Unique Binding Sites of Uricosuric Agent Dotinurad for Selective Inhibition of Renal Uric Acid Reabsorptive Transporter URAT1.

Dotinurad was developed as a uricosuric agent, inhibiting urate (UA) reabsorption through the UA transporter URAT1 in the kidneys. Due to its high selectivity for URAT1 among renal UA transporters, we investigated the mechanism underlying this selectivity by identifying dotinurad binding sites specific to URAT1. Dotinurad was docked to URAT1 using AutoDock4, utilizing the AlphaFold2-predicted structure. The inhibitory effects of dotinurad on wild-type and mutated URAT1 at the predicted binding sites were assessed through URAT1-mediated [14C]UA uptake in Xenopus oocytes. Nine amino acid residues in URAT1 were identified as dotinurad-binding sites. Sequence alignment with UA-transporting organic anion transporters (OATs) revealed that H142 and R487 were unique to URAT1 among renal UA-transporting OATs. For H142, IC50 values of dotinurad increased to 62, 55, and 76 nM for mutated URAT1 (H142A, H142E, and H142R, respectively) compared with 19 nM for the wild type, indicating that H142 contributes to URAT1-selective interaction with dotinurad. H142 was predicted to interact with the phenyl-hydroxyl group of dotinurad. The IC50 of the hydroxyl group methylated dotinurad (F13141) was 165 µM, 8420-fold higher than dotinurad, suggesting the interaction of H142 and the phenyl-hydroxyl group by forming a hydrogen bond. Regarding R487, URAT1-R487A exhibited a loss of activity. Interestingly, the URAT1-H142A/R487A double mutant restored UA transport activity, with the IC50 value of dotinurad for the mutant (388 nM) significantly higher than that for H142A (73.5 nM). These results demonstrate that H142 and R487 of URAT1 determine its selectivity for dotinurad, a uniqueness observed only in URAT1 among UA-transporting OATs. SIGNIFICANCE STATEMENT: Dotinurad selectively inhibits the urate reabsorption transporter URAT1 in renal urate-transporting organic ion transporters (OATs). This study demonstrates that dotinurad interacts with H142 and R487 of URAT1, located in the extracellular domain and unique among OATs when aligning amino acid sequences. Mutations in these residues reduce affinity of dotinurad for URAT1, confirming their role in conferring selective inhibition. Additionally, the interaction between dotinurad and URAT1 involving H142 is found to mediate hydrogen bonding.

Real-world experience with calcitonin gene-related peptide-targeted antibodies for migraine prevention: a retrospective observational cohort study at two Japanese headache centers.

BACKGROUND: Although randomized controlled trials (RCTs) have shown that calcitonin gene-related peptide (CGRP)-targeted monoclonal antibodies (CGRP mAbs) are an efficacious and safe therapeutic modality for migraine prevention, their clinical benefits have not been well validated in Japanese patients in the real-world setting. The present study aimed to evaluate the real-world efficacy and safety of galcanezumab, fremanezumab, and erenumab in Japanese patients with migraine. METHODS: This observational retrospective cohort study was conducted at two headache centers in Japan. Patients with migraine who had experienced treatment failure with at least one traditional oral migraine preventive agent were treated with a CGRP mAb de novo. The primary efficacy endpoints were the changes from baseline in monthly migraine days (MMDs) and Headache Impact Test-6 (HIT-6) score after 3 dosing intervals (V3). We explored whether demographic and clinical characteristics predicted therapeutic outcomes at V3. RESULTS: Sixty-eight patients who completed three doses of a CGRP mAb (85.3% female [58/68], mean age: 46.2 ± 13.1 years) were included in the analysis. There were 19 patients with chronic migraine. The baseline MMDs were 13.4 ± 6.0. After 3 doses, the MMDs significantly decreased to 7.4 ± 5.5 (p < 0.0001), and the 50% response rate was 50.0%. HIT-6 score was significantly reduced from 66.7 ± 5.4 to 56.2 ± 8.7 after 3 doses (P = 0.0001). There was a positive correlation between the changes in MMDs and HIT-6 score from baseline after 2 doses (p = 0.0189). Those who achieved a ≥ 50% therapeutic response after the first and second doses were significantly more likely to do so at V3 (crude odds ratio: 3.474 [95% CI: 1.037 to 10.4], p = 0.0467). The most frequent adverse event was constipation (7.4%). None of the adverse events were serious, and there was no need for treatment discontinuation. CONCLUSIONS: This real-world study demonstrated that CGRP mAbs conferred Japanese patients with efficacious and safe migraine prevention, and an initial positive therapeutic response was predictive of subsequent favorable outcomes. Concomitant measurement of MMDs and HIT-6 score was useful in evaluating the efficacy of CGRP mAbs in migraine prevention.

