precuneus (PCUN) and higher ALFF values in the anterior cingulate cortex (ACC). The ALFF values of these features were significantly correlated with the visual analog scale (VAS) scores, the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) scores, the subscales of RQLQ, and specific IgE, partly.We found changes in resting-state spontaneous brain activity in AR patients with hypoactivity in the PCUN and hyperactivity of the ACC. The brain-related symptoms of AR might be another potential clinical intervention target for improving the life quality of AR patients. Further attention to brain activity is essential for a deeper understanding of AR. Allergic rhinitis (AR) is an inflammatory disorder of the nasal mucosa induced by immunoglobulin E (IgE)-mediated immune response to allergens . In the The characteristic symptoms of AR are sneezing, itching, rhinorrhea, and nasal congestion . Apart fNeuroimaging techniques could help detect structural and functional brain abnormalities at an early stage. Studies incorporating structural and functional magnetic resonance imaging (MRI) can provide more comprehensive information on the underlying mechanisms of the various pathways in the pathogenesis of diseases . RestingIn this study, our primary goal was to observe the changes in resting-state spontaneous brain activity in ALFF in AR patients, aiming to make an initial study of the mechanisms of the brain-related symptoms in AR. Taking into account that few studies to date have examined the relationship between AR and brain-related disorders in individuals with AR, and that none of the fMRI measures of BOLD variability in this group was reported, we also investigated the relationship between alterations in ALFF and clinical indexes, as well as allergy indicators, using correlation analysis for our pilot neuroimaging study.A total of 20 AR patients were recruited from the Otorhinolaryngology Department of Renmin Hospital of Wuhan University. The inclusion criteria were as follows: 18–50 years old and moderate to severe AR for more than 1 year. The diagnostic criteria for AR are according to the Allergic Rhinitis and its Impact on Asthma Guidelines (ARIA) : (1) posTwenty age-, sex-, and education level-matched HCs were also enrolled as a control group in the present study. All of the subjects were right-handed according to the Edinburgh Handedness Inventory.This study was approved by the Human Research Ethics Committee of Renmin Hospital of Wuhan University . Written informed consent was given to all the participants .2, and flip angle = 12°. Echo planar images (EPIs) were acquired with the following parameters: 40 slices, repetition time = 2,000 ms, echo time = 25 ms, thickness = 3.0 mm, gap = 1.2 mm, acquisition matrix = 64 × 64, flip angle = 90°, field of view = 240 × 240 mm2, and voxel size = 3.6 × 3.6 × 3.6 mm3 during an 8-min scanning time. Three EPI series were collected from all participants, and they underwent MRI scans with their eyes closed, but not sleeping.Scanning of this study was performed at the Radiology Department of Renmin Hospital of Wuhan University  using a 3-T MR scanner  with an eight-channel head coil. Structural T1-weighted images were acquired with the following parameters: 192 slices, repetition time/echo time = 8.5/3.3, thickness = 1.00 mm, no intersection gap, acquisition matrix = 256 × 256, field of view = 240 × 240 mm1 and the toolbox for Data Processing Assistant and Analysis for Brain Imaging2 software.Resting-state functional images were preprocessed through Statistical Parametric Mapping SPM123. Normalized images were smoothed spatially with a 6 × 6 × 6-mm3 full width at a half maximum Gaussian kernel. Denoising methods were applied, including bandpass filtering and nuisance covariate regression . Subjects with head motion that exceeded the maximum displacement of 2 mm at each axis and an angular motion of 2° for each axis  were excluded from further analysis. Using this criterion, seven AR subjects and three control subjects were excluded, which resulted in 20 AR and 20 control subjects.Steps could be briefly generalized as follows: (a) Remove the first 10 time point functional images to achieve equilibrium because of lack of adaptation to the scanning environment and unstable initial MRI signal. (b) The intra-volume temporal mismatch and intervolume spatial displacement were subsequently corrected. EPIs were normalized to the Montreal Neurological Institute (MNI) standard space and resampled to a resolution of 3 × 3 × 3 mmz transformation amplitude of low-frequency fluctuations (zALFF) and used for subsequent group-level analysis. Calculations were performed using REST software version 1.83. Then, the mean ALFF value was extracted by averaging the ALFF values over all voxels for each individual.The BOLD time series for each voxel was first converted to the frequency domain using fast Fourier transform. The square root of the power spectrum was subsequently computed and averaged across the specified frequency range (0.01--0.08 Hz) at each voxel. The averaged square root was considered the ALFF. Finally, this value was transformed using Fisher’s t-test was performed for variables and the statistical threshold set at p < 0.05.Demographic and clinical data such as age, gender, year of education, disease duration, VAS score, and RQLQ score were analyzed using the Statistical Package for the Social Sciences version 26.0  between the two groups. The two-tailed t-test was used to compare the zALFF values in each voxel of the two groups . Pearson’s correlation analysis was used to investigate the relationship between the mean ALFF values in different brain regions and clinical performance for AR patients. Spearman’s correlation analysis was employed to investigate the correlation between the ALFF z-values in the precuneus (PCUN) and specific IgE. Partial correlation analyses were performed in the comparisons above, excluding the effects of gender, age, and years of education. A p-value < 0.05 was considered to represent a significant difference.The two-sample p > 0.05; see There were no significant differences in age or sex between the HC and AR groups  and RQLQ  scores. Moreover, the ALFF values in the PCUN also had significant positive correlations with the RQLQ subscale of non-nasal/eye symptoms  and emotional function , as shown in p > 0.05).Correlation analysis revealed that the mean ALFF values in the PCUN displayed significant positive correlations with the VAS  and the RQLQ subscale of practical problems , as shown in p > 0.05).The mean ALFF values in the ACC displayed significant positive correlations with the VAS score , as shown in r = 0.254, p > 0.05; ACC: r = 0.022, p > 0.05), as shown in z-values in the PCUN  and ACC , as shown in We also analyzed the fMRI results and the indexes of allergy. We found significant positive correlations between AR patients’ ALFF in the PCUN and the specific IgE results  physiological effects—the physiological role of nasal obstruction and its impairing impact on sleep may, together, subsequently affect psychiatric symptoms negatively ; (2) cytOur study also has limitations and caveats. The number of our case samples was small, which limited our comprehensive understanding of the relationship between the activated brain regions and the severity of AR. Moreover, we did not conduct a cognitive or psychological analysis using professional scales or a questionnaire for each patient. We will continue to collect clinical samples for further research. To the best of our knowledge, our current study is one of the first resting-state functional neuroimaging studies in the field of allergic rhinitis and is one of the first studies to connect clinical indexes with fMRI values. According to our results, early intervention and therapy for brain-related symptoms in AR will be recommended. AR patients, otherwise, may have a risk of AD or other neurodegeneration diseases.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Human Research Ethics Committee of Renmin Hospital of Wuhan University . The patients/participants provided their written informed consent to participate in this study.ZG and YX designed the whole study. RX, WZ, and LT selected the patients, analyzed the data, and prepared the questionnaires. XC and ZG performed the scanning for participants. PL undertook the statistical analysis. WF and HL participated in the interpretation of data. ZG and HL wrote the manuscript. PL and YX revised the manuscript. