Safety and efficacy of rimegepant orally disintegrating tablet for the acute treatment of migraine in China and South Korea: a phase 3, double-blind, randomised, placebo-controlled trial.

BACKGROUND: No acute treatments targeting calcitonin gene-related peptide (CGRP) have been approved for use in China or South Korea. We aimed to compare the efficacy and safety of rimegepant-an orally administered small molecule CGRP antagonist-with placebo in the acute treatment of migraine among adults in these countries. METHODS: This double-blind, randomised, placebo-controlled, multicentre phase 3 trial was done at 86 outpatient clinics at hospitals and academic medical centres (73 in China and 13 in South Korea). Participants were adults (≥18 years) with at least a 1-year history of migraine who had two to eight moderate or severe attacks per month and fewer than 15 headache days per month within the 3 months before the screening visit. Participants were randomly assigned (1:1) to 75 mg rimegepant or placebo to treat a single migraine attack of moderate or severe pain intensity. Randomisation was stratified by the use of preventive medication and by country. The allocation sequence was generated and implemented by study personnel using an interactive web-response system accessed online from each study centre. All participants, investigators, and the sponsor were masked to treatment assignment. The coprimary endpoints of freedom from pain and freedom from the most bothersome symptom (nausea, phonophobia, or photophobia) 2 h after dosing were assessed in the modified intention-to-treat (mITT) population (randomly assigned participants who took study medication for a migraine attack of moderate or severe pain intensity, and provided at least one efficacy datapoint after treatment) using Cochran-Mantel Haenszel tests. Safety was assessed in all participants who received rimegepant or placebo. The study is registered with ClinicalTrials.gov, number NCT04574362, and is completed. FINDINGS: 1431 participants were randomly assigned (716 [50%] to rimegepant and 715 [50%] to placebo). 668 (93%) participants in the rimegepant group and 674 (94%) participants in the placebo group received treatment. 1340 participants were included in the mITT analysis (666 [93%] in the rimegepant group and 674 [94%] in the placebo group). 2 h after dosing, rimegepant was superior to placebo for pain freedom (132 [20%] of 666 vs 72 [11%] of 674, risk difference 9·2, 95% CI 5·4-13·0; p<0·0001) and freedom from the most bothersome symptom (336 [50%] of 666 participants vs 241 [36%] of 674 participants, 14·8, 9·6-20·0; p<0·0001). The most common (≥1%) adverse events were protein in urine (8 [1%] of 668 participants in the rimepegant group vs 7 [1%] of 674 participants in the placebo group), nausea (7 [1%] of 668 vs 18 [3%] of 674), and urinary tract infection (5 [1%] of 668 vs 8 [1%] of 674). There were no rimegepant-related serious adverse events. INTERPRETATION: Among adults living in China or South Korea, a single dose of 75 mg rimegepant was effective for the acute treatment of migraine. Safety and tolerability were similar to placebo. Our findings suggest that rimegepant might be a useful new addition to the range of medications for the acute treatment of migraine in China and South Korea, but further studies are needed to support long-term efficacy and safety and to compare rimegepant with other medications for the acute treatment of migraine in this population. FUNDING: BioShin Limited. TRANSLATIONS: For the Chinese and Korean translations of the abstract see Supplementary Materials section.

Surface Analysis of Fermented Wheat and Rice Starch Used for Coating Traditional Korean Textiles.

Wheat and rice starches, traditionally used to stiffen fabric, become less contaminated and more antiseptic after fermentation for several years, thus enhancing their functional activity. In the present study, analytical techniques using particle size analysis, a gloss meter and a colorimeter were used to measure the physical properties of wheat and rice starches that had been fermented for 5 and 7 years, respectively. Their chemical contents and composition were determined by nutrient measurements and time-of-flight secondary ion mass spectrometry (ToF-SIMS). The ToF-SIMS spectra and ion images showed that fermented starch contained more carbohydrate and less lipid than fresh starch. The surface morphologies of the fermented starch granules and starch-coated textiles were examined by scanning electron microscopy and compared with the surface morphologies of fresh starch granules. The fermented wheat and rice starch granules were smaller and more rounded with a lower level of N-containing compounds (proteins) and exhibited more antiseptic properties than fresh starch granules. The results showed that physical measurements and chemical analysis were simple and complementary techniques for investigating traditional Korean starch materials and textiles.