Potentiation of the Uricosuric Effect of Dotinurad by Trans-Inhibition of the Uric Acid Reabsorptive Transporter 1.

Urate transporter 1 (URAT1) is a transporter responsible for uric acid (UA) reabsorption by renal proximal tubules and a pharmacological target of uricosuric agents. Probenecid and benzbromarone have been used as uricosuric agents, while dotinurad was recently approved in Japan. Notably, the in vitro IC 50 of dotinurad on URAT1 is not strong enough to explain its in vivo uricosuric effect estimated based on clinical unbound plasma concentrations, suggesting the presence of mechanisms other than competition with UA uptake at the extracellular domain of URAT1 (cis-inhibition). In this study, trans-inhibition was hypothesized as the mechanism underlying URAT1 inhibition by dotinurad, wherein intracellularly accumulated dotinurad inactivates URAT1. In URAT1-expressing Madin-Darby Canine Kidney-II cells and Xenopus oocytes, pre-incubation with dotinurad potentiated the inhibitory effect more than co-incubation alone, but this effect was not observed with benzbromarone or probenecid. Under co-incubation, dotinurad inhibited UA uptake in a competitive manner (cis-inhibition). When we pre-injected dotinurad directly into oocytes and immediately measured [14C]UA uptake without coincubation (only trans-inhibition), dotinurad noncompetitively inhibited UA uptake. URAT1 is an exchange transporter for UA and monocarboxylates such as nicotinic acid (NA). Pre-injected dotinurad and extracellular UA attenuated and facilitated efflux of [3H]NA, respectively, whereas pre-injection of benzbromarone or probenecid did not affect it, suggesting that dotinurad exhibits trans-inhibition by attenuating URAT1-mediated efflux of monocarboxylates, which is a driving force for UA uptake by URAT1. Accordingly, dotinurad ameliorates URAT1-mediated UA reabsorption by both cis- and trans-inhibition, explaining its clinically stronger uricosuric effect than that estimated by the in vitro IC50 value. SIGNIFICANCE STATEMENT: The uricosuric agent dotinurad inhibits uric acid reabsorptive transporter (URAT) 1 with a clinical potency stronger than that estimated from IC 50 obtained by in vitro URAT1 inhibition. This in vivo-in vitro discrepancy was explained by the trans-inhibition effect of dotinurad on URAT1. Trans-inhibition was due to the attenuation of monocarboxylates efflux via URAT1, which is a driving force for URAT1-mediated exchange transport of uric acid. Overall, this is the first study to experimentally demonstrate trans-inhibition mechanism of URAT1.

Cytological examination of peripheral blood cell block to diagnose small cell variant ALK-positive anaplastic large cell lymphoma.

In small cell variant ALK-positive anaplastic large cell lymphoma (SC-ALCL), large hallmark cells are few and the preponderance are small- to medium-sized tumour cells. The cell block method is advantageous in SC-ALCL with small numbers of CD30-positive hallmark cells, in order to evaluate cell morphology and marker expression simultaneously. Accurate diagnosis of ALK-positive anaplastic large cell lymphoma (ALK+ ALCL) requires detection of CD30-positive hallmark cells. In small cell variant ALCL (SC-ALCL), large hallmark cells are few with the preponderance being small- to medium-sized tumour cells. The cell block method is advantageous in SC-ALCL with small numbers of CD30-positive hallmark cells in order to evaluate cell morphology and marker expression simultaneously.

Effects of increasing non-paretic step length on paretic leg movement during hemiparetic gait: a pilot study.