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The URIS® neuromodulation system, engineered to provide Peroneal eTNM®, consists of the URIS® device, URIS® active electrodes, and the biofeedback foot sensor (BFS). The unique design of the URIS® device and URIS® active electrodes allows for the use of a low voltage and current during neuromodulation, which significantly reduces the unpleasant sensations. The BFS allows for precise localization of the active electrodes and for continuous adjustment of the voltage and frequency to achieve the optimal therapeutic effect. The URIS® system adopts several principles of telemedicine, which makes it compatible with the US Food and Drug Administration (FDA) and European Union (EU) regulations for home-based use. This article describes both the Peroneal eTNM® method and the URIS® neuromodulation system, including its technical specifications and data from laboratory testing. Preclinical and early clinical data demonstrate the feasibility of this new method for noninvasive OAB treatment and possible implications for clinical practice.Overactive bladder syndrome (OAB) is a prevalent medical problem with a significant impact on the quality of life of the affected individuals. Pharmacotherapy is considered the main treatment method, although it is discontinued in a significant proportion of patients due to inefficacy or associated side effects. If pharmacotherapy fails, patients can undergo peripheral neuromodulation of the somatic nerves of the lower limb or sacral neuromodulation; however, neither of these represents an ideal therapeutic tool. The Peroneal electric Transcutaneous NeuroModulation (Peroneal eTNM Overactive bladder syndrome (OAB) represents lower urinary tract dysfunction; it is a sudden, compelling desire to pass urine that is difficult to defer (urgency), with or without involuntary loss of urine associated with the urgency (urgency urinary incontinence) . A signiInitial conservative treatment includes lifestyle interventions, behavioral techniques, and pelvic floor muscle exercises. Pharmacotherapy is the most widely used treatment method. However, its efficacy is insufficient in at least 30% of patients . In addiGiven these limitations, surface electrodes were introduced to deliver impulses to the tibial nerve in transcutaneous tibial nerve stimulation (TTNS) . TTNS shGiven that neuromodulation may represent a causal treatment for at least a certain proportion of OAB patients, the development of a new method that would address the limitations of both PTNS and TTNS is highly desirable.®) that is intended to treat the OAB syndrome.This paper includes a description and critical evaluation of a new fully noninvasive neuromodulation method called Peroneal electric Transcutaneous NeuroModulation  is detected using the discrete corrections of the electrode position. The OSP is an area of about 0.8 cm2 and can be localized based on eliciting both sensation and visible motor response characterized by rhythmic lateromedial foot movement  designed to provide Peroneal eTNM® consists of the URIS® device, specially engineered URIS® active electrodes, and the biofeedback foot sensor (BFS).The novel URIS® generator is designed as a voltage source. The generator provides impulses with a primarily monophasic rectangular waveform; the voltage amplitude is adjustable, in the range of 0–90 V, the frequency range is 0–10 Hz, and the impulse width is 2 ms. After the impulse time has elapsed, the patient is electronically disconnected from the electric circuit completely. The electrical safety of the URIS® device was tested under the IEC 60601-1 and IEC 60601-2-10 requirements.This device consists of the impulse generator, which is controlled by the microcontroller unit (MCU). The MCU has its own hardware (HW) periphery and firmware. Unlike the other generators currently used for PTNS and TTNS, the URIS® electrodes are shown in Electrical impulses are delivered to the patient's body through the active electrodes connected to the device. The electrode was designed to allow for selective stimulation of the individual nerve (similar to the needle electrode) while maintaining simple and noninvasive detection of the OSP . The sma® device that is attached to the feet of the patient. The BFS contains an analog accelerometer that detects the motor response elicited by every stimulation impulse. The arithmetic mean of the signal amplitude in each of the accelerometer axes is processed by an analog/digital (A/D) converter, filtered, and passed to the MCU.The BFS is an accessory of the URISThe localization of the OSP is crucial for achieving the clinical effect of neuromodulation. Based on the information from the BFS confirming the adequate motor response, the MCU determines the precise localization of the OSP at the beginning of each neuromodulation session. Only after the OSP has been confirmed, does the MCU enable initiation of the neuromodulation.Thanks to the continuous analysis of the data from the BFS, the MCU will adjust the frequency during the neuromodulation session so that the next impulse is enabled only after the motor response to the previous impulse has completely elapsed. This limits muscle fatigue and contributes to the patient's comfort. The intensity of the motor response may vary after a certain period of exposure; therefore, the BFS also allows for continual adjustment of the voltage. This guarantees that the nerve will be permanently exposed to the energy, eliciting the optimal response. Thanks to the closed biofeedback loop, the neuromodulation process is under direct control throughout its duration, as required by the European Union authorities .® neuromodulation system is shown in The entire scheme of the URIS® electrode electric output characteristics with those of the electrodes used during PTNS and TTNS in current clinical practice.We aimed to compare the URIS® active electrode to both the L-type needle electrode of diameter 0.23 mm  and the Stimex® adhesive electrode 50 × 50 mm .We compared the URIS® electrode was positioned just below the fluid level. All types of active electrodes were consecutively connected to the URIS® device, the output voltage was set to 20 V, the impulse width was 2 ms, and the electric output characteristics were measured.The measurement was performed in a saline-filled vessel in which a neutral electrode of diameter 1 cm was placed 50 mm below the fluid level. Subsequently, all three types of electrodes mentioned above were consecutively inserted into the vessel. The needle electrode was submerged so that its tip was 40 mm below the fluid level. The adhesive electrode floated on the fluid surface, and the hemispherical part of the URIS® generator with those of the TTNS generator . The measurement was performed as shown in R = 1 kΩ); (ii) a parallel RC element  simulating the human body; and (iii) a human volunteer.We compared the VA characteristics and other output variables of the URIS® generator. An output voltage of 15 V was set for the URIS® generator and an output current of 10 mA for the UROstim2® generator.For measurements involving the resistor and RC element, an impulse width of 0.2 ms was used for both generators, representing the standard impulse width for the UROstim2® active electrode and neutral electrode were used. An impulse width of 0.2 ms and the minimal voltage and current values that elicited the motor response of the individual were used (19 V for the URIS® generator and 10 mA for the UROstim2® generator). Subsequently, we performed additional measurement with the URIS® generator set to the standard impulse width of 2 ms and the UROstim2® generator set to the impulse width of 0.4 ms (maximum available impulse width).For measurements involving the human volunteer, the URIS® and Stimex® electrodes as reference. A total of 14 healthy volunteers  whose average age was 30.9 ± 9.9 years were enrolled. The sequence of stimulations in each individual subject was determined randomly.We compared the subjective perception of neuromodulation using several combinations of devices and electrodes using the standard TTNS device UROstim2® testing, the neutral electrode was placed on the lower abdomen, and the OSP in the popliteal fossa was detected using the URIS® active electrodes. The URIS® device was set at a frequency of 4 Hz and impulse width of 2 ms, and the voltage was then gradually increased until the first motor response was observed. In addition, several measurements were performed as the combination of devices, electrodes, and frequencies was changed.For standard Peroneal eTNMFor the standard TTNS testing, the neutral electrode was placed behind the internal malleolus and the active electrode was placed cranially at approximately 10 cm from the neutral electrode, according to Amarenco . The freAfter 1 minute of stimulation, the subject was asked to evaluate his/her perception using a visual analog scale (VAS) ranging from 0  to 100 (the procedure causes me unbearable/unpleasant/painful feelings).® electrode delivered 4 times higher energy and 30 times higher current density compared to the Stimex® electrode. These data suggest that the generally recommended standard size self-adhesive surface electrode is not suitable for selective nerve stimulation. Results are summarized in The measured current intensity was significantly higher than that of the in vivo measurement due to the much lower impedance of saline compared to the human body. At the given output voltage, the measured current and charge values were comparable, while the delivered energy and the current density differed significantly. The needle electrode gave the highest energy and current density. When comparing the noninvasive electrodes, the URISWhen only the resistor was included in the circuit, a rectangular monophasic impulse with a defined width was measured in both generators Figures .® and TTNS generators. However, in the TTNS generator, there was a signal overshoot to the opposite polarity caused by connection of the active electrode to the neutral potential of the generator after the impulse had elapsed. This represented the active discharging from the electric RC circuit , and abdominal hysterectomy due to benign condition, had been suffering from OAB symptoms for 2 years. Previous treatment using several anticholinergics and betamimetics failed due to adverse events. According to the 3-day bladder diary, the patient reported 7 episodes of micturition per day before Peroneal eTNM®. According to the 3-day bladder diary, the patient had an average of 17 episodes of micturition per day at baseline. Ten of those were preceded by severe urgency. The urodynamic assessment revealed the bladder oversensitivity during filling cystometry. After Peroneal eTNM® treatment, the micturition frequency was reduced to 11 per day  and the number of severe urgency episodes was reduced to 3 per day (−70%). The patient reported significant improvement in her bladder condition by 2 points, as documented by the 6-point Patient Perception of the Bladder Condition (PPBC) scale.This patient, an otherwise healthy woman with a history of OAB since childhood (over 20 years), had been previously treated with several anticholinergics without any notable effect. After the treatment trial with betamimetics, the patient observed a partial reduction in symptoms but did not consider this sufficient. Therefore, she was referred for treatment with Peroneal eTNMThis patient had a history of multiple sclerosis diagnosed in 2012, which was later classified as a relapsing-remitting course; she had been treated with interferon and subsequently with fingolimod. The expanded disability status scale (EDSS) score was 5.0/10.0.