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Abstract Background To establish simple screening tests to suspect Alzheimer’s disease (AD) pathology, the clinical sign “head-turning sign” (HTS), which is a patient’s behavior of turning their head towards their partner to seek assistance with questions posed by the examiner during the interview, and the simple screening questionnaire for dementia named “Neucop-Q” were validated in participants diagnosed with amyloid and tau positron emission tomography (PET). Methods We enrolled 155 patients: 47 cognitive normal, 36 with mild cognitive impairment, 64 with dementia, and 8 with psychiatric disorders. All participants underwent Neucop-Q [three questions: Consciousness/self-awareness of cognitive disabilities (C) normal/impaired (nor/imp), Pleasure/pastime (P) nor/imp, and News/knowledge on current topics (N) nor/imp] and amyloid/tau PET. Additionally, we measured plasma amyloid β (Aβ) 42/40 ratio, phosphorylated tau 181 (pTau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NFL) levels and compared with HTS and Neucop-Q results. Results The specificity and positive predictive value (PPV) of HTS positivity (HTSpos) were the highest (amyloid PET: 0.930 and 0.870, tau PET: 0.944 and 0.957, respectively), while Cimp and Nimp had a high negative predictive value (NPV) for amyloid PET (negativity) (0.750 and 0.725). Pimp showed high specificity for predicting non-AD tau positivity among non-AD participants without amyloid PET positivity (0.854). To validate these findings with PET results, we examined the correlation between well-established AD blood biomarkers and results obtained from these screening tests. HTSpos, Cimp, and Nimp were strongly associated with Aβ42/40 ratio (P

ABSTRACT Aims/Introduction We conducted a 5 year post‐trial monitoring study of our previous randomized 24 week, open‐label, active‐controlled trial that showed beneficial effects of ipragliflozin on metabolic dysfunction‐associated steatotic liver disease (MASLD), identical to those of pioglitazone. Materials and Methods In our previous trial, 66 patients with MASLD and type 2 diabetes were randomly assigned to receive either ipragliflozin (n = 32) or pioglitazone (n = 34). Upon its conclusion, 61 patients were monitored for 5 years for outcome measures of MASLD, glycemic, and metabolic parameters. Differences between the two groups were analyzed at baseline, 24 weeks, and 5 years; changes in outcome measures from baseline were also evaluated. Results At 5 years, the mean liver‐to‐spleen attenuation ratio increased by 0.20 (from 0.78 ± 0.24 to 0.98 ± 0.20) in the ipragliflozin group and by 0.26 (from 0.76 ± 0.26 to 1.02 ± 0.20) in the pioglitazone group (P = 0.363). Similarly, ipragliflozin and pioglitazone significantly improved serum aminotransferase, HbA1c, and fasting plasma glucose levels over 5 years. In the ipragliflozin group, significant reductions in body weight and visceral fat area observed at 24 weeks were sustained throughout the 5 years (−4.0%, P = 0.0075 and −7.6%, P = 0.045, respectively). Moreover, ipragliflozin significantly reduced the values of fibrosis markers (serum ferritin and FIB‐4 index), was well tolerated, and had a higher continuation rate for 5 years compared with pioglitazone. Conclusions Ipragliflozin and pioglitazone improved MASLD and glycemic parameters over 5 years. In the ipragliflozin group, significant reductions in body weight and visceral fat mass persisted for 5 years.

Abstract Objective To reveal the clinical features and assess risk factors linked to brain fog and its societal implications, including labor productivity, providing valuable insights for the future care of individuals who have experienced coronavirus disease 2019 (COVID‐19). Methods We analyzed a comprehensive cohort dataset comprising 1,009 patients with COVID‐19 admitted to Japanese hospitals. To assess brain fog, we analyzed patients who responded to a questionnaire indicating symptoms such as memory impairment and poor concentration. Results The prevalence of brain fog symptoms decreased 3 months posthospitalization but remained stable up to 12 months. Neurological symptoms such as taste and smell disorders and numbness at hospitalization correlated with a higher frequency of identifying brain fog as a long COVID manifestation. Our findings indicated that advanced age, female sex, a high body mass index, oxygen required during hospitalization, chronic obstructive pulmonary disease, asthma, and elevated C‐reactive protein and elevated D‐dimer levels were risk factors in patients exhibiting brain fog. Additionally, we demonstrated the negative impact of brain fog on labor productivity by presenteeism scores. Interpretations This study clarified the clinical characteristics of patients experiencing brain fog as a long COVID manifestation, specifically emphasizing neurological symptoms during hospitalization and their correlation with brain fog. Additionally, the study identified associated risk factors for its onset and revealed that the emergence of brain fog was linked to a decline in labor productivity.

Abstract Background Extracellular vesicles (EVs) hold the potential for elucidating the pathogenesis of amyotrophic lateral sclerosis (ALS) and serve as biomarkers. Notably, the comparative and longitudinal alterations in the protein profiles of EVs in serum (sEVs) and cerebrospinal fluid (CSF; cEVs) of sporadic ALS (SALS) patients remain uncharted. Ropinirole hydrochloride (ROPI; dopamine D2 receptor [D2R] agonist), a new anti-ALS drug candidate identified through induced pluripotent stem cell (iPSC)-based drug discovery, has been suggested to inhibit ALS disease progression in the Ropinirole Hydrochloride Remedy for Amyotrophic Lateral Sclerosis (ROPALS) trial, but its mechanism of action is not well understood. Therefore, we tried to reveal longitudinal changes with disease progression and the effects of ROPI on protein profiles of EVs. Methods We collected serum and CSF at fixed intervals from ten controls and from 20 SALS patients participating in the ROPALS trial. Comprehensive proteomic analysis of EVs, extracted from these samples, was conducted using liquid chromatography/mass spectrometer (LC/MS). Furthermore, we generated iPSC-derived astrocytes (iPasts) and performed RNA sequencing on astrocytes with or without ROPI treatment. Results The findings revealed notable disparities yet high congruity in sEVs and cEVs protein profiles concerning disease status, time and ROPI administration. In SALS, both sEVs and cEVs presented elevated levels of inflammation-related proteins but reduced levels associated with unfolded protein response (UPR). These results mirrored the longitudinal changes after disease onset and correlated with the revised ALS Functional Rating Scale (ALSFRS-R) at sampling time, suggesting a link to the onset and progression of SALS. ROPI appeared to counteract these changes, attenuating inflammation-related protein levels and boosting those tied to UPR in SALS, proposing an anti-ALS impact on EV protein profiles. Reverse translational research using iPasts indicated that these changes may partly reflect the DRD2-dependent neuroinflammatory inhibitory effects of ROPI. We have also identified biomarkers that predict diagnosis and disease progression by machine learning-driven biomarker search. Conclusions Despite the limited sample size, this study pioneers in reporting time-series proteomic alterations in serum and CSF EVs from SALS patients, offering comprehensive insights into SALS pathogenesis, ROPI-induced changes, and potential prognostic and diagnostic biomarkers.

Abstract Background Extracellular vesicle-derived (EV)-miRNAs have potential to serve as biomarkers for the diagnosis of various diseases. miRNA microarrays are widely used to quantify circulating EV-miRNA levels, and the preprocessing of miRNA microarray data is critical for analytical accuracy and reliability. Thus, although microarray data have been used in various studies, the effects of preprocessing have not been studied for Toray’s 3D-Gene chip, a widely used measurement method. We aimed to evaluate batch effect, missing value imputation accuracy, and the influence of preprocessing on measured values in 18 different preprocessing pipelines for EV-miRNA microarray data from two cohorts with amyotrophic lateral sclerosis using 3D-Gene technology. Results Eighteen different pipelines with different types and orders of missing value completion and normalization were used to preprocess the 3D-Gene microarray EV-miRNA data. Notable results were suppressed in the batch effects in all pipelines using the batch effect correction method ComBat. Furthermore, pipelines utilizing missForest for missing value imputation showed high agreement with measured values. In contrast, imputation using constant values for missing data exhibited low agreement. Conclusions This study highlights the importance of selecting the appropriate preprocessing strategy for EV-miRNA microarray data when using 3D-Gene technology. These findings emphasize the importance of validating preprocessing approaches, particularly in the context of batch effect correction and missing value imputation, for reliably analyzing data in biomarker discovery and disease research.