[Purpose] Gait training that increases non-paretic step length in stroke patients increases the propulsive force of the paretic leg. However, it limits knee flexion during the swing phase of gait, and this may cause gait disturbances such as worsening of gait pattern and increased risk of falling. Therefore, this study aimed to investigate the effects of increasing non-paretic step length on the joint movement and muscle activity of a paretic lower limb during hemiparetic gait. [Participants and Methods] A total of 15 hemiparetic patients with chronic stroke were enrolled in this study. Spatiotemporal parameters, along with kinematic and electromyography data of their paretic lower limbs, were measured during a 10-m distance overground walking. Two walking conditions were assessed: normal (comfortable gait) and non-paretic-long (gait with increased non-paretic step length) conditions. [Results] Under the non-paretic-long condition, the trailing limb angle was larger than under the normal condition. However, no significant difference was observed in the knee flexion angle during the swing phase. [Conclusion] Increasing non-paretic step length during gait is unlikely to limit knee flexion during the swing phase and can safely improve the propulsive force of a paretic leg.

[Association between locomotive syndrome and cognitive decline in community-dwelling older adults].

Objectives　Cognitive function is an important component of health and quality of life in older adults. Locomotive syndrome (LS) is associated with cognitive decline, but this has not been sufficiently shown. Therefore, the purpose of this study was to determine the association between LS and cognitive decline in community-dwelling older adults.Methods　Study participants were 3,751 community-dwelling elderly people (1,914 men and 1,837 women; mean age 71.9±5.7 years) who completed the 25-question Geriatric Locomotive Function Scale (GLFS-25) and the Kihon Checklist administered by the local government in Japan between 2014 and 2016. LS stage was assessed using the total score from the GLFS-25 (non-LS: a score of ≤6, Stage 1: a score of ≥7, and Stage 2: a score of ≥16). The risk of cognitive decline was assessed by the applicable number of 3 cognitive-related items on the Kihon Checklist (mild decline: applicable number ≥1, moderate decline: applicable number ≥2). Multinomial logistic regression analysis adjusted for age, BMI, nutritional status, oral function, and homebound status was used to calculate the odds ratios (ORs) of the LS stage for the risk of cognitive decline.Results　In the multinomial logistic regression model, participants in both stages 1 and 2 of LS had significantly higher ORs for mild cognitive decline than those without LS in men and women. Similar results were observed with moderate cognitive decline. The ORs of LS stages for moderate cognitive decline were as follows: in the multinomial logistic regression model, OR was 1.65 (95% CI, 0.97-2.81) in stage 1 of LS and 2.99 (95% CI, 1.56-5.73) in stage 2 of LS in men (P<0.001), and OR was 1.97 (95%CI, 1.11-3.50) in LS stage 1 and 2.43 (95% CI, 1.14-5.19) in stage 2 of LS in women (P<0.01).Conclusion　This study showed that LS stage had a significant positive association with the decline in cognitive function in older adults and it was more remarkable in cases of increased cognitive decline. Our results suggest that LS might be an independent factor of cognitive decline in community-dwelling elderly people. A longitudinal survey is needed to clarify the association between LS and cognitive function.

Design of Surfactant Tails for Effective Surface Tension Reduction and Micellization in Water and/or Supercritical CO2.

The interfacial properties and water-in-CO2 (W/CO2) microemulsion (µE) formation with double- and novel triple-tail surfactants bearing trimethylsilyl (TMS) groups in the tails are investigated. Comparisons of these properties are made with those for analogous hydrocarbon (HC) and fluorocarbon (FC) tail surfactants. Surface tension measurements allowed for critical micelle concentrations (CMC) and surface tensions at the CMC (γCMC) to be determined, resulting in the following trend in surface activity FC > TMS > HC. Addition of a third surfactant tail gave rise to increased surface activity, and very low γCMC values were recorded for the double/triple-tail TMS and HC surfactants. Comparing effective tail group densities (ρlayer) of the respective surfactants allowed for an understanding of how γCMC is affected by both the number of surfactant tails and the chemistry of the tails. These results highlight the important role of tail group chemical structure on ρlayer for double-tail surfactants. For triple-tail surfactants, however, the degree to which ρlayer is affected by tail group architecture is harder to discern due to formation of highly dense layers. Stable W/CO2 µEs were formed by both the double- and the triple-tail TMS surfactants. High-pressure small-angle neutron scattering (HP-SANS) has been used to characterize the nanostructures of W/CO2 µEs formed by the double- and triple-tail surfactants, and at constant pressure and temperature, the aqueous cores of the microemulsions were found to swell with increasing water-to-surfactant ratio (W0). A maximum W0 value of 25 was recorded for the triple-tail TMS surfactant, which is very rare for nonfluorinated surfactants. These data therefore highlight important parameters required to design fluorine-free environmentally responsible surfactants for stabilizing W/CO2 µEs.