®. At the baseline, the patient was bothered by an average of 16.3 episodes of micturition, 2.7 episodes of severe urgency, and 0.7 episodes of urgency incontinence per day, as reported in her 3-day bladder diary. A reduced cystometric capacity (230 mL), normal compliance, and terminal detrusor overactivity (maximum detrusor pressure of 37 cm H2O) were documented during filling cystometry, while the voiding phase was not impaired with complete emptying. After Peroneal eTNM® treatment, the micturition frequency decreased to an average of 10 episodes per day  and the number of severe urgency episodes reduced to 1.0 per day (−71%). The patient reported complete disappearance of urgency incontinence and a significant reduction in nocturia episodes from 2.7 to 0.7 (−74%). This contributed to the reduction of her chronic fatigue and allowed for an increase in her daily activity. The patient reported significant improvement in her bladder condition by 2 points as documented by the PPBC scale.The patient was referred to a urologist due to OAB symptoms she had suffered for 4 years. Initial treatment attempt with betamimetics was not effective and the patient was subsequently suggested for Peroneal eTNMOAB syndrome is a chronic medical condition with a proven detrimental impact on QoL and well-documented health consequences for affected individuals . Its tre® device has a number of advantages. The course of the peroneal nerve makes it possible to precisely define the OSP. Exact localization of this small area in the popliteal fossa is a prerequisite for eliciting an adequate motor response. Determination of the OSP based on both the sensation and visible motor response  represents a fundamental difference compared to the TTNS method, in which the OSP is not clearly defined. Some authors recommend placing the active electrode approximately 5–10 cm above the inner ankle, while others recommend placing it just posterior to the inner ankle [The selective stimulation of the peroneal nerve using the URISer ankle , 20. In ® device to be pointed out. The URIS® device represents a constant voltage source with current intensity decreasing over the impulse duration. The electrical disconnection of the patient from the URIS® generator after the impulse has subsided warrants that the patient is not exposed to any additional current flow. Other features that contribute to patient safety are galvanic separation of the patient and the presence of a voltage boost converter that cuts off the patient's exposure to the voltage in the event of a hardware or firmware failure. The entire design of the URIS® device makes it possible to achieve a clinical effect at a significantly lower voltage and current compared to the currently used TTNS devices which are designed as current generators.There are several technical features of the URIS® electrodes allows for high current density at the tip of the electrode and for its gentle impression into the tissue, reducing the resistance. These facts, along with impulse modulation by the magnetic field, enable selective nerve stimulation without simultaneous excitation or irritation of the surrounding structures, including the nociceptive receptors in the skin and subcutaneous tissue, thus reducing the unpleasant and painful sensations during the neuromodulation. Compared to the standard self-adhesive electrodes routinely used in TTNS, a much lower impulse intensity is required to deliver the same energy to the target nerve even in obese patients, where the distance between the electrode and the peroneal nerve is longer due to fat tissue deposits. Based on the laboratory testing, the effect of the URIS® electrode is close to that of the needle electrode, without the need to compromise the skin integrity. In addition, presented data on treatment perception show that the URIS® electrodes, which are an integral part of the URIS® neuromodulation system, cannot be replaced by any type of self-adhesive surface electrodes used in TTNS.One of the major advantages of the URIS® system has to do with the URIS® active electrodes. The human body is considered a conductor of the II type because the electric current is conducted in the body by ions. The most significant change in the electric field compared to a homogeneous medium occurs in the skin, which is responsible for more than 99% of the body's resistance to the electric current flow . The vas® system represents another significant advantage. The BFS allows for precise localization of the OSP and ensures that the treatment session does not start until the optimal position of the active electrode has been achieved. After the neuromodulation has been initiated, based on the feedback data, the MCU will continuously adjust the voltage and frequency in order to keep the output energy as high as necessary for effective neuromodulation and as low as possible to prevent side effects. The URIS® system software records and stores the retrospective data on impulse voltage, impulse frequency, and number and length of individual neuromodulation sessions that the patient has completed. With its noninvasiveness and biofeedback features, the URIS® system is compatible with the FDA and EU regulations for home-based use. The device is able to check the patient's adherence and, if necessary, reminds the patient of the correct treatment schedule. The URIS® system allows the physician to share the patients' data on treatment progress and change the stimulation parameters or treatment schedule as needed using remote access. This technology ensures that, even in home-based use, the treatment can be fully under professional control and continuously modified in order to achieve the optimal therapeutic effect.The incorporation of the biofeedback loop into the URIS® may seem to be similar, these two methods differ in principle. While Peroneal eTNM® is based on selective stimulation of the nerve with minimal excitation of other sensory receptors, TTNS produces stimulation over a large area of the skin surface, which, according to the gate control theory, can cause blocking of a certain proportion of the afferent stimuli at the level of the synapsis between the primary and secondary neurons. This may attenuate its clinical efficacy. In addition, there are a number of other factors that distinguish Peroneal eTNM® from TTNS. Our data show that, due to the combination of several original technical innovations, including different generator constructions with unique impulse patterns and effective URIS® electrodes, Peroneal eTNM® is much better perceived than TTNS. Its noninvasiveness and use of the biofeedback control make Peroneal eTNM® easy to use by patients themselves in their home environment without any assistance.PTNS is considered the standard peripheral neuromodulation method currently used in OAB treatment. The use of the needle electrode represents its most significant limitation. The placement of the electrode tip in the proximity of the tibial nerve can be challenging and may be associated with uncomfortable sensations or pain. Transcutaneous electrical nerve stimulation (TENS) has been used in pain treatment since the end of the 1960s . The mec® may represent a feasible method for OAB treatment. In a small cohort of patients with OAB, we observed a significant reduction in OAB symptoms, as demonstrated using standardized tools in response to Peroneal eTNM®. At the same time, we did not observe any adverse event during the treatment. Although these preliminary results are encouraging, they need to be confirmed by large well-designed prospective clinical trials.During the clinical testing, we were able to demonstrate that Peroneal eTNM® using the URIS® neuromodulation system represents a new method for the treatment of OAB symptoms. It boasts unique features that differentiate it significantly from other currently available neuromodulation techniques. Further well-designed prospective clinical trials are required to assess its efficacy and safety.Peroneal eTNM