Abstract Background Restoring shoulder function is critical for upper-extremity rehabilitation following a stroke. The complex musculoskeletal anatomy of the shoulder presents a challenge for safely assisting elevation movements through robotic interventions. The level of shoulder elevation assistance in rehabilitation is often based on clinical judgment. There is no standardized method for deriving an optimal level of assistance, underscoring the importance of addressing abnormal movements during shoulder elevation, such as abnormal synergies and compensatory actions. This study aimed to investigate the effectiveness and safety of a newly developed shoulder elevation exoskeleton robot by applying a novel optimization technique derived from the muscle synergy index. Methods Twelve chronic stroke participants underwent an intervention consisting of 100 robot-assisted shoulder elevation exercises (10 × 10 times, approximately 40 min) for 10 days (4–5 times/week). The optimal robot assist rate was derived by detecting the change points using the co-contraction index, calculated from electromyogram (EMG) data obtained from the anterior deltoid and biceps brachii muscles during shoulder elevation at the initial evaluation. The primary outcomes were the Fugl–Meyer assessment-upper extremity (FMA-UE) shoulder/elbow/forearm score, kinematic outcomes (maximum angle of voluntary shoulder flexion and elbow flexion ratio during shoulder elevation), and shoulder pain outcomes (pain-free passive shoulder flexion range of motion [ROM] and visual analogue scale for pain severity during shoulder flexion). The effectiveness and safety of robotic therapy were examined using the Wilcoxon signed-rank sum test. Results All 12 patients completed the procedure without any adverse events. Two participants were excluded from the analysis because the EMG of the biceps brachii was not obtained. Ten participants (five men and five women; mean age: 57.0 [5.5] years; mean FMA-UE total score: 18.7 [10.5] points) showed significant improvement in the FMA-UE shoulder/elbow/forearm score, kinematic outcomes, and pain-free passive shoulder flexion ROM (P

Abstract Previous studies have developed and explored magnetic resonance imaging (MRI)-based machine learning models for predicting Alzheimer’s disease (AD). However, limited research has focused on models incorporating diverse patient populations. This study aimed to build a clinically useful prediction model for amyloid-beta (Aβ) deposition using source-based morphometry, using a data-driven algorithm based on independent component analyses. Additionally, we assessed how the predictive accuracies varied with the feature combinations. Data from 118 participants clinically diagnosed with various conditions such as AD, mild cognitive impairment, frontotemporal lobar degeneration, corticobasal syndrome, progressive supranuclear palsy, and psychiatric disorders, as well as healthy controls were used for the development of the model. We used structural MR images, cognitive test results, and apolipoprotein E status for feature selection. Three-dimensional T1-weighted images were preprocessed into voxel-based gray matter images and then subjected to source-based morphometry. We used a support vector machine as a classifier. We applied SHapley Additive exPlanations, a game-theoretical approach, to ensure model accountability. The final model that was based on MR-images, cognitive test results, and apolipoprotein E status yielded 89.8% accuracy and a receiver operating characteristic curve of 0.888. The model based on MR-images alone showed 84.7% accuracy. Aβ-positivity was correctly detected in non-AD patients. One of the seven independent components derived from source-based morphometry was considered to represent an AD-related gray matter volume pattern and showed the strongest impact on the model output. Aβ-positivity across neurological and psychiatric disorders was predicted with moderate-to-high accuracy and was associated with a probable AD-related gray matter volume pattern. An MRI-based data-driven machine learning approach can be beneficial as a diagnostic aid.

Objective: Machine learning models were employed to discern patients' impressions from the therapists' facial expressions during a virtual online video counselling session. Methods: Eight therapists simulated an online video counselling session for the same patient. The facial emotions of the therapists were extracted from the session videos; we then utilized a random forest model to determine the therapist's impression as perceived by the patients. Results: The therapists' neutral facial expressions were important controlling factors for patients' impressions. A predictive model with three neutral facial features achieved an accuracy of 83% in identifying patients' impressions. Conclusions: Neutral facial expressions may contribute to patient impressions in an online video counselling environment with spatiotemporal disconnection. Innovation: Expression recognition techniques were applied innovatively to an online counselling setting where therapists' expressions are limited. Our findings have the potential to enhance psychiatric clinical practice using Information and Communication Technology.

Although many interventions for acute spinal cord injury (SCI) appear promising in experimental models, translation directly from experimental animals to human patients is a large step that can be problematic. Acute SCI occurs frequently in companion dogs and may provide a model to ease translation. Recently, incision of the dura has been highlighted in both research animals and human patients as a means of reducing intraspinal pressure, with a view to improving perfusion of the injured tissue and enhancing functional recovery. Observational clinical data in humans and dogs support the notion that it may also improve functional outcome. Here, we report the results of a multi-center randomized controlled trial of durotomy as an adjunct to traditional decompressive surgery for treatment of severe thoracolumbar SCI caused by acute intervertebral disc herniation in dogs. Sample-size calculation was based on the proportion of dogs recovering ambulation improving from an expected 55% in the traditional surgery group to 70% in the durotomy group. Over a 3.5-year period, we enrolled 140 dogs, of which 128 had appropriate duration of follow-up. Overall, 65 (51%) dogs recovered ambulation. Recovery in the traditional decompression group was 35 of 62 (56%) dogs, and in the durotomy group 30 of 66 (45%) dogs, associated with an odds ratio of 0.643 (95% confidence interval: 0.320?1.292) and z-score of ?1.24. This z-score indicates trial futility to reach the target 15% improvement over traditional surgery, and the trial was terminated at this stage. We conclude that durotomy is ineffective in improving functional outcome for severe acute thoracolumbar SCI in dogs. In the future, these data can be compared with similar data from clinical trials on duraplasty in human patients and will aid in determining the predictive validity of the ?companion dog model? of acute SCI.

Background: Despite evidence regarding the benefits of transcranial direct current stimulation (tDCS) in patients with severe traumatic brain injury, few trials have examined the treatment safety. Therefore, we created a phase I trial in Japan to investigate the safety of tDCS after severe brain injury. Methods: We verified the safety of tDCS through constant left frontal anodal stimulation at 2 mA for 20 min for 5 consecutive days. Additionally, we added a variable stimuli period to explore the effects of stimulus intensity, location, and duration. We adapted a traditional 3 + 3 study design. We assessed the rate of adverse effects, including skin burns and clinical seizure. Changes in neurological symptoms were evaluated using the Glasgow Coma Scale, Coma Recovery Scale-Revised, and 4 states of consciousness (coma, unresponsive wakefulness syndrome, minimally conscious state, and severe disability). Results: Six patients completed the study. No obvious adverse events were observed during the constant stimulation period or the variable stimulation period (right frontal anodal stimulation, stimulation frequency 2–4 mA, 1 or 5 times per week for a period of 4 weeks). Regarding the Coma Recovery Scale-Revised, patients in 4 out of 6 instances (66.7 %) improved by more than 1 point. Conclusion: Our phase I safety study indicated that a single course of tDCS was safe in patients with severe traumatic brain injury. The next step is a phase II trial to investigate the preliminary efficacy and safety of tDCS at 2 mA (in comparison with sham stimulation).

Abstract Background Plasma biomarkers have emerged as promising screening tools for Alzheimer’s disease (AD) because of their potential to detect amyloid β (Aβ) accumulation in the brain. One such candidate is the plasma Aβ42/40 ratio (Aβ42/40). Unlike previous research that used traditional immunoassay, recent studies that measured plasma Aβ42/40 using fully automated platforms reported promising results. However, its utility should be confirmed using a broader patient population, focusing on the potential for early detection. Methods We recruited 174 participants, including healthy controls (HC) and patients with clinical diagnoses of AD, frontotemporal lobar degeneration, dementia with Lewy bodies/Parkinson’s disease, mild cognitive impairment (MCI), and others, from a university memory clinic. We examined the performance of plasma Aβ42/40, measured using the fully automated high-sensitivity chemiluminescence enzyme (HISCL) immunoassay, in detecting amyloid-positron emission tomography (PET)-derived Aβ pathology. We also compared its performance with that of Simoa-based plasma phosphorylated tau at residue 181 (p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL). Results Using the best cut-off derived from the Youden Index, plasma Aβ42/40 yielded an area under the receiver operating characteristic curve (AUC) of 0.949 in distinguishing visually assessed 18F-Florbetaben amyloid PET positivity. The plasma Aβ42/40 had a significantly superior AUC than p-tau181, GFAP, and NfL in the 167 participants with measurements for all four biomarkers. Next, we analyzed 99 participants, including only the HC and those with MCI, and discovered that plasma Aβ42/40 outperformed the other plasma biomarkers, suggesting its ability to detect early amyloid accumulation. Using the Centiloid scale (CL), Spearman’s rank correlation coefficient between plasma Aβ42/40 and CL was -0.767. Among the 15 participants falling within the CL values indicative of potential future amyloid accumulation (CL between 13.5 and 35.7), plasma Aβ42/40 categorized 61.5% (8/13) as Aβ-positive, whereas visual assessment of amyloid PET identified 20% (3/15) as positive. Conclusion Plasma Aβ42/40 measured using the fully automated HISCL platform showed excellent performance in identifying Aβ accumulation in the brain in a well-characterized cohort. This equipment may be useful for screening amyloid pathology because it has the potential to detect early amyloid pathology and is readily applied in clinical settings.