Pedaling improves gait ability of hemiparetic patients with stiff-knee gait: fall prevention during gait.

BACKGROUND AND PURPOSE: Stiff-knee gait, which is a gait abnormality observed after stroke, is characterized by decreased knee flexion angles during the swing phase, and it contributes to a decline in gait ability. This study aimed to identify the immediate effects of pedaling exercises on stiff-knee gait from a kinesiophysiological perspective. METHODS: Twenty-one patients with chronic post-stroke hemiparesis and stiff-knee gait were randomly assigned to a pedaling group and a walking group. An ergometer was set at a load of 5 Nm and rotation speed of 40 rpm, and gait was performed at a comfortable speed; both the groups performed the intervention for 10 min. Kinematic and electromyographical data while walking on flat surfaces were immediately measured before and after the intervention. RESULTS: In the pedaling group, activity of the rectus femoris significantly decreased from the pre-swing phase to the early swing phase during gait after the intervention. Flexion angles and flexion angular velocities of the knee and hip joints significantly increased during the same period. The pedaling group showed increased step length on the paralyzed side and gait velocity. CONCLUSIONS: Pedaling increases knee flexion during the swing phase in hemiparetic patients with stiff-knee gait and improves gait ability.

Contribution of muscle activity at different gait phases for improving walking performance in chronic stroke patients with hemiparesis.

[Purpose] The aim of this study was to clarify the optimal timing for increasing muscle activity in the paralyzed lower limb of stroke survivors by evaluating the relationship between gait muscle activity patterns and gait parameters. [Participants and Methods] Electromyography of the tibialis anterior, soleus, rectus femoris, and biceps femoris on the paralyzed side and spatiotemporal gait parameters were evaluated in 40 chronic post-stroke patients as they walked at a comfortable speed. The normalized average amplitude and asymmetry indexes of each gait phase were calculated. The correlations between gait velocity or asymmetry indexes and the activity amplitudes of various muscles during each gait phase were analyzed. Multiple regression analysis was performed with gait velocity or asymmetry indexes as the response variable and the muscle activity amplitudes in the various gait phases as explanatory variables. [Results] The major determinants of gait velocity were the tibialis anterior activity (ß=-0.35) and biceps femoris activity (ß=0.45) during the swing phase. In addition, the biceps femoris activity during the swing phase was the major determinant of the asymmetry index for the swing phase duration (ß=-0.41). [Conclusion] For patients with hemiparesis, increasing the biceps femoris activity during the swing phase is considered optimal, which may lead to improvement in walking performance.

Is it safe to control the car pedal with the lower limb of the unaffected side in patients with stroke?

OBJECTIVES: Few studies have examined motor function in determining the suitability of patients with stroke to resume driving a car. Patients with hemiplegia usually control car pedals with the unaffected lower limb. However, motor control on the unaffected side is also impaired in patients with stroke. This study aimed to clarify the neurophysiological characteristics of pedal switching control during emergency braking in patients with hemiplegia. METHODS: The study participants consisted of 10 drivers with left hemiplegia and 10 age-matched healthy drivers. An experimental pedal was used to measure muscle activity and kinematic data during braking, triggered by the light from a light-emitting diode placed in front of the drivers. RESULTS: The patient group took the same reaction time as the healthy group. However, from the visual stimulus to the release of the accelerator pedal, the patient group had higher muscle activity in the tibialis anterior and rectus femoris and had faster angular velocities of hip and knee flexion than the healthy group. In addition, the patient group had higher co-contraction activities between flexors and extensors. From the accelerator pedal release to brake contact, the patient group had slower angular velocities of hip adduction, internal rotation, ankle dorsiflexion, internal return, and internal rotation than the healthy group. CONCLUSIONS: Patients with hemiplegia exhibited poor control of pedal switching using their unaffected side throughout the pedal-switching task. These results indicate that the safety related to car-pedal control should be carefully evaluated while deciding whether a patient can resume driving a car after a stroke.