Altered insular functional connectivity in isolated REM sleep behavior disorder: a data-driven functional MRI study.

OBJECTIVE: Functional connectivity (FC) changes can occur prior to structural changes. This study aimed to evaluate data-driven whole-brain FC associated with isolated rapid eye movement sleep behavior disorder (iRBD) using multivariate pattern analysis (MVPA). METHODS: This was a cross-sectional study of 50 polysomnography-confirmed iRBD patients and 20 age- and sex-matched controls. We used MVPA implemented in the connectome-MVPA CONN toolbox to identify data-driven seed regions for post hoc seed-to-voxel connectivity analysis. The association between FC changes and clinical characteristics, including cognition, depression, autonomic function, and daytime sleepiness, was evaluated. RESULTS: MVPA revealed one significant cluster located in the left posterior insular cortex. Seed-to-voxel FC analysis using the cluster as a seed showed significantly reduced FC with two clusters located in the precuneus in iRBD patients compared to the controls. The degree of FC was associated with the Montreal Cognitive Assessment-Korean version scores (r = 0.317, p = 0.025). CONCLUSION: This study emphasizes the insula as an important neural correlate associated with iRBD that was associated with cognitive function.

Proximal Junctional Kyphosis in Degenerative Sagittal Deformity After Under- and Overcorrection of Lumbar Lordosis: Does Overcorrection of Lumbar Lordosis Instigate PJK?

STUDY DESIGN: Retrospective study. OBJECTIVE: To analyze proximal junctional kyphosis (PJK) occurrence and surgical outcomes according to degree of lumbar lordosis (LL) correction relative to pelvic incidence (PI). In addition, risk factors of PJK including LL and sagittal vertical axis (SVA) correction were investigated. SUMMARY OF BACKGROUND DATA: PJK is a common complication after adult spinal deformity surgery, and many factors are known to be associated with PJK. However, the effect of degree of LL correction on PJK occurrence is not fully understood. METHODS: Eighty-three degenerative sagittal imbalance patients treated with deformity correction and long instrumented fusion to the sacrum with a minimum follow-up of 2 years were studied. Patients were divided into three groups according to their postoperative LL angle relative to PI using the SRS-Schwab classification: Group A (undercorrection, PI-LL> 10°), Group B (ideal correction, -10°

Structural homogeneity and mass density of bulk metallic glasses revealed by their rough surfaces and ultra-small angle neutron scattering (USANS).

The ultra-small angle neutron scattering (USANS) measures the microscale structure of heterogeneity and the scattering from rough surfaces with small scattering volumes can be neglected. But this is not true in amorphous alloys. The small angle scattering from such surfaces is not negligible, regardless of scattering volume. However, we demonstrate that the unwanted rough surfaces can be utilized to determine the homogeneity and mass density of amorphous metallic glasses using the USANS and surface neutron contrast matching technique. The power law scattering of the homogeneous Cu50Zr50 amorphous alloy disappeared under the surface contrast-matched environment, a mixture of hydrogenated/deuterated ethanol having low surface tension against the metallic alloys, indicating that the scattering originated not from its internal structure but from the rough surface. This confirms the structural homogeneity not only at the atomic level but also on a larger scale of micrometer. On the other hand, the crystallized Cu50Zr50 alloy showed strong power-law scattering under the matching environment due to the structural heterogeneity inside the alloy. This technique can apply to the bulk samples when the transmission is high enough not causing multiple scattering that is easily detected with USANS and when the surface roughness is dominant source of scattering.

Reduced P300 amplitude during a visuospatial attention task in idiopathic rapid eye movement sleep behavior disorder.