Various individual resources for successful aging have improved during the last decades. However, a limited number of studies have examined historical changes in how older individuals view their own aging. This study examined cohort differences in aging self-perceptions among Japanese older adults. Using nationally representative data obtained 9 years apart in 1987 and 1996, we compared two cohorts born in the 1920s versus the 1930s. To control for relevant correlates, we identified case-matched controls based on age, sex, and education (age range = 60–65 years; n = 499 per cohort). Results indicated that the later-born cohort held more positive self-perceptions of aging than the earlier-born cohort, even after adjusting for relevant correlates. The correlates with self-perceptions of aging did not differ across cohorts. Our findings suggest that self-perceptions of aging have improved over the historical time. We discuss the potential role of societal forces on personal views on aging.

The sulfide solid electrolyte Li4SnS4 has gained attention owing to its high moisture durability. In this study, we quantitatively investigated the changes in the electrochemical properties and chemical/physical states of Li4SnS4 resulted from moisture exposure using the XRD, Raman spectroscopy, and high-frequency electrochemical impedance spectroscopy (HF-EIS). Li4SnS4 was subjected to Ar gas flow at a dew point ranging from −20 °C to 0 °C for 1 h, and sulfide hydrolysis generated only a minute amount of H2S. The XRD patterns and Raman spectra revealed the formation of Li4SnS4·4H2O with increasing dew point. The HF-EIS analysis, which was conducted to clarify the spatial distribution of the hydrate within the particle, revealed a significant decrease in the ionic conductivity of Li4SnS4; this result can be attributed to the increased grain-boundary (SE/SE particle contact) resistance due to the formation of Li4SnS4·4H2O at the particle surface, despite the generation of a minute amount of H2S. By combining these multifaceted analytical methods, we demonstrated that the thermodynamically stable surface hydrate Li4SnS4·4H2O reduced the lithium-ion conductivity without H2S generation owing to the hydrolysis of sulfide. Thus, we chemically, spatially, and quantitatively verified the mechanism underlying the observed decrease in the ionic conductivity.

Abstract Background Alzheimer’s disease (AD) is the most common cause of dementia worldwide. In AD, abnormal tau accumulates within neurons of the brain, facilitated by extracellular β‐amyloid deposition, leading to neurodegeneration, and eventually, cognitive impairment. As this process is thought to be irreversible, early identification of abnormal tau in the brain is crucial for the development of new therapeutic interventions. Aims 18F‐PI‐2620 is one of the second‐generation tau PET tracers with presumably less off‐target binding than its predecessors. Although a few clinical studies have recently reported the use of 18F‐PI‐2620 tau PET in patients with AD, its applicability to AD is yet to be thoroughly examined. Methods In the present pilot study, we performed 18F‐PI‐2620 tau PET in seven cases of probable AD (AD group) and seven healthy controls (HC group). Standardized uptake value ratios (SUVR) in regions of interest (ROIs) in the medial temporal region and neocortex were compared between the AD and HC groups. Furthermore, correlations between regional SUVR and plasma p‐tau181 as well as cognitive test scores were also analyzed. Results The uptake of 18F‐PI‐2620 was distinctly increased in the AD group across all the ROIs. SUVR in all the target ROIs were significantly correlated with plasma p‐tau181 levels, as well as with MMSE and ADAS‐cog scores. Discussion & Conclusion Our results add to accumulating evidence suggesting that 18F‐PI‐2620 is a promising tau PET tracer that allows patients with AD to be distinguished from healthy controls, although a study with a larger sample size is warranted.

Abstract Background Proliferative glomerulonephritis with monoclonal immunoglobulin G (IgG) deposits (PGNMID) is a rare monoclonal gammopathy of renal significance with dense deposits of monoclonal immunoglobulin. Case presentation We report a 78-year-old Japanese male patient with mild proteinuria and lower extremity edema. Monoclonal immunoglobulin could not be identified in his serum or urine. Although his bone marrow biopsy was negative, renal biopsy found features of membranoproliferative glomerulonephritis (MPGN) with deposition of monoclonal IgG2 kappa. Electron microscopy examination revealed non-organized electron-dense deposits in the subepithelial, and subendothelial mesangial regions. Steroid monotherapy was performed after diagnosis of PGNMID but complete remission was not achieved. Conclusion PGNMID with IgG3 kappa deposits is the most common in cases with the histological feature of MPGN. There are few cases of PGNMID with IgG2 kappa deposits exhibiting MPGN. This report describes a very rare case of PGNMID with the histological feature of MPGN.

Abstract Objective Patients with spinal and bulbar muscular atrophy (SBMA) often experience muscular weakness under cold exposure. Methods In our previously conducted observational study, we assessed nerve conduction and grip strength to examine the effect of cold exposure on motor function, based on which we conducted a randomized controlled trial to evaluate the efficacy and safety of mexiletine hydrochloride in SBMA (MEXPRESS). Results In the observational study, 51 consecutive patients with SBMA and 18 healthy controls (HCs) were enrolled. Of the patients with SBMA, 88.0% experienced cold paresis. Patients with SBMA exhibited greater prolongation of ulnar nerve distal latency under cold (SBMA, 5.6 ± 1.1 msec; HC, 4.3 ± 0.6 msec; p

Abstract This study aimed to develop a functional measurement that combines quantitative motor evaluation index of various body regions in patients with spinal and bulbar muscular atrophy (SBMA). We assessed subjects with SBMA and healthy controls with quantitative muscle strength measurements and functional scales. We selected tongue pressure, grip power, % peak expiratory flow (%PEF), timed walking test, and % forced vital capacity (%FVC) as components. By combining these values with Z-score, we created a functional composite (SBMA functional composite: SBMAFC). We also calculated the standardized response mean to compare the sensitivity of SBMAFC with that of existing measurements. A total of 97 genetically confirmed patients with SBMA and 36 age- and sex-matched healthy controls were enrolled. In the longitudinal analysis, the standardized response mean of SBMAFC was larger than that of existing rating scales. Receiver operating characteristic (ROC) analysis demonstrated that the SBMAFC is capable of distinguishing between subjects with early-stage SBMA and healthy controls. SBMAFC is more sensitive to disease progression than existing functional rating scales and is a potential outcome measure in clinical trials of SBMA.

Plasmodium species cause malaria, and in the instance of Plasmodium falciparum is responsible for a societal burden of over 600,000 deaths annually. The symptoms and pathology of malaria are due to intraerythocytic parasites. Erythrocyte invasion is mediated by the parasite merozoite stage, and is accompanied by the formation of a parasitophorous vacuolar membrane (PVM), within which the parasite develops. The merozoite apical rhoptry organelle contains various proteins that contribute to erythrocyte attachment and invasion. RON3, a rhoptry bulb membrane protein, undergoes protein processing and is discharged into the PVM during invasion. RON3-deficient parasites fail to develop beyond the intraerythrocytic ring stage, and protein export into erythrocytes by the Plasmodium translocon of exported proteins (PTEX) apparatus is abrogated, as well as glucose uptake into parasites. It is known that truncated N- and C-terminal RON3 fragments are present in rhoptries, but it is unclear which RON3 fragments contribute to protein export by PTEX and glucose uptake through the PVM. To investigate and distinguish the roles of the RON3 C-terminal fragment at distinct developmental stages, we used a C-terminus tag for conditional and post-translational control. We demonstrated that RON3 is essential for blood-stage parasite survival, and knockdown of RON3 C-terminal fragment expression from the early schizont stage induces a defect in erythrocyte invasion and the subsequent development of ring stage parasites. Protein processing of full-length RON3 was partially inhibited in the schizont stage, and the RON3 C-terminal fragment was abolished in subsequent ring-stage parasites compared to the RON3 N-terminal fragment. Protein export and glucose uptake were abrogated specifically in the late ring stage. Plasmodial surface anion channel (PSAC) activity was partially retained, facilitating small molecule traffic across the erythrocyte membrane. The knockdown of the RON3 C-terminal fragment after erythrocyte invasion did not alter parasite growth. These data suggest that the RON3 C-terminal fragment participates in erythrocyte invasion and serves an essential role in the progression of ring-stage parasite growth by the establishment of the nutrient-permeable channel in the PVM, accompanying the transport of ring-stage parasite protein from the plasma membrane to the PVM.