Role of Organic Anion Transporter NPT4 in Renal Handling of Uremic Toxin 3-indoxyl Sulfate.

Sodium-phosphate transporter NPT4 (SLC17A3) is a membrane transporter for organic anionic compounds localized on the apical membranes of kidney proximal tubular epithelial cells and plays a role in the urinary excretion of organic anionic compounds. However, its physiological role has not been sufficiently elucidated because its substrate specificity is yet to be determined. The present study aimed to comprehensively explore the physiological substrates of NPT4 in newly developed Slc17a3-/- mice using a metabolomic approach. Metabolomic analysis showed that the plasma concentrations of 11 biological substances, including 3-indoxyl sulfate, were more than two-fold higher in Slc17a3-/- mice than in wild-type mice. Moreover, urinary excretion of 3-indoxyl sulfate was reduced in Slc17a3-/- mice compared to that in wild-type mice. The uptake of 3-indoxyl sulfate by NPT4-expressing Xenopus oocytes was significantly higher than that by water-injected oocytes. The calculated Km and Vmax values for NPT4-mediated 3-indoxyl sulfate uptake were 4.52 ± 1.18 mM and 1.45 ± 0.14 nmol/oocyte/90 min, respectively. In conclusion, the present study revealed that 3-indoxyl sulfate is a novel substrate of NPT4 based on the metabolomic analysis of Slc17a3-/- mice, suggesting that NPT4 regulates systemic exposure to 3-indoxyl sulfate by regulating its urinary excretion.

Preliminary External Validation Results of the Artificial Intelligence-Based Headache Diagnostic Model: A Multicenter Prospective Observational Study.

The misdiagnosis of headache disorders is a serious issue, and AI-based headache model diagnoses with external validation are scarce. We previously developed an artificial intelligence (AI)-based headache diagnosis model using a database of 4000 patients' questionnaires in a headache-specializing clinic and herein performed external validation prospectively. The validation cohort of 59 headache patients was prospectively collected from August 2023 to February 2024 at our or collaborating multicenter institutions. The ground truth was specialists' diagnoses based on the initial questionnaire and at least a one-month headache diary after the initial consultation. The diagnostic performance of the AI model was evaluated. The mean age was 42.55 ± 12.74 years, and 51/59 (86.67%) of the patients were female. No missing values were reported. Of the 59 patients, 56 (89.83%) had migraines or medication-overuse headaches, and 3 (5.08%) had tension-type headaches. No one had trigeminal autonomic cephalalgias or other headaches. The models' overall accuracy and kappa for the ground truth were 94.92% and 0.65 (95%CI 0.21-1.00), respectively. The sensitivity, specificity, precision, and F values for migraines were 98.21%, 66.67%, 98.21%, and 98.21%, respectively. There was disagreement between the AI diagnosis and the ground truth by headache specialists in two patients. This is the first external validation of the AI headache diagnosis model. Further data collection and external validation are required to strengthen and improve its performance in real-world settings.

Enantioselective Construction of Consecutive Tetrasubstituted Stereogenic Centers by Reaction of α-Substituted ß-Nitroacrylates with Oxazol-5-(4H)-ones Catalyzed by Cinchona Alkaloid Sulfonamide Catalysts.

The enantioselective reaction of α-substituted ß-nitroacrylates with oxazol-5-(4H)-ones (oxazolones) to construct consecutive tetrasubstituted stereogenic centers was accomplished. A cinchona alkaloid sulfonamide catalyst afforded products bearing vicinal chiral centers with excellent enantio- and diastereoselectivities. The obtained products were successively converted into various chiral compounds without loss of their enantiopurity. Furthermore, density functional theory (DFT) calculations were performed to elucidate the mechanism and origin of the observed stereoselectivity of the reaction.

SMARCB1/INI1-deficient intrathoracic neoplasm with rhabdoid/plasmacytoid cytomorphology in a patient with plasma cell myeloma: A case report.