OBJECTIVES: Idiopathic rapid eye movement sleep behavior disorder (IRBD) patients are prone to cognitive deficits, which include attention, executive, and visuospatial dysfunctions. Even patients with normal cognition may exhibit subclinical electrophysiological dysfunction. This study aimed to evaluate visuospatial attention processing in IRBD patients with normal cognition and to compare their findings with those of age- and sex-matched healthy controls. METHODS: We recorded event-related potentials (ERPs) and performance measures during a variant of the Posner task in 14 IRBD patients and 14 control subjects. Behavioral data and the mean P300 amplitude were compared between groups. RESULTS: No group difference was found for reaction time or accuracy, but a significant group effect was observed for the P300 amplitude. IRBD patients had reduced P300 amplitude (µV) than controls in both valid (IRBD: 0.53 ± 1.05 vs Controls: 1.61 ± 0.95; p = 0.008) and invalid (IRBD: 0.74 ± 0.99 vs Controls: 1.73 ± 0.86; p = 0.009) conditions. The P300 amplitude was correlated with Montreal cognitive assessment (MOCA) scores (r = 0.424, p = 0.024). CONCLUSION: Reduced P300 amplitude during the Posner task provides electrophysiological evidence for subclinical visuospatial attention deficits in cognitively normal IRBD patients. The results of this study imply that cortical dysfunction is already present in patients with IRBD in their early disease stage.

Understanding dual precipitation strengthening in ultra-high strength low carbon steel containing nano-sized copper precipitates and carbides.

Low carbon ferritic steel alloyed with Ti, Mo and Cu was hot rolled and interrupt cooled to produce nano-sized precipitates of copper and (Ti,Mo)C carbides. The steel had a tensile strength of 840 MPa, an increase in yield strength of 380 MPa over that of the plain carbon steel and reasonable ductility. Transmission electron microscopy and small angle neutron scattering were used to characterize size and volume fraction of the precipitates in the steels designed to form only copper precipitates and only (Ti,Mo)C carbides. The individual and combined precipitation strengthening contributions was calculated using the size and volume fraction of precipitates and compared with the measured values.

The effect of solvents and hydrophilic additive on stable coating and controllable sirolimus release system for drug-eluting stent.

Various drug-eluting stents (DESs) have been developed to prevent restenosis after stent implantation. However, DES still needs to improve the drug-in-polymer coating stability and control of drug release for effective clinical treatment. In this study, the cobalt-chromium (CoCr) alloy surface was coated with biodegradable poly(D,L-lactide) (PDLLA) and sirolimus (SRL) mixed with hydrophilic Pluronic F127 additive by using ultrasonic spray coating system in order to achieve a stable coating surface and control SRL release. The degradation of PDLLA/SRL coating was studied under physiological solution. It was found that adding F127 reduced the degradation of PDLLA and improved the coating stability during 60days. The effects of organic solvent such as chloroform and tetrahydrofuran (THF) on the coating uniformity were also examined. It was revealed that THF produced a very smooth and uniform coating compared to chloroform. The patterns of in vitro drug release according to the type of organic solvent and hydrophilic additive proposed the possibility of controllable drug release design in DES. It was found that using F127 the drug release was sustained regardless of the organic solvent used. In addition, THF was able to get faster and controlled release profile when compared to chloroform. The structure of SRL molecules in different organic solvents was investigated using ultra-small angle neutron scattering. Furthermore, the structure of SRL is concentration-dependent in chloroform with tight nature under high concentration, but concentration-independent in THF. These results strongly demonstrated that coating stability and drug release patterns can be changed by physicochemical properties of various parameters such as organic solvents, additive, and coating strategy.

Erratum to: Understanding dual precipitation strengthening in ultra-high strength low carbon steel containing nano-sized copper precipitates and carbides.

[This corrects the article DOI: 10.1186/s40580-017-0110-5.].

Assessment of the C1 Lateral Mass Screw Trajectory and Position Using Plain Radiographs: A Comparison With Computed Tomography.

