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Sook Joung Lee,1,* Min Kyu Park,2,* Dong-Seong Shin,3 Min Ho Chun4 1Department of Physical Medicine and Rehabilitation, Dong-A University College of Medicine, Dong-A University Hospital, 2Department of Pharmacology and Clinical Pharmacology, Dong-A University College of Medicine, Dong-A University Hospital, Busan, 3Clinical Trials Center, Gachon University Gil Medical Center, Incheon, 4Department of Rehabilitation Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea *These authors contributed equally to this work Purpose: Cyclooxygenase (COX) is the main pharmacodynamic target of nonsteroidal anti-inflammatory drugs (NSAIDs). We investigated the inhibitory effects on COX-2 after NSAIDs administration using a lipopolysaccharide (LPS)-derived COX-2 induction model in whole blood, according to the genotypes of COX-2 single-nucleotide polymorphisms (SNPs). Patients and methods: Seven genotypes of COX-2 SNPs were selected from public databases and analyzed in 324 healthy subjects. Two genotypes showing a high percentage of variability were selected. A clinical trial examining pharmacodynamics according to the genotype of two SNPs (rs5275 and rs689466) was conducted. Twenty subjects were administered a single oral dose of 200 mg of celecoxib, and pharmacokinetic and pharmacodynamic analyses were performed. Results: In the analysis of the pharmacokinetic parameters, significant differences in drug exposure were not investigated for each SNP genotype. The pharmacodynamic analysis revealed that the maximum effect of COX-2 inhibition was achieved at 2.0 hours for all genotypes of COX-2 SNPs after a single oral administration of 200 mg celecoxib. The inhibitory effects according to the genotype of COX-2 SNPs were investigated, and the area under the effect curve of the rs689466 GG genotype was significantly lower than that for the AA or AG genotype. Conclusion: Our results demonstrated that inhibitory effects of celecoxib on COX-2 induction were different according to the genotype of COX-2 SNPs. In the present study, rs689466 is responsible for the variability of the response to celecoxib, suggesting that a subject with the GG genotype of rs689466 would be more responsive to celecoxib in terms of COX-2 inhibition. Keywords: nonsteroidal anti-inflammatory agent, cyclooxygenase-2, single-nucleotide polymorphism, drug response, pharmacodynamics, clinical trial

OBJECTIVES: Although fatigue after stroke is common, little is known about the effect of fatigue on functional outcomes in stroke patients. We, therefore, evaluated the influence of fatigue on functional outcomes after stroke. DESIGN: Forty consecutive outpatients were evaluated 32.7 +/- 27.4 mos after the onset of stroke. Poststroke fatigue was scored using the Fatigue Severity Scale, activity of daily living function was assessed using the Modified Barthel Index, motor function was assessed using the Motricity Index, and cognitive function was evaluated using the Korean-Mini Mental State Examination. The Beck Depression Inventory was used to assess depression, and patients were interviewed about sleeping problems. RESULTS: The average Fatigue Severity Scale score was 3.6 +/- 1.5 in stroke patients, with 12 patients (30.0%) having Fatigue Severity Scale scores >or=4 points. Twenty-two patients (55.0%) had depression, and 12 (30%) had sleeping problems. Fatigue Severity Scale score was significantly correlated with Beck Depression Inventory and sleep disturbance (P < 0.05) but was not significantly correlated with Modified Barthel Index, Motricity Index or Korean-Mini Mental State Examination. CONCLUSIONS: We found that 30% of stroke victims had poststroke fatigue. Poststroke fatigue was not closely associated with motor function, activity of daily living, or cognitive function, but showed significant correlation with depression and sleeping problems. These findings emphasize the need for careful clinical screening of both fatigue and depression in individuals after stroke. [ABSTRACT FROM AUTHOR]

BACKGROUND AND AIMS: To investigate the gait, sit-to-stand and upper extremity performance in the elderly compared with young adults. METHODS: Individuals over 60 and under 35 years old, with no medical, neurological or orthopedic problems participated in this study. Three-dimensional motion analyses of gait, sit-to-stand and upper extremity performance were performed, and results in the two age groups were compared. RESULTS: Compared with the younger cohort, the gait pattern of the elderly included slower velocity, decreased single stance period, decreased maximal knee extension, and decreased ankle dorsiflexion and plantarflexion. On sit-to-stand, the elderly had decreased knee extension angle, minimal knee extension and maximal ankle plantarflexion moment. On hand-at-object, the elderly had reduced maximal angle of shoulder flexion and increased maximal angle of anterior pelvic tilt. On hand-to-head and hand-to-mouth, the elderly had decreased maximal angle of shoulder flexion. CONCLUSIONS: The most debilitating motion factors in the elderly were limitation of shoulder flexion and decreased knee extension and ankle plantarflexion. Therapeutic programs for elderly individuals should target maintenance of flexibility and strengthening of ankle plantarflexors, strengthening knee extensors, and maintenance of the shoulder joint ROM. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To determine whether proton magnetic resonance spectroscopy (1H-MRS) could be a useful tool for detecting microscopic diffuse axonal injury to evaluate the functional status of patients with traumatic brain injury (TBI). DESIGN: A comparative study. SETTING: An inpatient rehabilitation unit in Korea. SUBJECTS: We examined eight adult patients who had severe TBI approximately five months before. Fourteen normal controls were employed for comparison. MAIN MEASURES: Image-guided localized in vivo 1H-MRS was performed in the parietal white matter and occipital grey matter regions in brain in which no definite abnormalities in MR imaging were found at the time of 1H-MRS examination. We evaluated functional status for all patients with the Functional Independence Measure (FIM) on the same day as the 1H-MRS examination and compared the results. RESULTS: In the parietal white matter, the [N-acetyl aspartate/creatine] ratios were significantly lower, and the [choline/creatine] and [myo-inositol/creatine] ratios were significantly higher than those of normal controls. Significant correlations of the IN-acetyl aspartate/creatine] and [myo-inositol/creatine] ratios in the parietal white matter with FIM scores were observed (p < 0.05). CONCLUSIONS: A spectral feature of the decreased [N-acetyl aspartate/creatine] and increased [choline/creatine] and [myo-inositol/creatine] ratios in parietal white matter may be a marker for diffuse axonal injury in patients with TBI and has a significant correlation with the functional status of the patients. Localized 1H-MRS has the potential to be used for detecting diffuse axonal injury in vivo in TBI patients, which can be used to guide evaluation of the functional status of TBI patients receiving rehabilitation. [ABSTRACT FROM AUTHOR]

Previous studies have shown the appearance of right-sided language-related brain activity in right-handed patients after a stroke. Non-invasive brain stimulation such as transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS) have been shown to modulate excitability in the brain. Moreover, rTMS and tDCS have been found to improve naming in non-fluent post-stroke aphasic patients. Here, we investigated the effect of tDCS on the comprehension of aphasic patients with subacute stroke. We hypothesized that tDCS applied to the left superior temporal gyrus (Wernicke's area) or the right Wernicke's area might be associated with recovery of comprehension ability in aphasic patients with subacute stroke. Participants included right-handed subacute stroke patients with global aphasia due to ischemic infarct of the left M1 or M2 middle cerebral artery. Patients were randomly divided into three groups: patients who received anodal tDCS applied to the left superior temporal gyrus, patients who received cathodal tDCS applied to the right superior temporal gyrus, and patients who received sham tDCS. All patients received conventional speech and language therapy during each period of tDCS application. The Korean-Western Aphasia Battery (K-WAB) was used to assess all patients before and after tDCS sessions. After intervention, all patients had significant improvements in aphasia quotients, spontaneous speech, and auditory verbal comprehension. However, auditory verbal comprehension improved significantly more in patients treated with a cathode, as compared to patients in the other groups. These results are consistent with the role of Wernicke's area in language comprehension and the therapeutic effect that cathodal tDCS has on aphasia patients with subacute stroke, suggesting that tDCS may be an adjuvant treatment approach for aphasia rehabilitation therapy in patients in an early stage of stroke. [ABSTRACT FROM AUTHOR]