SMARCB1 (INI1) is one of the switch/sucrose nonfermentable (SWI/SNF) complexes whose loss is associated with several tumors. SMARCB1 (INI1)-deficient intrathoracic neoplasms are extremely rare and known to be highly malignant and lethal. This report presents the case of a patient diagnosed with SMARCB1 (INI1)-deficient intrathoracic neoplasm during chemotherapy for plasma cell myeloma. A 77-year-old male patient complained of cough, bloody sputum, and fever with an enlarged right lung mass and pleural effusion. His cytological examination revealed undifferentiated epithelioid and rhabdoid/plasmacytoid cells with bi- or multinucleation, vacuolization, mitosis, and pleomorphism. However, it was difficult to distinguish the relapse of plasma cell myeloma as atypical plasmacytoid cells were detected. Immunohistochemically, the neoplastic cells showed a loss of SMARCB1 (INI1) expression in the cell block of pleural fluid and in the right lung of the autopsy specimen. Further, the patient was diagnosed with SMARCB1 (INI1)-deficient intrathoracic neoplasm of the right lung based on histological and autopsy findings. To the best of our knowledge, this is the first report of cytomorphology in a SMARCB1 (INI1)-deficient intrathoracic neoplasm.

The predictive power of physical function assessed by questionnaire and physical performance measures for subsequent disability.

BACKGROUND AND AIMS: To compare the predictive power of physical function assessed by questionnaire and physical performance measures for subsequent disability in community-dwelling elderly persons. METHODS: Prospective cohort study. Participants were 813 aged 70 years and older, elderly Japanese residing in the community, included in the Tsurugaya Project, who were not disabled at the baseline in 2003. Physical function was assessed by the questionnaire of "Motor Fitness Scale". Physical performance measures consisted of maximum walking velocity, timed up and go test (TUG), leg extension power, and functional reach test. The area under the curve (AUC) of the receiver operating characteristic curve for disability was used to compare screening accuracy between Motor Fitness Scale and physical performance measures. Incident disability, defined as certification for long-term care insurance, was used as the endpoint. RESULTS: We observed 135 cases of incident disability during follow-up. The third or fourth quartile for each measure was associated with a significantly increased risk of disability in comparison with the highest quartile. The AUC was 0.70, 0.72, 0.70, 0.68, 0.69 and 0.74, for Motor Fitness Scale, maxi- mum walking velocity, TUG, leg extension power, functional reach test, and total performance score, respectively. CONCLUSIONS: The predictive power of physical function assessed by the Motor Fitness Scale was equivalent to that assessed by physical performance measures. Since Motor Fitness Scale can evaluate physical function safely and simply in comparison with physical performance tests, it would be a practical tool for screening persons at high risk of disability.

Relationship between Moral Values for Driving Behavior and Brain Activity: An NIRS Study.

Although there are clear moral components to traffic violations and risky and aggressive driving behavior, few studies have examined the relationship between moral values and risky driving. This study aimed to examine the relationship between moral views of driving behavior and brain activity. Twenty healthy drivers participated in this study. A questionnaire regarding their moral values concerning driving behavior was administered to the participants. Brain activity was measured using near-infrared spectroscopy while eliciting moral emotions. Based on the results of the questionnaire, the participants were divided into two groups: one with high moral values and the other with low moral values. Brain activity was statistically compared between the two groups. Both groups had significantly lower activity in the prefrontal cortex during the self-risky driving task. The low moral group had significantly lower activity in the left dorsolateral prefrontal cortex than the high moral group, while it had lower activity in the right dorsolateral prefrontal cortex in the self-risky driving task than in the safe driving task. Regardless of their moral values, the participants were less susceptible to moral emotions during risky driving. Furthermore, our findings suggest that drivers with lower moral values may be even less susceptible to moral emotions.

Differences in causes of stiff knee gait in knee extensor activity or ankle kinematics: A cross-sectional study.