Summary: Arginine-rich dipeptide repeat proteins (R-DPRs), poly(PR) and poly(GR), translated from the hexanucleotide repeat expansion in the amyotrophic lateral sclerosis (ALS)-causative C9ORF72 gene, contribute significantly to pathogenesis of ALS. Although both R-DPRs share many similarities, there are critical differences in their subcellular localization, phase separation, and toxicity mechanisms. We analyzed localization, protein-protein interactions, and phase separation of R-DPR variants and found that sufficient segregation of arginine charges is necessary for nucleolar distribution. Proline not only efficiently separated the charges, but also allowed for weak, but highly multivalent binding. In contrast, because of its high flexibility, glycine cannot fully separate the charges, and poly(GR) behaves similarly to the contiguous arginines, being trapped in the cytoplasm. We conclude that the amino acid that spaces the arginine charges determines the strength and multivalency of the binding, leading to differences in localization and toxicity mechanisms.

Extensive control efforts have significantly reduced malaria cases and deaths over the past two decades, but in recent years, coupled with the COVID-19 pandemic, success has stalled. The WHO has urged the implementation of a number of interventions, including vaccines. The modestly effective RTS,S/AS01 pre-erythrocytic vaccine has been recommended by the WHO for use in sub-Saharan Africa against Plasmodium falciparum in children residing in moderate to high malaria transmission regions. A second pre-erythrocytic vaccine, R21/Matrix-M, was also recommended by the WHO on 3 October 2023. However, the paucity and limitations of pre-erythrocytic vaccines highlight the need for asexual blood-stage malaria vaccines that prevent disease caused by blood-stage parasites. Few asexual blood-stage vaccine candidates have reached phase 2 clinical development, and the challenges in terms of their efficacy include antigen polymorphisms and low immunogenicity in humans. This review summarizes the history and progress of asexual blood-stage malaria vaccine development, highlighting the need for novel candidate vaccine antigens/molecules.

Abstract Aim Frailty assessment in elderly patients is crucial to predict the postoperative course, considering that frailty is highly associated with postoperative complications and mortality. The aim of this study was to evaluate the value of osteopenia as a risk factor for severe postoperative complications in elderly patients who underwent emergency gastrointestinal surgery. Methods This study comprised 103 elderly patients who underwent emergency gastrointestinal surgery. Osteopenia was diagnosed by measuring bone mineral density, which was calculated as the average pixel density in the midvertebral core at the 11th thoracic vertebra on the preoperative plain computed tomography image. We retrospectively investigated the relationship between preoperative osteopenia and severe postoperative complications (Clavien–Dindo classification ≥III). Univariate and multivariate analyses were performed to evaluate the risk factors for severe postoperative complications. Results Twenty‐three patients (22.3%) developed severe postoperative complications. The optimal cutoff value of bone mineral density for severe postoperative complications was 119.5 Hounsfield unit (HU) and 39 patients (37.9%) were diagnosed with osteopenia. The univariate analysis revealed that the American Society of Anesthesiologists Physical Status of ≥3 (P = .0084), hemoglobin levels (P = .0026), albumin levels (P

Abstract Background Heterotopic pancreas (HP) refers to the presence of abnormally located pancreatic tissue without any anatomic or vascular continuity with the main body of the pancreas. HP can occur in the gastrointestinal tract and be complicated by gastrointestinal bleeding, pancreatitis, obstruction, or malignant generation. Specifically, perforation of the gastrointestinal tract because of HP is extremely rare. Case presentation A 91-year-old woman was diagnosed with duodenal perforation, and an emergency laparoscopic operation was performed. The operative findings indicated a tumor and duodenal wall perforation. The tumor and the perforated site were resected with a linear stapler. Histopathological examination revealed the presence of HP tissue in the submucosal layer around the diverticulum without any signs of inflammation. The perforated site was not covered by HP tissues, and the duodenal wall might have been weaker than the other areas, which could have caused the internal pressure to increase and led to the perforation. Conclusions Preoperative HP diagnosis is difficult, and it is crucial to consider HP as the differential diagnosis in gastrointestinal perforations. The duodenal diverticula can be perforated due to increased internal pressure of the duodenum caused by the imbalanced localization of HP.

Abstract Aim To investigate the cognitive function and its relation to the home discharge of patients following subacute stroke. Methods This retrospective cohort study included 1,229 convalescent patients experiencing their first subacute stroke. We determined discharge destination and demographic and clinical information. We recorded the following measurement scores: Mini-Mental State Examination (MMSE) score, Stroke Impairment Assessment Set score, grip strength, and Functional Independence Measure (FIM). We performed a multivariable logistic regression analysis with the forced-entry method to identify factors related to home discharge. Results Of the 1,229 participants (mean age: 68.7 ± 13.5 years), 501 (40.8%), 735 (59.8%), and 1,011 (82.3%) were female, had cerebral infarction, and were home discharged, respectively. Multivariable logistic regression analysis revealed that age (odds ratio [OR], 0.93; 95% confidence interval [CI], 0.91 – 0.96; P

Abstract Objective To quantitatively evaluate upper limb ataxia using a novel pen‐like sensor device in patients with spinocerebellar ataxia (SCA) and to assess its validity, reliability, and sensitivity to disease progression. Methods We designed a cross‐sectional and longitudinal study of patients with SCA and healthy controls. Upper limb ataxia was evaluated using a device that measures the three‐dimensional position every 10 msec. Participants were instructed to move a pen‐like part of the device iteratively between two buttons. We evaluated the time, length, velocity, and variation coefficient of the stroke, and calculated the distortion index using the mean squared error. The following scales were also evaluated: Scale for the Assessment and Rating of Ataxia (SARA), the International Cooperative Ataxia Rating Scale (ICARS), and the nine‐hole pegboard test. Subjects were followed 12 months after the baseline evaluation. Results A total of 42 patients with SCA and 33 healthy controls were enrolled and evaluated. For all ataxia indices measured using the device there were significant differences between healthy controls and patients with SCA. Among the ataxia indices, the distortion index showed the strongest correlation with the SARA and ICARS upper limb score (Pearson's r = 0.647 and 0.722, respectively). Test–retest reliability was high for most of the ataxia indices. In the longitudinal analysis, the distortion index showed high standardized response mean and adjusted effect size, regardless of disease severity. Interpretation Our study demonstrated that the distortion index is a reliable functional marker that is sensitive to longitudinal change in patients with SCA.

This retrospective cross-sectional study is aimed at investigating the prevalence and characteristics of behavioral and psychological symptoms (BPS) in subacute stroke patients with cognitive impairment. The Neuropsychiatric Inventory-Questionnaire (NPI-Q) was used to assess BPS. A total of 358 consecutive patients with first-ever stroke admitted to rehabilitation wards and with Mini-Mental State Examination (MMSE) scores

Abstract Background Suture granuloma with hydronephrosis after abdominal surgery is extremely rare. We herein report a successfully treated case of suture granuloma with hydronephrosis caused by ileostomy closure after rectal cancer surgery. Case presentation A 63-year-old male underwent laparoscopic low anterior resection with covering ileostomy. Two months after primary operation, ileostomy closure was performed with two layered hand-sewn suture (Albert–Lembert method) using absorbable suture. In that operation, marginal blood vessels in the mesentery were ligated with silk suture. The patient had remained in remission with no evidence of tumor recurrence, however, 2 years and 5 months after primary surgery, a contrast-enhanced computed tomography (CT) scan showed a mass-forming lesion on the right external iliac artery (43 × 26 mm) and hydronephrosis. Positron emission tomography/computed tomography (PET/CT) showed a mass-forming lesion without high accumulation, which obstructed the right ureter. Recurrence could not be ruled out due to the rapid appearance of tumor and hydronephrosis in the short-term period. Thus, the patient underwent laparotomy. The tumor located in the mesentery near the anastomosis of ileostomy closure and it was strongly adherent to the retroperitoneum, which obstructed the right ureter. The adhesion between the tumor and ureter was carefully dissected and tumor resection with partial small bowel resection was then performed with preservation of the ureter using ureteral stents. Pathological examination of the tumor revealed fibrous proliferation of foreign body granuloma. In the resected tumor, sutures with foreign giant cells were found. Therefore, we diagnosed the tumor as silk suture granuloma, which was caused by the silk suture used to ligate blood vessels of the mesentery at the ileostomy closure. The patient remained well with no evidence of tumor recurrence as 5 years after the primary operation of rectal cancer. Conclusions Suture granuloma is a rare surgery-related complication in the postoperative surveillance of patients with colorectal cancer. If suture granuloma mimicking local recurrence is a differential diagnosis, it would be important to consider to avoid unnecessary extended resection.