Background: Upper limb dysfunction is one of the most common sequelae of stroke and robotic therapy is considered one of the promising methods for upper limb rehabilitation., Objective: This study aimed to explore the clinical effectiveness of upper limb training using a rehabilitation robotic device (Rebless®) for patients with stroke., Methods: In this prospective, unblinded, randomized controlled trial, patients were randomly assigned to receive robotic training (experimental group, n = 15) or conventional therapy (control group, n = 15). Both groups received upper limb training lasting for 30 minutes per session with a total of 10 training sessions within 4 weeks. Motor function, functional evaluation, and spasticity were clinically assessed before and after the training. Cortical activation was measured using functional near-infrared spectroscopy at the 1st and 10th training sessions., Results: The experimental group demonstrated a significant improvement in the Fugl-Meyer assessment-upper extremity score and the modified Ashworth scale grade in elbow flexors. The cortical activity of the unaffected hemisphere significantly decreased after 10 training sessions in the experimental group compared with the control group., Conclusions: The experimental group showed significant improvement in the Fugl-Meyer assessment-upper extremity score and spasticity of elbow flexors and had significantly decreased cortical activity of the unaffected hemisphere. Training with Rebless® may help patients with chronic stroke in restoring upper limb function and recovering the contralateral predominance of activation in motor function., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Previous studies report an association between maternal diabetes mellitus (MDM) and attention-deficit/hyperactivity disorder (ADHD), often overlooking unmeasured confounders such as shared genetics and environmental factors. We therefore conducted a multinational cohort study with linked mother-child pairs data in Hong Kong, New Zealand, Taiwan, Finland, Iceland, Norway and Sweden to evaluate associations between different MDM (any MDM, gestational diabetes mellitus (GDM) and pregestational diabetes mellitus (PGDM)) and ADHD using Cox proportional hazards regression. We included over 3.6 million mother-child pairs between 2001 and 2014 with follow-up until 2020. Children who were born to mothers with any type of diabetes during pregnancy had a higher risk of ADHD than unexposed children (pooled hazard ratio (HR) = 1.16, 95% confidence interval (CI) = 1.08-1.24). Higher risks of ADHD were also observed for both GDM (pooled HR = 1.10, 95% CI = 1.04-1.17) and PGDM (pooled HR = 1.39, 95% CI = 1.25-1.55). However, siblings with discordant exposure to GDM in pregnancy had similar risks of ADHD (pooled HR = 1.05, 95% CI = 0.94-1.17), suggesting potential confounding by unmeasured, shared familial factors. Our findings indicate that there is a small-to-moderate association between MDM and ADHD, whereas the association between GDM and ADHD is unlikely to be causal. This finding contrast with previous studies, which reported substantially higher risk estimates, and underscores the need to reevaluate the precise roles of hyperglycemia and genetic factors in the relationship between MDM and ADHD., (© 2024. The Author(s).)

Botulinum toxin type A (BTX-A) injection is a commonly used therapeutic intervention for upper limb spasticity in stroke patients. This study was designed as a randomized, active-drug-controlled, double-blind, multicenter, phase 3 clinical trial to evaluate the safety and efficacy of Liztox ® in comparison to onabotulinum toxin A (Botox ® ) for individuals with post-stroke upper limb spasticity. The primary outcome was the alteration in wrist flexor muscle tone from the initial assessment to the fourth week, evaluated using the modified Ashworth scale (MAS). Secondary outcomes included MAS score changes for the wrist at weeks 8 and 12 from baseline; MAS score changes for finger and elbow flexors; and changes in the Disability Assessment Scale (DAS), Subject's Global Assessment (SGA), the Investigator's Global Assessment (IGA), and Caregiver Burden Scale (CBS) at weeks 4, 8, and 12 from baseline. The MAS score for wrist flexor spasticity decreased by -1.14 ± 0.59 in the Liztox ® group and -1.22 ± 0.59 in the Botox ® group from baseline to week 4. The difference [97.5% confidence interval (CI)] between the test and control groups was 0.08 [-∞, 0.26], confirming the non-inferiority of the test group compared to the control group. Furthermore, there were consistent improvements in the IGA, SGA, and CBS scores across all assessment intervals, with no statistically significant variances detected between the two groups. No safety-related concerns were reported during the study. In conclusion, Liztox ® injection proved to be a secure and efficacious intervention for managing upper extremity spasticity in post-stroke patients.

Objectives: To investigate the effects of exoskeleton-assisted gait training in stroke patients., Design: Prospective randomized controlled trial., Setting: Rehabilitation department in a single tertiary hospital., Participants: Thirty (N=30) chronic stroke patients with Functional Ambulatory Category scale (FAC) between 2 and 4., Intervention: Patients were randomly assigned to 1 of 2 groups: training with Healbot G, a wearable powered exoskeleton (Healbot G group; n=15), or treadmill training (control group; n=15). All participants received 30 minutes of training, 10 times per week, for 4 weeks., Outcome Measurements: The primary outcome was oxyhemoglobin level changes, representing cortical activity in both motor cortices using functional near-infrared spectroscopy. The secondary outcomes included FAC, Berg Balance Scale, Motricity Index for the lower extremities (MI-Lower), 10-meter walk test, and gait symmetry ratio (spatial step and temporal symmetry ratio)., Results: Compared to the control group, during the entire training session, the pre-training and post-training mean cortical activity, and the amount of increment between pre- and post-training were significantly higher in the Healbot G group (∆mean ± SD; pre-training, 0.245±0.119, post-training, 0.697±0.429, between pre- and post-training, 0.471±0.401μmol, P<.001). There was no significant difference in cortical activity between affected- and unaffected hemispheres after Healbot G training. FAC (∆mean ± SD; 0.35 ± 0.50, P=.012), MI-Lower (∆mean ± SD; 7.01 ± 0.14, P=.001), and spatial step gait symmetry ratio (∆mean ± SD; -0.32 ± 0.25, P=.049) were improved significantly in the Healbot G group., Conclusion: Exoskeleton-assisted gait training induces cortical modulation effect in both motor cortices, a balanced cortical activation pattern with improvements in spatial step symmetry ratio, walking ability, and voluntary strength., (Copyright © 2023 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

This clinical practice guideline (CPG) is the fourth edition of the Korean guideline for stroke rehabilitation, which was last updated in 2016. The development approach has been changed from a consensus-based approach to an evidence-based approach using the Grading of Recommendations Assessment Development and Evaluation (GRADE) method. This change ensures that the guidelines are based on the latest and strongest evidence available. The aim is to provide the most accurate and effective guidance to stroke rehabilitation teams, and to improve the outcomes for stroke patients in Korea. Fifty-five specialists in stroke rehabilitation and one CPG development methodology expert participated in this development. The scope of the previous clinical guidelines was very extensive, making it difficult to revise at once. Therefore, it was decided that the scope of this revised CPG would be limited to Part 1: Rehabilitation for Motor Function. The key questions were selected by considering the preferences of the target population and referring to foreign guidelines for stroke rehabilitation, and the recommendations were completed through systematic literature review and the GRADE method. The draft recommendations, which were agreed upon through an official consensus process, were refined after evaluation by a public hearing and external expert evaluation., Competing Interests: Among the development members, if there was even a slight interest in the result of the declaration of interest, it was excluded from the development process of individual clinical questions with interest and the official agreement process. Prior to reaching a formal consensus, a preliminary consensus was reached through a review meeting for each team, and an additional preliminary consensus meeting was held at the operating committee. The recommendations revised and supplemented through informal consensus were subsequently followed by a formal consensus-building process using the RAND-UCLA Appropriateness Method (RAM) method.Conflict of Interests: All researchers involved in the development of this clinical guideline were instructed to indicate any conflicting interests related to the study (involvement in similar clinical guideline development, employment, financial understanding, and other potential conflicts). All researchers except for six declared that they have no conflicting interests. Researchers with personal interests in the content of this clinical guideline have excluded themselves from making recommendations regarding specific items (botulinum toxin, virtual reality, robot rehabilitation, medication)., (Copyright © 2023. Korean Society for Neurorehabilitation.)