Plasmodium falciparum to current artemisinin-based combination therapies necessitate the discovery of new medicines. Pharmacophoric hybridization has become an alternative for drug resistance that lowers the risk of drug–drug adverse interactions. In this study, we synthesized a new series of hybrids by covalently linking the scaffolds of pyranopyrazole with 4-aminoquinoline via an ethyl linker. All synthesized hybrid molecules were evaluated through in vitro screenings against chloroquine-resistant (K1) and -sensitive (3D7) P. falciparum strains, respectively. Data from in vitro assessments showed that hybrid 4b displayed significant antiplasmodial activities against the 3D7 strain (EC50 = 0.0130 ± 0.0002 μM) and the K1 strain (EC50 = 0.02 ± 0.01 μM), with low cytotoxic effect against Vero mammalian cells. The high selectivity index value on the 3D7 strain (SI > 1000) and the K1 strain (SI > 800) and the low resistance index value from compound 4b suggested that the pharmacological effects of this compound were due to selective inhibition on the 3D7 and K1 strains. Molecular docking analysis also showed that 4b recorded the highest binding energy on P. falciparum lactate dehydrogenase. Thus, P. falciparum lactate dehydrogenase is considered a potential molecular target for the synthesized compound.Widespread resistance of  Malaysia has made significant progress in the control of malaria. However, the fatality rate fluctuated throughout the period 2001–2012. The National Strategic Plan for Malaria Elimination 2011–2020 was initiated to stop locally-acquired malaria in Peninsular Malaysia by 2015 and East Malaysia by 2020. To date, reports on the development of resistance towards artemisinin in Southeast Asian countries have initiated a ‘Global Plan for Artemisinin Resistance Containment’ by the World Health Organization (WHO) Global Malaria Program in 2011 to prevent the emergence and spread of artemisinin resistance. According to the public health perspective, the goal of treatment of malaria is to reduce transmission of the infection to others by reducing the infectious population and the spread of resistance to antimalarial medicines. The development of a multi-therapeutic approach, advanced analogs, and identification of novel leads were examined as potential alternatives because artemisinin-based combination therapy (ACT) is the only standard treatment recommended by the WHO facing similar situations of antimalarial resistance pentyl}carbomyl)amino] urea (VI) being the most active compound . N-substituted aminoquinoline-pyrimidine hybrids (VII) synthesized by Maurya et al. diazepines derivatives, and the compound was found to be active against the Plasmodium parasite (IC50 = 11.3 ± 2.3 μg/mL) pyrazole hybrid (4), as depicted in A hybrid scaffold  and Gibbs free energy (∆rGθ) of the reaction, were obtained via DFT calculation. The measured enthalpy change involved synthesizing the hybrids from the deprotonated 1d, and aminoquinoline was , the highest positively charged atom of the pyranopyrazole derivative is C3, sandwiched between two electronegative oxygen atoms . The nexP. falciparum 3D7 and chloroquine-resistant P. falciparum K1. The results in EC50 values (μM) against the 3D7 and K1 strains are presented in 50 < 1 μM as potent, 2–20 μM as active, 21–100 μM as moderately active, 101–200 as weakly active, and EC50 > 201 as inactive pyrazole has increased the potency of 4b against the K1 and 3D7 strains. We suggest that both quinolines and pyrazole pharmacophores are responsible for the antimalarial effects shown by 4b. As of now, this is the first report on the antimalarial properties of the hybrid 4-aminoquinoline-pyranopyrazole derivatives against P. falciparum 3D7 and KI. Previous studies revealed that hybrid quinoline-pyrimidine showed significant antimalarial activities in the nanomolar range pyrazole-3-carboxylate hed data .1H NMR : δ 8.34 , 8.21 , 7.74 , 7.40 , 7.24 , 6.46 , 4.81 , 3.62 , 3.30 ; 13C NMR  δ 45.6 (CH2N), 59.3 (CH2Br), 99.2 (Ar C), 118.0 (quat. C), 124.6 (Ar C), 124.6 (Ar C), 128.0 (Ar C), 133.9 (quat. C), 149.6 (quat. C), 150.8 (quat. C), 152.4 (Ar C).A mixture of 4,7-dichloroquinoline  and ethanolamine  was mixed in a three-neck round-bottom flask. The reaction was refluxed for 180 min, and the temperature was monitored using a thermometer. The reaction flask was cooled with an ice-water bath and stirring was continued until the precipitation of a colorless solid. Yield: 1.04 g (93%); Melting point: 210–211 °C; 1H NMR : δ 8.36 , 8.06 , 7.77 , 7.40 , 6.56 , 3.79 , 3.64 ; 13C NMR : δ 28.9 (CH2N), 44.3 (CH2Br), 98.4 (ArC), 117.4 (quat. C), 122.9 (ArC), 125.0 (ArC), 126.3 (ArC), 135.2 (quat. C), 148.3 (quat. C), 150.9 (quat. C), 151.1 (ArC).To a solution of hydrogen bromide, 33% , 4-(ethanolamine)-7-chloroquinoline  was added dropwise, together with sulfuric acid . The resulting mixture was refluxed for 60 min, and the progress of the reaction was monitored using TLC. The reaction mixture was left to cool at room temperature and poured into ice water. The solution was added with ammonia hydroxide until pH 9 to yield a solid colorless precipitate. The solid was filtered and heated in a solution of toluene and activated charcoal. The mixture was filtered and refrigerated at 4 °C to yield a colorless solid. Yield: 0.57 g (40%); Melting point: 140–141 °C; 1a–e compounds  and sodium bicarbonate  were mixed in a DMSO at 30–40 °C for 24 h. The mixture was left to cool at room temperature and extracted using a mixture of 20 mL ethyl acetate and 80 mL of brine. The organic layer was separated, concentrated using a rotary evaporator, and purified using silica column chromatography by elution with a mixture of ethanol:ethylacetate: hexane (1:3:1) (A mixture of 4-(bromoethylamino)-7-chloroquinoline  and corresponding pyranopyrazole-3-carboxylate  (1:3:1) .1H NMR :δ 8.33 , 8.00 , 7.74 , 7.35 , 7.35, 7.21 , 7.14 , 6.98 , 6.98 , 6.43 , 4.75–4.41 , 4.6  3.74–3.51 , 3.74–3.51 , 0.68 ; 13C NMR : δ 160.2 (CNH2), 158.6 (C=O), 154.8 (quat. Ar C), 152.3 (Ar C), 150.2 (quat. Ar C), 149.6 (quat. Ar C) 145.3 (quat. Ar C), 133.9 (quat. Ar C), 129.6 (quat. Ar C), 128.8 (Ar C), 128.0 (Ar C), 127.6 (Ar C), 127.1 (Ar C), 124.7 (Ar C), 124.3 (Ar C), 120.7 (CN), 117.9 (quat. C), 105.5 (quat. C), 99.1 (Ar C), 61.3 (CH2C), 58.5 (quat. C), 49.7 (CH2N), 42.7 (CH2N), 37.8 (CH), 13.7 (CH3). Anal. Calc. for C27H23ClN6O3, C 62.97, H 4.50, N 16.32. Found: C 62.42, H 4.47, N 16.29.Yield: 0.34 g (13%); Melting point: 260–261 °C; 1H NMR : δ 8.32 , 7.98 , 7.73 , 7.34 , 7.34 , 7.02 , 6.95 , 6.85 , 6.42 , 4.61 , 4.57 , 4.08 , 3.69–3.60 , 3.59 , 2.51 , 1.09 , 0.63 . 13C NMR : δ 160.1 (CNH2), 158.6 (C=O), 154.8 (quat. Ar C), 152.3 (Ar C), 150.2 (quat. Ar C) 149.5 (quat. Ar C), 142.6 (quat. Ar C),142.4 (quat. Ar C), 133.9 (quat. Ar C), 129.7 (quat. Ar C), 128.1 (Ar C), 127.9 (Ar C), 127.5 (Ar C), 124.7 (Ar C), 117.9 (Ar C), 120.8 (CN), 117.9 (CNH), 105.6 (quat. C), 99.1 (Ar C), 61.2 (CH2C), 58.7 (quat. C), 49.7 (CH2N), 42.4 (CH2N), 37.4 (CH), 28.3 (CH2C), 16.1 (CH3), 13.8 (CH3). Anal. Calc. for C29H27ClN6O3, C 64.14, H 5.01, N 15.48. Found: C 62.99, H 5.02, N 15.38.Yield: 0.41 g (15%); Melting point: 145–147 °C; 1H NMR : δ 8.34 , 8.03 , 7.75 , 7.43 , 7.40 , 7.36 , 7.10 , 6.44 , 6.28 , 5.97 , 4.79 , 4.76–4.44 , 3.85–3.69 , 3.64 , 0.86 .). 13C NMR : δ 161.1 (CNH2), 158.7 (C=O), 156.1 (quat. C), 154.6 (quat. Ar C), 152.3 (Ar C), 150.1 (quat. Ar C) 149.6 (quat. Ar C), 133.9 (quat. Ar C), 129.8 (quat. C), 128.0 (Ar C), 124.8 (Ar C), 124.3 (Ar C), 120.6 (CN), 117.9 (CNH), 110.8 (Ar C), 105.7 (Ar C), 103.0 (quat. C), 99.1 (Ar C), 61.5 (CH2C), 55.3 (quat. C), 49.7 (CH2N), 42.7 (CH2N), 31.6 (CH), 13.9 (CH3). Anal. Calc. for C25H21ClN6O4, C 59.47, H 4.19, N 16.64. Found: C 59.15, H 4.12, N 16.64.Yield: 0.51 g (20%); Melting point: 232–234 °C; 1H NMR : δ 8.31 , 8.01 , 7.74 , 7.38 , 7.36 , 7.01 , 6.41 , 4.76–4.48 , 4.00–3.80  3.63 , 3.47 , 1.89–1.69 , 1.04 , 0.87 , 0.51 . 13C NMR : δ 163.4 (CNH2), 159.2 (C=O), 156.5 (quat. C), 152.3 (Ar C), 150.2 (quat. Ar C) 149.5 (quat. Ar C), 134.0 (quat. Ar C), 128.7 (quat. C), 127.9 (Ar C), 124.7 (Ar C), 124.3 (Ar C), 122.2 (CN), 117.9 (CNH), 106.9 (Ar C), 99.1 (Ar C), 61.6 (CH2C), 51.8 (quat. C), 49.8 (CH2N), 42.7 (CH2N), 38.0 (CH), 35.7 (CH), 20.6 (CH3), 17.1 (CH3), 13.9 (CH3). Anal. Calc. for C24H25ClN6O3, C 59.94, H 5.24, N 17.47. Found: C 59.76, H 5.19, N 17.66.Yield: 0.24 g (10%); Melting point: 221–223 °C; 1H NMR : δ 9.25 , 8.33 , 8.00 , 7.74 , 7.36 , 7.36  6.94 , 6.77 , 6.59 , 6.42 , 4.70–4.51 , 4.51 , 3.74–3.51 , 3.74–3.51 , 0.74 . 13C NMR : δ 160.0 (CNH2), 158.7 (C=O), 156.5 (quat. C), 154.7 (quat. Ar C), 152.3 (Ar C), 150.1 (quat. Ar C) 149.6 (quat. Ar C), 135.8 (quat. Ar C), 133.9 (quat. C), 129.6 (quat. C), 128.6 (Ar C), 128.0 (Ar C), 124.7 (Ar C), 124.4 (Ar C), 120.8 (CN), 117.9 (CNH), 115.4 (Ar C), 106.2 (quat. C), 99.1 (Ar C), 61.3 (CH2C), 59.0 (quat. C), 49.7 (CH2N), 42.7 (CH2N), 37.0 (CH), 13.8 (CH3). Anal. Calc. for C27H23ClN6O4, C 61.08, H 4.37, N 15.83. Found: C 60.97, H 4.72, N 15.95.Yield: 0.13 g (5%); Melting point: 233–234 °C; P. falciparum 3D7 and chloroquine-resistant P. falciparum K1. P. falciparum 3D7 (chloroquine-sensitive) (MRA-102), and P. falciparum K1 (chloroquine-resistant) (MRA-159) were originally obtained from BEI. Resources, NIAID, NIH . The parasites were maintained in continuous culture in fresh group O (Rhesus positive) human erythrocytes suspended in 2% hematocrit in RPMI 1640 containing 10% Albumax I, glucose (3 g/L), hypoxanthine (45 μg/L), and gentamicin (50 μg/L). Plasmodium lactate dehydrogenase (pLDH) assays were performed as described by Makler et al., with slight modification pyrazole derivatives was measured using the MTT assay described by Mossmann . Before 50 of cytotoxicity and EC50 of antimalarial activities (MTT/pLDH). Test pure compounds with SI values greater than 100 (SI > 100) are considered strong and selective antimalarial agents pyrazole derivatives were determined by a ratio of values from CCl agents . Resistaarasites .All compounds were modeled (GaussView 5.0) and optimized using density functional theory (DFT) with the B3LYP/6–31++G theoretical model and the Gaussian09 program . The vibA series of hybrid compounds were constructed using Marvin Sketch version 1.5.6. These ligand structures were converted into 3D formats and geometrically optimized with OPLS3 using Ligand Preparation Wizard in Schrodinger Small Molecule Drug Discovery Suite 2017-1.http://www.rcsb.org, accessed on 12 May 2020). All water molecules of the crystal structures were removed, while hydrogen atoms were added in their standard geometry, adjusting the bond orders and formal charges. The ligand-binding site was identified based