STUDY DESIGN: A prospective study. OBJECTIVE: The aim of this study was to provide methods for predicting ideal trajectory and position of C1 lateral mass screw (C1LMS) from plain radiographs. SUMMARY OF BACKGROUND DATA: There has been no study on prediction of C1LMS position using plain radiographs. METHODS: A total of 40 consecutive subjects (with 79 screws) who had undergone C1LMS placement were enrolled. To evaluate the C1LMS position, the positions of screw head and tips on anteroposterior radiographs, screw length, and height on lateral radiograph were graded as 0, I, and II, respectively. On the postoperative computed tomography images, we analyzed lateral mass (LM) perforation, screw-thread engagement percent (%), bicortical fixation, extruded screw length, and violation of adjacent joints. RESULTS: Screws with tip located medial to LM (tip 0) showed LM perforation in all cases. Polyaxial head located within the LM (head 0) or crossing the lateral margin of the LM (head I) showed no LM perforation. Screw-thread engagement percent was the highest with head I-tip I (medial half of LM) position (97.6%), followed by head 0-tip I (90.5%) and head I-tip II (lateral half of LM) (86.4%). Screws longer than the posterior half of C1 anterior arch (AA) showed bicortical fixation in all cases with mean extruded screw length of 1.9 mm. Adjacent joint was not violated in 98%, with the screw height below half of C1AA. CONCLUSIONS: On an anteroposterior radiograph, a C1LMS with the screw head located on the lateral margin of the LM and with the screw tip in the medial half of the LM resulted in the safest and longest trajectory. On lateral radiograph, a screw tip that is placed within the anterior-inferior quadrant of the C1AA results in safe bicortical fixation without injury to the adjacent structures. These plain radiographic findings may be helpful both postoperatively and intraoperatively for assessing the trajectory and length of the screw.

Aspiration pneumonia caused by fentanyl-induced cough -a case report-.

Although fentanyl-induced cough is generally transient and benign, it can give rise to serious problems in patients to whom increasing intracranial, intraocular or intraabdominal pressures may create dangerous situations. This case demonstrates aspiration pneumonia as a complication, exhibiting severe cough induced by intravenous injection of fentanyl.

Tapia's syndrome following cervical laminoplasty -A case report-.

Tapia's syndrome is the palsy of the 10th and 12th cranial nerves, resulting in ipsilateral paralysis of the vocal cord and tongue. It is a rare complication which is related to the anesthetic airway management and positioning of the patient's head during the surgery. We describe a patient with a postoperative unilateral Tapia's syndrome, after general anesthesia, with uncomplicated endotracheal intubation. The patient's symptoms improved gradually for three months.

Decreased Metabolism in the Cerebral Cortex in Early-Stage Huntington's Disease: A Possible Biomarker of Disease Progression?

BACKGROUND AND PURPOSE: Huntington's disease (HD) is an autosomal-dominant inherited neurodegenerative disorder. Genetic analysis of abnormal CAG expansion in the IT15 gene allows disease confirmation even in the preclinical stage. However, because there is no treatment to cure or delay the progression of this disease, monitoring of biological markers that predict progression is warranted. METHODS: FDG-PET was applied to 13 patients with genetically confirmed HD in the early stage of the disease. We recorded the initial and follow-up statuses of patients using the Independence Scale (IS) of the Unified Huntington's Disease Rating Scale. The progression rate (PR) was calculated as the annual change in the IS. The patients were divided into two groups with faster and slower progression, using the median value of the PR as the cut-off. FDG-PET data were analyzed using regions of interest, and compared among the two patient groups and 11 age- and sex-matched controls. RESULTS: The mean CAG repeat size in patients was 44.7. The CAG repeat length was inversely correlated with the age at onset as reported previously, but was not correlated with the clinical PR. Compared with normal controls, hypometabolism was observed even at very early stages of the disease in the bilateral frontal, temporal, and parietal cortices on FDG-PET. The decreases in metabolism in the bilateral frontal, parietal, and right temporal cortices were much greater in the faster-progression group than in the slower-progression group. CONCLUSIONS: A decrease in cortical glucose metabolism is suggested as a predictor for identifying a more rapid form of progression in patients with early-stage HD.

Does cast immobilization contribute to posterior stability after posterior cruciate ligament reconstruction?