This study aimed to compare functional outcomes after rehabilitation with initial degree of urinary retention (UR) in patients operated on for brain tumors. Medical records of 61 patients transferred to the Department of Rehabilitation Medicine of single center, from January 2011 to December 2021, were reviewed retrospectively. Patient data included post-void residual (PVR) urine, tumor characteristics, and functional status. Functional status was evaluated on the Mini-Mental Status Examination (MMSE), Modified Barthel Index (MBI), Functional Ambulation Category (FAC), Modified Rankin Scale (mRS), Motricity Index (MI)-lower limb, and Berg Balance Scale (BBS). MMSE, FAC, mRS, and MI-lower limb were re-evaluated 3 weeks after standard inpatient rehabilitation. Twenty-four patients were in the UR group and 37 in the non-UR group. Initial MMSE, MBI, BBS, FAC, and mRS were significantly worse in the UR group, and both groups showed significant functional improvement after rehabilitation. After rehabilitation, MMSE, FAC, MRS, MI-lower were still worse in the UR group, but the degree of improvement between the groups was not significantly different. Rehabilitation was shown to be effective for brain tumor patients regardless of UR. Initial UR after brain tumor surgery is significantly associated with poor functional status in both the early stages of rehabilitation and after rehabilitation., Competing Interests: Conflict of Interest: The authors have no potential conflicts of interest to disclose., (Copyright © 2023. Korean Society for Neurorehabilitation.)

Dysphagia affects 60-75% of patients treated for head and neck cancer (HNC). We aimed to evaluate the association between residue severity and airway invasion severity using a videofluoroscopic swallowing study and identify risk factors for poor penetration-aspiration outcomes in patients with dysphagia treated for HNC. Penetration-Aspiration Scale (PAS) was used to assess airway invasion severity, while residue severity was assessed using both the Bolus Residue Scale (BRS) for residue location and the Normalized Residue Ratio Scale (NRRS) for residue amount. Relevant covariates were adjusted in the logistic regression models to account for potential confounding. Significantly higher abnormal PAS was reported for increased piriform sinus NRRS (NRRSp) [odds ratio (OR), 4.81; p = 0.042] with liquid swallowing and increased BRS value (OR, 1.52; p = 0.014) for semi-liquid swallowing in multivariate analysis. Tumor location, older age, and poorer Functional Oral Intake Scale (FOIS) were significant factors for abnormal PAS in both texture swallowings. After adjusting for confounding factors (sex, age, and FOIS score), NRRS model in liquid swallowing (area under the curve [AUC], 0.83; standard error = 0.04, 95% confidence interval [CI]: 0.75, 0.91) and BRS in semi-liquid swallowing (AUC, 0.83; SE = 0.04; 95% CI: 0.76, 0.91) predicted abnormal PAS. The results indicate that while assessing residue and swallowing aspiration in patients with HNC, it is important to consider age, tumor location, and functional swallowing status. The good predictability of abnormal PAS with BRS and NRRS indicated that residue location and amount were both related to the aspiration event in patients with HNC., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: A sandy beach provides an unstable support surface and may influence walking ability in patients with stroke., Primary Study Objective: To investigate the effect of gait training on a sandy beach in patients with chronic stroke., Methods/design: This was a randomized controlled trial., Setting: Patients were recruited from a community center., Participants: A total of 28 patients with chronic stroke participated in the study., Intervention: Patients were randomly assigned to receive gait training either on a sandy beach (sand group) or firm ground (control group). All patients received gait training for 30 minutes per session, 2 sessions every day for 5 days., Context: Primary Outcome Measures • Primary outcomes were 10-minute walk test (10MWT) and Berg Balance Scale (BBS) scores. Secondary outcomes were Functional Ambulatory Category (FAC), Timed Up and Go (TUG) and spatiotemporal parameters of gait evaluated with a wearable inertial sensor. Psychological parameters, including the Beck Depression Inventory (BDI) and State-Trait Anxiety Inventory (STAI), were also measured. Outcome measurements were evaluated at baseline and after the intervention., Results: The 10MWT and BBS scores were significantly improved in the sand group (P < .05). Compared with the changes from pre- to post-treatment between the groups, 10MWT showed a large effect size and BBS score showed a medium effect size. Regarding spatiotemporal parameters, cadence and gait velocity were significantly higher after training than before training in the sand group (P < .05). Compared with the changes from pre- to post-treatment between groups, cadence and gait velocity showed large effect sizes and affected-side stride length showed a medium effect size. There was no difference in the changes from pre- to post-treatment in BDI and STAI between the 2 groups (P > .05). No adverse events occurred during the study., Conclusion: Gait training on a sandy beach may be beneficial for improving walking ability and balance in patients with stroke.

Background: Upper limb robotic rehabilitation can be beneficial to the patients when applied appropriately. HEXO-UR30A is a novel exoskeletal type upper limb rehabilitation robot that provides continuous passive motion to the shoulder joint., Objective: The purpose of this study is to evaluate the effectiveness of HEXO-UR30A on the patient's functional change, spasticity, and range of motion (ROM)., Methods: We included stroke patients with upper limb hemiparesis of age > 19 years with spasticity grading of modified Ashworth scale < 3 and Brunnstrom recovery stage ≥ 4. The efficacy of the robot was investigated based on a rehabilitation program for 3 weeks. Patient's functions were compared before vs after treatment and between the HEXO group vs control. We conducted the Fugl-Meyer Assessment of the Upper Extremity, modified Barthel index, modified Ashworth scale, ROM, and Motricity Index upper limb. Patients' satisfaction was evaluated using a questionnaire after every 10 sessions of training., Results: In the HEXO group, the Fugl-Meyer assessment for shoulder improved significantly (P value = .006*) compared with the control group (P value = .075). Both groups showed significant improvement (P value < .05) in Motricity Index upper limb after treatment. There were some improvements in the passive and active ROM. Patients in the HEXO group reported high satisfaction with upper limb rehabilitation., Conclusion: These results show that HEXO-UR30A can improve functional ability in chronic stroke patients. Moreover, the high satisfaction in patients might promote active involvement in upper limb rehabilitation., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Balance training on an unstable support surface has been known to improve postural control. The aim of this study was to investigate the effect of a gait and balance training program on an unstable mudflats surface in older adults., Methods: A total of 28 older people were assigned to participate in a gait and balance training program on an unstable mudflats surface (experimental group) or on firm ground (control group). All participants received the training program for 55 minutes per session, 2 sessions per day for 5 days. The primary outcomes were the Berg Balance Scale (BBS) and single-leg stance (SLS) test. Secondary outcomes were Timed Up and Go (TUG), 10-meter walk test (10MWT), Modified Falls Efficacy Scale (MFES), Motricity Index (MI) of the lower extremities, and medical research council (MRC) scale of lower extremities., Results: SLS with eyes open and the MRC of the left and right ankles showed a large effect size whereas the MI of the left and right lower extremities and MRC of the left and right knees showed a medium effect size in the experimental group. Intergroup differences in changes from baseline to after the exercise program included a large effect size of the SLS with eye open and MI of the right lower extremity and a medium effect size of the MI of the left lower extremity and MRC of the right ankle and left hip., Conclusions: Muscle strength and balance of older people could be improved with gait and balance training on an unstable mudflat surface., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: Development and evaluation of a drug-safety signal detection system integrating data-mining tools in longitudinal data is essential. This study aimed to construct a new triage system using longitudinal data for drug-safety signal detection, integrating data-mining tools, and evaluate adaptability of such system., Patients and Methods: Based on relevant guidelines and structural frameworks in Taiwan's pharmacovigilance system, we constructed a triage system integrating sequence symmetry analysis (SSA) and tree-based scan statistics (TreeScan) as data-mining tools for detecting safety signals. We conducted an exploratory analysis utilizing Taiwan's National Health Insurance Database and selecting two drug classes (sodium-glucose co-transporter-2 inhibitors (SGLT2i) and non-fluorinated quinolones (NFQ)) as chronic and episodic treatment respectively, as examples to test feasibility of the system., Results: Under the proposed system, either cohort-based or self-controlled mining with SSA and TreeScan was selected, based on whether the screened drug had an appropriate comparator. All detected alerts were further classified as known adverse drug reactions (ADRs), events related to other causes or potential signals from the triage algorithm, building on existing drug labels and clinical judgement. Exploratory analysis revealed greater numbers of signals for NFQ with a relatively low proportion of known ADRs; most were related to indication, patient characteristics or bias. No safety signals were found. By contrast, most SGLT2i signals were known ADRs or events related to patient characteristics. Four were potential signals warranting further investigation., Conclusion: The proposed system facilitated active and systematic screening to detect and classify potential safety signals. Countries with real-world longitudinal data could adopt it to streamline drug-safety surveillance., Competing Interests: Ms Miyuki Hsing-Chun Hsieh reports grants from Taiwan Food and Drug Administration, during the conduct of the study. Ms Hsun-Yin Liang reports grants from Taiwan Food and Drug Administration, during the conduct of the study. Ms Chih-Ying Tsai reports grants from Taiwan Food and Drug Administration, during the conduct of the study. Ms Yu-Ting Tseng reports grants from Taiwan Food and Drug Administration (TFDA), during the conduct of the study. Mr Pi-Hui Chao reports grants from Taiwan Food and Drug Administration, during the conduct of the study. Ms Wei-I Huang reports grants from Taiwan Food and Drug Administration, during the conduct of the study. Dr Wen-Wen Chen reports grants from Taiwan Food and Drug Administration, during the conduct of the study. The authors declare no other competing interests., (© 2023 Hsieh et al.)