We report a patient with logopenic variant primary progressive aphasia (lv-PPA) who was diagnosed as having non-Alzheimer's disease (AD) tauopathy after multiple biophysical/biological examinations, including amyloid and 18F-florzolotau tau positron emission tomography (PET), had been performed. A woman in her late 60s who had previously been diagnosed as having AD was referred to us for a further, detailed examination. She had been unaware of any symptoms at the time of AD diagnosis, but she subsequently became gradually aware of a speech impairment. She talked nearly completely and fluently, although she occasionally exhibited word-finding difficulty and made phonological errors during naming, word fluency testing, and sentence repetition; these findings met the criteria for the diagnosis of lv-PPA, which is known to be observed more commonly in AD than in other proteinopathies. Magnetic resonance imaging, single photon emission computed tomography, and plasma phosphorylated tau and plasma neurofilament light chain measurements showed an AD-like pattern. However, both 11C-Pittsburgh compound-B and 18F-florbetaben amyloid PET showed negative results, whereas 18F-florzolotau tau PET yielded positive results, with radio signals predominantly in the left superior temporal gyrus, middle temporal gyrus, supramarginal gyrus, and frontal operculum. Whole-genome sequencing revealed no known dominantly inherited mutations in AD or frontotemporal lobar degeneration genes, including the genes encoding amyloid precursor protein, microtubule-associated protein tau, presenilin 1 and 2. To the best of our knowledge, this patient was a rare case of lv-PPA who was diagnosed as having non-AD tauopathy based on the results of multiple examinations, including whole-genome sequencing, plasma measurement, and amyloid and 18F-florzolotau tau PET. This case underscores the clinicopathologically heterogeneous nature of this syndrome.

Summary: It is known that the human cellular models of Alzheimer’s disease (AD) and tauopathy can only recapitulate the very early stage of the disease. To overcome these limitations, we developed a technology to make forebrain organoids (FBOs) from feeder-free induced pluripotent stem cells (iPSC)s by regulating a FGF2 concentration and applied this method to generate FBOs from patients with familial AD (fAD FBOs). The obtained fAD FBOs recapitulated the amyloid-β pathology and increased tau phosphorylation but not tau aggregates. To fully induce the tau pathology, FBOs were injected with adeno-associated virus (AAV)-expressing P301L mutant tau. In these Tau-P301L FBOs, tau fibrils were observed in the neuronal cell body and neurites with immunoelectron microscopy, in addition to the sarkosyl-insoluble and thioflavin S-positive phospho-tau aggregates. Collectively, this model can be used as a platform for investigating pathogenetic mechanisms and evaluation of target molecules for drug discovery for tauopathy. Motivation: One of the reasons why drug development for Alzheimer’s disease (AD) and tauopathy has been difficult to date is the lack of appropriate models. Rodent models cannot fully recapitulate the disease pathology due to species differences between rodents and humans. Due to the low accessibility of patient brain for experimental use, human induced pluripotent stem cell (iPSC) technology is a promising approach for the generation of human cell models as an alternative research tool. However, even using human iPSCs, most cellular models of AD and tauopathy can only recapitulate the early stage of the disease, and it is challenging to display protein aggregation, such as amyloid-β plaques and tau fibrils, which are hallmarks of AD. To overcome these limitations, we made an improvement to increase the efficiency of neuroepithelia formation, leading to an increase in the efficiency of brain organoid generation. Furthermore, we established an efficient system of gene transfer by adeno-associated virus (AAV) injection into brain organoids and applied this to generate brain organoids with pronounced tau pathology, including tau fibrils.

Two-phase pressure drop in the debris has been studied by many researchers concerning the debris cooling characteristics during a severe accident in a nuclear reactor. However, its flow regime transition of the two-phase flow in the debris has not been well understood, which strongly affects the interfacial drag and the pressure drop. Conventional models for gas-liquid two-phase flow pressure drop have not been established to evaluate interfacial drag accurately. In this study, high-speed imaging of a two-dimensional network model was performed to clarify the effect of flow patterns on interfacial drag and pressure drop. Usually, it would not be easy to visualize such two-phase flow behavior in a randomly packed bed due to the reflection/refraction of light and/or overlapping bubbles, even if the test section is made of transparent materials. Therefore, in this study, a test section, which simulates a two-dimensional network of porous structures, was fabricated to avoid overlapping bubbles. The two-phase flow pattern in the porous structure has been identified by high-speed imaging of the two-dimensional network model. The flow regime map based on the flow pattern visualization results is applied to the pressure drop evaluation and it could reduce the overestimation of experimental values. The experimental results suggested that the interfacial drag term should be modified in the gas-liquid two-phase flow pressure drop model.

Sporadic Alzheimer’s disease (sAD) is a neurodegenerative disease that has the highest prevalence among patients with dementia. The genetic risk factors for sAD are comprised of many single nucleotide polymorphisms (SNPs), as indicated by genome-wide association studies. Herein, we generated the KEIOi005-A-induced pluripotent stem cell (iPSC) line from urine-derived cells (UDCs) of a mild Alzheimer’s disease (AD) patient with multiple sAD risk SNPs comprising T > C heterozygous APOE ε3/ε4 (rs429358), A > G heterozygous BIN1 (rs744373), and T > G homozygous MS4A6A (rs610932). The established iPSC line demonstrates normal stemness and pluripotency and can be used for in vitro disease modeling of AD.

Abstract Background The skin wound healing process is regulated by various cytokines, chemokines, and growth factors. Recent reports have demonstrated that spermine/spermidine (SPD) promote wound healing through urokinase-type plasminogen activator (uPA)/uPA receptor (uPAR) signaling in vitro. Here, we investigated whether the systemic and topical administration of SPD would accelerate the skin wound-repair process in vivo. Methods A skin wound repair model was established using C57BL/6 J mice. SPD was mixed with white petrolatum for topical administration. For systemic administration, SPD mixed with drinking water was orally administered. Changes in wound size over time were calculated using digital photography. Results Systemic and topical SPD treatment significantly accelerated skin wound healing. The administration of SPD promoted the uPA/uPAR pathway in wound sites. Moreover, topical treatment with SPD enhanced the expression of IL-6 and TNF-α in wound sites. Scratch and cell proliferation assays revealed that SPD administration accelerated scratch wound closure and cell proliferation in vitro. Conclusion These results indicate that treatment with SPD promotes skin wound healing through activation of the uPA/uPAR pathway and induction of the inflammatory response in wound sites. The administration of SPD might contribute to new effective treatments to accelerate skin wound healing. Video Abstract

Plasmodium malaria parasites use erythrocyte-binding-like (EBL) ligands to invade erythrocytes in their vertebrate host. EBLs are released from micronemes, which are secretory organelles located at the merozoite apical end and bind to erythrocyte surface receptors. Because of their essential nature, EBLs have been studied as vaccine candidates, such as the Plasmodium vivax Duffy binding protein. Previously, we showed through using the rodent malaria parasite Plasmodium yoelii that a single amino acid substitution within the EBL C-terminal Cys-rich domain (region 6) caused mislocalization of this molecule and resulted in alteration of the infection course and virulence between the non-lethal 17X and lethal 17XL strains. In the present study, we generated a panel of transgenic P. yoelii lines in which seven of the eight conserved Cys residues in EBL region 6 were independently substituted to Ala residues to observe the consequence of these substitutions with respect to EBL localization, the infection course, and virulence. Five out of seven transgenic lines showed EBL mislocalizations and higher parasitemias. Among them, three showed increased virulence, whereas the other two did not kill the infected mice. The remaining two transgenic lines showed low parasitemias similar to their parental 17X strain, and their EBL localizations did not change. The results indicate the importance of Cys residues in EBL region 6 for EBL localization, parasite infection course, and virulence and suggest an association between EBL localization and the parasite infection course.