on the position of the inhibitor-binding site, as reported in the literature. The in-house CDOCKER protocol was used for the docking analysis of active compounds to the binding site. Different conformations were performed for each ligand through high-temperature molecular dynamics. The ligands were heated (700 K in 2000 steps) followed by cooling (300 K), and they were then subjected to refinement by grid-based (GRID 1) simulated annealing and full force minimization after random rotation. The ligand was allowed to flex while the receptor was held rigid during the refinement process. The generated ligand conformations were clustered according to their binding interactions. For validation of the docking protocol, the co-crystallized ligands were re-docked to the binding site.The X-ray crystal structures of the protein-ligand complex for PfLDH (PDB IDs: 1CET and 1U5A) were retrieved from the Protein Database Bank (PDB) , human intestinal absorption (HIA), atom-based log P (Alog P98), aqueous solubility, polar surface area (PSA), blood–brain barrier (BBB) penetration, cytochrome P450 2D6 (CYP2D6) enzyme inhibition, and hepatotoxicity.4b is considered the most potent, with high a selectivity index against both the 3D7 and K1 strains and a low resistance index value. The compound also exerted high-affinity binding on PfLDH, which suggests a potential molecular target in malarial infection. The findings from pharmacophoric hybridization in this study are crucial as an alternative therapy to combat drug resistance in malarial infection. Further, in vivo, antimalarial activity needs to be carried out, and we envisage the expansion of a hybrid antimalarial medicine series based on these derivatives.In summary, we developed a simple reaction protocol for a new series of antimalarial hybrid compounds containing pyranopyrazole-aminoquinoline pharmacophoric units. From the antimalarial assessment, compound


Recent advances in the field of neural rehabilitation, facilitated through technological innovation and improved neurophysiological knowledge of impaired motor control, have opened up new research directions. Such advances increase the relevance of existing interventions, as well as allow novel methodologies and technological synergies. New approaches attempt to partially overcome long-term disability caused by spinal cord injury, using either invasive bridging technologies or noninvasive human–machine interfaces. Muscular dystrophies benefit from electromyography and novel sensors that shed light on underlying neuromotor mechanisms in people with Duchenne. Novel wearable robotics devices are being tailored to specific patient populations, such as traumatic brain injury, stroke, and amputated individuals. In addition, developments in robot-assisted rehabilitation may enhance motor learning and generate movement repetitions by decoding the brain activity of patients during therapy. This is further facilitated by artificial intelligence algorithms coupled with faster electronics. The practical impact of integrating such technologies with neural rehabilitation treatment can be substantial. They can potentially empower nontechnically trained individuals—namely, family members and professional carers—to alter the programming of neural rehabilitation robotic setups, to actively get involved and intervene promptly at the point of care. This narrative review considers existing and emerging neural rehabilitation technologies through the perspective of replacing or restoring functions, enhancing, or improving natural neural output, as well as promoting or recruiting dormant neuroplasticity. Upon conclusion, we discuss the future directions for neural rehabilitation research, diagnosis, and treatment based on the discussed technologies and their major roadblocks. This future may eventually become possible through technological evolution and convergence of mutually beneficial technologies to create hybrid solutions. Neural rehabilitation, to the extent this is possible, aims to restore the functionality of impaired neurological circuits or complement remaining functionality. This aims to enhance patient independence and quality of life through exploitation of neural plasticity ,2. PredoThe idea of robotic devices for rehabilitation dates back to the beginning of the previous century , and it Better understanding of the neurophysiological specifics that underlie impaired motor control should therefore be considered particularly important and should also drive technological rehabilitation developments to increase their clinical impact . In SectThe field of rehabilitation robotics is a multidisciplinary field and involves the combination of numerous technologies ,19,20, wAs our knowledge and understanding related to impaired human motor control is improving ,2, robotIn our research we applied a narrative review approach see , which oStroke refers to the interruption of blood supply and drainage to the brain or to the interruption of brain blood vessel wall continuity and extravasation of blood that leads to brain tissue damage . In 2017Robotics provide a way to deliver effective rehabilitation as a standalone modality or in combination with traditional rehabilitation ,15,24. TRehabilitation robots together with conventional therapy in the clinic can deliver intensive training with beneficial effects, especially early after stroke . Novel dSensorimotor, cognitive, and psychosocial function impairments, either temporary or permanent, are common long-term outcomes following acute insults to the brain due to external mechanical forces. This condition and its sequelae are covered by the term traumatic brain injury (TBI) . Long-teRehabilitation for TBI aims at improving the quality of life and specific disorders of TBI populations and robotics have seen a particular rise in interest for sensorimotor deficits, aiming to enhance compensatory and recovery-associated neural plasticity mechanisms . RoboticMotor vehicle accidents and falls account for almost 8 out of 10 incidents of spinal cord injury (SCI). This condition affects predominantly young male adults, although the average age at injury has reportedly increased in recent years to 42 years in the US . Life exRehabilitation of SCI victims remains a significant challenge, aimed at restoring independence in activities of daily living (ADL) and walking in those patients . Still, It has been demonstrated that adaptive plasticity in the sensorimotor networks of the brain and spinal cord can be promoted even in chronic stages of the condition . RecentlUnobtrusiveness of robotic devices aiming at upper limb rehabilitation and assisting ADLs is also a key goal within reach of technological advances in this field, which the category of “soft robotics” is aiming at . Body–maNearly 2.1 million people were living with amputation in the United States in 2019, which is 0.63% of the population, and that number is estimated to double by 2050 . WorldwiImportant progress has been made over the past several years in creating prosthetic technologies aiming to restore human functions to those that suffer from the partial or full loss of their limbs . Some ofProsthetic types should be selected based on a patient’s individual needs and preferences. There are indications that body-powered prostheses have benefits in durability, frequency of adjustment, maintenance, training time, and feedback, but control can still be further improved. Myoelectric prostheses are more well-established for light-intensity work, and they can improve phantom-limb pain and cosmesis . However, many challenges remain, such as the complexity of neural changes after amputation and the still enigmatic fundamentals of motor control in amputees, to understand and address the barriers in patient adoption of technology . UnderstDMD is an X chromosome-linked progressive neuromuscular disease that results in muscle fiber degeneration, motor deficiencies , and shoRobotic exoskeletons have the potential to increase their quality of life by supporting the upper limb to improve their independence . Such exCurrent studies for the use of robotic exoskeletons in DMD are not many and are limited by a small number of participants ,87. MoreImmersive affective applications based on robotics and related technologies have been well under consideration in the study and treatment of psychiatric disorders ,91. ImmeHuman–robot control interfaces (invasive and noninvasive) are technologies that acquire, decode, and communicate the intention of a human user to a device via control commands . Such a Digital–neural interfaces are connections that enable two-way information exchange between the nervous system and the user . Such inNeural sensing and control interfaces used for the first time back in the 1960s were technologically primitive by modern standards and were mostly focused on prosthetics. Muscles were activated as a group, essentially reducing multiple degrees of freedom (DOF) to a single movement . In the decades that followed, several key technological advances relevant to neural rehabilitation have taken place. Fueled by rapid development in digital electronics, microcontrollers, signal processing, control and machine learning algorithms, robotics engineering advanced and synergistically converged with prosthetics engineering, leading to ever more sophisticated artificial limbs. Implantable wireless electronic devices subsequently appeared capable of transmitting signals directly to and from the PNS, avoiding the necessity to maintain an open skin wound. The prospect consequently appeared for mixed-signal assistive electronics to help bypass irreparable trauma to the nervous system by acting as signal amplifier, repeater, and