Purpose: Taiwan launched reimbursement of prophylactic coagulation factor replacement therapy (CFRT) for patients with severe hemophilia type A (severe PWHA) in 2014. However, since then, the effectiveness of prophylactic CFRT in real-world practice has not been evaluated thoroughly. This study aimed to evaluate the effectiveness of prophylactic CFRT in severe PWHA cases on the outcome of bleeding risks., Patients and Methods: We included male, severe PWHA cases from a nationwide, population-based database in Taiwan. Given that the database lacked details of the dosing regimen for prophylactic CFRT, we applied group-based trajectory modeling using the proportion of days covered (PDC) by CFRT from 2014 to 2015 in order to classify patients. A high PDC level corresponded to a greater proportion of time under CFRT, thus implying that the patient was probably receiving prophylactic therapy. We followed up patients from January 01, 2016 until occurrence of any bleeding events, death or December 31st 2017., Results: We identified a total of 420 severe PWHA and classified them into high- (n = 88), medium- (n = 181) and low- (n = 151) PDC groups. The mean (±SD) PDC values of the three groups were 0.78 (±0.1), 0.40 (±0.1) and 0.12 (±0.1), respectively. Using Cox regression models with propensity score adjustment, we found patients with medium- (hazard ratio: 0.69; 95% CI: 0.56-0.89) or high-PDC (0.45; 0.36-0.68) under CFRT had reduced risks of any bleeding, compared to the low PDC group., Conclusion: The findings demonstrated the effectiveness of prophylactic CFRT in the prevention of bleeding events in real-life severe PWHA., Competing Interests: The authors had received research funding from Takeda Pharmaceutical Company and Ministry of Science and Technology. However, the funders had no roles in study design, analysis or interpretation. The authors report no other conflicts of interest in this work., (© 2022 Hsieh et al.)

Objectives: For patients with glottic insufficiency disease, injection laryngoplasty is a rapid and efficient management option that complements voice therapy. Some studies have indicated that respiratory muscle training may also show promise in patients with voice disorders. However, the effect of respiratory muscle training in patients with glottic insufficiency was reported to be limited, and whether it provides additional benefit after standard management requires further evaluation. We aimed to investigate the effectiveness of inspiratory muscle training on glottis closure and patient-reported voice quality in glottic insufficiency patients who had been treated with hyaluronic acid injection., Study Design: Retrospective observational study., Methods: We included 46 patients with glottic insufficiency who had undergone hyaluronic acid injection. Twenty of them had undergone inspiratory muscle training during three months. We measured patients' changes in glottic status according to the normalized glottal gap area and bowing index, as well as voice quality of life according to the voice handicap index 10 and the voice outcome survey, before and after training., Results: Patients who underwent inspiratory muscle training had higher odds of experiencing better improvement in all scores. The range of odds ratios ranged from 2.5 to 6.3 for changes in scores, and from 3.8 to 22.2 for changes in score percentages. Of note, the effect of training on percentage changes in the normalized glottal gap area score was significant (P= 0.0127) after adjustment for the duration of vocal disease, body mass index and BMI, and history of gastroesophageal reflux disease., Conclusions: Inspiratory muscle training can improve the glottal gap after injection laryngoplasty, and may be applied in clinical practice., Competing Interests: Conflict of interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2022 The Voice Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The effect of robot-assisted gait training has been demonstrated to improve gait recovery in patients with stroke. The aim of this study was to determine effects of robot-assisted gait training with various training modes in patients post stroke., Methods: Forty-seven patients post stroke were randomly assigned to one of 4 groups: Healbot T with pelvic off mode (pelvic off group; n = 11); Healbot T with pelvic control mode (pelvic on group; n = 12); Healbot T with constraint-induced movement therapy (CIMT) mode (CIMT group; n = 10); and conventional physiotherapy (control group; n = 10). All patients received a 30-minute session 10 times for 4 weeks. The primary outcomes were the 10-meter walk test (10MWT) and Berg Balance Scale (BBS). The secondary outcomes were functional ambulation category, timed up and go (TUG), and motricity index of the lower extremities (MI-Lower)., Results: The pelvic off group showed significant improvements in BBS, TUG, and MI-Lower (P < .05). The pelvic on and CIMT groups showed significant improvement in 10MWT, BBS, TUG, and MI-Lower (P < .05). Compared with control group, the pelvic on group showed greater improvement in the TUG and BBS scores; the CIMT group showed greater improvement in 10MWT and MI-Lower (P < .05)., Conclusion: This study suggested that Healbot T-assisted gait training benefited patients with stroke. The Healbot T with pelvic motion and CIMT modes were more helpful in improving balance and walking ability and lower limb strength, respectively, compared with conventional physiotherapy., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Botulinum toxin type A injection is widely used treatment option for the treatment of upper limb spasticity in stroke patients. The purpose of this study was to explore the safety and efficacy of MT10107, a new botulinum toxin type A, in patients with post-stroke upper limb spasticity., Methods: A prospective, randomized, double-blind, active drug-controlled, multi-center, phase I clinical trial. Thirty patients with post-stroke upper limb spasticity were received either MT10107 or onabotulinumtoxinA. Primary endpoint was change of modified Ashworth scale (MAS) score for wrist flexor from baseline to week 4. The secondary endpoints were changes of MAS scores for elbow and finger flexors, response rate, Disability Assessment Scale (DAS), and global assessment of treatment. The safety endpoints such as adverse events, vital signs, physical examination, and laboratory test were evaluated. The outcome measures were evaluated from baseline to week 4., Results: The primary endpoints were -1.07 ± 0.70 and -1.23 ± 0.56 for the MT10107 and onabotulinumtoxinA groups, respectively. The intergroup difference of change between the 2 groups was 0.17 (95% confidence interval -0.31 to 0.64, P = .5769). In secondary endpoints, both groups showed a significant improvement in both MAS and DAS. There was no significant between-group difference in all secondary endpoints and safety measures., Conclusion: The safety and efficacy of MT10107 showed no significant difference compared to onabotulinumtoxinA in post-stroke upper limb spasticity treatment., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Botulinum toxin type A (BTX-A) is widely used for treating post-stroke upper limb spasticity. We evaluated the safety and efficacy of HU-014 in treating post-stroke upper limb spasticity. Thirteen patients were administered with HU-014. The primary outcome was safety, including adverse events, vital signs, physical examination, laboratory tests, and antibody formation test. The secondary outcomes were changes in the Modified Ashworth Scale (MAS) score for wrist, elbow, and finger flexor; Disability Assessment Scale (DAS); Investigator's Global Assessment (IGA) and Subject's Global Assessment (SGA); Caregiver Burden Scale (CBS); and Columbia Suicide Severity Rating Scale (C-SSRS) at weeks 4, 8, and 12 from baseline. No notable safety-related issues were reported. MAS and DAS scores were significantly decreased from those at baseline at 4, 8, and 12 weeks ( p < 0.05). At weeks 4, 8, and 12, the IGA and SGA scores were 5.85 ± 0.55, 5.69 ± 0.48, and 5.62 ± 0.65 and 5.46 ± 1.20, 5.85 ± 0.38, and 5.77 ± 0.73, respectively. CBS scores decreased at all timepoints and those for cutting fingernails significantly decreased at 8 and 12 weeks compared with baseline ( p < 0.05). C-SSRS scores showed that suicidal ideation in all patients was "low" at all timepoints. HU-014 is a safe treatment that can improve post-stroke upper limb spasticity.