Parkinson's disease (PD) is a neurodegenerative disorder caused by the selective loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc). Lewy bodies (LBs), another histological hallmark of PD, are observed in patients with familial or sporadic PD. The therapeutic potential of reducing the accumulation of α‐synuclein, a major LB component, has been investigated, but it remains unknown whether the formation of LBs results in the loss of DA neurons. PARK4 patients exhibit multiplication of the α‐synuclein gene (SNCA) without any pathological mutations, but their symptoms develop relatively early. Therefore, study of PARK4 might help elucidate the mechanism of α‐synuclein aggregation. In this study, we investigated the dynamics of α‐synuclein during the early stage of immature DA neurons, which were differentiated from human‐induced pluripotent stem cells (hiPSCs) derived from either a PARK4 patient with SNCA triplication or a healthy donor. We observed increased α‐synuclein accumulation in PARK4 hiPSC‐derived DA neurons relative to those derived from healthy donor hiPSCs. Interestingly, α‐synuclein accumulation disappeared over time in the PARK4 patient‐derived DA neurons. Moreover, an SNCA‐specific antisense oligonucleotide could reduce α‐synuclein levels during the accumulation stage. These observations may help reveal the mechanisms that regulate α‐synuclein levels, which may consequently be useful in the development of new therapies for patients with sporadic or familial PD.

Abstract A 3‐month‐old male cross‐breed dog presented with signs of progressive diffuse brain disease. Noncommunicating congenital hydrocephalus concurrent with cervical syringomyelia was diagnosed on magnetic resonance images. On time‐spatial labeling inversion pulse (Time‐SLIP) images CSF flow through the mesencephalic aqueduct was poorly defined and there was flow into the syrinx across the craniocervical junction. After percutaneous ventricular drainage and ventriculoperitoneal shunting, CSF flow through the aqueduct was clearly detected and flow into the syrinx disappeared. In addition, CSF flow in the subarachnoid space at the pons and ventral aspect of the cervical subarachnoid space was restored. Signs of neurological dysfunction improved after ventriculoperitoneal shunting and the cerebral parenchyma was increased in thickness on 2‐year follow‐up computed tomography images. Patterns of CSF flow on Time‐SLIP images before and after CSF drainage or ventriculoperitoneal shunting aid in clarifying disease pathogenesis and confirm effects of CSF drainage.

Abstract A biomembrane's role is to be a barrier for interior cytosol from an exterior environment to execute the cell's normal biological functions. However, a water-soluble peptide called cell-penetrating peptide (CPP) has been known for its ability to directly penetrate through the biomembranes into cells (cytolysis) without perturbating cell viability and expected to be a promising drug delivery vector. Examples of CPP include peptides with multiple arginine units with strong cationic properties, which is the key to cytolysis. Here we show the conclusive evidence to support the mechanism of CPP’s cytolysis and way to control it. The mechanism we proposed is attributed to biomembrane’s physicochemical nature as lamellar liquid crystal (Lα). Cytolysis occurs as the temporal and local dynamic phase transitions from Lα to an undulated lamellar with pores called Mesh1. We have shown this phase transfer of Lα composed of dioleoyl-phosphatidylcholine (DOPC) with water by adding oligo-arginine (Rx) as CPP at the equilibrium. Using giant unilamellar vesicle composed of DOPC as a single cell model, we could control the level of cytolysis of CPP (FITC-R8) by changing the curvature of the membrane through osmotic pressure modulation. The cytolysis of CPP utilizes biomembrane's inherent topological and functional flexibility corresponding to the stimuli.

Background. The global point prevalence survey (Global-PPS) is the standard for the surveillance of prescribed antimicrobials among inpatients and provides data for the development of hospital antimicrobial stewardship programs. Aim. To evaluate the prevalence and quality of antimicrobial prescriptions using the universally standardized Global-PPS protocol in a non-acute care hospital in Saitama Prefecture, Japan. Methods. Antimicrobial prescriptions for inpatients, staying at the hospital overnight, were surveyed on three separate week days in November 2018, January 2019, and May 2019. Information on the prescribed antimicrobials on the survey target day was obtained from the in-hospital pharmacy. Survey data were collected by physicians, based on the extracted information. Patient information was anonymized and entered in the Global-PPS Web application by physicians. We report the antimicrobial use prevalence, the indication for prescription, diagnosis, the most prescribed antimicrobials, and a set of quality indicators related to antimicrobial prescribing. Results. In total, 6.7% of the surveyed inpatients (120/1796) were prescribed antimicrobials on the survey day. Sulfamethoxazole/trimethoprim was the most commonly prescribed, with 20.0% of systemic antibiotic prescriptions (ATC J01). Of all antibiotics for systemic use, up to 58.4% were Watch antibiotics, as defined by the World Health Organization AWaRe classification. The most prescribed group of systemic antibiotics was non-penicillin beta-lactam antibiotics (34.4%), followed by penicillin antibiotics in combination with beta-lactamase inhibitors (25.6%), and sulfonamides with trimethoprim (20.8%). Healthcare-associated infections and medical prophylaxis were the most common indications reported in 69.3% and 26.3% of prescriptions, respectively. The most common diagnosis for systemic antibiotic prescriptions was pneumonia (49.6%). Reasons for antimicrobial prescriptions were indicated in the medical records for 67.1% of prescriptions, and the stop/review date was documented to be 50.3%. Compliance with local guidelines reached 66.7%. Conclusions. This study highlights important challenges related to antimicrobial prescription in a highly specific, non-acute care patient population.

Objectives: To investigate the physical, cognitive, and psychological factors related to daily step count in patients with subacute stroke. Design: Prospective cohort study. Setting: A subacute rehabilitation ward with 160 beds. Participants: Patients with subacute stroke who could walk independently (N=101). Among the 101 participants enrolled in this study (mean age, 64.5±13.5y), 64.4% (n=65) were men and 69.3% (n=70) were patients with cerebral infarction. Interventions: We assessed ambulatory activity using a pedometer placed in the pants pocket on the nonparalyzed side continuously for 7 consecutive days. We also obtained demographic and clinical information and recorded the following measurement scores: Stroke Impairment Assessment Set, FIM, Mini-Mental State Examination (MMSE), Self-Rating Depression Scale, and Apathy Scale. All measurements were collected at admission and discharge. Main Outcome Measures: The outcomes assessed were ambulatory activity, motor and sensory functions, functional disability, cognitive function, depressive symptoms, and motivation. Results: The median daily steps ambulated at admission and discharge were 5584 steps (interquartile range, 3763-7096 steps) and 5991 steps (interquartile range, 4329-8204 steps), respectively. In the univariate regression analysis, age, sex, serum albumin level, affected side of the brain, and MMSE score at admission were significantly associated with the daily step count at discharge. Multiple regression analysis using these 5 items as independent variables revealed that the MMSE score at admission (reference, 28-30 points; B, −2.07; 95% confidence interval, −3.89 to −0.35; β, −0.22; P=.027) was significantly associated with the daily step count at discharge. Conclusions: Cognitive function at admission had a significant association with the daily step count at discharge in patients with subacute stroke who could walk independently.

BackgroundThe education system can serve as a community-based resource to support the provision of long-term follow-up care after large-scale disasters. While school-based interventions conducted after a disaster have been confirmed to reduce symptoms of depression and posttraumatic stress disorder (PTSD), adolescents often exhibit low treatment motivation. Traditional methods used to encourage treatment motivation include fun activities, such as applied improv (AIM). This study evaluated the intervention effects and improved motivation of an intervention program combining AIM with the behavioral activation approach (BAA).MethodsParticipants were 253 tenth graders, who were in fifth grade at the time the Great East Japan Earthquake of 2011, and 239 students were included in the analyses. Participants were divided into two groups: the BAA and AIM + BAA groups. Students in each group participated in one class-wide intervention session, which lasted 60 min. Depression, PTSD symptoms, behavioral activation, avoidance, and resilience were evaluated using psychological scales. A participant’s evaluations of the intervention were confirmed using the impression sheet consisting of six items that measure comprehension, difficulty, efficacy, generalization, confirmation of a specific situation, and motivation.ResultsA two-way analysis of variance (ANOVA) conducted using data from the psychological scale did not reveal a significant effect from the intervention program. However, the Mann-Whitney U-test, which used data from the impression sheet, showed a significant effect on comprehension (p = 0.001), generalization (p = 0.023), and motivation (p = 0.025).ConclusionThis study did not confirm the effectiveness of the BAA in reducing symptoms of depression and PTSD in adolescents. Regarding treatment motivation, the AIM + BAA group reported higher motivation than the BAA group. Thus, one session of AIM may contribute to improved treatment motivation in adolescents. AIM creates a safe environment and encourages engagement and participation in interventions. Treatment motivation is an important issue in adolescent therapy, and AIM may help solve this problem.