filter.Interfacing with the PNS via neural electrodes is considered one of the most promising ways to control sophisticated neuroprosthetics . For dirAt the point that this paper went to press, there is a technological trend toward wireless and less invasive implantable electrodes, as well as toward further shrinking the electrode contact features from the micron to the submicron scale . Neural cuff electrodes with embedded electronics—which can handle wireless power, data transfer, and have adequate computing power for fundamental signal processing—is, in our opinion, one of the most promising sets of converging technologies. It can potentially provide selective, low impedance signal recording and stimulation without requiring an open skin wound for wire passage.Despite the aforementioned technological advances, numerous challenges still remain in the application and widespread adoption of digital–neural interfaces. Frequently, significant compromises have to be made regarding the accuracy, response time, and number of degrees of muscle movement freedom . Issues To elicit motion, the human nervous system recruits motor units (MUs), motor neurons, and muscle fibers innervated by that motor neuron . The eleEMG uses electrical current to measure motor unit activity noninvasively on the surface of the overlying skin  or invasDespite the variety of options EMG offers for wearable robotics control, its implementation is in practice limited by multiple factors. Wearable robotics or prosthetics for daily use need to be able to perform unrestricted dynamic motions . CurrentBCIs refer to computer-based systems that interface with the brain to acquire, decode, and translate the brain activity of the user into control commands for various devices . A complThe latter presents an exciting clinical application of BCIs, which investigates their use in neurorehabilitation or ADL assistance of people suffering CNS-impairing trauma or disease, or limb amputation ,138,140.However, it is still unclear if the therapeutic effects of BCIs are because of their standalone application or due to combination with other therapies . AdditioExoskeletons are devices that aim to interface with the human  and assiStroke patients who receive electromechanical gait training assistance in addition to physiotherapy are more likely to achieve independent walking . Some ofThe actuation system of exoskeletons is a determinant factor since it affects their design and defines their portability, performance, and effectiveness . There aEarly upper limb (UL) rehabilitation robotic devices were end-effector type, which means that they were simpler in design and had only one point of attachment to the user’s limb . The InMWearable exoskeletons can be active, with one or more actuators that actively augment the user, or passive, in which case they do not use an external power source and have the ability to store energy and use it when required. Some examples of passive exoskeletons are the Armeo Spring, which allows variable upper limb gravity assistance , the GENRepresentative examples of active UL wearable exoskeletons include: the NeReBot, which is a cable-driven exoskeleton actuated by three motors that maneuver the user’s arm ; the ArmLL assistance-as-needed rehabilitation exoskeletons aim to help users regain functional abilities through repetitive exercise with progressively reduced assistance. Thus, the control is partially predefined and uses online modifications so that it only assists when it is necessary based on patient feedback. Rehabilitation exoskeletons are traditionally stationary and fixed to a treadmill. The Lokomat  is an exProsthesis (a word that comes from Greek and means addition and attachment) is a device or system that replaces a missing body part to supplement its functionality . Thus, aThe purpose of controlled neuroprosthetics is to transfer control intent from the central nervous system to drive the prosthetic devices of users with immobilized body parts . Such coRegarding control, the key technologies used for interfacing prosthetics with an amputee are EMG, neural and BCI interfaces (interfacing directly or indirectly with the PNS), and body-powered and impedance/admittance control  ,102,168.Some of the most common decoding algorithms for neuroprosthetics control can be categorized as (1) independent models, (2) dynamic models, (3) reinforcement, and (4) classifiers. In the first category we have algorithms such as, Bang-Bang control, which is activated when a specific limit for a measured variable is reached, used in cases such as the delivery of cortical electrical stimulation  and the For UL amputees, existing commercial prosthetic hands offer single-DOF actuator designs to open and close the fingers and thumb, such as Ottobock’s Sensorhand Speed, products from Motion Control Inc. and RLSSteeper Inc., or multiple-DOF actuator designs with articulated fingers, such as the Touch Bionics i-LIMB and the BeBionic hand . The OttFor LL amputees, neuroprosthetics assist with movement and balance . While pVR is an artificial simulation or a reproduction of a real-life environment using immersive projections of virtual objects . FurtherContemporary literature on motor control indicates that enhancing functional tasks may benefit from task-oriented biofeedback therapy ,200,201.Advances in technology and affordability, as well as their advent popularization, allow for critical study of the aforementioned systems’ efficacy and ecological validity ,204. As It should be noted that multimodality and synergistic effects of VR with other novel neural rehabilitation technologies have also been recently shown in patients with motor impairment due to SCI  and thatFurthermore, VR/AR systems without robotic devices attached have also been demonstrated to offer significant gains in neural rehabilitation . For exaIn conclusion, VR/AR systems for neurorehabilitation offer significant results to the therapy process due to the feedback they provide to the patient. Additionally, task-oriented training and gamification of therapy provide the motivation necessary for the patient to perform repetitive tasks. This convergence between gamification and task-oriented training is one of the core components in VR/AR systems, thus making them a promising modality for neurorehabilitation and home-based therapy systems. There are, however, certain challenges in VR/AR-based rehabilitation therapies that need to be overcome. There is theoretical ambiguity and immaturity in clinical VR research for the contexts of immersion and presence, where the terms are mistakenly used interchangeably . ImmersiHuman–robot interaction (HRI) is a diverse research and development field that involves artificial intelligence, robotics, and the social sciences for the purpose of interaction and communication between humans and robots. It has a wide range of applications, such as industrial robots, medical robots, social robots, automated driving, search and rescue, and several more ,217. In Neurological disorders are globally one of the leading causes of disability and death, representing a severe public health problem ,219. RobAn essential task for most robotic systems is object classification (OC), during which the robot classifies features and attempts to perceive its environment. Currently, convolutional neural networks (CNNs) are considered part of the state-of-the-art among AI models for OC . BecauseAnother important task for robotic systems that interact with humans is natural language understanding (NLU), in which a human operator commands the robot through natural language. One of the state-of-the-art artificial neural network (ANN) architectures for NLU are recurrent neural networks (RNNs), which are based on the idea that decisions are influenced by past experiences. In other words, RNNs allow previous outputs to be used as inputs while considering hidden states. A state-of-the-art model for robotic NLU is the Mbot . In partAnother key component in almost all robotic systems is action planning. In machine learning (ML) the most promising approach for action planning is reinforcement learning (RL). RL refers to goal-oriented algorithms, which learn how to attain a complex objective  or how to maximize a particular function over multiple steps; for instance, RL networks can maximize the points won in a game over several moves. These algorithms are penalized, like a pet incentivized through scolding and punishment, when they make the wrong choices and are rewarded when they make the correct ones (hence the concept of reinforcement). One of the modern ANNs that leverage RL are deep Q-Networks (DQNs), which are based on the idea of Q-learning . In Q-le2)O2)O2) . Thus, qAnother concern regarding AI algorithms is safety risks due to the uncertainty of the robot’s actions under particular circumstances. So far, very few exoskeletons have secured Food and Drug Administration (FDA) approval for in-home use, and it is rather important to design rehabilitation robotic devices with tight and demonstrable safety standards to raise their trustworthiness in the consumer base. One emerging field that could potentially provide solutions to safety concerns, due to the nature of the materials used for the fabrication of mechanical components, is soft robotics . The fieWith the growing complexity and scale of neural recordings, the role of neural signal processing has been gaining significance in the field of neurorehabilitation. The aim of neural signal processing is to process and analyze neural signals from which useful information and insights about the brain’s information processing will be extracted and transmitted through neuronal ensembles. Reading out neural signals is