The study aimed to investigate the status of thickener use in dysphagia patients with brain lesions and incidence of adverse events based on fluid viscosity. Twenty dysphagia patients with brain lesions who were recommended to use thickeners following a videofluoroscopic swallowing study were enrolled in this observational pilot study. Patients were educated to use thickener as level 2 or 3 based on the International Dysphagia Diet Standardization Initiative flow test. We evaluated the viscosity of the fluid that patients drank once a week for 2 weeks, and reviewed medical records regarding adverse events. Patients were divided into 2 groups based on the average value obtained from the viscosity evaluations as thin (Levels 0-2) and thick fluid groups (Levels 3-4). Adverse events were compared between the groups. The number of patients who did not follow the recommendations increased from 35.0 to 45.0% during the 1-week follow-up period. No patient developed pneumonia or urinary tract infection. Constipation (P = 0.338) and dehydration status (P = 0.202) were not significantly different between the 2 groups. In 2 evaluations for 20 patients, 40.0% of the cases did not follow the educated viscosity, and the number gradually increased in the follow-up evaluation. Considering that there were no significant differences in the incidence of adverse effects including pneumonia according to the fluid viscosity, a further study is necessary to establish detailed criteria for thickener use in dysphagia patients with brain lesions., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: This study is aimed to compare the effect of robot-assisted gait training when the intensity is controlled using patients' biometric data to when controlled by therapist's subjective judgment., Design: This is non-blinded, prospective, randomized controlled study. Patients were randomly assigned to one of two groups. In biometric data control group, exercise intensity was controlled through the patient's heart rate or rating of perceived exertion (RPE). The intensity was raised to the next level when the patient's heart rate reserve was less than 40 percent or the RPE was less than 12 points. The exercise intensity of the therapist control group was adjusted according to the judgement of a therapist. All patients were instructed to perform robot (Morning Walk®)-assisted 20-minute gait training session five times a week during 3 weeks. The primary outcome was functional ambulation category (FAC). The secondary outcomes were modified Barthel index (MBI), Berg balance scale (BBS), timed up and go test (TUG) and 10-meter walk test (10MWT) The outcomes were evaluated at baseline and after 3-week gait training., Results: A total of 55 patients with stroke were enrolled. After robotic rehabilitation, the primary outcome, FAC improved significantly (P < .05) in both groups. Also, secondary outcomes, including MBI, BBS, TUG, 10MWT, showed significant improvement (P < .05) in all groups. In addition, when comparing the functional change from baseline to week 3 between the two groups, there was no statistically significant difference in FAC (P > .05). The difference of baseline and week 3 of secondary outcome measure, MBI, BBS, TUG, 10MWT, showed no significant difference (P > .05)., Conclusion: In conclusion, when the robot intensity was adjusted using the patient's heart rate or RPE, the treatment effect has no significant difference to when adjusting the intensity according to the know-how of the therapist., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

We evaluated objective and subjective swallowing function outcomes in patients with dysphagia treated for head and neck cancer (HNC) and identified risk factors for poor swallowing outcomes. Patients undergoing videofluoroscopic swallowing studies (VFSS) between January 2016 and March 2021 were divided into four groups according to primary tumor sites; post-treatment dysphagia was assessed. The penetration-aspiration scale (PAS) and bolus residue scale (BRS) were used to objectively assess swallowing function through VFSS. The Functional Oral Intake Scale (FOIS) was used for subjective analyses of swallowing statuses. To account for potential confounding, important covariates were adjusted for in logistic regression models. Oropharyngeal tumors were significantly more likely to have poor PAS and BRS scores than oral cavity tumors, and the patients with nasopharyngeal tumors were significantly less likely to have poor FOIS scores. Old age, having multiple HNCs, and a history of radiotherapy were associated with an increased odds of poor PAS scores (for all types of swallows), poor BRS scores (for semiliquid and solid swallows), and poor FOIS scores, respectively. This indicates using only subjective assessments may not allow for accurate evaluations of swallowing function in patients treated for HNC. Using both objective and subjective assessments may allow for comprehensive evaluations.

Background: Aging societies lead to higher demand for gait rehabilitation as age-related neurological disorders such as stroke and spinal cord injury increase. Since conventional methods for gait rehabilitation are physically and economically burdensome, robotic gait training systems have been studied and commercialized, many of which provided movements confined in the sagittal plane. For better outcomes of gait rehabilitation with more natural gait patterns, however, it is desirable to provide pelvic movements in the transverse plane. In this study, a robotic gait training system capable of pelvic motions in the transverse plane was used to evaluate the effect of the pelvic motions on stroke patients., Method: Healbot T, which is a robotic gait training system and capable of providing pelvic movements in the transverse plane as well as flexion/extension of the hip and knee joints and adduction/abduction of the hip joints, is introduced and used to evaluate the effect of the pelvic movement on gait training of stroke patients. Gait trainings in Healbot T with and without pelvic movements are carried out with stroke patients having hemiparesis., Experiment: Twenty-four stroke patients with hemiparesis were randomly assigned into two groups and 23 of them successfully completed the experiment except one subject who had dropped out due to personal reasons. Pelvis-on group was provided with pelvic motions whereas no pelvic movement was allowed for pelvis-off group during 10 sessions of gait trainings in Healbot T. Electromyography (EMG) signals and interaction forces as well as the joint angles of the robot were measured. Gait parameters such as stride length, cadence, and walking speed were measured while walking on the ground without assistance of Healbot T after gait training on 1st, 5th, and 10th day., Result: Stride length significantly increased in both groups. Furthermore, cadence and walking speed of the pelvis-on group were increased by 10.6% and 11.8%. Although interaction forces of both groups except the thighs showed no differences, EMG signals from gluteus medius of the pelvis-on group increased by 88.6% during stance phase. In addition, EMG signals of biceps femoris, gastrocnemius medial, and gastrocnemius lateral of the pelvis-on group increased whereas EMG signals of the pelvis-off group except gastrocnemius lateral showed no difference after gait trainings., Conclusion: Gait training using a robotic gait training system with pelvic movements was conducted to investigate the effects of lateral and rotational pelvic movements in gait training of stroke patients. The pelvic movements affected to increase voluntary muscle activation during the stance phase as well as cadence and walking speed., Clinical Trial Registration: KCT0003762, 2018-1254, Registered 28 October 2018, https://cris.nih.go.kr/cris/search/search&#95;result&#95;st01&#95;kren.jsp?seq=14310&ltype=&rtype=., (© 2021. The Author(s).)

Background: SUBAR is a new ground walking exoskeletal robot. The objective of this study is to investigate SUBAR-assisted gait training's effects in patients with chronic stroke., Methods: This preliminary study is a prospective randomized controlled trial. Thirty adults were enrolled 6 months after the onset of stroke with functional ambulation category scores ≥ 3. Patients were randomly assigned to receive robot-assisted gait training (SUBAR group, n = 15) or conventional physiotherapy (control group, n = 15). All patients received a total of 10 treatment sessions of 30 minutes each for 3 weeks. Before and after the 10-treatment sessions, patients were evaluated. The primary outcome is the 10 meter walk test and the secondary outcomes were the functional ambulation category scale, the Motricity Index-Lower, Modified Ashworth Scale (MAS), timed up and go, Rivermead Mobility Index, Berg Balance Scale (BBS), and gait analysis., Results: In the SUBAR group, MAS and step length were significantly improved between pre- and posttreatment measurements (Δmean ± SD: -1.1 ± 1.6 and 5.5 ± 7.6, P = .019 and .016, respectively). The SUBAR group improved the stride length and step length of the affected limb but not significantly. The control group had significant improvements in the BBS, MAS, and stride length between pre- and posttreatment measurements (Δmean ± SD: 3.5 ± 4.6, -0.8 ± 1.5, and 6.5 ± 9.5; P = .004, .031, and .035, respectively). The BBS improved more in the control group than in the SUBAR group. There were no other differences between the SUBAR group and the control group., Conclusion: Our results suggest that SUBAR-assisted gait training improved gait parameters in patients with chronic stroke. However, there was no significant difference in most outcome measures compared to conventional physiotherapy. Further research is warranted to measure the effects of SUBAR-assisted gait training., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Control strategy and quality by design (QbD) are widely used to develop pharmaceutical products and improve drug quality; however, studies on fixed-dose combination (FDC) bilayer tablets are limited. In this study, the bilayer tablet consisted of high-dose metformin HCl in a sustained-release layer and low-dose dapagliflozin l-proline in an immediate-release layer. The formulation and process of each layer were optimized using the QbD approach. A d-optimal mixture design and response surface design were applied to optimize critical material attributes and critical process parameters, respectively. The robust design space was developed using Monte Carlo simulations by evaluating the risk of uncertainty in the model predictions. Multivariate analysis showed that there were significant correlations among impeller speed, massing time, granule bulk density, and dissolution in the metformin HCl layer, and among roller pressure, ribbon density, and dissolution in the dapagliflozin l-proline layer. Process analytical technology (PAT) was used with in-line transmittance near-infrared spectroscopy to confirm the bulk and ribbon densities of the optimized bilayer tablet. Moreover, the in vitro drug release and in vivo pharmacokinetic studies showed that the optimized test drug was bioequivalent to the reference drug. This study suggested that integrated QbD, statistical, and PAT approaches can develop a robust control strategy for FDC bilayer tablets by implementing real-time release testing based on the relationships among various variables.