Abstract This study introduces injury risk curves for the lumbar spine for use in the risk assessment of low back pain (LBP) caused by manual lifting of heavy loads. LBP has been a longstanding problem among industrial workers, giving rise to the development of assistive devices. However, quantitative evaluation methods to verify the safety of such devices have not yet been established. The notable biomechanical criterion of 3.4 kN of lumbar compressive force, defined by the National Institute for Occupational Safety and Health, applies only to young, healthy workers with a fixed risk level. This study on injury risk curves clarified the risk level of injury to the lumbar spine due to lumbar compressive force for individuals within a wide age range. The findings can be applied for the design and evaluation of assistive devices as well as the design of ergonomic guidelines for manual work.

Abstract Background A cerebrospinal fluid (CSF)-mask algorithm has been developed to reduce the adverse influence of CSF-low-counts on the diagnostic utility of the specific binding ratio (SBR) index calculated with Southampton method. We assessed the effect of the CSF-mask algorithm on the diagnostic performance of the SBR index for parkinsonian syndromes (PS), including Parkinson’s disease, and the influence of cerebral ventricle dilatation on the CSF-mask algorithm. Methods We enrolled 163 and 158 patients with and without PS, respectively. Both the conventional SBR (non-CSF-mask) and SBR corrected with the CSF-mask algorithm (CSF-mask) were calculated from 123I-Ioflupane single-photon emission computed tomography (SPECT) images of these patients. We compared the diagnostic performance of the corresponding indices and evaluated whether the effect of the CSF-mask algorithm varied according to the extent of ventricle dilatation, as assessed with the Evans index (EI). A receiver-operating characteristics (ROC) analysis was used for statistical analyses. Results ROC analyses demonstrated that the CSF-mask algorithm performed better than the non-CSF-mask (no correction, area under the curve [AUC] = 0.917 [95% confidence interval (CI) 0.887–0.947] vs. 0.895 [95% CI 0.861–0.929], p

Abstract Background We sought to assess the machine learning-based combined diagnostic accuracy of three types of quantitative indices obtained using dopamine transporter single-photon emission computed tomography (DAT SPECT)—specific binding ratio (SBR), putamen-to-caudate ratio (PCR)/fractal dimension (FD), and asymmetry index (AI)—for parkinsonian syndrome (PS). We also aimed to compare the effect of two different types of volume of interest (VOI) settings from commercially available software packages DaTQUANT (Q) and DaTView (V) on diagnostic accuracy. Methods Seventy-one patients with PS and 40 without PS (NPS) were enrolled. Using SPECT images obtained from these patients, three quantitative indices were calculated at two different VOI settings each. SBR-Q, PCR-Q, and AI-Q were derived using the VOI settings from DaTQUANT, whereas SBR-V, FD-V, and AI-V were derived using those from DaTView. We compared the diagnostic value of these six indices for PS. We incorporated a support vector machine (SVM) classifier for assessing the combined accuracy of the three indices (SVM-Q: combination of SBR-Q, PCR-Q, and AI-Q; SVM-V: combination of SBR-V, FD-V, and AI-V). A Mann-Whitney U test and receiver-operating characteristics (ROC) analysis were used for statistical analyses. Results ROC analyses demonstrated that the areas under the curve (AUC) for SBR-Q, PCR-Q, AI-Q, SBR-V, FD-V, and AI-V were 0.978, 0.837, 0.802, 0.906, 0.972, and 0.829, respectively. On comparing the corresponding quantitative indices between the two types of VOI settings, SBR-Q performed better than SBR-V (p = 0.006), whereas FD-V performed better than PCR-Q (p = 0.0003). No significant difference was observed between AI-Q and AI-V (p = 0.56). The AUCs for SVM-Q and SVM-V were 0.988 and 0.994, respectively; the two different VOI settings displayed no significant differences in terms of diagnostic accuracy (p = 0.48). Conclusion The combination of the three indices obtained using the SVM classifier improved the diagnostic performance for PS; this performance did not differ based on the VOI settings and software used.

Erythrocyte recognition and invasion is critical for the intra-erythrocytic development of Plasmodium spp. parasites. The multistep invasion process involves specific interactions between parasite ligands and erythrocyte receptors. Erythrocyte-binding-like (EBL) proteins, type I integral transmembrane proteins released from the merozoite micronemes, are known to play an important role in the initiation and formation of tight junctions between the apical end of the merozoite and the erythrocyte surface. In Plasmodium yoelii EBL (PyEBL), a single amino acid substitution in the putative Duffy binding domain dramatically changes parasite growth rate and virulence. This suggests that PyEBL is important for modulating the virulence of P. yoelii parasites. Based on these observations, we sought to elucidate the receptor of PyEBL that mediates its role as an invasion ligand. Using the eukaryotic wheat germ cell-free system, we systematically developed and screened a library of mouse erythrocyte proteins against native PyEBL using AlphaScreen technology. We report that PyEBL specifically interacts with basigin, an erythrocyte surface protein. We further confirmed that the N-terminal cysteine-rich Duffy binding-like region (EBL region 2), is responsible for the interaction, and that the binding is not affected by the C351Y mutation, which was previously shown to modulate virulence of P. yoelii. The identification of basigin as the putative PyEBL receptor offers new insights into the role of this molecule and provides an important base for in-depth studies towards developing novel interventions against malaria.

BackgroundProblematic pornography use is considered an addictive behavior, which is an important clinical issue. Despite considerable research interest in problematic pornography use worldwide, to the best of our knowledge, there are no extant studies on the subject in Japan. Therefore, despite the fact that many people in Japan use pornography, the difference between problematic and non-problematic users among Japanese people is not known.ObjectiveThis study aimed to identify the characteristics of problematic pornography use among Japanese students, to the best of our knowledge. Specifically, we examined general psychopathological symptoms, sexual compulsivity, depression, anxiety, and low effortful control.MethodsThe participants were 150 college students aged 20–26 years (mean age = 21.5, SD = 1.21, males: n = 86, females: n = 64) at a university in midland Japan. An online questionnaire was administered that included items on pornography usage patterns, impaired control of pornography use, sexual compulsivity, depression, anxiety, and effortful control.ResultsMost men (97%) and approximately one-third of women (35.9%) used pornography at least once in the past month. Some users reported significant daily-life problems due to difficulty in controlling pornography use (5.7%). Participants with impaired control of pornography use had higher depression, anxiety, and sexual compulsivity, and lower effortful control than pornography users without impaired control.ConclusionSome Japanese students reported significant daily-life problems due to impaired control of pornography use. The characteristics of individuals with impaired control are consistent with previous studies. The results of this study suggest that individuals with impaired control may have poor mental health, and that there is need for further research and development of treatment systems to manage this issue in Japan. Further research exploring a more varied sample in Japan is required to effectively examine problematic pornography use.

Salvage radical prostatectomy (SRP) has been one of the common procedures for the patients with a failure after primary treatment. We present a case of SRP with rare surgical history. To our knowledge, this is the first report of salvage surgery for residual prostate gland including prostate cancer after unsuccessful radical prostatectomy. We indicated new possibility for salvage radical prostatectomy.