significant to transmit neurofeedback to the brain or computer devices that support communication through brain–machine interfaces (BMIs) in neural engineering. Furthermore, assessing neural feedback, monitoring/decoding brain activity, and controlling prosthetics are key components for BMIs used in neural rehabilitation. Therefore, BMIs that are involved in robot-aided neurorehabilitation can benefit the most from increasingly accurate neural signal processing because of the significance of neurofeedback involved in neural therapies . k-nearest neighbor (k-NN) [Neural signal processing involves an algorithmic framework that is often divided into the following stages: signal capture, signal preprocessing, and main processing . In signr (k-NN) . A clustr (k-NN) . The application of the aforementioned AI-based algorithmic framework aims to boost the accuracy of signal processors, which form an integral part of neural biofeedback-based rehabilitation and assistive device control tasks. For instance, a CNN developed for feature extraction and spike detection in epileptic cases using EEG recordings outperformed all other tested models, achieving 0.947 AUC . In addIn final analysis, neural signal decoding in real-time is a rather tough engineering challenge for all BMIs involved in neural rehabilitation and needs to be rather accurate to boost the BMIs’ effectiveness and usability. However, most of these algorithms can be successfully applied only on a limited number of neural signal inputs, in some cases only on one type. Therefore, an algorithmic framework for processing all types of neural signals in parallel is needed. Neural parallel processing is an emerging and rather promising field that can significantly boost neural signal processing tasks. In neural parallel processing, advanced algorithms are used for spike detection, feature extraction, and clustering in all parallel signals, such as exponential-component–power-component (EC-PC) spike detection and binary pursuit spike sorting . BecauseIn this article we have reviewed key robotic technologies that facilitate neural rehabilitation and discussed roadblocks in their development and application, as well as presented current and emerging directions in the field see . These tDuring this ongoing transformation of the field, certain technologies stand out with respect to the relative advantages they offer. Through a natural paradigm shift, neural interfaces can now be considered as connections that allow information to be reciprocally exchanged between robotics and the human nervous system. As such, BCIs can provide decades-worth of experience in signal recording from the central nervous system, interpretation of motor and sensory outputs, as well as modulation of its functionality. Retraining CNS circuits and promoting adaptive neural plasticity have been recognized among key principles of neural pathways repair by the US National Institute of Neurological Disorders and Stroke . Direct digital–neural interfaces and peripheral neurophysiological recordings, such as EMG, can provide pinpoint accuracy, increased resolution, and quality of neuronal signal detection, as well as the ability to exert command control. Exoskeletons, prostheses, wearable and soft robotics, rapid prototyping technologies, and electrical stimulation each demonstrate the unique ability to overcome neurological impairments and bridge lesions according to their applications and indications. These man–machine interfaces and robotics provide a way to deliver effective rehabilitation to, i.e., stroke survivors as a standalone modality or in combination with traditional rehabilitation ,14,15,24As scientific analysis and understanding of human motor control advances in tandem with modern electronics and computational power, the pursuit of more disruptive therapeutic interventions has become possible. For example, the use of robot-driven locomotor perturbations in order to manipulate an individual’s motor control strategy for therapeutic purposes is a radical and particularly promising new such approach ,246. SucFurthermore, fundamental lower-level technological improvements such as advances in software and hardware speed, accuracy, computational power, power autonomy, and the capacity to learn from data (machine learning) can be reasonably expected to continue offering incremental contributions to neural rehabilitation assistive technologies at an ever-increasing pace. To achieve further synergies, a multidisciplinary approach is essential: traditional research in physics and engineering must now work alongside chemical, biological, and medical science to develop new applications and acquire new capabilities . As an eSystem-on-chip integration has been revolutionizing the integration of analogue, digital, and radio frequency (RF) electronics on a monolithic piece of silicon during the past four decades. This technology has been merging with biologically targeted MEMS and creating new possibilities in the design of biochips, electrodes for neural interfacing, low-power implantable systems, and energy harvesting solutions. Apart from the obvious benefits of crafting less invasive and more effective electrodes, such technological convergence may also facilitate improvements in on-chip power transmission coils, so that power to implantable systems is supplied noninvasively from outside the body, in tandem with a wireless data link. These advances in electronics integration are not devoid of obstacles and roadblocks. Massive parallel distributed processing of information was once heralded to be around the corner, yet the lack of reliable, nonvolatile analogue on-chip memory has proven to be a formidable technological roadblock . Furthermore, inherently two-dimensional techniques used to fabricate modern electronic chips, as well as noise and heat distribution problems, have placed limits to further miniaturization and power density concentration offered by deep sub-micron system-on-chip fabrication technologies. Three-dimensional printing is clearly a socioeconomically disruptive manufacturing technology, with significant impact in several areas of biomedical engineering, including neural rehabilitation. Blueprints can be turned into 3D objects in minutes utilizing a variety of materials: thermoplastics, resins, ceramics , adhesivThis convergence of multi-composite and 3D printing technologies could be exceptionally valuable in neural rehabilitation, particularly in the creation of novel, flexible, personalized implantable sensing and targeted drug delivery devices, as well as for developing soft exoskeletal robotic aids . BioprinOn the software side, the most significant impact may be expected from the field of artificial intelligence, specifically machine learning. Right now, when designing devices directly interfacing with the peripheral nervous system, there is a tight balance between optimizing the electronic and mechanical properties, while facilitating surgical implantation and post-surgical signal processing adjustment. By opting for multiple nanoscale-level electrodes, possibly distributed around the neural tissue in a loose “smart dust” paradigm ,258, it We may choose to identify certain key future milestones in this continuous technological transformation. Conceiving the electromagnetic fields and waves generated by the human nervous systems as continuous and integral to the rest of the electromagnetic spectrum will help support and brainstorm novel approaches to signal acquisition, data flow, and information processing. Such systems could be communicating with the nervous system on biological terms and with devices on electronics terms utilizing closed feedback loops ,260. NerFinally, despite technological progress, innovative applications, synergies, demonstrations of feasibility, and a widening of the clinical base, in order to produce undisputable benefits for the patients, the field needs to successfully tackle clinical translational challenges that are impeding a lot of solutions to make a real impact. While identifying challenges and translational roadblocks is the primary key to focusing research efforts, prospective design of improved protocols, trials, interventions, and outcomes could be the key to achieve and demonstrate clear benefit ,267,268.The selection of the narrative review format, instead of a more systematic review approach, was motivated by our intention to discuss key technological synergies in a broad, flexible, and comprehensive fashion. The methodology of a systematic review approach would require a much tighter focus, which would be incompatible with the objectives of this paper. A narrative review format allows us to discuss the gap between robotic rehabilitation and various key technologies from which robotic rehabilitation can benefit and speculate on their integration and future directions. This approach can also better accommodate personal insights on synergistic technological convergence, leveraging the diverse mixture of expertise of the authors. On the other hand, lack of systematic methodology does not allow for acquiring the highest current level of evidence for most of the conditions and technologies discussed.Some other clear limitations of a narrative review include the fact that it does not ensure an unbiased cover of the scientific literature by locating all relevant literature but instead discusses pivotal articles known to the authors. However, we refer to a great number of studies from various disciplines and research groups, and in this way we attempt to avoid fixation of the discussion to a specific research group, institution, or trending theory. Instead, we discuss every technology, including various viewpoints and criticisms.