As an active pharmaceutical ingredient, dapagliflozin propanediol monohydrate (D-PD) has been used in the solvated form consisting of dapagliflozin compounded with (S)-propylene glycol and monohydrate at a 1:1:1 ratio. However, dapagliflozin propanediol loses the solvent's reduced lattice structure at slightly higher temperatures. Due to its sensitive solid-state stability, the temperature and humidity are strictly controlled during the production and storage of dapagliflozin. Thus, crystalline molecular complexes containing pharmaceutical salts, solvates, monohydrates, and cocrystals have recently been developed as alternative strategies. This study investigated the dapagliflozin free base (D-FB), D-PD, and dapagliflozin l-proline cocrystals (D-LP). Their solid-state behavior was also evaluated in stress stability studies. The compounds were analyzed using scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), Fourier-transform infrared (FT-IR) spectroscopy, dynamic vapor sorption (DVS), and powder rheology testing. In addition, Carr's index, the Hausner ratio, contact angle, and intrinsic dissolution rate were calculated. Dapagliflozin exhibited distinct physical properties depending upon the differences in solid form and also showed significant differences in solid-state behavior in the stress stability test. In conclusion, D-LP was superior to D-FB or D-PD in physicochemical and mechanical properties.

Introduction: Taiwan's National Health Insurance Program approved reimbursement of prophylactic coagulation factor replacement therapy (CFRT) for patients with haemophilia (PWH) in 2014., Aim: To examine 15-year trends and the impact of reimbursement for prophylactic CFRT on its utilization and related medical costs for PWH., Methods: We analysed Taiwan's National Health Insurance Database from 2003 to 2017. We included patients with haemophilia A (PWHA) or B (PWHB) receiving coagulating factor. Female patients were excluded because of small sample size. We analysed annual consumption of CFRT units and medical costs. High proportion of days covered (PDC) with CFRT served as an indicator for prophylactic treatment since it reflects routine use of CFRT. We applied interrupted time series analysis (ITSA) to evaluate the impact of reimbursement for prophylactic CFRT on usage patterns and medical costs., Results: We included 896 male PWHA and 181 male PWHB, with 38.1% and 37.0% aged under 18 years, respectively. By ITSA, we found the trends in coagulation factor consumption and PDC significantly increased after reimbursement for prophylactic CFRT in both PWHA and PWHB (p values for trend change <0.05). The overall medical costs per patient increased with increasing consumption of coagulation factor; however, ITSA revealed non-CFRT cost decreased after reimbursement of prophylactic CFRT for both PWHA and PWHB (p values <.05)., Conclusion: Reimbursement for prophylactic CFRT facilitated growth in rates of prophylactic CFRT and increased related costs, but curbed rising non-CFRT costs. These findings provide strong grounds for future cost-effectiveness studies to leverage prophylactic CFRT for its therapeutic benefits., (© 2021 John Wiley & Sons Ltd.)

In this study, we developed a control strategy for a drug product prepared by high-shear wet granulation and roller compaction using integrated quality by design (QbD). During the first and second stages, we optimized the process parameters through the design of experiments and identified the intermediate quality attributes (IQAs) and critical quality attributes (CQAs) relationship, respectively. In the first stage, we conducted an initial risk assessment by selecting critical process parameters with high impact on IQAs and CQAs and confirmed the correlation between control and response factors. Additionally, we performed Monte Carlo simulations by optimizing the process parameters to deriving and building a robust design space. In the second stage, we identified the IQAs and CQAs relationship for the control strategy, using multivariate analysis (MVA). Based on MVA, in the metformin layer, dissolution at 1 h was significantly correlated with intrinsic dissolution rate and granule size, and dissolution at 3 h was significantly correlated with bulk density and granule size. In dapagliflozin layer, dissolution at 10 min and 15 min was significantly correlated with granule size. Our results suggest that the desired drug quality may result through IQAs monitoring during the process and that the integrated QbD approach utilizing MVA can be used to develop a control strategy for producing high-quality drug products.

Objective: To investigate the effects of the robot-assisted gait training on cortical activation and functional outcomes in stroke patients., Methods: The patients were randomly assigned: training with Morning Walk® (Morning Walk group; n = 30); conventional physiotherapy (control group; n = 30). Rehabilitation was performed five times a week for 3 weeks. The primary outcome was the cortical activation in the Morning Walk group. The secondary outcomes included gait speed, 10-Meter Walk Test (10MWT), FAC, Motricity Index-Lower (MI-Lower), Modified Barthel Index (MBI), Rivermead Mobility Index (RMI), and Berg Balance Scale (BBS)., Results: Thirty-six subjects were analyzed, 18 in the Morning Walk group and 18 in the control group. The cortical activation was lower in affected hemisphere than unaffected hemisphere at the beginning of robot rehabilitation. After training, the affected hemisphere achieved a higher increase in cortical activation than the unaffected hemisphere. Consequently, the cortical activation in affected hemisphere was significantly higher than that in unaffected hemisphere (P = 0.036). FAC, MBI, BBS, and RMI scores significantly improved in both groups. The Morning Walk group had significantly greater improvements than the control group in 10MWT (P = 0.017), gait speed (P = 0.043), BBS (P = 0.010), and MI-Lower (P = 0.047) scores., Conclusion: Robot-assisted gait training not only improved functional outcomes but also increased cortical activation in stroke patients.

This study aimed to investigate walking ability and balance improvement of patients with ataxia caused by brain lesions after end-effector type robot (Morning Walk ® )-assisted gait training. This study randomly assigned 19 patients to one of two groups: 30 minutes of Morning Walk ® training with 1 hour of conventional physiotherapy (Morning Walk ® group; n = 10) or 1.5 hours of conventional physiotherapy (Control group; n = 9). Five treatment sessions per week were given for 3 weeks. The primary outcomes were walking ability and balance, which were assessed by the functional ambulation category (FAC) and Berg Balance Scale (BBS), respectively. The secondary outcomes included 10-meter Walk Test (10mWT), Rivermead Mobility Index (RMI), Motricity Index (MI), and Modified Barthel Index (MBI). At baseline, there was no statistically significant difference between the two groups except MBI. After the treatment, the Morning Walk ® group showed significant improvement in the FAC, BBS, 10mWT, RMI and MBI. The control group showed significant improvement in the BBS, 10mWT, RMI and MBI. Inter-group comparison demonstrated that the ∆FAC, ∆10mWT and ∆RMI of the Morning Walk ® group were significantly higher than those of the control group. Our results suggest that the patients with ataxia receiving Morning Walk ® -assisted gait training might improve greater in walking ability and balance than those trained with conventional physiotherapy., Competing Interests: Conflict of Interest: The authors have no potential conflicts of interest to disclose., (Copyright © 2020. Korean Society for Neurorehabilitation.)