BACKGROUND: Stiff knee gait (SKG), a common occurrence after the onset of stroke, is caused by hyperactivity of the rectus femoris during the swing phase. Another cause of SKG is the weakness of push-off in hemiparetic gait. Prior research did not consider the effect of the magnitude of knee extensors in their subjects. RESEARCH QUESTION: Does the cause of SKG differ between patients with high and low knee extensor activities during the swing phase? METHODS: We examined 38 patients with chronic stroke hemiplegia who presented with SKG. After placing an inertia sensor and an electromyogram, patients walked 10 m at a comfortable speed. All patients were categorized per the sign of the principal component 2 (PC2) as a component with large factor loadings of knee extensors attained from the electromyographic amplitude during the early swing phase of the paretic limb. Then, the kinematic parameters of knee flexion and other gait parameters in each group were compared, and a correlation analysis was performed. RESULTS: In the high PC2 group, the timing of peak knee flexion during the swing phase was early, and vastus lateralis activity during the preswing phase negatively correlated with the knee-flexion angle during the swing phase. In the low PC2 group, the angular velocity of ankle plantar flexion at the toe-off was slow, which positively correlated with the knee-flexion angle during the swing phase. SIGNIFICANCE: The cause of SKG could be an inappropriate activity of the vastus lateralis rather than the rectus femoris in patients with high knee extensor activity and slow plantar-flexion velocity at toe-off in patients with low knee extensor activity. Not all causes of SKG in patients with hemiplegia are common, and different treatment strategies are needed per the individuality of spastic knee extensor activity.

A comparative study of riverine 137Cs dynamics during high-flow events at three contaminated river catchments in Fukushima.

This study presents the temporal variations in riverine 137Cs concentrations and fluxes to the ocean during high-flow events in three coastal river catchments contaminated by the Fukushima Daiichi Nuclear Power Plant accident. River water samples were collected at points downstream in the Niida, Ukedo, and Takase Rivers during three high-flow events that occurred in 2019-2020. Variations in both the dissolved and particulate 137Cs concentrations appeared to reflect the spatial pattern of the 137Cs inventory in the catchments, rather than variations in physico-chemical properties of water and suspended solid. Negative relationships between the 137Cs concentration and δ15N in suspended solid were found in all rivers during the intense rainfall events, suggesting an increased contribution of sediment from forested areas to the elevation of particulate 137Cs concentration. The 137Cs flux ranged from 0.33 to 19 GBq, depending on the rainfall erosivity. The particulate 137Cs fluxes from the Ukedo River were relatively low compared with the other two rivers and were attributed to the effect of the Ogaki Dam reservoir upstream. The percentage of 137Cs desorbed in seawater relative to 137Cs in suspended solids ranged from 2.8% to 6.6% and tended to be higher with a higher fraction of exchangeable 137Cs. The estimated potential release of 137Cs desorbed from suspended solids to the ocean was 0.022-0.57 GBq, and its ratio to the direct flux of dissolved 137Cs was 0.12-6.2. Episodic sampling during high-flow events demonstrated that the particulate 137Cs flux depends on catchment characteristics and controls 137Cs transfer to the ocean.

Development of an artificial intelligence-based diagnostic model for Alzheimer's disease.

Introduction: The diagnosis of Alzheimer's disease (AD) is sometimes difficult for nonspecialists, resulting in misdiagnosis. A missed diagnosis can lead to improper management and poor outcomes. Moreover, nonspecialists lack a simple diagnostic model with high accuracy for AD diagnosis. Methods: Randomly assigned data, including training data, of 6000 patients and test data of 1932 from 7932 patients who visited our memory clinic between 2009 and 2021 were introduced into the artificial intelligence (AI)-based AD diagnostic model, which we had developed. Results: The AI-based AD diagnostic model used age, sex, Hasegawa's Dementia Scale-Revised, the Mini-Mental State Examination, the educational level, and the voxel-based specific regional analysis system for Alzheimer's disease (VSRAD) score. It had a sensitivity, specificity, and c-static value of 0.954, 0.453, and 0.819, respectively. The other AI-based model that did not use the VSRAD had a sensitivity, specificity, and c-static value of 0.940, 0.504, and 0.817, respectively. Discussion: We created an AD diagnostic model with high sensitivity for AD diagnosis using only data acquired in daily clinical practice. By using these AI-based models, nonspecialists could reduce missed diagnoses and contribute to the appropriate use of medical resources.