Endoscopic transpapillary gallbladder drainage is an alternative procedure for patients with acute cholecystitis. However, this procedure is technically challenging because the drainage stent is sometimes obstructed by an impacted cystic duct stone, even if the guidewire is advanced into the gallbladder. In this report, the front end of a standard endoscopic retrograde cholangiopancreatography catheter was cut to an appropriate length as a drainage stent for transpapillary gallbladder drainage. However, this modified stent became stuck because of an impacted cystic duct stone. The Soehendra stent retriever was used as a stent delivery device in this setting. A Soehendra stent retriever with clockwise rotation was coupled with the drainage stent. Integrated devices provide a stent tip for pushability and torqueability. The stuck drainage stent at the impacted cystic duct stone resumed advancement into the gallbladder. After stent indwelling, decoupling was easy under counterclockwise rotation of the Soehendra stent retriever. In patients with moderate/grade II acute cholecystitis (AC), urgent laparoscopic cholecystectomy (Lap‐C) is recommended after onset based on the patient's performance status.The Soehendra stent retriever  was originally developed for transpapillary biliary plastic stent exchange.In this study, we report the first case of AC in which the ETGBD stent was advanced using the SSR as an indweller to pass the impacted cystic duct stone.2 saturation rate of 99% at room air, and a Glasgow coma scale score of 15. The patient had an unremarkable previous history. Three months prior to this admission, she presented with cholelithiasis and choledocholithiasis. She underwent endoscopic lithotripsy following endoscopic sphincterotomy and was scheduled to undergo Lap‐C in 2 months at another institution. Blood test results upon admission indicated signs of infection with a white blood cell count of 7400 cells/μl and a C‐reactive protein of 19.4 mg/dl. Mildly elevated liver transaminase levels without jaundice were as follows: aspartate aminotransferase, 45 IU/L; alanine aminotransferase, 53 IU/L; total bilirubin, 1.0 mg/dl; and direct bilirubin, 0.4 mg/dl. Renal function was within the normal range as follows: blood urea nitrogen, 8.3 mg/dl, and creatinine, 0.67 mg/dl. Platelet count was 28.3 × 104 /μl and prothrombin time‐international normalized ratio was 1.02, both within the normal range. Additionally, computed tomography (CT) upon admission revealed a swollen gallbladder with gallstones. In line with the Tokyo Guidelines 2018,A 56‐year‐old female office worker was admitted to our emergency unit with epigastralgia. She presented with normal body temperature (36.6°C), high blood pressure (143/72 mmHg), normocardia (73 beats/min), OCholangiography revealed a crab's claw‐like impacted stone at the first inflection point of the cystic duct Figure . A standAn ERCP catheter that had previously passed through the impacted stone was cut 14 cm from the tip and used as an internal drainage stent. However, it also became lodged. Originally, a pusher catheter was changed to SSR  to remove the stuck drainage stent. The SSR handle was turned clockwise until it was screwed to the end of the drainage stent. The stent tip was advanced into the gallbladder by continuing to push and twist the SSR clockwise Figure . SubsequAbdominal CT performed the following day confirmed that the front end of the modified ERCP catheter was left in place as an ETGBD stent Figure . The patHerein, we report the first case of AC drained using the front end of an ERCP catheter that was screwed into the gallbladder by SSR.In line with the Tokyo Guidelines 2018,For the ETGBD, we handcrafted a gallbladder drainage stent using a 1.6‐mm tip‐ERCP catheter modified to be cut 14 cm in length and used SSR as a stent delivery device. There are three steps to this procedure. The first is a coupling of the SSR and drainage stent in the scope channel; the second is stent indwelling into the gallbladder, and the third is decoupling of both. After coupling, insertion of the SSR under clockwise twisting conferred this drainage stent with both pushability and torqueability. After stent indwelling, decoupling was easy with counterclockwise rotation of the SSR. If this drainage stent could not be advanced, the SSR could be used to easily remove the drainage stent. Generally, the SSR and plastic stents are firmly connected. The mechanism and tips to release this modified stent are as follows: if both devices are in a straight shape, this stent would just rotate through the counterclockwise rotation of the SSR. However, as shown in Figures Recent reports and studies exclusively used SSR as a dilator or access route creator.However, we were concerned about how long this small‐diameter ETGBD drainage stent would continue to function. This modified ERCP catheter was small in diameter and had no side holes. In a recent meta‐analysis, the rate of cholecystitis recurrence following ETGBD was reported to be 1.48% in inoperable patients with AC.In conclusion, SSR was a useful delivery device for a stuck drainage stent with an impacted cystic duct stone in a patient with AC.The authors declare no conflict of interest.This research did not receive any specific grant from funding agencies in the public, commercial, or not‐for‐profit sectors.The patient provided written informed consent for publication of details of the case, and the Gamagori Municipal Hospital Institutional Review Board granted permission to review the medical records. This study was conducted in accordance with the principles of the Declaration of Helsinki.


The students’ silence in the classroom has lately become an area of attention of educators and scholars similarly; however, the factors influencing students’ classroom silence are not mainly scrutinized. This construct has been regarded as a problem of the communication between the educator and the learners that not only impact completing the teaching objectives in the classroom but also affect the nurturing of learners’ achievement. In addition, teachers positively have a noteworthy function in learners’ growth and progress and its behavior such as their immediacy remains a significant issue toward stimulating effective educational methods. Whilst teacher immediacy in a classroom setting is important, there is growing awareness about its important effect on learners’ silence and hopelessness. This review tries to provide some considerations about the relationship between teacher immediacy, both verbal and non-verbal, and students’ active silence and hopelessness. Successively, some suggestions are offered to lighten the practice of educators, learners, and teacher instructors. Learners’ feelings are an integral part of individual well-being and mental health, affecting inspiration, attentiveness, self-adjusting education, and scholastic success . On the An intellectual circumstance that drives from deconstructive anticipations regarding the school is known as hopelessness that as it is declared by Alternatively, another issue that is the most explored subject in learning in general and in language learning, in particular, is the problem of learners’ silence in classes. Indeed, silence is regarded as an absence of speech and even the complete absence of hearable verbalization that is extended to involve learners who do not present in a certain topic . SilenceOf course, educators also need to consider learners’ feelings to promote language education and their success . EmerginOriginally taken into the mainstream educational communication by Moreover, immediacy is a significant dimension of social existence in learning and indeed the discerned immediacy of the teacher is related to constructive results like educational effectiveness, course fulfillment, and learners’ educational results . In partEducator immediacy has drawn educators’ interest among the different concepts studied in this area and it alludes to the educator’s verbal and non-verbal practices aimed at lessening the mental and physical distance from learners . The forAs stated by In a nutshell, silence can have a positive impact on learners by building space for further awareness and more profound assessments in some scholastic situations on the one hand  and on tThe notion of immediacy as a series of practices became apparent in communication studies in the late 1960s. It turns out that individuals are attracted to people and things that they like, appreciate, and have a preference for, and they keep away from what they do not like, what they do not appreciate, and what they do not have a preference for Immediacy can be categorized into non-verbal and verbal behaviors and teachers’ immediacy is designated as a group of these two kinds of manners that are prearranged by the educators to make an intellect of intimacy and friendship with the learners . It is kPractices that improve mental proximity between communicators are known as non-verbal immediacy. It is incorporated into the strengthening framework that underlies the theory of relational attraction. This concept primarily applies to a person’s emotional discernment of another . ReinforScholastic hopelessness is a deconstructive result consequence. People who experience hopelessness ascribe unwanted consequences they experience in life to static factors such as intellectual capacity and have low expectations for future results based on their prior experiences . LearnerSilence is reflected to be a subtle notion that cannot be consensually elaborated. Even though one’s perception may propose that silence is a formal negated of communication, scholars have claimed that it is vague and burdened with numerous communicative significances . ThroughBased on the modification of the efficiency of classroom silence, it is categorized into two types, namely the positive silence and negative silence. While the former refers to the state that learners are pondering after educators’ inquiring, the latter talks about the emotive aspects that learners show no interest, no care, no involvement in the learning subjects . MoreoveThe present review provides many suggestions and contributions. Immediacy, verbal/non-verbal, is one of the practices teachers should have in class and it can have a significant impact on learners’ characteristics. Based on the review of previous studies, enhancing educators’ immediacy developing practices will promote learners’ education, stress tolerance, self-realization, and self-confidence, thereby reducing their level of hopelessness. Likewise, this review helps managers and officials select the best educators for their school or faculty. In addition to the teacher’s knowledge, other important educator attributes like class management skills and the capability of building immediate connections with learners must also be regarded as effective elements. Educators can give their best to optimize their utilization of immediacy during instruction by grinning, having eye contact with all learners, motioning, utilizing voice swings, moving in class, and possessing an open body gesture.Furthermore, given the connection between feelings and discerned education, educators need to take into consideration how their behavior affects learners’ feelings. Teachers can advance pride and aspiration by recognizing learners’ work and offering constructive feedback. Moreover, teachers, who implement both types of immediacy, that is to say, verbal and non-verbal signs properly, being accessible to learners not only in the classroom but also out of the classroom and smiling, assist their students to be conscious of their aptitudes, capabilities and accordingly grasp their perspective that in this way, and due to this closeness, their levels of silences decreases and they become hopeful. Immediacy practice can be argued to prompt learners to better attain information, be more creative, develop, and increase their skills.It is advisable for teaching policymakers and officials to focus more on offering courses to enhance educators’ immediacy due to the significance of verbal/non-verbal immediacy in education and its specific impact on learners’ education and feelings. Immediacy enhancement courses offer educators a great chance to learn more about the significance of educational communication in the class and to help develop both verbal and non-verbal practices.English language organizations and school officials must ensure that educators with high verbal/non-verbal immediacy are selected to assist learners with burnout, low self-confidence, and other elements. Educator trainers are the other shareholders who will make use of this research by fostering the knowledge and immediacy execution in novice educators. They can provide classes, conferences, webinars, and other training programs where the educational, mental, interpersonal, and emotional dimensions of the classroom are instructed as well. In addition, Educators communicate continuously with learners through body language, glimpses, motions, and facial expressions. For this reason, teachers must be careful and consistent in teaching their learners constructive emotions and expressions. Educator trainers can help them by modeling practices that will allow them to acquire the abilities of verbal and non-verbal immediacy. This can be done by praising learners’ endeavors in the class, motivating them to speak, and openly and actively communicating with them outside the class via email, and so on .All authors listed have made a substantial, direct, and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.