Objective: To compare the efficacy and safety of MT10107 (Coretox) with those of onabotulinum toxin A (Botox) in patients with poststroke upper limb spasticity DESIGN: Prospective, randomized, double-blind, active drug-controlled, multicenter, phase III clinical trial., Setting: Seven university hospitals in the Republic of Korea., Participants: Patients (N=220) with poststroke upper limb spasticity., Interventions: All participants received a single injection of either MT10107 (Coretox group) or onabotulinum toxin A (Botox group)., Main Outcome Measures: The primary outcome was change in wrist flexor spasticity from baseline to week 4, which was assessed using the modified Ashworth scale (MAS). The secondary outcomes were MAS scores for wrist, elbow, and finger flexors; percentage of treatment responders (response rate); Disability Assessment Scale (DAS) score, and global assessment of treatment. Safety was evaluated based on adverse events, vital signs, physical examination findings, and laboratory test results. The efficacy and safety were evaluated at 4, 8, and 12 weeks postintervention., Results: The primary outcome was found to be -1.32±0.69 and -1.40±0.69 for the Coretox and Botox groups, respectively. MT10107 showed a non-inferior efficacy compared with onabotulinum toxin A, as the 95% confidence interval for between-group differences was -0.10 to 0.27 and the upper limit was less than the non-inferiority margin of 0.45. Regarding the secondary outcomes, MAS scores for all muscles and DAS scores showed a significant improvement at all time points in both groups, with no significant between-group difference. No significant between-group differences were observed regarding response rate, global assessment of treatment, and safety measures., Conclusions: MT10107 showed no significant difference in efficacy and safety compared with onabotulinum toxin A in poststroke upper limb spasticity treatment., (Copyright © 2020 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Clinical consensus statements (CCSs) aim to improve care for patients with Parkinson's disease (PD) and reduce the variability of rehabilitation methods in clinical practice. A literature search was conducted to find available evidence on the rehabilitation of patients with PD and to determine the scope of CCSs. The selection of PD rehabilitation domains and key questions was done using the modified Delphi method in 43 expert panels. These panels achieved a consensus on 11 key questions regarding rehabilitation assessment and goal setting, gait and balance, activities of daily living, and swallowing and communication disorders. After the completion of an agreement procedure, 11 key consensus statements were developed by the consensus panel. These statements addressed the needs of rehabilitation as a continuum in patients with PD. They included the appropriate rehabilitation initiation time, assessment items, rehabilitation contents, and complication management. This agreement can be used by physiatrists, rehabilitation therapists, and other practitioners who take care of patients with PD. The consensus panel also highlighted areas where a consensus could not be reached. The development of more focused CCS or clinical practice guidelines that target specific rehabilitation approaches is considered the next needed step., Competing Interests: Conflict of interest: The authors have no potential conflicts of interest to disclose., (Copyright © 2020. Korean Society for Neurorehabilitation.)

Metformin hydrochloride (MFM) is often used as a controlled-release (CR) tablet to reduce dosing frequency. However, the MFM CR tablet contains significant amounts of excipients and the tablet size is also large. Dosing convenience and patient compliance can be increased by reducing the size of the CR tablets. The aim of this study was to prepare and evaluate the MFM controlled-release tablet (MFM-CRT) using two types of release modulators, inner and outer. The MFM-CRT was prepared by coating the MFM granules using a binder solution containing aluminum stearate (ALS) as the inner release-modulator, and polyethylene oxide (PEO) as the outer release-modulator. The dispersion stability of the binder solution was optimized by the dispersion analyzer. The MFM-CRT was evaluated for dissolution rate and tablet volume. Additionally, dissolution behavior and dissolution kinetics of the MFM-CRT were analyzed using micro-computed tomography (micro-CT). Although the optimal MFM-CRT showed no difference in the release rate as compared to the commercially available product of Glucophage ® XR 500 mg ( f 2 value: 72), the length of the long axis was reduced by 6 mm and the weight was reduced by about 27%. We expect patient compliance to improve because of effective sustained release and volume reduction of MFM-CRT.

Objective: We investigated the effect of hypnotics on sleep quality, cognitive function, and depressive mood in patients with insomnia following brain tumor resection., Methods: From patients who underwent brain tumor resection, we recruited 10 patients with insomnia who received hypnotics for more than 1 week during a 3-week follow-up period (insomnia group). We also recruited 12 control patients with brain tumors but without insomnia (control group). We evaluated sleep quality at baseline and 3 weeks later using the Insomnia Severity Index (ISI), the Pittsburgh Sleep Quality Index (PSQI), the Stanford Sleepiness Scale (SSS), and the Epworth Sleepiness Scale (ESS) and investigated cognitive function and depression using the Computerized Neuropsychological Test and the Beck Depression Inventory (BDI)., Results: At baseline, SSS, ISI, PSQI, and BDI scores were significantly higher and visual continuous performance test (VCPT) and auditory continuous performance test (ACPT) scores were significantly lower in the insomnia than in the control group. Three weeks later, the patients who had received hypnotics had significantly higher ISI, PSQI, ESS, VCPT, ACPT, visual span forward and backward, and visual recognition test scores, and significantly lower BDI scores., Conclusion: Quality of sleep in patients with insomnia following brain tumor resection was initially poor but improved significantly after taking hypnotic medication. Further, the hypnotic medications appeared to contribute to the amelioration of cognitive impairments and depressive moods in patients who previously underwent brain tumor resection. We thus recommend the use of hypnotics for patients with brain tumors with insomnia.

Background: Robotic locomotion rehabilitation systems have been used for gait training in patients who have had a stroke. Most commercialized systems allow patients to perform simple exercises such as balancing or level walking, but an additional function such as stair-walk training is required to provide a wide range of recovery cycle rehabilitation. In this study, we analyzed stair-gait patterns and applied the result to a robotic rehabilitation system that can provide a vertical motion of footplates., Methods: To obtain applicable data for the robotic system with vertically movable footplates, stair-walk action was measured using an optical marker-based motion capture system. The spatial position data of joints during stair walking was obtained from six healthy adults who participated in the experiment. The measured marker data were converted into joint kinematic data by using an algorithm that included resampling and normalization. The spatial position data are represented as angular trajectories and the relative displacement of each joint on the anatomical sagittal plane and movements of hip joints on the anatomical transverse plane., Results: The average range of motion (ROM) of each joint was estimated as (-6.75°, 48.69°) at the hip, (8.20°, 93.78°) at the knee, and (-17.78°, 11.75°) at the ankle during ascent and as (6.41°, 31.67°) at the hip, (7.38°, 91.93°) at the knee, and (-24.89°, 24.18°) at the ankle during descent. Additionally, we attempted to create a more natural stair-gait pattern by analyzing the movement of the hip on the anatomical transverse plane. The hip movements were estimated to within ±1.57 cm and ±2.00 cm for hip translation and to within ±2.52° and ±2.70° for hip rotation during stair ascent and stair descent, respectively., Conclusions: Based on the results, standard patterns of stair ascent and stair descent were derived and applied to a lower-limb rehabilitation robot with vertically movable footplates. The relative trajectory from the experiment ascertained that the function of stair walking in the robotic system properly worked within a normal ROM., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2019 Sang-Eun Park et al.)

Objective:: To investigate the effects of Morning Walk ® -assisted gait training for patients with stroke., Design:: Prospective randomized controlled trial., Setting:: Three hospital rehabilitation departments (two tertiary and one secondary)., Patients:: We enrolled 58 patients with hemiparesis following a first-time stroke within the preceding year and with Functional Ambulation Category scores ⩾2., Intervention:: The patients were randomly assigned to one of two treatment groups: 30 minutes of training with Morning Walk ® , a lower limb rehabilitation robot, plus 1 hour of conventional physiotherapy (Morning Walk ® group; n = 28); or 1.5 hour of conventional physiotherapy (control group; n = 30). All received treatment five times per week for three weeks., Main Outcome Measurements:: The primary outcomes were walking ability, assessed using the Functional Ambulation Category scale, and lower limb function, assessed using the Motricity Index-Lower. Secondary outcomes included the 10 Meter Walk Test, Modified Barthel Index, Rivermead Mobility Index, and Berg Balance Scale scores., Results:: A total of 10 patients were lost to follow-up, leaving a cohort of 48 for the final analyses. After training, all outcome measures significantly improved in both groups. In Motricity Index-Lower of the affected limb, the Morning Walk ® group (∆mean ± SD; 19.68 ± 14.06) showed greater improvement ( p = .034) than the control group (∆mean ± SD; 11.70 ± 10.65). And Berg Balance Scale scores improved more ( p = .047) in the Morning Walk ® group (∆mean ± SD; 14.36 ± 9.01) than the control group (∆mean ± SD; 9.65 ± 8.14)., Conclusion:: Compared with conventional physiotherapy alone, our results suggest that voluntary strength and balance of stroke patients with hemiparesis might be improved with Morning Walk ® -assisted gait training combined with conventional physiotherapy.