PURPOSE: The purpose of this study was to confirm the contribution of long leg cast immobilization to posterior stability after reconstruction of isolated posterior cruciate ligament (PCL) injuries. METHODS: Of 84 patients who underwent arthroscopic PCL reconstruction between November 2006 and December 2009, 44 patients were randomly assigned to 2 groups and analyzed prospectively. For 22 patients (the cast group), long leg cast immobilization was applied until postoperative week 5 and then a 0° locking brace was worn until week 12. Full weight bearing was allowed immediately after operation. For the other 22 patients (the brace group), only a 0° locking brace was applied until postoperative week 12 without cast immobilization. Range of motion (ROM), clinical scores, Telos device (Telos, Marburg, Germany) posterior stress radiographic assessment results and International Knee Documentation Committee (IKDC) grades of both groups were analyzed preoperatively and at postoperative years 1 and 2. RESULTS: The mean preoperative side-to-side difference on Telos posterior stress radiographs was 11.3 ± 2.5 mm in the cast group and 12.7 ± 2.1 mm in the brace group, revealing no differences between the 2 groups (P = .743), but postoperatively the mean difference measured 2.5 ± 1.9 mm and 4.8 ± 2.4 mm, respectively, showing a significantly smaller difference in the cast group (P = .004); the improvement was 8.8 mm and 7.9 mm, respectively, and was statistically significant (P = .021). Preoperative IKDC grades were not different between the 2 groups (P > .05), but 2 years postoperatively, the cast group showed a significantly better distribution of grades (P = .012). The mean ROM, Lysholm scores, IKDC subjective scores, and Tegner scores 2 years postoperatively were not significantly different between the 2 groups (P > .05). CONCLUSIONS: The patients immobilized with long leg casts until 5 weeks after PCL reconstruction showed significantly better results in Telos posterior stress radiographs and distribution of IKDC grades 2 years postoperatively and did not show limited ROM when compared with the patients who wore braces only. However, IKDC subjective scores were not found to be different between the 2 groups. LEVEL OF EVIDENCE: Level I, prospective randomized comparative study.

Normokalemic periodic paralysis is not a distinct disease.

INTRODUCTION: Recent molecular studies of the original cases of normokalemic periodic paralysis (normoKPP) have raised suspicions that these families actually had hyperkalemic periodic paralysis (hyperKPP) due to mutations in the skeletal muscle sodium channel gene SCN4A. However, there is still a debate about the existence of normoKPP. METHODS: We screened 230 individuals with primary periodic paralysis for mutations in the SCN4A, CACNA1S, and KCNJ2 genes. All patients had either a hyperKPP or a hypoKPP phenotype, and none had a normoKPP phenotype. RESULTS: In 4 hyperKPP patients from 2 families, molecular analyses revealed Arg675Gly and Arg675Gln mutations of SCN4A, which were previously reported to cause normoKPP. Each patient exhibited the characteristic clinical and laboratory features (including hyperkalemia during spontaneous attacks) of hyperKPP. CONCLUSION: Our findings support the notion that normoKPP is not a distinct disease.

A sterile-freehand reduction technique for corrective osteotomy of fixed cervical kyphosis.

STUDY DESIGN: A technical note and a retrospective review of cervical osteotomy using an innovative reduction technique. OBJECTIVE: To present the clinical and radiological outcomes and effectiveness of the sterile-freehand reduction technique for cervical osteotomy. SUMMARY OF BACKGROUD DATA: For a successful osteotomy, controlled reduction of deformity after complete release of bony deformity is the most critical step. Conventional "unscrubbed-scrubbed" manual reduction techniques necessitate multiple releases and retightening of the clamp and are inconvenient for the surgeon to control the force and monitor the surgical field closely. METHODS: A total of 7 consecutive patients (5 male and 2 female; mean age, 52.6 yr) who underwent corrective osteotomy of the fixed cervical kyphosis by a single surgeon were enrolled. Radiographically, C2-C7 sagittal and coronal angle, and the chin-brow vertical angle were measured. In the prone position, the entire head and the Gardner-Wells tong were included in the surgical field, and a sterile rope was connected to a weight through a hole made in the surgical drape. After complete release of bony element and fixation of the caudal part of osteotomy with a prebent lordotic rod, the operator held the tong with right hand and gradually reduced the deformity to place the rod within the screw heads on the cranial part of osteotomy under close visual observation, with the support of the caudal part with left hand. RESULTS.: The type of osteotomy performed was pedicle-subtraction osteotomy in 5 cases and anterior-release-posterior osteotomy in 2 cases. The mean correction angle was 39.7° (28°-63°) on the sagittal plane and 9.3° (0°-16°) on the coronal plane. The mean correction of the chin-brow vertical angle was 37.1° (18°-61°). There was no neurovascular complication. CONCLUSION: Using the sterile-freehand reduction technique, the operator can obtain a safe, controlled reduction with close monitoring of the surgical field. The technique is potentially a simple and effective method to provide stable, 3-dimensional reduction for corrective osteotomies of the cervical spine.