Malaria causes a half a million deaths annually. The parasite intraerythrocytic lifecycle in the human bloodstream is the major cause of morbidity and mortality. Apical organelles of merozoite stage parasites are involved in the invasion of erythrocytes. A limited number of apical organellar proteins have been identified and characterized for their roles during erythrocyte invasion or subsequent intraerythrocytic parasite development. To expand the repertoire of identified apical organellar proteins we generated a panel of monoclonal antibodies against Plasmodium falciparum schizont-rich parasites and screened the antibodies using immunofluorescence assays. Out of 164 hybridoma lines, 12 clones produced monoclonal antibodies yielding punctate immunofluorescence staining patterns in individual merozoites in late schizonts, suggesting recognition of merozoite apical organelles. Five of the monoclonal antibodies were used to immuno-affinity purify their target antigens and these antigens were identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Two known apical organelle protein complexes were identified, the high-molecular mass rhoptry protein complex (PfRhopH1/Clags, PfRhopH2, and PfRhopH3) and the low-molecular mass rhoptry protein complex (rhoptry-associated proteins complex, PfRAP1, and PfRAP2). A novel complex was additionally identified by immunoprecipitation, composed of rhoptry-associated membrane antigen (PfRAMA) and rhoptry neck protein 3 (PfRON3) of P. falciparum. We further identified a region spanning amino acids Q221-E481 within the PfRAMA that may associate with PfRON3 in immature schizonts. Further investigation will be required as to whether PfRAMA and PfRON3 interact directly or indirectly.

Introduction The rapid spread of COVID-19 posed a global burden. Substantial number of people died of the disease in the acute phase of infection. In addition, a significant proportion of patients have been reported to suffer from post-acute phase symptoms, sequelae of COVID-19, which may negatively influence the quality of daily living and/or socioeconomic circumstances of the patients. However, no previous study has comprehensively and objectively assessed the quality of life of patients by using existing international scales. Further, evidence of socioeconomic consequences among patients with COVID-19 is scarce. To address the multidimensional issues from sequelae of COVID-19, evidence from comprehensive surveys beyond clinical perspectives is critical that investigates health, and social determinants of disease progression as well as socioeconomic consequences at a large scale.Methods and analysis In this study, we plan to conduct a nationwide and comprehensive survey for the sequelae of COVID-19 in a total of 1000 patients diagnosed at 27 hospitals throughout Japan. This study will evaluate not only the health-related status of patients from clinical perspectives but also the Health-related Quality of Life (HRQoL) scores, socioeconomic status and consequences to discuss the sequelae of the disease and the related risk factors. The primary endpoint is the frequency of long-term complications of COVID-19 infection. The secondary endpoints are risk factors for progression to sequelae of COVID-19 infection. The study will provide robust and important evidence as a resource to tackle the issues from the sequelae of COVID-19 from the multi-dimensional perspectives.Ethics and dissemination This trial was approved by the Keio University School of Medicine Ethics Committee (20200243, UMIN000042299). The results of this study will be reported at a society meeting or published in a peer-reviewed journal.

ABSTRACT Malaria parasites increase their host erythrocyte’s permeability to various nutrients, fueling intracellular pathogen development and replication. The plasmodial surface anion channel (PSAC) mediates this uptake and is linked to the parasite-encoded RhopH complex, consisting of CLAG3, RhopH2, and RhopH3. While interactions between these subunits are well established, it is not clear whether they remain associated from their synthesis in developing merozoites through erythrocyte invasion and trafficking to the host membrane. Here, we explored protein-protein interactions between RhopH subunits using live-cell imaging and Förster resonance energy transfer (FRET) experiments. Using the green fluorescent protein (GFP) derivatives mCerulean and mVenus, we generated single- and double-tagged parasite lines for fluorescence measurements. While CLAG3-mCerulean served as an efficient FRET donor for RhopH2-mVenus within rhoptry organelles, mCerulean targeted to this organelle via a short signal sequence produced negligible FRET. Upon merozoite egress and reinvasion, these tagged RhopH subunits were deposited into the new host cell’s parasitophorous vacuole; these proteins were then exported and trafficked to the erythrocyte membrane, where CLAG3 and RhopH2 remained fully associated. Fluorescence intensity measurements identified stoichiometric increases in exported RhopH protein when erythrocytes are infected with two parasites; whole-cell patch-clamp revealed a concomitant increase in PSAC functional copy number and a dose effect for RhopH contribution to ion and nutrient permeability. These studies establish live-cell FRET imaging in human malaria parasites, reveal that RhopH subunits traffic to their host membrane destination without dissociation, and suggest quantitative contribution to PSAC formation. IMPORTANCE Malaria parasites grow within circulating red blood cells and uptake nutrients through a pore on their host membrane. Here, we used gene editing to tag CLAG3 and RhopH2, two proteins linked to the nutrient pore, with fluorescent markers and tracked these proteins in living infected cells. After their synthesis in mature parasites, imaging showed that both proteins are packaged into membrane-bound rhoptries. When parasites ruptured their host cells and invaded new red blood cells, these proteins were detected within a vacuole around the parasite before they migrated and inserted in the surface membrane of the host cell. Using simultaneous labeling of CLAG3 and RhopH2, we determined that these proteins interact tightly during migration and after surface membrane insertion. Red blood cells infected with two parasites had twice the protein at their surface and a parallel increase in the number of nutrient pores. Our work suggests that these proteins directly facilitate parasite nutrient uptake from human plasma.

OBJECTIVES:As the population of patients with cognitive decline grows, physicians and caregivers need brief screening tools. Comprehensive neurocognitive batteries require special training and time for evaluation. We focused on accessibility and compared the diagnostic power of several easy questions. DESIGN:"Attended With" (AW) and "Head-Turning Sign" (HTS) factors and participants' replies to following questions were recorded: "Do you feel that you have more difficulties in your daily life than you used to?", [no consciousness (C-) or consciousness+ (C+)], "Could you tell me about your daily pleasures or pastimes?" [no pleasure (P-) or pleasure + (P+)], "What are notable current/recent news/topics?" [no news (N-) or news+ (N+)]. SETTING:This took place in our Memory Clinic between May 2016 and July 2019. PARTICIPANTS:We enrolled 162 consecutive cases (44 cognitive normal (CN), 55 amnestic mild cognitive impairment (aMCI), and 48 Alzheimer's disease (AD)). MEASUREMENTS:The sensitivity and specificity of each battery were calculated, and on account of those numbers, the population attributable risk percent % (PAR%) of (AW and HTS+), (C- and P-), (C- and N-), (P- and N-) as analysis of combination of questions, respectively, were calculated. RESULTS:AW had high sensitivity, 87.4, 95.8% (CN vs aMCI + AD, CN + aMCI vs AD) but the sensitivity of HTS was only 46.4, 57.7%, and HTS showed high specificity, 100.0, 71.8%. C- had high sensitivity, 80.6, 87.5%, whereas P- and N- had high specificity, both 83.9% in CN vs aMCI + AD, 88.1% and 75.9% in CN + aMCI vs AD, respectively. In combination analysis, the PAR% of (C- and N-) were as high as (AW and HTS+). CONCLUSIONS:The combination of (C- and N-) is as powerful as (AW and HTS+) in screening AD. Our findings provide novel insights for screening utility of brief questions "Consciousness of Impairment" and "Recent News."

Both exercise training (Ex) and superoxide dismutase (SOD) mimetic tempol have antihypertensive and renal protective effects in rodent models of several hypertensions. We recently reported that Ex increases nitric oxide (NO) production and the expression levels of endothelial and neuronal NO synthase (eNOS and nNOS) in the kidney and aorta of the spontaneously hypertensive rats (SHR) and normotensive Wistar–Kyoto rats (WKY). We also found that endogenous hydrogen peroxide (H2O2) upregulates the expression levels of eNOS and nNOS in SHR. To elucidate the mechanism of the Ex-upregulated NO system in the kidney, we examined the additive effect of Ex and tempol on the renal NO system in SHR and WKY. Our data showed that, in SHR, both Ex and tempol increase the levels of H2O2 and nitrate/nitrite (NOx) in plasma and urine. We also observed an increased renal NOS activity and upregulated expression levels of eNOS and nNOS with decreased NADPH oxidase activity. The effects of the combination of Ex and tempol on these variables were cumulate in SHR. On the other hand, we found that Ex increases these variables with increased renal NADPH oxidase activity, but tempol did not change these variables or affect the Ex-induced upregulation in the activity and expression of NOS in WKY. The SOD activity in the kidney and aorta was activated by tempol only in SHR, but not in WKY; whereas Ex increased SOD activity only in the aorta in both SHR and WKY. These results indicate that Ex-induced endogenous H2O2 produced in the blood vessel and other organs outside of the kidney may be carried to the kidney by blood flow and stimulates the NO system in the kidney.