Background: Balance impairment is a major clinical concern in patients with parkinsonism. Balance training with tetra-ataxiometric posturography (Tetrax) is known to improve balance function through visual biofeedback effects., Objective: In this study, we evaluated the effects of balance training with Tetrax in patients with parkinsonism., Methods: Patients with parkinsonism (idiopathic Parkinson's disease, multiple systemic atrophy, and multiple systemic atrophy) who were able to stand with or without an assistive device were recruited for the study. Twenty patients with parkinsonism were randomly assigned to one of the following two groups: (1) the Tetrax group, in which patients received Tetrax biofeedback balance training for 30 min/day for 2 weeks (10 sessions); and (2) the control group, in which patients received conventional balance training for 30 min/day for 2 weeks (10 sessions). One day before and after training, we measured patients' balance parameters using the Berg balance scale (BBS) and fall index (FI)., Results: The BBS and FI scores of the Tetrax group showed significant improvements after compared to before training. However, the scores in the control group were not significantly changed after vs. before conventional balance training., Conclusions: For patients with parkinsonism, Tetrax biofeedback balance training had a positive effect on balance function.

Little is known about dysphagia after pontine infarction. In this study, we evaluated the incidence of dysphagia after isolated pontine infarction and identified the predictive factors for the occurrence of dysphagia. A total of 146 patients were included in this study. All patients underwent clinical testing for dysphagia within 1 day after admission and at the time of discharge. We compared the incidence of dysphagia between patients with unilateral pontine infarction and those with bilateral pontine infarction. To evaluate the functional status of patients, we investigated their initial modified Rankin Scale (mRS) score and initial National Institutes of Health Stroke Scale (NIHSS) score within 1 day of admission. Of 146 patients, 50 (34.2%) had dysphagia initially within 1 day after admission. At the second evaluation at the time of discharge, dysphagia was diagnosed in 24 patients (16.4%). Patients with bilateral pontine infarction were more likely to present with dysphagia. In addition, clinical severity (in terms of mRS and NIHSS scores) was identified as a predictor of dysphagia in patients with cerebral infarction (multiple binary logistic regression analysis, mRS: P = 0.011, NIHSS: P = 0.004). Dysphagia frequently occurs in patients with isolated pontine infarction. Clinicians should pay particular attention to the occurrence of dysphagia, especially in patients with bilateral pontine infarction or high functional disability., Competing Interests: None

Gait rehabilitation training with robotic exoskeleton is drawing attention as a method for more advanced gait rehabilitation training. However, most of the rehabilitation robots are mainly focused on locomotion training in the sagittal plane. This study introduces a novel gait rehabilitation system with actuated pelvic motion to generate natural gait motion. The rehabilitation robot developed in this study, COWALK, is a lower-body exoskeleton system with 15 degrees of freedom (DoFs). The COWALK can generate multi-DoF pelvic movement along with leg movements. To produce natural gait patterns, the actuation of pelvic movement is essential. In the COWALK, the pelvic movement mechanism is designed to help hemiplegic patients regain gait balance during gait training. To verify the effectiveness of the developed system, the gait patterns with and without pelvic movement were compared to the normal gait on a treadmill. The experimental results show that the active control of pelvic movement combined with the active control of leg movement can make the gait pattern much more natural., Competing Interests: No potential conflict of interest relevant to this article was reported.

Rapidly aging society faces with increases in neurological disorders including stroke. Hemiplegia, which is one of the common sequelae due to stroke, causes difficulties in activities of daily living. As the number of stroke patients grows, demands for gait training increases, where robotic gait training systems are necessary. A robotic gait training system, called "COWALK-I," is designed to provide pelvic motion on the transverse plane as well as leg motions in the sagittal plane during gait training sessions. The pelvic motion allows weight-shifting as well as more natural gait patterns during gait training. In this research, effect of the pelvic motion during waking in the COWALK-I system is studied. Interaction force between the healthy subjects and the COWALK-I and electromyography(EMG) sensor data are measured. The average interaction forces did not show significant difference while each subject exhibited diverse patterns. The EMG signals shows that more activation of rectus femoris and less activation of gastrocnemius and gluteus medius.

Objective: A detailed knowledge of dysphagia outcomes in lateral medullary infarct (LMI) patients would enable proper establishment of swallowing therapy goals and strategies. However, little is known about the impact of infarct location on dysphagia outcomes in patients with LMI., Methods: Twenty patients with rostral LMI (rostral group) and 20 patients with caudal LMI (caudal group) participated in the study. All patients underwent swallowing therapy, which included compensatory treatments and strengthening exercises, for >3 months. Dysphagia evaluation was performed twice (during the subacute stage and six months after stroke onset) using videofluoroscopic swallowing studies. Dysphagia degree was assessed using the functional dysphagia scale (FDS), the penetration-aspiration scale (PAS) and the American Speech-Language-Hearing Association (ASHA) National Outcome Measurement System (NOMS) swallowing scale., Results: In the subacute stage, the rostral group had significantly higher FDS and PAS scores and a significantly lower ASHA NOMS score than the caudal group. Patients from both groups showed significant improvement from the initial evaluation to the six-month evaluation. There were no significant differences in these scale scores between the two groups at the six-month evaluation., Conclusion: In the subacute stage, patients in the rostral group had more severe dysphagia than those in the caudal group. Dysphagia improved in both groups after 3-6 months of swallowing therapy. At six months after onset, there were no significant differences in dysphagia severity between the two groups. Recovery from dysphagia after LMI was observed regardless of the infarct location.

Objective: To identify possible clinical predictors of intermittent oro-esophageal (OE) tube feeding success, and evaluate the clinical factors associated with OE tube treatment., Methods: A total of 135 dysphagic patients were reviewed, who received OE tube treatment and were hospitalized in the department of rehabilitation medicine between January 2005 and December 2014. The 76 eligible cases enrolled were divided into two groups, based on the OE tube training success. Clinical factors assessed included age, cause of brain lesion, gag reflex, cognitive function and reasons for OE tube training failure., Results: Of the 76 cases enrolled, 56 study patients were assigned to the success group, with the remaining 20 in the failure group. There were significant differences between these two groups in terms of age, gag reflex, ability to follow commands, and the score of Korean version of Mini-Mental Status Examination (K-MMSE). Location of the brain lesion showed a borderline significance. Multivariable analysis using logistic regression revealed that age, cause of brain lesion, gag reflex, and K-MMSE were the main predictors of OE tube training success., Conclusion: A younger age, impaired gag reflex and higher cognitive function (specifically a K-MMSE score ≥19.5) are associated with an increased probability of OE tube training success in dysphagic patients., Competing Interests: CONFLICT OF INTEREST: No potential conflict of interest relevant to this article was reported.

Objective: To investigate a new botulinum neurotoxin type A, termed letibotulinumtoxinA(Botulax ® ) and compare its efficacy and safety for post-stroke upper limb spasticity with that of onabotulinumtoxinA(Botox ® )., Design: A prospective, double-blinded, multicenter, randomized controlled clinical study., Setting: Six university hospitals in Korea., Subjects: A total of 187 stroke participants with upper limb spasticity., Interventions: Two kinds of botulinum neurotoxin type A were used. One set of injection was performed and total injected doses were 309.21±62.48U(Botulax) and 312.64±49.99U(Botox)( P>0.05)., Main Measures: Primary outcome was measured using the modified Ashworth scale for wrist flexors at week 4 and secondary outcome was measured using modified Ashworth scale for wrist flexors, elbow flexors, finger flexors, and thumb flexors as well as Global Assessment in spasticity, Disability Assessment Scale, and Caregiver Burden Scale. Safety measures including adverse events, vital signs and physical examination, and laboratory tests were also monitored., Results: The mean ages for the Botulax group were 56.81±9.49 and which for the Botox group were 56.93±11.93( P>0.05). In primary outcome, the change in modified Ashworth scale for wrist flexors was -1.45±0.61 in the Botulax group and -1.40±0.57 in the Botox group, and the difference between the two groups was -0.06(95% CI:-0.23-0.12, P>0.05). In secondary outcome, both groups demonstrated significant improvements with respect to modified Ashworth scale, Global Assessment in spasticity, Disability Assessment Scale, and Caregiver Burden Scale ( P<0.05), and no significant difference was observed between the two groups ( P>0.05). In addition, safety measures showed no significant differences between the two groups ( P>0.05)., Conclusions: The efficacy and safety of Botulax were comparable with those of Botox in treatment of post-stoke upper limb spasticity.