A case of rheumatoid meningitis: pathologic and magnetic resonance imaging findings.

Central nervous system (CNS) involvement is extremely rare in patients with rheumatoid arthritis (RA). Additionally, most patients with CNS involvement have chronic and severe RA. We present a report of a 66-year-old man who was diagnosed with rheumatoid meningitis and CNS vasculitis without a history of RA. His initial symptom was seizure. Brain magnetic resonance imaging showed leptomeningeal enhancement.CSF analysis revealed slight increase in the number of white blood cells. An examination of viral markers and culture studies for infectious etiology were unremarkable. However, the rheumatoid factor was positive and the levels of anti-cyclic citrullinated peptide antibody were very high. The patient was diagnosed with rheumatoid meningitis and received steroid therapy. However, he developed CNS vasculitis. We suggested that the possibility of rheumatoid meningitis should be considered during the differential diagnosis stage in patients with uncontrolled meningitis, even though RA does not typically show CNS involvement.

Inappropriate elevation of bispectral index values in robot assisted thyroidectomy with electromyographic endotracheal tube -A case report-.

We report a case of an erroneously elevated bispectral index (BIS) during robot assisted thyroidectomy using an electromyographic endotracheal tube (EMG tube), which is safe and useful for laryngeal electromyographic monitoring. Ten minutes after start of the operation, a sudden increase of BIS value up to 98 was noticed. The BIS values were not decreased to < 65 with supplemental anesthetics. The anesthetic method was changed from total intravenous anesthesia to balanced anesthesia. The BIS sensor and monitor were changed and other models were used. These interventions did not alter BIS values. BIS levels remained between 60 and 70 throughout the main procedure and intermittently increased to the mid-90s without any trace of poor signal quality. At the end of the surgery, the BIS values returned to normal range. The patient did not complain of intraoperative recall. Knowledge of potential interference from the use of an EMG tube must be considered when interpreting BIS.

Functional and histologic changes after repeated transcranial direct current stimulation in rat stroke model.

Transcranial direct current stimulation (tDCS) is associated with enhancement or weakening of the NMDA receptor activity and change of the cortical blood flow. Therefore, repeated tDCS of the brain with cerebrovascular injury will induce the functional and histologic changes. Sixty-one Sprague-Dawley rats with cerebrovascular injury were used. Twenty rats died during the experimental course. The 41 rats that survived were allocated to the exercise group, the anodal stimulation group, the cathodal stimulation group, or the control group according to the initial motor function. Two-week treatment schedules started from 2 days postoperatively. Garcia, modified foot fault, and rota-rod performance scores were checked at 2, 9, and 16 days postoperatively. After the experiments, rats were sacrificed for the evaluation of histologic changes (changes of the white matter axon and infarct volume). The anodal stimulation and exercise groups showed improvement of Garcia's and modified foot fault scores at 16 days postoperatively. No significant change of the infarct volume happened after exercise and tDCS. Neuronal axons at the internal capsule of infarct hemispheres showed better preserved axons in the anodal stimulation group. From these results, repeated tDCS might have a neuroprotective effect on neuronal axons in rat stroke model.

Novel compound heterozygous mutations of the SPG11 gene in Korean families with hereditary spastic paraplegia with thin corpus callosum.

Hereditary spastic paraplegia with thin corpus callosum (HSP-TCC) is one of the most common complicated forms of autosomal recessive hereditary spastic paraplegia (HSP). Mutation in SPG11 gene, which is mapped to chromosome 15q21, was recently found to be a major cause of this variant form of HSP. The aim of this study is to investigate SPG11 mutations and clinical manifestations in two Korean families with HSP-TCC. Direct sequencing of the 40 coding exons and boundaries of exon-intron in SPG11 gene, and descriptions of clinical findings in two nonconsanguineous families with HSP-TCC are presented. Three novel and one known compound heterozygous mutations were found in two affected families, which were not found in controls, including one deletion in exon (c.5410_5411delTG), two insertions (c.1834_1835InsT and c.2163_2164InsT), and one missense mutation (c.3291+1G>T). Both of our patients had impairments in frontal lobe functions. We present the first SPG11 mutations in Korean families, three of which are novel. SPG11 mutation should be suspected in Korean patients having HSP with TCC and executive dysfunction.